Sun Pharma Global Fze

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Sun Pharma Global Fze Drugs

Decitabine Kit

Decitabine Kit

There are two regimens for Decitabine for Injection administration. With either regimen it is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles.Complete blood counts and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of treatment.

2.1 Treatment Regimen - Option 1

Decitabine for Injection is administered at a dose of 15 mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. This cycle should be repeated every 6 weeks. Patients may be premedicated with standard anti-emetic therapy. If hematologic recovery (ANC greater than or equal to 1,000/μL and platelets greater than or equal to 50,000/μL) from a previous Decitabine for Injection treatment cycle requires more than 6 weeks, then the next cycle of Decitabine for Injection therapy should be delayed and dosing temporarily reduced by following this algorithm: • Recovery requiring more than 6, but less than 8 weeks − Decitabine for Injection dosing to be delayed for up to 2 weeks and the dose temporarily reduced to 11 mg/m2 every 8 hours (33 mg/m2/day, 99 mg/m2/cycle) upon restarting therapy. • Recovery requiring more than 8, but less than 10 weeks − Patient should be assessed for disease progression (by bone marrow aspirates); in the absence of progression, the Decitabine for Injection dose should be delayed up to 2 more weeks and the dose reduced to 11 mg/m2 every 8 hours (33 mg/m2/day, 99 mg/m2/cycle) upon restarting therapy, then maintained or increased in subsequent cycles as clinically indicated.

2.2 Treatment Regimen - Option 2

Decitabine for Injection is administered at a dose of 20 mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days. This cycle should be repeated every 4 weeks. Patients may be premedicated with standard anti-emetic therapy. If myelosuppression is present, subsequent treatment cycles of Decitabine for Injection should be delayed until there is hematologic recovery (ANC greater than or equal to 1,000/μL platelets greater than or equal to 50,000/μL).

2.3 Patients with Non-hematologic Toxicity

Following the first cycle of Decitabine for Injection treatment, if any of the following non-hematologic toxicities are present, Decitabine for Injection treatment should not be restarted until the toxicity is resolved: 1) serum creatinine greater than or equal to 2 mg/dL; 2) Serum Glutamate Pyruvate Transaminase (SGPT), total bilirubin greater than or equal to 2 times Upper Limit of Normal (ULN); 3) and active or uncontrolled infection.

2.4 Instructions for Intravenous Administration

Decitabine for Injection is a cytotoxic drug and caution should be exercised when handling and preparing Decitabine for Injection. Procedures for proper handling and disposal of antineoplastic drugs should be applied. Several guidances on this subject have been published1.

Decitabine for Injection 50 mg/vial should be aseptically reconstituted with 10 mL of Diluent for Decitabine for Injection; upon reconstitution, each mL contains approximately 5 mg of decitabine at pH 6.7 to 7.3. Immediately after reconstitution, the solution should be further diluted with 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection to a final drug concentration of 0.1 to 1 mg/mL. Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2˚C to 8˚C) infusion fluids and stored at 2˚C to 8˚C (36˚F to 46˚F) for up to a maximum of 7 hours until administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is evidence of particulate matter or discoloration.
Venlafaxine Hydrochlori...

Venlafaxine Hydrochloride

Venlafaxine hydrochloride extended-release tablets should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each tablet should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water.

2.1 Initial Treatment

Major Depressive DisorderFor most patients, the recommended starting dose for venlafaxine hydrochloride

extended-release tablets is 75 mg/day, administered in a single dose. In the clinical trials establishing the efficacy of venlafaxine hydrochloride extended-release capsules in moderately depressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship between dose and antidepressant response for venlafaxine hydrochloride extended-release capsules has not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the average doses were about 140 to 180 mg/day [see Clinical Studies (14)].It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg/day for venlafaxine hydrochloride immediate-release tablets, more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higher doses of venlafaxine hydrochloride

extended-release tablets are needed for more severely depressed patients is unknown; however, the experience with venlafaxine hydrochloride extended-release capsule doses higher than 225 mg/day is very limited. [See Warnings and Precautions (5.17)]

2.2 Maintenance Treatment

There is no body of evidence available from controlled trials to indicate how long patients with major depressive disorder should be treated with venlafaxine hydrochloride extended-release tablets.It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with venlafaxine hydrochloride extended-release capsules were assigned randomly to placebo or to the same dose of venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of venlafaxine hydrochloride immediate-release tablets in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or venlafaxine hydrochloride immediate-release tablets for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule)[see Clinical Studies (14)]. Based on these limited data, it is not known whether or not the dose of venlafaxine hydrochloride extended-release tablets 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.

2.3 Special Populations

Treatment of Pregnant Women During the Third Trimester Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations (8.1)]. When treating pregnant women with venlafaxine hydrochloride extended-release tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Patients with Hepatic Impairment Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared with normal subjects [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)], it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.Patients with Renal Impairment Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared with normal subjects [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)], it is recommended that the total daily dose be reduced by 25% to 50%. In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%. Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.Elderly PatientsNo dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

2.4 Discontinuing Venlafaxine Hydrochloride Extended-Release Tablets

Symptoms associated with discontinuation of venlafaxine hydrochloride extended-release capsules, other SNRI's, and SSRI's have been reported [see Warnings and Precautions (5.5)]. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. In clinical trials with venlafaxine hydrochloride extended-release capsules, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary.

2.5 Switching Patients from Venlafaxine Hydrochloride Immediate-Release Tablets

Depressed patients who are currently being treated at a therapeutic dose with venlafaxine hydrochloride immediate-release tablets may be switched to venlafaxine hydrochloride extended-release tablets at the nearest equivalent dose (mg/day), e.g., 37.5 mg venlafaxine two-times-a-day to 75 mg venlafaxine hydrochloride extended-release tablets once daily. However, individual dosage adjustments may be necessary.

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

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with venlafaxine hydrochloride extended-release tablets. Conversely, at least 7 days should be allowed after stopping venlafaxine hydrochloride extended-release tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

2.7 Use of Venlafaxine Hydrochloride Extended-Release Tablets with Other MAOIs, Such as Linezolid or Methylene Blue

Do not start venlafaxine hydrochloride extended-release tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see CONTRAINDICATIONS (4.1)]. In some cases, a patient already receiving venlafaxine hydrochloride extended-release tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, venlafaxine hydrochloride extended-release tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with venlafaxine hydrochloride extended-release tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see WARNINGS AND PRECAUTIONS (5.2)]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with venlafaxine hydrochloride

extended-release tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see WARNINGS AND PRECAUTIONS (5.2)].
Diphenhydramine Hydroch...

Diphenhydramine Hydrochloride Solution

For Reduction of Cumulative Renal Toxicity with Chemotherapy: The recommended starting dose of Amifostine for injection is 910 mg/m2 administered once daily as a 15-minute i.v. infusion, starting 30 minutes prior to chemotherapy.

The 15-minute infusion is better tolerated than more extended infusions. Further reductions in infusion times for chemotherapy regimens have not been systematically investigated.

Patients should be adequately hydrated prior to Amifostine for injection infusion and kept in a supine position during the infusion. Blood pressure should be monitored every 5 minutes during the infusion, and thereafter as clinically indicated.

The infusion of Amifostine for injection should be interrupted if the systolic blood pressure decreases significantly from the baseline value as listed in the guideline below:
Guideline for Interrupting Amifostine for injection Infusion Due to Decrease in Systolic Blood Pressure Baseline Systolic Blood Pressure (mm Hg) < 100 100 to 119 120 to 139 140 to 179 ≥180 Decrease in systolic blood pressure during infusion of Amifostine for injection(mm Hg) 20 25 30 40 50
If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted so that the full dose of Amifostine for injection may be administered. If the full dose of Amifostine for injection cannot be administered, the dose of Amifostine for injection for subsequent chemotherapy cycles should be 740 mg/m2.

It is recommended that antiemetic medication, including dexamethasone 20 mg i.v. and a serotonin 5HT3 receptor antagonist, be administered prior to and in conjunction with Amifostine for injection. Additional antiemetics may be required based on the chemotherapy drugs administered.

Reconstitution

Amifostine for Injection is supplied as a sterile powder requiring reconstitution for intravenous infusion. Each single-use vial contains 500 mg of amifostine on the anhydrous basis.

Prior to intravenous injection, Amifostine for injection is reconstituted with 9.7 mL of sterile 0.9% Sodium Chloride Injection, USP. The reconstituted solution (500 mg amifostine/10 mL) is chemically stable for up to 5 hours at room temperature (approximately 25°C) or up to 24 hours under refrigeration (2°C to 8°C).

Amifostine for injection prepared in polyvinylchloride (PVC) bags at concentrations ranging from 5 mg/mL to 40 mg/mL is chemically stable for up to 5 hours when stored at room temperature (approximately 25°C) or up to 24 hours when stored under refrigeration (2°C to 8°C). CAUTION: Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if cloudiness or precipitate is observed.

Incompatibilities

The compatibility of Amifostine for injection with solutions other than 0.9% Sodium Chloride for Injection, or Sodium Chloride solutions with other additives, has not been examined. The use of other solutions is not recommended.
Ketorolac Tromethamine ...

Ketorolac Tromethamine Solution Drops

2.1 Recommended Dosing

Patient Dosing The recommended dose of ketorolac tromethamine ophthalmic solution is one drop four times a day to the affected eye(s) for relief of ocular itching due to seasonal allergic conjunctivitis. For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of ketorolac tromethamine ophthalmic solution should be applied to the affected eye four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.

2.2 Use with Other Topical Ophthalmic Medications

Ketorolac tromethamine ophthalmic solution has been safely administered in conjunction with other ophthalmic medications such as antibiotics, alpha-agonists, beta blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. Drops should be administered at least 5 minutes apart.
Triple Antibiotic

Triple Antibiotic

2.1 Epilepsy

It is not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy.On occasion, the addition of topiramate tablets to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate tablets may require adjustment of the dose of topiramate tablets.Because of the bitter taste, tablets should not be broken.Topiramate tablets can be taken without regard to meals.Monotherapy Use Adults and Pediatric Patients 10 Years and OlderThe recommended dose for topiramate tablets monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titration according to the following schedule (Table 1):
Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older Morning Dose Evening Dose Week 1 25 mg 25 mg Week 2 50 mg 50 mg Week 3 75 mg 75 mg Week 4 100 mg 100 mg Week 5 150 mg 150 mg Week 6 200 mg 200 mg
Children Ages 2 to <10 YearsDosing of topiramate as initial monotherapy in children 2 to < 10 years of age with partial onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach [see Clinical Studies (14.1)].Dosing in patients 2 to <10 years is based on weight. During the titration period, the initial dose of topiramate tablets should be 25 mg/day administered nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day (25 mg twice daily) in the second week. Dosage can be increased by 25 to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (Table 2).
Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to <10 Years Weight (kg) Total Daily Dose (mg/day)* Minimum Maintenance Dose Total Daily Dose (mg/day)* Maximum Maintenance Dose * Administered in two equally divided doses Up to 11 150 250 12 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400
Adjunctive Therapy Use Adults 17 Years of Age and Over - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut SyndromeThe recommended total daily dose of topiramate tablets as adjunctive therapy in adults with partial onset seizures is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be initiated at 25 to 50 mg/day followed by titration to an effective dose in increments of 25 to 50 mg/day every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day (600, 800 or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures. Daily doses above 1,600 mg have not been studied.In the study of primary generalized tonic-clonic seizures, the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks [see Clinical Studies (14.1)].Pediatric Patients Ages 2 to 16 Years – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut SyndromeThe recommended total daily dose of topiramate tablets as adjunctive therapy for pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.In the study of primary generalized tonic-clonic seizures, the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks [see Clinical Studies (14.1)].Additional pediatric use information for patients ages 12 to 17 years is approved for Janssen Pharmaceuticals, Inc.’s TOPAMAX (topiramate) Tablets and Sprinkle Capsules. However, due to Janssen Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.4 Patients with Renal Impairment

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m2), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

2.5 Geriatric Patients (Ages 65 Years and Over)

Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate <70 mL/min/1.73 m2) is evident [see Clinical Pharmacology (12.3)].

2.6 Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

2.7 Patients with Hepatic Disease

In hepatically impaired patients, topiramate plasma concentrations may be increased. The mechanism is not well understood.
Vecuronium Bromide

Vecuronium Bromide

Vecuronium bromide for injection is for intravenous use only.

This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only, especially regarding enhancement of neuromuscular blockade of vecuronium bromide by volatile anesthetics and by prior use of succinylcholine (see PRECAUTIONS: Drug Interactions).

To obtain maximum clinical benefits of vecuronium bromide and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised.

The recommended initial dose of vecuronium bromide is 0.08 to 0.1 mg/kg (1.4 to 1.75 times the ED90) given as an intravenous bolus injection. This dose can be expected to produce good or excellent non-emergency intubation conditions in 2.5 to 3 minutes after injection. Under balanced anesthesia, clinically required neuromuscular blockade lasts approximately 25 to 30 minutes, with recovery to 25% of control achieved approximately 25 to 40 minutes after injection and recovery to 95% of control achieved approximately 45 to 65 minutes after injection. In the presence of potent inhalation anesthetics, the neuromuscular blocking effect of vecuronium bromide is enhanced. If vecuronium bromide is first administered more than 5 minutes after the start of inhalation agent or when steady-state has been achieved, the initial vecuronium bromide dose may be reduced by approximately 15%, i.e., 0.06 to 0.085 mg/kg.

Prior administration of succinylcholine may enhance the neuromuscular blocking effect and duration of action of vecuronium bromide. If intubation is performed using succinylcholine, a reduction of initial dose of vecuronium bromide to 0.04 to 0.06 mg/kg with inhalation anesthesia and 0.05 to 0.06 mg/kg with balanced anesthesia may be required.

During prolonged surgical procedures, maintenance doses of 0.01 to 0.015 mg/kg of vecuronium bromide are recommended; after the initial vecuronium bromide injection, the first maintenance dose will generally be required within 25 to 40 minutes. However, clinical criteria should be used to determine the need for maintenance doses.

Since vecuronium bromide lacks clinically important cumulative effects, subsequent maintenance doses, if required, may be administered at relatively regular intervals for each patient, ranging approximately from 12 to 15 minutes under balanced anesthesia, slightly longer under inhalation agents. (If less frequent administration is desired, higher maintenance doses may be administered.)

Should there be reason for the selection of larger doses in individual patients, initial doses ranging from 0.15 mg/kg up to 0.28 mg/kg have been administered during surgery under halothane anesthesia without ill effects to the cardiovascular system being noted as long as ventilation is properly maintained (see CLINICAL PHARMACOLOGY-Pharmacokinetics).

Use by Continuous Infusion: After an intubating dose of 80 to 100 mcg/kg, a continuous infusion of 1 mcg/kg/min can be initiated approximately 20 to 40 minutes later. Infusion of vecuronium bromide should be initiated only after early evidence of spontaneous recovery from the bolus dose. Long-term intravenous infusion to support mechanical ventilation in the intensive care unit has not been studied sufficiently to support dosage recommendations. (See PRECAUTIONS, Long Term Use in I.C.U.)

The infusion of vecuronium bromide should be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. An initial rate of 1 mcg/kg/min is recommended, with the rate of the infusion adjusted thereafter to maintain a 90% suppression of twitch response. Average infusion rates may range from 0.8 to 1.2 mcg/kg/min.

Inhalation anesthetics, particularly enflurane and isoflurane may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion 25 to 60 percent, 45 to 60 min after the intubating dose. Under halothane anesthesia it may not be necessary to reduce the rate of infusion.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of vecuronium bromide infusion may be expected to proceed at rates comparable to that following a single bolus dose (see CLINICAL PHARMACOLOGY).

Infusion solutions of vecuronium bromide can be prepared by adding vecuronium bromide with an appropriate infusion solution such as Dextrose 5% Injection, Sodium Chloride 0.9% Injection, Dextrose 5% and Sodium Chloride 0.9% Injection, or Lactated Ringer’s Injection.

Unused portions of infusion solutions should be discarded.

Infusion rates of vecuronium bromide can be individualized for each patient using the following table:
* 10 mg of Vecuronium bromide in 100 mL solution † 20 mg of Vecuronium bromide in 100 mL solution Drug Delivery Rate Infusion Delivery Rate (mcg/kg/min) (mL/kg/min) 0.1 mg/mL* 0.2 mg/mL† 0.7 0.007 0.0035 0.8 0.008 0.004 0.9 0.009 0.0045 1 0.01 0.005 1.1 0.011 0.0055 1.2 0.012 0.006 1.3 0.013 0.0065
The following table is guideline for mL/min delivery for a solution of 0.1 mg/mL (10 mg in 100 mL) with an infusion pump.
VECURONIUM BROMIDE INFUSION RATE - mL/min Amount of Drug mcg/kg/min Patient Weight -kg 40 50 60 70 80 90 100 0.7 0.28 0.35 0.42 0.49 0.56 0.63 0.7 0.8 0.32 0.4 0.48 0.56 0.64 0.72 0.8 0.9 0.36 0.45 0.54 0.63 0.72 0.81 0.9 1 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 0.44 0.55 0.66 0.77 0.88 0.99 1.1 1.2 0.48 0.6 0.72 0.84 0.96 1.08 1.2 1.3 0.52 0.65 0.78 0.91 1.04 1.17 1.3
NOTE: If a concentration of 0.2 mg/mL is used (20 mg in 100 mL), the rate should be decreased by one-half.

Use in Pediatrics: Pediatric patients (10 to 16 years of age) have approximately the same dosage requirements (mg/kg) as adults and may be managed the same way. Younger pediatric patients (1 to 10 years of age) may require a slightly higher initial dose and may also require supplementation slightly more often than adults.

Infants under 1 year of age but older than 7 weeks are moderately more sensitive to vecuronium bromide on a mg/kg basis than adults and take about 11/2 times as long to recover. See also subsection of PRECAUTIONStitled Pediatric Use. Information presently available does not permit recommendation on usage in pediatric patients less than 7 weeks of age (see PRECAUTIONS-Pediatric Use). There are insufficient data concerning continuous infusion of vecuronium in pediatric patients, therefore, no dosing recommendations can be made.

COMPATIBILITY: Vecuronium bromide is compatible in solution with:

Sodium Chloride 0.9% Injection

Dextrose 5% Injection

Sterile Water for Injection

Dextrose 5% in Sodium Chloride 0.9% Injection

Lactated Ringer’s Injection

Use within 24 hours of mixing with the above solutions.

Vecuronium bromide is also compatible in solution with: bacteriostatic water for injection (NOT FOR USE IN NEWBORNS) Use within 5 days of mixing with the above solution.

Reconstituted vecuronium bromide, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions such as thiopental) in the same syringe or administered simultaneously during intravenous infusion through the same needle or through the same intravenous line.

After Reconstitution:

See DOSAGE AND ADMINISTRATION-COMPATIBILITY for diluents compatible with Vecuronium Bromide for Injection.

Single-Dose Use: When reconstituted with compatible IV solutions not containing an antimicrobial preservative (e.g., sterile water for injection), refrigerate and use within 24 hours. Discard unused portion.



Multi-Dose Use: (NOT FOR USE IN NEWBORNS.) When reconstituted with bacteriostatic water for injection, use within 5 days. The reconstituted solution may be stored at room temperature or refrigerated.



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

Bicalutamide

The recommended dose for bicalutamide tablets therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide tablets be taken at the same time each day. Treatment with bicalutamide tablets should be started at the same time as treatment with an LHRH analog.

2.1. Dosage Adjustment in Renal Impairment

No dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations (8.7)].

2.2. Dosage Adjustment in Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n=4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide no dosage adjustment is necessary [see Use in Specific Populations (8.6)].
Metformin Hydrochloride...

Metformin Hydrochloride

2.1 Galantamine Hydrobromide Extended-Release Capsules

Galantamine hydrobromide extended-release capsules should be administered once daily in the morning, preferably with food.

The recommended starting dosage of galantamine hydrobromide extended-release capsules is 8 mg/day. The dosage should be increased to the initial maintenance dose of 16 mg/day after a minimum of 4 weeks. A further increase to 24 mg/day should be attempted after a minimum of 4 weeks at 16 mg/day. Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.The dosage of galantamine hydrobromide extended-release capsules shown to be effective in a controlled clinical trial is 16 to 24 mg/day.Patients currently being treated with galantamine hydrobromide tablets or oral solution can convert to galantamine hydrobromide extended-release capsules by taking their last dose of galantamine hydrobromide tablets or oral solution in the evening and starting galantamine hydrobromide extended-release capsules once daily treatment the next morning. Converting from galantamine hydrobromide tablets to galantamine hydrobromide extended-release capsules should occur at the same total daily dosage.Patients and caregivers should be advised to ensure adequate fluid intake during treatment. If therapy has been interrupted for more than three days, the patient should be restarted at the lowest dosage and the dosage escalated to the current dose.

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

2.3 Dosage in Patients with Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9), the dosage should generally not exceed 16 mg/day. The use of galantamine hydrobromide extended-release capsules in patients with severe hepatic impairment (Child-Pugh score of 10 to 15) is not recommended [see Clinical Pharmacology (12.3)].

2.4 Dosage in Patients with Renal Impairment

In patients with creatinine clearance of 9 to 59 mL/min, the dosage should generally not exceed 16 mg/day. In patients with creatinine clearance less than 9 mL/min, the use of galantamine hydrobromide extended-release capsules is not recommended [see Clinical Pharmacology (12.3)].
Fosphenytoin Sodium

Fosphenytoin Sodium

The dose, concentration in dosing solutions, and infusion rate of IV fosphenytoin sodium injection is expressed as phenytoin sodium equivalents (PE) to avoid the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin sodium injection should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). Fosphenytoin sodium injection has important differences in administration from those for parenteral phenytoin sodium (see below).

Products with particulate matter or discoloration should not be used. Prior to IV infusion, dilute fosphenytoin sodium injection in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL.

Status Epilepticus
The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full antiepileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of fosphenytoin sodium injection, or phenytoin either orally or parenterally.
If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.

IM fosphenytoin sodium injection should not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration. If IV access is impossible, loading doses of fosphenytoin sodium injection have been given by the IM route for other indications.

Nonemergent Loading and Maintenance Dosing
The loading dose of fosphenytoin sodium injection is 10 - 20 mg PE/kg given IV or IM. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions.
The initial daily maintenance dose of fosphenytoin sodium injection is 4 - 6 mg PE/kg/day.

IM or IV Substitution For Oral Phenytoin Therapy

Fosphenytoin sodium injection can be substituted for oral phenytoin sodium therapy at the same total daily dose.

Phenytoin sodium capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy.

The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.

In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing.

Dosing in Special Populations

Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see CLINICAL PHARMACOLOGY: Special Populations). Unbound phenytoin concentrations may be more useful in these patient populations. After IV fosphenytoin sodium injection administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).

Elderly Patients: Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

Pediatric: The safety of fosphenytoin sodium injection in pediatric patients has not been established.
Irinotecan Hydrochlorid...

Irinotecan Hydrochloride

Dosage in Patients with Reduced UGT1A1 Activity

When administered as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele (See CLINICAL PHARMACOLOGY and WARNINGS). However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment (See Tables 7-8).

Single-Agent Dosage Schedules

Dosage Regimens

Irinotecan hydrochloride injection should be administered as an intravenous infusion over 90 minutes for both the weekly and once-every-3-week dosage schedules (see Preparation of Infusion Solution). Single-agent dosage regimens are shown in Table 7.
Table 7. Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications * Subsequent doses may be adjusted as high as 150 mg/m 2 or to as low as 50 mg/m 2 in 25 to 50 mg/m 2 decrements depending upon individual patient tolerance. † Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. ‡ Subsequent doses may be adjusted as low as 200 mg/m 2 in 50 mg/m 2 decrements depending upon individual patient tolerance. Weekly Regimen* 125 mg/m2 IV over 90 min, d 1,8,15,22 then 2-wk rest Starting Dose & Modified Dose Levels† (mg/m2) Starting Dose Dose Level -1 Dose Level -2 125 100 75 Once-Every-3-Week Regimen‡ 350 mg/m2 IV over 90 min, once every 3 wks† Starting Dose & Modified Dose Levels (mg/m2) Starting Dose Dose Level -1 Dose Level-2 350 300 250
A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: age ≥65 years, prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.

It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. See PRECAUTIONS, General.

Dose Modifications

Patients should be carefully monitored for toxicity and doses of irinotecan hydrochloride injection should be modified as necessary to accommodate individual patient tolerance to treatment. Based on recommended dose-levels described in Table 7, Single-Agent Regimens of Irinotecan Hydrochloride Injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 8, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.

A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment related toxicity. If the patient has not recovered, consideration should be given to discontinuing this combination therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of irinotecan hydrochloride injection may be continued indefinitely as long as patients continue to experience clinical benefit.
Table 8. Recommended Dose Modifications For Single-Agent Schedules* * All dose modifications should be based on the worst preceding toxicity † National Cancer Institute Common Toxicity Criteria (version 1.0) ‡ Pretreatment § Excludes alopecia, anorexia, asthenia A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, and the platelet count has recovered to ≥100,000/mm3, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan hydrochloride injection. Worst Toxicity NCIGrade† (Value) During a Cycle of Therapy At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cycle* Weekly Weekly Once Every 3 Weeks No toxicity Maintain dose level ↑25 mg/m2 up to a maximum dose of 150 mg/m2 Maintain dose level Neutropenia 1 (1500 to 1999/mm3) Maintain dose level Maintain dose level Maintain dose level 2 (1000 to 1499/mm3) ↓25 mg/m2 Maintain dose level Maintain dose level 3 (500 to 999/mm3) Omit dose until resolved to ≤ grade 2, then ↓25 mg/m2 ↓25 mg/m2 ↓50 mg/m2 4 ( < 500/mm3) Omit dose until resolved to ≤ grade 2, then ↓50 mg/m2 ↓50 mg/m2 ↓50 mg/m2 Neutropenic fever Omit dose until resolved, then ↓50 mg/m2 when resolved ↓50 mg/m2 ↓50 mg/m2 Other hematologic toxicities Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Diarrhea 1 (2-3 stools/day > pretx‡) Maintain dose level Maintain dose level Maintain dose level 2 (4-6 stools/day > pretx) ↓25 mg/m2 Maintain dose level Maintain dose level 3 (7-9 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓25 mg/m2 ↓25 mg/m2 ↓50 mg/m2 4 (≥10 stools/day > pretx) Omit dose until resolved to ≤ grade 2 then ↓50 mg/m2 ↓50 mg/m2 ↓50 mg/m2 Other nonhematologic§ toxicities 1 Maintain dose level Maintain dose level Maintain dose level 2 ↓25 mg/m2 ↓25 mg/m2 ↓50 mg/m2 3 Omit dose until resolved to ≤ grade 2, then ↓25 mg/m2 ↓25 mg/m2 ↓50 mg/m2 4 Omit dose until resolved to ≤ grade 2, then ↓50 mg/m2 ↓50 mg/m2 ↓50 mg/m2
Preparation & Administration Precautions

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water.

Several published guidelines for handling and disposal of anticancer agents are available.1-8

Preparation of Infusion Solution

Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe.

Irinotecan hydrochloride injection must be diluted prior to infusion. Irinotecan hydrochloride injection should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 to 2.8 mg/mL. In most clinical trials, irinotecan hydrochloride injection was administered in 250 mL to 500 mL of 5 % Dextrose Injection, USP.

The solution is physically and chemically stable for up to 24 hours at room temperature (approximately 25°C) and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing irinotecan hydrochloride injection and admixtures of irinotecan hydrochloride injection may result in precipitation of the drug and should be avoided. Because of possible microbial contamination during dilution , it is advisable to use the admixture prepared with 5%Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 6 hours if kept at room temperature (15° to 30°C, 59° to 86°F).

Other drugs should not be added to the infusion solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Bupropion Hydrochloride...

Bupropion Hydrochloride

2.1 General Instructions for Use

To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions (5.3)]. Bupropion hydrochloride extended-release tablets, USP (SR) should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride extended-release tablets, USP (SR) may be taken with or without food.

The usual adult target dose for bupropion hydrochloride extended-release tablets, USP (SR) is 300 mg per day, given as 150 mg twice daily. Initiate dosing with 150 mg per day given as a single daily dose in the morning. After 3 days of dosing, the dose may be increased to the 300 mg per day target dose, given as 150 mg twice daily. There should be an interval of at least 8 hours between successive doses. A maximum of 400 mg per day, given as 200 mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg per day. To avoid high peak concentrations of bupropion and/or its metabolites, do not exceed 200 mg in any single dose.

It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride extended-release tablets, USP (SR) needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.

2.2 Dose Adjustment in Patients with Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride extended-release tablets, USP (SR) is 100 mg per day or 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.3 Dose Adjustment in Patients with Renal Impairment

Consider reducing the dose and/or frequency of bupropion hydrochloride extended-release tablets, USP (SR) in patients with renal impairment (Glomerular Filtration Rate <90 mL/min) [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.4 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with bupropion hydrochloride extended-release tablets, USP (SR). Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets, USP (SR) before starting an MAOI antidepressant [see Contraindications (4), Drug Interactions (7.6)].

2.5 Use of Bupropion Hydrochloride Extended-Release Tablets, USP (SR) With Reversible MAOIs Such as Linezolid or Methylene Blue

Do not start bupropion hydrochloride extended-release tablets, USP (SR) in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications (4), Drug Interactions (7.6)].

In some cases, a patient already receiving therapy with bupropion hydrochloride extended-release tablets, USP (SR) may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, bupropion hydrochloride extended-release tablets, USP (SR)should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with bupropion hydrochloride extended-release tablets, USP (SR) may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with bupropion hydrochloride extended-release tablets, USP (SR) is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications (4), Drug Interactions (7.6)].
Azelastine Hydrochlorid...

Azelastine Hydrochloride Solution Drops

The recommended dose is one drop instilled into each affected eye twice a day.
Atomoxetine Hydrochlori...

Atomoxetine Hydrochloride

2.1 Acute Treatment
Dosing of children and adolescents up to 70 kg body weight — Atomoxetine hydrochloride capsules should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day [see Clinical Studies (14)]. The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less. Dosing of children and adolescents over 70 kg body weight and adults — Atomoxetine hydrochloride capsules should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses [see Clinical Studies (14)]. The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg.
2.2 Maintenance/Extended Treatment
It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The physician who elects to use atomoxetine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
2.3 General Dosing Information
Atomoxetine hydrochloride capsules may be taken with or without food. Atomoxetine hydrochloride capsules can be discontinued without being tapered. Atomoxetine hydrochloride capsules are not intended to be opened, they should be taken whole [see Patient Counseling Information (17.6)]. The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated.
2.4 Dosing in Specific Populations
Dosing adjustment for hepatically impaired patients — For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI). For patients with severe HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal [see Use In Specific Populations (8.6)]. Dosing adjustment for use with a strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs — In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, atomoxetine hydrochloride capsules should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, atomoxetine hydrochloride capsules should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.
Flu Relief Bp

Flu Relief Bp

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
Sublingual NTG. May be taken as required to abort acute anginal attacks during diltiazem hydrochloride therapy. Prophylactic Nitrate Therapy. Diltiazem hydrochloride extended-release capsules may be safely coadministered with short- and long-acting nitrates. Beta-blockers (see WARNINGS and PRECAUTIONS). 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.
Rapid Release Pain Reli...

Rapid Release Pain Reliever

The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily subcutaneous injection. As with other drugs administered chronically by subcutaneous injection, the injection site should be varied periodically. Each 0.2 mL contains 1 mg of leuprolide acetate, sodium chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as preservative and water for injection. The pH may have been adjusted with sodium hydroxide and/or glacial acetic acid.

Follow the pictorial directions on the reverse side of this package insert for administration.

NOTE: As with all parenteral products, inspect the solution for discoloration and particulate matter before each use.
Gemcitabine

Gemcitabine

2.1 Ovarian Cancer

Recommended Dose and Schedule The recommended dose of gemcitabine for injection, USP is 1,000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after gemcitabine for injection administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.Dose Modifications Recommended gemcitabine for injection, USP dose modifications for myelosuppression are described in Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
Table 1: Dosage Reduction Guidelines for Gemcitabine for Injection for Myelosuppression on Day of Treatment in Ovarian Cancer TreatmentDay Absolute granulocyte count (x 106/L) Platelet count (x 106/L) % of full dose Day 1 ≥1,500 and ≥100,000 100% <1,500 or <100,000 Delay Treatment Cycle Day 8 ≥1,500 and ≥100,000 100% 1,000 to 1,499 or 75,000 to 99,999 50% <1,000 or <75,000 Hold Table 2: Gemcitabine for Injection Dose Modification for Myelosuppression in Previous Cycle In Ovarian Cancer Occurrence Myelosuppression During Treatment Cycle Dose Modification Initial Occurrence Absolute granulocyte count less than 500 x 106/L for more than 5 daysAbsolute granulocyte count less than 100 x 106/L for more than 3 daysFebrile neutropeniaPlatelets less than 25,000x106/LCycle delay of more than one week due to toxicity Permanently reduce gemcitabine for injection to 800 mg/m2 onDays 1 and 8 SubsequentOccurrence If any of the above toxicities occur after the initial dose reduction Permanently reduce gemcitabine for injection dose to 800 mg/m2 on Day 1 only
2.2 Breast Cancer

Recommended Dose and Schedule The recommended dose of gemcitabine for injection, USP is 1,250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion before gemcitabine for injection administration.Dose Modifications Recommended dose modifications for gemcitabine for injection, USP for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
Table 3: Recommended Dose Reductions for Gemcitabine for Injection for Myelosuppression on Day of Treatment in Breast Cancer Treatment Day Absolute granulocyte count(x 106/L) Platelet count(x 106/L) % of full dose Day 1 ≥1,500 and ≥100,000 100% less than 1,500 or less than 100,000 Hold Day 8 ≥1,200 and >75,000 100% 1,000 to 1,199 or 50,000 to 75,000 75% 700 to 999 and ≥50,000 50% <700 or <50,000 Hold
2.3 Non-Small Cell Lung Cancer

Recommended Dose and Schedule Every 4-week scheduleThe recommended dose of gemcitabine for injection, USP is 1,000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine for injection, USP.Every 3-week scheduleThe recommended dose of gemcitabine for injection, USP is 1,250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine for injection, USP.Dose Modifications Recommended dose modifications for gemcitabine for injection, USP myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for gemcitabine for injection, USP recommendations for non-hematologic adverse reactions.

2.4 Pancreatic Cancer

Recommended Dose and Schedule The recommended dose of gemcitabine for injection, USP is 1,000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule is as follows:
Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one week rest. After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles.
Dose Modifications Recommended dose modifications for gemcitabine for injection, USP for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.Patients receiving gemcitabine for injection, USP should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 4.
Table 4: Recommended Dose Reductions for Gemcitabine for Injection, USP for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer Absolute granulocyte count(x 106/L) Platelet count(x 106/L) % of full dose ≥1,000 And ≥100,000 100% 500 to 999 Or 50,000 to 99,999 75% <500 Or <50,000 Hold
2.5 Dose Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue gemcitabine for injection, USP for any of the following:
Unexplained dyspnea or other evidence of severe pulmonary toxicity Severe hepatic toxicity Hemolytic-uremic syndrome Capillary leak syndrome Posterior reversible encephalopathy syndrome
Withhold gemcitabine for injection, USP or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

2.6 Preparation and Administration Precautions

Exercise caution and wear gloves when preparing gemcitabine for injection, USP solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if gemcitabine for injection, USP contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling gemcitabine for injection, USP go to “OSHA Hazardous Drugs” (refer to antineoplastic weblinks including OSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

2.7 Preparation for Intravenous Infusion Administration

Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives.Add 5 mL to the 200 mg vial or 25 mL to the 1 g vial. These dilutions each yield a gemcitabine for injection, USP concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine for injection, USP. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.Reconstituted gemcitabine for injection is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine for injection solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not refrigerate as crystallization can occur.No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Cetirizine Hydrochlorid...

Cetirizine Hydrochloride

may be taken with or without water
For 5 mg:
adults and children 6 years and over 1 to 2 tablets once daily depending upon severity of symptoms; do not take more than 2 tablets in 24 hours. adults 65 years and over 1 tablet once a day; do not take more than 1 tablet in 24 hours children under 6 years of age ask a doctor consumers with liver or kidney disease ask a doctor
For 10 mg:
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
Cetirizine Hydrochlorid...

Cetirizine Hydrochloride

may be taken with or without water
For 5 mg:
adults and children 6 years and over 1 to 2 tablets once daily depending upon severity of symptoms; do not take more than 2 tablets in 24 hours. adults 65 years and over 1 tablet once a day; do not take more than 1 tablet in 24 hours children under 6 years of age ask a doctor consumers with liver or kidney disease ask a doctor For 10 mg: 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
Alfuzosin Hydrochloride...

Alfuzosin Hydrochloride

The recommended dosage is one 10 mg alfuzosin hydrochloride extended-release tablet once daily. The extent of absorption of alfuzosin is 50% lower under fasting conditions. Therefore, alfuzosin hydrochloride extended-release tablets should be taken with food and with the same meal each day. The tablets should not be chewed or crushed.
Clopidogrel Bisulfate

Clopidogrel Bisulfate

2.1 Acute Coronary Syndrome

Clopidogrel

tablets can be administered with or without food [see Clinical Pharmacology (12.3)].
For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75 mg to 325 mg once daily) and continue in combination with clopidogrel tablets [see Clinical Studies (14.1)]. For patients with STEMI, the recommended dose of clopidogrel tablets is 75 mg once daily orally, administered in combination with aspirin (75 mg to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets may be initiated with or without a loading dose [see Clinical Studies (14.1)].
2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

The recommended daily dose of clopidogrel

tablets is 75 mg once daily orally, with or without food [see Clinical Pharmacology (12.3)].

2.3 CYP2C19 Poor Metabolizers

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response [see Clinical Pharmacology (12.5)], an appropriate dose regimen for this patient population has not been established.

2.4 Use with Proton Pump Inhibitors (PPI)

Avoid using omeprazole or esomeprazole with clopidogrel tablets. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite [see Warnings and Precautions (5.1), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Lipodox

Lipodox

Breast Cancer/Ovarian cancer: Lipodox should be administered intravenously at a dose of 50 mg/m 2 at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related adverse events are observed, the rate of infusion can be increased to complete administration of the drug over one hour. The patient should be dosed once every 4 weeks, for as long as the patient responds satisfactorily or tolerates treatment. In those patients who experience an infusion reaction, the method of infusion should be modified as follows: 5% of the total dose should be infused slowly over the first 15 minutes. If tolerated without reaction, the infusion rate may then be doubled for the next 15 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes.
The median time to response in clinical trials was reported to be 4 months therefore, a minimum of 4 courses is recommended. To manage adverse effects such as PPE, stomatitis or hematologic toxicity the doses may be delayed or reduced. Concomitant or pretreatment with antiemetics should be considered.

AIDS-KS patients: Lipodox should be administered intravenously at a dose of 20 mg/m2 over 30 minutes once every three weeks for as long as the patient responds satisfactorily and tolerates treatment.

General information: Do not administer as a bolus injection or an undiluted solution. Rapid infusion may increase the risk of infusion related reactions. No compatibility data are available for liposomal doxorubicin and therefore, it is not recommended that it be mixed with other drugs.

If any signs and symptoms of extravasation are observed, the infusion must be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction.

Lipodox must not be given by the intramuscular or the subcutaneous route.
Dose modification guidelines: There should be careful monitoring of the patient for toxicity. Adverse events such as PPE, hematologic toxicities and stomatitis may be managed by dose delays and adjustments. Following the first appearance of a grade 2 or higher adverse event, the dosing should be adjusted or delayed as described in the following tables. Once the dose has been reduced, it should not be increased at a later time. PALMAR- PLANTAR ERYTHRODYSESTHESIA Toxicity Grade Dose Adjustment 1-(Mild erythema, swelling or desquamation not interfering with daily activities). Redose unless patient has experienced previous grade 3 or 4 toxicity. If so, delay upto 2 weeks and decrease dose by 25%. Return to original dose interval. 2- (Erythema, desquamation or swelling interfering with but not precluding normal physical activities, small blisters or ulceration less than 2 cm in diameter). Delay dosing upto 2 weeks or until resolved to grade 0-1. If after 2 weeks there is no resolution, Lipodox should be discontinued. 3- (Blistering, ulceration or swelling interfering with walking or normal daily activities; cannot wear regular clothing). Delay dosing upto 2 weeks or until resolved to grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Lipodox should be discontinued. 4- (Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization). Delay dosing upto 2 weeks or until resolved to grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Lipodox should be discontinued STOMATITIS Toxicity Grade Dose Adjustment 1- (Painless ulcers, erythema or mild soreness). Redose unless patient has experienced grade 3 or 4 toxicity. If so, delay upto 2 weeks and decrease dose by 25%. Return to original dose interval. 2- (Painful erythema, edema or ulcers but can eat). Delay dosing upto 2 weeks or until resolved to grade 0-1. If after 2 weeks there is no resolution, Lipodox should be discontinued. 3- (Painful erythema, edema or ulcers and cannot eat). Delay dosing upto 2 weeks or until resolved to grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Lipodox should be discontinued. 4- (Requires parenteral or enteral support). Delay dosing upto 2 weeks or until resolved to grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Lipodox should be discontinued. HEMATOLOGICAL TOXICITY Grade ANC Platelets Modification 1 1500 - 1900 75,000 - 150,000 Resume treatment with no dose reduction. 2 1000 - <1500 50,000 - <75,000 Wait until ANC ≥ 1500 and platelets ≥ 75,000; redose with no dose reduction. 3 500 - 999 25,000 - <50,000 Wait until ANC ≥ 1500 and platelets ≥ 75,000; redose with no dose reduction. 4 <500 <25,000 Wait until ANC ≥ 1500 and platelets ≥ 75,000; redose at 25% dose reduction or continue full dose with cytokine support. Pediatric patients: Safety and effectiveness in patients less than 18 years of age is not established. Elderly: No overall differences were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Hepatic impairment: Liposomal doxorubicin pharmacokinetics determined in a small number of patients with elevated total bilirubin levels do not differ from patients with normal total bilirubin; however, until further experience is gained, the liposomal doxorubicin dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian clinical trial programmes as follows: At initiation of therapy, if bilirubin is between 1.2-3.0 mg/dl, the first dose is reduced by 25%. If the bilirubin is > 3.0 mg/dl, the first dose is reduced by 50%. If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level, i.e., if reduced by 25% for the first dose, increase to full dose for cycle 2; if reduced by 50% for the first dose, increase to 75% of full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated. Liposomal doxorubicin can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes upto 4 x the upper limit of the normal range. Prior to liposomal doxorubicin administration the hepatic function should be evaluated using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase and bilirubin. Renal impairment: As doxorubicin is metabolised by the liver and excreted in the bile, dose modification will not be required. Population pharmacokinetic data (in the range of creatinine clearance of 30-156 ml/min) demonstrate that liposomal doxorubicin clearance is not influenced by renal function. No pharmacokinetic data are available in patients with creatinine clearance of less than 30 ml/min.
Preparation for intravenous administration: The appropriate dose of liposomal doxorubicin upto a maximum of 90 mg must be diluted in 250 ml of 5% Dextrose Injection USP prior to administration. Doses exceeding 90 mg should be diluted in 500 ml of 5% dextrose injection USP prior to administration. Aseptic technique must be strictly observed since no preservative or bacteriostatic agents is present in Lipodox. Diluted liposomal doxorubicin should be refrigerated at 2°C to 8°C and administered within 24 hours. Lipodox should not be used with in line filters and should not be mixed with other drugs. It should not be used with any other diluent other than Dextrose injection 5%. Partially used vials should be discarded.

Lipodox is not a clear solution but a transluscent, red liposomal dispersion.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.

Doxorubicin is not a vesicant but should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of liposomal doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. The application of ice over the side of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction.
Caution should be exercised in the handling and preparation of liposomal doxorubicin. The use of gloves is required. If Lipodox comes into contact with skin or mucosa, immediately wash thoroughly with soap or water. It should be handled and disposed off in a manner consistent with other anticancer drugs.
Carbidopa

Carbidopa

Carbidopa, levodopa and entacapone tablets should be used as a substitute for patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. However, some patients who have been stabilized on a given dose of carbidopa/levodopa may be treated with carbidopa, levodopa and entacapone tablets if a decision has been made to add entacapone (see below). Therapy should be individualized and adjusted according to the desired therapeutic response.

2.1 Dosing Information

The optimum daily dosage of carbidopa, levodopa and entacapone tablets must be determined by careful titration in each patient.

Clinical experience with daily doses above 1,600 mg of entacapone is limited. The maximum recommended daily dose of carbidopa, levodopa and entacapone tablets depends on the strength used. Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 mg per day to 100 mg per day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.
Table 1: Maximum Recommended Dose of Carbidopa, Levodopa and Entacapone Tablets in a 24 hour Period Carbidopa, Levodopa and Entacapone Tablets Dosage Strength Maximum Number of Tablets in a 24‑hour Period 25 mg/100 mg/200 mg37.5 mg/150 mg/200 mg 8
2.2 Converting Patients from Carbidopa, Levodopa, and Entacapone to Carbidopa, Levodopa and Entacapone Tablets

Patients currently treated with entacapone 200 mg with each dose of non-extended release carbidopa/levodopa tablet, can switch to the corresponding strength of carbidopa, levodopa and entacapone tablets containing the same amounts of levodopa and carbidopa. For example, patients receiving one tablet of carbidopa/levodopa 25 mg/100 mg and one tablet of entacapone 200 mg at each administration can switch to a single carbidopa, levodopa and entacapone tablet 25 mg/100 mg/200 mg (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone).

2.3 Converting Patients from Carbidopa and Levodopa Products to Carbidopa, Levodopa and Entacapone Tablets

There is no experience in transferring patients currently treated with extended release formulations of carbidopa/levodopa, or carbidopa/levodopa products that are not combined in a 1:4 ratio of carbidopa to levodopa.

Patients with a history of moderate or severe dyskinesias or taking more than 600 mg of the levodopa component per day are likely to require a reduction in their daily levodopa dose when entacapone is added. Because dose adjustment of the individual carbidopa or levodopa component is not possible with fixed-dose products, initially titrate patients to a dose that is tolerated and that meets their individual therapeutic need using a separate carbidopa/levodopa tablet (1:4 ratio) plus an entacapone tablet. Once the patient’s individual dose of carbidopa/levodopa plus entacapone dose has been established using two separate tablets; switch the patient to a corresponding single tablet of carbidopa, levodopa and entacapone.

When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa either by decreasing the strength of carbidopa, levodopa and entacapone tablets at each administration or by decreasing the frequency of administration by extending the time between doses.

2.4 Concomitant Use with Other Anti-Parkinson's Disease Drugs

Anticholinergic agents, dopamine agonists, monoamine oxidase (MAO) - B inhibitors, amantadine, and other standard drugs for Parkinson's disease may be used concomitantly while carbidopa, levodopa and entacapone tablets are being administered; however, dosage adjustments of the concomitant medication or carbidopa, levodopa and entacapone tabletsmay be required.

2.5 Decrease or Interruption of Dosing

Avoid interruption of carbidopa, levodopa and entacapone tabletsdosing because hyperpyrexia has been reported in patients who suddenly discontinue or reduce their use of levodopa [see Warnings and Precautions (5.7)].

2.6 Important Administration Instructions

Do not split, crush or chew carbidopa, levodopa and entacapone tablets. Administer only one tablet at each dosing interval. All strengths of carbidopa, levodopa and entacapone tablets contain 200 mg of entacapone. Combining multiple tablets or portions of tablets to achieve a higher levodopa dose may lead to an overdose of entacapone.Administer carbidopa, levodopa and entacapone tablets with or without food. However, a high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours[see Clinical Pharmacology (12.3)].
Entacapone

Entacapone

The recommended dose of entacapone tablets is one 200 mg tablet administered concomitantly with each levodopa/carbidopa dose to a maximum of 8 times daily (200 mg x 8 = 1600 mg per day). Clinical experience with daily doses above 1600 mg is limited. Entacapone tablets should always be administered in association with levodopa/carbidopa. Entacapone has no antiparkinsonian effect of its own. In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been ≥ 800 mg or if patients had moderate or severe dyskinesias before beginning treatment. To optimize an individual patient’s response, reductions in daily levodopa dose or extending the interval between doses may be necessary. In clinical trials, the average reduction in daily levodopa dose was about 25% in those patients requiring a levodopa dose reduction. (More than 58% of patients with levodopa doses above 800 mg daily required such a reduction.) Entacapone tablets can be combined with both the immediate and sustained-release formulations of levodopa/carbidopa. Entacapone tablets may be taken with or without food (see CLINICAL PHARMACOLOGY). Patients With Impaired Hepatic Function : Patients with hepatic impairment should be treated with caution. The AUC and C max of entacapone approximately doubled in patients with documented liver disease, compared to controls. However, these studies were conducted with single-dose entacapone without levodopa/dopa decarboxylase inhibitor coadministration, and therefore the effects of liver disease on the kinetics of chronically administered entacapone have not been evaluated (see CLINICAL PHARMACOLOGY, Pharmacokinetics of Entacapone). Withdrawing Patients from Entacapone Tablets: Rapid withdrawal or abrupt reduction in the entacapone tablet dose could lead to emergence of signs and symptoms of Parkinson’s Disease (see CLINICAL PHARMACOLOGY, Clinical Studies), and may lead to Hyperpyrexia and Confusion, a symptom complex resembling the neuroleptic malignant syndrome (see PRECAUTIONS, Other Events Reported With Dopaminergic Therapy). This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. If a decision is made to discontinue treatment with entacapone tablets, patients should be monitored closely and other dopaminergic treatments should be adjusted as needed. Although tapering entacapone tablets have not been systematically evaluated, it seems prudent to withdraw patients slowly if the decision to discontinue treatment is made.
Docefrez

Docefrez

For all indications, toxicities may warrant dosage adjustments [see Dosage and Administration (2.7)]. Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).

2.1 Breast Cancer
For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of DOCEFREZ is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.
2.2 Non-Small Cell Lung Cancer
For treatment after failure of prior platinum-based chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose is 75 mg/m2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5), Clinical Studies (14)].For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin. The recommended dose of DOCEFREZ is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every 3 weeks [see Dosage and Administration (2.7)].
2.3 Prostate Cancer
For hormone-refractory metastatic prostate cancer, the recommended dose of DOCEFREZ is 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously [see Dosage and Administration (2.7)].
2.6 Premedication Regimen

All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to DOCEFREZ administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.4)]. For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the DOCEFREZ infusion [see Warnings and Precautions (5.4)].

2.7 Dosage Adjustments During Treatment

Breast Cancer Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during DOCEFREZ therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during DOCEFREZ therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have DOCEFREZ treatment discontinued entirely. Non-Small Cell Lung Cancer Monotherapy with DOCEFREZ for NSCLC treatment after failure of prior platinum-based chemotherapy Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during DOCEFREZ treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have DOCEFREZ treatment discontinued entirely.Combination therapy with DOCEFREZ for chemotherapy-naïve NSCLC For patients who are dosed initially at DOCEFREZ 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the DOCEFREZ dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers’ prescribing information. Prostate Cancer Combination therapy with DOCEFREZ for hormone-refractory metastatic prostate cancer DOCEFREZ should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during DOCEFREZ therapy should have the dosage of DOCEFREZ reduced from 75 mg/m² to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued. Combination Therapy with Strong CYP3A4 inhibitors:Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require coadministration of a strong CYP3A4 inhibitor. [see Drug Interactions (7), Clinical Pharmacology (12.3)].

2.8 Administration Precautions

DOCEFREZ is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing DOCEFREZ solutions. The use of gloves is recommended. Please refer to [see How Supplied/ Storage and Handling (16.3)]. If DOCEFREZ lyophilized powder, reconstituted solution, or infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If DOCEFREZ lyophilized powder, reconstituted solution or infusion solution should come into contact with mucosa, immediately and thoroughly wash with water.Contact of the DOCEFREZ reconstituted solution with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the DOCEFREZ infusion solution should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.DOCEFREZ (Lyophilized Powder for Injection and Diluent) DOCEFREZ for Injection requires reconstitution with Diluent and one further dilution with infusion solution prior to administration. Please follow the preparation instructions provided below.The table below provides the fill range of the Diluent, the volume of Diluent to be added for the reconstitution and the concentration of the reconstituted solution for DOCEFREZ 20 mg and DOCEFREZ 80 mg (See Table 1).
Table 1- Reconstitution of DOCEFREZ (docetaxel) for Injection Product Fill Range of the Diluent (35.4% w/w ethanol in polysorbate 80) Volume of Diluent to be added for the reconstitution Concentration of the reconstituted solution Docetaxel 20 mg vial 1.10 – 1.15 mL 1 mL 20 mg/0.8 mL Docetaxel 80 mg vial 4.13 – 4.29 mL 4 mL 24 mg/mL
2.9 Preparation and Administration

DOCEFREZ (Lyophilized Powder for Injection and Diluent) A. Preparation of the Reconstituted Solution
DOCEFREZ vials should be stored between 2°C and 8°C (36°F and 46°F). Allow the appropriate number of vials of DOCEFREZ (docetaxel) for Injection and diluent (35.4% ethanol in polysorbate 80) vials to stand at room temperature for approximately 5 minutes. a) For DOCEFREZ 20: Use 1 mL syringe with needle of 18- to 21-gauge, 1½-inch for withdrawing diluent for DOCEFREZ 20.b) For DOCEFREZ 80: Use 4 mL syringe with needle of 18- to 21-gauge, 1½-inch for withdrawing diluent for DOCEFREZ 80. a) For DOCEFREZ 20: Aseptically withdraw 1 mL from the diluent vial into a syringe by partially inverting the vial, and transfer it to product vial of DOCEFREZ (docetaxel) for Injection. b) For DOCEFREZ 80: Aseptically withdraw 4 mL from the diluent vial into a syringe by partially inverting the vial, and transfer it to product vial of DOCEFREZ (docetaxel) for Injection . Shake the reconstituted vial well in order to completely dissolve the docetaxel powder present in the vial. For the 20 mg vial, the resultant concentration is 20 mg/0.8 mL. For the 80 mg vial, the resultant concentration is 24 mg/mL .
The reconstituted DOCEFREZ solution should be clear; however, there may be some air bubbles in the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any air bubbles to dissipate. The reconstituted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours.B. Preparation of the Infusion Solution
Aseptically withdraw the required amount of reconstituted DOCEFREZ solution with a calibrated syringe and inject into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/mL. If a dose greater than 200 mg of DOCEFREZ is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded. Thoroughly mix the infusion by manual rotation. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If the DOCEFREZ reconstituted solution or infusion solution is not clear or appears to have precipitation, these should be discarded. DOCEFREZ reconstituted solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.
The final DOCEFREZ infusion solution should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25° C) and lighting conditions.

2.10 Stability

DOCEFREZ infusion solution, if stored between 2°C and 25°C (36°F and 77°F) is stable for 6 hours. DOCEFREZ infusion solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 6 hours (including the 1 hour intravenous administration). In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C (36°F and 46°F).
Pantoprazole Sodium

Pantoprazole Sodium

2.1 Recommended Dosing Schedule
Pantoprazole sodium is supplied as delayed-release tablets. The recommended dosages are outlined in Table 1. Table 1: Recommended Dosing Schedule for Pantoprazole Sodium Delayed-Release Tablets Indication Dose Frequency * For adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium delayed-release tablets may be considered. † Dosage regimens should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 240 mg daily have been administered. Short-Term Treatment of Erosive Esophagitis Associated With GERD Adults 40 mg Once daily for up to 8 weeks* Maintenance of Healing of Erosive Esophagitis Adults 40 mg Once daily Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Adults 40 mg Twice daily† Pediatric dosing information in pediatric patients ages five years and older with erosive esophagitis associated with GERD is approved for Wyeth Pharmaceuticals Inc.’s pantoprazole sodium delayed-release tablets. However, due to Wyeth Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
2.2 Administration Instructions
Directions for method of administration for each dosage form are presented in Table 2. Table 2: Administration Instructions Formulation Route Instructions* * Patients should be cautioned that pantoprazole sodium delayed-release tablets should not be split, chewed, or crushed. Delayed-Release Tablets Oral Swallowed whole, with or without food Pantoprazole sodium delayed-release tablets should be swallowed whole, with or without food in the stomach. If patients are unable to swallow a 40 mg tablet, two 20 mg tablets may be taken. Concomitant administration of antacids does not affect the absorption of pantoprazole sodium delayed-release tablets.
Myambutol

Myambutol

Prior to initiation of caffeine citrate, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine. Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta.

The recommended loading dose and maintenance doses of caffeine citrate follow.
* using a syringe infusion pump † beginning 24 hours after the loading dose Dose of Caffeine Citrate Dose of Caffeine Citrate Route Frequency Volume mg/kg Loading Dose 1 mL/kg 20 mg/kg Intravenous* One Time (over 30 minutes) Maintenance 0.25 mL/kg 5 mg/kg Intravenous* Every Dose (over 10 24 hours† minutes) or Orally
NOTE THAT THE DOSE OF CAFFEINE BASE IS ONE-HALF THE DOSE WHEN EXPRESSED AS CAFFEINE CITRATE (e.g., 20 mg of caffeine citrate is equivalent to 10 mg of caffeine base).

Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity. Serious toxicity has been associated with serum levels greater than 50 mg/L.

Caffeine citrate injection and caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to administration. Vials containing discolored solution or visible particulate matter should be discarded.

Drug Compatibility

To test for drug compatibility with common intravenous solutions or medications, 20 mL of caffeine citrate injection were combined with 20 mL of a solution or medication, with the exception of an Intralipid® admixture, which was combined as 80 mL/80 mL. The physical appearance of the combined solutions was evaluated for precipitation. The admixtures were mixed for 10 minutes and then assayed for caffeine. The admixtures were then continually mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours.

Based on this testing, caffeine citrate injection, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products.
Dextrose Injection, USP 5% 50% Dextrose Injection USP Intralipid® 20% IV Fat Emulsion Aminosyn® 8.5% Crystalline Amino Acid Solution Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5% Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca+2/mL) Heparin Sodium Injection, USP 1000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5%
Fentanyl Citrate Injection, USP 50 µg/mL diluted to 10 µg/mL with Dextrose Injection, USP 5%
Carbidopa

Carbidopa

Carbidopa, levodopa and entacapone tablets should be used as a substitute for patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. However, some patients who have been stabilized on a given dose of carbidopa/levodopa may be treated with carbidopa, levodopa and entacapone tablets if a decision has been made to add entacapone (see below). Therapy should be individualized and adjusted according to the desired therapeutic response.

2.1 Dosing Information

The optimum daily dosage of carbidopa, levodopa and entacapone tablets must be determined by careful titration in each patient.

Clinical experience with daily doses above 1,600 mg of entacapone is limited. The maximum recommended daily dose of carbidopa, levodopa and entacapone tablets depends on the strength used. The maximum number of tablets to be used in a 24-hour period is less with the highest strength (carbidopa, levodopa and entacapone tablets 50 mg/200 mg/200 mg) than with lower strengths (see Table 1). Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 mg per day to 100 mg per day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.
Table 1: Maximum Recommended Dose of Carbidopa, Levodopa and Entacapone Tablets in a 24 hour Period Carbidopa, Levodopa and Entacapone Tablets Dosage Strength Maximum Number of Tablets in a 24‑hour Period 12.5 mg/50 mg/200 mg18.75 mg/75 mg/200 mg25 mg/100 mg/200 mg31.25 mg/125 mg/200 mg37.5 mg/150 mg/200 mg 8 50 mg/200 mg/200 mg 6
2.2 Converting Patients from Carbidopa, Levodopa, and Entacapone to Carbidopa, Levodopa and Entacapone Tablets

Patients currently treated with entacapone 200 mg with each dose of non-extended release carbidopa/levodopa tablet, can switch to the corresponding strength of carbidopa, levodopa and entacapone tablets containing the same amounts of levodopa and carbidopa. For example, patients receiving one tablet of carbidopa/levodopa 25 mg/100 mg and one tablet of entacapone 200 mg at each administration can switch to a single carbidopa, levodopa and entacapone tablet 25 mg/100 mg/200 mg (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone).

2.3 Converting Patients from Carbidopa and Levodopa Products to Carbidopa, Levodopa and Entacapone Tablets

There is no experience in transferring patients currently treated with extended release formulations of carbidopa/levodopa, or carbidopa/levodopa products that are not combined in a 1:4 ratio of carbidopa to levodopa.

Patients with a history of moderate or severe dyskinesias or taking more than 600 mg of the levodopa component per day are likely to require a reduction in their daily levodopa dose when entacapone is added. Because dose adjustment of the individual carbidopa or levodopa component is not possible with fixed-dose products, initially titrate patients to a dose that is tolerated and that meets their individual therapeutic need using a separate carbidopa/levodopa tablet (1:4 ratio) plus an entacapone tablet. Once the patient’s individual dose of carbidopa/levodopa plus entacapone dose has been established using two separate tablets; switch the patient to a corresponding single tablet of carbidopa, levodopa and entacapone.

When less levodopa is required, reduce the total daily dosage of carbidopa/levodopa either by decreasing the strength of carbidopa, levodopa and entacapone tablets at each administration or by decreasing the frequency of administration by extending the time between doses.

2.4 Concomitant Use with Other Anti-Parkinson's Disease Drugs

Anticholinergic agents, dopamine agonists, monoamine oxidase (MAO) - B inhibitors, amantadine, and other standard drugs for Parkinson's disease may be used concomitantly while carbidopa, levodopa and entacapone tablets are being administered; however, dosage adjustments of the concomitant medication or carbidopa, levodopa and entacapone tabletsmay be required.

2.5 Decrease or Interruption of Dosing

Avoid interruption of carbidopa, levodopa and entacapone tabletsdosing because hyperpyrexia has been reported in patients who suddenly discontinue or reduce their use of levodopa [see Warnings and Precautions (5.7)].

2.6 Important Administration Instructions

Do not split, crush or chew carbidopa, levodopa and entacapone tablets. Administer only one tablet at each dosing interval. All strengths of carbidopa, levodopa and entacapone tablets contain 200 mg of entacapone. Combining multiple tablets or portions of tablets to achieve a higher levodopa dose may lead to an overdose of entacapone.Administer carbidopa, levodopa and entacapone tablets with or without food. However, a high-fat, high-calorie meal may delay the absorption of levodopa by about 2 hours[see Clinical Pharmacology (12.3)].
Rizatriptan Benzoate

Rizatriptan Benzoate

2.1 Dosing Information in Adults

The recommended starting dose of rizatriptan benzoate tablets is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10 mg dose may provide a greater effect than the 5 mg dose, but may have a greater risk of adverse reactions [see Clinical Studies (14.1)].Redosing in AdultsAlthough the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose. The maximum daily dose should not exceed 30 mg in any 24-hour period. The safety of treating, on average, more than four headaches in a 30-day period has not been established.

2.2 Dosing Information in Pediatric Patients (Age 6 to 17 Years)

Information related to dosage of rizatriptan benzoate in pediatric patients (6 to 17 years old) is approved for Merck & Co., Inc.’s Rizatriptan Benzoate Tablets. However, due to Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that dosage information.

2.4 Dosage Adjustment for Patients on Propranolol

Adult Patients In adult patients taking propranolol, only the 5 mg dose of rizatriptan benzoate tablets is recommended, up to a maximum of 3 doses in any 24-hour period (15 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Pediatric Patients Dosage adjustment information of rizatriptan benzoate for pediatric patients (6 to 17 years old) taking propranolol is approved for Merck & Co., Inc.’s Rizatriptan Benzoate Tablets. However, due to Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that dosage adjustment information.
Doxorubicin Hydrochlori...

Doxorubicin Hydrochloride Injectable

2.1 Important Use Information

Do not substitute doxorubicin hydrochloride liposome injection for doxorubicin hydrochloride injection. Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2)].

2.2 Ovarian Cancer

The recommended dose of doxorubicin hydrochloride liposome injection is 50 mg/m2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.

2.3 AIDS-Related Kaposi's Sarcoma

The recommended dose of doxorubicin hydrochloride liposome injection is 20 mg/m2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.

2.4 Multiple Myeloma

The recommended dose of doxorubicin hydrochloride liposome injection is 30 mg/m2 intravenously over 60 minutes on day 4 of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer doxorubicin hydrochloride liposome injection after bortezomib on day 4 of each cycle [see Clinical Studies (14.3)].

2.5 Dose Modifications for Adverse Reactions

Do not increase doxorubicin hydrochloride liposome injection after a dose reduction for toxicity.
Table 1: Recommended Dose Modifications for Hand-Foot Syndrome, Stomatitis, or Hematologic Adverse Reactions Toxicity Dose Adjustment Hand-Foot Syndrome (HFS) Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activities If no previous Grade 3 or 4 HFS: no dose adjustment. If previous Grade 3 or 4 HFS: delay dose up to 2 weeks, then decrease dose by 25%. Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter Delay dosing up to 2 weeks or until resolved to Grade 0-1. Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks. If resolved to Grade 0-1 within 2 weeks: And no previous Grade 3 or 4 HFS: continue treatment at previous dose. And previous Grade 3 or 4 toxicity: decrease dose by 25%. Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing Delay dosing up to 2 weeks or until resolved to Grade 0-1, then decrease dose by 25%. Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks. Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization Delay dosing up to 2 weeks or until resolved to Grade 0-1, thendecrease dose by 25%. Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks. Stomatitis Grade 1: Painless ulcers, erythema, or mild soreness If no previous Grade 3 or 4 toxicity: no dose adjustment. If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%. Grade 2: Painful erythema, edema, or ulcers, but can eat Delay dosing up to 2 weeks or until resolved to Grade 0-1. Discontinue doxorubicin hydrochloride liposome injection if there is no resolution after 2 weeks. If resolved to Grade 0-1 within 2 weeks: And no previous Grade 3 or 4 stomatitis: resume treatment at previous dose. And previous Grade 3 or 4 toxicity: decrease dose by 25%. Grade 3: Painful erythema, edema, or ulcers, and cannot eat Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection. Grade 4: Requires parenteral or enteral support Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval.If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection. Neutropenia or Thrombocytopenia Grade 1 No dose reduction Grade 2 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose Grade 3 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose Grade 4 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factor Table 2: Recommended Dose Modifications of Doxorubicin Hydrochloride Liposome Injection for Toxicity When Administered in Combination With Bortezomib Toxicity Doxorubicin Hydrochloride Liposome Injection Fever ≥38°C and ANC <1,000/mm3 Withhold dose for this cycle if before Day 4; Decrease dose by 25%, if after Day 4 of previous cycle. On any day of drug administration after Day 1 of each cycle:Platelet count <25,000/mm3 Hemoglobin <8 g/dL ANC <500/mm3 Withhold dose for this cycle if before Day 4; Decrease dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity. Grade 3 or 4 non-hematologic drug related toxicity Do not dose until recovered to Grade <2, then reduce dose by 25%.
For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for doxorubicin hydrochloride liposome injection. Refer to bortezomib manufacturer's prescribing information.

2.6 Preparation and Administration

Preparation Dilute doxorubicin hydrochloride liposome injection doses up to 90 mg in 250 mL of 5% Dextrose Injection, USP prior to administration. Dilute doses exceeding 90 mg in 500 mL of 5% Dextrose Injection, USP prior to administration. Refrigerate diluted doxorubicin hydrochloride liposome injection at 2°C to 8°C (36°F to 46°F) and administer within 24 hours. Administration Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. Do not use with in-line filters. Administer the first dose of doxorubicin hydrochloride liposome injection at an initial rate of 1 mg/min. If no infusion-related adverse reactions are observed, increase the infusion rate to complete the administration of the drug over one hour [see Warnings and Precautions (5.2)]. Do not rapidly flush the infusion line. Do not mix doxorubicin hydrochloride liposome injection with other drugs. Management of Suspected Extravasation Discontinue doxorubicin hydrochloride liposome injection for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:
Do not remove the needle until attempts are made to aspirate extravasated fluid Do not flush the line Avoid applying pressure to the site Apply ice to the site intermittently for 15 min 4 times a day for 3 days If the extravasation is in an extremity, elevate the extremity
2.7 Procedure for Proper Handling and Disposal

Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If doxorubicin hydrochloride liposome injection comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.
Zoledronic Acid

Zoledronic Acid

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

2.1 Hypercalcemia of Malignancy

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL). Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)]. Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings and Precautions (5.2)].

2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl)greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].
Table 1: Reduced Doses for Patients with Baseline CrCl Less than or Equal to 60 mL/min Baseline Creatinine Clearance (mL/min) Zoledronic Acid Injection Recommended Dose* * Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75 mL/min) greater than 60 4 mg 50 to 60 3.5 mg 40 to 49 3.3 mg 30 to 39 3 mg
During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:For patients with normal baseline creatinine, increase of 0.5 mg/dLFor patients with abnormal baseline creatinine, increase of 1 mg/dLIn the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily.

2.3 Preparation of Solution

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.4 mg/5 mL Single-Use Vial Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection. To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 2).
Table 2: Preparation of Reduced Doses-Zoledronic Acid Injection Concentrate Remove and Use Zoledronic Acid Injection Volume (mL) Dose (mg) 4.4 3.5 4.1 3.3 3.8 3
The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

2.4 Method of Administration

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injectionshould not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injectiondose.
Zoledronic Acid Kit

Zoledronic Acid Kit

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

The maximum recommended dose of zoledronic acid for injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid for injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid for injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 µmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of zoledronic acid for injection [see Warnings And Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid for injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.
Retreatment with zoledronic acid for injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid for injection and serum creatinine must be assessed prior to retreatment with zoledronic acid for injection [ see Warnings And Precautions (5.2)].
2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors

The recommended dose of zoledronic acid for injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.
Upon treatment initiation, the recommended zoledronic acid for injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula [ see Warnings And Precautions (5.2)]. Table 1: Reduced Doses for Patients with Baseline CrCl less than or equal to 60 mL/min Baseline Creatinine Clearance (mL/min) Zoledronic Acid for InjectionRecommended Dose* * Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl=75 mL/min) greater than 60 4 mg 50 to 60 3.5 mg 40 to 49 3.3 mg 30 to 39 3 mg
During treatment, serum creatinine should be measured before each zoledronic acid for injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

For patients with normal baseline creatinine, increase of 0.5 mg/dL

For patients with abnormal baseline creatinine, increase of 1 mg/dL

In the clinical studies, zoledronic acid for injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid for injection should be reinitiated at the same dose as that prior to treatment interruption.
Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.
2.3 Preparation of Solution

Zoledronic acid for injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg Dose

Zoledronic acid for injection is reconstituted by adding 5 mL of Sterile Water for Injection, USP, to each vial. The resulting solution allows for withdrawal of 4 mg of zoledronic acid. The drug must be completely dissolved before the solution is withdrawn. The maximum recommended 4 mg dose must be further diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store reconstituted solution in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid for injection reconstituted solution for the dose required (see Table 3).
Table 3: Preparation of Reduced Doses - Zoledronic Acid for Injection Reconstituted Solution Remove and Use Zoledronic Acid for Injection Reconstituted Solution Volume (mL) Dose (mg) 4.4 3.5 4.1 3.3 3.8 3
The withdrawn reconstituted solution must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.
If not used immediately after dilution of reconstituted solution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between reconstitution, dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.
2.4 Method of Administration
Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid for injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [ see Warnings And Precautions (5.2)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid for injection dose.
Lidocaine Hydrochloride...

Lidocaine Hydrochloride

The recommended starting dose of memantine hydrochloride tablets are 5 mg once daily. The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice daily), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice daily). The minimum recommended interval between dose increases is one week. The dosage shown to be effective in controlled clinical trials is 20 mg/day. Memantine hydrochloride tablets can be taken with or without food. If a patient misses a single dose of memantine hydrochloride tablets, that patient should not double up on the next dose. The next dose should be taken as scheduled. If a patient fails to take memantine hydrochloride tablets for several days, dosing may need to be resumed at lower doses and retitrated as described above. Special Populations Renal Impairment A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine clearance of 5 to 29 mL/min based on the Cockroft-Gault equation). Hepatic Impairment Memantine hydrochloride tablets should be administered with caution to patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].
Entacapone

Entacapone

The recommended dose of Entacapone Tablets is one 200 mg tablet administered concomitantly with each levodopa and carbidopa dose to a maximum of 8 times daily (200 mg x 8 = 1,600 mg per day). Clinical experience with daily doses above 1,600 mg is limited.

Entacapone Tablets should always be administered in association with levodopa and carbidopa. Entacapone has no antiparkinsonian effect of its own.

In clinical studies, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been greater than or equal to 800 mg or if patients had moderate or severe dyskinesia before beginning treatment.

To optimize an individual patient’s response, reductions in daily levodopa dose or extending the interval between doses may be necessary. In clinical studies, the average reduction in daily levodopa dose was about 25% in those patients requiring a levodopa dose reduction. (More than 58% of patients with levodopa doses above 800 mg daily required such a reduction.)

Entacapone Tablets can be combined with both the immediate and sustained-release formulations of levodopa and carbidopa.

Entacapone Tablets may be taken with or without food (see CLINICAL PHARMACOLOGY).

Patients With Impaired Hepatic Function: Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease, compared to controls. However, these studies were conducted with single-dose entacapone without levodopa and dopa decarboxylase inhibitor coadministration, and therefore the effects of liver disease on the kinetics of chronically administered entacapone have not been evaluated (see CLINICAL PHARMACOLOGY, Pharmacokinetics of Entacapone).

Withdrawing Patients from Entacapone Tablets: Rapid withdrawal or abrupt reduction in the Entacapone Tablets dose could lead to emergence of signs and symptoms of Parkinson’s disease (see CLINICAL PHARMACOLOGY, Clinical Studies), and may lead to hyperpyrexia and confusion, a symptom complex resembling NMS (see PRECAUTIONS, Other Events Reported With Dopaminergic Therapy). This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. If a decision is made to discontinue treatment with Entacapone Tablets, patients should be monitored closely and other dopaminergic treatments should be adjusted as needed. Although tapering Entacapone Tablets have not been systematically evaluated, it seems prudent to withdraw patients slowly if the decision to discontinue treatment is made.
Ciclopirox

Ciclopirox

Swallow duloxetine delayed-release capsules whole. Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric coating. Duloxetine delayed-release capsules can be given without regard to meals. If a dose of duloxetine delayed-release capsule is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of duloxetine delayed-release capsules at the same time.

2.1 Dosage for Treatment of Major Depressive Disorder

Administer duloxetine delayed-release capsules at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)].

2.2 Dosage for Treatment of Generalized Anxiety Disorder

Adults — For most patients, initiate duloxetine delayed-release capsules 60 mg once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].Pediatric use information for patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.'s CYMBALTA® (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain

Administer duloxetine delayed-release capsules 60 mg once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, consider a lower starting dose and gradual increase in dose for patients with renal impairment [see Dosage and Administration (2.6), Use in Specific Populations (8.10), and Clinical Pharmacology (12.3)].

2.5 Dosage for Treatment of Chronic Musculoskeletal Pain

Administer duloxetine delayed-release capsules 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)].

2.6 Dosing in Special Populations

Hepatic Impairment - Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions (5.14) and Use in Specific Populations (8.9)].Severe Renal Impairment — Avoid use in patients with severe renal impairment, GFR <30 mL/min [see Warnings and Precautions (5.14) and Use in Specific Populations (8.10)].

2.7 Discontinuing Duloxetine Delayed-Release Capsules

Adverse reactions after discontinuation of duloxetine delayed-release capsules, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)].

2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with duloxetine delayed-release capsules. Conversely, at least 5 days should be allowed after stopping duloxetine delayed-release capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)].

2.9 Use of Duloxetine Delayed-Release Capsules with Other MAOIs such as Linezolid or Methylene Blue

Do not start duloxetine delayed-release capsules in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)].In some cases, a patient already receiving duloxetine delayed-release capsules therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, duloxetine delayed-release capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with duloxetine delayed-release capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4)].The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with duloxetine delayed-release capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].
Lansoprazole

Lansoprazole

Lansoprazole is available as a capsule in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration for this dosage form is presented below. Lansoprazole delayed-release capsules should be taken before eating. Lansoprazole delayed-release capsules SHOULD NOT BE CRUSHED OR CHEWED. In the clinical trials, antacids were used concomitantly with lansoprazole delayed-release capsules.

2.1 Recommended Dose
Indication Recommended Dose Frequency * Please refer to amoxicillin and clarithromycin full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally-impaired patients. † Controlled studies did not extend beyond indicated duration. ‡ For patients who do not heal with lansoprazole for 8 weeks (5 to 10%), it may be helpful to give an additional 8 weeks of treatment. If there is a recurrence of erosive esophagitis, an additional 8 week course of lansoprazole may be considered. § The lansoprazole dose was increased (up to 30 mg twice daily) in some pediatric patients after 2 or more weeks of treatment if they remained symptomatic. For pediatric patients unable to swallow an intact capsule please see Administration Options. ¶ Varies with individual patient. Recommended adult starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Dosages up to 90 mg twice daily have been administered. Daily dose of greater than 120 mg should be administered in divided doses. Some patients with Zollinger-Ellison Syndrome have been treated continuously with lansoprazole for more than 4 years. Duodenal Ulcers Short-Term Treatment 15 mg Once daily for 4 weeks Maintenance of Healed 15 mg Once daily H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence* Triple Therapy: Lansoprazole 30 mg Twice daily (q12h) for 10 or 14 days Amoxicillin 1 gram Twice daily (q12h) for 10 or 14 days Clarithromycin 500 mg Twice daily (q12h) for 10 or 14 days Dual Therapy: Lansoprazole 30 mg Three times daily (q8h) for 14 days Amoxicillin 1 gram Three times daily (q8h) for 14 days Benign Gastric Ulcer Short-Term Treatment 30 mg Once daily for up to 8 weeks NSAID-associated Gastric Ulcer Healing 30 mg Once daily for 8 weeks† Risk Reduction 15 mg Once daily for up to 12 weeks† Gastroesophageal Reflux Disease (GERD) Short-Term Treatment of Symptomatic GERD 15 mg Once daily for up to 8 weeks Short-Term Treatment of Erosive Esophagitis 30 mg Once daily for up to 8 weeks‡ Pediatric (1 to 11 years of age) Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of Erosive Esophagitis ≤ 30 kg 15 mg Once daily for up to 12 weeks§ > 30 kg 30 mg Once daily for up to 12 weeks§ (12 to 17 years of age) Short-Term Treatment of Symptomatic GERD Nonerosive GERD 15 mg Once daily for up to 8 weeks Erosive Esophagitis 30 mg Once daily for up to 8 weeks Maintenance of Healing of Erosive Esophagitis 15 mg Once daily Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 60 mg Once daily¶
Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose.

2.2 Special Populations

Renal impairment patients and geriatric patients do not require dosage adjustment. However, consider dose adjustment in patients with severe liver impairment [see Use in Specific Populations (8.5, 8.6 and 8.7)].

2.3 Important Administration Information

Administration Options Lansoprazole Delayed-Release Capsules -Oral Administration
Lansoprazole delayed-release capsules should be swallowed whole. Alternatively, for patients who have difficulty swallowing capsules, lansoprazole delayed-release capsules can be opened and administered as follows: Open capsule. Sprinkle intact pellets on one tablespoon of either applesauce, ENSURE* pudding, cottage cheese, yogurt or strained pears. Swallow immediately. Lansoprazole delayed-release capsules may also be emptied into a small volume of either apple juice, orange juice or tomato juice and administered as follows: Open capsule. Sprinkle intact pellets into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately 2 ounces). Mix briefly. Swallow immediately. To ensure complete delivery of the dose, the glass should be rinsed with two or more volumes of juice and the contents swallowed immediately.
Lansoprazole Delayed-Release Capsules -Nasogastric Tube (≥16 French) Administration
For patients who have a nasogastric tube in place, lansoprazole delayed-release capsules can be administered as follows: Open capsule. Mix intact pellets into 40 mL of apple juice. DO NOT USE OTHER LIQUIDS. Inject through the nasogastric tube into the stomach. Flush with additional apple juice to clear the tube.
USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED.
Extra Strength Headache...

Extra Strength Headache Relief

Finasteride tablets 1 mg may be administered with or without meals.The recommended dose of finasteride tablets 1 mg is one tablet (1 mg) taken once daily.In general, daily use for three months or more is necessary before benefit is observed. Continued use is recommended to sustain benefit, which should be re-evaluated periodically. Withdrawal of treatment leads to reversal of effect within 12 months.
Alprazolam

Alprazolam

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.Anxiety Disorders and Transient Symptoms of Anxiety: Treatment for patients with anxiety should be initiated with a dose of 0.25 to 0.5 mg given three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment. In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. Panic Disorder: The successful treatment of many panic disorder patients has required the use of alprazolam tablets at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam tablets in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean dosage employed was approximately 5 to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received alprazolam tablets in dosages of greater than 7 mg/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response. Dose Titration: Treatment may be initiated with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg/day may be advisable to allow full expression of the pharmacodynamic effect of alprazolam tablets. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule. Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained. Dose Maintenance: For patients receiving doses greater than 4 mg/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam tablets greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided. (See WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE.) The necessary duration of treatment for panic disorder patients responding to alprazolam tablets is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena. Dose Reduction: Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.Dosing in Special Populations: In elderly patients, in patients with advanced liver disease or in patients with debilitating disease, the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered.
Desmopressin Acetate So...

Desmopressin Acetate Solution

Central Cranial Diabetes Insipidus: Desmopressin Acetate Nasal Solution 0.01% (Nasal Spray) dosage must be determined for each individual patient and adjusted according to the diurnal pattern of response. Response should be estimated by two parameters: adequate duration of sleep and adequate, not excessive, water turnover. Patients with nasal congestion and blockage have often responded well to intranasal desmopressin acetate. The usual dosage range in adults is 0.1 mL to 0.4 mL daily, either as a single dose or divided into two or three doses. Most adults require 0.2 mL daily in two divided doses. The morning and evening doses should be separately adjusted for an adequate diurnal rhythm of water turnover. For children aged 3 months to 12 years, the usual dosage range is 0.05 mL to 0.3 mL daily, either as a single dose or divided into two doses. About 1/4 to 1/3 of patients can be controlled by a single daily dose of desmopressin acetate administered intranasally. Fluid restriction should be observed. (See WARNINGS, PRECAUTIONS, Pediatric Useand Geriatric Use.)

The nasal spray pump can only deliver doses of 0.1 mL (10 mcg) or multiples of 0.1 mL. If doses other than these are required, the rhinal tube delivery system may be used.

The spray pump must be primed prior to the first use. To prime pump, press down four times. The bottle will now deliver 10 mcg of drug per spray. Discard Desmopressin Acetate Nasal Solution 0.01% (Nasal Spray) after 50 sprays since the amount delivered thereafter per spray may be substantially less than 10 mcg of drug.

Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY, Human Pharmacokinetics, CONTRAINDICATIONS, and PRECAUTIONS,Geriatric Use.)
Esomeprazole Sodium

Esomeprazole Sodium

Esomeprazole sodium for injection should not be administered concomitantly with any other medications through the same intravenous site and or tubing. The intravenous line should always be flushed with either 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of esomeprazole sodium for injection.The admixture should be stored at room temperature up to 30°C (86°F) and should be administered within the designated time period as listed in the Table 1 below. No refrigeration is required.
Table 1: Diluent Administer within: 0.9% Sodium Chloride Injection, USP 12 hours Lactated Ringer’s Injection, USP 12 hours 5% Dextrose Injection, USP 6 hours
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.As soon as oral therapy is possible or appropriate, intravenous therapy with esomeprazole sodium for injection should be discontinued and the therapy should be continued orally.Special Populations Hepatic Insufficiency: No dosage adjustment is necessary in patients with mild to moderate liver impairment (Child Pugh Classes A and B). For patients with severe liver impairment (Child Pugh Class C), a dose of 20 mg of esomeprazole should not be exceeded [see Use in Specific Populations (8.6) and Clinical Pharmacology, Pharmacokinetics (12.3)].

2.1 GERD with Erosive Esophagitis

Adults The recommended adult dose is either 20 mg or 40 mg esomeprazole given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 minutes to 30 minutes).Safety and efficacy of esomeprazole sodium for injection as a treatment of GERD patients with erosive esophagitis for more than 10 days have not been demonstrated.Pediatric The recommended doses for children ages 1 month to 17 years, inclusive, are provided below. Dose should be infused over 10 minutes to 30 minutes.1 year to 17 years:Body weight less than 55 kg: 10 mgBody weight 55 kg or greater: 20 mg1 month to less than 1 year of age: 0.5 mg/kg

2.2 Preparations for Use and Administration

Adults Intravenous Injection (20 mg or 40 mg vial) over no less than 3 minutes The freeze-dried powder should be reconstituted with 5 mL of 0.9% Sodium Chloride Injection, USP. Withdraw 5 mL of the reconstituted solution and administer an intravenous injection over no less than 3 minutes.Intravenous Infusion (20 mg or 40 mg) over 10 minutes to 30 minutes A solution for intravenous infusion is prepared by first reconstituting the contents of one vial with 5 mL of 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP and further diluting the resulting solution to a final volume of 50 mL. The solution (admixture) should be administered as an intravenous infusion over a period of 10 minutes to 30 minutes.The reconstituted solution should be stored at room temperature up to 30°C (86°F) and administered within 12 hours after reconstitution. No refrigeration is required.Pediatric Population Intravenous Infusion over 10 minutes to 30 minutes (0.5 mg/kg) for patients ages 1 month to less than 1 year of age A solution for intravenous infusion is prepared by first reconstituting the contents of one vial with 5 mL of 0.9% Sodium Chloride Injection, USP and further diluting the resulting solution to a final volume of 50 mL. The resultant concentration after diluting to a final volume of 50 mL is as follows:40 mg vial: 0.8 mg/mL20 mg vial: 0.4 mg/mLWithdraw appropriate amount of volume for desired dose (0.5 mg/kg) and administer as an intravenous infusion over 10 minutes to 30 minutesIntravenous Infusion (10 mg and 20 mg) over 10 minutes to 30 minutes for Pediatric Patients, ages 1 year to 17 years of age 40 mg vial A solution for intravenous infusion is prepared by first reconstituting the contents of one vial with 5 mL of 0.9% Sodium Chloride Injection, USP and further diluting the resulting solution to a final volume of 50 mL. The resultant concentration after diluting to a final volume of 50 mL is 0.8 mg/mL.20 mg dose: Withdraw 25 mL of the final solution and administer as an intravenous infusion over 10 minutes to 30 minutes10 mg dose: Withdraw 12.5 mL of the final solution and administer as an intravenous infusion over 10 minutes to 30 minutes20 mg vial A solution for intravenous infusion is prepared by first reconstituting the contents of one vial with 5 mL of 0.9% Sodium Chloride Injection, USP and further diluting the resulting solution to a final volume of 50 mL. The resultant concentration after diluting to a final volume of 50 mL is 0.4 mg/mL.20 mg dose: Administer the final solution (50 mL) as an intravenous infusion over 10 minutes to 30 minutes10 mg dose: Withdraw 25 mL of the final solution and administer as an intravenous infusion over 10 minutes to 30 minutes
Naltrexone Hydrochlorid...

Naltrexone Hydrochloride

To reduce the risk of precipitated withdrawal in patients dependent on opioids, or exacerbation of a preexisting subclinical withdrawal syndrome, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting naltrexone hydrochloride treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short-acting opioids.

Switching from Buprenorphine, Buprenorphine/Naloxone, or Methadone

There are no systematically collected data that specifically address the switch from buprenorphine or methadone to naltrexone hydrochloride; however, review of postmarketing case reports have indicated that some patients may experience severe manifestations of precipitated withdrawal when being switched from opioid agonist therapy to opioid antagonist therapy (see WARNINGS). Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Healthcare providers should be prepared to manage withdrawal symptomatically with non-opioid medications.

Treatment of Alcoholism

A dose of 50 mg once daily is recommended for most patients. The placebo-controlled studies that demonstrated the efficacy of naltrexone hydrochloride as an adjunctive treatment of alcoholism used a dose regimen of naltrexone hydrochloride 50 mg once daily for up to 12 weeks. Other dose regimens or durations of therapy were not evaluated in these trials.

Naltrexone hydrochloride should be considered as only one of many factors determining the success of treatment of alcoholism. Factors associated with a good outcome in the clinical trials with naltrexone hydrochloride were the type, intensity, and duration of treatment; appropriate management of comorbid conditions; use of community-based support groups; and good medication compliance. To achieve the best possible treatment outcome, appropriate compliance-enhancing techniques should be implemented for all components of the treatment program, especially medication compliance.

Treatment of Opioid Dependence

Treatment should be initiated with an initial dose of 25 mg of naltrexone hydrochloride. If no withdrawal signs occur, the patient may be started on 50 mg a day thereafter. A dose of 50 mg once a day will produce adequate clinical blockade of the actions of parenterally administered opioids. As with many non-agonist treatments for addiction, naltrexone hydrochloride is of proven value only when given as part of a comprehensive plan of management that includes some measure to ensure the patient takes the medication.

Naloxone Challenge Test

Clinicians are reminded that there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. A naloxone challenge test may be helpful if there is any question of occult opioid dependence. If signs of opioid withdrawal are still observed following naloxone challenge, treatment with naltrexone hydrochlorideshould not be attempted. The naloxone challenge can be repeated in 24 hours. The naloxone challenge test should not be performed in a patient showing clinical signs or symptoms of opioid withdrawal, or in a patient whose urine contains opioids. The naloxone challenge test may be administered by either the intravenous or subcutaneous routes.Intravenous:

Inject 0.2 mg naloxone.

Observe for 30 seconds for signs or symptoms of withdrawal.

If no evidence of withdrawal, inject 0.6 mg of naloxone.

Observe for an additional 20 minutes.Subcutaneous:

Administer 0.8 mg naloxone.

Observe for 20 minutes for signs or symptoms of withdrawal.

Note: Individual patients, especially those with opioid dependence, may respond to lower doses of naloxone. In some cases, 0.1 mg IV naloxone has produced a diagnostic response.

Interpretation of the Challenge

Monitor vital signs and observe the patient for signs and symptoms of opioid withdrawal. These may include, but are not limited to: nausea, vomiting, dysphoria, yawning, sweating, tearing, rhinorrhea, stuffy nose, craving for opioids, poor appetite, abdominal cramps, sense of fear, skin erythema, disrupted sleep patterns, fidgeting, uneasiness, poor ability to focus, mental lapses, muscle aches or cramps, pupillary dilation, piloerection, fever, changes in blood pressure, pulse or temperature, anxiety, depression, irritability, backache, bone or joint pains, tremors, sensations of skin crawling or fasciculations. If signs or symptoms of withdrawal appear, the test is positive and no additional naloxone should be administered.

Warning: If the test is positive, do NOT initiate naltrexone hydrochloride therapy. Repeat the challenge in 24 hours. If the test is negative, naltrexone hydrochloride therapy may be started if no other contraindications are present. If there is any doubt about the result of the test, hold naltrexone hydrochloride and repeat the challenge in 24 hours.

Alternative Dosing Schedules

A flexible approach to a dosing regimen may need to be employed in cases of supervised administration. Thus, patients may receive 50 mg of naltrexone hydrochloride every weekday with a 100 mg dose on Saturday, 100 mg every other day, or 150 mg every third day. The degree of blockade produced by naltrexone hydrochloride may be reduced by these extended dosing intervals.

There may be a higher risk of hepatocellular injury with single doses above 50 mg, and use of higher doses and extended dosing intervals should balance the possible risks against the probable benefits (see WARNINGS).

Patient Compliance

Naltrexone hydrochloride should be considered as only one of many factors determining the success of treatment. To achieve the best possible treatment outcome, appropriate compliance-enhancing techniques should be implemented for all components of the treatment program, including medication compliance.
Montelukast Sodium

Montelukast Sodium

Finasteride tablets 5 mg may be administered with or without meals.

2.1 Monotherapy

The recommended dose of finasteride tablets 5 mg is one tablet (5 mg) taken once a day [see Clinical Studies (14.1)].

2.2 Combination with Alpha-Blocker

The recommended dose of finasteride tablets 5 mg is one tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin [see Clinical Studies (14.2)].
Alprazolam

Alprazolam

2.1 General Instruction for Use

The recommended dose for desvenlafaxine extended-release tablets is 50 mg once daily, with or without food. In clinical studies, doses of 50 mg to 400 mg per day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg per day, and adverse reactions and discontinuations were more frequent at higher doses. When discontinuing therapy, gradual dose reduction is recommended whenever possible to minimize discontinuation symptoms [see Dosage and Administration (2.4) and Warnings and Precautions (5.7)]. Desvenlafaxine extended-release tablets should be taken at approximately the same time each day. Tablets must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

2.2 Special Populations

Patients with Renal Impairment The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance [CrCl] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum recommended dose in patients with severe renal impairment (24-hr CrCl less than 30 mL/min, C-G) or end-stage renal disease (ESRD) is 50 mg every other day. Supplemental doses should not be given to patients after dialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment The recommended dose in patients with moderate to severe hepatic impairment is 50 mg per day. Dose escalation above 100 mg per day is not recommended [see Clinical Pharmacology (12.3)].

2.3 Maintenance/Continuation/Extended Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Patients should be periodically reassessed to determine the need for continued treatment.

2.4 Discontinuing Desvenlafaxine Extended-Release Tablets

Symptoms associated with discontinuation of desvenlafaxine extended-release tablets, other SNRIs and SSRIs have been reported [see Warnings and Precautions (5.7)]. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

2.5 Switching Patients From Other Antidepressants to Desvenlafaxine Extended-Release Tablets

Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to desvenlafaxine extended-release tablets. Tapering of the initial antidepressant may be necessary to minimize discontinuation symptoms.

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

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with desvenlafaxine extended-release tablets. Conversely, at least 7 days should be allowed after stopping desvenlafaxine extended-release tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)]. Use of Desvenlafaxine Extended-Release Tablets with other MAOIs such as Linezolid or Methylene Blue Do not start desvenlafaxine extended-release tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)]. In some cases, a patient already receiving desvenlafaxine extended-release tablet therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, desvenlafaxine extended-release tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with desvenlafaxine extended-release tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with desvenlafaxine extended-release tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].
Oxaliplatin

Oxaliplatin

Oxaliplatin injection should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

2.1 Dosage

Administer oxaliplatin injection in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):Day 1: Oxaliplatin injection 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.Figure 1

The administration of oxaliplatin injection does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.For information on 5-fluorouracil and leucovorin, see the respective package inserts.

2.2 Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for oxaliplatin injection from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.Adjuvant Therapy in Patients with Stage III Colon Cancer Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)]. For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin injection to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.A dose reduction of oxaliplatin injection to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin injection to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered. A dose reduction of oxaliplatin injection to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.Dose Modifications in Therapy for Patients with Renal Impairment In patients with normal renal function or mild to moderate renal impairment, the recommended dose of oxaliplatin injection is 85 mg/m2. In patients with severe renal impairment, the initial recommended oxaliplatin injection dose should be reduced to 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Preparation of Infusion Solution

Do not freeze and protect from light the concentrated solution. A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions. The solution must be further diluted in an infusion solution of 250 to 500 mL of 5% Dextrose Injection, USP. After dilution with 250 to 500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20° to 25°C (68° to 77°F)] or up to 24 hours under refrigeration [2° to 8°C (36° to 46°F)]. After final dilution, protection from light is not required.Oxaliplatin injection is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.Needles or intravenous administration sets containing aluminum parts that may come in contact with oxaliplatin injection should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
Eszopiclone

Eszopiclone

Use the lowest effective dose for the patient.

2.1 Dosage in Adults

The recommended starting dose is 1 mg. Dosing can be raised to 2 mg or 3 mg if clinically indicated. In some patients, the higher morning blood levels of eszopiclone tablets following use of the 2 mg or 3 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see Warnings and Precautions (5.1)]. The total dose of eszopiclone tablets should not exceed 3 mg, once daily immediately before bedtime [see Warnings and Precautions (5.6)].

2.2 Geriatric or Debilitated Patients

The total dose of eszopiclone tablets should not exceed 2 mg in elderly or debilitated patients.

2.3 Patients with Severe Hepatic Impairment, or Taking Potent CYP3A4 Inhibitors

In patients with severe hepatic impairment, or in patients coadministered eszopiclone tablets with potent CYP3A4 inhibitors, the total dose of eszopiclone tablets should not exceed 2 mg [see Warning and Precautions (5.7)].

2.4 Use with CNS Depressants

Dosage adjustments may be necessary when eszopiclone tablets is combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].

2.5 Administration with Food

Taking eszopiclone tablets with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of eszopiclone tablets on sleep latency [see Clinical Pharmacology (12.3)].
Timolol Maleate

Timolol Maleate

2.1 Recommended Dosing

Levetiracetam extended-release tablet is administered once daily.Initiate treatment with a dose of 1,000 mg once daily. The once daily dosage may be adjusted in increments of 1,000 mg every 2 weeks to a maximum recommended daily dose of 3,000 mg/day.

2.2 Dosage Adjustment in Adult Patients with Renal Impairment

Levetiracetam extended-release tablets dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatine clearance adjusted for body surface area must be calculated. To do this, an estimate of the patient's creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

Then CLcr is adjusted for body surface area (BSA) as follows:
Table 1: Dosage Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance (mL/min/1.73m2) Dosage (mg) Frequency Normal > 80 1,000 to 3,000 Every 24 hours Mild 50 to 80 1,000 to 2,000 Every 24 hours Moderate 30 to 50 500 to 1,500 Every 24 hours Severe < 30 500 to 1,000 Every 24 hours
Benzamycin

Benzamycin

2.1 Dosing Information

The recommended starting dose of zolmitriptan tablets is 1.25 mg or 2.5 mg. The 1.25 mg dose can be achieved by manually breaking the functionally-scored 2.5 mg tablet in half. The maximum recommended single dose of zolmitriptan tablets is 5 mg.In controlled clinical trials, a greater proportion of patients had headache response following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were more frequent with the 5 mg dose.If the migraine has not resolved by 2 hours after taking zolmitriptan tablets, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 10 mg in any 24-hour period.The safety of zolmitriptan tablets in the treatment of an average of more than three migraines in a 30-day period has not been established.

2.3 Dosing in Patients with Hepatic Impairment

The recommended dose of zolmitriptan tablets in patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg zolmitriptan tablet) because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. Limit the total daily dose in patients with severe hepatic impairment to no more than 5 mg per day.

2.4 Dosing in Patients taking Cimetidine

If zolmitriptan tablets are coadministered with cimetidine, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Drug Interactions (7.5), Clinical Pharmacology (12.3)].
Risedronate Sodium

Risedronate Sodium

2.1 Treatment of Postmenopausal Osteoporosis

[see Indications and Usage (1.1)]The recommended regimen is:
one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month or one 150 mg tablet orally, taken once-a-month
2.2 Prevention of Postmenopausal Osteoporosis

[see Indications and Usage (1.1)]The recommended regimen is:
alternatively, one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month may be considered or alternatively, one 150 mg tablet orally, taken once-a-month may be considered
2.6 Important Administration Instructions

Instruct patients to do the following:
Take risedronate sodium tablets at least 30 minutes before the first food or drink of the day other than water, and before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, [see Drug Interactions (7.1)]. Avoid the use of water with supplements, including mineral water, because they may have a higher concentration of calcium. Swallow risedronate sodium tabletswhole with a full glass of plain water (6 to 8 ounces). Avoid lying down for 30 minutes after taking the medication [see Warnings and Precautions (5.1)]. Do not chew or suck the tablet because of a potential for oropharyngeal ulceration. Do not eat or drink anything except plain water, or take other medications for at least 30 minutes after taking risedronate sodium tablets.
2.7 Recommendations for Calcium and Vitamin D Supplementation

Instructpatients to take supplemental calcium and vitamin D if their dietary intake isinadequate; and to take calcium supplements, antacids, magnesium-basedsupplements or laxatives, and iron preparations at a different time of the dayas they interfere with the absorption of risedronate sodium.

2.8 Administration Instructions for Missed Doses

Instruct patients about missing risedronate sodium tablets doses as follows:
If one or both risedronate sodium tablets 75 mg on two consecutive days per month are missed, and the next month’s scheduled doses are more than 7 days away: If both tablets are missed, take one risedronate sodium tablet 75 mg in the morning after the day it is remembered and then the other tablet on the next consecutive morning. If only one risedronate sodium tablet 75 mg is missed, take the missed tablet in the morning after the day it is remembered Return to taking their risedronate sodium tablet 75 mg on two consecutive days per month as originally scheduled. Do not take more than two 75 mg tablets within 7 days. If one or both risedronate sodium tablets 75 mg on two consecutive days per month are missed, and the next month's scheduled doses are within 7 days: Wait until their next month’s scheduled doses and then continue taking risedronate sodium tablets 75 mg on two consecutive days per month as originally scheduled. If the dose of risedronate sodium tablet 150 mg once-a-month is missed, and the next month’s scheduled dose is more than 7 days away: Take the missed tablet in the morning after the day it is remembered and then return to taking their risedronate sodium tablet 150 mg once-a-month as originally scheduled. Do not take more than one 150 mg tablet within 7 days. If the dose of risedronate sodium tablet 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days: Wait until their next month’s scheduled dose and then continue taking risedronate sodium tablet 150 mg once-a-month as originally scheduled.
Carboplatin

Carboplatin

NOTE: Aluminum reacts with carboplatin injection causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin injection.

Single-Agent Therapy

Carboplatin injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of carboplatin injection should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

Combination Therapy with Cyclophosphamide

In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:

Carboplatin injection - 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles (alternatively see Formula Dosing).

Cyclophosphamide - 600 mg/m2 IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert. (See CLINICAL STUDIES.)

Intermittent courses of carboplatin injection in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 and the platelet count is at least 100,000.

Dose Adjustment Recommendations

Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.

The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.
Platelets Neutrophils Adjusted Dose * (From Prior Course) >100,000 >2,000 125% 50 to 100,000 500 to 2,000 No Adjustment <50,000 <500 75%
* Percentages apply to carboplatin injection as a single agent or to both carboplatin injection and cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50% to 60%) for severe myelosuppression. Escalations above 125% were not recommended for these studies.

Carboplatin injection is usually administered by an infusion lasting 15 minutes or longer. No pre - or post -treatment hydration or forced diuresis is required.

Patients with Impaired Kidney Function

Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single-agent carboplatin injection therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.
Baseline Creatinine Clearance Recommended Dose on Day 1 41 to 59 mL/min 250 mg/m2 16 to 40 mL/min 200 mg/m2
The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment.

These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance based on the degree of bone marrow suppression.

Formula Dosing

Another approach for determining the initial dose of carboplatin injection is the use of mathematical formulae, which are based on a patient’s pre-existing renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin. (See CLINICAL PHARMACOLOGY.) The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function).

A simple formula for calculating dosage, based upon a patient's glomerular filtration rate (GFR in mL/min) and carboplatin target area under the concentration versus time curve (AUC in mg/mL·min), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance.

CALVERT FORMULA FOR CARBOPLATIN INJECTION DOSING

Total Dose (mg) = (target AUC) x (GFR + 25)

Note: With the Calvert formula, the total dose of carboplatin injection is calculated in mg, not mg/m2.

The target AUC of 4 mg/mL•min to 6 mg/mL•min using single-agent carboplatin injectionappears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single-agent carboplatin injectionadministered to previously treated patients and the likelihood of developing toxicity.
% Actual Toxicity in Previously Treated Patients AUC (mg/mL·min) Gr 3 or Gr 4 Thrombocytopenia Gr 3 or Gr 4 Leukopenia 4 to 5 16% 13% 6 to 7 33% 34%
Geriatric Dosing

Because renal function is often decreased in elderly patients, formula dosing of carboplatin injectionbased on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin AUCs and thereby minimize the risk of toxicity.

PREPARATION OF INTRAVENOUS SOLUTIONS

Carboplatin injectionis a premixed aqueous solution of 10 mg/mL carboplatin. Carboplatin injectioncan be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP.

When prepared as directed, carboplatin injection

is stable for 8 hours at room temperature (25° C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin injection be discarded 8 hours after dilution.
Niacin

Niacin

Niacin extended-release tablets, USP should be taken at bedtime, after a low-fat snack, and doses should be individualized according to patient response. Therapy with niacin extended-release tablets, USP must be initiated at 500 mg at bedtime in order to reduce the incidence and severity of side effects which may occur during early therapy. The recommended dose escalation is shown in Table 1 below.
Week(s) Daily dose Niacin Extended-Release Dosage INITIAL TITRATION 1 to 4 500 mg 1 niacin extended-release 500 mg tablet at bedtime SCHEDULE 5 to 8 1,000 mg 1 niacin extended-release 1,000 mg tablet or 2 niacin extended-release 500 mg tablets at bedtime 1,500 mg 2 niacin extended-release 750 mg tablets or 3 niacin extended-release 500 mg tablets at bedtime 1,500 mg 2 niacin extended-release 750 mg tablets or 3 niacin extended-release 500 mg tablets at bedtime
Maintenance Dose

The daily dosage of niacin extended-release tablets, USP should not be increased by more than 500 mg in any 4–week period. The recommended maintenance dose is 1,000 mg (two 500 mg tablets or one 1,000 mg tablet) to 2,000 mg (two 1,000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2,000 mg daily are not recommended. Women may respond at lower niacin extended-release tablets, USP doses than men [see Clinical Studies (14.2)].

Single-dose bioavailability studies have demonstrated that two of the 500 mg and one of the 1,000 mg tablet strengths are interchangeable but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable.

Flushing of the skin [see Adverse Reactions (6.1)] may be reduced in frequency or severity by pretreatment with aspirin (up to the recommended dose of 325 mg taken 30 minutes prior to niacin extended-release tablets, USP dose). Tolerance to this flushing develops rapidly over the course of several weeks. Flushing, pruritus, and gastrointestinal distress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of niacin extended-release tablets, USP ingestion.

Equivalent doses of niacin extended-release tablets, USP should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin [see Warnings and Precautions (5)]. Patients previously receiving other niacin products should be started with the recommended niacin extended-release tablets, USP titration schedule (see Table 1), and the dose should subsequently be individualized based on patient response.

If niacin extended-release tablets, USP therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 1).

Niacin extended-release tablets, USP should be taken whole and should not be broken, crushed or chewed before swallowing.

Dosage in Patients with Renal or Hepatic Impairment

Use of niacin extended-release tablets, USP in patients with renal or hepatic impairment has not been studied. Niacin extended-release tablets, USP are contraindicated in patients with significant or unexplained hepatic dysfunction. Niacin extended-release tablets, USP should be used with caution in patients with renal impairment [see Warnings and Precautions (5)].
Tramadol Hydrochloride

Tramadol Hydrochloride

Tramadol hydrochloride extended-release tablets should not be used in patients with:
creatinine clearance less than 30 mL/min, severe hepatic impairment (Child-Pugh Class C)
(See PRECAUTIONS, Use in Renal and Hepatic Disease).

Tramadol hydrochloride extended-release tablets must be swallowed whole and must not be chewed, crushed, or split (see WARNINGS, Misuse, Abuse and Diversion of Opioids and DRUG ABUSE AND ADDICTION).

Adults (18 years of age and over)

Patients Not Currently on Tramadol Immediate-Release Products

For patients not currently treated with tramadol immediate-release (IR) products, tramadol hydrochloride extended-release tablets should be initiated at a dose of 100 mg once daily and titrated up as necessary by 100 mg increments every five days to relief of pain and depending upon tolerability. Tramadol hydrochloride extended-release tablets should not be administered at a dose exceeding 300 mg per day.

Patients Currently on Tramadol Immediate-Release Products

For patients maintained on tramadol IR products, calculate the 24-hour tramadol immediate-release (IR) dose and initiate a total daily dose of tramadol hydrochloride extended-release tablets rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with tramadol hydrochloride extended-release tablets, some patients maintained on tramadol IR products may not be able to convert to tramadol hydrochloride extended-release tablets. Tramadol hydrochloride extended-release tablets should not be administered at a dose exceeding 300 mg per day. The concomitant use of tramadol hydrochloride extended-release tablets with other tramadol products is not recommended (see WARNINGS).

Individualization of Dose

Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Start at the lowest possible dose and titrate upward as tolerated to achieve an adequate effect. Clinical studies of tramadol hydrochloride extended-release tablets have not demonstrated a clinical benefit at a total daily dose exceeding 300 mg.

In general, dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Tramadol hydrochloride extended-release tablets should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.
Tramadol Hydrochloride

Tramadol Hydrochloride

Tramadol hydrochloride extended-release tablets should be taken once a day. The tablets should be swallowed whole with liquid and not split, chewed, dissolved or crushed. Tramadol hydrochloride extended-release tablets produce a continuous release of active ingredient over 24 hours: a repeat dosage within 24 hours is not recommended.

Patients Not Currently on Tramadol Immediate-Release Products:

Treatment with tramadol hydrochloride extended-release tablets should be initiated at a dose of 100 mg/day. Daily doses should be titrated by 100 mg/day increments every 2 to 3 days (i.e., start 200 mg/day on day 3 or 4 of therapy) to achieve a balance between adequate pain control and tolerability for the individual patient. For patients requiring the 300 mg daily dose, titration should take at least 4 days (i.e. 300 mg/day on day 5). The usual daily dose is 200 or 300 mg. The daily dose and titration should be individualized for each patient. Therapy should be continued with the lowest effective dose. Tramadol hydrochloride extended-release tablets should not be administered at a dose exceeding 300 mg per day.

Clinical experience suggests that signs and symptoms of withdrawal may be reduced by tapering medication when discontinuing tramadol therapy.

Patients Currently on Tramadol Immediate-Release Products:

For patients maintained on tramadol immediate-release (IR) products, the 24-hour tramadol IR dose should be calculated and the patient should be initiated on a total daily dose of tramadol hydrochloride extended-release tablets rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with tramadol hydrochloride extended-release tablets, some patients maintained on tramadol IR products may not be able to convert to tramadol hydrochloride extended-release tablets. Tramadol hydrochloride extended-release tablets should not be administered at a dose exceeding 300 mg per day. Do not use tramadol hydrochloride extended-release tablets with other tramadol products. (see WARNINGS).

Individualization of Dose

Good pain management practice dictates that analgesic dose be individualized according to patient need using the lowest beneficial dose. Studies with tramadol products in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability.

Renal and Hepatic Disease

Tramadol hydrochloride extended-release tablets should not be used in patients with:
Creatinine clearance less than 30 mL/min, Hepatic impairment.
(See WARNINGS, Use in Renal and Hepatic Disease).

Geriatric patients (65 years of age and older)

In general, dose selection for patients over 65 years of age who may have decreased hepatic or renal function, or other concomitant diseases, should be initiated cautiously, usually starting at the low end of the dosing range. Tramadol hydrochloride extended-release tablets should be administered with greater caution at the lowest effective dose in patients over 75 years, due to the potential for greater frequency of adverse events in this population.
Allerfed Cold And Aller...

Allerfed Cold And Allergy

2.1 General Dosing Considerations

The chronic daily dose of tetrabenazine tablets used to treat chorea associated with Huntington's disease (HD) is determined individually for each patient. When first prescribed, tetrabenazine tablets therapy should be titrated slowly over several weeks to identify a dose of tetrabenazine tablets that reduces chorea and is tolerated. Tetrabenazine tablets can be administered without regard to food [see Clinical Pharmacology (12.3)].

2.2 Individualization of Dose

The dose of tetrabenazine tablets should be individualized. Dosing Recommendations Up to 50 mg per day The starting dose should be 12.5 mg per day given once in the morning. After one week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. Tetrabenazine tablets should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. If a dose of 37.5 to 50 mg per day is needed, it should be given in a three times a day regimen. The maximum recommended single dose is 25 mg. If adverse reactions such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing tetrabenazine tablets treatment or initiating other specific treatment (e.g., antidepressants) [see Adverse Reactions (6.1)]. Dosing Recommendations Above 50 mg per day Patients who require doses of tetrabenazine tablets greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of tetrabenazine tablets should then be individualized accordingly to their status as PMs or EMs [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Extensive and Intermediate CYP2D6 Metabolizers

Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of tetrabenazine tablets above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. Doses above 50 mg per day should be given in a three times a day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing tetrabenazine tablets treatment or initiating other specific treatment (e.g., antidepressants) [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Poor CYP2D6 Metabolizers In PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.3 Dosage Adjustments with CYP2D6 Inhibitors

Strong CYP2D6 Inhibitors Medications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g., fluoxetine, paroxetine) significantly increase the exposure to α-HTBZ and β-HTBZ, therefore, the total dose of tetrabenazine tablets should not exceed a maximum of 50 mg and the maximum single dose should not exceed 25 mg [see Warnings and Precautions (5.3), Drug Interactions (7.1), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.4 Discontinuation of Treatment

Treatment with tetrabenazine tablets can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of tetrabenazine tablets [see Drug Abuse and Dependence (9.2)].

2.5 Resumption of Treatment

Following treatment interruption of greater than five (5) days, tetrabenazine tablets therapy should be re-titrated when resumed. For short-term treatment interruption of less than five (5) days, treatment can be resumed at the previous maintenance dose without titration.
Zenatane

Zenatane

2.1 Important Administration Instructions

Quetiapine fumarate tablets can be taken with or without food.

2.2 Recommended Dosing

The recommended initial dose, titration, dose range and maximum quetiapine fumarate tablets dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies (14.1 and 14.2)].
Table 1: Recommended Dosing for Quetiapine Fumarate Tablets * N/A Not applicable Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia-Adults Day 1: 25 mg twice daily. Increase in increments of 25 mg to 50 mg divided two or three times on Days 2 and 3 to range of 300 to 400 mg by Day 4. Further adjustments can be made in increments of 25 to 50 mg twice a day, in intervals of not less than 2 days. 150 to 750 mg/day 750 mg/day Schizophrenia- Adolescents (13 to 17 years) Day 1: 25 mg twice daily.Day 2: Twice daily dosing totaling 100 mg. Day 3: Twice daily dosing totaling 200 mg. Day 4: Twice daily dosing totaling 300 mg. Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 800 mg/day. Based on response and tolerability, may be administered three times daily. 400 to 800 mg/day 800 mg/day Schizophrenia-Maintenance N/A* 400 to 800 mg/day 800 mg/day Bipolar Mania- AdultsMonotherapy or as anadjunct to lithium ordivalproex Day 1: Twice daily dosing totaling 100 mg. Day 2: Twice daily dosing totaling 200 mg. Day 3: Twice daily dosing totaling 300 mg. Day 4: Twice daily dosing totaling 400 mg. Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day. 400 to 800 mg/day 800 mg/day Bipolar Mania-Children and Adolescents (10 to 17 years), Monotherapy Day 1: 25 mg twice daily. Day 2: Twice daily dosing totaling 100 mg. Day 3: Twice daily dosing totaling 200 mg. Day 4: Twice daily dosing totaling 300 mg. Day 5: Twice daily dosing totaling 400 mg. Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 600 mg/day. Based on response and tolerability, may be administered three times daily. 400 to 600 mg/day 600 mg/day Bipolar Depression- Adults Administer once daily at bedtime. Day 1: 50 mgDay 2: 100 mg Day 3: 200 mg Day 4: 300 mg 300 mg/day 300 mg/day Bipolar I Disorder Maintenance Therapy- Adults Administer twice daily totaling 400 to 800 mg/day as adjunct to lithium or divalproex. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized. 400 to 800 mg/day 800 mg/day
Maintenance Treatment for Schizophrenia and Bipolar I Disorder

Maintenance Treatment—Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].

2.3 Dose Modifications in Elderly Patients

Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.

Elderly patients should be started on quetiapine fumarate tablets 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.

2.4 Dose Modifications in Hepatically Impaired Patients

Patients with hepatic impairment should be started on 25 mg/day. The dose should be increased daily in increments of 25 mg/day to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.

2.5 Dose Modifications when used with CYP3A4 Inhibitors

Quetiapine fumarate tablets dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of quetiapine fumarate tablets should be increased by 6 fold [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)].

2.6 Dose Modifications when used with CYP3A4 Inducers

Quetiapine fumarate tablets dose should be increased up to 5 fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7 to 14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). The dose should be titrated based on the clinical response and tolerability of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate tablets should be reduced to the original level within 7 to 14 days [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)].

2.7 Reinitiation of Treatment in Patients Previously Discontinued

Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off quetiapine fumarate tablets for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine fumarate tablets for less than one week, gradual dose escalation may not be required and the maintenance dose may be reinitiated.

2.8 Switching from Antipsychotics

There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine fumarate tablets, or concerning concomitant administration with antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine fumarate tablets therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.
Ribavirin

Ribavirin

2.1 Recommended Dosing and Dose Modification Guidelines

Dosage of temozolomide must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and the neutrophil and platelet counts at the time of initiating the next cycle. For temozolomide dosage calculations based on body surface area (BSA) see Table 5. For suggested capsule combinations on a daily dose see Table 6.Patients with Newly Diagnosed High Grade Glioma: Concomitant Phase: Temozolomide capsules are administered at 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by maintenance temozolomide for 6 cycles. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. No dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. The temozolomide dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count greater than or equal to 1.5 × 109/L, platelet count greater than or equal to 100 × 109/L, common toxicity criteria (CTC) nonhematological toxicity less than or equal to Grade 1 (except for alopecia, nausea, and vomiting). During treatment a complete blood count should be obtained weekly. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and nonhematological toxicity criteria as noted in Table 1. Pneumocystis pneumonia (PCP)prophylaxis is required during the concomitant administration of temozolomide and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC Grade less than or equal to 1).
TABLE 1: Temozolomide Dosing Interruption or Discontinuation During Concomitant Radiotherapy and Temozolomide * Treatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count greater than or equal to 1.5 × 109/L; platelet count greater than or equal to 100 × 109/L; CTC nonhematological toxicity less than or equal to Grade 1 (except for alopecia, nausea, vomiting). TMZ=temozolomide; CTC=Common Toxicity Criteria. Toxicity TMZ Interruption* TMZ Discontinuation Absolute Neutrophil Count greater than or equal to 0.5 and less than 1.5 × 109/L less than 0.5 × 109/L Platelet Count greater than or equal to 10 and less than 100 × 109/L less than 10 × 109/L CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 2 CTC Grade 3 or 4
Maintenance Phase: Cycle 1: Four weeks after completing the temozolomide + RT phase, temozolomide is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment.Cycles 2 to 6: At the start of Cycle 2, the dose can be escalated to 200 mg/m2, if the CTC nonhematologic toxicity for Cycle 1 is Grade less than or equal to 2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (ANC) is greater than or equal to 1.5 × 109 /L, and the platelet count is greater than or equal to 100 × 109/L. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.Dose Reduction or Discontinuation During Maintenance: Dose reductions during the maintenance phase should be applied according to Tables 2 and 3. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of temozolomide) or within 48 hours of that day, and weekly until the ANC is above 1.5 × 109/L (1,500/µL) and the platelet count exceeds 100 × 109/L (100,000/µL). The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. Dose reductions or discontinuations during the maintenance phase should be applied according to Tables 2 and 3.
TABLE 2: Temozolomide Dose Levels for Maintenance Treatment Dose Level Dose (mg/m2/day) Remarks -1 100 Reduction for prior toxicity 0 150 Dose during Cycle 1 1 200 Dose during Cycles 2 to 6 in absence of toxicity TABLE 3: Temozolomide Dose Reduction or Discontinuation During Maintenance Treatment * TMZ dose levels are listed in Table 2. † TMZ is to be discontinued if dose reduction to less than 100 mg/m2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. Toxicity Reduce TMZ by 1 Dose Level* Discontinue TMZ Absolute Neutrophil Count less than 1 × 109/L See footnote† Platelet Count less than 50 × 109/L See footnote† CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 3 CTC Grade 4†
TMZ=temozolomide; CTC=Common Toxicity Criteria. Patients with Refractory Anaplastic Astrocytoma: For adults the initial dose is 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle. For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are greater than or equal to 1.5 × 109/L (1,500/µL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are greater than or equal to 100 × 109/L (100,000/µL), the temozolomide dose may be increased to 200 mg/m2/day for 5 consecutive days per 28-day treatment cycle. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 × 109/L (1,500/µL) and the platelet count exceeds 100 × 109/L (100,000/µL). The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. If the ANC falls to less than 1 × 109/L (1,000/µL) or the platelet count is less than 50 × 109/L (50,000/µL) during any cycle, the next cycle should be reduced by 50 mg/m2, but not below 100 mg/m2, the lowest recommended dose (see Table 4). Temozolomide therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known.
TABLE 5: Daily Dose Calculations by Body Surface Area (BSA) Total BSA (m2) 75 mg/m2 (mg daily) 150 mg/m2 (mg daily) 200 mg/m2 (mg daily) 1 75 150 200 1.1 82.5 165 220 1.2 90 180 240 1.3 97.5 195 260 1.4 105 210 280 1.5 112.5 225 300 1.6 120 240 320 1.7 127.5 255 340 1.8 135 270 360 1.9 142.5 285 380 2 150 300 400 2.1 157.5 315 420 2.2 165 330 440 2.3 172.5 345 460 2.4 180 360 480 2.5 187.5 375 500 TABLE 6: Suggested Capsule Combinations Based on Daily Dose in Adults Number of Daily Capsules by Strength (mg) Total Daily Dose (mg) 250 mg 180 mg 140 mg 100 mg 20 mg 5 mg 75 0 0 0 0 3 3 82.5 0 0 0 0 4 0 90 0 0 0 0 4 2 97.5 0 0 0 1 0 0 105 0 0 0 1 0 1 112.5 0 0 0 1 0 2 120 0 0 0 1 1 0 127.5 0 0 0 1 1 1 135 0 0 0 1 1 3 142.5 0 0 1 0 0 0 150 0 0 1 0 0 2 157.5 0 0 1 0 1 0 165 0 0 1 0 1 1 172.5 0 0 1 0 1 2 180 0 1 0 0 0 0 187.5 0 1 0 0 0 1 195 0 1 0 0 0 3 200 0 1 0 0 1 0 210 0 0 0 2 0 2 220 0 0 0 2 1 0 225 0 0 0 2 1 1 240 0 0 1 1 0 0 255 1 0 0 0 0 1 260 1 0 0 0 0 2 270 1 0 0 0 1 0 280 0 0 2 0 0 0 285 0 0 2 0 0 1 300 0 0 0 3 0 0 315 0 0 0 3 0 3 320 0 1 1 0 0 0 330 0 1 1 0 0 2 340 0 1 1 0 1 0 345 0 1 1 0 1 1 360 0 2 0 0 0 0 375 0 2 0 0 0 3 380 0 1 0 2 0 0 400 0 0 0 4 0 0 420 0 0 3 0 0 0 440 0 0 3 0 1 0 460 0 2 0 1 0 0 480 0 1 0 3 0 0 500 2 0 0 0 0 0
2.2 Preparation and Administration

In clinical trials, temozolomide capsules were administered under both fasting and nonfasting conditions; however, absorption is affected by food [see Clinical Pharmacology (12.3)], and consistency of administration with respect to food is recommended. There are no dietary restrictions with temozolomide capsules. To reduce nausea and vomiting, temozolomide capsules should be taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may be administered prior to and/or following administration of temozolomide capsules. Temozolomide capsules should not be opened or chewed. They should be swallowed whole with a glass of water.If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation or contact with the skin or mucous membranes [see How Supplied/Storage and Handling (16.1)].
Caffeine Citrate

Caffeine Citrate

Prior to initiation of caffeine citrate, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine. Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta.

The recommended loading dose and maintenance doses of caffeine citrate follow.
* using a syringe infusion pump † beginning 24 hours after the loading dose Dose of Caffeine Citrate Dose of Caffeine Citrate Route Frequency Volume mg/kg Loading Dose 1 mL/kg 20 mg/kg Intravenous* One Time (over 30 minutes) Maintenance 0.25 mL/kg 5 mg/kg Intravenous* Every Dose (over 10 24 hours† minutes) or Orally
NOTE THAT THE DOSE OF CAFFEINE BASE IS ONE-HALF THE DOSE WHEN EXPRESSED AS CAFFEINE CITRATE (e.g., 20 mg of caffeine citrate is equivalent to 10 mg of caffeine base).

Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity. Serious toxicity has been associated with serum levels greater than 50 mg/L.

Caffeine citrate injection and caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to administration. Vials containing discolored solution or visible particulate matter should be discarded.

Drug Compatibility

To test for drug compatibility with common intravenous solutions or medications, 20 mL of caffeine citrate injection were combined with 20 mL of a solution or medication, with the exception of an Intralipid® admixture, which was combined as 80 mL/80 mL. The physical appearance of the combined solutions was evaluated for precipitation. The admixtures were mixed for 10 minutes and then assayed for caffeine. The admixtures were then continually mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours.

Based on this testing, caffeine citrate injection, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products.
Dextrose Injection, USP 5% 50% Dextrose Injection USP Intralipid® 20% IV Fat Emulsion Aminosyn® 8.5% Crystalline Amino Acid Solution Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5% Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca+2/mL) Heparin Sodium Injection, USP 1000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5% Fentanyl Citrate Injection, USP 50 µg/mL diluted to 10 µg/mL with Dextrose Injection, USP 5%
Diclofenac Sodium Delay...

Diclofenac Sodium Delayed Release

do not divide, crush, chew or dissolve the tablet; swallow tablet whole adults and children 12 years of age and over take 1 tablet with a glass of water every 12 hours on an empty stomach; do not take more than 2 tablets in 24 hours children under 12 years of age do not use adults 65 years of age and older ask a doctor consumers with kidney disease ask a doctor

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