Cardinal Health

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General Dosing Considerations: It is particularly important to administer Bupropion Hydrochloride Extended-Release Tablets (XL) in a manner most likely to minimize the risk of seizure (see WARNINGS). Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped. Bupropion hydrochloride extended-release tablets (XL) should be swallowed whole and not crushed, divided, or chewed, as this may lead to an increased risk of adverse effects including seizures. Bupropion hydrochloride extended-release tablets (XL) may be taken without regard to meals.

Major Depressive Disorder: Initial Treatment:The usual adult target dose for bupropion hydrochloride extended-release tablets (XL) is 300 mg/day, given once daily in the morning. Dosing with bupropion hydrochloride extended-release tablets (XL) should begin at 150 mg/day given as a single daily dose in the morning. If the 150 mg initial dose is adequately tolerated, an increase to the 300 mg/day target dose, given as once daily, may be made as early as day 4 of dosing. There should be an interval of at least 24 hours between successive doses.

Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full antidepressant effect of bupropion hydrochloride extended-release tablets (XL) may not be evident until 4 weeks of treatment or longer. An increase in dosage to the maximum of 450 mg/day, given as a single dose, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day.

Maintenance Treatment: It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. It is unknown whether or not the dose of bupropion hydrochloride extended-release tablets (XL) needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

Seasonal Affective Disorder: For the prevention of seasonal major depressive episodes associated with seasonal affective disorder, bupropion hydrochloride extended-release tablets (XL) should generally be initiated in the autumn prior to the onset of depressive symptoms. Treatment should continue through the winter season and should be tapered and discontinued in early spring. The timing of initiation and duration of treatment should be individualized based on the patient's historical pattern of seasonal major depressive episodes. Patients whose seasonal depressive episodes are infrequent or not associated with significant impairment should not generally be treated prophylactically.

Dosing with bupropion hydrochloride extended-release tablets (XL) should begin at 150 mg/day given as a single daily dose in the morning. If the 150 mg initial dose is adequately tolerated, the dose of bupropion hydrochloride extended-release tablets (XL) should be increased to the 300 mg/day dose after 1 week. If the 300 mg dose is not adequately tolerated, the dose can be reduced to 150 mg/day. The usual adult target dose for bupropion hydrochloride extended-release tablets (XL) is 300 mg/day, given once daily in the morning.

For patients taking 300 mg/day during the autumn-winter season, the dose should be tapered to 150 mg/day for 2 weeks prior to discontinuation.

Doses of bupropion hydrochloride extended-release tablets (XL) above 300 mg/day have not been studied for the prevention of seasonal major depressive episodes.

Switching Patients from WELLBUTRIN® Tablets (bupropion hydrochloride tablets) or from WELLBUTRIN SR® Sustained-Release Tablets (bupropion hydrochloride extended-release tablets (SR)): When switching patients from WELLBUTRIN® Tablets (bupropion hydrochloride tablets) to bupropion hydrochloride extended-release tablets (XL), or from WELLBUTRIN SR® Sustained-Release Tablets (bupropion hydrochloride extended-release tablets (SR)) to bupropion hydrochloride extended-release tablets (XL), give the same total daily dose when possible. Patients who are currently being treated with WELLBUTRIN® Tablets (bupropion hydrochloride tablets) at 300 mg/day (for example, 100 mg 3 times a day) may be switched to bupropion hydrochloride extended-release tablets (XL) 300 mg once daily. Patients who are currently being treated with WELLBUTRIN SR® Sustained-Release Tablets (bupropion hydrochloride extended-release tablets (SR)) at 300 mg/day (for example, 150 mg twice daily) may be switched to bupropion hydrochloride extended-release tablets (XL) 300 mg once daily.

Dosage Adjustment for Patients With Impaired Hepatic Function:

Bupropion hydrochloride extended-release tablets (XL) should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 150 mg every other day in these patients. Bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS).

Dosage Adjustment for Patients With Impaired Renal Function: Bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

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adults and children 6 years and over

one 10 mg tablet once daily; do not take more than one 10 mg tablet in 24 hours. A 5 mg product may be appropriate for less severe symptoms.

adults 65 years and over

ask a doctor

children under 6 years of age

ask a doctor

consumers with liver or kidney disease

ask a doctor

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Metoprolol succinate extended-release is an extended release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate release metoprolol to metoprolol succinate extended-release tablets, use the same total daily dose of metoprolol succinate extended-release tablets. Individualize the dosage of metoprolol succinate extended-release tablets. Titration may be needed in some patients. Metoprolol succinate extended-release tablets are scored and can be divided; however, do not crush or chew the whole or half tablet.

2.1 Hypertension

Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. Dosages above 400 mg per day have not been studied. Pediatric Hypertensive Patients ≥ 6 Years of age: Due to AstraZeneca's marketing exclusivity rights, this generic drug product is not labeled for pediatric use. Dosage and administration information in pediatric patients 6 years and older is approved for AstraZeneca's metoprolol succinate extended-release tablets.

2.2 Angina Pectoris

Individualize the dosage of metoprolol succinate extended-release tablets. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 - 2 weeks [see Warnings and Precautions (5)].

2.3 Heart Failure

Dosage must be individualized and closely monitored during up-titration. Prior to initiation of metoprolol succinate extended-release tablets, stabilize the dose of other heart failure drug therapy. The recommended starting dose of metoprolol succinate extended-release tablet is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of metoprolol succinate extended-release tablets. Initial difficulty with titration should not preclude later attempts to introduce metoprolol succinate extended-release tablets. If patients experience symptomatic bradycardia, reduce the dose of metoprolol succinate extended-release tablets. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of metoprolol succinate extended-release tablets or temporarily discontinuing it. The dose of metoprolol succinate extended-release tablets should not be increased until symptoms of worsening heart failure have been stabilized.

2.1 Hypertension

Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. Dosages above 400 mg per day have not been studied. Pediatric Hypertensive Patients ≥ 6 Years of age: Due to AstraZeneca's marketing exclusivity rights, this generic drug product is not labeled for pediatric use. Dosage and administration information in pediatric patients 6 years and older is approved for AstraZeneca's metoprolol succinate extended-release tablets.

2.2 Angina Pectoris

Individualize the dosage of metoprolol succinate extended-release tablets. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 - 2 weeks [see Warnings and Precautions (5)].

2.3 Heart Failure

Dosage must be individualized and closely monitored during up-titration. Prior to initiation of metoprolol succinate extended-release tablets, stabilize the dose of other heart failure drug therapy. The recommended starting dose of metoprolol succinate extended-release tablet is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of metoprolol succinate extended-release tablets. Initial difficulty with titration should not preclude later attempts to introduce metoprolol succinate extended-release tablets. If patients experience symptomatic bradycardia, reduce the dose of metoprolol succinate extended-release tablets. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of metoprolol succinate extended-release tablets or temporarily discontinuing it. The dose of metoprolol succinate extended-release tablets should not be increased until symptoms of worsening heart failure have been stabilized.

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2.1 General Dosing Information

The recommended dose of ZETIA is 10 mg once daily.

ZETIA can be administered with or without food.

2.2 Concomitant Lipid-Lowering Therapy

ZETIA may be administered with a statin (in patients with primary hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of ZETIA may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications.

2.3 Coadministration with Bile Acid Sequestrants

Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.4)].

2.4 Patients with Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.4)].

2.5 Patients with Renal Impairment

No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology (12.3)]. When given with simvastatin in patients with moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m2), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring [see Use in Specific Populations (8.6)].

2.6 Geriatric Patients

No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology (12.3)].

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Valproic Acid Syrup (Valproic Acid Oral Solution, USP) is administered orally. Valproic acid is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the valproic acid dosage is titrated upward, concentrations of phenobarbital, carbamazepine, and/or phenytoin may be affected (see PRECAUTIONS - Drug Interactions).

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Valproic acid has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of valproic acid therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Valproic acid may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to divalproex sodium tablets, no adjustment of carbamazepine or phenytoin dosage was needed (see Clinical Trials). However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs (see Drug Interactions), periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy (see PRECAUTIONS - Drug Interactions).

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations (see CLINICAL PHARMACOLOGY).

As the valproic acid dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected (see PRECAUTIONS).

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

The following table is a guide for the initial daily dose of Valproic Acid Syrup (Valproic Acid Oral Solution, USP) (15 mg/kg/day):

Weight Total Daily Dose (mg) Teaspoonfuls of Syrup (Kg) (Lb) Dose 1 Dose 2 Dose 3

10-24.9

22-54.9

250

0

0

1

25-39.9

55-87.9

500

1

0

1

40-59.9

88-131.9

750

1

1

1

60-74.9

132-164.9

1,000

1

1

2

75-89.9

165-197.9

1,250

2

1

2

General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response (see WARNINGS).

Dose-Related Adverse Events

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of 110 mcg/mL (females) or 135 mcg/mL (males) (see PRECAUTIONS). The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level.

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The recommended initial dose is 15 mg daily (7.5 mg b.i.d.). To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed. The maximum daily dosage should not exceed 60 mg per day. In clinical trials allowing dose titration, divided doses of 20 mg to 30 mg per day were commonly employed.

The bioavailability of buspirone is increased when given with food as compared to the fasted state (see CLINICAL PHARMACOLOGY). Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food.

When buspirone is to be given with a potent inhibitor of CYP3A4 the dosage recommendations described in the PRECAUTIONS: Drug Interactions section should be followed.

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Lorazepam is administered orally. For optimal results, dose, frequency of administration, and duration of therapy should be individualized according to patient response. To facilitate this, 0.5 mg, 1 mg, and 2 mg tablets are available.

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

For anxiety, most patients require an initial dose of 2 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 to 4 mg may be given, usually at bedtime.

For elderly or debilitated patients, an initial dosage of 1 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.

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

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Dosage must be adjusted to the individual needs of each patient but is typically in the range of 20 mEq per day for the prevention of hypokalemia to 40-100 mEq per day or more for the treatment of potassium depletion.

The usual adult dose is 20-100 mEq of potassium per day (one Potassium Chloride 20 mEq packet 1 to 5 times daily after meals.

The contents of each Potassium Chloride packet should be dissolved in at least 4 ounces of cold water or other beverage. These preparations, like other potassium supplements, must be properly diluted to avoid the possibility of gastrointestinal irritation.

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DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND THE RESPONSE OF THE PATIENT.

A single oral dose of diphenhydramine hydrochloride is quickly absorbed with maximum activity occurring in approximately one hour. The duration of activity following an average dose of diphenhydramine hydrochloride is from four to six hours.

Adults

25 to 50 mg three or four times daily. The nighttime sleep-aid dosage is 50 mg at bedtime.

Pediatric Patients, other than premature infants and neonates

12.5 to 25 mg three or four times daily. Maximum daily dosage not to exceed 300 mg. For physicians who wish to calculate the dose on the basis of body weight or surface area, the recommended dosage is 5 mg/kg/24 hours or 150 mg/m2/24 hours.

Data are not available on the use of diphenhydramine hydrochloride as a nighttime sleep-aid in children under 12 years.

The basis for determining the most effective dosage regimen will be the response of the patient to medication and the condition under treatment.

In motion sickness, full dosage is recommended for prophylactic use, the first dose to be given 30 minutes before exposure to motion and similar doses before meals and upon retiring for the duration of exposure.

STORAGE:Keep tightly closed. Store at 20° to 25°C (67° to 77°F). [See USP Controlled Room Temperature]. Protect from freezing and light.

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2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

Ondansetron injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

Adults: The recommended adult intravenous dosage of ondansetron injection is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)]. The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron injection.Pediatrics: For pediatric patients 6 months through 18 years of age, the intravenous dosage of ondansetron injection is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Studies (14.1), Clinical Pharmacology (12.2, 12.3)]. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron injection. The drug should be infused intravenously over 15 minutes.

2.2 Prevention of Postoperative Nausea and Vomiting

Ondansetron injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate may form.Adults: The recommended adult intravenous dosage of ondansetron injection is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.Pediatrics: For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1 mg/kg dose for patients weighing 40 kg or less, or a single 4 mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ondansetron injection.

2.3 Stability and Handling

After dilution, do not use beyond 24 hours. Although ondansetron injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.Ondansetron injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously.

2.4 Dosage Adjustment for Patients with Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].

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Therapy with metoclopramide tablets should not exceed 12 weeks in duration.

For The Relief Of Symptomatic Gastroesophageal Reflux: Administer from 10 mg to 15 mg of metoclopramide tablets, USP orally up to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response (see CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). If symptoms occur only intermittently or at specific times of the day, use of metoclopramide in single doses up to 20 mg prior to the provoking situation may be preferred rather than continuous treatment. Occasionally, patients (such as elderly patients) who are more sensitive to the therapeutic or adverse effects of metoclopramide will require only 5 mg per dose.

Experience with esophageal erosions and ulcerations is limited, but healing has thus far been documented in one controlled trial using q.i.d. therapy at 15 mg/dose, and this regimen should be used when lesions are present, so long as it is tolerated (see ADVERSE REACTIONS). Because of the poor correlation between symptoms and endoscopic appearance of the esophagus, therapy directed at esophageal lesions is best guided by endoscopic evaluation.

Therapy longer than 12 weeks has not been evaluated and cannot be recommended.

For The Relief Of Symptoms Associated With Diabetic Gastroparesis (Diabetic Gastric Stasis): Administer 10 mg of metoclopramide 30 minutes before each meal and at bedtime for two to eight weeks, depending upon response and the likelihood of continued well-being upon drug discontinuation.

The initial route of administration should be determined by the severity of the presenting symptoms. If only the earliest manifestations of diabetic gastric stasis are present, oral administration of metoclopramide may be initiated. However, if severe symptoms are present, therapy should begin with metoclopramide injection (consult labeling of the injection prior to initiating parenteral administration).

Administration of metoclopramide injection up to 10 days may be required before symptoms subside, at which time oral administration may be instituted. Since diabetic gastric stasis is frequently recurrent, metoclopramide therapy should be reinstituted at the earliest manifestation.

Use in Patients with Renal or Hepatic Impairment: Since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half the recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.

See OVERDOSAGE section for information regarding dialysis.

Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal.

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• Valacyclovir hydrochloride tablets may be given without regard to meals.

Labeling describing use of valacyclovir hydrochloride tablets 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 information 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 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 Episode:

  The recommended dosage of valacyclovir hydrochloride tablets 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 a 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 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 additional dosing of valacyclovir hydrochloride tablets for 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 creatinine clearance <50 mL/min/1.73 m2.  

Table 1. Valacyclovir Hydrochloride Tablets Dosage Recommendations for Adults With Renal Impairment

Indications

Normal Dosage Regimen(Creatinine Clearance ≥50 mL/min)

Creatinine Clearance (mL/min)

30-49

10-29

<10

   Cold sores (Herpes labialis)    Do not exceed 1 day of treatment.

Two 2 gramdoses taken12 hours apart

Two 1 gramdoses taken12 hours apart

Two 500 mgdoses taken12 hours apart

500 mg single dose

   Genital herpes:       Initial episode

1 gram every 12 hours

no reduction

1 gram every24 hours

500 mg every 24 hours

   Genital herpes:       Recurrent episode

500 mg every 12 hours

no reduction

500 mg every24 hours

500 mg every 24 hours

   Genital herpes:        Suppressive therapy      Immunocompetent patients       Alternate dose for      immunocompetent       patient with       ≤9 recurrences/year       HIV-infected patients

1 gram every 24 hours 500 mg every 24 hours 500 mg every 12 hours

no reduction no reduction no reduction

500 mg every24 hours 500 mg every48 hours 500 mg every24 hours

500 mg every24 hours 500 mg every48 hours 500 mg every24 hours

   Herpes zoster

1 gram every 8 hours

1 gram every12 hours

1 gram every24 hours

500 mg every24 hours

Hemodialysis:

Patients requiring hemodialysis should receive the recommended dose of valacyclovir hydrochloride tablets after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of valacyclovir hydrochloride tablets 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 tablets 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 tablets should not be required following CAPD or CAVHD.

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do not take more than the recommended dose (see overdose warning) adults and children 12 years and older: take 2 caplets with water repeat every 6 hours, as needed do not exceed 6 caplets per day children under 12 years: ask a doctor

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• flush the affected eye(s) as needed • control the rate of flow of solution by pressure on the bottle

When using an eye cup

• rinse the cup with clean water immediately before each use • avoid contamination of the rim and inside surfaces of the cup • fill the cup half full and apply the cup to the affected eye(s), pressing tightly to prevent the escape of the liquid • tilt the head backward. Open eyelids wide and rotate eyeball to ensure thorough bathing with the wash or lotion • rinse the cup with clean water after each use

Other information

• store at 15º–30ºC (59º–86ºF) • keep tightly closed

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2.1 Schizophrenia

Adults

Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should 4 generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended. 

Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not indicated for use in doses above 20 mg/day. 

Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients. 

Maintenance Treatment —The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on olanzapine for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies (14.1)]. The physician who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. 

Adolescents

Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.  

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies (14.1)].

Maintenance Treatment — The efficacy of olanzapine for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

2.2 Bipolar I Disorder (Manic or Mixed Episodes)

Adults

Dose Selection for Monotherapy — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended. 

Short-term (3 to 4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies (14.2)]. 

Maintenance Monotherapy — The benefit of maintaining bipolar I patients on monotherapy with oral olanzapine at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see Clinical Studies (14.2)]. The physician who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. 

Dose Selection for Adjunctive Treatment — When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals. 

Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies (14.2)]. The safety of doses above 20 mg/day has not been evaluated in clinical trials. 

Adolescents

Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.  

The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies (14.2)].  

Maintenance Treatment — The efficacy of olanzapine for the maintenance treatment of bipolar I disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

2.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. 

Adults

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg.  Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Children and Adolescents (10 to 17 years of age)

Dosage and Administration information for pediatric patients (10 to 17 years) is approved for Eli Lilly and Company’s olanzapine tablets. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. 

Table 1: Approximate Dose Correspondence Between Symbyaxa and the Combination of Olanzapine and Fluoxetine 

  

 Use in Combination

For Symbyax

(mg/day)

Olanzapine

(mg/day)

Fluoxetine

(mg/day)

 3 mg olanzapine/25 mg fluoxetine

 2.5

 20

 6 mg olanzapine/25 mg fluoxetine

 5

 20

 12 mg olanzapine/25 mg fluoxetine

 10+2.5

 20

 6 mg olanzapine/50 mg fluoxetine

 5

 40+10

 12 mg olanzapine/50 mg fluoxetine

 10+2.5

 40+10

a Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine and fluoxetine. 

While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy. 

Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

2.7  Olanzapine and Fluoxetine in Combination: Dosing in Special Populations

The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Olanzapine and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients under < 10 years of age. [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)].

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2.1. Adults

The usual initial antihypertensive oral dose of amlodipine besylate tablets is 5 mg once daily with a maximum dose of 10 mg once daily.

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

Adjust dosage according to each patient’s need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient’s response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

The recommended dose for chronic stable or vasospastic angina is 5 to10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect [see Adverse Reactions (6)].

The recommended dose range for patients with coronary artery disease is 5 to10 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)].

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Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration and it is recommended in emergency situations.

Since the duration of action of some opioids may exceed that of naloxone the patient should be kept under continued surveillance. Repeated doses of naloxone should be administered, as necessary.

Intravenous Infusion

Naloxone hydrochloride injection may be diluted for intravenous infusion in 0.9% sodium chloride or 5% dextrose injection. The addition of 2 mg of naloxone hydrochloride in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused solution must be discarded. The rate of administration should be titrated in accordance with the patient’s response.

Naloxone hydrochloride injection should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No drug or chemical agent should be added to naloxone hydrochloride injection unless its effect on the chemical and physical stability of the solution has first been established.

General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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Carefully consider the potential benefits and risks of ibuprofen oral suspension and other treatment options before deciding to use ibuprofen oral suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with ibuprofen oral suspension, the dose and frequency should be adjusted to suit an individual patient's needs.

Pediatric Patients

Fever Reduction

For reduction of fever in children, 6 months up to 2 years of age, the dosage should be adjusted on the basis of the initial temperature level (see CLINICAL PHARMACOLOGY). The recommended dose is 5 mg/kg if the baseline temperature is less than 102.5°F, or 10 mg/kg if the baseline temperature is 102.5°F or greater. The duration of fever reduction is generally 6 to 8 hours.The recommended maximum daily dose is 40 mg/kg.

Analgesia

For relief of mild to moderate pain in children 6 months up to 2 years of age, the recommended dosage is 10 mg/kg, every 6 to 8 hours. The recommended maximum daily dose is 40 mg/kg. Doses should be given so as not to disturb the child's sleep pattern.

Juvenile Arthritis

The recommended dose is 30 to 40 mg/kg/day divided into three to four doses (see Individualization of Dosage). Patients with milder disease may be adequately treated with 20 mg/kg/day.

In patients with juvenile arthritis, doses above 50 mg/kg/day are not recommended because they have not been studied and doses exceeding the upper recommended dose of 40 mg/kg/day may increase the risk of causing serious adverse events. The therapeutic response may require from a few days to several weeks to be achieved. Once a clinical effect is obtained, the dosage should be lowered to the smallest dose of ibuprofen oral suspension needed to maintain adequate control of symptoms.

Pediatric patients receiving doses above 30 mg/kg/day or if abnormal liver function tests have occurred with previous NSAID treatments should be carefully followed for signs and symptoms of early liver dysfunction.

Adults

Primary Dysmenorrhea

For the treatment of primary dysmenorrhea, beginning with the earliest onset of such pain, ibuprofen oral suspension should be given in a dose of 400 mg every 4 hours, as necessary, for the relief of pain.

Rheumatoid Arthritis And Osteoarthritis

Suggested dosage: 1200-3200 mg daily (300 mg q.i.d. or 400 mg, 600 mg or 800 mg t.i.d. or q.i.d.). Individual patients may show a better response to 3200 mg daily, as compared with 2400 mg, although in well-controlled clinical trials patients on 3200 mg did not show a better mean response in terms of efficacy. Therefore, when treating patients with 3200 mg/day, the physician should observe sufficient increased clinical benefits to offset potential increased risk.

Individualization of Dosage

The dose of ibuprofen oral suspension should be tailored to each patient, and may be lowered or raised from the suggested doses depending on the severity of symptoms either at time of initiating drug therapy or as the patient responds or fails to respond.

One fever study showed that, after the initial dose of ibuprofen oral suspension, subsequent doses may be lowered and still provide adequate fever control.

In a situation when low fever would require the ibuprofen oral suspension 5 mg/kg dose in a child with pain, the dose that will effectively treat the predominant symptom should be chosen.

In chronic conditions, a therapeutic response to ibuprofen therapy is sometimes seen in a few days to a week, but most often is observed by two weeks. After a satisfactory response has been achieved, the patient's dose should be reviewed and adjusted as required.

Patients with rheumatoid arthritis seem to require higher doses than do patients with osteoarthritis. The smallest dose of ibuprofen oral suspension that yields acceptable control should be employed.

Ibuprofen Oral Suspension may be used in combination with gold salts and/or corticosteroids.

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Carefully consider the potential benefits and risks of naproxen tablets and other treatment options before deciding to use naproxen tablets.  Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with naproxen tablets, the dose and frequency should be adjusted to suit an individual patient’s needs.

Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation.

Although naproxen tablets, naproxen suspension, naproxen delayed-release tablets and naproxen sodium tablets all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 1 hour in patients taking naproxen.

The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events.  A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS).

Geriatric Patients

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly.  Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients.  As with other drugs used in the elderly, it is prudent to use the lowest effective dose.

Patients with Moderate to Severe Renal Impairment

Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects).

Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis

Naproxen Tablets

250 mgor 375 mgor 500 mg

twice dailytwice dailytwice daily

During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary.

In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk.  The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY).

Juvenile Arthritis

The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (i.e., 5 mg/kg given twice a day). Naproxen tablets are not well suited to this dosage so use of naproxen oral suspension is recommended for this indication.

Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis

Because the sodium salt of naproxen is more rapidly absorbed, naproxen sodium is recommended for the management of acute painful conditions when prompt onset of pain relief is desired.  Naproxen may also be used.  The recommended starting dose of Naproxen is 500 mg, followed by 500 mg every 12 hours or 250 mg every 6 to 8 hours as required.  The initial total daily dose should not exceed 1250 mg of naproxen.  Thereafter, the total daily dose should not exceed 1000 mg of naproxen.

Acute Gout

The recommended starting dose is 750 mg of naproxen tablets followed by 250 mg every 8 hours until the attack has subsided.

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The dosage of nifedipine needed to suppress angina and that can be tolerated by the patient must be established by titration. Excessive doses can result in hypotension.

Therapy should be initiated with the 10 mg capsule. The starting dose is one 10 mg capsule, swallowed whole, 3 times/day. The usual effective dose range is 10 to 20 mg three times daily. Some patients, especially those with evidence of coronary artery spasm, respond only to higher doses, more frequent administration, or both. In such patients, doses of 20 to 30 mg three or four times daily may be effective. Doses above 120 mg daily are rarely necessary. More than 180 mg per day is not recommended.

In most cases, nifedipine titration should proceed over a 7 to 14 day period so that the physician can assess the response to each dose level and monitor the blood pressure before proceeding to higher doses.

If symptoms so warrant, titration may proceed more rapidly provided that the patient is assessed frequently. Based on the patient’s physical activity level, attack frequency, and sublingual nitroglycerin consumption, the dose of nifedipine may be increased from 10 mg t.i.d. to 20 mg t.i.d. and then to 30 mg t.i.d. over a three-day period.

In hospitalized patients under close observation, the dose may be increased in 10 mg increments over four- to six-hour periods as required to control pain and arrhythmias due to ischemia. A single dose should rarely exceed 30 mg.

Avoid co-administration of nifedipine with grapefruit juice (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Other Interactions).

No “rebound effect” has been observed upon discontinuation of nifedipine. However, if discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision.

Co-Administration with Other Antianginal Drugs:

Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during nifedipine titration. See PRECAUTIONS, Drug Interactions, for information on co-administration of nifedipine with beta blockers or long-acting nitrates.

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Patients controlled on diltiazem alone or in combination with other medications may be switched to diltiazem hydrochloride extended-release capsules at the nearest equivalent total daily dose. Higher doses of diltiazem hydrochloride extended-release capsules may be needed in some patients. Patients should be closely monitored. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. There is limited general clinical experience with doses above 360 mg, but doses to 540 mg have been studied in clinical trials. The incidence of side effects increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose.

Hypertension: Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied in clinical trials was 240 to 360 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily.

Angina: Dosages for the treatment of angina should be adjusted to each patient’s needs, starting with a dose of 120 or 180 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily. When necessary, titration may be carried out over a 7- to 14-day period.

CONCOMITANT USE WITH OTHER CARDIOVASCULAR AGENTS:

1. Sublingual NTG - May be taken as required to abort acute anginal attacks during diltiazem hydrochloride extended-release capsules therapy.

2. Prophylactic Nitrate Therapy - Diltiazem hydrochloride extended-release capsules may be safely coadministered with short-and long-acting nitrates.

3. Beta-Blockers: (See WARNINGS and PRECAUTIONS).

4. Antihypertensives - Diltiazem hydrochloride extended-release capsules have an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem hydrochloride extended-release capsules or the concomitant antihypertensives may need to be adjusted when adding one to the other.

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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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride per day in divided doses. Although a t.i.d. regimen was used in 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 coexisting diseases such as angina or hypertension (see above).

Migraine

The initial dose is 80 mg propranolol hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride three or four times daily before meals and at bedtime.

Pheochromocytoma

The usual dosage is 60 mg propranolol hydrochloride 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.

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Adults

(For children’s dosage and administration, see below.) Dosage should be increased more gradually in debilitated or emaciated patients.

Elderly Patients

In general, dosages in the lower range are sufficient for most elderly patients. Since they appear to be more susceptible to hypotension and neuromuscular reactions, such patients should be observed closely. Dosage should be tailored to the individual, response carefully monitored, and dosage adjusted accordingly. Dosage should be increased more gradually in elderly patients.

1. To Control Severe Nausea and Vomiting

Adjust dosage to the response of the individual. Begin with the lowest recommended dosage.

Oral Dosage – Tablets

Usually one 5 mg or 10 mg tablet 3 or 4 times daily. Daily dosages above 40 mg should be used only in resistant cases.

2. In Adult Psychiatric Disorders

Adjust dosage to the response of the individual and according to the severity of the condition. Begin with the lowest recommended dose. Although response ordinarily is seen within a day or two, longer treatment is usually required before maximal improvement is seen.

Oral Dosage

Non-Psychotic Anxiety – Usual dosage is 5 mg 3 or 4 times daily. Do not administer in doses of more than 20 mg per day or for longer than 12 weeks.

Psychotic Disorders including Schizophrenia – In relatively mild conditions, as seen in private psychiatric practice or in outpatient clinics, dosage is 5 or 10 mg 3 or 4 times daily.

In moderate to severe conditions, for hospitalized or adequately supervised patients, usual starting dosage is 10 mg 3 or 4 times daily. Increase dosage gradually until symptoms are controlled or side effects become bothersome. When dosage is increased by small increments every 2 or 3 days, side effects either do not occur or are easily controlled. Some patients respond satisfactorily on 50 to 75 mg daily.

In more severe disturbances, optimum dosage is usually 100 to 150 mg daily.

Children

Do not use in pediatric surgery.

Children seem more prone to develop extrapyramidal reactions, even on moderate doses. Therefore, use lowest effective dosage. Tell parents not to exceed prescribed dosage, since the possibility of adverse reactions increases as dosage rises.

Occasionally the patient may react to the drug with signs of restlessness and excitement; if this occurs, do not administer additional doses. Take particular precaution in administering the drug to children with acute illnesses or dehydration (see under Dystonia).

1. Severe Nausea and Vomiting In Children

Prochlorperazine should not be used in pediatric patients under 20 pounds in weight or 2 years of age. It should not be used in conditions for which children’s dosages have not been established. Dosage and frequency of administration should be adjusted according to the severity of the symptoms and the response of the patient. The duration of activity following intramuscular administration may last up to 12 hours. Subsequent doses may be given by the same route if necessary.

Oral Dosage

More than 1 day’s therapy is seldom necessary.

Weight

Usual Dosage

Not to Exceed

under 20 lbs not recommended

20 to 29 lbs

2½ mg 1 or 2 times a day

7.5 mg per day

30 to 39 lbs

2½ mg 2 or 3 times a day

10 mg per day

40 to 85 lbs

2½ mg 3 times a day or

5 mg 2 times a day

15 mg per day

2. In Children with Schizophrenia

Oral Dosage

For children 2 to 12 years, starting dosage is 2-1/2 mg 2 or 3 times daily. Do not give more than 10 mg the first day. Then increase dosage according to patient’s response.

FOR AGES 2 to 5, total daily dosage usually does not exceed 20 mg.

FOR AGES 6 to 12, total daily dosage usually does not exceed 25 mg.

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• do not exceed the maximum recommended daily dose in a 24 hour period • shake well before use • dose may be taken once a day preferably at bedtime, in divided doses, or as directed by a doctor • drink a full glass (8 oz) of liquid with each dose • for accurate dosing, use dose cup provided • mL = milliliter; TBSP = Tablespoon

adults and children 12 years and older

30 mL (2 TBSP) to 60 mL (4 TBSP)

children 6 to 11 years

15 mL (1 TBSP) to 30 mL (2 TBSP)

children under 6 years

ask a doctor

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BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, AMIODARONE SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF AMIODARONE THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT.

In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of amiodarone has not been determined. Because of the food effect on absorption, amiodarone should be administered consistently with regard to meals (see CLINICAL PHARMACOLOGY). Individual patient titration is suggested according to the following guidelines:

For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia:

Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Because of the serious nature of the arrhythmia and the lack of predictable time course of effect, loading should be performed in a hospital setting. Loading doses of 800 to 1,600 mg/day are required for 1 to 3 weeks (occasionally longer) until initial therapeutic response occurs. (Administration of amiodarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced. Elimination of recurrence of ventricular fibrillation and tachycardia usually occurs within 1 to 3 weeks, along with reduction in complex and total ventricular ectopic beats.

Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see PRECAUTIONS, Drug Interactions).

Upon starting amiodarone therapy, an attempt should be made to gradually discontinue prior antiarrhythmic drugs (see section on Drug Interactions).When adequate arrhythmia control is achieved, or if side effects become prominent, amiodarone dose should be reduced to 600 to 800 mg/day for one month and then to the maintenance dose, usually 400 mg/day (see CLINICAL PHARMACOLOGY-Monitoring Effectiveness). Some patients may require larger maintenance doses, up to 600 mg/day, and some can be controlled on lower doses. Amiodarone may be administered as a single daily dose, or in patients with severe gastrointestinal intolerance, as a b.i.d. dose. In each patient, the chronic maintenance dose should be determined according to antiarrhythmic effect as assessed by symptoms, Holter recordings, and/or programmed electrical stimulation and by patient tolerance. Plasma concentrations may be helpful in evaluating nonresponsiveness or unexpectedly severe toxicity (see CLINICAL PHARMACOLOGY).

The lowest effective dose should be used to prevent the occurrence of side effects. In all instances, the physician must be guided by the severity of the individual patient’s arrhythmia and response to therapy.

When dosage adjustments are necessary, the patient should be closely monitored for an extended period of time because of the long and variable half-life of amiodarone and the difficulty in predicting the time required to attain a new steady-state level of drug. Dosage suggestions are summarized below:

Loading Dose (Daily)

Adjustment and Maintenance Dose (Daily)

Ventricular Arrhythmias 

1 to 3 weeks 

~1 month 

usual maintenance

800 to 1,600 mg 

600 to 800 mg 

400 mg

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• take every 4 to 6 hours • do not take more than 6 doses in 24 hours

adults and children 12 years and over

1 to 2 capsules

children 6 to under 12 years

1 capsule

children under 6 years

do not use this product in children under 6 years of age

---

• shake well before using • do not take more than 6 doses in any 24-hour period • measure only with dosing cup provided • keep dosing cup with product • mL - milliliter • this adult product is not intended for use in children under 12 years of age

age

dose

adults and children

12 years and over

10 mL every 4 hours

children under 12 years

do not use

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• if you are under 18 years of age, ask a doctor before use • before using this product, read the enclosed User’s Guide for complete directions and other important information • begin using the gum on your quit day • if you smoke your first cigarette within 30 minutes of waking up, use Nicotine Polacrilex Gum, 4 mg • if you smoke your first cigarette more than 30 minutes after waking up, use Nicotine Polacrilex Gum, 2 mg according to the following 12 week schedule:

Weeks 1 to 6

Weeks 7 to 9

Weeks 10 to 12

1 piece every 1 to 2 hours

1 piece every 2 to 4 hours

1 piece every 4 to 8 hours

• nicotine gum is a medicine and must be used a certain way to get the best results • chew the gum slowly until it tingles. Then park it between your cheek and gum. When the tingle is gone, begin chewing again, until the tingle returns. • repeat this process until most of the tingle is gone (about 30 minutes) • do not eat or drink for 15 minutes before chewing the nicotine gum, or while chewing a piece • to improve your chances of quitting, use at least 9 pieces per day for the first 6 weeks • if you experience strong or frequent cravings, you may use a second piece within the hour. However, do not continuously use one piece after another since this may cause you hiccups, heartburn, nausea or other side effects. • do not use more than 24 pieces a day • it is important to complete treatment. If you feel you need to use the gum for a longer period to keep from smoking, talk to your health care provider.

---

• take every 4 to 6 hours, not more than 6 doses in 24 hours

adults and children 12 years of age and over

1 or 2 tablets

children 6 to under 12 years of age

1 tablet

children 4 to under 6 years of age

do not use unless directed by a doctor

children under 4 years of age

do not use

---

• adults and children 6 to under 12 years of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours. Do not exceed 2 doses in any 24-hour period. • children under 6 years of age: ask a doctor

To spray, squeeze bottle quickly and firmly. Do not tilt head backward while spraying. Wipe nozzle clean after use. Replace cap tightly to maintain child resistance.

---

• adults and children 6 to under 12 years of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours. Do not exceed 2 doses in any 24-hour period. • children under 6 years of age: ask a doctor

To spray, squeeze bottle quickly and firmly. Do not tilt head backward while spraying. Wipe nozzle clean after use. Replace cap tightly to maintain child resistance.

---

The recommended dose of Midodrine HCl Tablets is 10 mg, 3 times daily. Dosing should take place during the daytime hours when the patient needs to be upright, pursuing the activities of daily living. A suggested dosing schedule of approximately 4-hour intervals is as follows: shortly before, or upon arising in the morning, midday and late afternoon (not later than 6 P.M.). Doses may be given in 3-hour intervals, if required, to control symptoms, but not more frequently. Single doses as high as 20 mg have been given to patients, but severe and persistent systolic supine hypertension occurs at a high rate (about 45%) at this dose. In order to reduce the potential for supine hypertension during sleep, Midodrine HCl Tablets should not be given after the evening meal or less than 4 hours before bedtime. Total daily doses greater than 30 mg have been tolerated by some patients, but their safety and usefulness have not been studied systematically or established. Because of the risk of supine hypertension, Midodrine HCl Tablets should be continued only in patients who appear to attain symptomatic improvement during initial treatment.

The supine and standing blood pressure should be monitored regularly, and the administration of Midodrine HCl Tablets should be stopped if supine blood pressure increases excessively.

Because desglymidodrine is excreted renally, dosing in patients with abnormal renal function should be cautious; although this has not been systematically studied, it is recommended that treatment of these patients be initiated using 2.5 mg doses.

Dosing in children has not been adequately studied.

Blood levels of midodrine and desglymidodrine were similar when comparing levels in patients 65 or older vs. younger than 65 and when comparing males vs. females, suggesting dose modifications for these groups are not necessary.

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Oral administration is preferred. Although most patients with malabsorption cannot absorb food folates, they are able to absorb folic acid given orally. Parenteral administration is not advocated but may be necessary in some individuals (e.g., patients receiving parenteral or enteral alimentation). Doses greater than 0.1 mg should not be used unless anemia due to vitamin B12 deficiency has been ruled out or is being adequately treated with a cobalamin. Daily doses greater than 1 mg do not enhance the hematologic effect, and most of the excess is excreted unchanged in the urine.

The usual therapeutic dosage in adults and children (regardless of age) is up to 1 mg daily. Resistant cases may require larger doses.

When clinical symptoms have subsided and the blood picture has become normal, a daily maintenance level should be used, i.e., 0.1 mg for infants and up to 0.3 mg for children under 4 years of age, 0.4 mg for adults and children 4 or more years of age, and 0.8 mg for pregnant and lactating women, but never less than 0.1 mg/day. Patients should be kept under close supervision and adjustment of the maintenance level made if relapse appears imminent.

In the presence of alcoholism, hemolytic anemia, anticonvulsant therapy, or chronic infection, the maintenance level may need to be increased.

---

The recommended initial dose is 15 mg daily (7.5 mg b.i.d.). To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed. The maximum daily dosage should not exceed 60 mg per day. In clinical trials allowing dose titration, divided doses of 20 mg to 30 mg per day were commonly employed.

The bioavailability of buspirone is increased when given with food as compared to the fasted state (see CLINICAL PHARMACOLOGY). Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food.

When buspirone is to be given with a potent inhibitor of CYP3A4 the dosage recommendations described in the PRECAUTIONS: Drug Interactions section should be followed.

---

Patients controlled on diltiazem alone or in combination with other medications may be switched to Diltiazem Hydrochloride Extended-Release Capsules, USP at the nearest equivalent total daily dose. Higher doses of diltiazem hydrochloride extended-release capsules may be needed in some patients. Patients should be closely monitored. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. There is limited general clinical experience with doses above 360 mg, but doses to 540 mg have been studied in clinical trials. The incidence of side effects increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose.

Hypertension: Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied in clinical trials was 240 to 360 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily.

Angina: Dosages for the treatment of angina should be adjusted to each patient’s needs, starting with a dose of 120 or 180 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily. When necessary, titration may be carried out over a 7- to 14-day period.

Concomitant Use With Other Cardiovascular Agents

1. Sublingual NTG - May be taken as required to abort acute anginal attacks during diltiazem hydrochloride extended-release capsules therapy. 2. Prophylactic Nitrate Therapy - Diltiazem hydrochloride extended-release capsules may be safely coadministered with short-and long-acting nitrates. 3. Beta-Blockers - (See WARNINGS and PRECAUTIONS). 4. Antihypertensives - Diltiazem hydrochloride extended-release capsules have an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem hydrochloride extended-release capsules or the concomitant antihypertensives may need to be adjusted when adding one to the other.

---

Therapy with metoclopramide tablets, USP should not exceed 12 weeks in duration.

For the Relief of Symptomatic Gastroesophageal Reflux

Administer from 10 mg to 15 mg of metoclopramide tablet, USP orally up to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response (see CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). If symptoms occur only intermittently or at specific times of the day, use of metoclopramide in single doses up to 20 mg prior to the provoking situation may be preferred rather than continuous treatment. Occasionally, patients (such as elderly patients) who are more sensitive to the therapeutic or adverse effects of metoclopramide will require only 5 mg per dose.

Experience with esophageal erosions and ulcerations is limited, but healing has thus far been documented in one controlled trial using q.i.d. therapy at 15 mg/dose, and this regimen should be used when lesions are present, so long as it is tolerated (see ADVERSE REACTIONS). Because of the poor correlation between symptoms and endoscopic appearance of the esophagus, therapy directed at esophageal lesions is best guided by endoscopic evaluation.

Therapy longer than 12 weeks has not been evaluated and cannot be recommended.

For the Relief of Symptoms Associated With Diabetic Gastroparesis (Diabetic Gastric Stasis)

Administer 10 mg of metoclopramide 30 minutes before each meal and at bedtime for two to eight weeks, depending upon response and the likelihood of continued well-being upon drug discontinuation.

The initial route of administration should be determined by the severity of the presenting symptoms. If only the earliest manifestations of diabetic gastric stasis are present, oral administration of metoclopramide tablets, USP may be initiated. However, if severe symptoms are present, therapy should begin with metoclopramide injection (consult labeling of the injection prior to initiating parenteral administration).

Administration of metoclopramide injection up to 10 days may be required before symptoms subside, at which time oral administration may be instituted. Since diabetic gastric stasis is frequently recurrent, metoclopramide tablet, USP therapy should be reinstituted at the earliest manifestation.

Use in Patients With Renal or Hepatic Impairment

Since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half the recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.

See OVERDOSAGE section for information regarding dialysis.

Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use has been described in patients with advanced liver disease whose renal function was normal.

---

Adults

The dose of clonidine hydrochloride tablets must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration.

Initial Dose

0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose.

Maintenance Dose

Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses.

Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed.

Renal Impairment

Patients with renal impairment may benefit from a lower initial dose. Patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

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Table 1Recommended 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

1mg

1 to 6mg

1 to 6 mg

Bipolar mania:  children and  adolescents  (2.2) 

0.5 mg

0.5 to 1mg

1 to 2.5 mg

1 to 6 mg

Irritability in autistic  disorder (2.3) 

0.25 mgCan increase to0.5 mg by Day 4:(body weight lessthan 20 kg)0.5 mgCan increase to1 mg by Day 4:(body weightgreater than orequal to 20 kg)

After Day 4, atintervals of > 2weeks:0.25 mg(body weight lessthan 20 kg)0.5 mg(body weightgreater than orequal to 20 kg)

0.5 mg:(body weight lessthan 20 kg)1 mg:(body weightgreater than orequal 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 one week or longer

2.1 Schizophrenia

Adults

Usual Initial Dose

RISPERIDONE 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 day. 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 RISPERIDONE 2 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 Clinical Studies (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 1mg 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 (8.6 and 8.7)].

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, RISPERIDONE should 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)].

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Carbidopa and levodopa extended-release tablet contains carbidopa and levodopa in a 1:4 ratio as either the 50 mg/200 mg tablet or the 25 mg/100 mg tablet. The daily dosage of carbidopa and levodopa extended-release tablets must be determined by careful titration. Patients should be monitored closely during the dose adjustment period, particularly with regard to appearance or worsening of involuntary movements, dyskinesias or nausea. Carbidopa and levodopa extended-release tablets should not be chewed or crushed.Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly while carbidopa and levodopa extended-release tablet is being administered, although their dosage may have to be adjusted. Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, carbidopa and levodopa extended-release tablets can be given to patients receiving supplemental pyridoxine (vitamin B6).

Initial Dosage

Patients currently treated with conventional carbidopa and levodopa preparations: Studies show that peripheral dopa-decarboxylase is saturated by the bioavailable carbidopa at doses of 70 mg a day and greater. Because the bioavailabilities of carbidopa and levodopa in carbidopa and levodopa tablets and carbidopa and levodopa extended-release tablets are different, appropriate adjustments should be made, as shown in Table 2.

Table 2. Approximate Bioavailabilities at Steady State* Tablet Amount of Levodopa (mg) in Each Tablet Approximate Bioavailability Approximate Amount of Bioavailable Levodopa (mg) in Each Tablet * This table is only a guide to bioavailabilities since other factors such as food, drugs, and inter-patient variabilities may affect the bioavailability of carbidopa and levodopa. † The extent of availability of levodopa from carbidopa and levodopa extended-release tablets was about 70 to 75% relative to intravenous levodopa or standard carbidopa and levodopa tablets in the elderly. ‡ The extent of availability of levodopa from carbidopa and levodopa tablets was 99% relative to intravenous levodopa in the healthy elderly.

Carbidopa and levodopa extended-release tablets 50 mg/200 mg

200

0.7 to 0.75†

140 to 150

Carbidopa and levodopa tablets 25 mg/100 mg

100

0.99‡

99

Dosage with carbidopa and levodopa extended-release tablets should be substituted at an amount that provides approximately 10% more levodopa per day, although this may need to be increased to a dosage that provides up to 30% more levodopa per day depending on clinical response (see DOSAGE AND ADMINISTRATION, Titration with carbidopa and levodopa extended-release tablets). The interval between doses of carbidopa and levodopa extended-release tablets should be 4 to 8 hours during the waking day. (See CLINICAL PHARMACOLOGY, Pharmacodynamics.) A guideline for initiation of carbidopa and levodopa extended-release tablets is shown in Table 3.

Table 3. Guidelines for Initial Conversion from Carbidopa and Levodopa Tablets to Carbidopa and Levodopa Extended-Release Tablets Carbidopa and levodopa tablets Carbidopa and levodopa extended-release tablets * For dosing ranges not shown in the table see DOSAGE AND ADMINISTRATION, Initial Dosage-Patients currently treated with conventional carbidopa and levodopa preparations.

Total Daily Dose*

Suggested

Levodopa (mg)

Dosage Regimen

300 to 400

200 mg b.i.d.

500 to 600

300 mg b.i.d.or 200 mg t.i.d.

700 to 800

A total of 800 mg in 3 or more divided doses (e.g., 300 mg a.m., 300 mg early p.m., and 200 mg later p.m.)

900 to 1000

A total of 1000 mg in 3 or more divided doses (e.g., 400 mg a.m., 400 mg early p.m., and 200 mg later p.m.)

Patients currently treated with levodopa without a decarboxylase inhibitor: Levodopa must be discontinued at least twelve hours before therapy with carbidopa and levodopa extended-release tablets is started. Carbidopa and levodopa extended-release tablets should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage. In patients with mild to moderate disease, the initial dose is usually 1 tablet of carbidopa and levodopa extended-release tablets 50 mg/200 mg b.i.d. Patients not receiving levodopa: In patients with mild to moderate disease, the initial recommended dose is 1 tablet of carbidopa and levodopa extended-release tablets 50 mg/200 mg b.i.d. Initial dosage should not be given at intervals of less than 6 hours.

Titration with Carbidopa and Levodopa Extended-Release Tablets

Following initiation of therapy, doses and dosing intervals may be increased or decreased depending upon therapeutic response. Most patients have been adequately treated with doses of carbidopa and levodopa extended-release tablets that provide 400 to 1600 mg of levodopa per day, administered as divided doses at intervals ranging from 4 to 8 hours during the waking day. Higher doses of carbidopa and levodopa extended-release tablets (2400 mg or more of levodopa per day) and shorter intervals (less than 4 hours) have been used, but are not usually recommended.When doses of carbidopa and levodopa extended-release tablets are given at intervals of less than 4 hours, and/or if the divided doses are not equal, it is recommended that the smaller doses be given at the end of the day.An interval of at least 3 days between dosage adjustments is recommended.

Maintenance

Because Parkinson's disease is progressive, periodic clinical evaluations are recommended; adjustment of the dosage regimen of carbidopa and levodopa extended-release tablets may be required.

Addition of Other Antiparkinson Medications

Anticholinergic agents, dopamine agonists, and amantadine can be given with carbidopa and levodopa extended-release tablets. Dosage adjustment of carbidopa and levodopa extended-release tablets may be necessary when these agents are added.

A dose of carbidopa and levodopa tablets  25 mg/100 mg or 10 mg/100 mg (one half or a whole tablet) can be added to the dosage regimen of carbidopa and levodopa extended-release tablets in selected patients with advanced disease who need additional immediate-release levodopa for a brief time during daytime hours.

Interruption of Therapy

Sporadic cases of a symptom complex resembling Neuroleptic Malignant Syndrome (NMS) have been associated with dose reductions and withdrawal of carbidopa and levodopa tablets or carbidopa and levodopa extended-release tablets.Patients should be observed carefully if abrupt reduction or discontinuation of carbidopa and levodopa extended-release tablets is required, especially if the patient is receiving neuroleptics. (See WARNINGS).If general anesthesia is required, carbidopa and levodopa extended-release tablets may be continued as long as the patient is permitted to take oral medication. If therapy is interrupted temporarily, the patient should be observed for symptoms resembling NMS, and the usual dosage should be administered as soon as the patient is able to take oral medication.

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Usual Adult Dosage:

Type of Infection

Dose

Frequency

Moderate to severe infections

500 mg to 1 gram

every 6 to 8 hours

Mild infections caused by susceptible gram-positive cocci

250 mg to 500 mg

every 8 hours

Acute, uncomplicated urinary tract infections

1 gram

every 12 hours

Pneumococcal pneumonia

500 mg

every 12 hours

Severe, life threatening infections (e.g., endocarditis, septicemia)*

1 gram to 1.5 grams

every 6 hours

 *In rare instances, doses of up to 12 grams of cefazolin per day have been used.

Perioperative Prophylactic Use

To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended doses are:

a. 1 gram IV or IM administered one half to 1 hour prior to the start of surgery.

b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV or IM during surgery (administration modified depending on the duration of the operative procedure).

c. 500 mg to 1 gram IV or IM every 6 to 8 hours for 24 hours postoperatively.

It is important that (1) the preoperative dose be given just prior (one half to 1 hour) to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision and (2) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

Dosage Adjustment for Patients with Reduced Renal Function

Cefazolin may be used in patients with reduced renal function with the following dosage adjustments. Patients with a creatinine clearance of 55 mL/min or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min or serum creatinine of 1.6 to 3 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min or serum creatinine of 3.1 to 4.5 mg % should be given one half the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min or less or serum creatinine of 4.6 mg % or greater should be given one half the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis, see CLINICAL PHARMACOLOGY.

Pediatric Dosage

In pediatric patients, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg/lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

Pediatric Dosage Guide

Weight

25 mg/kg/day Divided into 3 Doses

lbs

kg

Approximate Single Dose

mg/q8h

Vol (mL) needed with dilution of 125 mg/mL

10

20

30

40

50

4.5

9

13.6

18.1

22.7

40 mg

75 mg

115 mg

150 mg

190 mg

0.35 mL

0.6 mL

0.9 mL

1.2 mL

1.5 mL

Weight

25 mg/kg/day Divided into 4 Doses

lbs

kg

Approximate Single Dose

mg/q6h

Vol (mL) needed with dilution of 125 mg/mL

10

20

30

40

50

4.5

9

13.6

18.1

22.7

30 mg

55 mg

85 mg

115 mg

140 mg

0.25 mL

0.45 mL

0.7 mL

0.9 mL

1.1 mL

Weight

50 mg/kg/day Divided into 3 Doses

lbs

kg

Approximate Single Dose

mg/q8h

Vol (mL) needed with dilution of 225 mg/mL

10

20

30

40

50

4.5

9

13.6

18.1

22.7

75 mg

150 mg

225 mg

300 mg

375 mg

0.35 mL

0.7 mL

1 mL

1.35 mL

1.7 mL

Weight

50 mg/kg/day Divided into 4 Doses

lbs

kg

Approximate Single Dose

mg/q6h

Vol (mL) needed with dilution of 225 mg/mL

10

20

30

40

50

4.5

9

13.6

18.1

22.7

55 mg

110 mg

170 mg

225 mg

285 mg

0.25 mL

0.5 mL

0.75 mL

1 mL

1.25 mL

 

In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60% of the normal daily dosage given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min), 25% of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min) may be given 10% of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

Perioperative Prophylactic Use

To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended doses are:

a. 1 gram IV or IM administered one half to 1 hour prior to the start of surgery.

b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV or IM during surgery (administration modified depending on the duration of the operative procedure).

c. 500 mg to 1 gram IV or IM every 6 to 8 hours for 24 hours postoperatively.

It is important that (1) the preoperative dose be given just prior (one half to 1 hour) to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision and (2) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

Dosage Adjustment for Patients with Reduced Renal Function

Cefazolin may be used in patients with reduced renal function with the following dosage adjustments. Patients with a creatinine clearance of 55 mL/min or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min or serum creatinine of 1.6 to 3 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min or serum creatinine of 3.1 to 4.5 mg % should be given one half the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min or less or serum creatinine of 4.6 mg % or greater should be given one half the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis, see CLINICAL PHARMACOLOGY.

Pediatric Dosage

In pediatric patients, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg/lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

Pediatric Dosage Guide

Weight

25 mg/kg/day Divided into 3 Doses

lbs

kg

Approximate Single Dose

mg/q8h

Vol (mL) needed with dilution of 125 mg/mL

10

20

30

40

50

4.5

9

13.6

18.1

22.7

40 mg

75 mg

115 mg

150 mg

190 mg

0.35 mL

0.6 mL

0.9 mL

1.2 mL

1.5 mL

Weight

25 mg/kg/day Divided into 4 Doses

lbs

kg

Approximate Single Dose

mg/q6h

Vol (mL) needed with dilution of 125 mg/mL

10

20

30

40

50

4.5

9

13.6

18.1

22.7

30 mg

55 mg

85 mg

115 mg

140 mg

0.25 mL

0.45 mL

0.7 mL

0.9 mL

1.1 mL

Weight

50 mg/kg/day Divided into 3 Doses

lbs

kg

Approximate Single Dose

mg/q8h

Vol (mL) needed with dilution of 225 mg/mL

10

20

30

40

50

4.5

9

13.6

18.1

22.7

75 mg

150 mg

225 mg

300 mg

375 mg

0.35 mL

0.7 mL

1 mL

1.35 mL

1.7 mL

Weight

50 mg/kg/day Divided into 4 Doses

lbs

kg

Approximate Single Dose

mg/q6h

Vol (mL) needed with dilution of 225 mg/mL

10

20

30

40

50

4.5

9

13.6

18.1

22.7

55 mg

110 mg

170 mg

225 mg

285 mg

0.25 mL

0.5 mL

0.75 mL

1 mL

1.25 mL

 

In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60% of the normal daily dosage given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min), 25% of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min) may be given 10% of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

Intramuscular Administration

Reconstitute vials with Sterile Water for Injection according to the dilution table above. Shake well until dissolved. Cefazolin for Injection, USP should be injected into a large muscle mass. Pain on injection is infrequent with Cefazolin for Injection, USP.

Intravenous Administration

Direct (bolus) injection–Following reconstitution according to the above table, further dilute vials with approximately 5 mL Sterile Water for Injection. Inject the solution slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below).

Intermittent or continuous infusion–Dilute reconstituted Cefazolin for Injection, USP in 50 to 100 mL of one of the following solutions:

Sodium Chloride Injection, USP

5% or 10% Dextrose Injection, USP

5% Dextrose in Lactated Ringer’s Injection, USP

5% Dextrose and 0.9% Sodium Chloride Injection, USP

5% Dextrose and 0.45% Sodium Chloride Injection, USP

5% Dextrose and 0.2% Sodium Chloride Injection, USP

Lactated Ringer’s Injection, USP

Invert Sugar 5% or 10% in Sterile Water for Injection

Ringer’s Injection, USP

5% Sodium Bicarbonate Injection, USP

Prior to administration parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

Intramuscular Administration

Reconstitute vials with Sterile Water for Injection according to the dilution table above. Shake well until dissolved. Cefazolin for Injection, USP should be injected into a large muscle mass. Pain on injection is infrequent with Cefazolin for Injection, USP.

Intravenous Administration

Direct (bolus) injection–Following reconstitution according to the above table, further dilute vials with approximately 5 mL Sterile Water for Injection. Inject the solution slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below).

Intermittent or continuous infusion–Dilute reconstituted Cefazolin for Injection, USP in 50 to 100 mL of one of the following solutions:

Sodium Chloride Injection, USP

5% or 10% Dextrose Injection, USP

5% Dextrose in Lactated Ringer’s Injection, USP

5% Dextrose and 0.9% Sodium Chloride Injection, USP

5% Dextrose and 0.45% Sodium Chloride Injection, USP

5% Dextrose and 0.2% Sodium Chloride Injection, USP

Lactated Ringer’s Injection, USP

Invert Sugar 5% or 10% in Sterile Water for Injection

Ringer’s Injection, USP

5% Sodium Bicarbonate Injection, USP

Prior to administration parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

---

• do not take more than 6 doses in any 24-hour period • measure only with dosing cup provided • keep dosing cup with product • mL = milliliter • this adult product is not intended for use in children under 12 years of age

age

dose

adults and children 12 years and over

10 mL every 4 hours

children under 12 years

do not use

---

Dosage should be adjusted according to severity of pain and response of the patient. The usual adult dosage is:

 

 Single Doses (range)

 Maximum 24 Hour Dose

 Codeine Phosphate

 15 mg to 60 mg

360 mg

 Acetaminophen

 300 mg to 1000 mg

  4000 mg

The usual dose of codeine phosphate in children is 0.5 mg/kg.

Doses may be repeated up to every 4 hours.

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours based upon the above dosage guidance. This information should be conveyed in the prescription.

It should be kept in mind, however, that tolerance to codeine 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 but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects. Equivalently high doses in children would have similar effects.

---

The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage. Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.

Dose Selection

An initial dose of 150 mg/day in divided doses is suggested. The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses

• Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response. • Patients should be monitored for withdrawal symptoms when discontinuing treatment with trazodone hydrochloride tablets. The dose should be gradually reduced whenever possible [see Warnings and Precautions (5.13)].

Maintenance Treatment

The efficacy of trazodone hydrochloride tablets for the maintenance treatment of MDD has not been evaluated. While there is no body of evidence available to answer the question of how long a patient treated with trazodone hydrochloride tablets should continue the drug, it is generally recommended that treatment be continued for several months after an initial response. Patients should be maintained on the lowest effective dose and be periodically reassessed to determine the continued need for maintenance treatment.

Important Administration Instructions

Trazodone hydrochloride tablets are scored to provide flexibility in dosing.

Trazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line.

---

• if you are under 18 years of age, ask a doctor before use • before using this product, read the enclosed User’s Guide for complete directions and other important information • begin using the lozenge on your quit day • if you smoke your first cigarette more than 30 minutes after waking up, use 2 mg nicotine lozenge • if you smoke your first cigarette within 30 minutes of waking up, use 4 mg nicotine lozenge according to the following 12 week schedule:

Weeks 1 to 6

Weeks 7 to 9

Weeks 10 to 12

1 lozenge every

1 to 2 hours

1 lozenge every

2 to 4 hours

1 lozenge every

4 to 8 hours

• nicotine lozenge is a medicine and must be used a certain way to get the best results • place the lozenge in your mouth and allow the lozenge to slowly dissolve. Minimize swallowing. Do not chew or swallow lozenge. • you may feel a warm or tingling sensation • occasionally move the lozenge from one side of your mouth to the other until completely dissolved • do not eat or drink 15 minutes before using or while the lozenge is in your mouth • to improve your chances of quitting, use at least 9 lozenges per day for the first 6 weeks • do not use more than one lozenge at a time or continuously use one lozenge after another since this may cause you hiccups, heartburn, nausea or other side effects • do not use more than 5 lozenges in 6 hours. Do not use more than 20 lozenges per day. • it is important to complete treatment. If you feel you need to use the lozenge for a longer period to keep from smoking, talk to your health care provider.

---

• if you are under 18 years of age, ask a doctor before use • before using this product, read the enclosed User’s Guide for complete directions and other important information • begin using the lozenge on your quit day • if you smoke your first cigarette within 30 minutes of waking up, use 4 mg nicotine lozenge • if you smoke your first cigarette more than 30 minutes after waking up, use 2 mg nicotine lozenge according to the following 12 week schedule:

Weeks 1 to 6

Weeks 7 to 9

Weeks 10 to 12

1 lozenge every 1 to 2 hours

1 lozenge every 2 to 4 hours

1 lozenge every 4 to 8 hours

• nicotine lozenge is a medicine and must be used a certain way to get the best results • place the lozenge in your mouth and allow the lozenge to slowly dissolve. Minimize swallowing. Do not chew or swallow lozenge. • you may feel a warm or tingling sensation • occasionally move the lozenge from one side of your mouth to the other until completely dissolved • do not eat or drink 15 minutes before using or while the lozenge is in your mouth • to improve your chances of quitting, use at least 9 lozenges per day for the first 6 weeks • do not use more than one lozenge at a time or continuously use one lozenge after another since this may cause you hiccups, heartburn, nausea or other side effects • do not use more than 5 lozenges in 6 hours. Do not use more than 20 lozenges per day. • it is important to complete treatment. If you feel you need to use the lozenge for a longer period to keep from smoking, talk to your health care provider.

---

Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of Xylocaine Injection for various types of anesthetic procedures.  The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions.  When larger volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated.

There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Xylocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures.  The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient.  In all cases the lowest concentration and smallest dose that will produce the desired result should be given.  Dosages should be reduced for children and for the elderly and debilitated patients and patients with cardiac and/or liver disease.

The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (ie, total dose) of local anesthetic used.  Thus, an increase in volume and concentration of Xylocaine Injection will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia.  However, increasing the volume and concentration of Xylocaine Injection may result in a more profound fall in blood pressure when used in epidural anesthesia.  Although the incidence of side effects with lidocaine HCl is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected.

For intravenous regional anesthesia, only the 50 mL single dose vial containing Xylocaine (lidocaine HCl) 0.5% Injection should be used.

Epidural Anesthesia

For epidural anesthesia, only the following dosage forms Xylocaine Injection are recommended:

1% without epinephrine                         10 mL Plastic Ampule

1% without epinephrine                         30 mL single dose solutions

1% with epinephrine   1:200,000           30 mL single dose solutions

1.5% without epinephrine                      10 mL Plastic Ampule

1.5% without epinephrine                      20 mL Plastic Ampule

1.5% with epinephrine  1:200,000         30 mL ampules, 30 mL single dose solutions

2% without epinephrine                         10 mL Plastic Ampule

2% with epinephrine   1:200,000           20 mL ampules, 20 mL single dose solutions

 

Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single dose units.  These solutions contain no bacteriostatic agent. 

In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

Caudal and Lumbar Epidural Block

As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block.  The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter.  Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.  Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure.  Adequate time should be allowed for onset of anesthesia after administration of each test dose.  The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

Epidural Anesthesia

For epidural anesthesia, only the following dosage forms Xylocaine Injection are recommended:

1% without epinephrine                         10 mL Plastic Ampule

1% without epinephrine                         30 mL single dose solutions

1% with epinephrine   1:200,000           30 mL single dose solutions

1.5% without epinephrine                      10 mL Plastic Ampule

1.5% without epinephrine                      20 mL Plastic Ampule

1.5% with epinephrine  1:200,000         30 mL ampules, 30 mL single dose solutions

2% without epinephrine                         10 mL Plastic Ampule

2% with epinephrine   1:200,000           20 mL ampules, 20 mL single dose solutions

 

Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single dose units.  These solutions contain no bacteriostatic agent. 

In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

Caudal and Lumbar Epidural Block

As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block.  The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter.  Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.  Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure.  Adequate time should be allowed for onset of anesthesia after administration of each test dose.  The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

---

Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of Xylocaine Injection for various types of anesthetic procedures.  The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions.  When larger volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated.

There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Xylocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures.  The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient.  In all cases the lowest concentration and smallest dose that will produce the desired result should be given.  Dosages should be reduced for children and for the elderly and debilitated patients and patients with cardiac and/or liver disease.

The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (ie, total dose) of local anesthetic used.  Thus, an increase in volume and concentration of Xylocaine Injection will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia.  However, increasing the volume and concentration of Xylocaine Injection may result in a more profound fall in blood pressure when used in epidural anesthesia.  Although the incidence of side effects with lidocaine HCl is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected.

For intravenous regional anesthesia, only the 50 mL single dose vial containing Xylocaine (lidocaine HCl) 0.5% Injection should be used.

Epidural Anesthesia

For epidural anesthesia, only the following dosage forms Xylocaine Injection are recommended:

1% without epinephrine                         10 mL Plastic Ampule

1% without epinephrine                         30 mL single dose solutions

1% with epinephrine   1:200,000           30 mL single dose solutions

1.5% without epinephrine                      10 mL Plastic Ampule

1.5% without epinephrine                      20 mL Plastic Ampule

1.5% with epinephrine  1:200,000         30 mL ampules, 30 mL single dose solutions

2% without epinephrine                         10 mL Plastic Ampule

2% with epinephrine   1:200,000           20 mL ampules, 20 mL single dose solutions

 

Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single dose units.  These solutions contain no bacteriostatic agent. 

In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

Caudal and Lumbar Epidural Block

As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block.  The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter.  Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.  Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure.  Adequate time should be allowed for onset of anesthesia after administration of each test dose.  The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

Epidural Anesthesia

For epidural anesthesia, only the following dosage forms Xylocaine Injection are recommended:

1% without epinephrine                         10 mL Plastic Ampule

1% without epinephrine                         30 mL single dose solutions

1% with epinephrine   1:200,000           30 mL single dose solutions

1.5% without epinephrine                      10 mL Plastic Ampule

1.5% without epinephrine                      20 mL Plastic Ampule

1.5% with epinephrine  1:200,000         30 mL ampules, 30 mL single dose solutions

2% without epinephrine                         10 mL Plastic Ampule

2% with epinephrine   1:200,000           20 mL ampules, 20 mL single dose solutions

 

Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single dose units.  These solutions contain no bacteriostatic agent. 

In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

Caudal and Lumbar Epidural Block

As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block.  The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter.  Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.  Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure.  Adequate time should be allowed for onset of anesthesia after administration of each test dose.  The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.