Northstar Rxllc

Northstar Rxllc Drugs

• Capecitabine
  

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  Capecitabine

  

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  Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal. Do not crush or cut capecitabine tablets. Capecitabine tablets dose is calculated according to body surface area.

  2.1 Standard Starting Dose

  Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

  The recommended dose of capecitabine tablets are 1250 mg/m 2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m 2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles (see Table 1).

  Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months [ie, capecitabine tablets 1250 mg/m 2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks)].

  Table 1 Capecitabine Tablets Dose Calculation According to Body Surface Area Dose Level 1250 mg/m 2 Twice a Day Number of Tablets to be Taken at Each Dose (Morning and Evening) Surface Area (m 2) Total Daily Dose * (mg) 150 mg 500 mg * Total Daily Dose divided by 2 to allow equal morning and evening doses ≤ 1.25 3000 0 3 1.26 to 1.37 3300 1 3 1.38 to 1.51 3600 2 3 1.52 to 1.65 4000 0 4 1.66 to 1.77 4300 1 4 1.78 to 1.91 4600 2 4 1.92 to 2.05 5000 0 5 2.06 to 2.17 5300 1 5 ≥ 2.18 5600 2 5

  In Combination With Docetaxel (Metastatic Breast Cancer)

  In combination with docetaxel, the recommended dose of capecitabine tablets are 1250 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m 2 as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the capecitabine tablets plus docetaxel combination. Table 1 displays the total daily dose of capecitabine tablets by body surface area and the number of tablets to be taken at each dose.

  2.2 Dose Management Guidelines

  General

  Capecitabine tablets dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of capecitabine tablets should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14)] . Toxicity due to capecitabine tablets administration may be managed by symptomatic treatment, dose interruptions and adjustment of capecitabine tablets dose. Once the dose has been reduced, it should not be increased at a later time. Doses of capecitabine tablets omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.

  The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with capecitabine tablets [see Drug Interactions (7.1)] .

  Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

  Capecitabine tablets dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.

  Table 2 Recommended Dose Modifications of Capecitabine Tablets Toxicity NCIC Grades * During a Course of Therapy Dose Adjustment for Next Treatment (% of starting dose) * National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5)] . Grade 1 Maintain dose level Maintain dose level Grade 2 -1st appearance Interrupt until resolved to grade 0 to 1 100% -2nd appearance 75% -3rd appearance 50% -4th appearance Discontinue treatment permanently - Grade 3 -1st appearance Interrupt until resolved to grade 0 to 1 75% -2nd appearance 50% -3rd appearance Discontinue treatment permanently - Grade 4 -1st appearance Discontinue permanently OR If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0 to 1 50%

  In Combination With Docetaxel (Metastatic Breast Cancer)

  Dose modifications of capecitabine tablets for toxicity should be made according to Table 2 above for capecitabine tablets. At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine tablets or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.

  The dose reduction schedule for docetaxel when used in combination with capecitabine tablets for the treatment of metastatic breast cancer is shown in Table 3.

  Table 3 Docetaxel Dose Reduction Schedule in Combination with Capecitabine Tablets Toxicity NCIC Grades * Grade 2 Grade 3 Grade 4 * National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5)] . 1st appearance Delay treatment until resolved to grade 0 to 1; Resume treatment with original dose of 75 mg/m 2 docetaxel Delay treatment until resolved to grade 0 to 1; Resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel 2nd appearance Delay treatment until resolved to grade 0 to 1; Resume treatment at 55 mg/m 2 of docetaxel. Discontinue treatment with docetaxel - 3rd appearance Discontinue treatment with docetaxel - -

  2.3 Adjustment of Starting Dose in Special Populations

  Renal Impairment

  No adjustment to the starting dose of capecitabine tablets are recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the capecitabine tablets starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m 2 to 950 mg/m 2 twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)] . Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions (5.5)] . The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine tablets monotherapy and capecitabine tablets in combination use with docetaxel.

  Cockroft and Gault Equation: (140 - age [yrs]) (body wt [kg]) Creatinine clearance for males = ————————————— (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 × male value

  Geriatrics

  Physicians should exercise caution in monitoring the effects of capecitabine tablets in the elderly. Insufficient data are available to provide a dosage recommendation.

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• Venlafaxine
  

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  Venlafaxine

  

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  Initial Treatment The recommended starting dose for venlafaxine tablet is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness).Special Populations Treatment of Pregnant Women During the Third TrimesterNeonates exposed to venlafaxine tablets, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with venlafaxine tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Dosage for Patients with Hepatic ImpairmentGiven the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.Dosage for Patients with Renal ImpairmentGiven the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients.Dosage for Elderly PatientsNo dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.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. In one study, in which patients responding during 8 weeks of acute treatment with venlafaxine hydrochloride extended release capsules were assigned randomly to placebo or to the same dose of venlafaxine hydrochloride extended release capsules (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of venlafaxine tablets in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or venlafaxine tablets for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of venlafaxine tablets / venlafaxine hydrochloride extended release capsules needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Discontinuing venlafaxine tablets Symptoms associated with discontinuation of venlafaxine tablets, other SNRIs, and SSRIs, 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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• Quetiapine Fumarate
  

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  Quetiapine Fumarate

  

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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

  MaintenanceTreatment — 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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• Hydrochlorothiazide
  

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  Hydrochlorothiazide

  

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  For Control of Hypertension: The adult initial dose of hydrochlorothiazide capsules is one capsule given once daily whether given alone or in combination with other antihypertensives. Total daily doses greater than 50 mg are not recommended.

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• Famotidine
  

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  Famotidine

  

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  Duodenal UlcerAcute Therapy: The recommended adult oral dosage for active duodenal ulcer is 40 mg once a day at bedtime. Most patients heal within 4 weeks; there is rarely reason to use famotidine at full dosage for longer than 6 to 8 weeks. A regimen of 20 mg b.i.d. is also effective.Maintenance Therapy: The recommended adult oral dose is 20 mg once a day at bedtime.Benign Gastric UlcerAcute Therapy: The recommended adult oral dosage for active benign gastric ulcer is 40 mg once a day at bedtime.Gastroesophageal Reflux Disease (GERD)The recommended oral dosage for treatment of adult patients with symptoms of GERD is 20 mg b.i.d. for up to 6 weeks. The recommended oral dosage for the treatment of adult patients with esophagitis including erosions and ulcerations and accompanying symptoms due to GERD is 20 or 40 mg b.i.d. for up to 12 weeks (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).Dosage for Pediatric Patients <1 year of age Gastroesophageal Reflux Disease (GERD)   See PRECAUTIONS , Pediatric Patients <1 year of age.The studies described in PRECAUTIONS, Pediatric Patients <1 year of age suggest the following starting doses in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) - 0.5 mg/kg/dose of famotidine oral suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age and 0.5 mg/kg/dose twice daily in patients 3 months to <1 year of age. Patients should also be receiving conservative measures (e.g., thickened feedings). The use of intravenous famotidine in pediatric patients <1 year of age with GERD has not been adequately studied.Dosage for Pediatric Patients 1-16 years of age   See PRECAUTIONS, Pediatric Patients 1-16 years of age. The studies described in PRECAUTIONS, Pediatric Patients 1-16 years of age suggest the following starting doses in pediatric patients 1-16 years of age:Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day.Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d.While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients 1-16 years of age have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations. Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)  The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose for pathological hypersecretory conditions is 20 mg q 6 h. In some patients, a higher starting dose may be required. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated. Doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.Concomitant Use of AntacidsAntacids may be given concomitantly if needed.Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency   In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency, the elimination half-life of famotidine is increased. For patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients. Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of famotidine may be reduced to half the dose or the dosing interval may be prolonged to 36-48 hours as indicated by the patient's clinical response. Based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.

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• Vectical
  

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  Vectical

  

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  2.1 Recommended Dosage

  The recommended dosage of leflunomide is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient’s risk of leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly.

  ·            For patients who are at low risk for leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression the recommended leflunomide loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily.

  ·            For patients at high risk for leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomidedosage is 20 mg once daily without a loading dose [see Warnings and Precautions (5.2, 5.4)].

  The maximum recommended daily dosage is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1).

  Monitor patients carefully after dosage reduction and after stopping therapy with leflunomide, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [see Clinical Pharmacology (12.3)]. After stopping leflunomide treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide [see Warnings and Precautions (5.3)]. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide[see Clinical Pharmacology (12.3)].

  2.2 Evaluation and Testing Prior to Starting Leflunomide

  Prior to starting leflunomide treatment the following evaluations and tests are recommended:

  ·           Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [see Warnings and Precautions (5.4)]

  ·           Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [see Warnings and Precautions (5.2, 5.4)]

  ·           For females of reproductive potential, pregnancy testing [see Warnings and Precautions (5.1)]

  ·            Check blood pressure [see Warnings and Precautions (5.10)]

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• Sildenafil
  

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  Sildenafil

  

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  2.1 Sildenafil Tablets

  The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil doses 4 to 6 hours apart.

  In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended.

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• Donepezil Hydrochloride...
  

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  Donepezil Hydrochloride 5 Mg

  

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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 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 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. Moderate to Severe Alzheimer's Disease

    Donepezil hydrochloridehas 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 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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• Restasis
  

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  Restasis

  

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  Amoxicillin and clavulanate potassium may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium should be taken at the start of a meal.

  2.1 Adults

  The usual adult dose is one 500-mg tablet of amoxicillin and clavulanate potassium every 12 hours or one 250mg tablet of amoxicillin and clavulanate potassium every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one 875-mg tablet of amoxicillin and clavulanate potassium every 12 hours or one 500-mg tablet of amoxicillin and clavulanate potassium every 8 hours. Adults who have difficulty swallowing may be given the 125 mg/5 mL or 250 mg/5 mL suspension in place of the 500-mg tablet. The 200 mg/5 mL suspension or the 400 mg/5 mL suspension may be used in place of the 875-mg tablet.

  Two 250-mg tablets of amoxicillin and clavulanate potassium should not be substituted for one 500-mg tablet of amoxicillin and clavulanate potassium. Since both the 250-mg and 500-mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250-mg tablets are not equivalent to one 500-mg tablet of amoxicillin and clavulanate potassium.

  The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet should not be substituted for each other, as they are not interchangeable. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet do not contain the same amount of clavulanic acid (as the potassium salt). The 250-mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid, whereas the 250-mg chewable tablet contains 62.5 mg of clavulanic acid.

  2.2 Pediatric Patients

  Based on the amoxicillin component, amoxicillin and clavulanate potassium should be dosed as follows:

  Neonates and Infants Aged <12 weeks (<3 months): The recommended dose of Amoxicillin and clavulanate potassium is 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Experience with the 200 mg/5 mL formulation in this age group is limited, and thus, use of the 125 mg/5 mL oral suspension is recommended.

  Patients Aged 12 weeks (3 months) and Older: See dosing regimens provided in Table 1. The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see Clinical Studies (14.2)]. However, the every 12 hour suspension (200 mg/5 mL and 400 mg/5 mL) and chewable tablets (200 mg and 400 mg) contain aspartame and should not be used by phenylketonurics.

  Table 1. Dosing in Patients Aged 12 weeks (3 months) and Older * Each strength of suspension of amoxicillin and clavulanate potassium is available as a chewable tablet for use by older children. † Duration of therapy studied and recommended for acute otitis media is 10 days.

  DOSING REGIMEN

  Every 12 hours

  Every 8 hours

  INFECTION

  200 mg/5 mL or400 mg/5 mLoral suspension*

  125 mg/5 mL or250 mg/5 mLoral suspension*

  Otitis media†, sinusitis, lower respiratory tract infections, and more severe infections

  45 mg/kg/dayevery 12 hours

  40 mg/kg/dayevery 8 hours

  Less severe infections

  25 mg/kg/dayevery 12 hours

  20 mg/kg/dayevery 8 hours

  Patients Weighing 40 kg or More: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations.

  The 250-mg tablet of amoxicillin and clavulanate potassium should not be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250-mg tablet of amoxicillin and clavulanate potassium (250 mg/125 mg) versus the 250-mg chewable tablet of amoxicillin and clavulanate potassium (250 mg/62.5 mg).

  2.3 Patients with Renal Impairment

  Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of <30 mL/min should not receive the 875-mg dose. Patients with a glomerular filtration rate of 10 to 30 mL/min should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 mL/min should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection.

  Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis.

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• Atenolol
  

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  Atenolol

  

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  Hypertension

  The initial dose of atenolol is 50 mg given as one tablet a day either alone or added to diuretic therapy. The full effect of this dose will usually be seen within one to two weeks. If an optimal response is not achieved, the dosage should be increased to atenolol 100 mg given as one tablet a day. Increasing the dosage beyond 100 mg a day is unlikely to produce any further benefit.

  Atenolol may be used alone or concomitantly with other antihypertensive agents including thiazide-type diuretics, hydralazine, prazosin, and alpha-methyldopa.

  Angina Pectoris

  The initial dose of atenolol is 50 mg given as one tablet a day. If an optimal response is not achieved within one week, the dosage should be increased to atenolol 100 mg given as one tablet a day. Some patients may require a dosage of 200 mg once a day for optimal effect.

  Twenty-four hour control with once daily dosing is achieved by giving doses larger than necessary to achieve an immediate maximum effect. The maximum early effect on exercise tolerance occurs with doses of 50 to 100 mg, but at these doses the effect at 24 hours is attenuated, averaging about 50% to 75% of that observed with once a day oral doses of 200 mg.

  Acute Myocardial Infarction

  In patients with definite or suspected acute myocardial infarction, treatment with atenolol I.V. injection should be initiated as soon as possible after the patient's arrival in the hospital and after eligibility is established. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has stabilized. Treatment should begin with the intravenous administration of 5 mg atenolol over 5 minutes followed by another 5 mg intravenous injection 10 minutes later. Atenolol I.V. injection should be administered under carefully controlled conditions including monitoring of blood pressure, heart rate, and electrocardiogram. Dilutions of atenolol I.V. injection in Dextrose Injection USP, Sodium Chloride Injection USP, or Sodium Chloride and Dextrose Injection may be used. These admixtures are stable for 48 hours if they are not used immediately.

  In patients who tolerate the full intravenous dose (10 mg), atenolol tablets 50 mg should be initiated 10 minutes after the last intravenous dose followed by another 50 mg oral dose 12 hours later. Thereafter, atenolol can be given orally either 100 mg once daily or 50 mg twice a day for a further 6 to 9 days or until discharge from the hospital. If bradycardia or hypotension requiring treatment or any other untoward effects occur, atenolol should be discontinued. (See full prescribing information prior to initiating therapy with atenolol tablets.)

  Data from other beta-blocker trials suggest that if there is any question concerning the use of IV beta-blocker or clinical estimate that there is a contraindication, the IV beta-blocker may be eliminated and patients fulfilling the safety criteria may be given atenolol tablets 50 mg twice daily or 100 mg once a day for at least seven days (if the IV dosing is excluded).

  Although the demonstration of efficacy of atenolol tablet is based entirely on data from the first seven postinfarction days, data from other beta-blocker trials suggest that treatment with beta-blockers that are effective in the postinfarction setting may be continued for one to three years if there are no contraindications.

  Atenolol tablets are an additional treatment to standard coronary care unit therapy.

  Elderly Patients or Patients with Renal Impairment

  Atenolol is excreted by the kidneys; consequently dosage should be adjusted in cases of severe impairment of renal function. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Evaluation of patients with hypertension or myocardial infarction should always include assessment of renal function. Atenolol excretion would be expected to decrease with advancing age.

  No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73m2. Accumulation of atenolol and prolongation of its half-life were studied in subjects with creatinine clearance between 5 and 105 mL/min. Peak plasma levels were significantly increased in subjects with creatinine clearances below 30 mL/min.

  The following maximum oral dosages are recommended for elderly, renally-impaired patients and for patients with renal impairment due to other causes:

  Creatinine Clearance(mL/min/1.73m2) AtenololElimination Half-Life(h) Maximum Dosage 15-35 16-27 50 mg daily <15 >27 25 mg daily

   

  Some renally-impaired or elderly patients being treated for hypertension may require a lower starting dose of atenolol tablets: 25 mg given as one tablet a day. If this 25 mg dose is used, assessment of efficacy must be made carefully. This should include measurement of blood pressure just prior to the next dose ("trough" blood pressure) to ensure that the treatment effect is present for a full 24 hours.

  Although a similar dosage reduction may be considered for elderly and/or renally-impaired patients being treated for indications other than hypertension, data are not available for these patient populations.

  Patients on hemodialysis should be given 25 mg or 50 mg after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur.

  Cessation of Therapy in Patients with Angina Pectoris

  If withdrawal of atenolol therapy is planned, it should be achieved gradually and patients should be carefully observed and advised to limit physical activity to a minimum.

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• Tramadol Hydrochloride
  

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  Tramadol Hydrochloride

  

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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 tablets 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 tablets 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 tablets 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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• Allopurinol
  

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  Allopurinol

  

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  The dosage of allopurinol tablets to accomplish full control of gout and to lower serum uric acid to normal or near-normal levels varies with the severity of the disease. The average is 200 to 300 mg/day for patients with mild gout and 400 to 600 mg/day for those with moderately severe tophaceous gout. The appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300 mg-tablet. Dosage requirements in excess of 300 mg should be administered in divided doses. The minimal effective dosage is 100 to 200 mg daily and the maximal recommended dosage is 800 mg daily. To reduce the possibility of flare-up of acute gouty attacks, it is recommended that the patient start with a low dose of allopurinol tablets (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximal recommended dosage.

  Normal serum urate levels are usually achieved in 1 to 3 weeks. The upper limit of normal is about 7 mg/dL for men and postmenopausal women and 6 mg/dL for premenopausal women. Too much reliance should not be placed on a single serum uric acid determination since, for technical reasons, estimation of uric acid may be difficult. By selecting the appropriate dosage and, in certain patients, using uricosuric agents concurrently, it is possible to reduce serum uric acid to normal or, if desired, to as low as 2 to 3 mg/dL and keep it there indefinitely.

  While adjusting the dosage of allopurinol tablets in patients who are being treated with colchicine and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

  In transferring a patient from a uricosuric agent to allopurinol tablets, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the dose of allopurinol tablets gradually increased to the required dose needed to maintain a normal serum uric acid level.

  It should also be noted that allopurinol tablets are generally better tolerated if taken following meals. A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

  Since allopurinol and its metabolites are primarily eliminated only by the kidney, accumulation of the drug can occur in renal failure, and the dose of allopurinol tablets should consequently be reduced. With a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg of allopurinol is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not exceed 100 mg. With extreme renal impairment (creatinine clearance less than 3 mL/min) the interval between doses may also need to be lengthened.

  The correct size and frequency of dosage for maintaining the serum uric acid just within the normal range is best determined by using the serum uric acid level as an index.

  For the prevention of uric acid nephropathy during the vigorous therapy of neoplastic disease, treatment with 600 to 800 mg daily for 2 or 3 days is advisable together with a high fluid intake. Otherwise similar considerations to the above recommendations for treating patients with gout govern the regulation of dosage for maintenance purposes in secondary hyperuricemia.

  The dose of allopurinol tablets recommended for management of recurrent calcium oxalate stones in hyperuricosuric patients is 200 to 300 mg/day in divided doses or as the single equivalent. This dose may be adjusted up or down depending upon the resultant control of the hyperuricosuria based upon subsequent 24 hour urinary urate determinations. Clinical experience suggests that patients with recurrent calcium oxalate stones may also benefit from dietary changes such as the reduction of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake, as well as an increase in oral fluids and dietary fiber.

  Children, 6 to 10 years of age, with secondary hyperuricemia associated with malignancies may be given 300 mg allopurinol tablet daily while those under 6 years are generally given 150 mg daily. The response is evaluated after approximately 48 hours of therapy and a dosage adjustment is made if necessary.

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• Metoclopramide Hydrochl...
  

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  Metoclopramide Hydrochloride

  

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

  For the Relief of Symptomatic Gastroesophageal Reflux

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

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

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

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

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

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

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

  Use in Patients with Renal or Hepatic Impairment

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

  See OVERDOSAGE section for information regarding dialysis.

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

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• Clonidine Hydrochloride...
  

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  Clonidine Hydrochloride

  

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  Adults

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

  Initial Dose0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose. Maintenance DoseFurther increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed. 

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

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• Metoprolol Tartrate And...
  

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  Metoprolol Tartrate And Hydrochlorothiazide 50 Mg-25 Mg

  

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  Dosage should be determined by individual titration (see INDICATIONS AND USAGE).Hydrochlorothiazide is usually given at a dosage of 12.5 to 50 mg per day. The usual initial dosage of metoprolol tartrate tablets is 100 mg daily in single or divided doses. Dosage may be increased gradually until optimum blood pressure control is achieved. The effective dosage range is 100 to 450 mg per day. While once-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and larger or more frequent daily doses may be required. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. Beta1 selectivity diminishes as dosage of metoprolol tartrate tablets is increased.The following dosage schedule may be used to administer from 100 to 200 mg of metoprolol tartrate per day and from 25 to 50 mg of hydrochlorothiazide per day:  

  Metoprolol Tartrate and Hydrochlorothiazide Dosage Tablets of 50/25 2 tablets per day in single or divided doses Tablets of 100/25 1 to 2 tablets per day in single or divided doses Tablets of 100/50 1 tablet per day in single or divided doses

  Dosing regimens that exceed 50 mg of hydrochlorothiazide per day are not recommended. When necessary, another antihypertensive agent may be added gradually, beginning with 50% of the usual recommended starting dose to avoid an excessive fall in blood pressure.

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• Fluoxetine
  

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  Fluoxetine

  

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  2.1. Major Depressive Disorder

  Initial Treatment

  Adult –

  Initiate fluoxetine 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).The maximum fluoxetine dose should not exceed 80 mg/day.

  In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. [see Clinical Studies (14.1)].

  Pediatric (children and adolescents) – Initiate fluoxetine 10 or 20 mg/day. After 1 week at 10 mg/day, increase the dose to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed. In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1)].

  All patients – As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer.

  Periodically reassess to determine the need for maintenance treatment.

  Switching Patients to a Tricyclic Antidepressant (TCA) – Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Drug Interactions (7.7)].

  2.2. Obsessive Compulsive Disorder

  Initial Treatment

  Adult – Initiate fluoxetine 20 mg/day, orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Administer doses above 20 mg/day once daily in the morning or twice daily(i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day.

  In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated.

  Pediatric (children and adolescents) –In adolescents and higher weight children, initiate treatment with a dose of 10 mg/day. After 2 weeks, increase the dose to 20 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended.

  In lower weight children, initiate treatment with a dose of 10 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg.

  In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)].

  Periodically reassess to determine the need for treatment.

  2.3. Bulimia Nervosa

  Initial Treatment – Administer fluoxetine 60 mg/day in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)]. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting.

  Periodically reassess to determine the need for maintenance treatment.

  2.4. Panic Disorder

  Initial Treatment – Initiate treatment with fluoxetine 10 mg/day. After one week, increase the dose to 20 mg/day. Consider a dose increase after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day.

  Periodically reassess to determine the need for continued treatment.

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

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

  Adult —Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Make dosage adjustments, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Periodically re-examine the need for continued pharmacotherapy.

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

  Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of olanzapine and fluoxetine hydrochloride capsules (fixed-dose combination of olanzapine and fluoxetine). Olanzapine and fluoxetine hydrochloride capsules are dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus olanzapine and fluoxetine hydrochloride capsules.

  Adjust dosage, if indicated, with the individual components according to efficacy and tolerability.

   

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

  For Olanzapine and Fluoxetine Hydrochloride Capsules (mg/day) Use in Combination Olanzapine (mg/day) Fluoxetine (mg/day) 3 mg olanzapine / 25 mg fluoxetine 2.5 20 6 mg olanzapine / 25 mg fluoxetine 5 20 12 mg olanzapine / 25 mg fluoxetine 10 + 2.5 20 6 mg olanzapine / 50 mg fluoxetine 5 40 + 10 12 mg olanzapine / 50 mg fluoxetine 10 + 2.5 40 + 10 1Olanzapine and fluoxetine capsules (olanzapine / fluoxetine HCl) is a fixed-dose combination of fluoxetine and olanzapine.

  Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

  2.7. Dosing in Specific Populations

  Treatment of Pregnant Women –When treating pregnant women with fluoxetine, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to  SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. [see Use in Specific Populations (8.1)]. Geriatrics – Consider a lower or less frequent dosage for the elderly

  [see Use in Specific Populations (8.5)] Hepatic Impairment – As with many other medications, a lower or less frequent dosage in patients with hepatic impairment [see Clinical Pharmacology (12.4) and Use in Specific Populations (8.6)].  Concomitant Illness – Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.12)]. Fluoxetineand Olanzapine in Combination– Use a starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Titrate slowly and adjust dosage as needed in patients who exhibit a combination of factors that may slow metabolism. Fluoxetine and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 18 years of age [see Warnings and Precautions (5.16) and Drug Interactions (7.7)].

  2.8. Discontinuation of Treatment

  Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.15)].

  2.9 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 fluoxetine. Conversely, at least 5 weeks should be allowed after stopping Fluoxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

  2.10 Use of Fluoxetine with Other MAOIs such as Linezolid or Methylene Blue

  Do not start fluoxetine 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 fluoxetine 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, fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine 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 fluoxetine 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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• Pfizerpen
  

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  Pfizerpen

  

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  Oral Dosage

  Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.

  Initial Dosage for Adults

  For outpatients, 75 mg of amitriptyline HCl a day in divided doses is usually satisfactory. If necessary, this may be increased to a total of 150 mg per day. Increases are made preferably in the late afternoon and/or bedtime doses. A sedative effect may be apparent before the antidepressant effect is noted, but an adequate therapeutic effect may take as long as 30 days to develop.

  An alternate method of initiating therapy in outpatients is to begin with 50 to 100 mg amitriptyline HCl at bedtime. This may be increased by 25 or 50 mg as necessary in the bedtime dose to a total of 150 mg per day.

  Hospitalized patients may require 100 mg a day initially. This can be increased gradually to 200 mg a day if necessary. A small number of hospitalized patients may need as much as 300 mg a day.

  Adolescent and Elderly Patients

  In general, lower dosages are recommended for these patients. Ten mg 3 times a day with 20 mg at bedtime may be satisfactory in adolescent and elderly patients who do not tolerate higher dosages.

  Maintenance

  The usual maintenance dosage of amitriptyline HCl is 50 to 100 mg per day. In some patients, 40 mg per day is sufficient. For maintenance therapy, the total daily dosage may be given in a single dose, preferably at bedtime. When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.

  Usage in Pediatric Patients

  In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age.

  Plasma Levels

  Because of the wide variation in the absorption and distribution of tricyclic antidepressants in body fluids, it is difficult to directly correlate plasma levels and therapeutic effect. However, determination of plasma levels may be useful in identifying patients who appear to have toxic effects and may have excessively high levels, or those in whom lack of absorption or noncompliance is suspected. Because of increased intestinal transit time and decreased hepatic metabolism in elderly patients, plasma levels are generally higher for a given oral dose of amitriptyline hydrochloride than in younger patients. Elderly patients should be monitored carefully and quantitative serum levels obtained as clinically appropriate. Adjustments in dosage should be made according to the patient’s clinical response and not on the basis of plasma levels.2

  2 Hollister, L.E.; Monitoring Tricyclic Antidepressant Plasma Concentrations. JAMA 1979; 241(23):2530-2533.

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• Baclofen
  

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  Baclofen

  

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  The determination of optimal dosage requires individual titration. Start therapy at a low dosage and increase gradually until optimum effect is achieved (usually between 40-80 mg daily).

  The following dosage titration schedule is suggested:

                                                          5 mg t.i.d. for 3 days

                                                        10 mg t.i.d. for 3 days

                                                        15 mg t.i.d. for 3 days

                                                        20 mg t.i.d. for 3 days

  Thereafter additional increases may be necessary but the total daily dose should not exceed a maximum of 80 mg daily (20 mg q.i.d.).

  The lowest dose compatible with an optimal response is recommended. If benefits are not evident after a reasonable trial period, patients should be slowly withdrawn from the drug (see WARNINGSAbrupt Drug Withdrawal).

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• Gemfibrozil
  

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  Gemfibrozil

  

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  The recommended dose for adults is 1200 mg administered in two divided doses 30 minutes before the morning and evening meals (see CLINICAL PHARMACOLOGY).

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• Inderal Xl
  

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  Inderal Xl

  

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  General

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

  Hypertension

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

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

  Angina Pectoris

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

  Atrial Fibrillation

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

  Myocardial Infarction

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

  Migraine

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

  Essential Tremor

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

  Hypertrophic Subaortic Stenosis

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

  Pheochromocytoma

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

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• Badger Lavender Spf 30 ...
  

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  Badger Lavender Spf 30 Sunscreen

  

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

  2.1 Recommended Dose and Schedule

  The recommended dose for bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide be taken at the same time each day. Treatment with bicalutamide should be started at the same time as treatment with an LHRH analog. If a dose of bicalutamide is missed, take the next dose at the scheduled time. Do not take the missed dose and do not double the next dose.

  2.2 Dosage Adjustment in Renal Impairment

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

  2.3 Dosage Adjustment in Hepatic Impairment

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

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• Hydroxyzine Hydrochlori...
  

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  Hydroxyzine Hydrochloride

  

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  For symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested: Adults, 50 to 100 mg q.i.d.; children under 6 years, 50 mg daily in divided doses; children over 6 years, 50 to 100 mg daily in divided doses. 

  For use in the management of pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses and in histamine-mediated pruritus:  adults, 25 mg t.i.d. or q.i.d.; children under 6 years, 50 mg daily in divided doses; children over 6 years, 50 to 100 mg daily in divided doses. 

  As a sedative when used as a premedication and following general anesthesia: 50 to 100 mg for adults and 0.6 mg/kg of body weight in children.

  When treatment is initiated by the intramuscular route of administration, subsequent doses may be administered orally. 

  As with all potent medication, the dosage should be adjusted according to the patient's response to therapy.

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• Duloxetine Hydrochlorid...
  

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  Duloxetine Hydrochloride 20 Mg

  

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  Duloxetine delayed-release capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Duloxetine delayed-release capsules can be given without regard to meals.

  2.1 Initial Treatment

  Major Depressive Disorder - Duloxetine delayed-release capsule should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated [see Clinical Studies (14.1)]. Generalized Anxiety Disorder - For most patients, the recommended starting dose for duloxetine delayed-release capsules is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies (14.2)]. Diabetic Peripheral Neuropathic Pain - The recommended dose for duloxetine delayed-release capsules is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered.Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment  [see Dosage and Administration (2.3), Use in Specific Populations (8.10), Clinical Pharmacology (12.3)].Chronic Musculoskeletal Pain - The recommended dose for duloxetine delayed-release capsule is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)].

  2.2 Maintenance/Continuation/Extended Treatment

  Major Depressive Disorder - It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with duloxetine delayed-release capsules as monotherapy. Duloxetine delayed-release capsules should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)]. Generalized Anxiety Disorder - It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with duloxetine delayed-release capsules as monotherapy. Duloxetine delayed-release capsules should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)]. Diabetic Peripheral Neuropathic Pain - As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of duloxetine delayed-release capsules must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.

  Chronic Musculoskeletal Pain - The efficacy of duloxetine delayed-release capsules has not been established in placebo-controlled studies beyond 13 weeks.

  2.3 Dosing in Special Populations

  Hepatic Insufficiency - It is recommended that duloxetine delayed-release capsules should ordinarily not be administered to patients with any hepatic insufficiency [see Warnings and Precautions (5.13) and Use in Specific Populations (8.9)].Severe Renal Impairment - Duloxetine delayed-release capsule is not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see Warnings and Precautions (5.13) and Use in Specific Populations (8.10)]. Elderly Patients - No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose [see Use in Specific Populations (8.5)].Pregnant Women - There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine delayed-release capsule should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. Nursing Mothers - Because the safety of duloxetine in infants is not known, nursing while on duloxetine hydrochloride is not recommended [see Use in Specific Populations (8.3)].

  2.4 Discontinuing duloxetine delayed-release capsules

  Symptoms associated with discontinuation of duloxetine delayed-release capsule and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)].

  2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI)Intended to Treat Psychiatric Disorders

  At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with duloxetine delayed-release capsules.Conversely, at least 5 days should be allowed after stopping duloxetine delayed-release capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

  2.6 Use of Duloxetine delayed-release capsules with Other MAOIs such as Linezolid or Methylene Blue

  Do not start duloxetine delayed-release capsule 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 duloxetine delayed-release capsule therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, duloxetine delayed-release capsule should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with duloxetine delayed-release capsule may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions(5.4)].

  The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with duloxetine delayed-release capsule is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].

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• Ondansetron
  

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  Ondansetron

  

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  Nitrofurantoin capsules (monohydrate/macrocrystals)should be taken with food.

  Adults and Pediatric Patients Over 12 Years

  One 100 mg capsule every 12 hours for seven days.

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• Lamotrigine
  

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  Lamotrigine

  

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  2.1. General Dosing Considerations

  RashThere are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine tablets are exceeded and in patients with a history of allergy or rash to other AEDs. 

  It is recommended that lamotrigine tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

  Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit GlucuronidationBecause lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5 to 6, and 13.

  Target Plasma Levels for Patients with Epilepsy or Bipolar DisorderA therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)].

   

  Women Taking Estrogen-Containing Oral ContraceptivesStarting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on the concomitant AED or other concomitant medications (see Table 1, 5 and 7). See below for adjustments to maintenance  doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives.  

  Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives 

  1)      Taking Estrogen-Containing Oral Contraceptives:In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level

  2)      Starting Estrogen-Containing Oral Contraceptives:In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine should be necessary.

  3)      Stopping Estrogen-Containing Oral Contraceptives:In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. In women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir  that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary.  

  Women and Other Hormonal Contraceptive Preparations or Hormone Replacement TherapyThe effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine tablets in the presence of progestogens alone will likely not be needed.  

  Patients Taking Atazanavir/RitonavirWhile atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets and not taking glucuronidation inducers, the dose of lamotrigine tablets may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)]. 

  Patients with Hepatic ImpairmentExperience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment  [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)],

  the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. 

  Patients with Renal ImpairmentInitial doses of lamotrigine tablets should be based on patients’ concomitant medications (see Tables 1 to 3, and  5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients. 

  Discontinuation StrategyEpilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.  

  If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)].  

  Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine. 

  Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. Discontinuation of lamotrigine tablets should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)]. 

  2.2. Epilepsy - Adjunctive Therapy

  This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Older than 12 YearsRecommended dosing guidelines are summarized in Table 1.

                                                                                    Table 1

           Escalation Regimen for Lamotrigine Tablets in Patients Older than 12 Years with Epilepsy

    In Patients TAKING Valproatea In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneband NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Week 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks. Usual Maintenance Dose 100 to 200 mg/day with valproate alone   100 to 400 mg/day with valproate and other drugs that induce glucuronidation ( in 1 or 2 divided doses) 225 to 375 mg/day (in 2 divided doses) 300 to 500 mg/day (in 2 divided doses)

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

    Patients Aged 2 to 12 YearsRecommended dosing guidelines are summarized in Table 2.

  Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower  starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

                                                                   Table 2

  Escalation Regimen for Lamotrigine Tablets in Patients Aged 2 to 12 Years with Epilepsy  

    In Patients TAKING Valproatea In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or  Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneband NOT TAKING Valproatea Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide). 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet. 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet. Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide). 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet. 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet. Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual maintenance dose 1 to 5 mg/kg/day(maximum 200 mg/day in 1 or 2 divided doses).1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day(maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response

  Note: Only whole tablets should be used for dosing a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

                                                                Table 3

  The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy 

  If the patient’s weight is Give this daily dose, using the most appropriate combination of lamotrigine tablets 2- and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day

  Usual Adjunctive Maintenance Dose for EpilepsyThe usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials  in which the efficacy of lamotrigine tablets were established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate , maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone , maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 to 4 has not been established in controlled trials.

  2.3. Epilepsy - Conversion from Adjunctive Therapy to Monotherapy

  The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets.

  The recommended maintenance dose of lamotrigine tablets as monotherapy is 500 mg/day given in 2 divided doses.

  To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for lamotrigine tablets should not be exceeded [see Boxed Warning].

  Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine TabletsAfter achieving a dose of 500 mg/day of lamotrigine tablets using the guidelines in Table 1, the concomitant  enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine TabletsThe conversion regimen involves the 4 steps outlined in Table 4.

  Table 4

  Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets in Patients  Aged 16 Years and Older with Epilepsy 

    Lamotrigine Tablets Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1 Maintain established stable dose. Step 2 Maintain at 200 mg/day. Decrease dose by decrements no greater than 500 mg/day/ week to 500 mg/day and then maintain  for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue.

  Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine TabletsNo specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenytoin, phenobarbital,  primidone, or valproate.

  2.4. Bipolar Disorder

  The goal of maintenance treatment with lamotrigine tablets are to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy therapy [see Indications and Usage (1)]. Patients taking lamotrigine tablets for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.AdultsThe target dose of lamotrigine tablets are 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets are introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. In  patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). In  patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the  protease inhibitors lopinavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated.If other drugs are subsequently introduced, the dose of lamotrigine tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine tablets [see Drug Interactions (7), Clinical Pharmacology (12.3)].To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning].Table 5Escalation Regimen for Lamotrigine Tablets in Adults with Bipolar Disorder

    In Patients TAKING Valproatea In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology(12.3)].

  Table 6

  Dosage Adjustments to Lamotrigine Tablets in Adults with Bipolar Disorder Following Discontinuation of Psychotropic Medications  

    Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital Primidoneb) After Discontinuation of Valproatea After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb Current Dose of Lamotrigine Tablets (mg/day) 100 Current Dose of Lamotrigine Tablets (mg/day) 400 Week 1 Maintain current dose of Lamotrigine Tablets 150 400 Week 2 Maintain current dose of Lamotrigine Tablets 200 300 Week 3 onward Maintain current dose of Lamotrigine Tablets 200 200

  a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

  b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

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  Hypertension

  In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of enalapril maleate tablets, USP. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with enalapril maleate tablets, USP to reduce the likelihood of hypotension (see WARNINGS). If the patient's blood pressure is not controlled with enalapril maleate tablets USP alone, diuretic therapy may be resumed.

  If the diuretic cannot be discontinued an initial dose of 2.5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions).

  The recommended initial dose in patients not on diuretics is 5 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 10 mg to 40 mg per day administered in a single dose or two divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with enalapril maleate tablets, USP alone, a diuretic may be added. Concomitant administration of enalapril maleate tablets, USP with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS).

  Dosage Adjustment in Hypertensive Patients with Renal Impairment

  The usual dose of enalapril maleate tablets, USP is recommended for patients with a creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≤30 mL/min (serum creatinine ≥3 mg/dL), the first dose is 2.5 mg once daily. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

  * See WARNINGS, Anaphylactoid Reactions During Membrane Exposure. † Dosage on nondialysis days should be adjusted depending on the blood pressure response.

  Renal Status

  Creatinine-Clearance mL/min

  Initial Dose mg/day

  Normal Renal Function

  >80 mL/min

  5 mg

  Mild Impairment

  ≤80 >30 mL/min

  5 mg

  Moderate to Severe Impairment

  ≤30 mL/min

  2.5 mg

  Dialysis Patients*

  —

  2.5 mg on dialysis days†

  Heart Failure

  Enalapril maleate tablets, USP are indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis. In the placebo-controlled studies that demonstrated improved survival, patients were titrated as tolerated up to 40 mg, administered in two divided doses.

  The recommended initial dose is 2.5 mg. The recommended dosing range is 2.5 mg to 20 mg given twice a day. Doses should be titrated upward, as tolerated, over a period of a few days or weeks. The maximum daily dose administered in clinical trials was 40 mg in divided doses.

  After the initial dose of enalapril maleate tablets USP, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of enalapril maleate tablets, USP does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

  Asymptomatic Left Ventricular Dysfunction

  In the trial that demonstrated efficacy, patients were started on 2.5 mg twice daily and were titrated as tolerated to the targeted daily dose of 20 mg (in divided doses).

  After the initial dose of enalapril maleate tablets USP, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. (See WARNINGS and PRECAUTIONS, Drug Interactions). If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of enalapril maleate tablets, USP does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

  Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia

  In patients with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or with serum creatinine greater than 1.6 mg/dL, therapy should be initiated at 2.5 mg daily under close medical supervision (see DOSAGE AND ADMINISTRATION, Heart Failure; WARNINGS; and PRECAUTIONS, Drug Interactions). The dose may be increased to 2.5 mg b.i.d., then 5 mg b.i.d. and higher as needed, usually at intervals of 4 days or more if at the time of dosage adjustment there is not excessive hypotension or significant deterioration of renal function. The maximum daily dose is 40 mg.

  Pediatric Hypertensive Patients

  The usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. Dosage should be adjusted according to blood pressure response. Doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients).

  Enalapril maleate tablets, USP are not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2, as no data are available.

  Preparation of Suspension (for 200 mL of a 1 mg/mL Suspension)

  Add 50 mL of Bicitra®1 to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of enalapril maleate tablets and shake for at least 2 minutes. Let concentrate stand for 60 minutes. Following the 60 minute hold time, shake the concentrate for an additional minute. Add 150 mL of Ora-Sweet SF™2 to the concentrate in the PET bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2° to 8°C (36° to 46°F) and can be stored for up to 30 days. Shake the suspension before each use.

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