Roxane Laboratories, Inc

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Roxane Laboratories, Inc Drugs

Oxycodone Hydrochloride...

Oxycodone Hydrochloride Solution

Take care when prescribing and administering oxycodone hydrochloride oral solution to avoid dosing errors due to confusion between mg and mL, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Always use the enclosed calibrated oral syringe when administering oxycodone hydrochloride oral solution, 100 mg per 5 mL (20 mg/mL), to ensure the dose is measured and administered accurately.

Selection of patients for treatment with oxycodone hydrochloride should be governed by the same principles that apply to the use of similar opioid analgesics. Individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

2.1 Individualization of Dosage

As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of oxycodone hydrochloride, give attention to the following:
• the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; • the reliability of the relative potency estimate used to calculate the equivalent oxycodone hydrochloride dose needed; • the patient’s degree of opioid tolerance; • the general condition and medical status of the patient; • concurrent medications; • the type and severity of the patient’s pain; • risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.
The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual reevaluation of the patient receiving oxycodone hydrochloride is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. During chronic therapy, especially for non-cancer-related pain, periodically reassess the continued need for the use of opioid analgesics.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

2.2 Conversion to Oral Oxycodone Hydrochloride

The 100 mg per 5 mL (20 mg/mL) oral solution formulation is for use in opioid-tolerant patients only who have already been receiving opioid therapy. Use this strength only for patients that have already been titrated to a stable analgesic regimen using lower strengths of oxycodone hydrochloride and who can benefit from use of a smaller volume of oral solution.

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dose of oxycodone hydrochloride. It is better to underestimate a patient’s 24-hour oral oxycodone hydrochloride dose and make available rescue medication than to overestimate the 24-hour oral oxycodone hydrochloride dose and manage an adverse experience of overdose.

Consider the following general points regarding opioid conversions.

Conversion From Non-Oxycodone Opioids to Oral Oxycodone Hydrochloride.

In converting patients from other opioids to oxycodone hydrochloride, close observation and adjustment of dosage based upon the patient’s response to oxycodone hydrochloride is imperative. Physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate.

Conversion From Controlled-Release Oral Oxycodone to Oral Oxycodone Hydrochloride.

The relative bioavailability of oxycodone hydrochloride oral solution compound to controlled-release oxycodone is unknown. The extended duration of release of oxycodone hydrochloride from controlled-release tablets results in reduced maximum and increased minimum plasma oxycodone hydrochloride concentrations than with shorter acting oxycodone hydrochloride products. Conversion from controlled-release tablets could lead to excessive sedation at peak serum levels. Therefore, dosage adjustment with close observation is necessary.

Conversion From Oral Oxycodone Hydrochloride to Controlled-Release Oral Oxycodone

The relative bioavailability of oxycodone hydrochloride oral solution compared to controlled-release oxycodone is unknown, so conversion to controlled-release tablets must be accompanied by close observation for signs of excessive sedation.

2.3 Maintenance of Therapy

Continual reevaluation of the patient receiving oxycodone hydrochloride is important, with special attention to the maintenance of pain management and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.

2.4 Cessation of Therapy

When a patient no longer requires therapy with oxycodone hydrochloride gradually taper the dose to prevent signs and symptoms of withdrawal in the physically dependent patient.
Theraflu Expressmax Flu

Theraflu Expressmax Flu

2.1Seasonal Allergic Rhinitis

The recommended dose of azelastine hydrochloride nasal solution in adults and adolescent patients 12 years and older with seasonal allergic rhinitis is one or two sprays per nostril twice daily. The recommended dose of azelastine hydrochloride nasal solution in pediatric patients 5 years to 11 years of age is one spray per nostril twice daily.

2.2Vasomotor Rhinitis

The recommended dose of azelastine hydrochloride nasal solution in adults and adolescent patients 12 years and older with vasomotor rhinitis is two sprays per nostril twice daily.

2.3 Important Administration Instructions

Administer azelastine hydrochloride nasal solution by the intranasal route only.

Priming: Prime azelastine hydrochloride nasal solution before initial use by releasing 4 sprays or until a fine mist appears. When azelastine hydrochloride nasal solution has not been used for 3 or more days, reprime with 2 sprays or until a fine mist appears. Avoid spraying azelastine hydrochloride nasal solution into the eyes.
Aspirin And Dipyridamol...

Aspirin And Dipyridamole

Aspirin and extended release dipyridamole capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.

The recommended dose of aspirin and extended release dipyridamole is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. Aspirin and extended release dipyridamole capsules can be administered with or without food.

2.1 Alternative Regimen in Case of Intolerable Headaches

In the event of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become less of a problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.
Alosetron Hydrochloride...

Alosetron Hydrochloride

For safety reasons, only physicians who enroll in the Alosetron REMS Program should prescribe Alosetron Hydrochloride Tablets [see Warnings and Precautions (5.3)].

2.1 Adult Patients

To lower the risk of constipation, Alosetron Hydrochloride Tablets should be started at a dosage of 0.5 mg twice a day. Patients who become constipated at this dosage should stop taking Alosetron Hydrochloride Tablets until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, Alosetron Hydrochloride Tablets should be discontinued immediately.

Patients well controlled on 0.5 mg once or twice a day may be maintained on this regimen. If after 4 weeks the dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day. Alosetron Hydrochloride Tablets should be discontinued in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day.

Alosetron Hydrochloride Tablets can be taken with or without food [see Clinical Pharmacology (12.3)].

Alosetron Hydrochloride Tablets should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. Alosetron Hydrochloride Tablets should not be restarted in patients who develop ischemic colitis.

Clinical trial and postmarketing experience suggest that debilitated patients or patients taking additional medications that decrease gastrointestinal motility may be at greater risk of serious complications of constipation. Therefore, appropriate caution and follow-up should be exercised if Alosetron Hydrochloride Tablets are prescribed for these patients.

Postmarketing experience suggests that elderly patients may be at greater risk for complications of constipation; therefore, appropriate caution and follow-up should be exercised if Alosetron Hydrochloride Tablets are prescribed for these patients [see Warnings and Precautions (5.1)].

2.2 Patients With Hepatic Impairment

Alosetron Hydrochloride Tablets is extensively metabolized by the liver, and increased exposure to Alosetron Hydrochloride Tablets is likely to occur in patients with hepatic impairment. Increased drug exposure may increase the risk of serious adverse reactions. Alosetron Hydrochloride Tablets should be used with caution in patients with mild or moderate hepatic impairment and is contraindicated in patients with severe hepatic impairment [see CONTRAINDICATIONS (4)] and USE IN SPECIFIC POPULATIONS (8.6)].

2.3 Information for Pharmacists

Alosetron Hydrochloride Tablets may be dispensed only on presentation of a prescription for Alosetron Hydrochloride Tablets with a sticker for the Alosetron REMS Program attached. A Medication Guide for Alosetron Hydrochloride Tablets must be given to the patient each time Alosetron Hydrochloride Tablets are dispensed as required by law. No telephone, facsimile, or computerized prescriptions are permitted with this program. Refills are permitted to be written on prescriptions.
Quinapril Hydrochloride...

Quinapril Hydrochloride And Hydrochlorothiazide

Neoplastic Diseases

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.

Choriocarcinomaand similar trophoblastic diseases

Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

Leukemia

Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.

Lymphomas

In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

Mycosis Fungoides (cutaneous T cell lymphoma)

Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.

Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis

Adult Rheumatoid Arthritis

Recommended Starting Dosage Schedules
• Single oral doses of 7.5 mg once weekly. • Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.
Polyarticular-Course Juvenile Rheumatoid Arthritis

The recommended starting dose is 10 mg/m2 given once weekly.

For either adult RA or polyarticular-course JRA dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestional side effects if methotrexate is administered either intramuscularly or subcutaneously.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

The patient should befully informed of the risks involved and should be under constant supervision of the physician. (See Information for Patients under PRECAUTIONS.) Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS.) Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS.)

All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. (See ADVERSE REACTIONS.) Maximal myelosuppression usually occurs in seven to ten days.

Psoriasis

Recommended Starting Dose Schedules
• Weekly single oral, IM or IV dose schedule: 10 to 25 mg per week until adequate response is achieved. • Divided oral dose schedule: 2.5 mg at 12-hour intervals for three doses.
Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.

Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.
Leg Cramps

Leg Cramps

2.1   Adult Patients

The recommended dose for nevirapine is one 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. The lead-in period has been observed to decrease the incidence of rash. For concomitantly administered antiretroviral therapy, the manufacturer's recommended dosage and monitoring should be followed.

2.2   Pediatric Patients

The recommended oral dose for pediatric patients 15 days and older is 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.

Table 1 Calculation of the Volume of Nevirapine Oral Suspension (50 mg per 5 mL) Required for Pediatric Dosing Based on Body Surface and a Dose of 150 mg/m2
Table 1 Calculation of the Volume of Nevirapine Oral Suspension (50 mg per 5 mL) Required for Pediatric Dosing Based on Body Surface and a Dose of 150 mg/m2
BSA range (m2)

Volume (mL)

0.06 – 0.12

1.25

0.12 – 0.25

2.5

0.25 – 0.42

5

0.42 – 0.58

7.5

0.58 – 0.75

10

0.75 – 0.92

12.5

0.92 – 1.08

15

1.08 – 1.25

17.5

1.25+

20

Nevirapine suspension should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, particularly for volumes of 5 mL or less. If a dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the patient.

2.3   Monitoring of Patients

Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation, and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment [see Warnings and Precautions (5)]. In some cases, hepatic injury has progressed despite discontinuation of treatment.

2.4   Dosage Adjustment

Patients with Rash

Discontinue nevirapineif a patient experiences severe rash or any rash accompanied by constitutional findings [see Boxed Warning and Warnings and Precautions (5.2)]. Do not increase nevirapinedose if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved [see Warnings and Precautions (5.2)]. The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought.

Patients with Hepatic Events

If a clinical (symptomatic) hepatic event occurs, permanently discontinue nevirapine. Do not restart nevirapineafter recovery [see Warnings and Precautions (5.1)].

Patients with Dose Interruption

For patients who interrupt nevirapine dosing for more than 7 days, restart the recommended dosing, using one 200 mg tablet daily (150 mg/m2/day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (150 mg/m2 twice daily for pediatric patients).

Patients with Renal Impairment

Patients with CrCL greater than or equal to 20 mL per min do not require an adjustment in nevirapine dosing. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCL less than 20 mL per min. An additional 200 mg dose of nevirapine following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [see Clinical Pharmacology (12.3)].
Oxycodone Hydrochloride...

Oxycodone Hydrochloride Solution

Take care when prescribing and administering Oxycodone Hydrochloride Oral Solution USP to avoid dosing errors due to confusion between mg and mL, and other oxycodone solutions with different concentrations, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Always use the enclosed calibrated measuring cup when administering Oxycodone Hydrochloride Oral Solution USP to ensure the dose is measured and administered accurately.

Selection of patients for treatment with oxycodone hydrochloride should be governed by the same principles that apply to the use of similar opioid analgesics. Individualize treatment in every case, using non-opioid analgesics, opioids on as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

2.1 Individualization of Dosage

As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of oxycodone hydrochloride, give attention to the following:
• the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; • the reliability of the relative potency estimate used to calculate the equivalent oxycodone hydrochloride dose needed; • the patient’s degree of opioid tolerance; • the general condition and medical status of the patient; • concurrent medications; • the type and severity of the patient’s pain; • risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.
The following dosing recommendations, therefore, can only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual reevaluation of the patient receiving oxycodone hydrochloride is important, with special attention to the maintenance of pain management and the relative incidence of side effects associated with therapy. During chronic therapy, especially for non-cancer-related pain, periodically reassess the continued need for the use of opioid analgesics.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

2.2 Initiation of Therapy

Start patients who have not been receiving opioid analgesics on Oxycodone Hydrochloride Oral Solution USP in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain.

Titrate the dose based upon the individual patient's response to their initial dose of Oxycodone Hydrochloride Oral Solution USP. Adjust the dose to an acceptable level of analgesia taking into account the improvement in pain intensity and the tolerability of the oxycodone by the patient.

2.3 Conversion to Oral Oxycodone Oral Solution

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dose of Oxycodone Hydrochloride. It is better to underestimate a patient’s 24-hour oral Oxycodone Hydrochloride dose and make available rescue medication than to overestimate the 24-hour oral Oxycodone Hydrochloride dose and manage an adverse experience of overdose.

2.3.1 Conversion from Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs

When converting patients from fixed ratio opioid/non-opioid drug regimens it may be necessary to titrate the dose of Oxycodone Hydrochloride Oral Solution USP in response to the level of analgesia and adverse effects.

2.3.2 Conversion from Non-Oxycodone Opioids

In converting patients from other opioids to oxycodone hydrochloride, close observation and adjustment of dosage based upon the patient’s response to oxycodone hydrochloride is imperative. Physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate.

2.4 Conversion from Oral Oxycodone Hydrochloride to Controlled-Release Oral Oxycodone

The relative bioavailability of Oxycodone Hydrochloride Oral Solution USP compared to controlled-release oxycodone is unknown, so conversion to controlled-release tablets must be accompanied by close observation for signs of excessive sedation.

2.5 Maintenance of Therapy

Continual reevaluation of the patient receiving Oxycodone Hydrochloride Oral Solution USP is important, with special attention to the maintenance of pain management and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain.

During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), the continued need for the use of opioid analgesics should be re-assessed as appropriate.

2.6 Cessation of Therapy

When a patient no longer requires therapy with Oxycodone Hydrochloride Oral Solution USP for the treatment of their pain, it is important that therapy be gradually discontinued over time to prevent the development of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal [see Drug Abuse and Dependence (9.3) section for description of the signs and symptoms of withdrawal]. If the patient develops these signs or symptoms, the dose should be raised to the previous level and titrated down more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. It is not known at what dose of Oxycodone Hydrochloride Oral Solution USP that treatment may be discontinued without risk of the opioid abstinence syndrome.

2.7 Dosage in patients with Hepatic or Renal Impairment

Follow a conservative approach to dose initiation in patients with hepatic or renal impairment. Monitor patients closely and adjust dose based on clinical response.
Chemdetox

Chemdetox

2.1 Hypertension

Dosage must be individualized. The usual starting dose of telmisartan tablets is 40 mg once a day. Blood pressure response is dose-related over the range of 20 to 80 mg [see Clinical Studies (14.1)].

Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. When additional blood pressure reduction beyond that achieved with 80 mg telmisartan is required, a diuretic may be added.

No initial dosage adjustment is necessary for elderly patients or patients with renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored.

Telmisartan tablets may be administered with other antihypertensive agents.

Telmisartan tablets may be administered with or without food.

2.2 Cardiovascular Risk Reduction

The recommended dose of telmisartan tablets is 80 mg once a day and can be administered with or without food. It is not known whether doses lower than 80 mg of telmisartan are effective in reducing the risk of cardiovascular morbidity and mortality.

When initiating telmisartan therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary.
Glipizide

Glipizide

All dosing should be given in a twice-a-day regimen. Oxcarbazepine oral suspension and oxcarbazepine tablets may be interchanged at equal doses.

Oxcarbazepine should be kept out of the reach and sight of children.

Before using oxcarbazepine oral suspension, shake the bottle well and prepare the dose immediately afterwards. The prescribed amount of oral suspension should be withdrawn from the bottle using the oral dosing syringe supplied. Oxcarbazepine oral suspension can be mixed in a small glass of water just prior to administration or, alternatively, may be swallowed directly from the syringe. After each use, close the bottle and rinse the syringe with warm water and allow it to dry thoroughly.

Oxcarbazepine can be taken with or without food [see Clinical Pharmacology (12.3)].

2.1 Adjunctive Therapy for Adults

Treatment with oxcarbazepine should be initiated with a dose of 600 mg/day, given in a twice-a-day regimen. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects. It is recommended that the patient be observed closely and plasma levels of the concomitant AEDs be monitored during the period of oxcarbazepine titration, as these plasma levels may be altered, especially at oxcarbazepine doses greater than 1200 mg/day [see Drug Interacctions (7.1)].

2.2 Conversion to Monotherapy for Adults

Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with oxcarbazepine at 600 mg/day (given in a twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3 to 6 weeks, while the maximum dose of oxcarbazepine should be reached in about 2 to 4 weeks. Oxcarbazepine may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the recommended daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with oxcarbazepine. Patients should be observed closely during this transition phase.

2.3 Initiation of Monotherapy for Adults

Patients not currently being treated with AEDs may have monotherapy initiated with oxcarbazepine. In these patients, oxcarbazepine should be initiated at a dose of 600 mg/day (given in a twice-a-day regimen); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to oxcarbazepine monotherapy (see above).

2.4 Adjunctive Therapy for Pediatric Patients (Aged 2 to 16 Years)

In pediatric patients aged 4 to 16 years, treatment should be initiated at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. The target maintenance dose of oxcarbazepine should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart:

20 to 29 kg - 900 mg/day

29.1 to 39 kg - 1200 mg/day

>39 kg - 1800 mg/day

In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6 to 51 mg/kg.

In pediatric patients aged 2 to <4 years, treatment should be initiated at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. For patients under 20 kg, a starting dose of 16 to 20 mg/kg may be considered [see Clinical Pharmacology (12.3)]. The maximum maintenance dose of oxcarbazepine should be achieved over 2 to 4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen.

In the clinical trial in pediatric patients (2 to 4 years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day.

Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults.

2.5 Conversion to Monotherapy for Pediatric Patients (Aged 4 to 16 Years)

Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with oxcarbazepine at approximately 8 to 10 mg/kg/day given in a twice-a-day regimen, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks while oxcarbazepine may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase.

The recommended total daily dose of oxcarbazepine is shown in the table below.

2.6 Initiation of Monotherapy for Pediatric Patients (Aged 4 to 16 Years)

Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with oxcarbazepine. In these patients, oxcarbazepine should be initiated at a dose of 8 to 10 mg/kg/day given in a twice-a-day regimen. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below.
Table 1: Range of Maintenance Doses of Oxcarbazepine for Children by Weight During Monotherapy
Weight in kg

From Dose (mg/day)

To Dose (mg/day)

20

600

900

25

900

1200

30

900

1200

35

900

1500

40

900

1500

45

1200

1500

50

1200

1800

55

1200

1800

60

1200

2100

65

1200

2100

70

1500

2100

2.7 Patients with Hepatic Impairment

In general, dose adjustments are not required in patients with mild-to-moderate hepatic impairment [see Clinical Pharmacology (12.3)].

2.8 Patients with Renal Impairment

In patients with impaired renal function (creatine clearance <30 mL/min) oxcarbazepine therapy should be initiated at one-half the usual starting dose (300 mg/day) and increased slowly to achieve the desired clinical response [see Clinical Pharmacology (12.3)].
Disulfiram

Disulfiram

Disulfiram should never be administered until the patient has abstained from alcohol for at least 12 hours.

Initial Dosage Schedule

In the first phase of treatment, a maximum of 500 mg daily is given in a single dose for one to two weeks. Although usually taken in the morning, disulfiram may be taken on retiring by patients who experience a sedative effect. Alternatively, to minimize, or eliminate, the sedative effect, dosage may be adjusted downward.

Maintenance Regimen

The average maintenance dose is 250 mg daily (range, 125 to 500 mg), it should not exceed 500 mg daily.

Note: Occasionally patients, while seemingly on adequate maintenance doses of disulfiram, report that they are able to drink alcoholic beverages with impunity and without any symptomatology. All appearances to the contrary, such patients must be presumed to be disposing of their tablets in some manner without actually taking them. Until such patients have been observed reliably taking their daily disulfiram tablets (preferably crushed and well mixed with liquid), it cannot be concluded that disulfiram is ineffective.

Duration of Therapy

The daily, uninterrupted administration of disulfiram must be continued until the patient is fully recovered socially and a basis for permanent self-control is established. Depending on the individual patient, maintenance therapy may be required for months or even years.

Trial with Alcohol

During early experience with disulfiram, it was thought advisable for each patient to have at least one supervised alcohol-drug reaction. More recently, the test reaction has been largely abandoned. Furthermore, such a test reaction should never be administered to a patient over 50 years of age. A clear, detailed and convincing description of the reaction is felt to be sufficient in most cases.

However, where a test reaction is deemed necessary, the suggested procedure is as follows:

After the first one to two weeks’ therapy with 500 mg daily, a drink of 15 mL (1/2 oz) of 100 proof whiskey, or equivalent, is taken slowly. This test dose of alcoholic beverage may be repeated once only, so that the total dose does not exceed 30 mL (1 oz) of whiskey. Once a reaction develops, no more alcohol should be consumed. Such tests should be carried out only when the patient is hospitalized, or comparable supervision and facilities, including oxygen, are available.

Management of Disulfiram-Alcohol Reaction

In severe reactions, whether caused by an excessive test dose or by the patient’s unsupervised ingestion of alcohol, supportive measures to restore blood pressure and treat shock should be instituted. Other recommendations include: oxygen, carbogen (95% oxygen and 5% carbon dioxide), vitamin C intravenously in massive doses (1 g) and ephedrine sulfate. Antihistamines have also been used intravenously. Potassium levels should be monitored, particularly in patients on digitalis, since hypokalemia has been reported.
Galantamine Hydrobromid...

Galantamine Hydrobromide Oral Solution Solution

2.2 Galantamine Hydrobromide Oral Solution

The recommended starting dosage of Galantamine hydrobromide oral solutionis 4 mg twice a day (8 mg/day). The dosage should be increased to the initial maintenance dosage of 8 mg twice a day (16 mg/day) after a minimum of 4 weeks. A further increase to 12 mg twice a day (24 mg/day) should be attempted after a minimum of 4 weeks at 8 mg twice a day (16 mg/day).

Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

Galantamine hydrobromide oral solutionshould be administered twice a day, preferably with morning and evening meals.

Patients and caregivers should be advised to ensure adequate fluid intake during treatment. If therapy has been interrupted for more than three days, the patient should be restarted at the lowest dosage and the dosage escalated to the current dose.

The abrupt withdrawal of galantamine in those patients who had been receiving dosages in the effective range was not associated with an increased frequency of adverse events in comparison with those continuing to receive the same dosages of that drug. The beneficial effects of galantamine hydrobromide oral solution are lost, however, when the drug is discontinued.

2.3 Dosage in Patients with Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9), the dosage should generally not exceed 16 mg/day. The use of galantamine hydrobromide oral solution in patients with severe hepatic impairment (Child-Pugh score of 10 to15) is not recommended.

2.4 Dosage in Patients with Renal Impairment

In patients with creatinine clearance of 9 to 59 mL/min, the dosage should generally not exceed 16 mg/day. In patients with creatinine clearance less than 9 mL/min, the use of galantamine hydrobromide oral solution is not recommended [see Clinical Pharmacology (12.3)].
Lactulose Solution

Lactulose Solution

The usual dose is 1 to 2 tablespoonfuls (15 to 30 mL, containing 10 g to 20 g of lactulose) daily. The dose may be increased to 60 mL daily if necessary. Twenty-four to 48 hours may be required to produce a normal bowel movement.

Note: Some patients have found that lactulose solution may be more acceptable when mixed with fruit juice, water, or milk.
Megestrol Acetate

Megestrol Acetate

Breast Cancer: 160 mg/day (40 mg q.i.d.).

Endometrial Carcinoma: 40 mg/day to 320 mg/day in divided doses.

At least 2 months of continuous treatment is considered an adequate period for determining the efficacy of megestrol acetate.
Acetylcysteine Solution...

Acetylcysteine Solution

DOSAGE AND ADMINISTRATION

General

Acetylcysteine Solution, USP is available in rubber stoppered glass vials containing 10 mL or 30 mL. The 20% solution may be diluted to a lesser concentration with either Sodium Chloride Injection, Sodium Chloride for Inhalation, Sterile Water for Injection, or Sterile Water for Inhalation. The 10% solution may be used undiluted.

Acetylcysteine does not contain an antimicrobial agent, and care must be taken to minimize contamination of the sterile solution. If only a portion of the solution in a vial is used, store the remainder in a refrigerator and use for inhalation only within 96 hours.

Nebulization — Face Mask, Mouthpiece, Tracheostomy: When nebulized into a face mask, mouthpiece, or tracheostomy, 1 to 10 mL of the 20% solution or 2 to 20 mL of the 10% solution may be given every 2 to 6 hours; the recommended dose for most patients is 3 to 5 mL of the 20% solution or 6 to 10 mL of the 10% solution three to four times a day.

Nebulization — Tent, Croupette: In special circumstances it may be necessary to nebulize into a tent or Croupette, and this method of use must be individualized to take into account the available equipment and the patient’s particular needs. This form of administration requires very large volumes of the solution, occasionally as much as 300 mL during a single treatment period.

If a tent or Croupette must be used, the recommended dose is the volume of acetylcysteine (using 10 or 20%) that will maintain a very heavy mist in the tent or Croupette for the desired period. Administration for intermittent or continuous prolonged periods, including overnight, may be desirable.

Direct Instillation: When used by direct instillation, 1 to 2 mL of a 10% to 20% solution may be given as often as every hour.

When used for the routine nursing care of patients with tracheostomy, 1 to 2 mL of a 10% to 20% solution may be given every 1 to 4 hours by instillation into the tracheostomy.

Acetylcysteine may be introduced directly into a particular segment of the bronchopulmonary tree by inserting (under local anesthesia and direct vision) a small plastic catheter into the trachea. Two to 5 mL of the 20% solution may then be instilled by means of a syringe connected to the catheter.

Acetylcysteine may also be given through a percutaneous intratracheal catheter. One to 2 mL of the 20% or 2 to 4 mL of the 10% solution every 1 to 4 hours may then be given by a syringe attached to the catheter.

Diagnostic Bronchograms: For diagnostic bronchial studies, 2 or 3 administrations of 1 to 2 mL of the 20% solution or 2 to 4 mL of the 10% solution should be given by nebulization or by instillation intratracheally, prior to the procedure.

Administration of Aerosol

Materials: Acetylcysteine solution may be administered using conventional nebulizers made of plastic or glass. Certain materials used in nebulization equipment react with acetylcysteine. The most reactive of these are certain metals (notably iron and copper) and rubber. Where materials may come into contact with acetylcysteine solution, parts made of the following acceptable materials should be used: glass, plastic, aluminum, anodized aluminum, chromed metal, tantalum, sterling silver, or stainless steel. Silver may become tarnished after exposure, but this is not harmful to the drug action or to the patient.

Nebulizing Gases: Compressed tank gas (air) or an air compressor should be used to provide pressure for nebulizing the solution. Oxygen may also be used but should be used with usual precautions in patients with severe respiratory disease and CO2 retention.

Apparatus: Acetylcysteine solution is usually administered as fine nebulae and the nebulizer used should be capable of providing optimal quantities of a suitable range of particle sizes.

Commercially available nebulizers will produce nebulae of acetylcysteine satisfactory for retention in the respiratory tract. Most of the nebulizers tested will supply a high proportion of the drug solution as particles of less than 10 microns in diameter. Mitchell2 has shown that particles less than 10 microns should be retained in the respiratory tract satisfactorily.

Various intermittent positive pressure breathing devices nebulized acetylcysteine with a satisfactory efficiency including: No:40 Da Vilbiss (The Da Vilbiss Co., Somerset, PA) and the Bennett Twin-Jet Nebulizer (Puritan Bennett Corp., Oak at 13th, Kansas City, MO).

The nebulized solution may be inhaled directly from the nebulizer. Nebulizers may also be attached to plastic face masks or plastic mouthpieces. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines. The nebulizing equipment should be cleaned immediately after use because the residues may clog the smaller orifices or corrode metal parts.

Hand bulbs are not recommended for routine use for nebulizing acetylcysteine because their output is generally too small. Also, some hand-operated nebulizers deliver particles that are larger than optimum for inhalation therapy.

Acetylcysteine solution should not be placed directly into the chamber of a heated (hot pot) nebulizer. A heated nebulizer may be part of the nebulization assembly to provide a warm saturated atmosphere if the acetylcysteine aerosol is introduced by means of a separate unheated nebulizer. Usual precautions for administration of warm saturated nebulae should be observed.

The nebulized solution may be breathed directly from the nebulizer. Nebulizers may also be attached to plastic face masks, plastic face tents, plastic mouthpieces, conventional plastic oxygen tents, or head tents. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines.

The nebulizing equipment should be cleaned immediately after use, otherwise the residues may occlude the fine orifices or corrode metal parts.

Prolonged Nebulization: When three-fourths of the initial volume of acetylcysteine solution has been nebulized, a quantity of Sterile Water for Injection, USP (approximately equal to the volume of solution remaining) should be added to the nebulizer. This obviates any concentration of the agent in the residual solvent remaining after prolonged nebulization.

Compatibility: The physical and chemical compatibility of acetylcysteine solutions with certain other drugs that might be concomitantly administered by nebulization, direct instillation, or topical application, has been studied.

Acetylcysteine should not be mixed with certain antibiotics. For example, the antibiotics tetracycline hydrochloride, oxytetracycline hydrochloride and erythromycin lactobionate were found to be incompatible when mixed in the same solution. These agents may be administered from separate solutions if administration of these agents is desirable.

The supplying of these data should not be interpreted as a recommendation for combining acetylcysteine with other drugs. The table is not presented as positive assurance that no incompatibility will be present, since these data are based only on short-term compatibility studies done in the Mead Johnson Research Center. Manufacturers may change their formulations, and this could alter compatibilities. These data are intended to serve only as a guide for predicting compounding problems.

If it is deemed advisable to prepare an admixture, it should be administered as soon as possible after preparation. Do not store unused mixtures.

DOSAGE AND ADMINISTRATION

General

Regardless of the quantity of acetaminophen reported to have been ingested, administer acetylcysteine immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen. Do not await results of assays for acetaminophen level before initiating treatment with acetylcysteine solution. The following procedures are recommended:
The stomach should be emptied promptly by lavage or by inducing emesis with syrup of ipecac. Syrup of ipecac should be given in a dose of 15 mL for children up to age 12 and 30 mL for adolescents and adults followed immediately by drinking copious quantities of water. The dose should be repeated if emesis does not occur in 20 minutes. In the case of a mixed drug overdose, activated charcoal may be indicated. However, if activated charcoal has been administered, lavage before administering acetylcysteine treatment. Activated charcoal adsorbs acetylcysteine in vitro and may do so in patients and thereby may reduce its effectiveness. Draw blood for predetoxificaton acetaminophen plasma assay and for baseline SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes. Administer the loading dose of acetylcysteine, 140 mg per kg of body weight. (Prepare acetylcysteine for oral administration as described in the specific Dosage Guide and Preparation table.) Determine the subsequent action based on predetoxification plasma acetaminophen information. Choose ONE of the following four courses of therapy. Predetoxification plasma acetaminophen level is clearly in toxic range (See Acetaminophen Assays — Interpretation and Methodology below): Administer a first maintenance dose (70 mg/kg acetylcysteine) 4 hours after the loading dose. The maintenance dose is then repeated at 4-hour intervals for a total of 17 doses. Monitor hepatic and renal function and electrolytes throughout the detoxification process. Predetoxification acetominophen level could not be obtained: Proceed as in A. Predetoxification acetominophen level is clearly in the nontoxic range (beneath the dashed line on the nomogram) and you know that acetominophen overdose occurred at least 4 hours before the predetoxification acetaminophen plasma assays: Discontinue administration of acetylcysteine. Predetoxification acetominophen level was in the nontoxic range, but time of ingestion was unknown or less than 4 hours. Because the level of acetaminophen at the time of the predetoxification assay may not be a peak value (peak may not be achieved before 4 hours post-ingestion), obtain a second plasma level in order to decide wether or not the full 17-dose detoxification treatment is necessary. If the patient vomits any oral dose within 1 hour of administration, repeat that dose. In the occasional instances where the patient is persistently unable to retain the orally administered acetylcysteine, the antidote may be administered by duodenal intubation. Repeat SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes daily if the acetaminophen plasma level is in the potentially toxic range as discussed below.
Preparation of Acetylcysteine Solution for Oral Administration:

Oral administration requires dilution of the 20% solution with diet cola, or other diet soft drinks, to a final concentration of 5% (See Dosage Guide and Preparation table). If administered via gastric tube or Miller-Abbott tube, water may be used as the diluent. The dilutions should be freshly prepared and utilized within one hour. Remaining undiluted solutions in opened vials can be stored in the refrigerator up to 96 hours. ACETYLCYSTEINE SOLUTION IS NOT APPROVED FOR PARENTERAL INJECTION.

Acetaminophen Assays — Interpretation and Methodology:

The acute ingestion of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic toxicity. However, the reported history of the quantity of a drug ingested as an overdose is often inaccurate and is not a reliable guide to therapy of the overdose.

THEREFORE, PLASMA OR SERUM ACETAMINOPHEN CONCENTRATIONS, DETERMINED AS EARLY AS POSSIBLE, BUT NO SOONER THAN FOUR HOURS FOLLOWING AN ACUTE OVERDOSE, ARE ESSENTIAL IN ASSESSING THE POTENTIAL RISK OF HEPATOTOXICITY. IF AN ASSAY FOR ACETAMINOPHEN CANNOT BE OBTAINED, IT IS NECESSARY TO ASSUME THAT THE OVERDOSE IS POTENTIALLY TOXIC.

Interpretation of Acetaminophen Assays:
When results of the plasma acetaminophen assay are available refer to the nomogram below to determine if plasma concentration is in the potentially toxic range. Values above the solid line connecting 200 mcg/mL at 4 hours with 50 mcg/mL at 12 hours are associated with a possibility of hepatic toxicity if an antidote is not administered. (Do not wait for assay results to begin acetylcysteine treatment.) If the predetoxification plasma level is above the broken line, continue with maintenance doses of acetylcysteine. It is better to err on the safe side and thus the broken line is placed 25% below the solid line which defines possible toxicity. If the predetoxification plasma level is below the broken line described above, there is minimal risk of hepatic toxicity and acetylcysteine treatment can be discontinued.
Acetaminophen Assay Methodology: Assay procedures most suitable for determining acetaminophen concentrations utilize high pressure liquid chromatography (HPLC) or gas liquid chromatography (GLC). The assay should measure only parent acetaminophen and not conjugated. The assay procedures listed below fulfill this requirement:

Selected Techniques (noninclusive):

HPLC 1.     Blair D and Rumack BH, Clin Chem 1977, 23(4):743–745 (April).2.     Howie D, Andriaenssens PI and Prescott LF, J Pharm Pharmacol 1977, 29(4):235–237 (April).

GLC 3.     Prescott LF, J Pharm Pharmacol 1971, 23(10):807–808 (October).

Colorimetric 4.     Glynn JP and Kendal SE, Lancet 1975,1 (May 17):1147–1148.

Supportive Treatment of Acetaminophen Overdosage:
Maintain fluid and electrolyte balance based on clinical evaluation of state of hydration and serum electrolytes. Treat as necessary for hypoglycemia. Administer vitamin K1 if prothrombin time ratio exceeds 1.5 or fresh frozen plasma if the prothrombin time ratio exceeds 3.0. Diuretics and forced diuresis should be avoided.
Fluticasone Propionate ...

Fluticasone Propionate Spray

Administer fluticasone propionate nasal spray by the intranasal route only. Prime fluticasone propionate nasal spray before using for the first time or after a period of non-use (1 week or more) by shaking the contents well and releasing 6 sprays into the air away from the face. Shake fluticasone propionate nasal spray gently before each use.

Patients should use fluticasone propionate nasal spray at regular intervals since its effectiveness depends on its regular use. Maximum effect may take several days and individual patients will experience a variable time to onset and different degree of symptom relief.

2.1Adults

The recommended starting dosage in adults is 2 sprays (50 mcg of fluticasone propionate each) in each nostril once daily (total daily dose, 200 mcg). The same total daily dose, 1 spray in each nostril administered twice daily (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, patients may be able to reduce their dose to 1 spray in each nostril once daily for maintenance therapy.

Maximum total daily doses should not exceed 2 sprays in each nostril (total dose, 200 mcg/day). There is no evidence that exceeding the recommended dose is more effective.

2.2Adolescents and Children (Aged 4 Years and Older)

The recommended starting dosage in adolescents and children, aged 4 years and older is 1 spray in each nostril once daily (total daily dose, 100 mcg). Patients not adequately responding to 1 spray in each nostril may use 2 sprays in each nostril once daily (total daily dose, 200 mcg). Once adequate control is achieved, the dosage should be decreased to 1 spray in each nostril once daily.

The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day). There is no evidence that exceeding the recommended dose is more effective.
Crest Pro-health For Me...

Crest Pro-health For Me

Gastric irritation may be reduced if taken before, during, or immediately after meals or with food or milk.

The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocorticoid activity the least when given at the time of maximal activity (am) for single dose administration. Therefore, it is recommended that prednisone be administered in the morning prior to 9 am and when large doses are given, administration of antacids between meals to help prevent peptic ulcers. Multiple dose therapy should be evenly distributed in evenly spaced intervals throughout the day.

Dietary salt restriction may be advisable in patients.

Do not stop taking this medicine without first talking to your doctor. Avoid abrupt withdraw of therapy.

The initial dosage of prednisone may vary from 5 mg to 60 mg per day, depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice, while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, prednisone should be discontinued and the patient transferred to other appropriate therapy. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small increments at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation, it may be necessary to increase the dosage of prednisone for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it recommended that it be withdrawn gradually rather than abruptly.

Multiple Sclerosis

In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective. (Dosage range is the same for prednisone and prednisolone.)

Alternate Day Therapy

Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the cushingoid state, corticoid withdrawal symptoms, and growth suppression in children.

The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.

A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.

The diurnal rhythm of the HPA axis is lost in Cushing’s disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects.

During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1 1/4 to 1 1/2 days following a single dose) and thus are recommended for alternate day therapy.

The following should be kept in mind when considering alternate day therapy:
• Basic principles and indications for corticosteroid therapy should apply. The benefits of alternate day therapy should not encourage the indiscriminate use of steroids. • Alternate day therapy is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated. • In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with alternate day therapy. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended. Once control has been established, two courses are available: (a) change to alternate day therapy and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable. • Because of the advantages of alternate day therapy, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (e.g., patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on alternate day therapy may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum. • As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (e.g., dexamethasone and betamethasone). • The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am). • In using alternate day therapy it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of alternate day therapy will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed. • In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be re-instituted. • Although many of the undesirable features of corticosteroid therapy can be minimized by alternate day therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.
Naratriptan

Naratriptan

2.1 Dosing Information

The recommended dose of naratriptan is 1 mg or 2.5 mg.

If the migraine returns or if the patient has only partial response, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period.

The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established.

2.2 Dosage and Adjustment in Patients With Renal Impairment

Naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug [see Contraindications (4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

In patients with mild to moderate renal impairment, the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a 1 mg starting dose is recommended [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.3 Dosage Adjustment in Patients With Hepatic Impairment

Naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) because of decreased clearance [see Contraindications (4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

In patients with mild to moderate hepatic impairment (Child-Pugh grade A or B), the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a 1 mg starting dose is recommended [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
Minocycline Hydrochlori...

Minocycline Hydrochloride

2.1 Hypertension

Use in Uncomplicated Hypertensive Patients

In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses.

Use in Elderly Patients

The recommended initial daily dosage of perindopril for the elderly is 4 mg daily, given in one or two divided doses. Experience with perindopril is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration [see Use in Specific Populations (8.5)].

Use with Diuretics

In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of perindopril. Consider reducing the dose of diuretic prior to starting perindopril erbumine tablets [see Drug Interactions (7.1)].

2.2 Stable Coronary Artery Disease

In patients with stable coronary artery disease, perindopril should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (greater than 70 years), perindopril should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated.

2.3 Dose Adjustment in Renal Impairment and Dialysis

Perindoprilat elimination is decreased in renally impaired patients. Perindopril is not recommended in patients with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.
Zolpidem Tartrate

Zolpidem Tartrate

2.1 Dosage in Adults

Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see Warnings and Precautions (5.1)]. The total dose of Zolpidem Tartrate Tablets should not exceed 10 mg once daily immediately before bedtime.

The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

2.2 Special Populations

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate tablets. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of zolpidem in both of these patient populations is 5 mg once daily immediately before bedtime [seeWarnings and Precautions (5.1); Use in Specific Populations (8.5)].

2.3 Use with CNS Depressants

Dosage adjustment may be necessary when Zolpidem Tartrate Tablets are combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].

2.4 Administration

The effect of Zolpidem Tartrate Tablets may be slowed by ingestion with or immediately after a meal.
Dipyridamole

Dipyridamole

Adjunctive Use in Prophylaxis of Thromboembolism after Cardiac Valve Replacement. The recommended dose is 75-100 mg four times daily as an adjunct to the usual warfarin therapy. Please note that aspirin is not to be administered concomitantly with coumarin anticoagulants.
Calcitriol Solution

Calcitriol Solution

The optimal daily dose of Calcitriol Oral Solution must be carefully determined for each patient. Calcitriol Oral Solution is administered orally as an oral solution (1 mcg/mL). Calcitriol therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of serum calcium.

The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate but not excessive daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

Because of improved calcium absorption from the gastrointestinal tract, some patients on Calcitriol Oral Solution may be maintained on a lower calcium intake. Patients who tend to develop hypercalcemia may require only low doses of calcium or no supplementation at all.

During the titration period of treatment with calcitriol, serum calcium levels should be checked at least twice weekly. When the optimal dosage of calcitriol has been determined, serum calcium levels should be checked every month (or as given below for individual indications). Samples for serum calcium estimation should be taken without a tourniquet.

Dialysis Patients

The recommended initial dose of calcitriol is 0.25 mcg/day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 mcg/day at 4 to 8 week intervals. During this titration period, serum calcium levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: General).

Phosphorus, magnesium, and alkaline phosphatase should be determined periodically.

Patients with normal or only slightly reduced serum calcium levels may respond to calcitriol doses of 0.25 mcg every other day. Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.

Oral calcitriol may normalize plasma ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction. In these individuals with autonomous parathyroid hyperfunction, oral calcitriol may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism.

Hypoparathyroidism

The recommended initial dosage of calcitriol is 0.25 mcg/day given in the morning. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease is not observed, the dose may be increased at 2 to 4 week intervals. During the dosage titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, calcitriol should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: General). Careful consideration should also be given to lowering the dietary calcium intake. Serum calcium, phosphorus, and 24 hour urinary calcium should be determined periodically.

Most adult patients and pediatric patients age 6 years and older have responded to dosages in the range of 0.5 mcg to 2 mcg daily. Pediatric patients in the 1 to 5 year age group with hypoparathyroidism have usually been given 0.25 mcg to 0.75 mcg daily. The number of treated patients with pseudohypoparathyroidism less than 6 years of age is too small to make dosage recommendations.

Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of calcitriol may be needed.

Predialysis Patients

The recommended initial dosage of calcitriol is 0.25 mcg/day in adults and pediatric patients 3 years of age and older. This dosage may be increased if necessary to 0.5 mcg/day.

For pediatric patients less than 3 years of age, the recommended initial dosage of calcitriol is 10 to 15 ng/kg/day.
Tinidazole

Tinidazole

2.1 Dosing Instructions

It is advisable to take tinidazole with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of tinidazole [see Clinical Pharmacology (12.3)].

Alcoholic beverages should be avoided when taking tinidazole and for 3 days afterwards [see Drug Interactions (7.1)].

2.2 Compounding of the Oral Suspension

For those unable to swallow tablets, tinidazole tablets may be crushed in artificial cherry syrup to be taken with food.

Procedure for Extemporaneous Pharmacy Compounding of the Oral Suspension: Pulverize four 500 mg oral tablets with a mortar and pestle. Add approximately 10 mL of cherry syrup to the powder and mix until smooth. Transfer the suspension to a graduated amber container. Use several small rinses of cherry syrup to transfer any remaining drug in the mortar to the final suspension for a final volume of 30 mL. The suspension of crushed tablets in artificial cherry syrup is stable for 7 days at room temperature. When this suspension is used, it should be shaken well before each administration.

2.3 Trichomoniasis

The recommended dose in both females and males is a single 2 g oral dose taken with food. Since trichomoniasis is a sexually transmitted disease, sexual partners should be treated with the same dose and at the same time.

2.4 Giardiasis

The recommended dose in adults is a single 2 g dose taken with food. In pediatric patients older than three years of age, the recommended dose is a single dose of 50 mg/kg (up to 2 g) with food.

2.5 Amebiasis

Intestinal: The recommended dose in adults is a 2 g dose per day for 3 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3 days with food.

Amebic Liver Abscess: The recommended dose in adults is a 2 g dose per day for 3-5 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3-5 days with food. There are limited pediatric data on durations of therapy exceeding 3 days, although a small number of children were treated for 5 days without additional reported adverse reactions. Children should be closely monitored when treatment durations exceed 3 days.

2.6 Bacterial Vaginosis

The recommended dose in non-pregnant females is a 2 g oral dose once daily for 2 days taken with food or a 1 g oral dose once daily for 5 days taken with food. The use of tinidazole in pregnant patients has not been studied for bacterial vaginosis.
Calcium Carbonate Suspe...

Calcium Carbonate Suspension

Shake well before using. Take 5 mL (one teaspoonful) two to three times daily with meals or as directed by a physician.
Anastrozole

Anastrozole

2.1 Recommended Dose

The dose of anastrozole is one 1 mg tablet taken once a day. For patients with advanced breast cancer, anastrozole should be continued until tumor progression. Anastrozole can be taken with or without food.

For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, anastrozole was administered for five years [see Clinical Studies (14.1)].

No dosage adjustment is necessary for patients with renal impairment or for elderly patients [see Use in Specific Populations (8.6)].

2.2 Patients with Hepatic Impairment

No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].
Hydromorphone Hydrochlo...

Hydromorphone Hydrochloride

The usual starting dose for Hydromorphone Hydrochloride Tablets, USP is 2 mg to 4 mg, orally, every 4 to 6 hours. Appropriate use of the Hydromorphone Hydrochloride Tablets, USP must be decided by careful evaluation of each clinical situation.

The usual adult oral dosage of Hydromorphone Hydrochloride Oral Solution, USP is one-half (2.5 mL) to two teaspoonfuls (10 mL) (2.5 mg to 10 mg) every 3 to 6 hours as directed by the clinical situation. Oral dosages higher than the usual may be required in some patients.

A gradual increase in dose may be required if analgesia is inadequate, as tolerance develops, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.

Patients with hepatic and renal impairment should be started on a lower starting dose (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism).
Propranolol Hydrochlori...

Propranolol Hydrochloride Solution

General

Because of the variable bioavailability of propranolol, the dose should be individualized based on response.

Hypertension

The usual initial dosage is 40 mg propranolol twice daily, whether used alone or added to a diuretic. Dosage may be increased gradually until adequate blood pressure control is achieved. The usual maintenance dosage is 120 mg to 240 mg per day. In some instances a dosage of 640 mg a day may be required. The time needed for full antihypertensive response to a given dosage is variable and may range from a few days to several weeks.

While twice-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, some patients, especially when lower doses are used, may experience a modest rise in blood pressure toward the end of the 12-hour dosing interval. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. If control is not adequate, a larger dose, or 3-times-daily therapy may achieve better control.

Angina Pectoris

Total daily doses of 80 mg to 320 mg propranolol, when administered orally, twice a day, three times a day, or four times a day, have been shown to increase exercise tolerance and to reduce ischemic changes in the ECG. If treatment is to be discontinued, reduce dosage gradually over a period of several weeks. (See WARNINGS.)

Atrial Fibrillation

The recommended dose is 10 mg to 30 mg propranolol three or four times daily before meals and at bedtime.

Myocardial Infarction

In the Beta-Blocker Heart Attack Trial (BHAT), the initial dose was 40 mg t.i.d., with titration after 1 month to 60 mg to 80 mg t.i.d. as tolerated. The recommended daily dosage is 180 mg to 240 mg propranolol per day in divided doses. Although a t.i.d. regimen was used in the BHAT and a q.i.d. regimen in the Norwegian Multicenter Trial, there is a reasonable basis for the use of either a t.i.d. or b.i.d. regimen (see PHARMACODYNAMICS AND CLINICAL EFFECTS). The effectiveness and safety of daily dosages greater than 240 mg for prevention of cardiac mortality have not been established. However, higher dosages may be needed to effectively treat co-existing diseases such as angina or hypertension (see above).

Migraine

The initial dose is 80 mg propranolol daily in divided doses. The usual effective dose range is 160 mg to 240 mg per day. The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, propranolol therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks.

Essential Tremor

The initial dosage is 40 mg propranolol twice daily. Optimum reduction of essential tremor is usually achieved with a dose of 120 mg per day. Occasionally, it may be necessary to administer 240 mg to 320 mg per day.

Hypertrophic Subaortic Stenosis

The usual dosage is 20 mg to 40 mg propranolol three or four times daily before meals and at bedtime.

Pheochromocytoma

The usual dosage is 60 mg propranolol daily in divided doses for three days prior to surgery as adjunctive therapy to alpha-adrenergic blockade. For the management of inoperable tumors, the usual dosage is 30 mg daily in divided doses as adjunctive therapy to alpha-adrenergic blockade.
Diazepam Solution Diaze...

Diazepam Solution Diazepam Intensol Solution

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects.
Adults: Usual Daily Dosage Management of Anxiety Disorders and Relief of Symptoms of Anxiety. Depending upon severity of symptoms – 2 mg to 10 mg, 2 to 4 times daily. Symptomatic Relief in Acute Alcohol Withdrawal. 10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed. Adjunctively for Relief of Skeletal Muscle Spasm. 2 mg to 10 mg, 3 or 4 times daily. Adjunctively in Convulsive Disorders. 2 mg to 10 mg, 2 to 4 times daily. Geriatric Patients or in the presence of debilitating disease. 2 mg to 2 1/2 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated. Children: Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in children under 6 months. 1 mg to 2 1/2 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated.
Proper Use of an Intensol™

An Intensol is a concentrated oral solution as compared to standard oral liquid medications. It is recommended that an Intensol be mixed with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce and puddings.

Use only the calibrated dropper provided with this product. Draw into the dropper the amount prescribed for a single dose. Then squeeze the dropper contents into a liquid or semi-solid food. Stir the liquid or food gently for a few seconds. The Intensol formulation blends quickly and completely. The entire amount of the mixture, of drug and liquid or drug and food, should be consumed immediately. Do not store for future use.
Methadone Hydrochloride...

Methadone Hydrochloride Concentrate

Methadone differs from many other opioid agonists in several important ways. Methadone's pharmacokinetic properties, coupled with high interpatient variability in its absorption, metabolism, and relative analgesic potency, necessitate a cautious and highly individualized approach to prescribing. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration.

While methadone’s duration of analgesic action (typically 4 to 8 hours) in the setting of single-dose studies approximates that of morphine, methadone’s plasma elimination half-life is substantially longer than that of morphine (typically 8 to 59 hours vs. 1 to 5 hours). Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. Also, with repeated dosing, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations. For these reasons, steady-state plasma concentrations, and full analgesic effects, are usually not attained until 3 to 5 days of dosing. Additionally, incomplete cross-tolerance between mu-opioid agonists makes determination of dosing during opioid conversion complex.

The complexities associated with methadone dosing can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists.

Detoxification and Maintenance Treatment of Opiate Dependence

For detoxification and maintenance of opiate dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Induction/Initial Dosing

The initial methadone dose should be administered, under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. Initially, a single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg. If same-day dosing adjustments are to be made, the patient should be asked to wait 2 to 4 hours for further evaluation, when peak levels have been reached. An additional 5 to 10 mg of methadone may be provided if withdrawal symptoms have not been suppressed or if symptoms reappear. The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Dose adjustments should be made over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). Dose adjustment should be cautious; deaths have occurred in early treatment due to the cumulative effects of the first several days’ dosing. Patients should be reminded that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Initial doses should be lower for patients whose tolerance is expected to be low at treatment entry. Loss of tolerance should be considered in any patient who has not taken opioids for more than 5 days. Initial doses should not be determined by previous treatment episodes or dollars spent per day on illicit drug use.

For Short-Term Detoxification

For patients preferring a brief course of stabilization followed by a period of medically supervised withdrawal, it is generally recommended that the patient be titrated to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. Stabilization can be continued for 2 to 3 days, after which the dose of methadone should be gradually decreased. The rate at which methadone is decreased should be determined separately for each patient. The dose of methadone can be decreased on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed.

For Maintenance Treatment

Patients in maintenance treatment should be titrated to a dose at which opioid symptoms are prevented for 24 hours, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are blocked or attenuated, and the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

For Medically Supervised Withdrawal After a Period of Maintenance Treatment

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. Patients should be apprised of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.
Megestrol Acetate Suspe...

Megestrol Acetate Suspension

There is no fixed dosage regimen for the management of diabetes mellitus with acarbose or any other pharmacologic agent. Dosage of acarbose must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended dose of 100 mg t.i.d. Acarbose should be taken three times daily at the start (with the first bite) of each main meal. Acarbose should be started at a low dose, with gradual dose escalation as described below, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. If the prescribed diet is not observed, the intestinal side effects may be intensified. If strongly distressing symptoms develop in spite of adherence to the diabetic diet prescribed, the doctor must be consulted and the dose temporarily or permanently reduced.

During treatment initiation and dose titration (see below), one-hour postprandial plasma glucose may be used to determine the therapeutic response to acarbose and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both postprandial plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of acarbose, either as monotherapy or in combination with sulfonylureas, insulin or metformin.

Initial Dosage

The recommended starting dosage of acarbose is 25 mg given orally three times daily at the start (with the first bite) of each main meal. However, some patients may benefit from more gradual dose titration to minimize gastrointestinal side effects. This may be achieved by initiating treatment at 25 mg once per day and subsequently increasing the frequency of administration to achieve 25 mg t.i.d.

Maintenance Dosage

Once a 25 mg t.i.d. dosage regimen is reached, dosage of acarbose should be adjusted at 4 to 8 week intervals based on one-hour postprandial glucose or glycosylated hemoglobin levels, and on tolerance. The dosage can be increased from 25 mg t.i.d. to 50 mg t.i.d. Some patients may benefit from further increasing the dosage to 100 mg t.i.d. The maintenance dose ranges from 50 mg t.i.d. to 100 mg t.i.d. However, since patients with low body weight may be at increased risk for elevated serum transaminases, only patients with body weight > 60 kg should be considered for dose titration above 50 mg t.i.d. (see PRECAUTIONS). If no further reduction in postprandial glucose or glycosylated hemoglobin levels is observed with titration to 100 mg t.i.d., consideration should be given to lowering the dose. Once an effective and tolerated dosage is established, it should be maintained.

Maximum Dosage

The maximum recommended dose for patients ≤ 60 kg is 50 mg t.i.d. The maximum recommended dose for patients > 60 kg is 100 mg t.i.d.

Patients Receiving Sulfonylureas or Insulin

Sulfonylurea agents or insulin may cause hypoglycemia. Acarbose given in combination with a sulfonylurea or insulin will cause a further lowering of blood glucose and may increase the potential for hypoglycemia. If hypoglycemia occurs, appropriate adjustments in the dosage of these agents should be made.
Calcium Carbonate

Calcium Carbonate

Shake well before using.
Morphine Sulfate

Morphine Sulfate

Selection of patients for treatment with morphine sulfate should be governed by the same principles that apply to the use of similar opioid analgesics. Individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

2.1 Individualization of Dosage

As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of morphine sulfate, give attention to the following:
• the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; • the reliability of the relative potency estimate used to calculate the equivalent morphine sulfate dose needed; • the patient’s degree of opioid tolerance; • the general condition and medical status of the patient; • concurrent medications; • the type and severity of the patient’s pain; • risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.
The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual re-evaluation of the patient receiving morphine sulfate is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. During chronic therapy, especially for non-cancer-related pain, periodically re-assess the continued need for the use of opioid analgesics.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

2.2 Initiation of Therapy in Opioid-Naïve Patients

Start patients who have not been receiving opioid analgesics on morphine sulfate in the following dosing range using tablets, 15 mg or 30 mg strengths:

Morphine Sulfate Tablets: 15 to 30 mg every 4 hours as needed for pain.

Titrate the dose based upon the individual patient’s response to their initial dose of morphine sulfate. Adjust the dose to an acceptable level of analgesia taking into account the improvement in pain intensity and the tolerability of the morphine by the patient.

2.3 Conversion to Oral Morphine Sulfate

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dose of morphine sulfate. It is better to underestimate a patient’s 24-hour oral morphine sulfate dose and make available rescue medication than to overestimate the 24-hour oral morphine sulfate dose and manage an adverse experience of overdose.

Consider the following general points regarding opioid conversions.

Conversion From Parenteral Morphine to Oral Morphine Sulfate

For conversion from parenteral to oral morphine sulfate, anywhere from 3 to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine.

Conversion From Parenteral Oral Non-Morphine Opioids to Oral Morphine Sulfate

In converting patients from other opioids to morphine sulfate, close observation and adjustment of dosage based upon the patient’s response to morphine sulfate is imperative. Physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate.

Conversion From Controlled-Release Oral Morphine to Oral Morphine Sulfate

For a given dose, the same total amount of morphine sulfate is available from Morphine Sulfate Tablets, Morphine Sulfate Oral Solution, and controlled-release and extended-release morphine capsules. The extended duration of release of morphine sulfate from controlled-release tablets or extended-release tablets results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products. Conversion from oral solution or immediate-release tablets to the same total daily dose of controlled-release tablets or extended-release tablets could lead to excessive sedation at peak serum levels. Therefore, dosage adjustment with close observation is necessary.

2.4 Maintenance of Therapy

Continual re-evaluation of the patient receiving morphine sulfate is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.

2.5 Cessation of Therapy

When the patient no longer requires therapy with morphine sulfate, gradually taper the dose to prevent signs and symptoms of withdrawal in the physically dependent patient.
Cilostazol

Cilostazol

The recommended dosage of cilostazol is 100 mg twice daily taken at least half an hour before or two hours after breakfast and dinner.

A dose reduction to 50 mg twice daily should be considered during co-administration with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin and diltiazem) and during co-administration with CYP2C19 inhibitors (e.g., ticlopidine, fluconazole and omeprazole. (see PRECAUTIONS and Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions) twice daily.

Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced. If symptoms are unimproved after 3 months, discontinue cilostazol.

Discontinuation of Therapy

The available data suggest that the dosage of cilostazol can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).
Calcitriol

Calcitriol

The optimal daily dose of calcitriol must be carefully determined for each patient. Calcitriol Capsules should be administered orally. Calcitriol therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of serum calcium.

The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate but not excessive daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

Because of improved calcium absorption from the gastrointestinal tract, some patients on calcitriol may be maintained on a lower calcium intake. Patients who tend to develop hypercalcemia may require only low doses of calcium or no supplements at all.

During the titration period of treatment with calcitriol, serum calcium levels should be checked at least twice weekly. When the optimal dosage of calcitriol has been determined, serum calcium levels should be checked every month (or as given below for individual indications). Samples for serum calcium estimation should be taken without a tourniquet.

Dialysis Patients

The recommended initial dose of calcitriol is 0.25 mcg/day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 mcg/day at 4 to 8 week intervals. During this titration period, serum calcium levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: General). Phosphorus, magnesium, and alkaline phosphatase should be determined periodically.

Patients with normal or only slightly reduced serum calcium levels may respond to calcitriol doses of 0.25 mcg every other day. Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.

Oral calcitriol may normalize plasma ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction. In these individuals with autonomous parathyroid hyperfunction, oral calcitriol may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism.

Hypoparathyroidism

The recommended initial dosage of calcitriol is 0.25 mcg/day given in the morning. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease is not observed, the dose may be increased at 2- to 4-week intervals. During the dosage titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, calcitriol should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: General). Careful consideration should also be given to lowering the dietary calcium intake. Serum calcium, phosphorus, and 24-hour urinary calcium should be determined periodically.

Most adult patients and pediatric patients age 6 years and older have responded to dosages in the range of 0.5 mcg to 2 mcg daily. Pediatric patients in the 1 to 5 year age group with hypoparathyroidism have usually been given 0.25 mcg to 0.75 mcg daily. The number of treated patients with pseudohypoparathyroidism less than 6 years of age is too small to make dosage recommendations.

Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of calcitriol may be needed.

Predialysis Patients

The recommended initial dosage of calcitriol is 0.25 mcg/day in adults and pediatric patients 3 years of age and older. This dosage may be increased if necessary to 0.5 mcg/day.

For pediatric patients less than 3 years of age, the recommended initial dosage of calcitriol is 10 to 15 ng/kg/day.
Furosemide

Furosemide

Edema

Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response.

Adults

The usual initial dose of furosemide is 20 to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (e.g., at 8 am and 2 pm). The dose of furosemide may be carefully titrated up to 600 mg/day in patients with clinically severe edematous states.

Edema may be most efficiently and safely mobilized by giving furosemide on 2 to 4 consecutive days each week.

When doses exceeding 80 mg/day are given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable. (See PRECAUTIONS: Laboratory Tests.)

Geriatric Patients

In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range. (See PRECAUTIONS: Geriatric Use.)

Pediatric Patients

The usual initial dose of oral furosemide in pediatric patients is 2 mg/kg body weight, given as a single dose. If the diuretic response is not satisfactory after the initial dose, dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the previous dose. Doses greater than 6 mg/kg body weight are not recommended. For maintenance therapy in pediatric patients, the dose should be adjusted to the minimum effective level.

Hypertension

Therapy should be individualized according to the patient’s response to gain maximal therapeutic response and to determine the minimal dose needed to maintain the therapeutic response.

Adults

The usual initial dose of furosemide for hypertension is 80 mg, usually divided into 40 mg twice a day. Dosage should then be adjusted according to response. If response is not satisfactory, add other antihypertensive agents.

Changes in blood pressure must be carefully monitored when furosemide is used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50 percent when furosemide is added to the regimen. As the blood pressure falls under the potentiating effect of furosemide, a further reduction in dosage or even discontinuation of other antihypertensive drugs may be necessary.

Geriatric Patients

In general, dose selection and dose adjustment for the elderly patient should be cautious, usually starting at the low end of the dosing range. (See PRECAUTIONS: Geriatric Use.)
Meperidine Hydrochlorid...

Meperidine Hydrochloride

For Relief of Pain

Dosage should be adjusted according to the severity of the pain and the response of the patient. Meperidine is less effective orally than with parenteral administration. The dose of meperidine should be proportionately reduced (usually by 25 to 50 percent) when administered concomitantly with phenothiazines and many other tranquilizers since they potentiate the action of meperidine.

Adults: The usual dosage is 50 mg to 150 mg orally, every 3 or 4 hours as necessary.

Pediatric Patients: The usual dosage is 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 or 4 hours as necessary (see PRECAUTIONS, Pediatric Use).

Each dose of the oral solution should be taken in one-half glass of water, since if taken undiluted, it may exert a slight topical anesthetic effect on mucous membranes.
Lithium Carbonate

Lithium Carbonate

Doses of extended-release tablets are usually given b.i.d. (approximately 12-hour intervals). When initiating therapy with immediate-release or extended-release lithium, dosage must be individualized according to serum levels and clinical response.

When switching a patient from immediate-release capsules to the Lithium Carbonate Extended Release Tablets, give the same total daily dose when possible. Most patients on maintenance therapy are stabilized on 900 mg daily, e.g., Lithium Carbonate Extended Release Tablets, 450 mg b.i.d. When the previous dosage of immediate-release lithium is not a multiple of 450 mg, e.g., 1500 mg, initiate lithium extended-release tablet at the multiple of 450 mg nearest to, but below, the original daily dose, i.e., 1350 mg. When the two doses are unequal, give the larger dose in the evening. In the above example, with a total daily dose of 1350 mg, generally 450 mg of Lithium Carbonate Extended Release Tablets should be given in the morning and 900 mg of Lithium Carbonate Extended Release Tablets in the evening. If desired, the total daily dose of 1350 mg can be given in three equal 450 mg doses of Lithium Carbonate Extended Release Tablets. These patients should be monitored at 1- to 2-week intervals, and dosage adjusted if necessary, until stable and satisfactory serum levels and clinical state are achieved.

When patients require closer titration than that available with doses of lithium carbonate extended-release tablets in increments of 450 mg, immediate-release capsules should be used.

Acute Mania

Optimal patient response to lithium can usually be established and maintained with 1800 mg per day in divided doses. Such doses will normally produce the desired serum lithium level ranging between 1 and 1.5 mEq/L.

Dosage must be individualized according to serum levels and clinical response. Regular monitoring of the patient's clinical state and serum lithium levels is necessary. Serum levels should be determined twice per week during the acute phase, and until the serum level and clinical condition of the patient have been stabilized.

Long-Term Control

The desirable serum lithium levels are 0.6 to 1.2 mEq/L. Dosage will vary from one individual to another, but usually 900 mg to 1200 mg per day in divided doses will maintain this level. Serum lithium levels in uncomplicated cases receiving maintenance therapy during remission should be monitored at least every two months.

Patients unusually sensitive to lithium may exhibit toxic signs at serum levels below 1 mEq/L.

N.B.

Blood samples for serum lithium determinations should be drawn immediately prior to the next dose when lithium concentrations are relatively stable (i.e., 8 to 12 hours after the previous dose). Total reliance must not be placed on serum levels alone. Accurate patient evaluation requires both clinical and laboratory analysis.

Elderly patients often respond to reduced dosage, and may exhibit signs of toxicity at serum levels ordinarily tolerated by younger patients.
Lithium Carbonate

Lithium Carbonate

Acute Mania

Optimal patient response can usually be established with 1800 mg/day in the following dosages:
ACUTE MANIA Morning Afternoon Nighttime Lithium Carbonate Extended Release Tablets
3 tabs

(900 mg)

3 tabs

(900 mg)

Such doses will normally produce an effective serum lithium concentration ranging between 1 and 1.5 mEq/L. Dosage must be individualized according to serum concentrations and clinical response. Regular monitoring of the patient’s clinical state and of serum lithium concentrations is necessary. Serum concentrations should be determined twice per week during the acute phase, and until the serum concentrations and clinical condition of the patient have been stabilized.

Long-Term Control

Desirable serum lithium concentrations are 0.6 to 1.2 mEq/L which can usually be achieved with 900 to 1200 mg/day. Dosage will vary from one individual to another, but generally the following dosages will maintain this concentration:
* Can be administered on TID recommended dosing interval up to 1200 mg/day LONG-TERM CONTROL Morning Afternoon Nighttime Lithium Carbonate Extended Release Tablets*
2 tabs

(600 mg)

2 tabs

(600 mg)

Serum lithium concentrations in uncomplicated cases receiving maintenance therapy during remission should be monitored at least every two months. Patients abnormally sensitive to lithium may exhibit toxic signs at serum concentrations of 1 to 1.5 mEq/L. Geriatric patients often respond to reduced dosage, and may exhibit signs of toxicity at serum concentrations ordinarily tolerated by other patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Important Considerations
Blood samples for serum lithium determinations should be drawn immediately prior to the next dose when lithium concentrations are relatively stable (i.e., 8 to 12 hours after previous dose). Total reliance must not be placed on serum concentrations alone. Accurate patient evaluation requires both clinical and laboratory analysis. Lithium Carbonate Extended Release Tablets USP must be swallowed whole and never chewed or crushed.
Digoxin Solution

Digoxin Solution

2.1 General Dosing Considerations

The dose of digoxin should be based on clinical assessment but individual patient factors should be taken into consideration. Those factors are:
• Lean body weight • Renal function • Patient age • Concurrent disease [see Warnings and Precautions (5)] • Concomitant medication [see Drug Interactions (7)]
Because the pharmacokinetics of digoxin are complex, and because toxic levels of digoxin are only slightly higher than therapeutic levels, digoxin dosing can be difficult. The recommended approach is to
• estimate the patient’s daily maintenance dose • adjust the estimate to account for patient-specific factors • choose a dosing regimen • decide whether to initiate therapy with a loading dose • monitor the patient for toxicity and for therapeutic effect • adjust the dose
Dose titration may be accomplished by either of two general approaches that differ in dosage and frequency of administration, but reach the same total amount of digoxin accumulated in the body.
1. If rapid titration is considered medically appropriate, administer a loading dose based upon projected peak digoxin body stores. Maintenance dose can be calculated as a percentage of the loading dose. 2. More gradual titration may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives of the drug for the individual patient. Depending upon the patient’s renal function, this will take between 1 and 3 weeks.
2.2 Serum Digoxin Concentrations

In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication.

Studies have shown diminished efficacy at serum levels < 0.5 ng/mL, while levels above 2 ng/mL are associated with increased toxicity without increased benefit. The inotropic effects of digoxin tend to appear at lower concentrations than the electrophysiological effects. Based on retrospective analysis, adverse events may be higher in the upper therapeutic range.

Perform sampling of serum concentrations just before the next scheduled dose of the drug. If this is not possible, sample at least 6 hours or later after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient’s renal function. On a twice-daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. The serum concentration of digoxin should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug.

When decision-making is to be guided by serum digoxin levels, the clinician must consider the possibility of reported concentrations that have been falsely elevated by endogenous digoxin-like immunoreactive substances [see Drug Interactions (7.4)]. If the assay being used is sensitive to these substances, it may be prudent to obtain a baseline measurement before digoxin therapy is started, and correct later values by the reported baseline level.

2.3 Loading Dose

Loading doses for each age group are given in Table 1 below.

In pediatric patients, if a loading dose is needed, it can be administered with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 4- to 8-hour intervals, with careful assessment of clinical response before each additional dose. If the patient’s clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given as the loading dose [see Table 1 and 2].
Table 1: Estimate the Loading Dose
Age

Oral Loading Dose, mcg/kg

Premature

20 - 30

Full-Term

25 - 35

1 to 24 months

35 - 60

2 to 5 years

30 - 45

5 to 10 years

20 - 35

Over 10 years

10 - 15

More gradual attainment of digoxin levels can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided in Table 2 (2.4 Estimate of Daily Maintenance Dose) can be used in calculating this dose for patients with normal renal function. Steady state will be attained after approximately 5 days in subjects with normal renal function.

2.4 Estimate of Daily Maintenance Dose

The recommended daily maintenance doses for each age group are given in Table 2 below. These recommendations assume the presence of normal renal function.
Table 2: Estimate of the Daily Maintenance Dose
Age

Daily Oral Maintenance Dose, mcg/kg/day

Dose Regimen, mcg/kg/dose

Premature

4.7 – 7.8

2.3 – 3.9 Twice daily

Full-Term

7.5 – 11.3

3.8 – 5.6 Twice daily

1 to 24 months

11.3 – 18.8

5.6 – 9.4 Twice daily

2 to 5 years

9.4 – 13.1

4.7 – 6.6 Twice daily

5 to 10 years

5.6 – 11.3

2.8 – 5.6 Twice daily

Over 10 years

3.0 – 4.5

3.0 – 4.5 Once daily

Dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, dosage selection must be based upon clinical assessment and ultimately therapeutic drug level monitoring of the patient.

Divided daily dosing is recommended for pediatric patients under age 10. In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be made as shown in Tables 1 and 2. Renal clearance is further reduced in the premature infant. Beyond the immediate newborn period, pediatric patients generally require proportionally larger doses than adults on the basis of body weight or body surface area. Pediatric patients over 10 years of age require adult dosages in proportion to their body weight. Some researchers have suggested that infants and young pediatric patients tolerate slightly higher serum concentrations than do adults. For pediatric patients with known or suspected renal dysfunction, lower starting doses should be considered combined with frequent monitoring of digoxin levels.

NOTE: The calibrated dropper supplied with the 60 mL bottle of digoxin oral solution is not appropriate to measure doses below 0.2 mL. Doses less than 0.2 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient, such as a graduated syringe.

2.5 Adjustment of Dose

The body’s handling of digoxin can be affected by many different patient-specific factors. Some of the possible effects are small, so anticipatory dose adjustment might not be required, but others should be considered before initial dosing [see Clinical Pharmacology (12.2) and Drug Interactions (7)].

Both adults and pediatric patients with abnormal renal function need to have the dose of digoxin proportionally reduced. Recommended maintenance doses based upon lean body weight and renal function are listed in Table 3. Developmental changes in pediatric renal function were factored into Table 3. However, age-related and other changes in adult renal function were not.

The volume of distribution of digoxin is proportional to lean body weight and doses listed in Table 3 assume average body composition. The dose of digoxin must be reduced in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema.
Table 3: Usual Maintenance Dose*† Requirements (mcg) of Digoxin Based upon Age, Lean Body Weight and Renal Function * The doses are rounded to whole numbers. † Twice daily dosing is recommended for pediatric patients under 10 years of age. Once daily dosing is recommended for pediatric patients above 10 years of age and adults. ‡ Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m 2 body surface area. Foradults, if only serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg body weight) may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. Note: This equation cannot be used for estimating creatinine clearance in infants or pediatric patients. For pediatric patients, the modified Schwartz equation may be used as listed below. The formula was based on height in cm and Scr in mg/dL where k is a constant. Ccr is corrected to 1.73 m 2 body surface area. During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants. The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys. GFR (mL/min/1.73 m 2) = (k x Height)/Scr.
Corrected Ccr

(mL/min per 70 kg)‡

Dose* to be given Twice Daily†

Dose‡ to be given Once Daily†

Number of Days Before Steady State Achieve

< 10 years of age

> 10 years of age and adults

Lean Body Weight

Lean Body Weight

kg

5

10

20

30

40

50

60

40

50

60

70

80

90

100

lb

11

22

44

66

88

110

132

88

110

132

154

176

198

220

10

10

20

40

60

80

100

120

80

100

120

140

160

180

200

19

20

11

23

45

68

90

113

135

90

113

135

158

180

203

225

16

30

13

25

50

75

100

125

150

100

125

150

175

200

225

250

14

40

14

28

55

83

110

138

165

110

138

165

193

220

248

275

13

50

15

30

60

90

120

150

180

120

150

180

210

240

270

300

12

60

16

33

65

98

130

163

195

130

163

195

228

260

293

325

11

70

18

35

70

105

140

175

210

140

175

210

245

280

315

350

10

80

19

38

75

113

150

188

225

150

188

225

263

300

338

375

9

90

20

40

80

120

160

200

240

160

200

240

280

320

360

400

8

100

21

43

85

128

170

213

255

170

213

255

298

340

383

425

7

Determination of the target dose in milliliters of Digoxin Oral Solution based on body weight is shown in Table 4. Provided is the volume required per dose, NOT per day.
Table 4: Dose in Milliliters

Table 4: Dose in Milliliters
Target Dose in mcg/kg
Volume to be given in mL

2

3

4

5

6

8

10

12

14

16

18

20

30

Table 4: Dose in Milliliters
Weight in kg

2

0.08b

0.12b

0.16b

0.2

0.2

0.3

0.4

0.5

0.6

0.6

0.7

0.8

1.2

3

0.12b

0.18b

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1.0

1.1

1.2

1.8

4

0.16b

0.2

0.3

0.4

0.5

0.6

0.8

1.0

1.1

1.3

1.4

1.6

2.4

5

0.2

0.3

0.4

0.5

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

3.0

6

0.2

0.4

0.5

0.6

0.7

1.0

1.2

1.4

1.7

1.9

2.2

2.4

3.6

7

0.3

0.4

0.6

0.7

0.8

1.1

1.4

1.7

2.0

2.2

2.5

2.8

4.2

8

0.3

0.5

0.6

0.8

1.0

1.3

1.6

1.9

2.2

2.6

2.9

3.2

4.8

9

0.4

0.5

0.7

0.9

1.1

1.4

1.8

2.2

2.5

2.9

3.2

3.6

5.4

10

0.4

0.6

0.8

1.0

1.2

1.6

2.0

2.4

2.8

3.2

3.6

4.0

6.0

11

0.4

0.7

0.9

1.1

1.3

1.8

2.2

2.6

3.1

3.5

4.0

4.4

6.6

12

0.5

0.7

1.0

1.2

1.4

1.9

2.4

2.9

3.4

3.8

4.3

4.8

7.2

13

0.5

0.8

1.0

1.3

1.6

2.1

2.6

3.1

3.6

4.2

4.7

5.2

7.8

14

0.6

0.8

1.1

1.4

1.7

2.2

2.8

3.4

3.9

4.5

5.0

5.6

8.4

15

0.6

0.9

1.2

1.5

1.8

2.4

3.0

3.6

4.2

4.8

5.4

6.0

9.0

20

0.8

1.2

1.6

2.0

2.4

3.2

4.0

4.8

5.6

6.4

7.2

8.0

12.0

30

1.2

1.8

2.4

3.0

3.6

4.8

6.0

7.2

8.4

9.6

10.8

12.0

18.0

40

1.6

2.4

3.2

4.0

4.8

6.4

8.0

9.6

11.2

12.8

14.4

16.0

24.0

50

2.0

3.0

4.0

5.0

6.0

8.0

10.0

12.0

14.0

16.0

18

20.0

30.0

60

2.4

3.6

4.8

6.0

7.2

9.6

12.0

14.4

16.8

19.2

21.6

24.0

36.0

70

2.8

4.2

5.6

7.0

8.4

11.2

14.0

16.8

19.6

22.4

25.2

28.0

42.0

80

3.2

4.8

6.4

8.0

9.6

12.8

16.0

19.2

22.4

25.6

28.8

32.0

48.0

90

3.6

5.4

7.2

9.0

10.8

14.4

18.0

21.6

25.2

28.8

32.4

36.0

54.0

100

4.0

6.0

8.0

10.0

12.0

16.0

20.0

24.0

28.0

32.0

36.0

40.0

60.0

a Recommended dosing regimen for pediatric patients under 10 years of age is twice daily. Recommended dosing regimen for pediatric patients over 10 years of age and adults is once daily.

b Use calibrated dropper for measurement. In the case of required volume less than 0.2 mL, a separate device such as a graduated syringe is recommended for adequate measurement.

On the left side of the chart, locate the patient’s weight in kilograms. At the top of the chart, identify which dose in mcg/kg will be used for this patient. The block on the chart at which the two rows (weight and target dose) intersect is the milliliter amount that should be given to the patient.

The monitoring described in Section 2.2 may suggest increases or decreases in digoxin doses. Additional monitoring, and in some cases anticipatory dose adjustment, may be indicated around the time of various changes to the patient including:
• normal development through childhood; • concomitant drug use should be considered when adjusting the estimated digoxin dose [seeDrug Interactions (7)]; • new co-administration of an antibiotic, especially if the patient had required high doses of digoxin in order to achieve modest serum concentrations, raising the suspicion that a substantial fraction of administered digoxin was being destroyed by colonic bacteria; and • changes in renal function [see Table 3: Usual Maintenance Dose Requirements (mcg) of Digoxin above].
Torsemide

Torsemide

General

Torsemide tablets may be given at any time in relation to a meal, as convenient. Special dosage adjustment in the elderly is not necessary.

Congestive Heart Failure

The usual initial dose is 10 mg or 20 mg of once-daily oral torsemide. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied.

Chronic Renal Failure

The usual initial dose of torsemide is 20 mg of once-daily oral torsemide. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied.

Hepatic Cirrhosis

The usual initial dose is 5 mg or 10 mg of once-daily oral torsemide, administered together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 40 mg have not been adequately studied.

Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.

Hypertension

The usual initial dose is 5 mg once daily. If the 5 mg dose does not provide adequate reduction in blood pressure within 4 to 6 weeks, the dose may be increased to 10 mg once daily. If the response to 10 mg is insufficient, an additional antihypertensive agent should be added to the treatment regimen.
Diphenoxylate Hydrochlo...

Diphenoxylate Hydrochloride And Atropine Sulfate Solution

DO NOT EXCEED RECOMMENDED DOSAGE.

Adults

The recommended initial dosage is 10 mL (two regular teaspoonfuls) of oral solution four times daily (20 mg per day). Most patients will require this dosage until initial control has been achieved, after which the dosage may be reduced to meet individual requirements. Control may often be maintained with as little as 5 mg (10 mL of solution) daily.

Clinical improvement of acute diarrhea is usually observed within 48 hours. If clinical improvement of chronic diarrhea after treatment with a maximum daily dose of 20 mg of diphenoxylate hydrochloride is not observed within 10 days, symptoms are unlikely to be controlled by further administration.

Children

Diphenoxylate hydrochloride and atropine sulfate is not recommended in children under 2 years of age and should be used with special caution in young children (seeWARNINGS and PRECAUTIONS). The nutritional status and degree of dehydration must be considered. In children under 13 years of age, use the oral solution. Do not use the tablets for this age group.

Only the plastic dropper should be used when measuring the oral solution for administration to children.

Dosage Schedule for Children

The recommended initial total daily dosage of the oral solution for children is 0.3 to 0.4 mg/kg administered in four divided doses. The following table provides an approximate initial daily dosage recommendation for children.
Age Approximate Weight Dosage in mL (Years) (kg) (lbs.) (four times daily) 2 11-14 24-31 1.5-3.0 3 12-16 26-35 2.0-3.0 4 14-20 31-44 2.0-4.0 5 16-23 35-51 2.5-4.5 6-8 17-32 38-71 2.5-5.0 9-12 23-55 51-121 3.5-5.0
These pediatric schedules are the best approximation of an average dose recommendation which may be adjusted downward according to the overall nutritional status and degree of dehydration encountered in the sick child. Reduction of dosage may be made as soon as initial control of symptoms has been achieved. Maintenance dosage may be as low as one-fourth of the initial daily dosage. If no response occurs within 48 hours, diphenoxylate hydrochloride and atropine sulfate is unlikely to be effective.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
Propantheline Bromide

Propantheline Bromide

The usual initial adult dose of propantheline bromide tablets is 15 mg taken 30 minutes before each meal and 30 mg at bedtime (a total of 75 mg daily). Subsequent dosage adjustment should be made according to the patient’s individual response and tolerance.
Lorazepam Solution

Lorazepam Solution

Proper Use of an Intensol™

An Intensol is a concentrated oral solution as compared to standard oral liquid medications. It is recommended that an Intensol be mixed with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce and puddings.

Use only the calibrated dropper provided with this product. Draw into the dropper the amount prescribed for a single dose. Then squeeze the dropper contents into a liquid or semi-solid food. Stir the liquid or food gently for a few seconds. The Intensol formulation blends quickly and completely. The entire amount of the mixture, of drug and liquid or drug and food, should be consumed immediately. Do not store for future use.

Lorazepam is administered orally. For optimal results, dose, frequency of administration, and duration of therapy should be individualized according to patient response.

The usual range is 2 mg/day to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 mg/day to 10 mg/day.

For anxiety, most patients require an initial dose of 2 mg/day to 3 mg/day given b.i.d. or t.i.d.

For insomnia due to anxiety or transient situational stress, a single daily dose of 2 mg to 4 mg may be given, usually at bedtime.

For elderly or debilitated patients, an initial dosage of 1 mg/day to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated.

The dosage of lorazepam should be increased gradually when needed to help avoid adverse effects. When higher dosage is indicated, the evening dose should be increased before the daytime doses.
Oxcarbazepine

Oxcarbazepine

All dosing should be given in a twice-a-day regimen. Oxcarbazepine oral suspension and oxcarbazepine tablets may be interchanged at equal doses.

Oxcarbazepine should be kept out of the reach and sight of children.

Oxcarbazepine can be taken with or without food [see Clinical Pharmacology (12.3)].

2.1 Adjunctive Therapy for Adults

Treatment with oxcarbazepine should be initiated with a dose of 600 mg/day, given in a twice-a-day regimen. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects. It is recommended that the patient be observed closely and plasma levels of the concomitant AEDs be monitored during the period of oxcarbazepine titration, as these plasma levels may be altered, especially at oxcarbazepine doses greater than 1200 mg/day [see Drug Interacctions (7.1)].

2.2 Conversion to Monotherapy for Adults

Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with oxcarbazepine at 600 mg/day (given in a twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3 to 6 weeks, while the maximum dose of oxcarbazepine should be reached in about 2 to 4 weeks. Oxcarbazepine may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the recommended daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with oxcarbazepine. Patients should be observed closely during this transition phase.

2.3 Initiation of Monotherapy for Adults

Patients not currently being treated with AEDs may have monotherapy initiated with oxcarbazepine. In these patients, oxcarbazepine should be initiated at a dose of 600 mg/day (given in a twice-a-day regimen); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to oxcarbazepine monotherapy (see above).

2.4 Adjunctive Therapy for Pediatric Patients (Aged 2 to 16 Years)

In pediatric patients aged 4 to 16 years, treatment should be initiated at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. The target maintenance dose of oxcarbazepine should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart:

20 to 29 kg to 900 mg/day

29.1 to 39 kg to 1200 mg/day

>39 kg to 1800 mg/day

In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6 to 51 mg/kg.

In pediatric patients aged 2 to <4 years, treatment should be initiated at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. For patients under 20 kg, a starting dose of 16 to 20 mg/kg may be considered [see Clinical Pharmacology (12.3)]. The maximum maintenance dose of oxcarbazepine should be achieved over 2 to 4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen.

In the clinical trial in pediatric patients (2 to 4 years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day.

Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults.

2.5 Conversion to Monotherapy for Pediatric Patients (Aged 4 to 16 Years)

Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with oxcarbazepine at approximately 8 to 10 mg/kg/day given in a twice-a-day regimen, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks while oxcarbazepine may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase.

The recommended total daily dose of oxcarbazepine is shown in the table below.

2.6 Initiation of Monotherapy for Pediatric Patients (Aged 4 to 16 Years)

Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with oxcarbazepine. In these patients, oxcarbazepine should be initiated at a dose of 8 to 10 mg/kg/day given in a twice-a-day regimen. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below.
Table 1: Range of Maintenance Doses of Oxcarbazepine for Children by Weight During Monotherapy
Weight in kg

From Dose (mg/day)

To Dose (mg/day)

20

600

900

25

900

1200

30

900

1200

35

900

1500

40

900

1500

45

1200

1500

50

1200

1800

55

1200

1800

60

1200

2100

65

1200

2100

70

1500

2100

2.7 Patients with Hepatic Impairment

In general, dose adjustments are not required in patients with mild-to-moderate hepatic impairment [see Clinical Pharmacology (12.3)].

2.8 Patients with Renal Impairment

In patients with impaired renal function (creatine clearance <30 mL/min) oxcarbazepine therapy should be initiated at one-half the usual starting dose (300 mg/day) and increased slowly to achieve the desired clinical response [see Clinical Pharmacology (12.3)].
Leucovorin Calcium

Leucovorin Calcium

Leucovorin calcium tablets are intended for oral administration. Because absorption is saturable, oral administration of doses greater than 25 mg is not recommended.

Impaired Methotrexate Elimination or Inadvertent Overdosage

Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see WARNINGS). Leucovorin 15 mg (10 mg/m2) should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.

Serum creatinine and methotrexate levels should be determined at 24-hour intervals. If the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater than 5 x 10-6 M or the 48-hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 150 mg (100 mg/m2) IV every 3 hours until the methotrexate level is less than 10-8 M. Doses greater than 25 mg should be given parenterally (see CLINICAL PHARMACOLOGY).

Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

The recommended dose of leucovorin to counteract hematologic toxicity from folic acid antagonists with less affinity for mammalian dihydrofolate reductase than methotrexate (i.e., trimethoprim, pyrimethamine) is substantially less, and 5 to 15 mg of leucovorin per day has been recommended by some investigators.

Patients who experience delayed early methotrexate elimination are likely to develop reversible non-oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.
Midazolam Hydrochloride...

Midazolam Hydrochloride Syrup

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients. Midazolam HCl syrup is not intended for chronic administration.

Monitoring

Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see WARNINGS). For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional. Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation (see PRECAUTIONS: Drug Interactions). This is especially true in pediatric patients. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression. Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see WARNINGS and Monitoring subsection of DOSAGE AND ADMINISTRATION. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg. In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need (see WARNINGS and PRECAUTIONS). The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg. A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical. For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants. As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup. In obese pediatric patients, the dose should be calculated based on ideal body weight. Midazolam HCl syrup has not been studied, nor is it intended for chronic use.
Zidovudine

Zidovudine

2.1 Treatment of HIV-1 Infection

Adults

The recommended oral dose of zidovudine is 600 mg per day in divided doses in combination with other antiretroviral agents.

Pediatric Patients (Aged 4 Weeks to <18 Years)

Healthcare professionals should pay special attention to accurate calculation of the dose of zidovudine, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors.

Prescribers should calculate the appropriate dose of zidovudine for each child based on body weight (kg) and should not exceed the recommended adult dose.

Before prescribing zidovudine capsules or tablets, children should be assessed for the ability to swallow capsules or tablets. If a child is unable to reliably swallow a zidovudine capsule or tablet, the zidovudine oral solution formulation should be prescribed.

The recommended dosage in pediatric patients 4 weeks of age and older and weighing ≥4 kg is provided in Table 1. Zidovudine oral solution should be used to provide accurate dosage when whole tablets or capsules are not appropriate.
Table 1: Recommended Pediatric Dosage of Zidovudine
Body Weight (kg)

Total Daily Dose

Dosage Regimen and Dose

Twice Daily

Three Times Daily

4 to <9

24 mg/kg/day

12 mg/kg

8 mg/kg

≥9 to <30

18 mg/kg/day

9 mg/kg

6 mg/kg

≥30

600 mg/day

300 mg

200 mg

Alternatively, dosing for zidovudine can be based on body surface area (BSA) for each child. The recommended oral dose of zidovudine is 480 mg/m2/day in divided doses (240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by mg/kg will not be the same as that calculated by BSA.

2.2 Prevention of Maternal-Fetal HIV-1 Transmission

The recommended dosage regimen for administration to pregnant women (>14 weeks of pregnancy) and their neonates is:

Maternal Dosing

100 mg orally 5 times per day until the start of labor [see Clinical Studies (14.3)]. During labor and delivery, intravenous zidovudine should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg/kg/hour (total body weight) until clamping of the umbilical cord.

Neonatal Dosing

Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered zidovudine intravenously. See Table 2.
Table 2: Recommended Neonatal Dosages of Zidovudine
Route

Total Daily Dose

Dose and Dosage Regimen

Oral

8 mg/kg/day

2 mg/kg every 6 hours

IV

6 mg/kg/day

1.5 mg/kg infused over 30 minutes, every 6 hours

2.3 Patients With Severe Anemia and/or Neutropenia

Significant anemia (hemoglobin <7.5 g/dL or reduction >25% of baseline) and/or significant neutropenia (granulocyte count <750 cells/mm3 or reduction >50% from baseline) may require a dose interruption until evidence of marrow recovery is observed [see Warnings and Precautions(5.1)]. In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level and patient tolerance.

2.4 Patients With Renal Impairment

End-Stage Renal Disease

In patients maintained on hemodialysis or peritoneal dialysis, the recommended dosage is 100 mg every 6 to 8 hours [see Clinical Pharmacology(12.3)].

2.5 Patients With Hepatic Impairment

There are insufficient data to recommend dose adjustment of zidovudine in patients with mild to moderate impaired hepatic function or liver cirrhosis.
Balsalazide Disodium

Balsalazide Disodium

2.1 Adult Dose

For treatment of active ulcerative colitis in adult patients, the usual dose is three 750 mg balsalazide capsules to be taken 3 times a day (6.75 g per day) for up to 8 weeks. Some patients in the adult clinical trials required treatment for up to 12 weeks.

2.3 Administration Alternatives

Balsalazide capsules may also be administered by carefully opening the capsule and sprinkling the capsule contents on applesauce. The entire drug/applesauce mixture should be swallowed immediately; the contents may be chewed, if necessary, since contents of balsalazide are NOT coated beads/granules. Patients should be instructed not to store any drug/applesauce mixture for future use.

If the capsules are opened for sprinkling, color variation of the powder inside the capsules ranges from orange to yellow and is expected due to color variation of the active pharmaceutical ingredient.

Teeth and/or tongue staining may occur in some patients who use balsalazide in sprinkle form with food.
Risperidone

Risperidone

Treatment of Malignant Diseases

Adults and Children:

Oral cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. Transient decreases in the total white blood cell count to 2000 cells/mm3 (following short courses) or more persistent reduction to 3000 cells/mm3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia.

When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide, as well as that of the other drugs.

Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. Patients with compromised renal function may show some measurable changes in pharmacokinetic parameters of cyclophosphamide metabolism, but there is no consistent evidence indicating a need for cyclophosphamide dosage modification in patients with renal function impairment.

Treatment of Nonmalignant Diseases

Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children:

An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the incidence of oligospermia and azoospermia increases if the duration of cyclophosphamide treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility. Adrenocorticosteroid therapy may be tapered and discontinued during the course of cyclophosphamide therapy (see PRECAUTIONS: Laboratory Tests).

Preparation and Handling of Solutions

Extemporaneous liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, N.F. Such preparations should be stored under refrigeration in glass containers and used within 14 days.
Flecainide Acetate

Flecainide Acetate

For patients with sustained VT, no matter what their cardiac status, flecainide, like other antiarrhythmics, should be initiated in-hospital with rhythm monitoring.

Flecainide has a long half-life (12 to 27 hours in patients). Steady-state plasma levels, in patients with normal renal and hepatic function, may not be achieved until the patient has received 3 to 5 days of therapy at a given dose. Therefore, increases in dosage should be made no more frequently than once every four days, since during the first 2 to 3 days of therapy the optimal effect of a given dose may not be achieved.

For patients with PSVT and patients with PAF the recommended starting dose is 50 mg every 12 hours. Flecainide doses may be increased in increments of 50 mg bid every four days until efficacy is achieved. For PAF patients, a substantial increase in efficacy without a substantial increase in discontinuations for adverse experiences may be achieved by increasing the flecainide dose from 50 mg to 100 mg bid. The maximum recommended dose for patients with paroxysmal supraventricular arrhythmias is 300 mg/day.

For sustained VT the recommended starting dose is 100 mg every 12 hours. This dose may be increased in increments of 50 mg bid every four days until efficacy is achieved. Most patients with sustained VT do not require more than 150 mg every 12 hours (300 mg/day), and the maximum dose recommended is 400 mg/day.

In patients with sustained VT, use of higher initial doses and more rapid dosage adjustments have resulted in an increased incidence of proarrhythmic events and CHF, particularly during the first few days of dosing (see WARNINGS). Therefore, a loading dose is not recommended.

Intravenous lidocaine has been used occasionally with flecainide while awaiting the therapeutic effect of flecainide. No adverse drug interactions were apparent. However, no formal studies have been performed to demonstrate the usefulness of this regimen.

An occasional patient not adequately controlled by (or intolerant to) a dose given at 12-hour intervals may be dosed at eight-hour intervals.

Once adequate control of the arrhythmia has been achieved, it may be possible in some patients to reduce the dose as necessary to minimize side effects or effects on conduction. In such patients, efficacy at the lower dose should be evaluated.

Flecainide should be used cautiously in patients with a history of CHF or myocardial dysfunction (see WARNINGS).

Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. Because of the evolving nature of information in this area, specialized literature should be consulted. Under six months of age, the initial starting dose of flecainide in children is approximately 50 mg/M2 body surface area daily, divided into two or three equally spaced doses. Over six months of age, the initial starting dose maybe increased to 100 mg/M2 per day. The maximum recommended dose is 200 mg/M2 per day. This dose should not be exceeded. In some children on higher doses, despite previously low plasma levels, the level has increased rapidly to far above therapeutic values while taking the same dose. Small changes in dose may also lead to disproportionate increases in plasma levels. Plasma trough (less than one hour pre-dose) flecainide levels and electrocardiograms should be obtained at presumed steady state (after at least five doses) either after initiation or change in flecainide dose, whether the dose was increased for lack of effectiveness, or increased growth of the patient. For the first year on therapy, whenever the patient is seen for reasons of clinical follow-up, it is suggested that a 12-lead electrocardiogram and plasma trough flecainide level are obtained. The usual therapeutic level of flecainide in children is 200 to 500 ng/mL. In some cases, levels as high as 800 ng/mL may be required for control.

In patients with severe renal impairment (creatinine clearance of 35 mL/min/1.73 square meters or less), the initial dosage should be 100 mg once daily (or 50 mg bid); when used in such patients, frequent plasma level monitoring is required to guide dosage adjustments (see Plasma Level Monitoring ). In patients with less severe renal disease, the initial dosage should be 100 mg every 12 hours; plasma level monitoring may also be useful in these patients during dosage adjustment. In both groups of patients, dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days), observing the patient closely for signs of adverse cardiac effects or other toxicity. It should be borne in mind that in these patients it may take longer than four days before a new steady-state plasma level is reached following a dosage change.

Based on theoretical considerations, rather than experimental data, the following suggestion is made: when transferring patients from another antiarrhythmic drug to flecainide allow at least two to four plasma half-lives to elapse for the drug being discontinued before starting flecainide at the usual dosage. In patients where withdrawal of a previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, the physician should consider hospitalizing the patient.

When flecainide is given in the presence of amiodarone, reduce the usual flecainide dose by 50% and monitor the patient closely for adverse effects.

Plasma level monitoring is strongly recommended to guide dosage with such combination therapy (see below).

Plasma Level Monitoring

The large majority of patients successfully treated with flecainide were found to have trough plasma levels between 0.2 and 1 mcg/mL. The probability of adverse experiences, especially cardiac, may increase with higher trough plasma levels, especially when these exceed 1 mcg/mL. Periodic monitoring of trough plasma levels may be useful in patient management. Plasma level monitoring is required in patients with severe renal failure or severe hepatic disease, since elimination of flecainide from plasma may be markedly slower. Monitoring of plasma levels is strongly recommended in patients on concurrent amiodarone therapy and may also be helpful in patients with CHF and in patients with moderate renal disease.
Fluconazole

Fluconazole

Dosage and Administration in Adults

Single Dose: Vaginal candidiasis: The recommended dosage of fluconazole for vaginal candidiasis is 150 mg as a single oral dose.

Multiple Dose: SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy.

The daily dose of fluconazole for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.

Oropharyngeal Candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.

Esophageal Candidiasis: The recommended dosage of fluconazole for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.

Systemic Candida Infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used.

Urinary Tract Infections and Peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50 to 200 mg have been used in open, noncomparative studies of small numbers of patients.

Cryptococcal Meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of fluconazole for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily.

Prophylaxis in Patients Undergoing Bone Marrow Transplantation: The recommended fluconazole daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start fluconazole prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm.

Dosage and Administration in Children

The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients:
* Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended.
Pediatric Patients

Adults

3 mg/kg

100 mg

6 mg/kg

200 mg

12* mg/kg

400 mg

Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns (see CLINICAL PHARMACOLOGY). Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding fluconazole pharmacokinetics in full-term newborns is available.

Oropharyngeal Candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.

Esophageal Candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of fluconazole in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms.

Systemic Candida Infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6 to 12 mg/kg/day have been used in an open, noncomparative study of a small number of children.

Cryptococcal Meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of fluconazole is 6 mg/kg once daily.

Dosage in Patients with Impaired Renal Function

Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table:

Creatinine Clearance (mL/min)

Percent of Recommended Dose

>50

100%

≤50 (no dialysis)

50%

Regular dialysis

100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.

These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition.

When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults:

Males:

Weight (kg) x (140-age)

72 x serum creatinine (mg/100 mL)

Females: 0.85 x above value

Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children:

K x

linear length or height (cm)

serum creatinine (mg/100 mL)

(Where K=0.55 for children older than 1 year and 0.45 for infants.)

Administration

Fluconazole for Oral Suspension is administered orally. Fluconazole can be taken with or without food.

Directions for Mixing the Oral Suspension

Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows:

Fluconazole Contentper Bottle

Concentration ofReconstituted Suspension

350 mg

10 mg/mL

1400 mg

40 mg/mL

Note: Shake oral suspension well before using. Before Reconstitution: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. After Reconstitution: Store suspension at 5° to 25°C (41° to 77°F). Discard unused portion after 2 weeks. Protect from freezing.
Loprox

Loprox

Morphine Sulfate Oral Solution is available in three concentrations: 10 mg per 5 mL, 20 mg per 5 mL and 100 mg per 5 mL (20 mg/mL).

Take care when prescribing and administering Morphine Sulfate Oral Solution to avoid dosing errors due to confusion between different concentrations and between mg and mL, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Always use the enclosed calibrated oral syringe when administering Morphine Sulfate Oral Solution 100 mg per 5 mL (20 mg/mL) to ensure the dose is measured and administered accurately.

Selection of patients for treatment with morphine sulfate should be governed by the same principles that apply to the use of similar opioid analgesics. Individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

2.1 Individualization of Dosage

As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of morphine sulfate, give attention to the following:
• the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; • the reliability of the relative potency estimate used to calculate the equivalent morphine sulfate dose needed; • the patient’s degree of opioid tolerance; • the general condition and medical status of the patient; • concurrent medications; • the type and severity of the patient’s pain; • risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.
The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual re-evaluation of the patient receiving morphine sulfate is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. During chronic therapy, especially for non-cancer-related pain, periodically re-assess the continued need for the use of opioid analgesics.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

2.2 Initiation of Therapy in Opioid-Naïve Patients

Start patients who have not been receiving opioid analgesics on morphine sulfate in the following dosing range using Oral Solution, 10 mg per 5 mL or 20 mg per 5 mL strengths:

Morphine Sulfate Oral Solution: 10 to 20 mg every 4 hours as needed for pain.

Titrate the dose based upon the individual patient’s response to their initial dose of morphine sulfate. Adjust the dose to an acceptable level of analgesia taking into account the improvement in pain intensity and the tolerability of the morphine by the patient.

The 100 mg per 5 mL (20 mg/mL) oral solution formulation is for use in opioid-tolerant patients only who have already been receiving opioid therapy. Use this strength only for patients that have already been titrated to a stable analgesic regimen using lower strengths of morphine sulfate and who can benefit from use of a smaller volume of oral solution.

2.3 Conversion to Oral Morphine Sulfate

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dose of morphine sulfate. It is better to underestimate a patient’s 24-hour oral morphine sulfate dose and make available rescue medication than to overestimate the 24-hour oral morphine sulfate dose and manage an adverse experience of overdose.

Consider the following general points regarding opioid conversions.

Conversion From Parenteral Morphine to Oral Morphine Sulfate

For conversion from parenteral to oral morphine sulfate, anywhere from 3 to 6 mg of oral morphine sulfate may be required to provide pain relief equivalent to 1 mg of parenteral morphine.

Conversion From Parenteral Oral Non-Morphine Opioids to Oral Morphine Sulfate

In converting patients from other opioids to morphine sulfate, close observation and adjustment of dosage based upon the patient’s response to morphine sulfate is imperative. Physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate.

Conversion From Controlled-Release Oral Morphine to Oral Morphine Sulfate

For a given dose, the same total amount of morphine sulfate is available from Morphine Sulfate Oral Solution, Morphine Sulfate Tablets, and controlled-release and extended-release morphine capsules. The extended duration of release of morphine sulfate from controlled-release tablets or extended-release tablets results in reduced maximum and increased minimum plasma morphine sulfate concentrations than with shorter acting morphine sulfate products. Conversion from oral solution or immediate-release tablets to the same total daily dose of controlled-release tablets or extended-release tablets could lead to excessive sedation at peak serum levels. Therefore, dosage adjustment with close observation is necessary.

2.4 Maintenance of Therapy

Continual re-evaluation of the patient receiving morphine sulfate is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.

2.5 Cessation of Therapy

When the patient no longer requires therapy with morphine sulfate, gradually taper the dose to prevent signs and symptoms of withdrawal in the physically dependent patient.
Montelukast Sodium

Montelukast Sodium

2.1 Asthma

Montelukast sodium should be taken once daily in the evening. The following doses are recommended:

For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet.

Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.

There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.

2.2 Exercise-Induced Bronchoconstriction (EIB)

For prevention of EIB, a single 10 mg dose of montelukast sodium should be taken at least 2 hours before exercise. An additional dose of montelukast should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist. Safety and effectiveness in patients younger than 15 years of age have not been established. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Allergic Rhinitis

For allergic rhinitis, montelukast sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.

The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended:

For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet

Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.

The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet.

Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.

2.4 Asthma and Allergic Rhinitis

Patients with both asthma and allergic rhinitis should take only one montelukast sodium dose daily in the evening.
Calcium Acetate

Calcium Acetate

The recommended initial dose of calcium acetate capsules for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.
Cevimeline Hydrochlorid...

Cevimeline Hydrochloride

The recommended dose of cevimeline hydrochloride is 30 mg taken three times a day. There is insufficient safety information to support doses greater than 30 mg tid. There is also insufficient evidence for additional efficacy of cevimeline hydrochloride at doses greater than 30 mg tid.
Buprenorphine Hcl

Buprenorphine Hcl

Buprenorphine sublingual tablets are administered sublingually as a single daily dose. Buprenorphine sublingual tablets contain no naloxone and are preferred for use only during induction. Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets are preferred due to the presence of naloxone when clinical use includes unsupervised administration. The use of buprenorphine sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets; for example, those patients who have been shown to be hypersensitive to naloxone.

Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits.

2.1 Induction

Prior to induction, consideration should be given to the type of opioid dependence (i.e. long- or short-acting opioid), the time since last opioid use, and the degree or level of opioid dependence. To avoid precipitating withdrawal, induction with buprenorphine sublingual tablets should be undertaken when objective and clear signs of withdrawal are evident.

It is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapidly as possible. In a one-month study, patients received 8 mg of buprenorphine sublingual tablets on Day 1 and 16 mg buprenorphine sublingual tablets on Day 2. From Day 3 onward, patients received either buprenorphine and naloxone sublingual tablets or buprenorphine sublingual tablets at the same buprenorphine dose as Day 2 based on their assigned treatment. Induction in the studies of buprenorphine solution was accomplished over 3-4 days, depending on the target dose. In some studies, gradual induction over several days led to a high rate of drop-out of buprenorphine patients during the induction period.

Patients Taking Heroin or Other Short-acting Opioids: At treatment initiation, the dose of buprenorphine sublingual tablets should be administered at least 4 hours after the patient last used opioids or preferably when moderate objective signs of opioid withdrawal appear.

Patients on Methadone or Other Long-acting Opioids: There is little controlled experience with the transfer of methadone-maintained patients to buprenorphine. Available evidence suggests that withdrawal signs and symptoms are possible during induction onto buprenorphine. Withdrawal appears more likely in patients maintained on higher doses of methadone (>30 mg) and when the first buprenorphine dose is administered shortly after the last methadone dose. Buprenorphine sublingual tablet dosing should be initiated preferably when moderate objective signs of opioid withdrawal appear.

2.2 Maintenance
• Buprenorphine and naloxone is preferred for maintenance treatment. • Where buprenorphine sublingual tablets are used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of buprenorphine sublingual tablets should be progressively adjusted in increments / decrements of 2 mg or 4 mg buprenorphine to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms. • The maintenance dose is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient. Doses higher than this have not been demonstrated to provide any clinical advantage.
2.3 Method of Administration

Buprenorphine sublingual tablets should be placed under the tongue until it is dissolved. For doses requiring the use of more than two tablets, patients are advised to either place all the tablets at once or alternatively (if they cannot fit in more than two tablets comfortably), place two tablets at a time under the tongue. Either way, the patients should continue to hold the tablets under the tongue until they dissolve; swallowing the tablets reduces the bioavailability of the drug. To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.

Proper administration technique should be demonstrated to the patient.

2.4 Clinical Supervision

Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits. The use of buprenorphine sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone, for example those patients with known hypersensitivity to naloxone. Buprenorphine and naloxone and buprenorphine sublingual tablets are both subject to diversion and abuse. When determining the size of the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability of the patient to manage supplies of take-home medication.

Ideally, patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment) based upon the individual circumstances of the patient. Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits. Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.

Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives. Continuation or modification of pharmacotherapy should be based on the physician’s evaluation of treatment outcomes and objectives such as:
1. Absence of medication toxicity. 2. Absence of medical or behavioral adverse effects. 3. Responsible handling of medications by the patient. 4. Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and/or other psychosocial modalities). 5. Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).
If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of continuing the current treatment.

2.5 Patients With Hepatic Impairment

Severe Hepatic Impairment: Consider reducing the starting and titration incremental dose by half compared to patients with normal liver function, and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Moderate Hepatic Impairment: Although no dose adjustment is necessary for patients with moderate hepatic impairment, buprenorphine sublingual tablets should be used with caution in these patients and prescribers should monitor patients for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Mild Hepatic Impairment: No clinically significant differences in pharmacokinetic parameters were observed in subjects with mild hepatic impairment. No dose adjustment is needed in patients with mild hepatic impairment. [see Warnings and Precautions (5.11)]

2.6 Unstable Patients

Physicians will need to decide when they cannot appropriately provide further management for particular patients. For example, some patients may be abusing or dependent on various drugs, or unresponsive to psychosocial intervention such that the physician does not feel that he/she has the expertise to manage the patient. In such cases, the physician may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment. Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment.

Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.

2.7 Stopping Treatment

The decision to discontinue therapy with buprenorphine and naloxone or buprenorphine sublingual tablets after a period of maintenance should be made as part of a comprehensive treatment plan. Both gradual and abrupt discontinuation of buprenorphine has been used, but the data are insufficient to determine the best method of dose taper at the end of treatment.
Oxycodone Hydrochloride...

Oxycodone Hydrochloride Solution

Take care when prescribing and administering oxycodone hydrochloride oral solution to avoid dosing errors due to confusion between mg and mL, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Always use the enclosed calibrated oral syringe when administering oxycodone hydrochloride oral solution, 100 mg per 5 mL (20 mg/mL), to ensure the dose is measured and administered accurately.

Selection of patients for treatment with oxycodone hydrochloride should be governed by the same principles that apply to the use of similar opioid analgesics. Individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

2.1 Individualization of Dosage

As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of oxycodone hydrochloride, give attention to the following:
• the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; • the reliability of the relative potency estimate used to calculate the equivalent oxycodone hydrochloride dose needed; • the patient’s degree of opioid tolerance; • the general condition and medical status of the patient; • concurrent medications; • the type and severity of the patient’s pain; • risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.
The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual reevaluation of the patient receiving oxycodone hydrochloride is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. During chronic therapy, especially for non-cancer-related pain, periodically reassess the continued need for the use of opioid analgesics.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

2.2 Conversion to Oral Oxycodone Hydrochloride

The 100 mg per 5 mL (20 mg/mL) oral solution formulation is for use in opioid-tolerant patients only who have already been receiving opioid therapy. Use this strength only for patients that have already been titrated to a stable analgesic regimen using lower strengths of oxycodone hydrochloride and who can benefit from use of a smaller volume of oral solution.

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dose of oxycodone hydrochloride. It is better to underestimate a patient’s 24-hour oral oxycodone hydrochloride dose and make available rescue medication than to overestimate the 24-hour oral oxycodone hydrochloride dose and manage an adverse experience of overdose.

Consider the following general points regarding opioid conversions.

Conversion From Non-Oxycodone Opioids to Oral Oxycodone Hydrochloride.

In converting patients from other opioids to oxycodone hydrochloride, close observation and adjustment of dosage based upon the patient’s response to oxycodone hydrochloride is imperative. Physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate.

Conversion From Controlled-Release Oral Oxycodone to Oral Oxycodone Hydrochloride.

The relative bioavailability of oxycodone hydrochloride oral solution compound to controlled-release oxycodone is unknown. The extended duration of release of oxycodone hydrochloride from controlled-release tablets results in reduced maximum and increased minimum plasma oxycodone hydrochloride concentrations than with shorter acting oxycodone hydrochloride products. Conversion from controlled-release tablets could lead to excessive sedation at peak serum levels. Therefore, dosage adjustment with close observation is necessary.

Conversion From Oral Oxycodone Hydrochloride to Controlled-Release Oral Oxycodone

The relative bioavailability of oxycodone hydrochloride oral solution compared to controlled-release oxycodone is unknown, so conversion to controlled-release tablets must be accompanied by close observation for signs of excessive sedation.

2.3 Maintenance of Therapy

Continual reevaluation of the patient receiving oxycodone hydrochloride is important, with special attention to the maintenance of pain management and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.

2.4 Cessation of Therapy

When a patient no longer requires therapy with oxycodone hydrochloride gradually taper the dose to prevent signs and symptoms of withdrawal in the physically dependent patient.
Oxycodone Hydrochloride...

Oxycodone Hydrochloride And Acetaminophen

There is currently no dosage information available for this product. We apologize for any inconvenience.
Nighttime Multi-symptom...

Nighttime Multi-symptom Cold And Flu Relief

2.1 Recommended Dose

The recommended dose of letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals.

2.2 Use in Adjuvant Treatment of Early Breast Cancer

In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. Treatment should be discontinued at relapse [see CLINICAL STUDIES (14.1)].

2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer

In the extended adjuvant setting, the optimal treatment duration with letrozole is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see CLINICAL STUDIES (14.2)].

2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer

In patients with advanced disease, treatment with letrozole should continue until tumor progression is evident [see CLINICAL STUDIES (14.4, 14.5)].

2.5 Use in Hepatic Impairment

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although letrozole blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see WARNINGS AND PRECAUTIONS (5.3)]. The recommended dose of letrozole for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

2.6 Use in Renal Impairment

No dosage adjustment is required for patients with renal impairment if creatinine clearance is ≥ 10 mL/min [see CLINICAL PHARMACOLOGY (12.3)].
Cyclophosphamide

Cyclophosphamide

During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, cyclophosphamide should be administered in the morning.

2.1 Dosing for Malignant Diseases

Adults and Pediatric Patients

Oral cyclophosphamide dosing is usually in the range of 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage.

When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs.

2.2 Dosing for Minimal Change Nephrotic Syndrome in Pediatric Patients

An oral dose of 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended. Treatment beyond 90 days increases the probability of sterility in males [see 8 USE IN SPECIFIC POPULATIONS(8.4)].

2.3 Handling and Administration

Handle and dispose of cyclophosphamide in a manner consistent with other cytotoxic drugs.1 Caution should be exercised when handling cyclophosphamide containers and capsules. To minimize the risk of dermal exposure, always wear gloves when handling cyclophosphamide containers and capsules. To prevent inadvertent exposure to the active substance, the cyclophosphamide capsules should be swallowed whole. The capsules should not be opened, chewed, or crushed. Exposure to broken capsules should be avoided. If contact with broken capsules occurs, wash hands immediately and thoroughly.
Glynase

Glynase

There is currently no dosage information available for this product. We apologize for any inconvenience.
Chateal

Chateal

Emetogenic Chemotherapy

The recommended adult dosage of oral granisetron hydrochloride is 2 mg once daily or 1 mg twice daily. In the 2 mg once-daily regimen, two 1 mg tablets are given up to 1 hour before chemotherapy. In the 1 mg twice-daily regimen, the first 1 mg tablet is given up to 1 hour before chemotherapy, and the second tablet, 12 hours after the first. Either regimen is administered only on the day(s) chemotherapy is given. Continued treatment, while not on chemotherapy, has not been found to be useful.

Use in the Elderly, Renal Failure Patients or Hepatically Impaired Patients

No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Radiation (Either Total Body Irradiation or Fractionated Abdominal Radiation)

The recommended adult dosage of oral granisetron is 2 mg once daily. Two 1 mg tablets or are taken within 1 hour of radiation.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in the Elderly

No dosage adjustment is recommended.
Diskets

Diskets

Consider the following important factors that differentiate methadone from other opioids:
• The peak respiratory depressant effect of methadone occurs later and persists longer than its peak pharmacologic effect. • A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other opioid agonists. • There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based conversion ratios between methadone and other opioids are not accurate when applied to individuals. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Steady-state plasma concentrations are not attained until 3 to 5 days after initiation of dosing . • Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.1 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

DISKETS are intended for dispersion in a liquid immediately prior to oral administration of the prescribed dose. The tablets should not be chewed or swallowed before dispersing in liquid. DISKETS are cross-scored, allowing for flexible dosage adjustment. Each cross-scored tablet may be broken or cut in half to yield two 20-mg doses, or in quarters to yield four 10-mg doses. Prior to administration, the desired dose of DISKETS should be dispersed in approximately 120 mL (4 ounces) of water, orange juice, or other acidic fruit beverage prior to taking. Methadone hydrochloride is very soluble in water, but there are some insoluble excipients that will not entirely dissolve. If residue remains in the cup after initial administration, a small amount of liquid should be added and the resulting mixture administered to the patient.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (i.e., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Because DISKETS can be administered only in 10 mg increments, DISKETS may not be the appropriate product for initial dosing in many patients. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use. Also consider concurrent medications and the general condition and medical status of the patient when selecting the initial dose.

Short-term Detoxification

For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone. Decrease the dose of methadone on a daily basis or at 2-day intervals, keeping the amount of methadone sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule. Because DISKETS can be administered only in 10 mg increments, DISKETS may not be the appropriate product for gradual dose reduction in many patients.

2.2 Titration and Maintenance Treatment of Opioid Dependence

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.3 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Because DISKETS can be administered only in 10 mg increments, it may not be the appropriate product for gradual dose reduction in many patients. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.4 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.5 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.6 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Clotrimazole Lozenge

Clotrimazole Lozenge

Clotrimazole Troches (clotrimazole lozenges) USP are administered only as a lozenge that must be slowly dissolved in the mouth. The recommended dose is one troche five times a day for fourteen consecutive days. Only limited data are available on the safety and effectiveness of the clotrimazole troche after prolonged administration; therefore, therapy should be limited to short term use, if possible.

For prophylaxis to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation, the recommended dose is one troche three times daily for the duration of chemotherapy or until steroids are reduced to maintenance levels.
Pioglitazone

Pioglitazone

Factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, the use of other drugs, type of anesthesia to be used, and surgical procedure involved. Use in the elderly, in patients with hepatic or renal disease, or in labor requires extra caution (see PRECAUTIONS section and Individualization of Dosage in CLINICAL PHARMACOLOGYsection). The following doses are for patients who do not have impaired hepatic or renal function and who are not on CNS active agents.

Use for Pain

The usual recommended dose for initial nasal administration is 1 mg (1 spray in one nostril). Adherence to this dose reduces the incidence of drowsiness and dizziness. If adequate pain relief is not achieved within 60 to 90 minutes, an additional 1 mg dose may be given.

The initial dose sequence outlined above may be repeated in 3 to 4 hours as required after the second dose of the sequence.

Depending on the severity of the pain, an initial dose of 2 mg (1 spray in each nostril) may be used in patients who will be able to remain recumbent in the event drowsiness or dizziness occurs. In such patients single additional 2 mg doses should not be given for 3 to 4 hours.

Use in Balanced Anesthesia

The use of butorphanol tartrate nasal spray is not recommended because it has not been studied in induction or maintenance of anesthesia.

Labor

The use of butorphanol tartrate nasal spray is not recommended as it has not been studied in labor.

Safety and Handling

Butorphanol tartrate nasal spray is an open delivery system with increased risk of exposure to health care workers.

In the priming process, a certain amount of butorphanol may be aerosolized; therefore, the pump sprayer should be aimed away from the patient or other people or animals.

The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations. The unit should be disposed of by unscrewing the cap, rinsing the bottle, and placing the parts in a waste container.
Zaleplon

Zaleplon

The dose of zaleplon should be individualized. The recommended dose of zaleplon for most nonelderly adults is 10 mg. For certain low weight individuals, 5 mg may be a sufficient dose. Although the risk of certain adverse events associated with the use of zaleplon appears to be dose dependent, the 20 mg dose has been shown to be adequately tolerated and may be considered for the occasional patient who does not benefit from a trial of a lower dose. Doses above 20 mg have not been adequately evaluated and are not recommended.

Zaleplon should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep (see PRECAUTIONS). Taking zaleplon with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of zaleplon on sleep latency (see Pharmacokinetics under CLINICALPHARMACOLOGY).

Special Populations

Elderly patients and debilitated patients appear to be more sensitive to the effects of hypnotics, and respond to 5 mg of zaleplon. The recommended dose for these patients is therefore 5 mg. Doses over 10 mg are not recommended.

Hepatic Insufficiency

Patients with mild to moderate hepatic impairment should be treated with zaleplon 5 mg because clearance is reduced in this population. Zaleplon is not recommended for use in patients with severe hepatic impairment.

Renal Insufficiency

No dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment.

An initial dose of 5 mg should be given to patients concomitantly taking cimetidine because zaleplon clearance is reduced in this population (see Drug Interactionsunder PRECAUTIONS).
Mefloquine Hydrochlorid...

Mefloquine Hydrochloride

Malaria Treatment in Adults

Treatment of mild to moderate malaria in adults caused by mefloquine-susceptible strains of P. falciparum or by P. vivax: Dosage: Five tablets (1250 mg) mefloquine hydrochloride USP to be given as a single oral dose. The drug should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.

If a full-treatment course with mefloquine does not lead to improvement within 48 to 72 hours, mefloquine should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, mefloquine should not be used for curative treatment (see INDICATIONS AND USAGE).

Note: Patients with acute P. vivax malaria, treated with mefloquine, are at high risk of relapse because mefloquine does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse after initial treatment of the acute infection with mefloquine, patients should subsequently be treated with an 8-aminoquinoline derivative (e.g., primaquine).

Malaria Prophylaxis in Adults

Dosage: One 250 mg mefloquine hydrochloride tablet once weekly.

Prophylactic drug administration should begin 1 week before arrival in an endemic area. Subsequent weekly doses should be taken regularly, always on the same day of each week, preferably after the main meal. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued for 4 additional weeks to ensure suppressive blood levels of the drug when merozoites emerge from the liver. Tablets should not be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.

In certain cases, e.g., when a traveler is taking other medication, it may be desirable to start prophylaxis 2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is well tolerated (see PRECAUTIONS: Drug Interactions).

When prophylaxis with mefloquine fails, physicians should carefully evaluate which antimalarial to use for therapy

Malaria Treatment in Pediatric Patients

Treatment of mild to moderate malaria in pediatric patients caused by mefloquine-susceptible strains of P. falciparum: Dosage: 20 to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses taken 6 to 8 hours apart may reduce the occurrence or severity of adverse effects. The pediatric dose should not exceed the adult dose.

Experience with mefloquine in pediatric patients weighing less than 20 kg is limited.

The drug shouId not be taken on an empty stomach and should be administered with ample water. The tablets may be crushed and suspended in a small amount of water, milk or other beverage for administration to small children and other persons unable to swallow them whole.

If a full-treatment course with mefloquine does not lead to improvement within 48 to 72 hours, mefloquine should not be used for retreatment. An alternative therapy should be used. Similarly, if previous prophylaxis with mefloquine has failed, mefloquine should not be used for curative treatment.

In pediatric patients, the administration of mefloquine for the treatment of malaria has been associated with early vomiting. In some cases, early vomiting has been cited as a possible cause of treatment failure (see PRECAUTIONS). If a significant loss of drug product is observed or suspected because of vomiting, a second full dose of mefloquine should be administered to patients who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60 minutes after a dose, an additional half-dose should be given. If vomiting recurs, the patient should be monitored closely and alternative malaria treatment considered if improvement is not observed within a reasonable period of time.

The safety and effectiveness of mefloquine to treat malaria in pediatric patients below the age of 6 months have not been established.

Malaria Prophylaxis in Pediatric Patients

The recommended prophylactic dose of mefloquine hydrochloride is approximately 5 mg/kg body weight once weekly. One 250 mg mefloquine hydrochloride tablet should be taken once weekly in pediatric patients weighing over 45 kg. In pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body weight:

30 to 45 kg: 3/4 tablet

20 to 30 kg: 1/2 tablet

Experience with mefloquine in pediatric patients weighing less than 20 kg is limited
Clarithromycin

Clarithromycin

Clarithromycin Tablets, USP, may be given with or without food.

Clarithromycin may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function. In patients with severe renal impairment (CLCR < 30 mL/min), the dose of clarithromycin should be reduced by 50%. However, when patients with moderate or severe renal impairment are taking clarithromycin concomitantly with atazanavir or ritonavir, the dose of clarithromycin should be reduced by 50% or 75% for patients with CLCR of 30 to 60 mL/min or < 30 mL/min, respectively.

ADULT DOSAGE GUIDELINES

Clarithromycin Tablets

Infection

Dosage (q12h)

Duration (days)

Pharyngitis/Tonsillitis due to

S. pyogenes

250 mg

10

Acute Maxillary Sinusitis due to

500 mg

14

H. influenzae

M. catarrhalis

S. pneumoniae

Acute Exacerbation of Chronic Bronchitis due to

H. influenzae

500 mg

7 to 14

H. parainfluenzae

500 mg

7

M. catarrhalis

250 mg

7 to 14

S. pneumoniae

250 mg

7 to 14

Community-Acquired Pneumonia due to

H. influenzae

250 mg

7

H. parainfluenzae

-

-

M. catarrhalis

-

-

S. pneumoniae

250 mg

7 to 14

C. pneumoniae

250 mg

7 to 14

M. pneumoniae

250 mg

7 to 14

Uncomplicated Skin and Skin Structure

250 mg

7 to 14

S. aureus

S. pyogenes

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Triple Therapy: clarithromycin/lansoprazole/amoxicillin

The recommended adult dose is 500 mg clarithromycin, 30 mg lansoprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 10 or 14 days (see INDICATIONS AND USAGEand CLINICAL STUDIESsections).

Triple Therapy: clarithromycin/omeprazole/amoxicillin

The recommended adult dose is 500 mg clarithromycin, 20 mg omeprazole, and 1 gram amoxicillin, all given twice daily (q12h) for 10 days (see INDICATIONS AND USAGEand CLINICAL STUDIESsections). In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual Therapy: clarithromycin/omeprazole

The recommended adult dose is 500 mg clarithromycin given three times daily (q8h) and 40 mg omeprazole given once daily (qAM) for 14 days (see INDICATIONS AND USAGEand CLINICAL STUDIESsections). An additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual Therapy: clarithromycin/ranitidine bismuth citrate

The recommended adult dose is 500 mg clarithromycin given twice daily (q12h) or three times daily (q8h) and 400 mg ranitidine bismuth citrate given twice daily (q12h) for 14 days. An additional 14 days of 400 mg twice daily is recommended for ulcer healing and symptom relief. Clarithromycin and ranitidine bismuth citrate combination therapy is not recommended in patients with creatinine clearance less than 25 mL/min (see INDICATIONS AND USAGEand CLINICAL STUDIESsections).

Children

The usual recommended daily dosage is 15 mg/kg/day divided q12h for 10 days.

PEDIATRIC DOSAGE GUIDELINES

Based on Body Weight

Dosing Calculated on 7.5 mg/kg q12h

Weight

Dose

kg

lbs

(q12h)

9

20

62.5 mg

17

37

125 mg

25

55

187.5 mg

33

73

250 mg

Mycobacterial Infections

Prophylaxis

The recommended dose of clarithromycin for the prevention of disseminated Mycobacterium avium disease is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. No studies of clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses recommended for prophylaxis are derived from MAC treatment studies in children. Dosing recommendations for children are in the table above.

Treatment

Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to Mycobacterium avium complex. Clarithromycin should be used in combination with other antimycobacterial drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment (see CLINICAL STUDIES). The recommended dose for mycobacterial infections in adults is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. Dosing recommendations for children are in the table above.

Clarithromycin therapy should continue if clinical response is observed. Clarithromycin can be discontinued when the patient is considered at low risk of disseminated infection.
Amlodipine Besylate

Amlodipine Besylate

2.1 Adults

The usual initial antihypertensive oral dose of amlodipine is 5 mg once daily, and the maximum dose of 10 mg once daily.

Small, fragile, or elderly patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine to other antihypertensive therapy.

Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titrate more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

Angina

The recommended dose for chronic stable or vasospastic angina is 5 to 10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect.

Coronary Artery Disease:

The recommended dose range for patients with coronary artery disease is 5 to 10 mg once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4)].

2.2 Children

The effective antihypertensive oral dose in pediatric patients ages 6 to 17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.4), Clinical Studies (14.1)].
Atenolol

Atenolol

Take care when prescribing and administering Oxycodone Hydrochloride Oral Solution USP to avoid dosing errors due to confusion between mg and mL, and other oxycodone solutions with different concentrations, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Always use the enclosed calibrated measuring cup when administering Oxycodone Hydrochloride Oral Solution USP to ensure the dose is measured and administered accurately.

Selection of patients for treatment with oxycodone hydrochloride should be governed by the same principles that apply to the use of similar opioid analgesics. Individualize treatment in every case, using non-opioid analgesics, opioids on as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality, and the American Pain Society.

2.1 Individualization of Dosage

As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of oxycodone hydrochloride, give attention to the following:
• the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; • the reliability of the relative potency estimate used to calculate the equivalent oxycodone hydrochloride dose needed; • the patient’s degree of opioid tolerance; • the general condition and medical status of the patient; • concurrent medications; • the type and severity of the patient’s pain; • risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.
The following dosing recommendations, therefore, can only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual reevaluation of the patient receiving oxycodone hydrochloride is important, with special attention to the maintenance of pain management and the relative incidence of side effects associated with therapy. During chronic therapy, especially for non-cancer-related pain, periodically reassess the continued need for the use of opioid analgesics.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

2.2 Initiation of Therapy

Start patients who have not been receiving opioid analgesics on Oxycodone Hydrochloride Oral Solution USP in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain.

Titrate the dose based upon the individual patient's response to their initial dose of Oxycodone Hydrochloride Oral Solution USP. Adjust the dose to an acceptable level of analgesia taking into account the improvement in pain intensity and the tolerability of the oxycodone by the patient.

2.3 Conversion to Oral Oxycodone Oral Solution

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dose of Oxycodone Hydrochloride. It is better to underestimate a patient’s 24-hour oral Oxycodone Hydrochloride dose and make available rescue medication than to overestimate the 24-hour oral Oxycodone Hydrochloride dose and manage an adverse experience of overdose.

2.3.1 Conversion from Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs

When converting patients from fixed ratio opioid/non-opioid drug regimens it may be necessary to titrate the dose of Oxycodone Hydrochloride Oral Solution USP in response to the level of analgesia and adverse effects.

2.3.2 Conversion from Non-Oxycodone Opioids

In converting patients from other opioids to oxycodone hydrochloride, close observation and adjustment of dosage based upon the patient’s response to oxycodone hydrochloride is imperative. Physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate.

2.4 Conversion from Oral Oxycodone Hydrochloride to Controlled-Release Oral Oxycodone

The relative bioavailability of Oxycodone Hydrochloride Oral Solution USP compared to controlled-release oxycodone is unknown, so conversion to controlled-release tablets must be accompanied by close observation for signs of excessive sedation.

2.5 Maintenance of Therapy

Continual reevaluation of the patient receiving Oxycodone Hydrochloride Oral Solution USP is important, with special attention to the maintenance of pain management and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain.

During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), the continued need for the use of opioid analgesics should be re-assessed as appropriate.

2.6 Cessation of Therapy

When a patient no longer requires therapy with Oxycodone Hydrochloride Oral Solution USP for the treatment of their pain, it is important that therapy be gradually discontinued over time to prevent the development of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal [see Drug Abuse and Dependence (9.3) section for description of the signs and symptoms of withdrawal]. If the patient develops these signs or symptoms, the dose should be raised to the previous level and titrated down more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. It is not known at what dose of Oxycodone Hydrochloride Oral Solution USP that treatment may be discontinued without risk of the opioid abstinence syndrome.

2.7 Dosage in patients with Hepatic or Renal Impairment

Follow a conservative approach to dose initiation in patients with hepatic or renal impairment. Monitor patients closely and adjust dose based on clinical response.
Triazolam

Triazolam

It is important to individualize the dosage of triazolam tablets for maximum beneficial effect and to help avoid significant adverse effects.

The recommended dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg may be found to be sufficient for some patients (e.g., low body weight). A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded.

In geriatric and/or debilitated patients the recommended dosage range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125 mg in these groups and the 0.25 mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose. A dose of 0.25 mg should not be exceeded in these patients.

As with all medications, the lowest effective dose should be used.
Doxercalciferol

Doxercalciferol

Adult Administration

The optimal dose of Doxercalciferol Capsules must be carefully determined for each patient. Table 4 provides the current recommended therapeutic target levels for iPTH in patients with chronic kidney disease:
Table 4: Target Range of Intact Plasma PTH by Stage of CKD
CKD Stage

GFR (mL/min/1.73 m2)

Target "intact" PTH (pg/mL)

3

30 to 59

35 to 70

4

15 to 29

70 to 110

5

<15 (or dialysis)

150 to 300

From Table 15 of National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 42:S1-S202, 2003 (suppl 3)

Dialysis

The recommended initial dose of Doxercalciferol Capsules is 10 mcg administered three times weekly at dialysis (approximately every other day). The initial dose should be adjusted, as needed, in order to lower blood iPTH into the range of 150 to 300 pg/mL. The dose may be increased at 8-week intervals by 2.5 mcg if iPTH is not lowered by 50% and fails to reach the target range. The maximum recommended dose of doxercalciferol is 20 mcg administered three times a week at dialysis for a total of 60 mcg per week. Drug administration should be suspended if iPTH falls below 100 pg/mL and restarted one week later at a dose that is at least 2.5 mcg lower than the last administered dose. During titration, iPTH, serum calcium, and serum phosphorus levels should be obtained weekly. If hypercalcemia, hyperphosphatemia, or a serum calcium times serum phosphorus product greater than 55 mg2/dL2 is noted, the dose of Doxercalciferol Capsules should be decreased or suspended and/or the dose of phosphate binders should be appropriately adjusted. If suspended, the drug should be restarted at a dose that is at least 2.5 mcg lower.

Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus levels. The following is a suggested approach in dose titration:
Table 5: Dialysis Dosing Recommendations
Initial Dosing

iPTH Level

Doxercalciferol Dose

>400 pg/mL

10 mcg three times per week at dialysis

Dose Titration

iPTH Level

Doxercalciferol Dose

Above 300 pg/mL

Increase by 2.5 mcg at eight-week intervals as necessary

150 to 300 pg/mL

Maintain

<100 pg/mL

Suspend for one week, then resume at a dose that is at least 2.5 mcg lower

Pre-Dialysis

The recommended initial dose of Doxercalciferol Capsules is 1 mcg administered once daily. The initial dose should be adjusted, as needed, in order to lower blood iPTH to within target ranges (see table below). The dose may be increased at 2-week intervals by 0.5 mcg to achieve the target range of iPTH. The maximum recommended dose of Doxercalciferol Capsules is 3.5 mcg administered once per day.

Serum levels of calcium and phosphorus and plasma levels of iPTH should be monitored at least every two weeks for 3 months after initiation of Doxercalciferol Capsules therapy or following dose adjustments in Doxercalciferol Capsules therapy, then monthly for 3 months, and every 3 months thereafter. If hypercalcemia, hyperphosphatemia, or a serum calcium times phosphorus product greater than 55 mg2/dL2 is noted, the dose of Doxercalciferol Capsules should be decreased or suspended and/or the dose of phosphate binders should be appropriately adjusted. If suspended, the drug should be restarted at a dose that is at least 0.5 mcg lower.

Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus levels. Table 6 presents a suggested approach in dose titration:
Table 6: Pre-Dialysis Dosing Recommendations
Initial Dosing

iPTH Level

Doxercalciferol Dose

>70 pg/mL (Stage 3)

1 mcg once per day

>110 pg/mL (Stage 4)

Dose Titration

iPTH Level

Doxercalciferol Dose

Above 70 pg/mL (Stage 3)

Increase by 0.5 mcg at two-week intervals as necessary

110 pg/mL (Stage 4)

35 to 70 pg/mL (Stage 3)

Maintain

70 to 110 pg/mL (Stage 4)

<35 pg/mL (Stage 3)

Suspend for one week, then resume at a dose that is at least 0.5

<70 pg/mL (Stage 4)

mcg lower
Fluconazole

Fluconazole

2.1 Hypertension

The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with Ramipril Capsules USP alone, a diuretic can be added.

2.3 Heart Failure Post-Myocardial Infarction

For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the recommended starting dose of Ramipril Capsules USP is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.

After the initial dose of Ramipril Capsules USP, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of Ramipril Capsules USP does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see Warnings and Precautions (5.5), Drug Interactions (7.1)].

2.4 General Dosing Information

Generally, swallow ramipril capsules whole. The ramipril capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.

Concomitant administration of ramipril with potassium supplements, potassium salt substitutes, or potassium‑sparing diuretics can lead to increases of serum potassium [see Warnings and Precautions (5.8)].

2.5 Dosage Adjustment

Renal Impairment

Establish baseline renal function in patients initiating ramipril. Usual regimens of therapy with ramipril may be followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25% of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat [see Use in Specific Populations (8.6)].

Hypertension

For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ramipril once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg.

Heart Failure Post-Myocardial Infarction

For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ramipril once daily. The dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical response and tolerability.

Volume Depletion or Renal Artery Stenosis

Blood pressure decreases associated with any dose of ramipril depend, in part, on the presence or absence of volume depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, initiate dosing at 1.25 mg once daily. Adjust dosage according to blood pressure response
Metronidazole

Metronidazole

Oral

The usual recommended starting dose for oral administration is 2 mg. This may be repeated in 6 to 8 hours as needed, provided the patient is assessed for signs of hypoventilation and excessive sedation. If necessary, the dose may be increased to up to 3 mg every 6 to 8 hours, after adequate evaluation of the patient’s response. Higher doses may be appropriate in opioid tolerant patients. Dosage should be adjusted according to the severity of the pain; age, weight and physical status of the patient; the patient’s underlying diseases; use of concomitant medications; and other factors (see INDIVIDUALIZATION OF DOSAGE, WARNINGS and PRECAUTIONS). Total oral daily doses of more than 6 to 12 mg in 24 hours are generally not recommended as starting doses in nonopioid tolerant patients; lower total daily doses may be appropriate.

Use in Chronic Pain

The dosage of levorphanol in patients with cancer or with other conditions for which chronic opioid therapy is indicated must be individualized (see INDIVIDUALIZATION OF DOSAGE). Levorphanol is 4 to 8 times as potent as morphine and has a longer half-life. Because there is incomplete, cross-tolerance among opioids, when converting a patient from morphine to levorphanol, the total daily dose of levorphanol should begin at approximately 1/15 to 1/12 of the total daily dose of oral morphine that such patients had previously required and then the dose should be adjusted to the patient’s clinical response. If a patient is to be placed on fixed-schedule dosing (round-the-clock) with this drug, care should be taken to allow adequate time after each dose change (approximately 72 hours) for the patient to reach a new steady-state before a subsequent dose adjustment to avoid excessive sedation due to drug accumulation.

Note: As with all controlled substances, abuse by health care personnel is possible and the drug should be handled accordingly.
Imipramine Pamoate

Imipramine Pamoate

The following recommended dosages for Imipramine Pamoate Capsules should be modified as necessary by the clinical response and any evidence of intolerance.

Initial Adult Dosage

Outpatients

Therapy should be initiated at 75 mg/day. Dosage may be increased to 150 mg/day which is the dose level at which optimum response is usually obtained. If necessary, dosage may be increased to 200 mg/day.

Dosage higher than 75 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.

Hospitalized Patients

Therapy should be initiated at 100 to 150 mg/day and may be increased to 200 mg/day. If there is no response after two weeks, dosage should be increased to 250 to 300 mg/day.

Dosage higher than 150 mg/day may also be administered on a once-a-day basis after the optimum dosage and tolerance have been determined. The daily dosage may be given at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.

Adult Maintenance Dosage

Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased.

The usual maintenance dosage is 75 to 150 mg/day. The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted.

Adolescent and Geriatric Patients

Therapy in these age groups should be initiated with imipramine pamoate tablets at a total daily dosage of 25 to 50 mg, since imipramine pamoate capsules are not available in these strengths. Dosage may be increased according to response and tolerance, but it is generally unnecessary to exceed 100 mg/day in these patients. Imipramine pamoate capsules may be used when total daily dosage is established at 75 mg or higher.

The total daily dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

As with all tricyclics, the antidepressant effect of imipramine may not be evident for one to three weeks in some patients.

Adolescent and geriatric patients can usually be maintained at lower dosage. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission after which the dosage should gradually be decreased.

The total daily maintenance dosage can be administered on a once-a-day basis, preferably at bedtime. In some patients it may be necessary to employ a divided-dose schedule.

In cases of relapse due to premature withdrawal of the drug, the effective dosage of imipramine should be reinstituted.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with imipramine pamoate capsules. Conversely, at least 14 days should be allowed after stopping imipramine pamoate capsules before starting an MAOI intended to treat psychiatric disorders (see Contraindications).

Use of Imipramine Pamoate Capsules With Other MAOIs, Such as Linezolid or Methylene Blue

Do not start imipramine pamoate capsules in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see Contraindications).

In some cases, a patient already receiving imipramine pamoate capsules therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, imipramine pamoate capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with imipramine pamoate capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see Warnings).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with imipramine pamoate capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see Warnings).
Mercaptopurine

Mercaptopurine

Maintenance Therapy

Once a complete hematologic remission is obtained, maintenance therapy is considered essential. Maintenance doses will vary from patient to patient. The usual daily maintenance dose of Mercaptopurine Tablets is 1.5 to 2.5 mg/kg/day as a single dose. It is to be emphasized that in pediatric patients with acute lymphatic leukemia in remission, superior results have been obtained when Mercaptopurine Tablets have been combined with other agents (most frequently with methotrexate) for remission maintenance. Mercaptopurine Tablets should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Dosage with concomitant Allopurinol

When allopurinol and mercaptopurine are administered concomitantly, the dose of mercaptopurine must be reduced to one-third to one-quarter of the usual dose to avoid severe toxicity.

Dosage in TPMT-deficient Patients

Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections).

Most patients with heterozygous TPMT deficiency tolerated recommended mercaptopurine doses, but some required dose reduction. Genotypic and phenotypic testing of TPMT status are available (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections).

Dosage in Renal and Hepatic Impairment

It is probably advisable to start with lower dosages in patients with impaired renal function, due to slower elimination of the drug and metabolites and a greater cumulative effect. Consideration should be given to reducing the dosage in patients with impaired hepatic function.
Pilocarpine Hydrochlori...

Pilocarpine Hydrochloride

Regardless of the indication, the starting dose in patients with moderate hepatic impairment should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild hepatic insufficiency do not require dosage reductions. The use of pilocarpine in patients with severe hepatic insufficiency is not recommended. If needed, refer to the Hepatic Insufficiency subsection of the PRECAUTIONS section of this label for definitions of mild, moderate and severe hepatic impairment.

Head & Neck Cancer Patients

The recommended initial dose of pilocarpine hydrochloride tablets USP is one tablet (5 mg) taken three times a day. Dosage should be adjusted according to therapeutic response and tolerability. The usual dosage range is 15 to 30 mg per day. (Not to exceed 10 mg per dose.) Although early improvement may be realized, at least 12 weeks of uninterrupted therapy with pilocarpine hydrochloride tablets USP may be necessary to assess whether a beneficial response will be achieved. The incidence of the most common adverse events increases with dose. The lowest dose that is tolerated and effective should be used for maintenance.

Sjogren's Syndrome Patients

The recommended dose of pilocarpine hydrochloride tablets USP is one tablet (5 mg) taken four times a day. Efficacy was established by 6 weeks of use.
Oxycodone And Acetamino...

Oxycodone And Acetaminophen

Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. Oxycodone and acetaminophen tablets are given orally.

Oxycodone and Acetaminophen Tablets:

The usual adult dosage is one tablet every 6 hours as needed for pain. The total daily dose of acetaminophen should not exceed 4 grams. (Maximum daily dose is 12 tablets.)

Cessation of Therapy

In patients treated with oxycodone and acetaminophen for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.
Lymph Iii

Lymph Iii

2.1 Individualization of Dosage

As with any opioid drug product, it is necessary to adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of oxymorphone hydrochloride, attention should be given to the following:
• The total daily dose, potency and specific characteristics of the opioid the patient has been taking previously; • The relative potency estimate used to calculate the equivalent oxymorphone dose needed; • The patient’s degree of opioid tolerance; • The age, general condition, and medical status of the patient; • Concurrent non-opioid analgesics and other medications; • The type and severity of the patient’s pain; • The balance between pain control and adverse experiences; • Risk factors for abuse or addiction, including a prior history of abuse or addiction.
Once therapy is initiated, frequently assess pain relief and other opioid effects. Titrate dose to adequate pain relief (generally mild or no pain). Patients who experience breakthrough pain may require dosage adjustment.

If signs of excessive opioid-related adverse experiences are observed, the next dose may be reduced. Adjust dosing to obtain an appropriate balance between pain relief and opioid-related adverse experiences. If significant adverse events occur before the therapeutic goal of mild or no pain is achieved, the events should be treated aggressively. Once adverse events are adequately managed, continue upward titration to an acceptable level of pain control.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family. Advise patients and family members of the potential common adverse reactions associated with changing opioid doses.

The dosing recommendations below, therefore, can only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

2.2 Initiation of Therapy

Titrate dose to adequate pain relief (generally mild or no pain).

Opioid-Naïve Patients:

Patients who have not been receiving opioid analgesics should be started on oxymorphone hydrochloride in a dosing range of 10 to 20 mg every four to six hours depending on the initial pain intensity. If deemed necessary to initiate therapy at a lower dose (e.g., for renal or hepatic impairment or for geriatric patients), patients may be started with oxymorphone hydrochloride 5 mg. The dose should be titrated based upon the individual patient’s response to their initial dose of oxymorphone hydrochloride. This dose can then be adjusted to an acceptable level of analgesia taking into account the pain intensity and adverse reactions experienced by the patient.

Initiation of therapy with doses higher than 20 mg is not recommended because of potential serious adverse reactions [see Clinical Studies (14.1)].

Conversion from Parenteral Oxymorphone to Oxymorphone Hydrochloride:

Given oxymorphone hydrochloride’s absolute oral bioavailability of approximately 10%, patients receiving parenteral oxymorphone may be converted to oxymorphone hydrochloride by administering 10 times the patient’s total daily parenteral oxymorphone dose as oxymorphone hydrochloride, in four or six equally divided doses (e.g., [IV dose x 10] divided by 4 or 6). For example, approximately 10 mg of oxymorphone hydrochloride four times daily may be required to provide pain relief equivalent to a total daily IM dose of 4 mg oxymorphone. Due to patient variability with regard to opioid analgesic response, upon conversion patients should be closely monitored to ensure adequate analgesia and to minimize side effects.

Conversion from Other Oral Opioids to Oxymorphone Hydrochloride:

For conversion from other opioids to oxymorphone hydrochloride, physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate. In general, it is safest to start oxymorphone hydrochloride therapy by administering half of the calculated total daily dose of oxymorphone hydrochloride in 4 to 6 equally divided doses, every 4 to 6 hours. The initial dose of oxymorphone hydrochloride can be gradually adjusted until adequate pain relief and acceptable side effects have been achieved.

2.3 Maintenance of Therapy

During therapy, continual re-evaluation of the patient receiving oxymorphone hydrochloride is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose [see Dosage and Administration (2.1)].

2.4 Cessation of Therapy

When the patient no longer requires therapy with oxymorphone hydrochloride, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient [see Drug Abuse and Dependence (9.3)].

2.5 Patients with Hepatic Impairment

Oxymorphone hydrochloride is contraindicated in patients with moderate or severe hepatic impairment. Use oxymorphone hydrochloride with caution in patients with mild hepatic impairment, starting with the lowest dose (e.g., 5 mg) and titrating slowly while carefully monitoring side effects [see Warnings and Precautions (5.6) and

Clinical Pharmacology (12.3)].

2.6 Patients with Renal Impairment

There are 57% and 65% increases in oxymorphone bioavailability in patients with moderate and severe renal impairment, respectively; treated with extended-release oxymorphone tablets [see Clinical Pharmacology (12.3)]. Accordingly, oxymorphone hydrochloride should be administered cautiously and in reduced dosages to patients with creatinine clearance rates less than 50 mL/min.

2.7 Use with Central Nervous System Depressants

Oxymorphone hydrochloride, like all opioid analgesics, should be started at 1/3 to 1/2 of the usual dose in patients who are concurrently receiving other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol, because respiratory depression, hypotension and profound sedation, coma or death may result [see Warnings and Precautions (5.3) and Drug Interactions (7.1)]. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.

Although no specific interaction between oxymorphone and monoamine oxidase inhibitors has been observed, oxymorphone hydrochloride is not recommended for use in patients who have received MAO inhibitors within 14 days [see Drug Interactions (7.5)].

2.8 Geriatric Patients

Exercise caution in the selection of the starting dose of oxymorphone hydrochloride for an elderly patient by starting at the low end of the dosing range (e.g., 5 mg) [see Use in Specific Populations (8.5)].
Dolophine

Dolophine

2.1 Important General Information
• The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect. • A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.2 Initial Dosing for Management of Pain

DOLOPHINE should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Consider the following important factors that differentiate methadone from other opioid analgesics:
• There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. • The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. • Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose, and may take longer in some patients.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with DOLOPHINE [see Warnings and Precautions (5.2)].

Use of DOLOPHINE as the First Opioid Analgesic: Initiate treatment with DOLOPHINE with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to DOLOPHINE: Discontinue all other around-the-clock opioid drugs when DOLOPHINE therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.

Consider the following when using the information in Table 1:
• This is not a table of equinalgesic doses. • The conversion factors in this table are only for the conversion from another oral opioid analgesic to DOLOPHINE. • The table cannot be used to convert from DOLOPHINE to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. Table 1: Conversion Factors to DOLOPHINE
Total Daily Baseline Oral

Morphine Equivalent Dose

Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose

< 100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 mg to 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated DOLOPHINE dose using Table 1:
• For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate DOLOPHINE strength(s) available.

Example conversion from a single opioid to DOLOPHINE:
Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily) 50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine Step 2: Calculate the approximate equivalent dose of DOLOPHINE based on the total daily dose of Morphine using Table 1. 100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg DOLOPHINE daily Step 3: Calculate the approximate starting dose of DOLOPHINE to be given every 12 hours. Round down, if necessary, to the appropriate DOLOPHINE tablets strengths available. 15 mg daily / 2 = 7.5 mg DOLOPHINE every 12 hours Then 7.5 mg is rounded down to 5 mg DOLOPHINE every 12 hours
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to DOLOPHINE.

Conversion from Parenteral Methadone to DOLOPHINE: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).

2.3 Titration and Maintenance of Therapy for Pain

Individually titrate DOLOPHINE to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving DOLOPHINE to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T1/2) from 8 to 59 hours in different studies [see Clinical Pharmacology (12.3)]), titrate DOLOPHINE slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression).

Patients who experience breakthrough pain may require a dose increase of DOLOPHINE, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the DOLOPHINE dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of DOLOPHINE for Pain

When a patient no longer requires therapy with DOLOPHINE for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue DOLOPHINE.

2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the

treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of DOLOPHINE will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of DOLOPHINE if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of DOLOPHINE on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

Short-term Detoxification: For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of DOLOPHINE. Decrease the dose of DOLOPHINE on a daily basis or at 2-day intervals, keeping the amount of DOLOPHINE sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.

2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.10 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Methadone Hydrochloride...

Methadone Hydrochloride Solution

2.1 Important General Information
• The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect. • A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.2 Initial Dosing for Management of Pain

Methadone should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Consider the following important factors that differentiate methadone from other opioid analgesics:
• There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. • The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. • Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose, and may take longer in some patients.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with methadone [see Warnings and Precautions (5.2)].

Use of Methadone as the First Opioid Analgesic: Initiate treatment with methadone with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to Methadone: Discontinue all other around-the-clock opioid drugs when methadone therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.

Consider the following when using the information in Table 1:
• This is not a table of equianalgesic doses. • The conversion factors in this table are only for the conversion from another oral opioid analgesic to methadone. • The table cannot be used to convert from methadone to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. Table 1: Conversion Factors to Methadone
Total Daily Baseline Oral

Morphine Equivalent Dose

Estimated Daily Oral Methadone Requirement

as Percent of Total Daily Morphine Equivalent Dose

< 100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 mg to 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated methadone dose using Table 1:
• For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate methadone strength(s) available.

Example conversion from a single opioid to methadone:
Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily) 50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine Step 2: Calculate the approximate equivalent dose of Methadone Hydrochloride Oral Solution USP based on the total daily dose of Morphine using Table 1. 100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg Methadone Hydrochloride Oral Solution USP daily Step 3: Calculate the approximate starting dose of Methadone Hydrochloride Oral Solution USP to be given every 12 hours. Round down, if necessary, to the appropriate methadone tablets strengths available. 15 mg daily / 2 = 7.5 mg Methadone Hydrochloride Oral Solution USP every 12 hours Then 7.5 mg is rounded down to 5 mg Methadone Hydrochloride Oral Solution USP every 12 hours
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Methadone Hydrochloride Oral Solution USP.

Conversion from Parenteral Methadone to Methadone Hydrochloride Oral Solution USP: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).

2.3 Titration and Maintenance of Therapy for Pain

Individually titrate methadone to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving methadone to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T1/2) from 8 to 59 hours in different studies [see Clinical Pharmacology (12.3)]), titrate methadone slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression).

Patients who experience breakthrough pain may require a dose increase of methadone, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the methadone dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of Methadone for Pain

When a patient no longer requires therapy with methadone for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue methadone.

2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

Short-Term Detoxification: For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone. Decrease the dose of methadone on a daily basis or at 2-day intervals, keeping the amount of methadone sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.

2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.10 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Olanzapine

Olanzapine

Famciclovir Tablets may be taken with or without food.

2.1 Dosing Recommendation in Immunocompetent Adult Patients

Herpes Labialis (Cold Sores): The recommended dosage of famciclovir for the treatment of recurrent herpes labialis is 1500 mg as a single dose. Therapy should be initiated at the first sign or symptom of herpes labialis (e.g., tingling, itching, burning, pain, or lesion).

Genital Herpes: Recurrent Episodes: The recommended dosage of famciclovir for the treatment of recurrent episodes of genital herpes is 1000 mg twice daily for 1 day. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).

Suppressive Therapy: The recommended dosage of famciclovir for chronic suppressive therapy of recurrent episodes of genital herpes is 250 mg twice daily.

2.2 Dosing Recommendation in HIV-Infected Adult Patients

Recurrent Orolabial or Genital Herpes: Therecommended dosage of famciclovir for the treatment of recurrent orolabial or genital herpes in HIV-infected patients is 500 mg twice daily for 7 days. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).

2.3 Dosing Recommendation in Patients with Renal Impairment

Dosage recommendations for adult patients with renal impairment are provided in Table 1 [see Use in Specific Populations (8.6),Clinical Pharmacology (12.3)].
Table 1: Dosage Recommendations for Adult Patients with Renal Impairment * Hemodialysis
Indication and Normal Dosage Regimen

Creatinine Clearance (mL/min)

Adjusted Dosage Regimen Dose (mg)

Dosing Interval

Single-Day Dosing Regimens

Recurrent Genital Herpes

1000 mg every 12 hours for 1 day

≥60

1000

every 12 hours for 1 day

40 to 59

500

every 12 hours for 1 day

20 to 39

500

single dose

<20

250

single dose

HD*

250

single dose following dialysis

Recurrent Herpes Labialis

1500 mg single dose

≥60

1500

single dose

40 to 59

750

single dose

20 to 39

500

single dose

<20

250

single dose

HD*

250

single dose following dialysis

Multiple-Day Dosing Regimens

Suppression of Recurrent Genital

Herpes 250 mg every 12 hours

≥40

250

every 12 hours

20 to 39

125

every 12 hours

<20

125

every 24 hours

HD*

125

following each dialysis

Recurrent Orolabial or Genital Herpes in HIV-Infected Patients

500 mg every 12 hours

≥40

500

every 12 hours

20 to 39

500

every 24 hours

<20

250

every 24 hours

HD*

250

following each dialysis
Minoxidil For Men

Minoxidil For Men

2.1 Important General Information
• The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect. • A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Methadone has a narrow therapeutic index, especially when combined with other drug.
2.2 Initial Dosing for Management of Pain

Methadone should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Consider the following important factors that differentiate methadone from other opioid analgesics:
• There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. • The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. • Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose, and may take longer in some patients.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with methadone [see Warnings and Precautions (5.2)].

Use of Methadone as the First Opioid Analgesic: Initiate treatment with Methadone with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to Methadone: Discontinue all other around-the-clock opioid drugs when methadone therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.

Consider the following when using the information in Table 1:
• This is not a table of equianalgesic doses. • The conversion factors in this table are only for the conversion from another oral opioid analgesic to methadone. • The table cannot be used to convert from methadone to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1: Conversion Factors to Methadone
Total Daily Baseline Oral Morphine Equivalent Dose
Estimated Daily Oral Methadone Requirement

as Percent of Total Daily Morphine Equivalent Dose

< 100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 mg to 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated methadone dose using Table 1:
• For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate methadone strength(s) available.

Example conversion from a single opioid to methadone:

Step 1 : Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily)

50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine

Step 2 : Calculate the approximate equivalent dose of methadone based on the total daily dose of Morphine using Table 1.

100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg methadone daily

Step 3 : Calculate the approximate starting dose of methadone to be given every 12 hours. Round down, if necessary, to the appropriate methadone tablets strengths available.

15 mg daily / 2 = 7.5 mg methadone every 12 hours

Then 7.5 mg is rounded down to 5 mg methadone every 12 hours

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to methadone.

Conversion from Parenteral Methadone to Methadone: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).

2.3 Titration and Maintenance of Therapy for Pain

Individually titrate methadone to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving methadone to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T1/2) from 8 to 59 hours in different studies [see Clinical Pharmacology (12.3)]), titrate methadone slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression).

Patients who experience breakthrough pain may require a dose increase of methadone, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the methadone dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of Methadone for Pain

2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

Short-Term Detoxification: For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone. Decrease the dose of methadone on a daily basis or at 2-day intervals, keeping the amount of methadone sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.

2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.10 Dosage Adjustment During Pregnancy
Dexamethasone Sodium Ph...

Dexamethasone Sodium Phosphate

• Valacyclovir hydrochloride tablets may be given without regard to meals.
Labeling describing use of valacyclovir hydrochloride in pediatric patients for whom a solid dosage form is not appropriate is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that pediatric use is not approved for this valacyclovir hydrochloride tablet product

2.1 Adult Dosing Recommendations

Cold Sores (Herpes Labialis): The recommended dosage of valacyclovir hydrochloride tablets for the treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).

Genital Herpes: Initial Episodes: The recommended dosage of valacyclovir hydrochloride for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.

Recurrent Episodes: The recommended dosage of valacyclovir hydrochloride tablets for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode.

Suppressive Therapy: The recommended dosage of valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.

In HIV-infected patients with CD4+ cell count ≥100 cells/mm3, the recommended dosage of valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.

Reduction of Transmission: The recommended dosage of valacyclovir hydrochloride tablets for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.

Herpes Zoster: The recommended dosage of valacyclovir hydrochloride tablets for the treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash.

2.2 Pediatric Dosing Recommendations

Cold Sores (Herpes Labialis): The recommended dosage of valacyclovir hydrochloride tablets for the treatment of cold sores in pediatric patients ≥12 years of age is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).

Labeling describing use of valacyclovir hydrochloride in pediatric patients with chickenpox is approved for GlaxoSmithKline’s Valtrex® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that additional dosing information is not approved for this valacyclovir hydrochloride tablet product.

2.4 Patients with Renal Impairment

Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not available for the use of valacyclovir hydrochloride tablets in pediatric patients with a creatine clearance <50 mL/min/1.73 m2.
Table 1. Valacyclovir HCl Dosage Recommendations for Adults with Renal Impairment
Indications

Normal Dosage

Regimen

(Creatinine

Clearance ≥50 mL/min)

Creatinine Clearance (mL/min)

30 to 49

10 to 29

<10

Cold Sores

(herpes labialis)

Do not exceed 1 day of treatment.

Two 2 gram

doses taken

about 12 hours

apart

Two 1 gram

doses taken

about 12 hours

apart

Two 500 mg

doses taken

about 12 hours

apart

500 mg

single dose

Genital herpes

Initial episode

1 gram every

12 hours

no reduction

1 gram every

24 hours

500 mg every

24 hours

Genital herpes

Recurrent episodes

500 mg every

12 hours

no reduction

500 mg every

24 hours

500 mg every

24 hours

Genital herpes

Suppressive therapy

Immunocompetent patients

1 gram every

24 hours

no reduction

500 mg every

24 hours

500 mg every

24 hours

Alternate dose for immunocompetent patients with ≤9 recurrences/year

500 mg every 24 hours

no reduction

500 mg every 48 hours

500 mg every 48 hours

HIV-infected patients

500 mg every

12 hours

no reduction

500 mg every

24 hours

500 mg every

24 hours

Herpes zoster

1 gram every

8 hours

1 gram every

12 hours

1 gram every

24 hours

500 mg every

24 hours

Hemodialysis: Patients requiring hemodialysis should receive the recommended dose of valacyclovir hydrochloride after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of valacyclovir hydrochloride is approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session.

Peritoneal Dialysis: There is no information specific to administration of valacyclovir hydrochloride in patients receiving peritoneal dialysis. The effect of chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with end-stage renal disease (ESRD) not receiving hemodialysis. Therefore, supplemental doses of valacyclovir hydrochloride should not be required following CAPD or CAVHD.
Mycophenolate Mofetil C...

Mycophenolate Mofetil Capsule Mycophenolate Mofetil

Renal Transplantation

Adults

A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of mycophenolate mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil.

Pediatrics (3 months to 18 years of age)

The recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be dosed with mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose).

Cardiac Transplantation

Adults

A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.

Hepatic Transplantation

Adults

A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients.

Mycophenolate Mofetil Capsules, Tablets, and Oral Suspension

The initial oral dose of mycophenolate mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that mycophenolate mofetil be administered on an empty stomach. However, in stable renal transplant patients, mycophenolate mofetil may be administered with food if necessary.

Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take mycophenolate mofetil at the usual times.

Note: If required, mycophenolate mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).

Patients with Hepatic Impairment

No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Geriatrics

The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients (see PRECAUTIONS: Geriatric Use).

Mycophenolate Mofetil Intravenous

Adults

Mycophenolate mofetil intravenous is an alternative dosage form to mycophenolate mofetil capsules, tablets and oral suspension recommended for patients unable to take oral mycophenolate mofetil. Mycophenolate mofetil intravenous should be administered within 24 hours following transplantation. Mycophenolate mofetil intravenous can be administered for up to 14 days; patients should be switched to oral mycophenolate mofetil as soon as they can tolerate oral medication.

Mycophenolate mofetil intravenous must be reconstituted and diluted to a concentration of 6 mg/mL using 5% Dextrose Injection USP. Mycophenolate mofetil intravenous is incompatible with other intravenous infusion solutions. Following reconstitution, mycophenolate mofetil intravenous must be administered by slow intravenous infusion over a period of NO LESS THAN 2 HOURS by either peripheral or central vein.

CAUTION: MYCOPHENOLATE MOFETIL INTRAVENOUS SOLUTION SHOULD NEVER BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION (see WARNINGS).

Dosage Adjustments

In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of mycophenolate mofetil greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: Patients with Renal Impairment).

No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

If neutropenia develops (ANC <1.3 x 103/mcL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see WARNINGS:Neutropenia , ADVERSE REACTIONS, and PRECAUTIONS: Laboratory Tests).
Azathioprine

Azathioprine

TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING AZATHIOPRINE TABLETS. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity from azathioprine if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles). Azathioprine should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction.

Renal Homotransplantation

The dose of azathioprine required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. Azathioprine is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of azathioprine should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.

Rheumatoid Arthritis

Azathioprine is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. Azathioprine may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities.

Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance azathioprine has not been determined. Azathioprine can be discontinued abruptly, but delayed effects are possible.

Use in Renal Dysfunction

Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of azathioprine or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Fluriso

Fluriso

2.1General Dosing Recommendations

Ropinirole can be taken with or without food [see Clinical Pharmacology (12.3)].

If a significant interruption in therapy with ropinirole has occurred, retitration of therapy may be warranted.

2.2Dosing for Parkinson’s Disease

The recommended starting dose for Parkinson’s disease is 0.25 mg three times daily. Based on individual patient therapeutic response and tolerability, if necessary, the dose should then be titrated with weekly increments as described in Table 1. After week 4, if necessary, the daily dose may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a maximum recommended total daily dose of 24 mg/day (8 mg three time daily). Doses greater than 24 mg/day have not been tested in clinical trials.
Table 1: Ascending-Dose Schedule of Ropinirole for Parkinson's Disease
Week

Dosage

Total Daily Dose

1

0.25 mg 3 times daily

0.75 mg

2

0.5 mg 3 times daily

1.5 mg

3

0.75 mg 3 times daily

2.25 mg

4

1 mg 3 times daily

3 mg

Ropinirole should be discontinued gradually over a 7-day period in patients with Parkinson’s disease. The frequency of administration should be reduced from three times daily to twice daily for 4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of ropinirole.

Renal Impairment

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole for patients with end-stage renal disease on hemodialysis is 0.25 mg three times a day. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole in patients with severe renal impairment without regular dialysis has not been studied.

2.3Dosing for Restless Legs Syndrome

The recommended adult starting dose for RLS is 0.25 mg once daily 1 to 3 hours before bedtime. After 2 days, if necessary, the dose can be increased to 0.5 mg once daily and to 1 mg once daily at the end of the first week of dosing, then as shown in Table 2 as needed to achieve efficacy. Titration should be based on individual patient therapeutic response and tolerability, up to a maximum recommended dose of 4 mg daily. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established.
Table 2: Dose Titration Schedule of Ropinirole for Restless Legs Syndrome
Day/Week

Dosage to Be Taken Once Daily, 1 to 3 Hours Before Bedtime

Days 1 and 2

0.25 mg

Days 3-7

0.5 mg

Week 2

1 mg

Week 3

1.5 mg

Week 4

2 mg

Week 5

2.5 mg

Week 6

3 mg

Week 7

4 mg

In clinical trials of patients treated for RLS with doses up to 4 mg once daily, ropinirole was discontinued without a taper.

Renal Impairment

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole for patients with end-stage renal disease on hemodialysis is 0.25 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 3 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole in patients with severe renal impairment without regular dialysis has not been studied.
Methadone Hydrochloride...

Methadone Hydrochloride

2.1 Important General Information
• The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect. • A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists. • With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity. • Methadone has a narrow therapeutic index, especially when combined with other drugs.
2.2 Initial Dosing for Management of Pain

Methadone hydrochloride should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Consider the following important factors that differentiate methadone from other opioid analgesics:
• There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals. • The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours. • Steady-state plasma concentrations, and full analgesic effects, are not attained until at least 3 to 5 days on a dose, and may take longer in some patients.
Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with methadone hydrochloride [see Warnings and Precautions (5.2)].

Use of Methadone Hydrochloride as the First Opioid Analgesic: Initiate treatment with methadone hydrochloride with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to Methadone Hydrochloride: Discontinue all other around-the-clock opioid drugs when methadone hydrochloride therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.

Consider the following when using the information in Table 1:
• This is not a table of equinalgesic doses. • The conversion factors in this table are only for the conversion from another oral opioid analgesic to methadone hydrochloride. • The table cannot be used to convert from methadone hydrochloride to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. Table 1: Conversion Factors to Methadone Hydrochloride
Total Daily Baseline Oral

Morphine Equivalent Dose

Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose

< 100 mg

20% to 30%

100 to 300 mg

10% to 20%

300 to 600 mg

8% to 12%

600 mg to 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated methadone hydrochloride dose using Table 1:
• For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3). • For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate methadone hydrochloride strength(s) available.

Example conversion from a single opioid to methadone hydrochloride:
Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily) 50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine Step 2: Calculate the approximate equivalent dose of methadone hydrochloride based on the total daily dose of Morphine using Table 1. 100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg methadone hydrochloride daily Step 3: Calculate the approximate starting dose of methadone hydrochloride to be given every 12 hours. Round down, if necessary, to the appropriate methadone hydrochloride tablets strengths available. 15 mg daily / 2 = 7.5 mg methadone hydrochloride every 12 hours Then 7.5 mg is rounded down to 5 mg methadone hydrochloride every 12 hours
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to methadone hydrochloride.

Conversion from Parenteral Methadone to Methadone Hydrochloride: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).

2.3 Titration and Maintenance of Therapy for Pain

Individually titrate methadone hydrochloride to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving methadone hydrochloride to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T1/2) from 8 to 59 hours in different studies [see Clinical Pharmacology (12.3)]), titrate methadone slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life-threatening adverse reactions (e.g., CNS and respiratory depression).

Patients who experience breakthrough pain may require a dose increase of methadone hydrochloride, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the methadone hydrochloride dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of Methadone Hydrochloride for Pain

When a patient no longer requires therapy with methadone hydrochloride for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue methadone hydrochloride.

2.5 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the

treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of methadone hydrochloride will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of methadone hydrochloride if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of methadone hydrochloride on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

Short-term Detoxification: For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of methadone hydrochloride. Decrease the dose of methadone hydrochloride on a daily basis or at 2-day intervals, keeping the amount of methadone hydrochloride sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.

2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.

2.7 Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.8 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence (9.3)]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.9 Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.10 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
Fluarix Quadrivalent 20...

Fluarix Quadrivalent 20132014

The recommended adult initial dosage of Megestrol Acetate Oral Suspension USP is 800 mg/day (20 mL/day). Shake container well before using.

In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day were found to be clinically effective.

A plastic dosage cup with 5 mL, 10 mL, 15 mL and 20 mL markings is provided for convenience.
Dymista

Dymista

Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy

The recommended adult oral dosage of ondansetron is 24 mg given as three 8 mg tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥50 mg/m2. Multiday, single-dose administration of a 24 mg dosage has not been studied.

Pediatric Use

There is no experience with the use of a 24 mg dosage in pediatric patients.

Geriatric Use

The dosage recommendation is the same as for the general population.

Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy

The recommended adult oral dosage is one 8 mg ondansetron tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution, USP given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8 mg ondansetron tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution, USP should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.

Pediatric Use

For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4 mg ondansetron tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of Ondansetron Oral Solution, USP given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4 mg ondansetron tablet or 5 mL (1 teaspoonful equivalent to 4 mg of ondansetron) of Ondansetron Oral Solution, USP should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy.

Geriatric Use

The dosage is the same as for the general population.

Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen

The recommended oral dosage is one 8 mg ondansetron tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution, USP given 3 times a day.

For total body irradiation, one 8 mg ondansetron tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution, USP should be administered 1 to 2 hours before each fraction of radiotherapy administered each day.

For single high-dose fraction radiotherapy to the abdomen, one 8 mg ondansetron tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution, USP should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.

For daily fractionated radiotherapy to the abdomen, one 8 mg ondansetron tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of Ondansetron Oral Solution, USP should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.

Pediatric Use

There is no experience with the use of Ondansetron Oral Solution, USP in the prevention of radiation-induced nausea and vomiting in pediatric patients.

Geriatric Use

The dosage recommendation is the same as for the general population.

Postoperative Nausea and Vomiting

The recommended dosage is 16 mg given as two 8 mg ondansetron tablets or 20 mL (4 teaspoonfuls equivalent to 16 mg of ondansetron) of Ondansetron Oral Solution, USP 1 hour before induction of anesthesia.

Pediatric Use

There is no experience with the use of Ondansetron Oral Solution, USP in the prevention of postoperative nausea and vomiting in pediatric patients.

Geriatric Use

The dosage is the same as for the general population.

Dosage Adjustment for Patients With Impaired Renal Function

The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron.

Dosage Adjustment for Patients With Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a total daily dose of 8 mg should not be exceeded.
Beconase Aq

Beconase Aq

Selection of patients for treatment with codeine sulfate should be governed by the same principles that apply to the use of similar opioid analgesics. Physicians should individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management.

2.1 Individualization of Dosage

As with any opioid drug product, adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of codeine sulfate, attention should be given to the following:

• the total daily dose, potency and specific characteristics of the opioid the patient has been taking previously;

• the reliability of the relative potency estimate used to calculate the equivalent codeine sulfate dose needed;

• the patient’s degree of opioid tolerance;

• the general condition and medical status of the patient;

• concurrent medications;

• the type and severity of the patient’s pain;

• risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.

The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

Continual re-evaluation of the patient receiving codeine sulfate is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. During chronic therapy, especially for noncancer-related pain, the continued need for the use of opioid analgesics should be re-assessed as appropriate.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

2.2 Initiation of Therapy

The usual adult dosage for tablets is 15 mg to 60 mg repeated up to every four hours as needed for pain. The maximum 24 hour dose is 360 mg.

The initial dose should be titrated based upon the individual patient’s response to their initial dose of codeine. This dose can then be adjusted to an acceptable level of analgesia taking into account the improvement in pain intensity and the tolerability of the codeine by the patient.

It should be kept in mind, however, that tolerance to codeine sulfate can develop with continued use and that the incidence of untoward effects is dose-related. Adult doses of codeine higher than 60 mg fail to give commensurate relief of pain and are associated with an appreciably increased incidence of undesirable side effects.

2.3 Cessation of Therapy

When the patient no longer requires therapy with codeine sulfate, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.
Roxicet

Roxicet

Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. ROXICET is given orally.

ROXICET Tablets:

The usual adult dosage is one tablet every 6 hours as needed for pain. The total daily dose of acetaminophen should not exceed 4 grams. (Maximum daily dose is 12 tablets.)

ROXICET Oral Solution:

The usual adult dosage is 5 mL (one teaspoonful) every 6 hours as needed for pain. The total daily dose of acetaminophen should not exceed 4 grams. (Maximum daily dose is 12 teaspoonfuls or 60 mL.)

Cessation of Therapy

In patients treated with ROXICET for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.
Losartan Potassium

Losartan Potassium

Adult Hypertensive Patients

Losartan Potassium Tablets USP may be administered with other antihypertensive agents, and with or without food.

Dosing must be individualized. The usual starting dose of Losartan Potassium Tablets USP is 50 mg once daily, with 25 mg used in patients with possible depletion of intravascular volume (e.g., patients treated with diuretics) (see WARNINGS: Hypotension - Volume-Depleted Patients) and patients with a history of hepatic impairment (see PRECAUTIONS: General). Losartan Potassium Tablets USP can be administered once or twice daily with total daily doses ranging from 25 mg to 100 mg.

If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3 to 6 weeks (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Hypertension).

If blood pressure is not controlled by Losartan Potassium Tablets USP alone, a low dose of a diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Hypertension).

No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis.

Pediatric Hypertensive Patients Greater than or Equal to 6 Years of Age

The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total) administered as a tablet or a suspension (see Preparation of Suspension). Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations and Pharmacodynamics and Clinical Effects, and WARNINGS: Hypotension - Volume-Depleted Patients.)

Losartan Potassium Tablets USP are not recommended in pediatric patients less than 6 years of age or in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m2 (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Pharmacodynamics and Clinical Effects, and PRECAUTIONS).

Preparation of Suspension (for 200 mL of a 2.5 mg/mL suspension)

Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg losartan potassium tablets. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately prepare a 50/50 volumetric mixture of Ora-Plus™1 and Ora-Sweet SF™1. Add 190 mL of the 50/50 OraPlus™/Ora-Sweet SF™ mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to disperse the ingredients. The suspension should be refrigerated at 2° to 8°C (36° to 46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

1Ora-Plus™ and Ora-Sweet™ are the trademarks of Paddock Laboratories, Inc..

Hypertensive Patients with Left Ventricular Hypertrophy

The usual starting dose is 50 mg of Losartan Potassium Tablets USP once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of Losartan Potassium Tablets USP should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Reduction in the Risk of Stroke).

Nephropathy in Type 2 Diabetic Patients

The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Nephropathy in Type 2 Diabetic Patients). Losartan Potassium Tablets USP may be administered with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones and glucosidase inhibitors).
Levetiracetam Solution

Levetiracetam Solution

2.1 Important Administration Instructions

Levetiracetam Oral Solution, USP is given orally with or without food. The Levetiracetam Oral Solution, USP dosing regimen depends on the indication, age group, dosage form (tablets or oral solution), and renal function.

Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg. Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg.

When using the oral solution in pediatric patients, dosing is weight-based (mg per kg) using a calibrated measuring device (not a household teaspoon or tablespoon)

2.2 Partial Onset Seizures

Adults 16 Years And Older

In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose [see Clinical Studies (14.1)], a consistent increase in response with increased dose has not been shown.

Treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greater than 3000 mg/day have been used in open-label studies for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

Pediatric Patients

Dosing information in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.’s levetiracetam tablets and oral solution. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

4 Years To < 16 Years

Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical efficacy trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day.

Levetiracetam Oral Solution Weight-Based Dosing Calculation For Pediatric Patients

The following calculation should be used to determine the appropriate daily dose of oral solution for pediatric patients:

Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg)

100 mg/mL

2.3 Myoclonic Seizures In Patients 12 Years of Age and Older With Juvenile Myoclonic Epilepsy

Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.

2.4 Primary Generalized Tonic-Clonic Seizures

Adults 16 Years And Older

Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.

Pediatric Patients Ages 6 To <16 Years

Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied. Patients with body weight ≤20 kg should be dosed with oral solution. Patients with body weight above 20 kg can be dosed with either tablets or oral solution [see Dosage and Administration (2.1)]. Only whole tablets should be administered.

2.5 Adult Patients With Impaired Renal Function

Levetiracetam Oral Solution, USP dosing must be individualized according to the patient’s renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

CLcr =

[140-age (years)] x weight (kg)

(x 0.85 for female patients)

72 x serum creatinine (mg/dL)

CLcr (mL/min/1.73m2)= CLcr (mL/min) x BSA subject (m2)

Then CLcr is adjusted for body surface area (BSA) as follows:

CLcr (mL/min/1.73m2 )=

CLcr (mL/min)

x 1.73
BSA subject (m 2) Then CLcr is adjusted for body surface area (BSA) as follows:
CLcr (mL/min/1.73m2)= CLcr (mL/min) x BSA subject (m2)
Table 1: Dosing Adjustment Regimen for Adult Patients With Impaired Renal Function * Following dialysis, a 250 to 500 mg supplemental dose is recommended.
Group

Creatinine Clearance (mL/min/1.73m2)

Dosage (mg)

Frequency

Normal

> 80

500 to 1,500

Every 12 hours

Mild

50 - 80

500 to 1,000

Every 12 hours

Moderate

30 - 50

250 to 750

Every 12 hours

Severe

< 30

250 to 500

Every 12 hours

ESRD patients using dialysis

----

500 to 1,000

Every 24 hours*
Losartan Potassium And ...

Losartan Potassium And Hydrochlorothiazide

Hypertension

Dosing must be individualized. The usual starting dose of losartan is 50 mg once daily, with 25 mg recommended for patients with intravascular volume depletion (e.g., patients treated with diuretics) (see WARNINGS: Hypotension - Volume-Depleted Patients) and patients with a history of hepatic impairment (see WARNINGS: Impaired Hepatic Function). Losartan can be administered once or twice daily at total daily doses of 25 to 100 mg. If the antihypertensive effect measured at trough using once‑a‑day dosing is inadequate, a twice‑a‑day regimen at the same total daily dose or an increase in dose may give a more satisfactory response.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily and can be given at doses of 12.5 to 25 mg as losartan potassium and hydrochlorothiazide.

To minimize dose‑independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

The side effects (see WARNINGS) of losartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose‑dependent (primarily hypokalemia) and dose‑independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of losartan and hydrochlorothiazide will be associated with both sets of dose‑independent side effects.

Replacement Therapy

The combination may be substituted for the titrated components.

Dose Titration by Clinical Effect

A patient whose blood pressure is not adequately controlled with losartan monotherapy (see above) or hydrochlorothiazide alone, may be switched to losartan potassium and hydrochlorothiazide 50‑12.5 (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide 50‑12.5 once daily or one tablet of losartan potassium and hydrochlorothiazide 100‑25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily. A patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy (see above) may be switched to losartan potassium and hydrochlorothiazide 100-12.5 once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide 50-12.5 once daily or one tablet of losartan potassium and hydrochlorothiazide 100-25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily.

A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen, may be switched to losartan potassium and hydrochlorothiazide 50‑12.5 (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. The clinical response to losartan potassium and hydrochlorothiazide 50‑12.5 should be subsequently evaluated, and if blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide 50‑12.5 once daily or one tablet of losartan potassium and hydrochlorothiazide 100‑25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily.

The usual dose of losartan potassium and hydrochlorothiazide is one tablet of losartan potassium and hydrochlorothiazide 50-12.5 once daily. More than two tablets of losartan potassium and hydrochlorothiazide 50‑12.5 once daily or more than one tablet of losartan potassium and hydrochlorothiazide 100‑25 once daily is not recommended. The maximal antihypertensive effect is attained about 3 weeks after initiation of therapy.

Use in Patients with Renal Impairment

The usual regimens of therapy with losartan potassium and hydrochlorothiazide may be followed as long as the patient's creatinine clearance is greater than 30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so losartan potassium and hydrochlorothiazide is not recommended.

Patients with Hepatic Impairment

Losartan potassium and hydrochlorothiazide is not recommended for titration in patients with hepatic impairment (see WARNINGS: Impaired Hepatic Function) because the appropriate 25 mg starting dose of losartan cannot be given.

Severe Hypertension

The starting dose of losartan potassium and hydrochlorothiazide for initial treatment of severe hypertension is one tablet of losartan potassium and hydrochlorothiazide 50‑12.5 once daily (see CLINICALPHARMACOLOGY:Pharmacodynamics and Clinical Effects). For patients who do not respond adequately to losartan potassium and hydrochlorothiazide 50‑12.5 after 2 to 4 weeks of therapy, the dosage may be increased to one tablet of losartan potassium and hydrochlorothiazide 100‑25 once daily. The maximum dose is one tablet of losartan potassium and hydrochlorothiazide 100‑25 once daily. Losartan potassium and hydrochlorothiazide is not recommended as initial therapy in patients with hepatic impairment (see WARNINGS: Impaired Hepatic Function) because the appropriate 25 mg starting dose of losartan cannot be given. It is also not recommended for use as initial therapy in patients with intravascular volume depletion (e.g., patients treated with diuretics, see WARNINGS: Hypotension - Volume-Depleted Patients).

Hypertensive Patients with Left Ventricular Hypertrophy

Treatment should be initiated with losartan potassium 50 mg once daily. Hydrochlorothiazide 12.5 mg should be added or losartan potassium and hydrochlorothiazide 50-12.5 substituted if the blood pressure reduction is inadequate. If additional blood pressure reduction is needed, losartan potassium 100 mg and hydrochlorothiazide 12.5 mg or losartan potassium and hydrochlorothiazide 100-12.5 may be substituted, followed by losartan potassium 100 mg and hydrochlorothiazide 25 mg or losartan potassium and hydrochlorothiazide 100-25. For further blood pressure reduction other antihypertensives should be added (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: LosartanPotassium: Reduction in the Risk of Stroke).

Losartan potassium and hydrochlorothiazide may be administered with other antihypertensive agents.

Losartan potassium and hydrochlorothiazide may be administered with or without food.
Protriptyline Hydrochlo...

Protriptyline Hydrochloride

Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.

Usual Adult Dosage

Fifteen to 40 mg a day divided into 3 or 4 doses. If necessary, dosage may be increased to 60 mg a day. Dosages above this amount are not recommended. Increases should be made in the morning dose.

Adolescent and Elderly Patients

In general, lower dosages are recommended for these patients. Five mg 3 times a day may be given initially, and increased gradually if necessary. In elderly patients, the cardiovascular system must be monitored closely if the daily dose exceeds 20 mg.

When satisfactory improvement has been reached, dosage should be reduced to the smallest amount that will maintain relief of symptoms.

Minor adverse reactions require reduction in dosage. Major adverse reactions or evidence of hypersensitivity require prompt discontinuation of the drug.

The safety and effectiveness of protriptyline in pediatric patients have not been established.
Eszopiclone

Eszopiclone

Use the lowest effective dose for the patient.

2.1 Dosage in Adults

The recommended starting dose is 1 mg. Dosing can be raised to 2 mg or 3 mg if clinically indicated. In some patients, the higher morning blood levels of eszopiclone following use of the 2 mg or 3 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see Warnings and Precautions (5.1)]. The total dose of eszopiclone should not exceed 3 mg, once daily immediately before bedtime [see Warnings and Precautions (5.6)].

2.2 Geriatric or Debilitated Patients

Thetotal doseof eszopiclone should not exceed 2 mgin elderly ordebilitated patients.

2.3 Patients with Severe Hepatic Impairment, or Taking Potent CYP3A4 Inhibitors

In patients with severe hepatic impairment, or in patients coadministered eszopiclone with potent CYP3A4 inhibitors, the total dose of eszopiclone should not exceed 2 mg [see Warning and Precautions (5.7)].

2.4 Use with CNS Depressants

Dosage adjustments may be necessary when eszopiclone is combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].

2.5 Administration with Food

Taking eszopiclone with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of eszopiclone on sleep latency [see Clinical Pharmacology (12.3)].
Meloxicam Suspension

Meloxicam Suspension

2.1 General Instructions

Carefully consider the potential benefits and risks of meloxicam and other treatment options before deciding to use meloxicam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.4)].

After observing the response to initial therapy with meloxicam, adjust the dose to suit an individual patient's needs.

In adults, the maximum recommended daily oral dose of meloxicam is 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended [see Warnings and Precautions (5.6), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Meloxicam oral suspension 7.5 mg/5 mL or 15 mg/10 mL may be substituted for meloxicam tablets 7.5 mg or 15 mg, respectively.

Shake the oral suspension gently before using.

Meloxicam may be taken without regard to timing of meals.

2.2 Osteoarthritis

For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.

2.3 Rheumatoid Arthritis

For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.

2.4 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course

To improve dosing accuracy in smaller weight children, the use of the meloxicam oral suspension is recommended. meloxicam oral suspension is available in the strength of 7.5 mg/5 mL. For the treatment of juvenile rheumatoid arthritis, the recommended oral dose of meloxicam is 0.125 mg/kg once daily up to a maximum of 7.5 mg. There was no additional benefit demonstrated by increasing the dose above 0.125 mg/kg once daily in these clinical trials.

Juvenile Rheumatoid Arthritis dosing using the oral suspension should be individualized based on the weight of the child:

0.125 mg/kg

Weight

Dose (1.5 mg/mL)

Delivered dose

12 kg (26 lb)

1.0 mL

1.5 mg

24 kg (54 lb)

2.0 mL

3.0 mg

36 kg (80 lb)

3.0 mL

4.5 mg

48 kg (106 lb)

4.0 mL

6.0 mg

≥60 kg (132 lb)

5.0 mL

7.5 mg
Citalopram Solution

Citalopram Solution

Citalopram should be administered once daily, in the morning or evening, with or without food.

Initial Treatment

Citalopram should be administered at an initial dose of 20 mg once daily, with an increase to a maximum dose of 40 mg/day at an interval of no less than one week. Doses above 40 mg/day are not recommended due to the risk of QT prolongation. Additionally, the only study pertinent to dose response for effectiveness did not demonstrate an advantage for the 60 mg/day dose over the 40 mg/day dose.

Special Populations

20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers or those patients taking cimetidine or another CYP2C19 inhibitor (see WARNINGS).

No dosage adjustment is necessary for patients with mild or moderate renal impairment. Citalopram should be used with caution in patients with severe renal impairment.

Treatment of Pregnant Women During the Third Trimester

Neonates exposed to citalopram and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Maintenance Treatment

It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of citalopram in two studies has shown that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment (32 weeks total). In one study, patients were assigned randomly to placebo or to the same dose of citalopram (20 to 60 mg/day) during maintenance treatment as they had received during the acute stabilization phase, while in the other study, patients were assigned randomly to continuation of citalopram 20 or 40 mg/day, or placebo, for maintenance treatment. In the latter study, the rates of relapse to depression were similar for the two dose groups (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is not known whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. If adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered.

Discontinuation of Treatment with Citalopram

Symptoms associated with discontinuation of citalopram and other SSRIs and SNRIs have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Switching Patients To or From a Monoamine Oxidase lnhibitor(MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with citalopram. Conversely, at least 14 days should be allowed after stopping citalopram before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).

Use of Citalopramwith Other MAOIs, Such as Linezolid or Methylene Blue

Do not start citalopram in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).

In some cases, a patient already receiving citalopram therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, citalopram should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with citalopram may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with citalopram is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Sodium Polystyrene Sulf...

Sodium Polystyrene Sulfonate Suspension

The average daily adult dose is 15 g (60 mL) to 60 g (240 mL) of suspension. This is best provided by administering 15 g (60 mL) of sodium polystyrene sulfonate suspension one to four times daily. Each 60 mL of sodium polystyrene sulfonate suspension contains 1575 mg (68.5 mEq) per 60 mL which is equivalent to 1500 mg on the anhydrous basis of sodium. Since the in-vivo efficiency of sodium-potassium exchange resins is approximately 33%, about one-third of the resin’s actual sodium content is being delivered to the body.

In smaller children and infants, lower doses should be employed by using as a guide a rate of 1 mEq of potassium per gram of resin as the basis for calculation.

Sodium polystyrene sulfonate suspension may be introduced into the stomach through a plastic tube and, if desired, given with a diet appropriate for a patient in renal failure.

Sodium polystyrene sulfonate suspension may also be given, although with less effective results, as an enema consisting (for adults) of 30 g (120 mL) to 50 g (200 mL) every six hours. The enema should be retained as long as possible and followed by a cleansing enema.

After an initial cleansing enema, a soft, large size (French 28) rubber tube is inserted into the rectum for a distance of about 20 cm, with the tip well into the sigmoid colon, and taped in place. The suspension is introduced at body temperature by gravity. The suspension is flushed with 50 or 100 mL of fluid, following which the tube is clamped and left in place. If back leakage occurs, the hips are elevated on pillows or a knee-chest position is taken temporarily. The suspension is kept in the sigmoid colon for several hours, if possible. Then, the colon is irrigated with a sodium-free cleansing enema at body temperature in order to remove the resin. Two quarts of flushing solution may be necessary. The returns are drained constantly through a Y tube connection. While the use of sorbitol is not recommended, particular attention should be paid to this cleansing enema if sorbitol has been used.

The intensity and duration of therapy depend upon the severity and resistance of hyperkalemia.

Sodium polystyrene sulfonate suspension should not be heated for to do so may alter the exchange properties of the resin.
Exemestane

Exemestane

2.1 Recommended Dose

The recommended dose of exemestane tablets in early and advanced breast cancer is one 25 mg tablet once daily after a meal.
• adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy . • the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.
2.2 Dose Modifications

Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure. For patients receiving exemestane with a strong CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of exemestane is 50 mg once daily after a meal [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Klor-con

Klor-con

Take 1 to 16 tablets per day, in divided doses, preferably 1 to 2 hours after meals, or as directed by a physician.

Questions or Comments?

Call 1-800-962-8364. You may also report serious side effects to this phone number.

Roxane Laboratories, Inc.Columbus, Ohio 43216

Revised July 2015 © RLI, 2015
Quetiapine Fumarate

Quetiapine Fumarate

2.1 Important Administration Instructions

Quetiapine Fumarate Tablets can be taken with or without food.

2.2 Recommended Dosing

The recommended initial dose, titration, dose range and maximum quetiapine dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies (14.1 and 14.2)].
Table 1: Recommended Dosing for Quetiapine Fumarate Tablets * N/A Not Applicable
Indication

Initial Dose and Titration

Recommended Dose

Maximum Dose

Schizophrenia-Adults

Day 1: 25 mg twice daily.

Increase in increments of 25 mg to 50 mg divided two or three times on Days 2 and 3 to range of 300 to 400 mg by Day 4.

Further adjustments can be made in increments of 25 to 50 mg twice a day, in intervals of not less than 2 days.

150 to 750 mg/day

750 mg/day

Schizophrenia-Adolescents (13 to 17 years)

Day 1: 25 mg twice daily.Day 2: Twice daily dosing totaling 100 mg.Day 3: Twice daily dosing totaling 200 mg. Day 4: Twice daily dosing totaling 300 mg. Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 800 mg/day. Based on response and tolerability, may be administered three times daily.

400 to 800 mg/day

800 mg/day

Schizophrenia-Maintenance

N/A*

400 to 800 mg/day

800 mg/day

Bipolar Mania-Adults Monotherapy or as an adjunct to lithium or divalproex

Day 1: Twice daily dosing totaling 100 mg.Day 2: Twice daily dosing totaling 200 mg.Day 3: Twice daily dosing totaling 300 mg. Day 4: Twice daily dosing totaling 400 mg. Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

400 to 800 mg/day

800 mg/day

Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy

Day 1: 25 mg twice daily.Day 2: Twice daily dosing totaling 100 mg.Day 3: Twice daily dosing totaling 200 mg. Day 4: Twice daily dosing totaling 300 mg. Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 600 mg/day. Based on response and tolerability, may be administered three times daily.

400 to 600 mg/day

600 mg/day

Bipolar Depression-Adults

Administer once daily at bedtime. Day 1: 50 mg Day 2: 100 mg Day 3: 200 mg Day 4: 300 mg

300 mg/day

300 mg/day

Bipolar I Disorder Maintenance Therapy-Adults

Adults Administer twice daily totaling 400 to 800 mg/day as adjunct to lithium or divalproex. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized.

400 to 800 mg/day

800 mg/day

Maintenance Treatment for Schizophrenia and Bipolar I Disorder

Maintenance Treatment:Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].

2.3 Dose Modifications in Elderly Patients

Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.

Elderly patients should be started on quetiapine fumarate 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.

2.4 Dose Modifications in Hepatically Impaired Patients

Patients with hepatic impairment should be started on 25 mg/day. The dose should be increased daily in increments of 25 mg/day to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.

2.5 Dose Modifications When Used with CYP3A4 Inhibitors

Quetiapine fumarate dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g. ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of quetiapine fumarate should be increased by 6 fold [see Clinical Pharmacology (12.3) and DrugInteractions 7.1)].

2.6 Dose Modifications When Used with CYP3A4 Inducers

Quetiapine fumarate dose should be increased up to 5 fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7 to 14 days) of a potent CYP3A4 inducer (e.g. phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort, etc.). The dose should be titrated based on the clinical response and tolerability of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate should be reduced to the original level within 7 to 14 days [see Clinical Pharmacology (12.3)andDrug Interactions (7.1)].

2.7 Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off quetiapine fumarate for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine fumarate for less than one week, gradual dose escalation may not be required and the maintenance dose may be reinitiated.

2.8 Switching from Antipsychotics

There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine fumarate, or concerning concomitant administration with antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine fumarate therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.
Childrens Mucus Relief ...

Childrens Mucus Relief Multi Symptom Cold

The usual starting dose of telmisartan is 40 mg once a day; blood pressure response is dose related over the range of 20-80 mg. Patients with depletion of intravascular volume should have the condition corrected or telmisartan tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume-Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS).

Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg once daily.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. The side effects (see WARNINGS) of telmisartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of telmisartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

Telmisartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.

Telmisartan and hydrochlorothiazide tablets may be administered with or without food.

Replacement Therapy

The combination may be substituted for the titrated components.

Dose Titration by Clinical Effect

Telmisartan and hydrochlorothiazide tablets are available as tablets containing either telmisartan 40 mg and hydrochlorothiazide 12.5 mg, or telmisartan 80 mg and hydrochlorothiazide 12.5 mg or 25 mg. A patient whose blood pressure is not adequately controlled with telmisartan monotherapy 80 mg (see above) may be switched to telmisartan and hydrochlorothiazide tablets, telmisartan 80 mg/hydrochlorothiazide 12.5 mg once daily, and finally titrated up to 160/25 mg, if necessary.

A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide may be switched to telmisartan 80 mg/hydrochlorothiazide 12.5 mg or telmisartan 80 mg/hydrochlorothiazide 25 mg tablets once daily. The clinical response to telmisartan and hydrochlorothiazide tablets should be subsequently evaluated and if blood pressure remains uncontrolled after 2-4 weeks of therapy, the dose may be titrated up to 160/25 mg, if necessary. Those patients controlled by 25 mg hydrochlorothiazide but who experience hypokalemia with this regimen, may be switched to telmisartan 80 mg/hydrochlorothiazide 12.5 mg tablets once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response.

Patients with Renal Impairment

The usual regimens of therapy with telmisartan and hydrochlorothiazide tablets may be followed as long as the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so telmisartan and hydrochlorothiazide tablets are not recommended.

Patients with Hepatic Impairment

Telmisartan and hydrochlorothiazide tablets are not recommended for patients with severe hepatic impairment. Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision using the 40/12.5 mg combination (see PRECAUTIONS).
Irbesartan

Irbesartan

Irbesartan tablets may be administered with other antihypertensive agents and with or without food.

Hypertension

The recommended initial dose of irbesartan tablets is 150 mg once daily. Patients requiring further reduction in blood pressure should be titrated to 300 mg once daily.

A low dose of a diuretic may be added, if blood pressure is not controlled by irbesartan tablets alone. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY: Clinical Studies). Patients not adequately treated by the maximum dose of 300 mg once daily are unlikely to derive additional benefit from a higher dose or twice-daily dosing.

No dosage adjustment is necessary in elderly patients, or in patients with hepatic impairment or mild to severe renal impairment.

Nephropathy in Type 2 Diabetic Patients

The recommended target maintenance dose is 300 mg once daily. There are no data on the clinical effects of lower doses of irbesartan tablets on diabetic nephropathy (see CLINICAL PHARMACOLOGY:Clinical Studies).

Volume- and Salt-Depleted Patients

A lower initial dose of irbesartan tablets (75 mg) are recommended in patients with depletion of intravascular volume or salt (e.g., patients treated vigorously with diuretics or on hemodialysis) (see WARNINGS: Hypotension in Volume- or Salt-depleted Patients).
Irbesartan And Hydrochl...

Irbesartan And Hydrochlorothiazide

2.1 General Considerations

The side effects of irbesartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter [see Adverse Reactions (6)].

Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose.

Irbesartan and hydrochlorothiazide tablets may be administered with or without food.

Irbesartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.

Renal Impairment: The usual regimens of therapy with irbesartan and hydrochlorothiazide tablets may be followed as long as the patient's creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so irbesartan and hydrochlorothiazide tablets are not recommended.

Hepatic Impairment: No dosage adjustment is necessary in patients with hepatic impairment.

2.2 Add-On Therapy

In patients not controlled on monotherapy with irbesartan or hydrochlorothiazide, the recommended doses of irbesartan and hydrochlorothiazide tablets, in order of increasing mean effect, are (irbesartan and hydrochlorothiazide) 150/12.5 mg, 300/12.5 mg, and 300/25 mg. The largest incremental effect will likely be in the transition from monotherapy to 150/12.5 mg [see Clinical Studies (14.2)].

2.3 Replacement Therapy

Irbesartan and hydrochlorothiazide tablets may be substituted for the titrated components.

2.4 Initial Therapy

The usual starting dose is irbesartan and hydrochlorothiazide tablets 150/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of 300/25 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.2)]. Irbesartan and hydrochlorothiazide tablets are not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2)].
Risperidone Solution

Risperidone Solution

Table 1: Recommended Daily Dosage by Indication
Initial Dose

Titration (Increments)

Target Dose

Effective Dose Range

Schizophrenia: Adults (2.1)

2 mg

1 to 2 mg

4 to 8 mg

4 to 16 mg

Schizophrenia: Adolescents (2.2)

0.5 mg

0.5 to 1 mg

3 mg

1 to 6 mg

Bipolar Mania: Adults (2.2)

2 to 3 mg

1 mg

1 to 6 mg

1 to 6 mg

Bipolar Mania: Children and Adolescents (2.2)

0.5 mg

0.5 to 1 mg

1 to 2.5 mg

1 to 6 mg

Irritability in Autistic Disorder (2.3)

0.25 mg Can increase to 0.5 mg by Day 4: (body weight less than 20 kg)

0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg)

After Day 4, at intervals of > 2 weeks: 0.25 mg

(body weight less than 20 kg)

0.5 mg (body weight greater than or equal to 20 kg)

0.5 mg (body weight less than 20 kg)

1 mg (body weight greater than or equal to 20 kg)

0.5 to 3 mg

Severe Renal and Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice-daily. May increase to dosages above 1.5 mg twice-daily at intervals of at one week or longer.

2.1 Schizophrenia

Adults

Usual Initial Dose: Risperidone oral solution can be administered once or twice-daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per. However, doses above 6 mg per day for twice-daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg per day has not been evaluated in clinical trials [see Clinical Studies (14.1)].

Adolescents

The initial dose is 0.5 mg once-daily, administered as a single daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice-daily.

Maintenance Therapy

While it is unknown how long a patient with schizophrenia should remain on risperidone, the effectiveness of risperidone2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Both adult and adolescent patients who respond acutely should generally be maintained on their effective dose beyond the acute episode. Patients should be periodically reassessed to determine the need for maintenance treatment.

Reinitiation of Treatment in Patients Previously Discontinued: Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone, the initial titration schedule should be followed.

Switching From Other Antipsychotics: There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone, or treating patients with concomitant antipsychotics.

2.2 Bipolar Mania

Usual Dose

Adults: The initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1 mg to 6 mg per day [see ClinicalStudies(14.2,14.3)]. Risperidone doses higher than 6 mg per day were not studied.

Pediatrics: The initial dose is 0.5 mg once-daily, administered as a single daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.

Patients experiencing persistent somnolence may benefit from administering half the daily dose twice-daily.

Maintenance Therapy: There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

2.3 Irritability Associated with Autistic Disorder - Pediatrics (Children and Adolescents)

The dosage of risperidone should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone can be administered once daily, or half the total daily dose can be administered twice-daily.

For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg.

Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice-daily, or a reduction of the dose.

2.4 Dosing in Patients with Severe Renal or Hepatic Impairment

For patients with severe renal impairment (CLcr < 30 mL/min) or hepatic impairment (10 to 15 points on Child Pugh System), the initial starting dose is 0.5 mg twice daily. The dose may be increased in increments of 0.5 mg or less, administered twice daily. For doses above 1.5 mg twice daily, increase in intervals of one week or greater [see Use in Specific Populations(8.6and8.7)].

2.5 Dose Adjustments for Specific Drug Interactions

When risperidone is coadministered with enzyme inducers (e.g., carbamazepine), the dose of risperidone should be increased up to double the patient’s usual dose. It may be necessary to decrease the risperidone dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7.1)]. Similar effect may be expected with coadministration of risperidone with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).

When fluoxetine or paroxetine is coadministered with risperidone, the dose of risperidone should be reduced. The risperidone dose should not exceed 8 mg per day in adults when coadministered with these drugs. When initiating therapy, risperidoneshould be titrated slowly. It may be necessary to increase the risperidone dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued [see Drug Interactions (7.1)].

2.6 Administration of Risperidone Oral Solution

Risperidone Oral Solution can be administered directly from the calibrated pipette, or can be mixed with a beverage prior to administration. Risperidone Oral Solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea.

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