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Adult Hypertensive Patients

Losartan potassium tablets may be administered with other antihypertensive agents, and with or without food.

Dosing must be individualized. The usual starting dose of losartan potassium tablets is 50 mg once daily, with 25 mg used in patients with possible depletion of intravascular volume (e.g., patients treated with diuretics) (see WARNINGS, Hypotension — Volume-Depleted Patients) and patients with a history of hepatic impairment (see PRECAUTIONS, General). Losartan potassium tablets can be administered once or twice daily with total daily doses ranging from 25 mg to 100 mg.

If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3 to 6 weeks (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension).

If blood pressure is not controlled by losartan potassium tablets alone, a low dose of a diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension).

No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis.

Pediatric Hypertensive Patients ≥ 6 years of age

The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total) administered as a tablet or a suspension (see Preparation of Suspension). Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populationsand Pharmacodynamics and Clinical Effectsand WARNINGS, Hypotension — Volume-Depleted Patients).

Losartan potassium tablets are not recommended in pediatric patients <6 years of age or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics40, Special Populations, Pharmacodynamics and Clinical Effects, and PRECAUTIONS).

Preparation of Suspension (for 200 mL of a 2.5 mg/mL suspension)

Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg losartan potassium tablets. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately prepare a 50/50 volumetric mixture of Ora-Plus™*** and Ora-Sweet SF™***. Add 190 mL of the 50/50 Ora-Plus™ /Ora-Sweet SF™ mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to disperse the ingredients. The suspension should be refrigerated at 2 to 8°C (36 to 46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

Hypertensive Patients with Left Ventricular Hypertrophy

The usual starting dose is 50 mg of losartan potassium tablets once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of losartan potassium tablets should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke).

Nephropathy in Type 2 Diabetic Patients

The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Nephropathy in Type 2 Diabetic Patients). Losartan potassium may be administered with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones and glucosidase inhibitors).

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2.1 Dosing Information

The recommended starting dose of zolmitriptan tablets is 1.25 mg or 2.5 mg. The 1.25 mg dose can be achieved by manually breaking the functionally-scored 2.5 mg tablet in half. The maximum recommended single dose of zolmitriptan tablets is 5 mg.

In controlled clinical trials, a greater proportion of patients had headache response following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were more frequent with the 5 mg dose.

If the migraine has not resolved by 2 hours after taking zolmitriptan, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 10 mg in any 24 hour period.

The safety of zolmitriptan in the treatment of an average of more than three migraines in a 30 day period has not been established.

2.2 Administration of Zolmitriptan Orally Disintegrating Tablets

Instruct patients not to break zolmitriptan orally disintegrating tablets because they are not functionally-scored.

Administration with liquid is not necessary.

Orally disintegrating tablets are packaged in a blister pack. Instruct patients not to remove the tablet from the blister until just prior to dosing. Subsequently, instruct patients to peel the blister pack open, and to place the orally disintegrating tablet on the tongue, where it will dissolve and it will be swallowed with the saliva.

2.3 Dosing in Patients with Hepatic Impairment

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

The use of zolmitriptan orally disintegrating tablets is not recommended in patients with moderate or severe hepatic impairment because these orally disintegrating tablets should not be broken in half [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.4 Dosing in Patients taking Cimetidine

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

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Divalproex sodium extended-release tablet is an extended-release product intended for once-a-day oral administration. Divalproex sodium extended-release tablets should be swallowed whole and should not be crushed or chewed.

2.1 Mania

Divalproex sodium extended-release tablets are administered orally. The recommended initial dose is 25 mg/kg/day given once daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. The maximum recommended dosage is 60 mg/kg/day.

There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during divalproex sodium extended-release tablets treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of divalproex sodium extended-release tablets in such longer-term treatment (i.e., beyond 3 weeks).

2.2 Epilepsy

Divalproex sodium extended-release tablets are administered orally, and must be swallowed whole. As divalproex sodium extended-release tablet is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2)].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

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

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

Conversion to Monotherapy

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

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of divalproex sodium extended-release tablet therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

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

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see CLINICAL STUDIES (14.2)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see DRUG INTERACTIONS (7)]

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see CLINICAL PHARMACOLOGY (12.3)].

As divalproex sodium extended-release tablet dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see DRUG INTERACTIONS (7.2)].

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

2.3 Migraine

Divalproex sodium extended-release tablets are indicated for prophylaxis of migraine headaches in adults.

The recommended starting dose is 500 mg once daily for 1 week, thereafter increasing to 1000 mg once daily. Although doses other than 1000 mg once daily of divalproex sodium extended-release tablets have not been evaluated in patients with migraine, the effective dose range of divalproex sodium delayed-release tablets in these patients is 500 to 1000 mg/day. As with other valproate products, doses of divalproex sodium extended-release tablets should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with divalproex sodium extended-release tablets, divalproex sodium delayed-release tablets should be used instead.

2.4 Conversion from Divalproex Sodium Delayed-release Tablets to Divalproex Sodium Extended-release Tablets

In adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving divalproex sodium delayed-release tablets, divalproex sodium extended-release tablets should be administered once-daily using a dose 8 to 20% higher than the total daily dose of divalproex sodium delayed-release tablets (Table 1). For patients whose divalproex sodium delayed-release tablets total daily dose cannot be directly converted to divalproex sodium extended-release tablets, consideration may be given at the clinician’s discretion to increase the patient’s divalproex sodium delayed-release tablets total daily dose to the next higher dosage before converting to the appropriate total daily dose of divalproex sodium extended-release tablets.

Table 1Dose Conversion Divalproex Sodium  Divalproex Sodium  Delayed-release Tablets  Extended-release Tablets  Total Daily Dose (mg)  (mg)  * These total daily doses of divalproex sodium delayed-release tablets cannot be directly converted to an 8 to 20% higher total daily dose of divalproex sodium extended-release tablets because the required dosing strengths of divalproex sodium extended-release tablets are not available. Consideration may be given at the clinician’s discretion to increase the patient’s divalproex sodium delayed-release tablets total daily dose to the next higher dosage before converting to the appropriate total daily dose of divalproex sodium extended-release tablets. 500* to 625  750  750* to 875  1000  1000* to 1125  1250  1250 to 1375  1500  1500 to 1625  1750  1750  2000  1875 to 2000  2250  2125 to 2250  2500  2375  2750  2500 to 2750  3000  2875  3250  3000 to 3125  3500 

There is insufficient data to allow a conversion factor recommendation for patients with divalproex sodium delayed-release tablets doses above 3125 mg/day. Plasma valproate Cmin concentrations for divalproex sodium extended-release tablets on average are equivalent to divalproex sodium delayed-release tablets, but may vary across patients after conversion. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL) [see CLINICAL PHARMACOLOGY (12.2)].

2.5 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Starting doses in the elderly lower than 250 mg can only be achieved by the use of divalproex sodium delayed-release tablets. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see WARNINGS AND PRECAUTIONS (5.13), USE IN SPECIFIC POPULATIONS (8.5) and CLINICAL PHARMACOLOGY (12.3)].

Dose-Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see WARNINGS AND PRECAUTIONS (5.7)]. The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

G.I. Irritation

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

Compliance

Patients should be informed to take divalproex sodium extended-release tablets every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose.

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Parenteral Administration

In some hospitalized patients with pathological hypersecretory conditions or intractable duodenal ulcers, or in patients who are unable to take oral medication, ranitidine hydrochloride may be administered parenterally according to the following recommendations:

Intramuscular Injection

50 mg (2 mL) every 6 to 8 hours. (No dilution necessary.)

Intermittent Intravenous Injection

Intermittent Bolus

50 mg (2 mL) every 6 to 8 hours. Dilute ranitidine injection, 50 mg, in 0.9% sodium chloride injection or other compatible IV solution (see Stability) to a concentration no greater than 2.5 mg/mL (20 mL). Inject at a rate no greater than 4 mL/min (5 minutes).

Intermittent Infusion

50 mg (2 mL) every 6 to 8 hours. Dilute ranitidine injection, 50 mg, in 5% dextrose injection or other compatible IV solution (see Stability) to a concentration no greater than 0.5 mg/mL (100 mL). Infuse at a rate no greater than 5 to 7 mL/min (15 to 20 minutes).

In some patients it may be necessary to increase dosage. When this is necessary, the increases should be made by more frequent administration of the dose, but generally should not exceed 400 mg/day.

Continuous Intravenous Infusion

Add ranitidine injection to 5% dextrose injection or other compatible IV solution (see Stability). Deliver at a rate of 6.25 mg/hour (e.g., 150 mg [6 mL] of ranitidine injection in 250 mL of 5% dextrose injection at 10.7 mL/hour).

For Zollinger-Ellison patients, dilute ranitidine injection in 5% dextrose injection or other compatible IV solution (see Stability) to a concentration no greater than 2.5 mg/mL. Start the infusion at a rate of 1.0 mg/kg/hour. If after 4 hours either a measured gastric acid output is >10 mEq/hour or the patient becomes symptomatic, the dose should be adjusted upward in 0.5 mg/kg/hour increments, and the acid output should be remeasured. Dosages up to 2.5 mg/kg/hour and infusion rates as high as 220 mg/hour have been used.

Pediatric Use

While limited data exist on the administration of IV ranitidine to children, the recommended dose in pediatric patients is for a total daily dose of 2 to 4 mg/kg, to be divided and administered every 6 to 8 hours, up to a maximum of 50 mg given every 6 to 8 hours. This recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric patients. Limited data in neonatal patients (less than 1 month of age) receiving ECMO have shown that a dose of 2 mg/kg is usually sufficient to increase gastric pH to >4 for at least 15 hours. Therefore, doses of 2 mg/kg given every 12 to 24 hours or as a continuous infusion should be considered.

Dosage Adjustment for Patients with Impaired Renal Function

The administration of ranitidine as a continuous infusion has not been evaluated in patients with impaired renal function. On the basis of experience with a group of subjects with severely impaired renal function treated with ranitidine hydrochloride, the recommended dosage in patients with a creatinine clearance <50 mL/min is 50 mg every 18 to 24 hours. Should the patient’s condition require, the frequency of dosing may be increased to every 12 hours or even further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.

Elderly patients are more likely to have decreased renal function, therefore caution should be exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Geriatric Useand PRECAUTIONS: Geriatric Use).

Stability

Undiluted, ranitidine injection tends to exhibit a yellow color that may intensify over time without adversely affecting potency. Ranitidine injection is stable for 48 hours at room temperature when added to or diluted with most commonly used IV solutions, e.g., 0.9% sodium chloride injection, 5% dextrose injection, 10% dextrose injection, lactated ringer's injection, or 5% sodium bicarbonate injection.

Note

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

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

2.1 Recommended Dose

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

Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose.

2.2 Special Populations

Renal impairment patients and geriatric patients do not require dosage adjustment. However, consider dose adjustment in patients with severe liver impairment [see USE IN SPECIFIC POPULATIONS (8.5, 8.6 and 8.7)].

2.3 Important Administration Information

Administration Option

Lansoprazole Delayed-release Capsules – Oral Administration

Lansoprazole delayed-release capsules should be swallowed whole. Alternatively, for patients who have difficulty swallowing capsules, lansoprazole delayed-release capsules can be opened and administered as follows:

      о   Open capsule.

      о   Sprinkle intact granules on one tablespoon of either applesauce, ENSURE     pudding, cottage cheese, yogurt or strained pears.

      о   Swallow immediately.

Lansoprazole delayed-release capsules may also be emptied into a small volume of either apple juice, orange juice or tomato juice and administered as follows:

      о   Open capsule.

      о   Sprinkle intact granules into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately 2 ounces).

      о   Mix briefly.

      о   Swallow immediately.

      о   To ensure complete delivery of the dose, the glass should be rinsed with two or more volumes of juice and the contents swallowed immediately.

Lansoprazole delayed-release capsules - Nasogastric Tube (≥ 16 French) Administration

For patients who have a nasogastric tube in place, lansoprazole delayed-release capsules can be administered as follows:

      о   Open capsule.

      о   Mix intact granules into 40 mL of apple juice. DO NOT USE OTHER LIQUIDS.

      о   Inject through the nasogastric tube into the stomach.

      о   Flush with additional apple juice to clear the tube.

USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED.

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Sirolimus tablets are to be administered orally once daily, consistently with or without food [see DOSAGE AND ADMINISTRATION (2.4), CLINICAL PHARMACOLOGY (12.3)].

Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use. 

The initial dose of sirolimus tablets should be administered as soon as possible after transplantation. It is recommended that sirolimus tablets be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see DRUG INTERACTIONS (7.2)].

Frequent sirolimus tablets dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus tablets maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus tablets dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum sirolimus tablets dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

2.1 Patients at Low- to Moderate-Immunologic Risk

Sirolimus and Cyclosporine Combination Therapy

For de novo renal transplant patients, it is recommended that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range [see DOSAGE AND ADMINISTRATION (2.3)].

Sirolimus Following Cyclosporine Withdrawal

At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [see DOSAGE AND ADMINISTRATION (2.3)]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [see CLINICAL PHARMACOLOGY (12.3)].

2.2 Patients at High-Immunologic Risk

In patients with high-immunologic risk, it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [see CLINICAL STUDIES (14.3)]. The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months. Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.

 

For patients receiving sirolimus with cyclosporine, sirolimus therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should thereafter be adjusted [see DOSAGE AND ADMINISTRATION (2.3)].

The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations [see DOSAGE AND ADMINISTRATION (2.3)]. Prednisone should be administered at a minimum of 5 mg/day. 

Antibody induction therapy may be used. 

2.3 Therapeutic Drug Monitoring

Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see DRUG INTERACTIONS (7)].

Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters. 

When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range [see CLINICAL STUDIES (14), CLINICAL PHARMACOLOGY (12.3)]. Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL. 

The above recommended 24 hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable [see WARNINGS AND PRECAUTIONS (5.15), CLINICAL PHARMACOLOGY (12.3)]. Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see REFERENCES (15)].

2.4 Patients with Low Body Weight

The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2.

2.5 Patients with Hepatic Impairment

It is recommended that the maintenance dose of sirolimus be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the sirolimus loading dose [see CLINICAL PHARMACOLOGY (12.3)].

2.6 Patients with Renal Impairment

Dosage adjustment is not needed in patients with impaired renal function [see USE IN SPECIFIC POPULATIONS (8.7)].

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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 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 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 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), and CLINICAL PHARMACOLOGY (12.3)].

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. Duloxetine 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 as monotherapy. Duloxetine should be administered in a dose range of 60 to 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 must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.

2.3 Dosing in Special Populations

Hepatic Insufficiency

It is recommended that duloxetine 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 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 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 is not recommended [see USE IN SPECIFIC POPULATIONS ( 8.3 )].

2.4 Discontinuing Duloxetine

Symptoms associated with discontinuation of duloxetine 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 a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

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

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

Do not start duloxetine 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 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 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 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 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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Carefully consider the potential benefits and risks of etodolac extended-release tablets and other treatment options before deciding to use etodolac extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

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

Juvenile Rheumatoid Arthritis

For the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 6 to 16 years of age, the recommended dose given orally once per day should be based on body weight, according to the following table:

Table 4 Body Weight Range (kg) Dose  20 to 30  400 mg Tablet x 1 31 to 45  600 mg Tablet x 1 46 to 60  400 mg Tablet x 2 > 60  500 mg Tablet x 2

Rheumatoid Arthritis and Osteoarthritis

For the relief of the signs and symptoms of osteoarthritis or rheumatoid arthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day.

As with other NSAIDs, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.

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General Dosing Considerations

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

Major Depressive Disorder

Initial Treatment

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

Increasing the Dosage Above 300 mg/day

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

Maintenance Treatment

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

Seasonal Affective Disorder

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

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

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

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

Switching Patients from bupropion hydrochloride tablets or from bupropion hydrochloride sustained-release tablets:

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

Dosage Adjustment for Patients With Impaired Hepatic Function

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

Dosage Adjustment for Patients With Impaired Renal Function

Bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered (see CLINICAL PHARMACOLOGYand PRECAUTIONS).

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General:

Propranolol hydrochloride extended-release capsules provide propranolol hydrochloride in a sustained-release capsule for administration once daily. If patients are switched from propranolol hydrochloride tablets to propranolol hydrochloride extended-release capsules, care should be taken to assure that the desired therapeutic effect is maintained. Propranolol hydrochloride extended-release capsules should not be considered a simple mg-for-mg substitute for propranolol hydrochloride tablets. Propranolol hydrochloride extended-release capsules have different kinetics and produces lower blood levels. Retitration may be necessary, especially to maintain effectiveness at the end of the 24-hour dosing interval.

Hypertension:

The usual initial dosage is 80 mg propranolol hydrochloride extended-release capsules once daily, whether used alone or added to a diuretic. The dosage may be increased to 120 mg once daily or higher until adequate blood pressure control is achieved. The usual maintenance dosage is 120 to 160 mg once daily. In some instances a dosage of 640 mg may be required. The time needed for full hypertensive response to a given dosage is variable and may range from a few days to several weeks.

Angina Pectoris:

Starting with 80 mg propranolol hydrochloride extended-release capsules once daily, dosage should be gradually increased at three- to seven-day intervals until optimal response is obtained. Although individual patients may respond at any dosage level, the average optimal dosage appears to be 160 mg once daily. In angina pectoris, the value and safety of dosage exceeding 320 mg per day have not been established.

If treatment is to be discontinued, reduce dosage gradually over a period of a few weeks (see "WARNINGS").

Migraine:

The initial oral dose is 80 mg propranolol hydrochloride extended-release capsules once daily. The usual effective dose range is 160 to 240 mg once daily. The dosage may be increased gradually to achieve optimal migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximal dose, propranolol hydrochloride extended-release capsules therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks depending on the patient’s age, comorbidity, and dose of propranolol hydrochloride extended-release capsules.

Hypertrophic Subaortic Stenosis:

The usual dosage is 80 to 160 mg propranolol hydrochloride extended-release capsules once daily.

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

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

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

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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 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 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 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), and CLINICAL PHARMACOLOGY (12.3)].

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. Duloxetine 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 as monotherapy. Duloxetine should be administered in a dose range of 60 to 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 must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.

2.3 Dosing in Special Populations

Hepatic Insufficiency

It is recommended that duloxetine 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 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 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 is not recommended [see USE IN SPECIFIC POPULATIONS ( 8.3 )].

2.4 Discontinuing Duloxetine

Symptoms associated with discontinuation of duloxetine 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 a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

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

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

Do not start duloxetine 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 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 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 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 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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2.1 Dosing Instructions

Treatment with extended release potassium citrate should be added to a regimen that limits salt intake (avoidance of foods with high salt content and of added salt at the table) and encourages high fluid intake (urine volume should be at least two liters per day). The objective of treatment with potassium citrate extended-release tablets is to provide potassium citrate in sufficient dosage to restore normal urinary citrate (greater than 320 mg/day and as close to the normal mean of 640 mg/day as possible), and to increase urinary pH to a level of 6 or 7.

Monitor serum electrolytes (sodium, potassium, chloride and carbon dioxide), serum creatinine and complete blood counts every four months and more frequently in patients with cardiac disease, renal disease or acidosis. Perform electrocardiograms periodically. Treatment should be discontinued if there is hyperkalemia, a significant rise in serum creatinine or a significant fall in blood hemocrit or hemoglobin.

2.2 Severe Hypocitraturia

In patients with severe hypocitraturia (urinary citrate < 150 mg/day), therapy should be initiated at a dosage of 60 mEq/day (30 mEq two times/day or 20 mEq three times/day with meals or within 30 minutes after meals or bedtime snack). Twenty-four hour urinary citrate and/or urinary pH measurements should be used to determine the adequacy of the initial dosage and to evaluate the effectiveness of any dosage change. In addition, urinary citrate and/or pH should be measured every four months. Doses of potassium citrate extended-release tablets greater than 100 mEq/day have not been studied and should be avoided.

2.3 Mild to Moderate Hypocitraturia

In patients with mild to moderate hypocitraturia (urinary citrate > 150 mg/day) therapy should be initiated at 30 mEq/day (15 mEq two times/day or 10 mEq three times/day with meals or within 30 minutes after meals or bedtime snack). Twenty-four hour urinary citrate and/or urinary pH measurements should be used to determine the adequacy of the initial dosage and to evaluate the effectiveness of any dosage change. Doses of potassium citrate extended-release tablet greater than 100 mEq/day have not been studied and should be avoided.

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2.1 Hypertension

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

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

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

Telmisartan tablets may be administered with other antihypertensive agents.

Telmisartan  tablets may be administered with or without food.

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Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days.

Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days.

Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily.

The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re-evaluated to assess the need for continuation of therapy with acyclovir.

Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.

Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally 4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox.

Adults and Children over 40 kg: 800 mg 4 times daily for 5 days.

Intravenous acyclovir is indicated for the treatment of varicella-zoster infections in immunocompromised patients.

When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms.

Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose of Acyclovir Tablets should be modified as shown in Table 3.

Table 3. Dosage Modification for Renal Impairment Normal DosageRegimen Creatinine Clearance(mL/min/1.73 m2) Adjusted Dosage Regimen Dose (mg) Dosing Interval 200 mg every 4 hours >10 200 every 4 hours, 5x daily 0 to 10 200 every 12 hours 400 mg every 12 hours >10 400 every 12 hours 0 to 10 200 every 12 hours 800 mg every 4 hours >25 800 every 4 hours, 5x daily 10 to 25 800 every 8 hours 0 to 10 800 every 12 hours

Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the dosing interval.