Accord Healthcare, Inc.

Accord Healthcare, Inc. Drugs

• Buspirone Hydrochloride...
  

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  Buspirone Hydrochloride

  

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

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

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

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• Antimonium Tartaricum 3...
  

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  Antimonium Tartaricum 30c

  

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  Initial Treatment

  Dosage for Adults

  Major Depressive Disorder and Obsessive-Compulsive Disorder

  Sertraline hydrochloride tablets treatment should be administered at a dose of 50 mg once daily.

  Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder

  Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.

  While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50 to 200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride tablets for the treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.

  Premenstrual Dysphoric Disorder

  Sertraline hydrochloride treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.

  While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50 to 150 mg/day with dose increases at the onset of each new menstrual cycle (see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period.

  Sertraline hydrochloride tablets should be administered once daily, either in the morning or evening.

  Dosage for Pediatric Population (Children and Adolescents)

  Obsessive-Compulsive Disorder

  Sertraline hydrochloride tablets treatment should be initiated with a dose of 25 mg once daily in children (ages 6 to 12) and at a dose of 50 mg once daily in adolescents (ages 13 to 17).

  While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25 to 200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for pediatric patients (6 to 17 years) with OCD. Patients not responding to an initial dose of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For children with OCD, their generally lower body weights compared to adults should be taken into consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.

  Sertraline hydrochloride tablets should be administered once daily, either in the morning or evening.

  Maintenance/Continuation/Extended Treatment

  Major Depressive Disorder

  It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode. Systematic evaluation of sertraline hydrochloride tablets has demonstrated that its antidepressant efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50 to 200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL PHARMACOLOGY). It is not known whether the dose of sertraline hydrochloride 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.

  Posttraumatic Stress Disorder

  It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of sertraline hydrochloride tablets has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks following 24 weeks of treatment at a dose of 50 to 200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). It is not known whether the dose of sertraline hydrochloride 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.

  Social Anxiety Disorder

  Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of sertraline hydrochloride tablets has demonstrated that its efficacy in social anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50 to 200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment.

  Obsessive-Compulsive Disorder and Panic Disorder

  It is generally agreed that OCD and Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of continuing sertraline hydrochloride tablets for periods of up to 28 weeks in patients with OCD and Panic Disorder who have responded while taking sertraline hydrochloride tablets during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50 to 200 mg/day has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL PHARMACOLOGY). It is not known whether the dose of sertraline hydrochloride tablets needed for maintenance treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

  Premenstrual Dysphoric Disorder

  The effectiveness of sertraline hydrochloride tablets in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.

  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 sertraline hydrochloride tablets.

  Conversely, at least 14 days should be allowed after stopping sertraline hydrochloride tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).

  Use of Sertraline Hydrochloride Tablets With Other MAOIs Such as Linezolid or Methylene Blue: Do not start sertraline hydrochloride 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).

  In some cases, a patient already receiving sertraline hydrochloride 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, sertraline hydrochloride 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 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with sertraline hydrochloride may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see CONTRAINDICATIONS).

  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 sertraline hydrochloride tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).

  Special Populations

  Dosage for Hepatically Impaired Patients- The use of sertraline in patients with liver disease should be approached with caution. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

  Treatment of Pregnant Women During the Third Trimester- Neonates exposed to sertraline hydrochloride and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with sertraline hydrochloride tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

  Discontinuation of Treatment with Sertraline Hydrochloride Tablets

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

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• Up And Up Antibiotic Pl...
  

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  Up And Up Antibiotic Plus Pain Relief

  

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  Adults

  Initiation of Therapy

  The usual starting dosage of methyldopa tablet is 250 mg two to three times a day in the first 48 hours. The daily dosage then may be increased or decreased, preferably at intervals of not less than two days, until an adequate response is achieved. To minimize the sedation, start dosage increases in the evening. By adjustment of dosage, morning hypotension may be prevented without sacrificing control of afternoon blood pressure.

  When methyldopa is given to patients on other antihypertensives, the dose of these agents may need to be adjusted to effect a smooth transition. When methyldopa is given with anti-hypertensives other than thiazides, the initial dosage of methyldopa should be limited to 500 mg daily in divided doses; when methyldopa is added to a thiazide, the dosage of thiazide need not be changed.

  Maintenance of Therapy

  The usual daily dosage of methyldopa is 500 mg to 2 g in two to four doses. Although occasional patients have responded to higher doses, the maximum recommended daily dosage is 3 g. Once an effective dosage range is attained, a smooth blood pressure response occurs in most patients in 12 to 24 hours. Since methyldopa has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.

  Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 g of methyldopa daily.

  Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.

  Pediatric Patients

  Initial dosage is based on 10 mg/kg of body weight daily in two to four doses. The daily dosage then is increased or decreased until an adequate response is achieved. The maximum dosage is 65 mg/kg or 3 g daily, whichever is less (see PRECAUTIONS: Pediatric Use.)

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• Peptic Relief Maximum S...
  

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  Peptic Relief Maximum Strength

  

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  2.1 Recommendations for All Patients

  Pioglitazone tablets should be taken once daily and can be taken without regard to meals.

  The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.

  The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.

  The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.

  After initiation of pioglitazone tablets or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.5)] .

  Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating pioglitazone tablets. Routine periodic monitoring of liver tests during treatment with pioglitazone tablets are not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of pioglitazone tablets or who are found to have abnormal liver tests while taking pioglitazone tablets should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)] .

  2.2 Concomitant Use with an Insulin Secretagogue or Insulin

  If hypoglycemia occurs in a patient co-administered pioglitazone tablets and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

  If hypoglycemia occurs in a patient co-administered pioglitazone tablets and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

  2.3 Concomitant Use with Strong CYP2C8 Inhibitors

  Coadministration of pioglitazone tablets and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone tablet is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

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• Clonazepam
  

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  Clonazepam

  

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  Clonazepam is available as a tablet. The tablets should be administered with water by swallowing the tablet whole.

  Seizure Disorders:

  Adults:

  The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 mg to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.

  The use of multiple anticonvulsants may result in an increase of depressant adverse effects. This should be considered before adding clonazepam to an existing anticonvulsant regimen.

  Pediatric Patients:

  Clonazepam is administered orally. In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses. Dosage should be increased by no more than 0.25 mg to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring.

  Geriatric Patients:

  There is no clinical trial experience with clonazepam in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam and observed closely (see PRECAUTIONS: Geriatric Use).

  Panic Disorder:

  Adults:

  The initial dose for adults with panic disorder is 0.25 mg bid. An increase to the target dose for most patients of 1 mg/day may be made after 3 days. The recommended dose of 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects. Nevertheless, it is possible that some individual patients may benefit from doses of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 mg to 0.25 mg bid every 3 days until panic disorder is controlled or until side effects make further increases undesired. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.

  Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn.

  There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use clonazepam for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

  Pediatric Patients:

  There is no clinical trial experience with clonazepam in panic disorder patients under 18 years of age.

  Geriatric Patients:

  There is no clinical trial experience with clonazepam in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of clonazepam and observed closely (see PRECAUTIONS: Geriatric Use).

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• Cyclogyl
  

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  Cyclogyl

  

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  Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10)] .

  2.1 Ovarian Cancer

  Recommended Dose and Schedule

  The recommended dose of topotecan for injection is 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21‑day course.

  2.2 Small Cell Lung Cancer

  Recommended Dose and Schedule

  The recommended dose of topotecan for injection is 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course.

  2.3 Cervical Cancer

  Recommended Dose and Schedule

  The recommended dose of topotecan for injection is 0.75 mg/m 2 by intravenous infusion over 30 minutes daily on Days 1, 2, and 3 in combination with cisplatin 50 mg/m 2 on Day 1, repeated every 21 days.

  2.4 Dose Modifications

  Hematologic Toxicities

  For single-agent use, dose reduce topotecan for injection to 1.25 mg/m 2 for:

  neutrophil counts of less than 500 cells/mm 3, or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last dose of topotecan for injection. platelet counts less than 25,000 cells/mm 3 during previous cycle.

  For combination use with cisplatin, dose reduce topotecan for injection to 0.60 mg/m 2 (and further to 0.45 mg/m 2 if necessary) for :

  febrile neutropenia (defined as neutrophil counts less than 1,000 cells/mm 3 with temperature of greater than or equal to 38.0°C (100.4°F), or administer G‑CSF starting no sooner than 24 hours following the last dose of topotecan for injection. platelet counts less than 25,000 cells/mm 3 during previous cycle.

  Renal Impairment

  For single-agent use, dose reduce topotecan for injection to 0.75 mg/m 2 in patients with moderate renal impairment (creatinine clearance [Clcr] = 20 to 39 mL/min). Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation for topotecan for injection [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

  2.5 Preparation and Intravenous Administration

  Topotecan for injection is a cytotoxic drug. Follow applicable special handling and disposable procedures. 1

  Preparation and Administration

  Reconstitute each 4-mg vial of topotecan for injection with 4 mL Sterile Water for Injection, USP. Dilute the appropriate volume of the reconstituted solution in either 0.9% Sodium Chloride Intravenous Infusion, USP or 5% Dextrose in Water for Injection, USP prior to administration.

  Stability

  Unopened vials of topotecan for injection are stable until the date indicated on the package when stored between 20°C and 25°C (68°F and 77°F) [see USP] and protected from light in the original carton. Because the vials contain no preservative, contents should be used immediately after reconstitution.

  Reconstituted vials of topotecan for injection diluted for infusion are stable at approximately 20°C to 25°C (68°F to 77°F) and ambient lighting conditions for 24 hours.

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• Diltiazem Hydrochloride...
  

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  Diltiazem Hydrochloride

  

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  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 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 1

  400 to 800 mg/day

  800 mg/day

  Bipolar Mania- Adults Monotherapy or as an adjunct to lithium or divalproex

  Day 1: Twice daily dosing totaling 100 mg.

  Day 2: Twice daily dosing totaling 200 mg.

  Day 3: Twice daily dosing totaling 300 mg.

  Day 4: Twice daily dosing totaling 400 mg.

  Further dosage adjustments up to 800 mg/day by Day 6 should be in increments of no greater than 200 mg/day.

  400 to 800 mg/day

  800 mg/day

  Bipolar Mania- Children and Adolescents (10 to 17 years), Monotherapy

  Day 1: 25 mg twice daily.

  Day 2: Twice daily dosing totaling 100 mg.

  Day 3: Twice daily dosing totaling 200 mg.

  Day 4: Twice daily dosing totaling 300 mg.

  Day 5: Twice daily dosing totaling 400 mg.

  Further adjustments should be in increments no greater than 100 mg/day within the recommended dose range of 400 to 600 mg/day. Based on response and tolerability, may be administered three times daily.

  400 to 600 mg/day

  600 mg/day

  Bipolar Depression-Adults

  Administer once daily at bedtime.

  Day 1: 50 mg

  Day 2: 100 mg

  Day 3: 200 mg

  Day 4: 300 mg

  300 mg/day

  300 mg/day

  Bipolar I Disorder Maintenance Therapy- Adults

  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

  1N/A Not applicable

  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.

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• Donepezil Hydrochloride...
  

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  Donepezil Hydrochloride

  

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  Donepezil hydrochloride tablets should be taken in the evening, just prior to retiring.

  Donepezil hydrochloride tablets can be taken with or without food.

  2.1. Mild to Moderate Alzheimer's Disease

  The dosages of donepezil hydrochloride tablets shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.

  The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of donepezil hydrochloride tablets might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.

  2.2. Severe Alzheimer's Disease

  Donepezil hydrochloride has been shown to be effective in controlled clinical trials at a dose of 10 mg administered once daily.

  2.3. Titration

  The recommended starting dose of donepezil hydrochloride tablet is 5 mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer's disease indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5 mg dose. In open-label trials using a 6 week titration, the type and frequency of these same adverse events were similar between the 5 mg and 10 mg dose groups. Therefore, because donepezil hydrochloride steady state is achieved about 15 days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks.

  2.1. Mild to Moderate Alzheimer's Disease

  The dosages of donepezil hydrochloride tablets shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.

  The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of donepezil hydrochloride tablets might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.

  2.2. Severe Alzheimer's Disease

  Donepezil hydrochloride has been shown to be effective in controlled clinical trials at a dose of 10 mg administered once daily.

  2.3. Titration

  The recommended starting dose of donepezil hydrochloride tablet is 5 mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer's disease indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5 mg dose. In open-label trials using a 6 week titration, the type and frequency of these same adverse events were similar between the 5 mg and 10 mg dose groups. Therefore, because donepezil hydrochloride steady state is achieved about 15 days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks.

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• Mitomycin
  

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  Mitomycin

  

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

  Mitomycin should be given intravenously only, using care to avoid extravasation of the compound. If extravasation occurs, cellulitis, ulceration, and slough may result.

  Each vial contains either mitomycin 5 mg and mannitol 10 mg, mitomycin, 20 mg and mannitol 40 mg or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 10 mL, 40 mL or 80 mL respectively. Shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until solution is obtained.

  After full hematological recovery (see guide to dosage adjustment) from any previous chemotherapy, the following dosage schedule may be used at 6 to 8 week intervals:

  20 mg/m 2 intravenously as a single dose via a functioning intravenous catheter.

  Because of cumulative myelosuppression, patients should be fully reevaluated after each course of mitomycin, and the dose reduced if the patient has experienced any toxicities. Doses greater than 20 mg/m 2 have not been shown to be more effective, and are more toxic than lower doses.

  The following schedule is suggested as a guide to dosage adjustment:

  Nadir After Prior Dose Leukocytes/mm 3 Platelets/mm 3 Percentage of Prior Dose To Be Given >4000 >100,000 100% 3000–3999 75,000–99,999 100% 2000–2999 25,000–74,999 70% <2000 <25,000 50%

  No repeat dosage should be given until leukocyte count has returned to 4000/mm 3 and a platelet count to 100,000/mm 3. When mitomycin is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly. If the disease continues to progress after two courses of mitomycin, the drug should be stopped since chances of response are minimal.

  STABILITY

  Unreconstituted mitomycin stored at room temperature is stable for the lot life indicated on the package. Avoid excessive heat (over 40°C, 104°F). Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, mitomycin is stable for 14 days refrigerated or 7 days at room temperature. Diluted in various I.V. fluids at room temperature, to a concentration of 20 to 40 micrograms per mL: I.V. Fluid Stability 0.9% Sodium Chloride Injection 12 hours Sodium Lactate Injection 24 hours The combination of mitomycin (5 mg to 15 mg) and heparin (1,000 units to 10,000 units) in 30 mL of 0.9% Sodium Chloride Injection is stable for 48 hours at room temperature.

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

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• Hydrochlorothiazide
  

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  Hydrochlorothiazide

  

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  Therapy should be individualized according to patient response. Use the smallest dosage necessary to achieve the required response.

  Adults:For Edema: The usual adult dosage is 25 to 100 mg daily as a single or divided dose. Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on 3 to 5 days each week. With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.

  For Control of Hypertension: The usual initial dose in adults is 25 mg daily given as a single dose. The dose may be increased to 50 mg daily, given as a single or two divided doses. Doses above 50 mg are often associated with marked reductions in serum potassium (see also PRECAUTIONS).

  Patients usually do not require doses in excess of 50 mg of hydrochlorothiazide daily when used concomitantly with other antihypertensive agents.

  Infants and Children: For Diuresis and for Control of Hypertension: The usual pediatric dosage is 0.5 mg to 1 mg per pound (1 to 2 mg/kg) per day in single or two divided doses, not to exceed 37.5 mg per day in infants up to 2 years of age or 100 mg per day in children 2 to 12 years of age. In infants less than 6 months of age, doses up to 1.5 mg per pound (3 mg/kg) per day in two divided doses may be required (See PRECAUTIONS: Pediatric Use).

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• Mitomycin
  

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  Mitomycin

  

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

  Mitomycin should be given intravenously only, using care to avoid extravasation of the compound. If extravasation occurs, cellulitis, ulceration, and slough may result.

  Each vial contains mitomycin 5 mg and mannitol 10 mg. To administer, add Sterile Water for Injection, 10 mL. Shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until solution is obtained.

  After full hematological recovery (see guide to dosage adjustment) from any previous chemotherapy, the following dosage schedule may be used at 6 to 8 week intervals:

  20 mg/m2 intravenously as a single dose via a functioning intravenous catheter.

  Because of cumulative myelosuppression, patients should be fully reevaluated after each course of mitomycin, and the dose reduced if the patient has experienced any toxicities. Doses greater than 20 mg/m2 have not been shown to be more effective, and are more toxic than lower doses.

  The following schedule is suggested as a guide to dosage adjustment:

   Nadir After Prior Dose

  Leukocytes/mm3

  Platelets/mm3

  Percentage of Prior Dose To Be Given

  >4000

  >100,000

  100%

  3000–3999

  75,000–99,999

  100%

  2000–2999

  25,000–74,999

  70%

  <2000

  <25,000

  50%

  No repeat dosage should be given until leukocyte count has returned to 4000/mm3 and a platelet count to 100,000/mm3.

  When mitomycin is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly. If the disease continues to progress after two courses of mitomycin, the drug should be stopped since chances of response are minimal.

  STABILITY

  Unreconstituted mitomycin stored at room temperature is stable for the lot life indicated on the package. Avoid excessive heat (over 40°C, 104°F). Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, mitomycin is stable for 14 days refrigerated or 7 days at room temperature. Dilutedin various I.V. fluids at room temperature, to a concentration of 20 to 40 micrograms per mL: I.V. Fluid Stability 0.9% Sodium Chloride Injection 12 hours Sodium Lactate Injection 24 hours The combination of mitomycin (5 mg to 15 mg) and heparin (1,000 units to 10,000 units) in 30 mL of 0.9% Sodium Chloride Injection is stable for 48 hours at room temperature.

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

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• Mitomycin
  

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  Mitomycin

  

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

  Mitomycin should be given intravenously only, using care to avoid extravasation of the compound. If extravasation occurs, cellulitis, ulceration, and slough may result.

  Each vial contains mitomycin 20 mg and mannitol 40 mg or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 40 mL or 80 mL respectively. Shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until solution is obtained.

  After full hematological recovery (see guide to dosage adjustment) from any previous chemotherapy, the following dosage schedule may be used at 6 to 8 week intervals:

  20 mg/m2 intravenously as a single dose via a functioning intravenous catheter.

  Because of cumulative myelosuppression, patients should be fully reevaluated after each course of mitomycin, and the dose reduced if the patient has experienced any toxicities. Doses greater than 20 mg/m2 have not been shown to be more effective, and are more toxic than lower doses.

  The following schedule is suggested as a guide to dosage adjustment:

   Nadir After Prior Dose

  Leukocytes/mm3

  Platelets/mm3

  Percentage of Prior Dose To Be Given

  >4000

  >100,000

  100%

  3000–3999

  75,000–99,999

  100%

  2000–2999

  25,000–74,999

  70%

  <2000

  <25,000

  50%

  No repeat dosage should be given until leukocyte count has returned to 4000/mm3 and a platelet count to 100,000/mm3.

  When mitomycin is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly. If the disease continues to progress after two courses of mitomycin, the drug should be stopped since chances of response are minimal.

  STABILITY

  Unreconstituted mitomycin stored at room temperature is stable for the lot life indicated on the package. Avoid excessive heat (over 40°C, 104°F). Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, mitomycin is stable for 14 days refrigerated or 7 days at room temperature. Dilutedin various I.V. fluids at room temperature, to a concentration of 20 to 40 micrograms per mL: I.V. Fluid Stability 0.9% Sodium Chloride Injection 12 hours Sodium Lactate Injection 24 hours The combination of mitomycin (5 mg to 15 mg) and heparin (1,000 units to 10,000 units) in 30 mL of 0.9% Sodium Chloride Injection is stable for 48 hours at room temperature.

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

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• Mexiletine Hydrochlorid...
  

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  Mexiletine Hydrochloride

  

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  2.1 Asthma

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

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

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

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

  2.2 Exercise-Induced Bronchoconstriction (EIB) in Patients 15 Years of Age and Older

  For prevention of EIB, a single 10 mg dose of montelukast should be taken at least 2 hours before exercise. An additional dose of montelukast should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium tablets daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist.

  Safety and efficacy in patients younger than 15 years of age have not been established. Daily administration of montelukast sodium tablets for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

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

  2.3 Allergic Rhinitis

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

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

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

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

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

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

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

  2.4 Asthma and Allergic Rhinitis

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

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• Amlodipine Besylate
  

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  Amlodipine Besylate

  

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  2.1 Adults

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

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

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

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

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

  2.2 Children

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

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• Etoposide
  

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  Etoposide

  

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  Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used with undiluted Etoposide Injection USP.

  The usual dose of Etoposide Injection USP in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5.

  In small cell lung cancer, the Etoposide Injection USP dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days.

  For recommended dosing adjustments in patients with renal impairment see PRECAUTIONS section.

  Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity.

  Administration Precautions

  As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of Etoposide Injection USP. Skin reactions associated with accidental exposure to Etoposide Injection USP may occur. The use of gloves is recommended. If Etoposide Injection USP solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosawith water.

  Preparation for Intravenous Administration

  Etoposide Injection USP must be diluted prior to use with either 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur. Hypotension following rapid intravenous administration has been reported; hence, it is recommended that the Etoposide Injection USP solution be administered over a 30- to 60-minute period. A longer duration of administration may be used if the volume of fluid to be infused is a concern. Etoposide Injection USP should not be given by rapid intravenous injection.

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

  Stability

  Unopened vials of Etoposide Injection USP are stable for 24 months at room temperature (25°C). Vials diluted as recommended to a concentration of 0.2 or 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers.

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

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• Pentazocine And Naloxon...
  

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  Pentazocine And Naloxone

  

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  2.1 Recommended Dosing

  The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, simvastatin tablets can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.

  2.2 Restricted Dosing for 80 mg

  Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. [see Warnings and Precautions (5.1)]

  Patients who are currently tolerating the 80-mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.

  Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin tablets should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

  2.3 Coadministration with Other Drugs

  Patients taking Verapamil, Diltiazem, or Dronedarone

  The dose of simvastatin tablets should not exceed 10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)]. .

  Patients taking Amiodarone, Amlodipine or Ranolazine

  The dose of simvastatin tablets should not exceed 20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

  2.4 Patients with Homozygous Familial Hypercholesterolemia

  The recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)] . Simvastatin tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

  Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of simvastatin tablets should be reduced by 50% if initiating lomitapide. Simvastatin tablets dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken simvastatin tablets 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.

  2.5 Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia

  The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines 1 and Clinical Studies (14.2)]. Adjustments should be made at intervals of 4 weeks or more.

  1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 89(3):495-501. 1992.

  2.6 Patients with Renal Impairment

  Because simvastatin tablets do not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when simvastatin tablets are administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

  2.7 Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 1 g/day Niacin) of Niacin-Containing Products

  Because of an increased risk for myopathy, in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [see Warnings and Precautions (5.1)]

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• Glipizide
  

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  Glipizide

  

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  There is no fixed dosage regimen for the management of diabetes mellitus with glipizide or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.

  Short-term administration of glipizide may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

  In general, glipizide should be given approximately 30 minutes before a meal to achieve the greatest reduction in postprandial hyperglycemia.

  Initial Dose

  The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg.

  Titration

  Dosage adjustments should ordinarily be in increments of 2.5 to 5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. If response to a single dose is not satisfactory, dividing that dose may prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate caloric content. The maximum recommended total daily dose is 40 mg.

  Maintenance

  Some patients may be effectively controlled on a once-a-day regimen, while others show better response with divided dosing. Total daily doses above 15 mg should ordinarily be divided. Total daily doses above 30 mg have been safely given on a b.i.d. basis to long-term patients.

  In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypo glycemic reactions (see PRECAUTIONS section).

  Patients Receiving Insulin

  As with other sulfonylurea-class hypoglycemics, many stable non-insulin-dependent diabetic patients receiving insulin may be safely placed on glipizide. When transferring patients from insulin to glipizide, the following general guidelines should be considered:

  For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide therapy may begin at usual dosages. Several days should elapse between glipizide titration steps. For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between glipizide titration steps.

  During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period.

  Patients Receiving Other Oral Hypoglycemic Agents

  As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide due to potential overlapping of drug effect.

  When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, glipizide should be administered at least 4 hours prior to colesevelam.

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• Methotrexate
  

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  Methotrexate

  

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  Neoplastic Diseases:

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate Injection, USP (preservative free) formulations may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and similar trophoblastic diseases:

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

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

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.

  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia:

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

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.

  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when

  relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

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

  Meningeal Leukemia:

  In the treatment of prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:

  AGE (years) DOSE (mg) <1 6 1 8 2 10 3 or older 12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than one week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas:

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

  Mycosis fungoides (cutaneous T cell lymphoma):

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

  Osteosarcoma:

  An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.

  Drug* Dose* Treatment Week After Surgery Methotrexate 12 g/m2 IV as 4 hour infusion (starting dose) 4,5,6,7,11,12,15,16,29,30,44,45 15 mg orally every six hours for Leucovorin  10 doses starting at 24 hours after - - - start of methotrexate infusion Doxorubicin† as a single drug 30 mg/m2 day IV x 3 days 8,17 Doxorubicin† 50 mg/m2 IV 20,23,33,36 Cisplatin† 100 mg/m2 IV 20,23,33,36 Bleomycin† 15 units/m2 IV x 2 days 2,13,26,39,42 Cyclophosphamide† 600 mg/m2 IV x 2 days 2,13,26,39,42 Dactinomycin† 0.6 mg/m2 IV x 2 days 2,13,26,39,42

  *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606.

  †See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity.

  When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

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• Fluorouracil
  

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  Fluorouracil

  

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  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation. No dilution is required.

  All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil Injection, USP.

  Dosage

  Twelve mg/kg are given intravenously once daily for four successive days. The daily dose should not exceed 800 mg. If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs. No therapy is given on the 5th, 7th, 9th or 11th days. Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent. (See WARNINGS and PRECAUTIONS sections.)

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for three days. If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs. No therapy is given on the 4th, 6th or 8th days. The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a "course of therapy."

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

  Repeat dosage of first course every 30 days after the last day of the previous course of treatment. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose. Do not exceed 1 g per week.

  The patient's reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly. Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Handling and Disposal

  Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1 to 7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropiate.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

  Directions for proper use of pharmacy bulk package

  (Not for Direct Infusion)

  The 50 mL and 100 mL Pharmacy Bulk Packages are for use in a Pharmacy Admixture Service only. They should be inserted into a plastic hanging device and suspended as a unit in a laminar flow hood. Use only if clear and seal is intact and undamaged.

  Use of this product is restricted to a suitable work area, such as a laminar flow hood. Use only if clear and seal is intact and undamaged. Prior to entering the vial, remove the flip-off seal and cleanse the rubber closure with a suitable antiseptic agent. The container closure may be penetrated only one time, utilizing a suitable sterile transfer device or dispensing set which allows measured distribution of the contents. The date and time the vial was initially opened should be recorded in the space provided on the vial label. Transfer individual dose(s) to appropriate intravenous infusion solutions. Use of a syringe with a needle is not recommended. Multiple entries increase the potential of microbial and particulate contamination.

  The withdrawal of container contents should be accomplished without delay using aseptic technique. However, should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid transfer operations. It is recommended that the transferred fluids be used promptly.

  Instructions to Hang Vial

  1. Place oval portion of ring sling over vial neck

  2. Push bottom of vial through inner circle

  3. Hang vial using outer circle

  Recommended Storage Conditions After Opening

  Keep under laminar flow hood at room temperature.

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• Fluorouracil
  

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  Fluorouracil

  

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  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation. No dilution is required.

  All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil Injection, USP.

  Dosage

  Twelve mg/kg are given intravenously once daily for four successive days. The daily dose should not exceed 800 mg. If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs. No therapy is given on the 5th, 7th, 9th or 11th days. Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent. (See WARNINGS and PRECAUTIONS sections.)

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for three days. If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs. No therapy is given on the 4th, 6th or 8th days. The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a "course of therapy."

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

  Repeat dosage of first course every 30 days after the last day of the previous course of treatment. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose. Do not exceed 1 g per week.

  The patient's reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly. Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Handling and Disposal

  Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Although the fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected. If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

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• Clopidogrel
  

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  Clopidogrel

  

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  2.1 Acute Coronary Syndrome

  Clopidogrel tablets USP can be administered with or without food [see Clinical Pharmacology (12.3)]

  For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel bisulfate with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75 to 325 mg once daily) and continue in combination with clopidogrel bisulfate [see Clinical Studies (14.1)] . For patients with STEMI, the recommended dose of clopidogrel bisulfate is 75 mg once daily orally, administered in combination with aspirin (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel bisulfate 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 bisulfate 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 bisulfate. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel bisulfate. 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)].

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• Escitalopram
  

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  Escitalopram

  

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  Escitalopram tablets should be administered once daily, in the morning or evening, with or without food.

  2.1 Major Depressive Disorder

  Initial Treatment

  Adolescents

  The recommended dose of escitalopram tablet is 10 mg once daily. A flexible-dose trial of escitalopram tablets (10 to 20 mg/day) demonstrated the effectiveness of escitalopram oxalate [ see Clinical Studies ( 14.1) ]. If the dose is increased to 20 mg, this should occur after a minimum of three weeks.

  Adults

  The recommended dose of escitalopram tablet is 10 mg once daily. A fixed-dose trial of escitalopram tablets demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram tablets, but failed to demonstrate a greater benefit of 20 mg over 10 mg [ see Clinical Studies ( 14.1) ]. If the dose is increased to 20 mg, this should occur after a minimum of one week.

  Maintenance Treatment

  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. Systematic evaluation of continuing escitalopram tablets 10 or 20 mg/day in adults patients with major depressive disorder who responded while taking escitalopram tablets during an 8-week, acute-treatment phase demonstrated a benefit of such maintenance treatment [see Clinical Studies ( 14.1)]. Nevertheless, the physician who elects to use escitalopram tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.

  2.2 Generalized Anxiety Disorder

  Initial Treatment

  Adults

  The recommended starting dose of escitalopram tablet is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.

  Maintenance Treatment

  Generalized anxiety disorder is recognized as a chronic condition. The efficacy of escitalopram tablets in the treatment of GAD beyond 8 weeks has not been systematically studied. The physician who elects to use escitalopram tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

  2.3 Special Populations

  10 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment.

  No dosage adjustment is necessary for patients with mild or moderate renal impairment. Escitalopram tablets should be used with caution in patients with severe renal impairment.

  2.4 Discontinuation of Treatment with Escitalopram Tablets

  Symptoms associated with discontinuation of escitalopram tablets and other SSRIs and SNRIs have been reported [ see Warnings and Precautions ( 5.3) ]. 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 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 escitalopram tablets. Conversely, at least 14 days should be allowed after stopping escitalopram tablets before starting an MAOI intended to treat psychiatric disorders [ see Contraindications ( 4.1) ].

  2.6 Use of Escitalopram Tablets with Other MAOIs such as Linezolid or Methylene Blue

  Do not start escitalopram tablets 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 ( 4.1) ].

  In some cases, a patient already receiving escitalopram 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, escitalopram 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 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with escitalopram 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 escitalopram tablet 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) ].

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• Lisinopril
  

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  Lisinopril

  

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  2.1 Hypertension

  Initial Therapy in adults: The recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 20 to 40 mg per day administered in a single daily dose. Doses up to 80 mg have been used but do not appear to give greater effect.

  Use with diuretics in adults

  If blood pressure is not controlled with lisinopril alone, a low dose of a diuretic may be added (eg, hydrochlorothiazide, 12.5 mg). After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.

  The recommended starting dose in adult patients with hypertension taking diuretics is 5 mg once per day.

  Pediatric Patients 6 years of age and older with hypertension

  For pediatric patients with glomerular filtration rate > 30 mL/min/1.73m 2, the recommended starting dose is 0.07 mg per kg once daily (up to 5 mg total). Dosage should be adjusted according to blood pressure response up to a maximum of 0.61 mg per kg (up to 40 mg) once daily. Doses above 0.61 mg per kg (or in excess of 40 mg) have not been studied in pediatric patients [See Clinical Pharmacology (12.3)].

  Lisinopril is not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73m 2 [See Use in Specific Populations (8.4) and Clinical Studies (14.1)].

  2.2 Heart Failure

  The recommended starting dose for lisinopril, when used with diuretics and (usually) digitalis as adjunctive therapy for systolic heart failure, is 5 mg once daily. The recommended starting dose in these patients with hyponatremia (serum sodium < 130 mEq/L) is 2.5 mg once daily. Increase as tolerated to a maximum of 40 mg once daily.

  Diuretic dose may need to be adjusted to help minimize hypovolemia, which may contribute to hypotension [See Warnings and Precautions (5.4), and Drug Interactions (7.1)]. The appearance of hypotension after the initial dose of lisinopril does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

  2.3 Reduction of Mortality in Acute Myocardial Infarction

  In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, give lisinopril 5 mg orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily. Dosing should continue for at least six weeks.

  Initiate therapy with 2.5 mg in patients with a low systolic blood pressure (≤ 120 mmHg and > 100 mm Hg) during the first 3 days after the infarct [See Warnings and Precautions (5.4)]. If hypotension occurs (systolic blood pressure ≤ 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure < 90 mmHg for more than 1 hour) lisinopril should be withdrawn.

  2.4 Dose in Patients with Renal Impairment

  No dose adjustment of lisinopril is required in patients with creatinine clearance > 30 mL/min. In patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, reduce the initial dose of lisinopril to half of the usual recommended dose i.e., hypertension, 5 mg; systolic heart failure, 2.5 mg and acute MI, 2.5 mg. Up titrate as tolerated to a maximum of 40 mg daily. For patients on hemodialysis or creatinine clearance < 10 mL/min, the recommended initial dose is 2.5 mg once daily [See Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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• Glimepiride
  

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  Glimepiride

  

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  2.1 Recommended Dosing

  Glimepiride tablets should be administered with breakfast or the first main meal of the day.

  The recommended starting dose of glimepiride tablet is 1 mg or 2 mg once daily. Patients at increased risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1 mg once daily [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.5, 8.6)].

  After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.5, 8.6)].

  The maximum recommended dose is 8 mg once daily.

  Patients being transferred to glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for hypoglycemia.

  When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced. Therefore, glimepiride should be administered at least 4 hours prior to colesevelam.

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• Letrozole
  

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  Letrozole

  

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  2.1 Recommended Dose

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

  2.2 Use in Adjuvant Treatment of Early Breast Cancer

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

  2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer

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

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

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

  2.5 Use in Hepatic Impairment

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

  2.6 Use in Renal Impairment

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

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• Tacrolimus
  

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  Tacrolimus

  

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  2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of tacrolimus capsules should be administered no sooner than 6 hours after transplantation in the liver and heart transplant patients. In kidney transplant patients, the initial dose of tacrolimus capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see Dosage and Administration ( 2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults * In a second smaller trial, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12 [see Clinical Studies ( 14.1)]. Patient Population

  Recommended Tacrolimus Capsules Initial

  Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Adult kidney transplant patients In combination with azathioprine

  0.2 mg/kg/day

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

  In combination with MMF/IL-2 receptor antagonist *

  0.1 mg/kg/day

  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients 0.10 to 0.15 mg/kg/day month 1 to 12: 5 to 20 ng/mL Adult heart transplant patients 0.075 mg/kg/day

  month 1 to 3 : 10 to 20 ng/mL

  month ≥4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules dosages than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

  The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race Time After Transplant

  Caucasian

  n=114

  Black

  n=56

  Dose

  (mg/kg)

  Trough Concentrations

  (ng/mL)

  Dose

  (mg/kg) Trough Concentrations (ng/mL) Day 7 0.18 12.0 0.23 10.9 Month 1 0.17 12.8 0.26 12.9 Month 6 0.14 11.8 0.24 11.5 Month 12 0.13 10.1 0.19 11.0

  Initial Dose – Injection Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions ( 5.11)]

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration ( 2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Pediatric liver transplant patients 0.15 to 0.20 mg/kg/day Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

  In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus capsules should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery.

  2.4 Dosage Adjustments in Patients with Hepatic Impairment

  Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child Pugh ≥ 10) may require lower doses of tacrolimus capsules. Close monitoring of blood concentrations is warranted.

  The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.1), Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3[see Dosage and Administration ( 2.1, 2.2)] ; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration ( 2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology ( 12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions ( 7.2)].

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  2.6 Therapeutic Drug Monitoring

  Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Observed whole blood trough concentrations can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

  The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

  Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer they should be deep frozen at -20° C. One study showed drug recovery > 90% for samples stored at -20° C for 6 months, with reduced recovery observed after 6 months.

  2.1 Dosage in Adult Kidney, Liver, or Heart Transplant Patients

  The initial oral dosage recommendations for adult patients with kidney, liver, or heart transplants along with recommendations for whole blood trough concentrations are shown in Table 1. The initial dose of tacrolimus capsules should be administered no sooner than 6 hours after transplantation in the liver and heart transplant patients. In kidney transplant patients, the initial dose of tacrolimus capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. For blood concentration monitoring details see Dosage and Administration ( 2.6).

  Table 1. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Adults * In a second smaller trial, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12 [see Clinical Studies ( 14.1)]. Patient Population

  Recommended Tacrolimus Capsules Initial

  Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Adult kidney transplant patients In combination with azathioprine

  0.2 mg/kg/day

  month 1 to 3: 7 to 20 ng/mL

  month 4 to 12: 5 to 15 ng/mL

  In combination with MMF/IL-2 receptor antagonist *

  0.1 mg/kg/day

  month 1 to 12: 4 to 11 ng/mL

  Adult liver transplant patients 0.10 to 0.15 mg/kg/day month 1 to 12: 5 to 20 ng/mL Adult heart transplant patients 0.075 mg/kg/day

  month 1 to 3 : 10 to 20 ng/mL

  month ≥4: 5 to 15 ng/mL

  Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower tacrolimus capsules dosages than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.

  The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients ( Table 2).

  Table 2. Comparative Dose and Trough Concentrations Based on Race Time After Transplant

  Caucasian

  n=114

  Black

  n=56

  Dose

  (mg/kg)

  Trough Concentrations

  (ng/mL)

  Dose

  (mg/kg) Trough Concentrations (ng/mL) Day 7 0.18 12.0 0.23 10.9 Month 1 0.17 12.8 0.26 12.9 Month 6 0.14 11.8 0.24 11.5 Month 12 0.13 10.1 0.19 11.0

  Initial Dose – Injection Tacrolimus injection should be used only as a continuous IV infusion and when the patient cannot tolerate oral administration of tacrolimus capsules. Tacrolimus injection should be discontinued as soon as the patient can tolerate oral administration of tacrolimus capsules, usually within 2 to 3 days. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  The observed trough concentrations described above pertain to oral administration of tacrolimus only; while monitoring tacrolimus concentrations in patients receiving tacrolimus injection as a continuous IV infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.

  The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney and liver transplant and 0.01 mg/kg/day in heart transplant given as a continuous IV infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.

  Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as tacrolimus injection [see Warnings and Precautions ( 5.11)]

  2.2 Dosage in Pediatric Liver Transplant Patients

  The initial oral dosage recommendations for pediatric patients with liver transplants along with recommendations for whole blood trough concentrations are shown in Table 3. For blood concentration monitoring details see Dosage and Administration ( 2.6). If necessary, pediatric patients may start on an IV dose of 0.03 to 0.05 mg/kg/day.

  Table 3. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children Patient Population

  Recommended Tacrolimus Capsules Initial Oral Dosage

  Note: daily doses should be administered as two divided doses, every 12 hours Observed Tacrolimus Whole Blood Trough Concentrations Pediatric liver transplant patients 0.15 to 0.20 mg/kg/day Month 1 to 12: 5 to 20 ng/mL

  Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations.

  Experience in pediatric kidney and heart transplantation patients is limited.

  2.3 Dosage Adjustment in Patients with Renal Impairment

  Due to its potential for nephrotoxicity, consideration should be given to dosing tacrolimus capsules at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.

  In kidney transplant patients with post-operative oliguria, the initial dose of tacrolimus capsules should be administered no sooner than 6 hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery.

  2.4 Dosage Adjustments in Patients with Hepatic Impairment

  Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child Pugh ≥ 10) may require lower doses of tacrolimus capsules. Close monitoring of blood concentrations is warranted.

  The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.1), Use in Specific Populations ( 8.7) and Clinical Pharmacology ( 12.3)].

  2.5 Administration Instructions

  It is recommended that patients initiate oral therapy with tacrolimus capsules if possible.

  Initial dosage and observed tacrolimus whole blood trough concentrations for adults are shown in Table 1 and for pediatrics in Table 3[see Dosage and Administration ( 2.1, 2.2)] ; for blood concentration monitoring details in kidney transplant patients [see Dosage and Administration ( 2.1)].

  It is important to take tacrolimus capsules consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus capsules [see Clinical Pharmacology ( 12.3)].

  Patients should not eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions ( 7.2)].

  Tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

  In patients unable to take oral tacrolimus capsules, therapy may be initiated with tacrolimus injection as a continuous IV infusion. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. In patients receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion.

  2.6 Therapeutic Drug Monitoring

  Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Observed whole blood trough concentrations can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.

  The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.

  Methods commonly used for the assay of tacrolimus include high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore assay results obtained with immunoassays may have a positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; see assay instructions for specifics. If samples are to be kept longer they should be deep frozen at -20° C. One study showed drug recovery > 90% for samples stored at -20° C for 6 months, with reduced recovery observed after 6 months.

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• Gemcitabine Hydrochlori...
  

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  Gemcitabine Hydrochloride

  

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  2.1 Ovarian Cancer

  Recommended Dose and Schedule

        The recommended dose of Gemcitabine for Injection is 1000 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 dose modifications for myelosuppression are described 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 Treatment Day Absolute granulocyte count(x 106/L) Platelet count(x 106/L) % of full dose Day 1 ≥1500<1500 andor ≥100,000<100,000 100%Delay Treatment Cycle Day 8 ≥15001000-1499<1000 andoror ≥100,00075,000-99,999<75,000 10050Hold 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 on Days 1 and 8 Subsequent Occurrence 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 is 1250 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 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 ≥1500 and ≥100,000 100% less than 1500 or less than 100,000 Hold Day 8 ≥1200 and >75,000 100% 1000-1199 or 50,000-75,000 75% 700-999 and ≥50,000 50% <700 or <50,000 Hold

  2.3 Non-Small Cell Lung Cancer

  Recommended Dose and Schedule

  Every 4-week schedule

  The recommended dose of Gemcitabine for Injection is 1000 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

  Every 3-week schedule

  The recommended dose of Gemcitabine for Injection is 1250 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.

  Dose Modifications

  Recommended dose modifications for Gemcitabine for Injection myelosuppression are described in Table 4 [[see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for Gemcitabine for Injection recommendations for non-hematologic adverse reactions.

  2.4 Pancreatic Cancer

  Recommended Dose and Schedule

  The recommended dose of Gemcitabine for Injection is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule

  Weeks 1-8: 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 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 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 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 ≥1000 And ≥100,000 100 500-999 Or 50,000-99,999 75 <500 Or <50,000 Hold

  2.5 Dose Modifications for Non-Hematologic Adverse Reactions

  Permanently discontinue Gemcitabine for Injection 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 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 solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine for Injection contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling Gemcitabine for Injection 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 or 50 mL to the 2-g vial. These dilutions each yield a Gemcitabine for Injection concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg, 1 g or 2 g of Gemcitabine for Injection. 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). Do not refrigerate as crystallization can occur.

  No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

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• Finasteride
  

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  Finasteride

  

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  Finasteride tablets may be administered with or without meals.

  The recommended dose of finasteride tablets 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.

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• Finasteride
  

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  Finasteride

  

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

  2.1 Monotherapy

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

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• Mycophenolate Mofetil C...
  

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  Mycophenolate Mofetil Capsule Mycophenolate Mofetil

  

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

  Pediatrics (3 months to 18 years of age)

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

  Cardiac Transplantation

  Adults

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

  Hepatic Transplantation

  Adults

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

  Mycophenolate Mofetil Capsules, Tablets, and Oral Suspension

  The initial oral dose of mycophenolate mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that mycophenolate mofetil be administered on an empty stomach. However, in stable renal transplant patients, mycophenolate mofetil may be administered with food if necessary.

  Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take mycophenolate mofetil at the usual times.

  Note

  If required, mycophenolate mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).

  Patients With Hepatic Impairment

  No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

  No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

  Geriatrics

  The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients (see PRECAUTIONS: Geriatric Use).

  Dosage Adjustments In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of mycophenolate mofetil greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: Patients with Renal Impairment).

  No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

  If neutropenia develops (ANC <1.3× 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see WARNINGS: Neutropenia, ADVERSE REACTIONS, and PRECAUTIONS: Laboratory Tests).

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• Docetaxel Kit Docetaxel...
  

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  Docetaxel Kit Docetaxel

  

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  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 Docetaxel Injection is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks. For the adjuvant treatment of operable node-positive breast cancer, the recommended Docetaxel Injection dose is 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses. Prophylactic granulocyte - colony stimulating factor (G-CSF) may be used to mitigate the risk of hematological toxicities [see Dosage and Administration (2.7)].

  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 Docetaxel Injection 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 Docetaxel Injection 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)].

  2.4 Gastric Adenocarcinoma

  For gastric adenocarcinoma, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration [see Dosage and Administration (2.7)].

  2.5 Head and Neck Cancer

  Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the docetaxel containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

  Induction chemotherapy followed by radiotherapy (TAX323)For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. [see Dosage and Administration (2.7)]. Induction chemotherapy followed by chemoradiotherapy (TAX324)For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy [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 Docetaxel Injection 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 Docetaxel Injection 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 Docetaxel Injection 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 Docetaxel Injection therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.

  Combination Therapy with Docetaxel Injection in the Adjuvant Treatment of Breast Cancer

  Docetaxel Injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their Docetaxel Injection dose reduced to 60 mg/m2. Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection dose decreased to 60 mg/m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have their dosage of Docetaxel Injection reduced from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m, treatment should be discontinued.

  Non-Small Cell Lung Cancer

  Monotherapy with Docetaxel Injection 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 Docetaxel Injection 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 Docetaxel Injection treatment discontinued entirely.

  Combination therapy with Docetaxel Injection for chemotherapy-naïve NSCLC

  For patients who are dosed initially at Docetaxel Injection 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 Docetaxel Injection 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 Docetaxel Injection for hormone-refractory metastatic prostate cancer

  Docetaxel Injection 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 Docetaxel Injection therapy should have the dosage of Docetaxel Injection 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.

  Gastric or Head and Neck Cancer

  Docetaxel Injection in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer

  Patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist. [see Warnings and Precautions (5.3)].

  Recommended dose modifications for toxicities in patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil are shown in Table 1.

  Table 1 - Recommended Dose Modifications for Toxicities in Patients Treated with Docetaxel Injection in Combination with Cisplatin and Fluorouracil Toxicity Dosage adjustment Diarrhea grade 3 First episode: reduce fluorouracil dose by 20%.Second episode: then reduce Docetaxel Injection dose by 20%. Diarrhea grade 4 First episode: reduce Docetaxel Injection and fluorouracil doses by 20%.Second episode: discontinue treatment. Stomatitis/mucositis grade 3 First episode: reduce fluorouracil dose by 20%.Second episode: stop fluorouracil only, at all subsequent cycles.Third episode: reduce Docetaxel Injection dose by 20% Stomatitis/mucositis grade 4 First episode: stop fluorouracil only, at all subsequent cycles.Second episode: reduce Docetaxel Injection dose by 20%.

  Liver dysfunction:

  In case of AST/ALT >2.5 to ≤5 x ULN and AP ≤2.5 x ULN, or AST/ALT >1.5 to ≤5 x ULN and AP >2.5 to ≤5 x ULN, Docetaxel Injection should be reduced by 20%.

  In case of AST/ALT >5 x ULN and/or AP >5 x ULN Docetaxel Injection should be stopped.

  The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:

  Cisplatin dose modifications and delays

  Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:

  • Grade 2: Reduce cisplatin dose by 20%.

  • Grade 3: Discontinue treatment.

  Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

  Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

  For other cisplatin dosage adjustments, also refer to the manufacturers’ prescribing information.

  Table 2 –Dose Reductions for Evaluation of Creatinine Clearance        Creatinine clearance result before next cycle Cisplatin dose next cycle CrCl = Creatinine clearance CrCl ≥60 mL/min Full dose of cisplatin was given. CrCl was to be repeated before each treatment cycle. Dose of cisplatin was reduced by 50% at subsequent cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was reinstituted at the next cycle. CrCl between 40 and 59 mL/min If no recovery was observed, then cisplatin was omitted from the next treatment cycle. Dose of cisplatin was omitted in that treatment cycle only. If CrCl was still <40 mL/min at the end of cycle, cisplatin was discontinued. CrCl <40 mL/min If CrCl was >40 and <60 mL/min at end of cycle, a 50% cisplatin dose was given at the next cycle. If CrCl was >60 mL/min at end of cycle, full cisplatin dose was given at next cycle.

  Fluorouracil dose modifications and treatment delays

  For diarrhea and stomatitis, see Table 1.

  In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.

  For other >grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.

  For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribing information.

  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 Injection dose reduction if patients require co-administration of a strong CYP3A4 inhibitor. [see Drug Interactions(7) ,Clinical Pharmacology(12.3)].

  2.8 Administration Precautions

  Docetaxel Injection is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docetaxel Injection solutions. The use of gloves is recommended. Please refer to [see How Supplied/Storage and Handling (16.3)].

  If Docetaxel Injection, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Docetaxel Injection, initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.

  Contact of the Docetaxel Injection 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 final Docetaxel Injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

  Two-vial formulation (Injection Concentrate and Diluent)

  Docetaxel Injection requires two dilutions prior to administration. Please follow the preparation instructions provided below. Note: Both the Docetaxel Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL docetaxel.

  The table below provides the fill range of the Diluent, the approximate extractable volume of Diluent when the entire contents of the diluent vial are withdrawn, and the concentration of the initial diluted solution for Docetaxel Injection 20 mg and Docetaxel Injection 80 mg (see Table 3).

  Table 3 – Initial Dilution of Docetaxel Injection Product Diluent 13% (w/v) polyethylene glycol 400 in water for injection Fill Range (mL) Approximate extractable volume of Diluent when entire contents are withdrawn(mL) Concentration of the initial diluted solution (mg/mL docetaxel) Docetaxel Injection 20 mg/0.5 mL 1.5 to 2.08 mL 1.95 mL 10 mg/mL Docetaxel Injection 80 mg/2 mL 6 to 7.4 mL 7.2 mL 10 mg/mL

  One-vial formulation (Injection Concentrate)

  Docetaxel Injection Concentrate requires NO prior dilution with a diluent and is ready to add to the infusion solution.

  Please follow the preparation instructions provided below.

  2.9 Preparation and Administration

  DO NOT use the two-vial formulation (Injection Concentrate and diluent) with the one-vial formulation.

  Two-vial formulation (Injection Concentrate and Diluent)

  A.Initial Diluted Solution

  Docetaxel Injection vials should be stored at 25°C (77° F) or room temperature; excursions permitted from 15°C - 30°C (59°-86°F) [see USP Controlled Room Temperature], with protection from light. Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 1.95 mL for Docetaxel Injection 20 mg and approximately 7.2 mL for Docetaxel Injection 80 mg) into a syringe by partially inverting the vial, and transfer it to the appropriate vial of Docetaxel Injection. If the procedure is followed as described, an initial diluted solution of 10 mg docetaxel/mL will result. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixture of the Docetaxel Injection and diluent. Do not shake. The initial diluted Docetaxel Injection solution (10 mg docetaxel/mL) should be clear; however, there may be some foam on top of the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any foam to dissipate. It is not required that all foam dissipate prior to continuing the preparation process. The initial diluted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours.

  B.Final Dilution for Infusion

  Aseptically withdraw the required amount of initial diluted Docetaxel Injection solution (10 mg docetaxel/mL) 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 > 200 mg of Docetaxel Injection is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL Docetaxel Injection is not exceeded. Thoroughly mix the infusion by manual rotation. As with all parenteral products, Docetaxel Injection should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the Docetaxel Injection initial diluted solution or final dilution for intravenous infusion is not clear or appears to have precipitation, these should be discarded. The final Docetaxel Injection dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature and lighting conditions.

  One-vial formulation (Injection Concentrate)

  Docetaxel Injection Concentrate (20 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution. Use only a 21 gauge needle to withdraw docetaxel from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates.

  Docetaxel Injection Concentrate vials should be stored between 15°C and 25°C (59°F and 77°F). Using only a 21 gauge needle, aseptically withdraw the required amount of Docetaxel Injection Concentrate (20 mg docetaxel/mL) 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 mg/mL to 0.74 mg/mL. If a dose > 200 mg of docetaxel 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 gentle manual rotation. As with all parenteral products, docetaxel should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the docetaxel dilution for intravenous infusion is not clear or appears to have precipitation, it should be discarded.

  The docetaxel dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.

  2.10 Stability

  Docetaxel Injection final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours. Docetaxel Injection final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).

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• Kroger Nicotine Transde...
  

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  Kroger Nicotine Transdermal System Step 1

  

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  2.1 Hypertension

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

  2.3 Heart Failure Post-Myocardial Infarction

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

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

  2.4 General Dosing Information

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

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

  2.5 Dosage Adjustment

  Renal Impairement

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

  Hypertension

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

  Heart Failure Post-Myocardial Infarction

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

  Volume Depletion or Renal Artery Stenosis

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

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• Tramadol
  

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  Tramadol

  

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  Adults (17 years of age and over)

  For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of tramadol hydrochloride can be improved by initiating therapy with a titration regimen.The total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d). After titration, tramadol hydrochloride 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day.

  For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, tramadol hydrochloride 50 mg to 100 mg can be administered as needed for pain relief every four to six hours, not to exceed 400 mg per day.

  Individualization of Dose

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

  In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of tramadol hydrochloride be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis. The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours. In general, dose selection for an elderly patient over 65 years old should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. For elderly patients over 75 years old, total dose should not exceed 300 mg/day.

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• Doxazosin
  

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  Doxazosin

  

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  DOSAGE MUST BE INDIVIDUALIZED. The initial dosage of doxazosin tablets in patients with hypertension and/or BPH is 1 mg given once daily in the a.m. or p.m. This starting dose is intended to minimize the frequency of postural hypotension and first-dose syncope associated with doxazosin tablets. Postural effects are most likely to occur between 2 and 6 hours after a dose. Therefore, blood pressure measurements should be taken during this time period after the first dose and with each increase in dose. If doxazosin tablets administration is discontinued for several days, therapy should be restarted using the initial dosing regimen.

  Concomitant administration of doxazosin tablets with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking doxazosin tablets.

  A. BENIGN PROSTATIC HYPERPLASIA 1 to 8 mg once daily

  The initial dosage of doxazosin tablet is 1 mg, given once daily in the a.m. or p.m. Depending on the individual patient's urodynamics and BPH symptomatology, dosage may then be increased to 2 mg and thereafter to 4 mg and 8 mg once daily, the maximum recommended dose for BPH. The recommended titration interval is 1 to 2 weeks. Blood pressure should be evaluated routinely in these patients.

  B. HYPERTENSION 1 to 16 mg once daily

  The initial dosage of doxazosin tablet is 1 mg given once daily. Depending on the individual patient's standing blood pressure response (based on measurements taken at 2 to 6 hours post-dose and 24 hours post-dose), dosage may then be increased to 2 mg and thereafter if necessary to 4 mg, 8 mg and 16 mg to achieve the desired reduction in blood pressure. Increases in dose beyond 4 mg increase the likelihood of excessive postural effects, including syncope, postural dizziness/vertigo and postural hypotension. At a titrated dose of 16 mg once daily, the frequency of postural effects is about 12% compared to 3% for placebo.

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• Anastrozole
  

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  Anastrozole

  

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  2.1 Recommended Dose

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

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

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

  2.2 Patients with Hepatic Impairment

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

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• Naltrexone Hydrochlorid...
  

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  Naltrexone Hydrochloride

  

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  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 hydrochloride should 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 naltrexone hydrochloride tablets 50 mg 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.

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