Watson Laboratories, Inc.

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Watson Laboratories, Inc. Drugs

Meperidine Hcl

Meperidine Hcl

For Relief of Pain

Dosage should be adjusted according to the severity of the pain and the response of the patient. Meperidine is less effective orally than on parenteral administration. The dose of meperidine hydrochloride should be proportionately reduced (usually by 25 to 50 percent) when administered concomitantly with phenothiazines and many other tranquilizers since they potentiate the action of meperidine.

Adults

The usual dosage is 50 mg to 150 mg orally, every 3 or 4 hours as necessary.

Pediatric Patients

The usual dosage is 1.1 mg/kg to 1.8 mg/kg orally, up to the adult dose, every 3 or 4 hours as necessary.
Tramadol Hcl

Tramadol Hcl

Adults (17 years of age and over)

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

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 tablets 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.
Meloxicam

Meloxicam

Osteoarthritis

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

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

For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.

The maximum recommended daily oral dose of MELOXICAM is 15 mg.

Meloxicam may be taken without regard to timing of meals.
Diltiazem Hydrochloride...

Diltiazem Hydrochloride Extended Release

Diltiazem Hydrochloride Extended Release Tablets are an extended release formulation intended for once-a-day administration.

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

The tablet should be swallowed whole and not chewed or crushed.

Hypertension

Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The dosage range studied in clinical trials was 120 to 540 mg once daily. The dosage may be titrated to a maximum of 540 mg daily.

Diltiazem Hydrochloride Extended Release Tablets should be taken about the same time once each day either in the morning or at bedtime. The time of dosing should be considered when making dose adjustments based on trough effects.

Angina

Dosage for the treatment of angina should be individualized based on response. The initial dose of 180 mg once daily may be increased at intervals of 7 to14 days if adequate response is not obtained. Diltiazem doses above 360 mg appear to confer no additional benefit. Diltiazem Hydrochloride Extended Release Tablet can be given once daily, either in the evening or in the morning.

Concomitant Use with Other Cardiovascular Agents

Sublingual NTG. May be taken as required to abort acute anginal attacks during Diltiazem Hydrochloride Extended-release therapy.

Prophylactic Nitrate Therapy. Diltiazem Hydrochloride Extended Release Tablets may be safely coadministered with short-and long-acting nitrates.

Beta-blockers. (See WARNINGS and PRECAUTIONS.)

Antihypertensives. Diltiazem has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of Diltiazem Hydrochloride Extended Release Tablets or the concomitant antihypertensives may need to be adjusted when adding one to the other.
Vecuronium Bromide

Vecuronium Bromide

Vecuronium bromide for injection is for intravenous use only.

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

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

The recommended initial dose of vecuronium bromide is 0.08 to 0.10 mg/kg (1.4 to 1.75 times the ED90) given as an intravenous bolus injection. This dose can be expected to produce good or excellent non-emergency intubation conditions in 2.5 to 3 minutes after injection. Under balanced anesthesia, clinically required neuromuscular blockade lasts approximately 25-30 minutes, with recovery to 25% of control achieved approximately 25 to 40 minutes after injection and recovery to 95% of control achieved approximately 45-65 minutes after injection. In the presence of potent inhalation anesthetics, the neuromuscular blocking effect of vecuronium is enhanced. If vecuronium is first administered more than 5 minutes after the start of inhalation agent or when steady state has been achieved, the initial vecuronium bromide dose may be reduced by approximately 15%, i.e., 0.060 to 0.085 mg/kg.

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

During prolonged surgical procedures, maintenance doses of 0.010 to 0.015 mg/kg of vecuronium bromide are recommended; after the initial vecuronium injection, the first maintenance dose will generally be required within 25 to 40 minutes. However, clinical criteria should be used to determine the need for maintenance doses.

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

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

Use by Continuous Infusion

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

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

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

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

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

Unused portions of infusion solutions should be discarded.

Infusion rates of vecuronium bromide can be individualized for each patient using the following table:
Drug Delivery Rate Infusion Delivery Rate (mcg/kg/min) (mL/kg/min) 0.1 mg/mL* 0.2 mg/mL** * 10 mg of Vecuronium bromide in 100 mL solution ** 20 mg of Vecuronium bromide in 100 mL solution 0.7 0.007 0.0035 0.8 0.008 0.0040 0.9 0.009 0.0045 1.0 0.010 0.0050 1.1 0.011 0.0055 1.2 0.012 0.0060 1.3 0.013 0.0065
The following table is a guideline for mL/min delivery for a solution of 0.1 mg/mL (10 mg in 100 mL) with an infusion pump.
VECURONIUM BROMIDE INFUSION RATE - mL/MIN Amount of Drug Patient Weight–kg mcg/kg/min 40 50 60 70 80 90 100 NOTE: If a concentration of 0.2 mg/mL is used (20 mg in 100 mL), the rate should be decreased by one-half. 0.7 0.28 0.35 0.42 0.49 0.56 0.63 0.70 0.8 0.32 0.40 0.48 0.56 0.64 0.72 0.80 0.9 0.36 0.45 0.54 0.63 0.72 0.81 0.90 1.0 0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.1 0.44 0.55 0.66 0.77 0.88 0.99 1.10 1.2 0.48 0.60 0.72 0.84 0.96 1.08 1.20 1.3 0.52 0.65 0.78 0.91 1.04 1.17 1.30
Use in Pediatrics

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

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

Compatibility

Vecuronium bromide is compatible in solution with:0.9% Sodium Chloride Injection5% Dextrose InjectionSterile water for injectionDextrose 5% and Sodium Chloride InjectionLactated Ringer’s Injection

Use within 24 hours of mixing with the above solutions.
Trazodone Hydrochloride...

Trazodone Hydrochloride

The dosage should be initiated at a low level and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage. Trazodone hydrochloride should be taken shortly after a meal or light snack. Symptomatic relief may be seen during the first week, with optimal antidepressant effects typically evident within 2 weeks. Twenty-five percent of those who respond to trazodone require more than 2 weeks (up to 4 weeks) of drug administration.

Usual Adult Dosage

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

Maintenance

Dosage during prolonged maintenance therapy should be kept at the lowest effective level. Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.

Although there has been no systematic evaluation of the efficacy of trazodone beyond 6 weeks, it is generally recommended that a course of antidepressant drug treatment should be continued for several months.
Doxepin Hydrochloride

Doxepin Hydrochloride

For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is recommended. Dosage may subsequently be increased or decreased at appropriate intervals and according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day.

In more severely ill patients higher doses may be required with subsequent gradual increase to 300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a dose of 300 mg/day.

In patients with very mild symptomatology or emotional symptoms accompanying organic disease, lower doses may suffice. Some of these patients have been controlled on doses as low as 25-50 mg/day.

The total daily dosage of doxepin hydrochloride capsules may be given on a divided or once-a-day dosage schedule. If the once-a-day schedule is employed, the maximum recommended dose is 150 mg/day. This dose may be given at bedtime. The 150 mg capsule strength is intended for maintenance therapy only and is not recommended for initiation of treatment.

Anti-anxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect may not be evident for two to three weeks.
Citalopram Hydrobromide...

Citalopram Hydrobromide

Initial Treatment: Citalopram Tablets USP should be administered at an initial dose of 20 mg once daily, generally with an increase to a dose of 40 mg/day. Dose increases should usually occur in increments of 20 mg at intervals of no less than one week. Although certain patients may require a dose of 60 mg/day, the only study pertinent to dose response for effectiveness did not demonstrate an advantage for the 60 mg/day dose over the 40 mg/day dose; doses above 40 mg are therefore not ordinarily recommended. Citalopram Tablets USP should be administered once daily, in the morning or evening, with or without food.

Special Populations: 20 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment, with titration to 40 mg/day only for nonresponding patients.

No dosage adjustment is necessary for patients with mild or moderate renal impairment.

Citalopram should be used with caution in patients with severe renal impairment.

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

Maintenance Treatment:

It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of citalopram in two studies has shown that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment (32 weeks total). In one study, patients were assigned randomly to placebo or to the same dose of citalopram (20-60 mg/day) during maintenance treatment as they had received during the acute stabilization phase, while in the other study, patients were assigned randomly to continuation of citalopram 20 or 40 mg/day, or placebo, for maintenance treatment. In the latter study, the rates of relapse to depression were similar for the two dose groups (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is not known whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. If adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered.

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

Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of an MAOI and initiation of citalopram therapy. Similarly, at least 14 days should be allowed after stopping citalopram before starting an MAOI (see CONTRAINDICATIONS and WARNINGS).
Pitocin

Pitocin

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

The dosage of oxytocin is determined by the uterine response and must therefore be individualized and initiated at a very low level. The following dosage information is based upon various regimens and indications in general use.
Induction or Stimulation of Labor Intravenous infusion (drip method) is the only acceptable method of parenteral administration of oxytocin for the induction or stimulation of labor. Accurate control of the rate of infusion is essential and is best accomplished by an infusion pump. It is convenient to piggyback the ocytocin infusion on a physiologic electrolyte solution, permitting the oxytocin infusion to be stopped abruptly without interrupting the electrolyte infusion. This is done in the following way. Preparation The standard solution for infusion of oxytocin is prepared by adding the contents of one 1-mL vial containing 10 units of oxytocin to 1000 mL of 0.9% aqueous sodium chloride or Ringer’s lactate. The combined solution containing 10 milliunits (mU) of oxytocin/mL is rotated in the infusion bottle for thorough mixing. Establish the infusion with a separate bottle of physiologic electrolyte solution not cotaining oxytocin. Attach (piggyback) the oxytocin-containing bottle with the infusion pump to the infusion line as close to the infusion site as possible. Administration The initial dose should be 0.5–1 mU/min (equal to 3–6 mL of the dilute oxytocin solution per hour). At 30–60 minute intervals the dose should be gradually increased in increments of 1–2 mU/min until the desired contraction pattern has been established. Once the desired frequency of contractions has been reached and labor has progressed to 5–6 cm dilation, the dose may be reduced by similar increments. Studies of the concentrations of oxytocin in the maternal plasma during oxytocin infusion have shown that infusion rates up to 6 mU/min give the same oxytocin levels that are found in spontaneous labor. At term, higher infusion rates should be given with great care, and rates exceeding 9–10 mU/min are rarely required. Before term, when the sensitivity of the uterus is lower because of a lower concentration of oxytocin receptors, a higher infusion rate may be required. Monitoring Electronically monitor the uterine activity and the fetal heart rate throughout the infusion of oxytocin. Attention should be given to tonus, amplitude and frequency of contractions, and to the fetal heart rate in relation to uterine contractions. If uterine contractions become too powerful, the infusion can be abruptly stopped, and oxytocic stimulation of the uterine musculature will soon wane (see PRECAUTIONS section). Discontinue the infusion of oxytocin immediately in the event of uterine hyperactivity and/or fetal distress. Administer oxygen to the mother, who preferably should be put in a lateral position. The condition of mother and fetus should immediately be evaluated by the responsible physician and appropriate steps taken. Control of Postpartum Uterine Bleeding Intravenous infusion (drip method). If the patient has an intravenous infusion running, 10 to 40 units of oxytocin may be added to the bottle, depending on the amount of electrolyte or dextrose solution remaining (maximum 40 units to 1000 mL). Adjust the infusion rate to sustain uterine contraction and control uterine atony. Intramuscular administration. (One mL) Ten (10) units of oxytocin can be given after the delivery of the placenta. Treatment of Incomplete, Inevitable, or Elective Abortion Intravenous infusion of 10 units of oxytocin added to 500 mL of a physiologic saline solution or 5% dextrose-in-water solution may help the uterus contract after a suction or sharp curettagefor an incomplete, inevitable, or elective abortion. Subsequent to intra-amniotic injection of hypertonic saline, prostaglandins, urea, etc., for midtrimester elective abortion, the injection-toabortion time may be shortened by infusion of oxytocin at the rate of 10 to 20 milliunits (20 to 40 drops) per minute. The total dose should not exceed 30 units in a 12-hour period due to the risk of water intoxication.
Triamterene And Hydroch...

Triamterene And Hydrochlorothiazide

Note: 37.5 mg/25 mg=37.5 mg triamterene and 75 mg/50 mg=75 mg triamterene and 25 mg hydrochlorothiazide 50 mg hydrochlorothiazide

The usual dosage of Triamterene and Hydrochlorothiazide as a tablet is 37.5 mg/25 mg or 75 mg/50 mg daily, given as a single dose, with appropriate monitoring of serum potassium (seeWARNINGS). There is no experience with the use of more than 75 mg/50 mg daily of triamterene and hydrochlorothiazide. Clinical experience with the administration of 37.5 mg/25 mg of triamterene and hydrochlorothiazide twice daily (in divided doses rather than as a single dose) suggests an increased risk of electrolyte imbalance and renal dysfunction.

Patients receiving 50 mg of hydrochlorothiazide who become hypokalemia may be transferred to this 75 mg/ 50 mg product directly. Patients receiving 25 mg hydrochlorothiazide who become hypokalemic may be transferred to a 37.5 mg/25 mg product directly.

In patients requiring hydrochlorothiazide therapy and in whom hypokalemia cannot be risked, therapy may be initiated with 37.5 mg/25 mg of triamterene and hydrochlorothiazide. If an optimal blood pressure response is not obtained with 37.5 mg/25 mg of triamterene and hydrochlorothiazide, then the dose should be increased to 75 mg/ 50 mg daily as a single dose. If blood pressure still is not controlled, another antihypertensive agent may be added (seePRECAUTIONS, Drug Interactions).

Clinical studies have shown that patients taking less bioavailable formulations of triamterene and hydrochlorothiazide in daily doses of 25 to 50 mg hydrochlorothiazide and 50 to 100 mg of triamterene may be safely changed to 37.5 mg/25 mg of triamterene and hydrochlorothiazide daily. All patients changed from less bioavailable formulations to this product should be monitored clinically and for serum potassium after the transfer.
Enalapril Maleate

Enalapril Maleate

Hypertension

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

Concomitant administration of enalapril maleate 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 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.
Creatinine Clearance Initial Dose Renal Status mL/min mg/day ***See WARNINGS,Anaphylactoid reactions during membrane exposure. †Dosage on nondialysis days should be adjusted depending on the blood pressure response. Normal Renal Function >80 mL/min 5 mg Mild Impairment ≤80 >30 mL/min 5 mg Moderate to Severe Impairment ≤30 mL/mi 2.5 mg Dialysis Patients*** - 2.5 mg on dialysis days†
Heart Failure

Enalapril maleate is 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 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, 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 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, 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 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 four 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

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

Mexiletine Hcl

The dosage of mexiletine hydrochloride must be individualized on the basis of response and tolerance, both of which are dose-related. Administration with food or antacid is recommended. Initiate mexiletine therapy with 200 mg every eight hours when rapid control of arrhythmia is not essential. A minimum of two to three days between dose adjustments is recommended. Dose may be adjusted in 50 or 100 mg increments up or down.

As with any antiarrhythmic drug, clinical and electrocardiographic evaluation (including Holter monitoring if necessary for evaluation) are needed to determine whether the desired antiarrhythmic effect has been obtained and to guide titration and dose adjustment.

Satisfactory control can be achieved in most patients by 200 to 300 mg given every eight hours with food or antacid. If satisfactory response has not been achieved at 300 mg q8h, and the patient tolerates mexiletine well, a dose of 400 mg q8h may be tried. As the severity of CNS side effects increases with total daily dose, the dose should not exceed 1200 mg/day.

In general, patients with renal failure will require the usual doses of mexiletine hydrochloride. Patients with severe liver disease, however, may require lower doses and must be monitored closely. Similarly, marked right-sided congestive heart failure can reduce hepatic metabolism and reduce the needed dose. Plasma level may also be affected by certain concomitant drugs (seePRECAUTIONS: Drug Interactions).

Loading Dose: When rapid control of ventricular arrhythmia is essential, an initial loading dose of 400 mg of mexiletine hydrochloride may be administered, followed by a 200 mg dose in eight hours. Onset of therapeutic effect is usually observed within 30 minutes to two hours.

Q12H Dosage Schedule: Some patients responding to mexiletine may be transferred to a 12 hour dosage schedule to improve convenience and compliance. If adequate suppression is achieved on a mexiletine hydrochloride dose of 300 mg or less every eight hours, the same total daily dose may be given in divided doses every 12 hours while carefully monitoring the degree of suppression of ventricular ectopy. This dose may be adjusted up to a maximum of 450 mg every 12 hours to achieve the desired response.

Transferring to Mexiletine hydrochloride: The following dosage schedule, based on theoretical considerations rather than experimental data, is suggested for transferring patients from other Class 1 oral antiarrhythmic agents to mexiletine: Mexiletine hydrochloride treatment may be initiated with a 200 mg dose, and titrated to response as described above, 6 to 12 hours after the last dose of quinidine sulfate, 3 to 6 hours after the last dose of procainamide, 6 to 12 hours after the last dose of disopyramide or 8 to 12 hours after the last dose of tocainide.

In patients in whom withdrawal of the previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, hospitalization of the patient is recommended.

When transferring from lidocaine to mexiletine, the lidocaine infusion should be stopped when the first oral dose of mexiletine hydrochloride is administered. The infusion line should be left open until suppression of the arrhythmia appears to be satisfactorily maintained. Consideration should be given to the similarity of the adverse effects of lidocaine and mexiletine and the possibility that they may be additive.
Clonazepam

Clonazepam

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

Seizure Disorders

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

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

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

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

Panic Disorder

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

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

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

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

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

Sertraline Hydrochloride

Initial Treatment

Dosage for Adults

Major Depressive Disorder –Sertraline hydrochloride treatment should be administered at a dose of 50 mg once daily.

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

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

Maintenance/Continuation/Extended Treatment

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

Switching Patients to or from a Monoamine Oxidase Inhibitor–At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with sertraline hydrochloride. In addition, at least 14 days should be allowed after stopping sertraline hydrochloride before starting an MAOI (seeCONTRAINDICATIONS andWARNINGS).

Special Populations

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

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

Discontinuation of Treatment with Sertraline Hydrochloride

Symptoms associated with discontinuation of sertraline hydrochloride and other SSRIs and SNRIs, have been reported (seePRECAUTIONS). 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.
Pravastatin Sodium

Pravastatin Sodium

The patient should be placed on a standard cholesterol-lowering diet before receiving Pravastatin Sodium Tablets and should continue on this diet during treatment with Pravastatin Sodium Tablets (see NCEP Treatment Guidelines for details on dietary therapy).

Pravastatin Sodium Tablets can be administered orally as a single dose at any time of the day, with or without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.

Adult Patients

The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with a history of significant renal or hepatic dysfunction, a starting dose of 10 mg daily is recommended.

Pediatric Patients

Children (Ages 8 to 13 Years, Inclusive)

The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.

Adolescents (Ages 14 to 18 Years)

The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.

Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C (see INDICATIONS AND USAGE: Hyperlipidemia: Table 7: NCEP Treatment Guidelines).

In patients taking immunosuppressive drugs such as cyclosporine (see WARNINGS: Skeletal Muscle) concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day.

Concomitant Therapy

The lipid-lowering effects of Pravastatin Sodium Tablets on Total- and LDL-cholesterol are enhanced when combined with a bile-acid-binding resin. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, Pravastatin Sodium Tablets should be given either 1 hour or more before or at least 4 hours following the resin. (See also ADVERSE REACTIONS: Concomitant Therapy.)
Mirtazapine

Mirtazapine

Initial Treatment

The recommended starting dose for Mirtazapine tablets is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In the controlled clinical trials establishing the efficacy of mirtazapine in the treatment of major depressive disorder, the effective dose range was generally 15-45 mg/day. While the relationship between dose and satisfactory response in the treatment of major depressive disorder for mirtazapine has not been adequately explored, patients not responding to the initial 15 mg dose may benefit from dose increases up to a maximum of 45 mg/day.

Mirtazapine has an elimination half-life of approximately 20-40 hours; therefore, dose changes should not be made at intervals of less than one to two weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose.

Elderly and Patients with Renal or Hepatic Impairment

The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment (see PRECAUTIONS and CLINICAL PHARMACOLOGY).

Maintenance/Extended 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. Systemic evaluation of mirtazapine has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8-12 weeks of initial treatment at a dose of 15-45 mg/day. (See CLINICAL PHARMACOLOGY.) Based on these limited data, it is unknown whether or not the dose of mirtazapine 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.

Switching Patients To or From a Monoamine Oxidase Inhibitor

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with mirtazapine. In addition, at least 14 days should be allowed after stopping mirtazapine before starting an MAOI.
Galantamine Hydrobromid...

Galantamine Hydrobromide

Galantamine Hydrobromide Extended-Release Capsules

The dosage of galantamine hydrobromide extended-release capsules shown to be effective in a controlled clinical trial is 16-24 mg/day.

The recommended starting dose of galantamine hydrobromide extended-release capsules is 8 mg/day. The dose should be increased to the initial maintenance dose of 16 mg/day after a minimum of 4 weeks. A further increase to 24 mg/day should be attempted after a minimum of 4 weeks at 16 mg/day. Dose increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

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

Patients currently being treated with galantamine hydrobromide immediate-release tablets can convert to galantamine hydrobromide extended-release capsules by taking their last dose of galantamine hydrobromide immediate-release tablets in the evening and starting galantamine hydrobromide extended-release capsules once daily treatment the next morning. Converting from galantamine hydrobromide immediate-release tablets to galantamine hydrobromide extended-release capsules should occur at the same total daily dose.

Patients and caregivers should be advised to ensure adequate fluid intake during treatment. If therapy has been interrupted for several days or longer, the patient should be restarted at the lowest dose and the dose escalated to the current dose.

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

Doses in Special Populations

Galantamine plasma concentrations may be increased in patients with moderate to severe hepatic impairment. In patients with moderately impaired hepatic function (Child-Pugh score of 7-9), the dose should generally not exceed 16 mg/day. The use of galantamine hydrobromide extended-release capsules in patients with severe hepatic impairment (Child-Pugh score of 10-15) is not recommended.

For patients with moderate renal impairment the dose should generally not exceed 16 mg/day. In patients with severe renal impairment (creatinine clearance < 9 mL/min), the use of galantamine hydrobromide extendedrelease capsules are not recommended.
Methocarbamol

Methocarbamol

500 mg - Adults: initial dosage, 3 tablets q.i.d.; maintenance dosage, 2 tablets q.i.d.

750 mg - Adults: initial dosage, 2 tablets q.i.d.; maintenance dosage 1 tablet q.4h or 2 tablets t.i.d.

Six grams a day are recommended for the first 48 to 72 hours of treatment. (For severe conditions 8 grams a day may be administered). Thereafter, the dosage can usually be reduced to approximately 4 grams a day.
Prednisone

Prednisone

The initial dosage of prednisone tablets may vary from 5 mg to 60 mg per day, depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, prednisone should be discontinued and the patient transferred to other appropriate therapy. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of prednisone for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

Multiple Sclerosis

In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective. (Dosage range is the same for prednisone and prednisolone.)

Alternate Day Therapy

Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the cushingoid state, corticoid withdrawal symptoms, and growth suppression in children.

The rationale for this treatment schedule is based on two major premises: (a) the antiinflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.

A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.

The diurnal rhythm of the HPA axis is lost in Cushing’s disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects.

During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1¼ to 1½ days following a single dose) and thus are recommended for alternate day therapy.

The following should be kept in mind when considering alternate day therapy:

Basic principles and indications for corticosteroid therapy should apply. The benefits of alternate day therapy should not encourage the indiscriminate use of steroids.

Alternate day therapy is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.

In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with alternate day therapy. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended.Once control has been established, two courses are available: (a) change to alternate day therapy and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate-day schedule. Theoretically, course (a) may be preferable.

Because of the advantages of alternate day therapy, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (e.g., patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on alternate day therapy may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum.

As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (e.g., dexamethasone and betamethasone).

The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least when given at the time of maximal activity (am).

In using alternate day therapy it is important, as in all therapeutic situations, to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of alternate day therapy will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the offsteroid day. Other symptomatic therapy may be added or increased at this time if needed.

In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be reinstituted.

Although many of the undesirable features of corticosteroid therapy can be minimized by alternate day therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.
Ursodiol

Ursodiol

Gallstone Dissolution

The recommended dose for ursodiol treatment of radiolucent gallbladder stones is 8-10 mg/kg/day given in 2 or 3 divided doses.

Ultrasound images of the gallbladder should be obtained at 6-month intervals for the first year of ursodiol therapy to monitor gallstone response. If gallstones appear to have dissolved, ursodiol therapy should be continued and dissolution confirmed on a repeat ultrasound examination within 1-3 months. Most patients who eventually achieve complete stone dissolution will show partial or complete dissolution at the first on-treatment reevaluation. If partial stone dissolution is not seen by 12 months of ursodiol therapy, the likelihood of success is greatly reduced.

Gallstone Prevention

The recommended dosage of ursodiol for gallstone prevention in patients undergoing rapid weight loss is 600 mg/day (300 mg b.i.d.).
Probenecid And Colchici...

Probenecid And Colchicine

Therapy with probenecid and colchicine should not be started until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, probenecid and colchicine may be continued without changing the dosage, and additional colchicine or other appropriate therapy should be given to control the acute attack.

The recommended adult dosage is 1 tablet of probenecid and colchicine daily for one week, followed by 1 tablet twice a day thereafter.

Some degree of renal impairment may be present in patients with gout. A daily dosage of 2 tablets may be adequate. However, if necessary, the daily dosage may be increased by 1 tablet every four weeks within tolerance (and usually not above 4 tablets per day) if symptoms of gouty arthritis are not controlled or the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mL/minute or less.

Gastric intolerance may be indicative of overdosage, and may be corrected by decreasing the dosage.

As uric acid tends to crystallize out of an acid urine, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily) or potassium citrate (7.5 g daily) to maintain an alkaline urine (see PRECAUTIONS).

Alkalization of the urine is recommended until the serum urate level returns to normal limits and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at a high level. Thereafter, alkalization of the urine and the usual restriction of purine-producing foods may be somewhat relaxed.

Probenecid and colchicine (or probenecid) should be continued at the dosage that will maintain normal serum urate levels. When acute attacks have been absent for six months or more and serum urate levels remain within normal limits, the daily dosage of probenecid and colchicine may be decreased by 1 tablet every six months. The maintenance dosage should not be reduced to the point where serum urate levels tend to rise.
Rivastigmine Tartrate

Rivastigmine Tartrate

Dementia of the Alzheimer’s type

The dosage of Rivastigmine Tartrate Capsules shown to be effective in controlled clinical trials is 6-12 mg/day, given as twice-a-day dosing (daily doses of 3 to 6 mg BID). There is evidence from the clinical trials that doses at the higher end of this range may be more beneficial.

The starting dose of Rivastigmine Tartrate Capsules is 1.5 mg twice a day (BID). If this dose is well tolerated, after a minimum of two weeks of treatment, the dose may be increased to 3 mg BID. Subsequent increases to 4.5 mg BID and 6 mg BID should be attempted after a minimum of 2 weeks at the previous dose. If adverse effects (e.g., nausea, vomiting, abdominal pain, loss of appetite) cause intolerance during treatment, the patient should be instructed to discontinue treatment for several doses and then restart at the same or next lower dose level. If treatment is interrupted for longer than several days, treatment should be reinitiated with the lowest daily dose and titrated as described above (see WARNINGS). The maximum dose is 6 mg BID (12 mg/day).

Dementia associated with Parkinson’s Disease

The dosage of Rivastigmine Tartrate Capsules shown to be effective in the single controlled clinical trial conducted in dementia associated with Parkinson’s Disease is 3 to 12 mg/day, given as twice-a-day dosing (daily doses of 1.5 to 6 mg BID). In that medical condition, the starting dose of Rivastigmine Tartrate Capsules is 1.5 mg BID; subsequently, the dose may be increased to 3 mg BID and further to 4.5 mg BID and 6 mg BID, based on tolerability, with a minimum of 4 weeks at each dose.

Rivastigmine Tartrate Capsules should be taken with meals in divided doses in the morning and evening.
Sulindac

Sulindac

Carefully consider the potential benefits and risks of sulindac and other treatment options before deciding to use sulindac. 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 sulindac, the dose and frequency should be adjusted to suit an individual patient's needs.

Sulindac should be administered orally twice a day with food. The maximum dosage is 400 mg per day. Dosages above 400 mg per day are not recommended.

In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.

A prompt response (within one week) can be expected in about one-half of patients with osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis. Others may require longer to respond.

In acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis) and acute gouty arthritis, the recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may be reduced according to the response. In acute painful shoulder, therapy for 7-14 days is usually adequate. In acute gouty arthritis, therapy for 7 days is usually adequate.
Orphenadrine Citrate

Orphenadrine Citrate

Adults: 2 mL (60 mg) intravenously or intramuscularly - May be repeated every 12 hours. Relief may be maintained by one (100 mg) orphenadrine citrate tablet twice daily.

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

Minoxidil

Patients over 12 years of age: The recommended initial dosage of minoxidil tablets is 5 mg of minoxidil given as a single daily dose. Daily dosage can be increased to 10, 20 and then to 40 mg in single or divided doses if required for optimum blood pressure control. The effective dosage range is usually 10 to 40 mg per day. The maximum recommended dosage is 100 mg per day.

Patients under 12 years of age: The initial dosage is 0.2 mg/kg minoxidil as a single daily dose. The dosage may be increased in 50 to 100% increments until optimum blood pressure control is achieved. The effective dosage range is usually 0.25 to 1 mg/kg/day. The maximum recommended dosage is 50 mg daily (see 9. Pediatric Use under PRECAUTIONS).

Dose frequency: The magnitude of within-day fluctuation of arterial pressure during therapy with minoxidil is directly proportional to the extent of pressure reduction. If supine diastolic pressure has been reduced less than 30 mm Hg, the drug need be administered only once a day; if supine diastolic pressure has been reduced more than 30 mm Hg, the daily dosage should be divided into two equal parts.

Frequency of dosage adjustment: Dosage must be titrated carefully according to individual response. Intervals between dosage adjustments normally should be at least 3 days since the full response to a given dose is not obtained for at least that amount of time. Where a more rapid management of hypertension is required, dose adjustments can be made every 6 hours if the patient is carefully monitored.

Concomitant therapy: Diuretic and beta-blocker or other sympathetic nervous system suppressant.

Diuretics: Minoxidil must be used in conjunction with a diuretic in patients relying on renal function for maintaining salt and water balance. Diuretics have been used at the following dosages when starting therapy with minoxidil: hydrochlorothiazide (50 mg, b.i.d.) or other thiazides at equieffective dosage; chlorthalidone (50 to 100 mg, once daily); furosemide (40 mg, b.i.d.). If excessive salt and water retention results in a weight gain of more than 5 pounds, diuretic therapy should be changed to furosemide; if the patient is already taking furosemide, dosage should be increased in accordance with the patient’s requirements.

Beta-blocker or other sympathetic nervous system suppressants: When therapy with minoxidil is begun, the dosage of a beta-adrenergic receptor blocking drug should be the equivalent of 80 to 160 mg of propranolol per day in divided doses.

If beta-blockers are contraindicated, methyldopa (250 to 750 mg, b.i.d.) may be used instead. Methyldopa must be given for at least 24 hours before starting therapy with minoxidil because of the delay in the onset of methyldopa’s action. Limited clinical experience indicates that clonidine may also be used to prevent tachycardia induced by minoxidil; the usual dosage is 0.1 to 0.2 mg twice daily.

Sympathetic nervous system suppressants may not completely prevent an increase in heart rate due to minoxidil but usually do prevent tachycardia. Typically, patients receiving a beta-blocker prior to initiation of therapy with minoxidil have a bradycardia and can be expected to have an increase in heart rate toward normal when minoxidil is added. When treatment with minoxidil and beta-blocker or other sympathetic nervous system suppressant are begun simultaneously, their opposing cardiac effects usually nullify each other, leading to little change in heart rate.
Allopurinol

Allopurinol

The dosage of allopurinol 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 per day for patients with mild gout and 400 to 600 mg per 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 (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 one to three 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 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, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the dose of allopurinol gradually increased to the required dose needed to maintain a normal serum uric acid level.

It should also be noted that allopurinol is 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 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 two or three 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 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 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.
Morphine Sulfate

Morphine Sulfate

(See also: CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections)

MORPHINE SULFATE EXTENDED-RELEASE TABLETS IS AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE WITH AN ABUSE LIABILITY SIMILAR TO OTHER OPIOID AGONISTS. MORPHINE AND OTHER OPIOIDS USED IN ANALGESIA CAN BE ABUSED AND ARE SUBJECT TO CRIMINAL DIVERSION.

MORPHINE SULFATE EXTENDED-RELEASE TABLETS ARE TO BE SWALLOWED WHOLE, AND ARE NOT TO BE BROKEN, CHEWED, DISSOLVED OR CRUSHED. TAKING BROKEN, CHEWED, DISSOLVED, OR CRUSHED MORPHINE SULFATE EXTENDED-RELEASE TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE.

Physicians should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen to opioids in a plan of pain management such as those outlined by the World Health Organization, the Federation of State Medical Boards Model Guidelines, or the American Pain Society. Healthcare professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring (see BOXED WARNING).

Morphine Sulfate Extended-Release Tablets is an extended-release oral formulation of morphine sulfate indicated for the management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time. The extended-release nature of the formulation allows it to be administered on a more convenient schedule than conventional immediate-release oral morphine products. (See CLINICAL PHARMACOLOGY; PHARMACOKINETICS AND METABOLISM.) However, Morphine Sulfate Extended-Release Tablets do not release morphine continuously over the course of a dosing interval. The administration of single doses of Morphine Sulfate Extended-Release Tablets on a q12h dosing schedule will result in higher peak and lower trough plasma levels than those that occur when an identical daily dose of morphine is administered using conventional oral formulations on a q4h regimen. The clinical significance of greater fluctuations in morphine plasma level has not been systematically evaluated.

As with any potent opioid drug product, it is critical to adjust the dosing regimen for each patient individually, taking into account the patient's prior opioid and non-opioid analgesic treatment experience. Although it is clearly impossible to enumerate every consideration that is important to the selection of initial dose and dosing interval of Morphine Sulfate Extended-Release Tablets, attention should be given to 1) the daily dose, potency, and precise characteristics of the opioid the patient has been taking previously (e.g., whether it is a pure agonist or mixed agonist/antagonist), 2) the reliability of the relative potency estimate used to calculate the dose of morphine needed [N.B. potency estimates may vary with the route of administration], 3) the degree of opioid tolerance, if any, and 4) the general condition and medical status of the patient.

The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions in the management of the pain of an individual patient.

During periods of changing analgesic requirements including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

Conversion from Immediate-Release Oral Morphine to Morphine Sulfate Extended-Release Tablets

A patient's daily morphine requirement is established using immediate-release oral morphine (dosing every 4 to 6 hours). The patient is then converted to Morphine Sulfate Extended-Release Tablets in either of two ways: 1) by administering one-half of the patient's 24-hour requirement as Morphine Sulfate Extended-Release Tablets on an every 12-hour schedule; or, 2) by administering one-third of the patient's daily requirement as Morphine Sulfate Extended-Release Tablets on an every eight hour schedule. With either method, dose and dosing interval is then adjusted as needed (see discussion below). The 15 mg tablet should be used for initial conversion for patients whose total daily requirement is expected to be less than 60 mg. The 30 mg tablet strength is recommended for patients with a daily morphine requirement of 60 to 120 mg. When the total daily dose is expected to be greater than 120 mg, the appropriate combination of tablet strengths should be employed.

Conversion from Parenteral Morphine or Other Opioids (Parenteral or Oral) to Morphine Sulfate Extended-Release Tablets

Morphine Sulfate Extended-Release Tablets can be administered as the initial oral morphine drug product; in this case, however, particular care must be exercised in the conversion process. Because of uncertainty about, and intersubject variation in, relative estimates of opioid potency and cross tolerance, initial dosing regimens should be conservative. It is better to underestimate the 24-hour oral morphine requirement than to overestimate. To this end, initial individual doses of Morphine Sulfate Extended-Release Tablets should be estimated conservatively. In patients whose daily morphine requirements are expected to be less than or equal to 120 mg per day, the 30 mg tablet strength is recommended for the initial titration period. Once a stable dose regimen is reached, the patient can be converted to the 60 mg or 100 mg tablet strength, or an appropriate combination of tablet strengths, if desired.

Estimates of the relative potency of opioids are only approximate and are influenced by route of administration, individual patient differences, and possibly, by an individual's medical condition. Consequently, it is difficult to recommend any fixed rule for converting a patient to Morphine Sulfate Extended-Release Tablets directly. The following general points should be considered, however.
Parenteral to oral morphine ratio: Estimates of the oral to parenteral potency of morphine vary. Some authorities suggest that a dose of oral morphine only three times the daily parenteral morphine requirement may be sufficient in chronic use settings. Other parenteral or oral opioids to oral morphine: Because there is lack of systematic evidence bearing on these types of analgesic substitutions, specific recommendations are not possible.
Physicians are advised to refer to published relative potency data, keeping in mind that such ratios are only approximate. In general, it is safer to underestimate the daily dose of Morphine Sulfate Extended-Release Tablets required and rely upon ad hoc supplementation to deal with inadequate analgesia. (See discussion which follows.)

Use of Morphine Sulfate Extended-Release Tablets as the First Opioid Analgesic

There has been no systematic evaluation of Morphine Sulfate Extended-Release Tablets as an initial opioid analgesic in the management of pain. Because it may be more difficult to titrate a patient using an extended-release morphine, it is ordinarily advisable to begin treatment using an immediate-release formulation. (See Special Instructions for Morphine Sulfate Extended-Release 100 and 200 mg Tablets)

Considerations in the Adjustment of Dosing Regimens

Whatever the approach, if signs of excessive opioid effects are observed early in a dosing interval, the next dose should be reduced. If this adjustment leads to inadequate analgesia, that is, "breakthrough" pain occurs late in the dosing interval, the dosing interval may be shortened. Alternatively, a supplemental dose of a short-acting analgesic may be given. As experience is gained, adjustments can be made to obtain an appropriate balance between pain relief, opioid side effects, and the convenience of the dosing schedule.

In adjusting dosing requirements, it is recommended that the dosing interval never be extended beyond 12 hours because the administration of very large single doses may lead to acute overdose. (N.B. Morphine Sulfate Extended-Release Tablets is an extended-release formulation; it does not release morphine continuously over the dosing interval.)

For patients with low daily morphine requirements, the 15 mg tablet should be used.

Special Instructions for Morphine Sulfate Extended-Release 100 and 200 mg Tablets

(For use in opioid-tolerant patients only.)

Morphine Sulfate Extended-Release 100 mg and 200 mg Tablets are for use only in opioid-tolerant patients requiring daily morphine equivalent dosages of 200 mg or more for the 100 mg tablet and 400 mg or more for the 200 mg tablet. It is recommended that these strengths be reserved for patients that have already been titrated to a stable analgesic regimen using lower strengths of Morphine Sulfate Extended-Release Tablets or other opioids.

Supplemental Analgesia

Most patients given around-the-clock therapy with controlled-release opioids may need to have immediate-release medication available for exacerbations of pain or to prevent pain that occurs predictably during certain patient activities (including incident pain).

Continuation of Therapy

The intent of the titration period is to establish a patient-specific daily dose that will provide adequate analgesia with acceptable side effects and minimal rescue doses (2 or less) for as long as pain relief is necessary. Should pain recur, the dose can be increased to re-establish pain control as outlined above. During chronic, around-the-clock opioid therapy, especially for non-cancer pain syndromes, the continued need for around-the-clock opioid therapy should be reassessed periodically (e.g. every 6 to 12 months) as appropriate.

Cessation of Therapy

When the patient no longer requires therapy with Morphine Sulfate Extended-Release Tablets, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.

Conversion from Morphine Sulfate Extended-Release Tablets to Parenteral Opioids

When converting a patient from Morphine Sulfate Extended-Release Tablets to parenteral opioids, it is best to assume that the parenteral to oral potency is high. NOTE THAT THIS IS THE CONVERSE OF THE STRATEGY USED WHEN THE DIRECTION OF CONVERSION IS FROM THE PARENTERAL TO ORAL FORMULATIONS. IN BOTH CASES, HOWEVER, THE AIM IS TO ESTIMATE THE NEW DOSE CONSERVATIVELY. For example, to estimate the required 24-hour dose of morphine for IM use, one could employ a conversion of 1 mg of morphine IM for every 6 mg of morphine as Morphine Sulfate Extended-Release Tablets. The IM 24-hour dose would have to be divided by six and administered on a q4h regimen. This approach is recommended because it is least likely to cause overdose.
Estazolam

Estazolam

The recommended initial dose for adults is 1 mg at bedtime; however, some patients may need a 2 mg dose. In healthy elderly patients, 1 mg is also the appropriate starting dose, but increases should be initiated with particular care. In small or debilitated older patients, a starting dose of 0.5 mg, while only marginally effective in the overall elderly population, should be considered.
Fentanyl Buccal

Fentanyl Buccal

Physicians should individualize treatment using a progressive plan of pain management. Healthcare professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring. (See BOXED WARNING and Dosing.)

It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.

Dosing

1. Initial Dose

For opioid-tolerant patients not being converted from Actiq®‡, the initial dose of fentanyl buccal tablets is always 100 mcg.

For patients being converted from Actiq®‡, prescribers must use the Initial Dosing Recommendations table below (Table 7). The doses of fentanyl buccal tablets in this table are starting doses and not intended to represent equianalgesic doses to Actiq®‡. Patients must be instructed to stop the use of Actiq®‡ and dispose of any remaining units.
Table 7. Initial Dosing Recommendations for Patients on Actiq®‡ Current Actiq®‡ Dose (mcg) Initial Fentanyl Buccal Tablets Dose (mcg) 200 100 mcg tablet 400 100 mcg tablet 600 200 mcg tablet 800 200 mcg tablet 1200 2 x 200 mcg tablets 1600 2 x 200 mcg tablets
For patients converting from Actiq®‡ doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg fentanyl buccal tablet and should proceed using multiples of this tablet strength.

In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of fentanyl buccal tablets for any episode of breakthrough pain.

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablets.

2. Titration

From an initial dose, patients should be closely followed by the prescriber and the dosage strength changed until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Patients should record their use of fentanyl buccal tablets over several episodes of breakthrough pain and discuss their experience with their physician to determine if a dosage adjustment is warranted.

Patients whose initial dose is 100 mcg and who need to titrate to a higher dose, can be instructed to use two 100 mcg tablets (one on each side of the mouth in the buccal cavity) with their next breakthrough pain episode. If this dosage is not successful, the patient may be instructed to place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate using multiples of the 200 mcg fentanyl buccal tablet for doses above 400 mcg (600 mcg and 800 mcg). Note: Do not use more than 4 tablets simultaneously.

In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose of the same strength for that episode. Thus patients should take a maximum of two doses of fentanyl buccal tablets for any breakthrough pain episode. During titration, one dose of fentanyl buccal tablets may include administration of 1 to 4 tablets of the same dosage strength (100 mcg or 200 mcg).

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablets. To reduce the risk of overdosing during titration, patients should have only one strength of fentanyl buccal tablets available at any one time.

Patients should be strongly encouraged to use all of their fentanyl buccal tablets of one strength prior to being prescribed the next strength. If this is not practical, unused fentanyl buccal tablets should be disposed of safely. (See DISPOSAL OF FENTANYL BUCCAL TABLETS.) Dispose of any unopened fentanyl buccal tablets remaining from a prescription as soon as they are no longer needed.

3. Maintenance Dosing

Once titrated to an effective dose, patients should generally use only ONE fentanyl buccal tablet of the appropriate strength per breakthrough pain episode.

On occasion when the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode.

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablets.

Dosage adjustment of fentanyl buccal tablets may be required in some patients in order to continue to provide adequate relief of breakthrough pain.

Generally, the fentanyl buccal tablets dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes.

If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (around-the-clock) opioid used for persistent pain should be reevaluated.

Patients with hepatic and/or renal impairment

Caution should be exercised for patients with hepatic and/or renal impairment, and the lowest possible dose should be used in these patients. (See PRECAUTIONS.)

Patients receiving CYP3A4 inhibitors

Particular caution should be exercised for patients receiving CYP3A4 inhibitors, and the lowest possible dose should be used in these patients. (See PRECAUTIONS.)

Patients with mucositis

No dose adjustment appears necessary in patients with Grade 1 mucositis. The safety and efficacy of fentanyl buccal tablets when used in patients with mucositis more severe than Grade 1 have not been studied.

Opening the Blister Package

Patients should be instructed not to open the blister until ready to administer fentanyl buccal tablets.

The pull tab should be lifted where indicated.

The tab should be pulled around the curve and the blister should be pressed against the other side to push the tablet through.

The tablet should not be stored once it has been removed from the blister package as the tablet integrity may be compromised, and more importantly, because this increases the risk of accidental exposure to the tablet.

Tablet Administration

Once the tablet is removed from the blister unit, the patient should immediately place the entire fentanyl buccal tablet in the buccal cavity (above a rear molar, between the upper cheek and gum). Patients should not split the tablet.

The fentanyl buccal tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed.

The fentanyl buccal tablet should be left between the cheek and gum until it has disintegrated, which usually takes approximately 14 to 25 minutes.

After 30 minutes, if remnants from the fentanyl buccal tablet remain, they may be swallowed with a glass of water.

It is recommended that patients alternate sides of the mouth when administering subsequent doses of fentanyl buccal tablets.

SAFETY AND HANDLING

Fentanyl buccal tablets are supplied in individually sealed, child-resistant blister packages. The amount of fentanyl contained in fentanyl buccal tablets can be fatal to a child. Patients and their caregivers must be instructed to keep fentanyl buccal tablets out of the reach of children. (See BOXED WARNING, WARNINGS, PRECAUTIONS, and MEDICATION GUIDE.)

Store at 20º to 25ºC (68º to 77ºF) until ready to use. [See USP Controlled Room Temperature].

Fentanyl buccal tablets should be protected from freezing and moisture. Do not use if the blister package has been tampered with.

DISPOSAL OF FENTANYL BUCCAL TABLETS

Patients and members of their household must be advised to dispose of any tablets remaining from a prescription as soon as they are no longer needed. Information is available in the Information for Patients and Caregivers and in the Medication Guide. If additional assistance is required, referral to the Watson toll-free telephone number (1-866-510-7780) should be made.

To dispose of unused fentanyl buccal tablets, remove fentanyl buccal tablets from blister packages and flush down the toilet. Do not flush fentanyl buccal tablet blister packages or cartons down the toilet. If you need additional assistance with disposal of fentanyl buccal tablets, call Watson Laboratories, Inc., at 1-866-510-7780.
Losartan Potassium And ...

Losartan Potassium And Hydrochlorothiazide

Hypertension

Dosing must be individualized. The usual starting dose of losartan is 50 mg once daily, with 25 mg recommended for patients with intravascular volume depletion (e.g., patients treated with diuretics) (see WARNINGS, Hypotension — Volume-Depleted Patients) and patients with a history of hepatic impairment (see WARNINGS, Impaired Hepatic Function). Losartan can be administered once or twice daily at total daily doses of 25 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.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily and can be given at doses of 12.5 to 25 mg as Losartan Potassium and Hydrochlorothiazide tablets USP.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

The side effects (see WARNINGS) of losartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of losartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

Replacement Therapy: The combination may be substituted for the titrated components.

Dose Titration by Clinical Effect: A patient whose blood pressure is not adequately controlled with losartan monotherapy (see above) or hydrochlorothiazide alone, may be switched to Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 once daily or one tablet of Losartan Potassium and Hydrochlorothiazide tablets USP 100-25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily. A patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy (see above) may be switched to Losartan Potassium and Hydrochlorothiazide tablets USP 100-12.5 once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 once daily or one tablet of Losartan Potassium and Hydrochlorothiazide tablets USP 100-25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily.

A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen, may be switched to Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. The clinical response to Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 should be subsequently evaluated, and if blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 once daily or one tablet of Losartan Potassium and Hydrochlorothiazide tablets USP 100-25 (losartan 100 mg/hydrochlorothiazide 25 mg) once daily.

The usual dose of Losartan Potassium and Hydrochlorothiazide tablets USP is one tablet of Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 once daily. More than two tablets of Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 once daily or more than one tablet of Losartan Potassium and Hydrochlorothiazide tablets USP 100-25 once daily is not recommended. The maximal antihypertensive effect is attained about 3 weeks after initiation of therapy.

Use in Patients with Renal Impairment: The usual regimens of therapy with Losartan Potassium and Hydrochlorothiazide tablets USP may be followed as long as the patient's creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Losartan Potassium and Hydrochlorothiazide tablets USP are not recommended.

Patients with Hepatic Impairment: Losartan Potassium and Hydrochlorothiazide tablets USP are not recommended for titration in patients with hepatic impairment (see WARNINGS, Impaired Hepatic Function) because the appropriate 25 mg starting dose of losartan cannot be given.

Severe Hypertension

The starting dose of Losartan Potassium and Hydrochlorothiazide tablets USP for initial treatment of severe hypertension is one tablet of Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 once daily (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects). For patients who do not respond adequately to Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 after 2 to 4 weeks of therapy, the dosage may be increased to one tablet of Losartan Potassium and Hydrochlorothiazide tablets USP 100-25 once daily. The maximum dose is one tablet of Losartan Potassium and Hydrochlorothiazide tablets USP 100-25 once daily. Losartan Potassium and Hydrochlorothiazide tablets USP are not recommended as initial therapy in patients with hepatic impairment (see WARNINGS, Impaired Hepatic Function) because the appropriate 25 mg starting dose of losartan cannot be given. It is also not recommended for use as initial therapy in patients with intravascular volume depletion (e.g., patients treated with diuretics, see WARNINGS, Hypotension — Volume-Depleted Patients).

Hypertensive Patients with Left Ventricular Hypertrophy

Treatment should be initiated with Losartan Potassium tablets 50 mg once daily. Hydrochlorothiazide 12.5 mg should be added or Losartan Potassium and Hydrochlorothiazide tablets USP 50-12.5 substituted if the blood pressure reduction is inadequate. If additional blood pressure reduction is needed, Losartan Potassium tablets 100 mg and hydrochlorothiazide 12.5 mg or Losartan Potassium and Hydrochlorothiazide tablets USP 100-12.5 may be substituted, followed by Losartan Potassium tablets 100 mg and hydrochlorothiazide 25 mg or Losartan Potassium and Hydrochlorothiazide tablets USP 100-25. For further blood pressure reduction other antihypertensives should be added (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Losartan Potassium, Reduction in the Risk of Stroke).

Losartan Potassium and Hydrochlorothiazide tablets USP may be administered with other antihypertensive agents.

Losartan Potassium and Hydrochlorothiazide tablets USP may be administered with or without food.
Loxapine

Loxapine

Loxapine Capsules USP are administered, usually in divided doses, two to four times a day. Daily dosage (in terms of base equivalents) should be adjusted to the individual patient’s needs as assessed by the severity of symptoms and previous history of response to antipsychotic drugs.

Oral Administration

Initial dosage of 10 mg twice daily is recommended, although in severely disturbed patients initial dosage up to a total of 50 mg daily may be desirable. Dosage should then be increased fairly rapidly over the first seven to ten days until there is effective control of symptoms of schizophrenia. The usual therapeutic and maintenance range is 60 mg to 100 mg daily. However, as with other drugs used to treat schizophrenia, some patients respond to lower dosage and others require higher dosage for optimal benefit. Daily dosage higher than 250 mg is not recommended.

Maintenance Therapy

For maintenance therapy, dosage should be reduced to the lowest level compatible with symptom control; many patients have been maintained satisfactorily at dosages in the range of 20 to 60 mg daily.
Promethazine Hydrochlor...

Promethazine Hydrochloride

Promethazine Hydrochloride Tablets USP are contraindicated for children under 2 years of age (see WARNINGS-Black Box Warning and Use in Pediatric Patients).

Allergy

The average oral dose is 25 mg taken before retiring; however, 12.5 mg may be taken before meals and on retiring, if necessary. Single 25-mg doses at bedtime or 6.25 to 12.5 mg taken three times daily will usually suffice. After initiation of treatment in children or adults, dosage should be adjusted to the smallest amount adequate to relieve symptoms. The administration of promethazine HCl in 25-mg doses will control minor transfusion reactions of an allergic nature.

Motion Sickness

The average adult dose is 25 mg taken twice daily. The initial dose should be taken one-half to one hour before anticipated travel and be repeated 8 to 12 hours later, if necessary. On succeeding days of travel, it is recommended that 25 mg be given on arising and again before the evening meal. For children, promethazine hydrochloride tablets, syrup, or rectal suppositories, 12.5 to 25 mg twice daily, may be administered.

Nausea and Vomiting

Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see WARNINGS-Use in Pediatric Patients).

The average effective dose of promethazine hydrochloride for the active therapy of nausea and vomiting in children or adults is 25 mg. When oral medication cannot be tolerated, the dose should be given parenterally (cf. Promethazine Injection) or by rectal suppository. 12.5- to 25-mg doses may be repeated, as necessary, at 4- to 6-hour intervals.

For nausea and vomiting in children, the usual dose is 0.5 mg per pound of body weight, and the dose should be adjusted to the age and weight of the patient and the severity of the condition being treated.

For prophylaxis of nausea and vomiting, as during surgery and the postoperative period, the average dose is 25 mg repeated at 4- to 6-hour intervals, as necessary.

Sedation

This product relieves apprehension and induces a quiet sleep from which the patient can be easily aroused. Administration of 12.5 to 25 mg promethazine hydrochloride by the oral route or by rectal suppository at bedtime will provide sedation in children. Adults usually require 25 to 50 mg for nighttime, presurgical, or obstetrical sedation.

Pre- and Postoperative Use

Promethazine hydrochloride in 12.5- to 25-mg doses for children and 50-mg doses for adults the night before surgery relieves apprehension and produces a quiet sleep.

For preoperative medication, children require doses of 0.5 mg per pound of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug. Usual adult dosage is 50 mg promethazine HCl with an appropriately reduced dose of narcotic or barbiturate and the required amount of a belladonna alkaloid.

Postoperative sedation and adjunctive use with analgesics may be obtained by the administration of 12.5 to 25 mg in children and 25- to 50-mg doses in adults.

Promethazine hydrochloride tablets are contraindicated for children under 2 years of age.
Sucralfate

Sucralfate

Active Duodenal Ulcer. The recommended adult oral dosage for duodenal ulcer is 1 g four times a day on an empty stomach.

Antacids may be prescribed as needed for relief of pain but should not be taken within one-half hour before or after sucralfate.

While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination.

Maintenance Therapy. The recommended adult oral dosage is 1 g twice a day.
Primidone

Primidone

Adult Dosage

Patients 8 years of age and older who have received no previous treatment may be started on primidone according to the following regimen using either 50 mg or scored 250 mg primidone tablets.

Days 1 to 3: 100 to 125 mg at bedtime.Days 4 to 6: 100 to 125 mg b.i.d.Days 7 to 9: 100 to 125 mg t.i.d.Day 10 to maintenance: 250 mg t.i.d.

For most adults and children 8 years of age and over, the usual maintenance dosage is three to four 250 mg primidone tablets daily in divided doses (250 mg t.i.d. or q.i.d.). If required, an increase to five or six 250 mg tablets daily may be made but daily doses should not exceed 500 mg q.i.d.
INITIAL: ADULTS AND CHILDREN OVER 8 KEY: . = 50 mg tablet • = 250 mg tablet DAY 1 2 3 4 5 6 AM . . . . . . NOON PM . . . . . . . . . . . . DAY 7 8 9 10 11 12 AM . . . . . . • NOON . . . . . . • Adjust to Maintenance PM . . . . . . •
Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations of primidone may be necessary for optimal dosage adjustment. The clinically effective serum level for primidone is between 5 to 12 µg/mL.

In Patients Already Receiving Other Anticonvulsants

Primidone should be started at 100 to 125 mg at bedtime and gradually increased to maintenance level as the other drug is gradually decreased. This regimen should be continued until satisfactory dosage level is achieved for the combination, or the other medication is completely withdrawn. When therapy with primidone alone is the objective, the transition from concomitant therapy should not be completed in less than two weeks.

Pediatric Dosage

For children under 8 years of age, the following regimen may be used:

Days 1 to 3: 50 mg at bedtime.Days 4 to 6: 50 mg b.i.d.Days 7 to 9: 100 mg b.i.d.Day 10 to maintenance: 125 mg t.i.d. to 250 mg t.i.d.

For children under 8 years of age, the usual maintenance dosage is 125 to 250 mg three times daily or, 10 to 25 mg/kg/day in divided doses.
Trihexyphenidyl Hydroch...

Trihexyphenidyl Hydrochloride

Dosage should be individualized. The initial dose should be low and then increased gradually, especially in patients over 60 years of age. Whether trihexyphenidyl HCl may best be given before or after meals should be determined by the way the patient reacts. Postencephalitic patients, who are usually more prone to excessive salivation, may prefer to take it after meals and may, in addition, require small amounts of atropine which, under such circumstances, is sometimes an effective adjuvant. If trihexyphenidyl HCl tends to dry the mouth excessively, it may be better to take it before meals, unless it causes nausea. If taken after meals, the thirst sometimes induced can be allayed by mint candies, chewing gum or water.

Trihexyphenidyl HCl in Idiopathic Parkinsonism

As initial therapy for parkinsonism, 1 mg may be administered the first day. The dose may then be increased by 2 mg increments at intervals of three to five days, until a total of 6 to 10 mg is given daily. The total daily dose will depend upon what is found to be the optimal level. Many patients derive maximum benefit from this daily total of 6 to 10 mg, but some patients, chiefly those in the postencephalitic group, may require a total daily dose of 12 to 15 mg.

Trihexyphenidyl HCl in Drug-Induced Parkinsonism

The size and frequency of dose of trihexyphenidyl HCl needed to control extrapyramidal reactions to commonly employed tranquilizers, notably the phenothiazines, thioxanthenes, and butyrophenones, must be determined empirically. The total daily dosage usually ranges between 5 and 15 mg, although, in some cases, these reactions have been satisfactorily controlled on as little as 1 mg daily. It may be advisable to commence therapy with a single 1 mg dose. If the extrapyramidal manifestations are not controlled in a few hours, the subsequent doses may be progressively increased until satisfactory control is achieved. Satisfactory control may sometimes be more rapidly achieved by temporarily reducing the dosage of the tranquilizer on instituting trihexyphenidyl HCl therapy and then adjusting dosage of both drugs until the desired ataractic effect is retained without onset of extrapyramidal reactions.

It is sometimes possible to maintain the patient on a reduced trihexyphenidyl HCl dosage after the reactions have remained under control for several days. Instances have been reported in which these reactions have remained in remission for long periods after trihexyphenidyl HCl therapy was discontinued.

Concomitant Use of Trihexyphenidyl HCl with Levodopa

When trihexyphenidyl HCl is used concomitantly with levodopa, the usual dose of each may need to be reduced. Careful adjustment is necessary, depending on side effects and degree of symptom control. Trihexyphenidyl HCl dosage of 3 to 6 mg daily, in divided doses, is usually adequate.

Concomitant Use of Trihexyphenidyl HCl with Other Parasympathetic Inhibitors

Trihexyphenidyl HCl may be substituted, in whole or in part, for other parasympathetic inhibitors. The usual technique is partial substitution initially, with progressive reduction in the other medication as the dose of trihexyphenidyl HCl is increased.

Trihexyphenidyl Hydrochloride Tablets - The total daily intake of trihexyphenidyl HCl tablets is tolerated best if divided into 3 doses and taken at mealtimes. High doses (> 10 mg daily) may be divided into 4 parts, with 3 doses administered at meal times and the fourth at bedtime.
Testosterone Enanthate

Testosterone Enanthate

Dosage and duration of therapy with Testosterone Enanthate Injection will depend on age, sex, diagnosis, patient’s response to treatment, and appearance of adverse effects. When properly given, injections of testosterone enanthate are well tolerated. Care should be taken to inject the preparation deeply into the gluteal muscle following the usual precautions for intramuscular administration. In general, total doses above 400 mg per month are not required because of the prolonged action of the preparation. Injections more frequently than every two weeks are rarely indicated.

Male Hypogonadism:

As replacement therapy, i.e., for eunuchism, the suggested dosage is 50 to 400 mg every 2 to 4 weeks.

In Males With Delayed Puberty:

Various dosage regiments have been used; some call for lower dosages initially with gradual increases as puberty progresses, with or without a decrease to maintenance levels. Other regimens call for higher dosage to induce pubertal changes and lower dosage for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose. Dosage is within the range of 50 to 200 mg every 2 to 4 weeks for a limited duration, for example, 4 to 6 months. X-rays should be taken at appropriate intervals to determine the amount of bone maturation and skeletal development (See INDICATIONS AND USAGE, and WARNINGS).

Palliation of Inoperable Mammary Cancer in Women:

A dosage of 200 to 400 mg every 2 to 4 weeks is recommended. Women with metastatic breast carcinoma must be followed closely because androgen therapy occasionally appears to accelerate the disease.

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

Nabumetone

Carefully consider the potential benefits and risks of nabumetone tablets and other treatment options before deciding to use nabumetone 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 nabumetone tablets, the dose and frequency should be adjusted to suit an individual patient's needs.

Osteoarthritis and Rheumatoid Arthritis

The recommended starting dose is 1,000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day. Nabumetone tablets can be given in either a single or twice-daily dose. Dosages greater than 2,000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment (see WARNINGS, Renal Effects). Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.
Alendronate Sodium

Alendronate Sodium

Alendronate sodium tablets must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (see PRECAUTIONS, Information for Patients). Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate sodium tablets (see PRECAUTIONS, Drug Interactions). Waiting less than 30 minutes, or taking alendronate sodium tablets with food, beverages (other than plain water) or other medications will lessen the effect of alendronate sodium tablets by decreasing its absorption into the body.

Alendronate sodium tablets should only be taken upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, an alendronate sodium tablet should be swallowed with a full glass of water (6 to 8 oz). Patients should not lie down for at least 30 minutes and until after their first food of the day. Alendronate sodium tablets should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse experiences (see WARNINGS, PRECAUTIONS, Information for Patients).

Patients should receive supplemental calcium and vitamin D, if dietary intake is inadequate (see PRECAUTIONS, General).

No dosage adjustment is necessary for the elderly or for patients with mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). Alendronate sodium tablets are not recommended for patients with more severe renal insufficiency (creatinine clearance <35 mL/min) due to lack of experience.

Treatment of osteoporosis in postmenopausal women (see INDICATIONS AND USAGE)

The recommended dosage is:
one 70 mg tablet once weekly
or
one 10 mg tablet once daily
Treatment to increase bone mass in men with osteoporosis

The recommended dosage is:
one 70 mg tablet once weekly
or
one 10 mg tablet once daily
Prevention of osteoporosis in postmenopausal women (see INDICATIONS AND USAGE)

The recommended dosage is:
one 35 mg tablet once weekly
or
one 5 mg tablet once daily
The safety of treatment and prevention of osteoporosis with alendronate sodium has been studied for up to 7 years.

Treatment of glucocorticoid-induced osteoporosis in men and women:

The recommended dosage is one 5 mg tablet once daily, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is one 10 mg tablet once daily.

Paget's disease of bone in men and women

The recommended treatment regimen is 40 mg once a day for six months.

Retreatment of Paget's disease:

In clinical studies in which patients were followed every six months, relapses during the 12 months following therapy occurred in 9% (3 out of 32) of patients who responded to treatment with alendronate sodium tablets. Specific retreatment data are not available, although responses to alendronate sodium tablets were similar in patients who had received prior bisphosphonate therapy and those who had not. Retreatment with alendronate sodium tablets may be considered, following a six-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be measured periodically. Retreatment may also be considered in those who failed to normalize their serum alkaline phosphatase.
Gemcitabine Hydrochlori...

Gemcitabine Hydrochloride

      Gemcitabine for injection is for intravenous use only. Gemcitabine for injection may be administered on an outpatient basis.

2.1       Ovarian Cancer

      Gemcitabine for injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after gemcitabine for injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.

Dose Modifications

      Gemcitabine for injection dosage adjustment for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine for injection dosage should be modified according to guidelines in Table 1.
Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Carboplatin Absolute granulocyte count Platelet count % of full dose (x 106/L) (x 106/L) ≥1500 And ≥100,000 100 1000 to 1499 and/or 75,000 to 99,999 50 <1000 and/or <75,000 Hold
      In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with gemcitabine for injection should be held or decreased by 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see manufacturer’s prescribing information.

      Dose adjustment for gemcitabine for injection in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of gemcitabine for injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities:
Absolute granulocyte count <500 x 106/L for more than 5 days Absolute granulocyte count <100 x 106/L for more than 3 days Febrile neutropenia Platelets <25,000 x 106/L Cycle delay of more than one week due to toxicity
      If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, gemcitabine for injection should be given on Day 1 only at 800 mg/m2.

2.2       Breast Cancer

      Gemcitabine for injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before gemcitabine for injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.

Dose Modifications

      Gemcitabine for injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine for injection dosage should be modified according to the guidelines in Table 2.
Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Paclitaxel Absolute granulocyte count Platelet count % of full dose (x 106/L) (x 106/L) ≥1200 And >75,000 100 1000 to 1199 Or 50,000 to 75,000 75 700 to 999 And ≥50,000 50 <700 Or <50,000 Hold
      In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine for injection should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer’s prescribing information.

2.3       Non-Small Cell Lung Cancer

      Two schedules have been investigated and the optimum schedule has not been determined [see Clinical Studies (14.3)]. With the 4-week schedule, gemcitabine for injection should be administered intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine for injection. With the 3-week schedule, gemcitabine for injection should be administered intravenously at 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m2 should be administered intravenously after the infusion of gemcitabine for injection on Day 1. See prescribing information for cisplatin administration and hydration guidelines.

Dose Modifications

      Dosage adjustments for hematologic toxicity may be required for gemcitabine for injection and for cisplatin. Gemcitabine for injection dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving gemcitabine for injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer’s prescribing information.

      In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine for injection plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for gemcitabine for injection plus cisplatin was 5% versus 2% for cisplatin alone).

2.4       Pancreatic Cancer

      Gemcitabine for injection should be administered by intravenous infusion at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.

Dose Modifications

      Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

      Patients receiving gemcitabine for injection should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.
Table 3: Dosage Reduction Guidelines Absolute granulocyte count Platelet count % of full dose (x 106/L) (x 106/L) ≥1000 And ≥100,000 100 500 to 999 Or 50,000 to 99,999 75 <500 Or <50,000 Hold
      Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemcitabine for injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.

      Patients treated with gemcitabine for injection who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of gemcitabine for injection at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.

2.5       Preparation and Administration Precautions

      Caution should be exercised in handling and preparing gemcitabine for injection solutions. The use of gloves is recommended. If gemcitabine for injection solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug-related systemic toxicities (death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption.

      Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published [see References (15)].

2.6       Preparation for Intravenous Infusion Administration

      The recommended diluent for reconstitution of gemcitabine for injection is 0.9% Sodium Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration for gemcitabine for injection upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided.

      To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200-mg vial or 25 mL of 0.9% Sodium Chloride Injection to the 1-g vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200-mg vial or 1.3 mL for the 1-g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine, respectively. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.

      Reconstituted gemcitabine for injection is a clear, colorless to light straw-colored solution. After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3. The solution should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. If particulate matter or discoloration is found, do not administer.

      When prepared as directed, gemcitabine for injection solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Discard unused portion. Solutions of reconstituted gemcitabine for injection should not be refrigerated, as crystallization may occur.

      The compatibility of gemcitabine for injection with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Tetracycline Hydrochlor...

Tetracycline Hydrochloride

Adults:

Usual daily dose, 1 gram as 500 mg b.i.d. or 250 mg q.i.d. Higher doses such as 500 mg q.i.d. may be required for severe infections or for those infections which do not respond to the smaller doses.

Children above eight years of age:

Usual daily dose, 10 to 20 mg/lb (25 to 50 mg/kg) body weight divided in four equal doses.

Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.

For the treatment of brucellosis, 500 mg tetracycline q.i.d. for three weeks should be accompanied by streptomycin, 1 gram intramuscularly twice daily the first week and once daily the second week.

For the treatment of syphilis in patients allergic to penicillin, the following dosage of tetracycline is recommended: early syphilis (less than one year’s duration) —500 mg q.i.d. for 15 days. Syphilis of more than one year’s duration (except neurosyphilis)—500 q.i.d. for 30 days.

For treatment of gonorrhea, the recommended dose is 500 mg by mouth four times a day for seven days.

In cases of moderate to severe acne which, in the judgement of the clinician, require long-term treatment, the recommended initial dosage is 1 gram daily in divided doses. When improvement is noted, dosage should be gradually reduced to maintenance levels ranging from 125 mg to 500 mg daily. In some patients it may be possible to maintain adequate remission of lesions with alternate day or intermittent therapy. Tetracycline therapy of acne should augment the other standard measures known to be of value. Duration of long-term treatment which can safely be recommended has not been established (see WARNINGS and Carcinogenesis, Mutagenesis, Impairment of Fertility).

Concomitant Therapy:

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium and preparations containing iron, zinc or sodium bicarbonate.

Food and some dairy products also interfere with absorption.

In the treatment of streptococcal infections, a therapeutic dose of tetracycline should be administered for at least ten days.

In patients with renal impairment (see WARNINGS) total dosage should be decreased by reduction of recommended individual doses and/or by extending time intervals between doses.

Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydiatrachomatis: 500 mg, by mouth, four times a day for at least seven days.

Administration of adequate amounts of fluid with the capsule formulation of tetracycline is recommended to wash down the drug and reduce the risk of esophageal irritation and ulceration (see ADVERSE REACTIONS).
Tamoxifen Citrate

Tamoxifen Citrate

For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening).

In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit (see CLINICAL PHARMACOLOGY). In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant tamoxifen therapy for patients with breast cancer.

Ductal Carcinoma in Situ (DCIS):

The recommended dose is tamoxifen citrate tablets 20 mg daily for 5 years.

Reduction in Breast Cancer Incidence in High Risk Women:

The recommended dose is tamoxifen citrate tablets 20 mg daily for 5 years. There are no data to support the use of tamoxifen other than for 5 years (See CLINICAL PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer Incidence in High Risk Women).
Hydroxocobalamin

Hydroxocobalamin

Protect from light.

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

Hydroxocobalamin injection should be given only intramuscularly.

In patients with Addisonian Pernicious Anemia, parenteral therapy with vitamin B12 is the recommended method of treatment and will be required for the remainder of the patient’s life. Oral therapy is not dependable. In other patients with vitamin B12 deficiency, the duration of therapy and route of administration will depend upon the cause and whether or not it is reversible.

Confirmatory diagnostic studies should be performed prior to initiating therapy, if possible, and the patient should be followed with appropriate studies to demonstrate hematologic improvement (Hgb, hematocrit, RBC, reticulocyte count). A diagnostic trial utilizing physiologic doses of vitamin B12 (1 mcg daily) and observing daily reticulocyte counts after establishing a baseline may also be performed. The observation of reticulocytosis which usually occurs between the third and tenth day of therapy confirms the diagnosis of vitamin B12 deficiency.

In seriously ill patients it may be advisable to administer both vitamin B12 and folic acid while awaiting the results of distinguishing laboratory studies. It is not necessary to withhold vitamin B12 therapy until the precise cause of B12 deficiency is established since absorption studies can be performed at any time.

Serum potassium should be closely observed the first 48 hours and potassium should be administered if necessary.

Treatment of Vitamin B12 Deficiency

Thirty mcg daily for 5 to 10 days followed by 100 to 200 mcg monthly injected intramuscularly. If the patient is critically ill, or has neurologic disease, an infectious disease or hyperthyroidism, considerably higher doses may be indicated. However, current data indicate that the optimum obtainable neurologic response may be expected with a dosage of vitamin B12 sufficient to produce good hematologic response. Children may be given a total of 1 to 5 mg over a period of 2 or more weeks in doses of 100 mcg, then 30 to 50 mcg every 4 weeks for maintenance.

Patients who have normal intestinal absorption may be treated with an oral therapeutic multivitamin preparation, containing 15 mcg vitamin B12 daily.

Schilling Test

The flushing dose is 1000 mcg.
Probenecid

Probenecid

Gout

Therapy with probenecid should not be started until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, probenecid may be continued without changing the dosage, and full therapeutic dosage of colchicine or other appropriate therapy should be given to control the acute attack.

The recommended adult dosage is 250 mg (1/2 tablet of probenecid) twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter.

Some degree of renal impairment may be present in patients with gout. A daily dosage of 1000 mg may be adequate. However, if necessary, the daily dosage may be increased by 500 mg increments every 4 weeks within tolerance (and usually not above 2000 mg per day) if symptoms of gouty arthritis are not controlled or the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid may not be effective in chronic renal insufficiency, particularly when the glomerular filtration rate is 30 mL/minute or less.

Gastric intolerance may be indicative of overdosage, and may be corrected by decreasing the dosage.

As uric acid tends to crystallize out of an acid urine, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily), or potassium citrate (7.5 g daily) to maintain an alkaline urine (see PRECAUTIONS).

Alkalization of the urine is recommended until the serum urate level returns to normal limits and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at a high level. Thereafter, alkalization of the urine and the usual restriction of purine-producing foods may be somewhat relaxed.

Probenecid should be continued at the dosage that will maintain normal serum urate levels. When acute attacks have been absent for 6 months or more and serum urate levels remain within normal limits, the daily dosage may be decreased by 500 mg every 6 months. The maintenance dosage should not be reduced to the point where serum urate levels tend to rise.

Probenecid and Penicillin Therapy (General)

Adults

The recommended dosage is 2000 mg (4 tablets of probenecid) daily in divided doses. This dosage should be reduced in older patients in whom renal impairment may be present.

Children 2-14 years of age

Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface).

Maintenance dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses.

For children weighing more than 50 kg (110 lb) the adult dosage is recommended.

Probenecid is contraindicated in children under 2 years of age.

The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about one-fifth the normal rate when dosage of probenecid is adequate.

Penicillin Therapy (Gonorrhea)*

In uncomplicated gonococcal infections in men and women (urethral, cervical, rectal), 1 g of probenecid should be given orally with 4.8 million units of aqueous procaine penicillin G** (given IM), or 3 g of amoxicillin** (given orally), or 3.5 g of ampicillin** (given orally).

For further guidance, see CDC recommendations for definition of regimens of choice, alternative regimens, treatment of hypersensitive patients, and other aspects of therapy.

*Recommended by the Centers for Disease Control, U.S. Department of Health and Human Services, Public Health Service (Morbidity and Mortality Weekly Report Supplement, Volume 34, Number 4S, October 18, 1985).

**See package circulars of manufacturers for detailed information about CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS.
Nizatidine

Nizatidine

Active Duodenal Ulcer – The recommended oral dosage for adults is 300 mg once daily at bedtime. An alternative dosage regimen is 150 mg twice daily.

Maintenance of Healed Duodenal Ulcer – The recommended oral dosage for adults is 150 mg once daily at bedtime.

Gastroesophageal Reflux Disease – The recommended oral dosage in adults for the treatment of erosions, ulcerations, and associated heartburn is 150 mg twice daily.

Active Benign Gastric Ulcer – The recommended oral dosage is 300 mg given either as 150 mg twice daily or 300 mg once daily at bedtime. Prior to treatment, care should be taken to exclude the possibility of malignant gastric ulceration.

Dosage Adjustment for Patients With Moderate to Severe Renal Insufficiency – The dose for patients with renal dysfunction should be reduced as follows:
Active Duodenal Ulcer, GERD and Benign Gastric Ulcer Ccr Dose 20-50 mL/min 150 mg daily <20 mL/min 150 mg every other day Maintenance Therapy Ccr Dose 20-50 mL/min 150 mg every other day <20 mL/min 150 mg every 3 days
Some elderly patients may have creatinine clearances of less than 50 mL/min, and based on pharmacokinetic data in patients with renal impairment, the dose for such patients should be reduced accordingly. The clinical effects of this dosage reduction in patients with renal failure have not been evaluated.
Flutamide

Flutamide

The recommended dosage is 2 capsules 3 times a day at 8-hour intervals for a total daily dose of 750 mg.
Labetalol Hydrochloride...

Labetalol Hydrochloride

DOSAGE MUST BE INDIVIDUALIZED. The recommended initial dose is 100 mg twice daily whether used alone or added to a diuretic regimen. After 2 or 3 days, using standing blood pressure as an indicator, dosage may be titrated in increments of 100 mg b.i.d. every 2 or 3 days. The usual maintenance dosage of labetalol HCl is between 200 and 400 mg twice daily.

Since the full antihypertensive effect of labetalol HCl is usually seen within the first 1 to 3 hours of the initial dose or dose increment, the assurance of a lack of an exaggerated hypotensive response can be clinically established in the office setting. The antihypertensive effects of continued dosing can be measured at subsequent visits, approximately 12 hours after a dose, to determine whether further titration is necessary.

Patients with severe hypertension may require from 1200 to 2400 mg per day, with or without thiazide diuretics. Should side effects (principally nausea or dizziness) occur with these doses administered twice daily, the same total daily dose administered three times daily may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg twice daily.

When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol HCl dosage adjustment. As with most antihypertensive drugs, optimal dosages of labetalol HCl tablets are usually lower in patients also receiving a diuretic.

When transferring patients from other antihypertensive drugs, labetalol HCl tablets should be introduced as recommended and the dosage of the existing therapy progressively decreased.

Elderly Patients: As in the general patient population, labetalol therapy may be initiated at 100 mg twice daily and titrated upwards in increments of 100 mg b.i.d. as required for control of blood pressure. Since some elderly patients eliminate labetalol more slowly, however, adequate control of blood pressure may be achieved at a lower maintenance dosage compared to the general population. The majority of elderly patients will require between 100 and 200 mg b.i.d.
Oxycodone And Aspirin

Oxycodone And Aspirin

Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. Oxycodone and aspirin tablets are given orally.

The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams or 12 tablets.

Cessation of Therapy

In patients treated with oxycodone and aspirin tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.
Nateglinide

Nateglinide

Nateglinide tablets should be taken 1 to 30 minutes prior to meals.

Monotherapy and Combination with Metformin or a Thiazolidinedione

The recommended starting and maintenance dose of nateglinide tablets, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.

The 60-mg dose of nateglinide tablets, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA1C when treatment is initiated.

Dosage in Geriatric Patients

No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to nateglinide tablet therapy cannot be ruled out.

Dosage in Renal and Hepatic Impairment

No dosage adjustment is necessary in patients with mild-to-severe renal insufficiency or in patients with mild hepatic insufficiency. Dosing of patients with moderate-to-severe hepatic dysfunction has not been studied. Therefore, nateglinide tablets should be used with caution in patients with moderate-to-severe liver disease (see PRECAUTIONS, Hepatic Impairment).
Trimethoprim

Trimethoprim

The usual oral adult dosage is 100 mg of trimethoprim every 12 hours or 200 mg trimethoprim (two 100 mg tablets) every 24 hours, each for 10 days. The use of trimethoprim in patients with a creatinine clearance of less than 15 mL/min is not recommended.

For patients with a creatinine clearance of 15 to 30 mL/min, the dose should be 50 mg every 12 hours.
Morphine Sulfate

Morphine Sulfate

Morphine sulfate extended-release capsules may be administered once or twice daily.

Morphine sulfate extended-release capsules should be swallowed whole. The pellets in morphine sulfate extended-release capsules should not be chewed, crushed, or dissolved due to the risk of rapid release and absorption of a potentially fatal dose of morphine.

Alternatively, morphine sulfate extended-release capsules may be administered as a sprinkle on apple sauce or through a 16 French gastrostomy tube (see ALTERNATIVE METHODS OF ADMINISTRATION section).

The 100 mg capsules are for use only in opioid-tolerant patients.

Morphine sulfate extended-release capsules are not indicated for pre-emptive analgesia (administration pre-operatively for the management of post-operative pain), or for pain in the immediate post-operative period (the first 12 to 24 hours following surgery) for patients not previously taking the drug, because its safety in these settings have not been established.

Morphine sulfate extended-release capsules are only indicated for post-operative use if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

Patients who are already receiving morphine sulfate extended-release capsules as part of ongoing analgesic therapy may be safely continued on the drug if appropriate dosage adjustments are made considering the procedure, other drugs given, and the temporary changes in physiology caused by the surgical intervention.

Initiating Therapy with Morphine sulfate extended-release Capsules

Physicians should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the American Pain Society and the Federation of State Medical Boards Model Guidelines. Health care professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring.

It is critical to adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. In the selection of the initial dose of morphine sulfate extended-release capsules, USP, attention should be given to:
the total daily dose, potency and kind of opioid the patient has been taking previously; the reliability of the relative potency estimate used to calculate the equivalent dose of morphine needed (Note: potency estimates may vary with the route of administration); the patient's degree of opioid experience and opioid tolerance; the general condition and medical status of the patient; concurrent medication; the type and severity of the patient's pain.
Care should be taken to use low initial doses of morphine sulfate extended-release capsules in patients who are not already opioid-tolerant, especially those who are receiving concurrent treatment with muscle relaxants, sedatives, or other CNS active medications (see PRECAUTIONS).

During periods of changing analgesic requirements including initial titration, frequent communication is recommended between physician, other members of the healthcare team, the patient, and the caregiver/family.

The following dosing recommendations, therefore, can only be considered suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of an individual patient.

Conversion from Other Oral Morphine Formulations to Morphine sulfate extended-release capsules

Patients on other oral morphine formulations may be converted to morphine sulfate extended-release capsules by administering one-half of the patient's total daily oral morphine dose as morphine sulfate extended-release capsules every 12 hours (twice-a-day) or by administering the total daily oral morphine dose as morphine sulfate extended-release capsules every 24 hours (once-a-day). Morphine sulfate extended-release capsules should not be given more frequently than every 12 hours.

Conversion from Parenteral Morphine or Other Parenteral or Oral Opioids to Morphine sulfate extended-release capsules

Morphine sulfate extended-release capsules can be administered to patients previously receiving treatment with parenteral morphine or other opioids. While there are useful tables of oral and parenteral equivalents in cancer analgesia, there is substantial interpatient variation in the relative potency of different opioid drugs and formulations. For these reasons, it is better to underestimate the patient's 24-hour oral morphine requirement and provide rescue medication, than to overestimate and manage an adverse event. The following general points should be considered:
Parenteral to Oral Morphine Ratio: It may take anywhere from 2 to 6 mg of oral morphine to provide analgesia equivalent to 1 mg of parenteral morphine. A dose of oral morphine three times the daily parenteral morphine requirement may be sufficient in chronic use settings. Other Parenteral or Oral Opioids to Oral Morphine Sulfate: There is lack of systematic evidence bearing on these types of analgesic substitutions. Therefore, specific recommendations are not possible. Physicians are advised to refer to published relative potency data, keeping in mind that such ratios are only approximate. In general, it is safest to give half of the estimated daily morphine demand as the initial dose, and to manage inadequate analgesia by supplementation with immediate-release morphine. (See discussion which follows.)
The first dose of morphine sulfate extended-release capsules may be taken with the last dose of any immediate-release (short-acting) opioid medication due to the long delay until the peak effect after administration of morphine sulfate extended-release capsules.

Use of morphine sulfate extended-release capsules as the First Opioid Analgesic

There has been no evaluation of morphine sulfate extended-release capsules as an initial opioid analgesic in the management of pain. Because it may be more difficult to titrate a patient to adequate analgesia using an extended-release morphine, it is ordinarily advisable to begin treatment using an immediate-release morphine formulation.

Individualization of Dosage

The best use of opioid analgesics in the management of chronic malignant and non-malignant pain is challenging, and is well described in materials published by the World Health Organization and the Agency for Health Care Policy and Research which are available from Alpharma Pharmaceuticals LLC upon request. Morphine sulfate extended-release capsules, USP are a third step drug which is most useful when the patient requires a constant level of opioid analgesia as a "floor" or "platform" from which to manage breakthrough pain. When a patient has reached the point where comfort cannot be provided with a combination of non-opioid medications (NSAIDs and acetaminophen) and intermittent use of moderate or strong opioids, the patient's total opioid therapy should be converted into a 24 hour oral morphine equivalent.

Morphine sulfate extended-release capsules should be started by administering one-half of the estimated total daily oral morphine dose every 12 hours (twice-a-day) or by administering the total daily oral morphine dose every 24 hours (once-a-day). The dose should be titrated no more frequently than every-other-day to allow the patients to stabilize before escalating the dose. If breakthrough pain occurs, the dose may be supplemented with a small dose (less than 20% of the total daily dose) of a short-acting analgesic. Patients who are excessively sedated after a once-a-day dose or who regularly experience inadequate analgesia before the next dose should be switched to twice-a-day dosing.

Patients who do not have a proven tolerance to opioids should be started only on the 10 mg or 20 mg strength, and usually should be increased at a rate not greater than 20 mg every-other-day. Most patients will rapidly develop some degree of tolerance, requiring dosage adjustment until they have achieved their individual best balance between baseline analgesia and opioid side effects such as confusion, sedation and constipation. No guidance can be given as to the recommended maximal dose, especially in patients with chronic pain of malignancy. In such cases the total dose of morphine sulfate extended-release capsules should be advanced until the desired therapeutic endpoint is reached or clinically significant opioid-related adverse reactions intervene.

Alternative Methods of Administration

In a study of healthy volunteers, morphine sulfate extended-release pellets sprinkled over apple sauce were found to be bioequivalent to morphine sulfate extended-release capsules swallowed whole with apple sauce under fasting conditions. Other foods have not been tested. Patients who have difficulty swallowing whole capsules or tablets may benefit from this alternative method of administration.
Sprinkle the pellets onto a small amount of apple sauce. Apple sauce should be room temperature or cooler. The patient must be cautioned not to chew the pellets which could result in the immediate release of a potentially dangerous, even fatal dose of morphine. Use immediately. Rinse mouth to ensure all pellets have been swallowed. Patients should consume entire portion and should not divide apple sauce into separate doses.
The entire capsule contents may alternatively be administered through a 16 French gastrostomy tube.
Flush the gastrostomy tube with water to ensure that it is wet. Sprinkle the morphine sulfate extended-release pellets into 10 mL of water. Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel. Rinse the beaker with a further 10 mL of water and pour this into the funnel. Repeat rinsing until no pellets remain in the beaker.
THE ADMINISTRATION OF MORPHINE SULFATE EXTENDED-RELEASE PELLETS THROUGH A NASOGASTRIC TUBE SHOULD NOT BE ATTEMPTED.

Considerations in the Adjustment of Dosing Regimens

If signs of excessive opioid effects are observed early in the dosing interval, the next dose should be reduced. If this adjustment leads to inadequate analgesia, that is, if breakthrough pain occurs when morphine sulfate extended-release capsules are administered on an every 24 hours dosing regimen, consideration should be given to dosing every 12 hours. If breakthrough pain occurs on a 12 hour dosing regimen a supplemental dose of a short-acting analgesic may be given. As experience is gained, adjustments in both dose and dosing interval can be made to obtain an appropriate balance between pain relief and opioid side effects. To avoid accumulation the dosing interval of morphine sulfate extended-release capsules should not be reduced below 12 hours.

Cessation of Therapy

When the patient no longer requires therapy with morphine sulfate extended-release capsules, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.

Conversion from Morphine Sulfate Extended-Release Capsules to Other Extended-Release Oral Morphine Formulations

Morphine sulfate extended-release capsules are not bioequivalent to other extended-release morphine preparations. Although for a given dose the same total amount of morphine is available from morphine sulfate extended-release capsules as from morphine solution or extended-release morphine tablets, the slower release of morphine from morphine sulfate extended-release capsules results in reduced maximum and increased minimum plasma morphine concentrations than with shorter acting morphine products. Conversion from morphine sulfate extended-release capsules to the same total daily dose of other extended-release morphine preparations may lead to either excessive sedation at peak or inadequate analgesia at trough and close observation and appropriate dosage adjustments are recommended.

Conversion from Morphine Sulfate Extended-Release Capsules to Parenteral Opioids

When converting a patient from morphine sulfate extended-release capsules to parenteral opioids, it is best to calculate an equivalent parenteral dose, and then initiate treatment at half of this calculated value. For example, to estimate the required 24 hour dose of parenteral morphine for a patient taking morphine sulfate extended-release capsules, one would take the 24 hour morphine sulfate extended-release capsules dose, divide by an oral to parenteral conversion ratio of 3, divide the estimated 24 hour parenteral dose into six divided doses (for a four hour dosing interval), then halve this dose as an initial trial.

For example, to estimate the required parenteral morphine dose for a patient taking 360 mg of morphine sulfate extended-release capsules a day, divide the 360 mg daily oral morphine dose by a conversion ratio of 1 mg of parenteral morphine for every 3 mg of oral morphine. The estimated 120 mg daily parenteral requirement is then divided into six 20 mg doses, and half of this, or 10 mg, is then given every 4 hours as an initial trial dose.

This approach is likely to require a dosage increase in the first 24 hours for many patients, but is recommended because it is less likely to cause overdose than trying to establish an equivalent dose without titration.

Safety and Handling

Morphine sulfate extended-release capsules contain morphine sulfate which is a controlled substance under Schedule II of the Controlled Substances Act. Morphine, like all opioids, is liable to diversion and misuse and should be handled accordingly. Patients and their families should be instructed to flush any morphine sulfate extended-release capsules that are no longer needed.

Morphine sulfate extended-release capsules may be targeted for theft and diversion by criminals. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Morphine sulfate extended-release capsules consists of closed hard gelatin capsules containing polymer coated morphine sulfate pellets that pose no known handling risk to health care workers. Morphine sulfate extended-release capsules are liable to diversion and misuse both by the general public and health care workers, and should be handled accordingly.
Hydroxyzine Hydrochlori...

Hydroxyzine Hydrochloride

For symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested: in adults, 50-100 mg q.i.d.; children under 6 years, 50 mg daily in divided doses and over 6 years, 50-100 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: in adults, 25 mg t.i.d. or q.i.d.; children under 6 years, 50 mg daily in divided doses and over 6 years, 50-100 mg daily in divided doses.

As a sedative when used as a premedication and following general anesthesia: 50-100 mg in 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 medications, the dosage should be adjusted according to the patient’s response to therapy.
Metoclopramide Hydrochl...

Metoclopramide Hydrochloride

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

For the Relief of Symptomatic Gastroesophageal Reflux:

Administer from 10 mg to 15 mg metoclopramide hydrochloride, 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 per dose, and this regimen should be used when lesions are present, so long as it is tolerated (see ADVERSE REACTIONS). Because of the poor correlation between symptoms and endoscopic appearance of the esophagus, therapy directed at esophageal lesions is best guided by endoscopic evaluation.

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

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

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

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

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

Use in Patients with Renal or Hepatic Impairment:

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

See OVERDOSAGE section for information regarding dialysis.

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

Silver Sulfadiazene

FOR TOPICAL USE ONLY - NOT FOR OPHTHALMIC USE: Prompt institution of appropriate regimens for care of the burned patient is of prime importance and includes the control of shock and pain. The burn wounds are then cleansed and debrided and Silver Sulfadiazine Cream is applied under sterile conditions. The burn areas should be covered with Silver Sulfadiazine Cream at all times. The cream should be applied once to twice daily to a thickness of approximately 1/16 inch. Whenever necessary, the cream should be reapplied to any areas from which it has been removed due to patient activity. Administration may be accomplished in minimal time because dressings are not required. However, if individual patient requirements make dressings necessary, they may be used.

Reapply immediately after hydrotherapy.

Treatment with Silver Sulfadiazine Cream should be continued until satisfactory healing has occurred or until the burn site is ready for grafting. The drug should not be withdrawn from the therapeutic regimen while there remains the possibility of infection except if a significant adverse reaction occurs.
Vancomycin Hydrochlorid...

Vancomycin Hydrochloride

2.1 Adults

Vancomycin hydrochloride capsules, USP are used in treating C. difficile-associated diarrhea and staphylococcal enterocolitis.
C. difficile-associated diarrhea: The recommended dose is 125 mg administered orally 4 times daily for 10 days. Staphylococcal enterocolitis: Total daily dosage is 500 mg to 2 g administered orally in 3 or 4 divided doses for 7 to 10 days.
2.2 Pediatric Patients

The usual daily dosage is 40 mg/kg in 3 or 4 divided doses for 7 to 10 days. The total daily dosage should not exceed 2 g.
Sodium Ferric Gluconate...

Sodium Ferric Gluconate Complex

The dosage of sodium ferric gluconate complex in sucrose injection is expressed in terms of mg of elemental iron. Each 5 mL sterile, single-use vial contains 62.5 mg of elemental iron (12.5 mg/mL).

Do not mix sodium ferric gluconate complex in sucrose injection with other medications, or add to parenteral nutrition solutions for intravenous infusion. The compatibility of sodium ferric gluconate complex in sucrose injection with intravenous infusion vehicles other than 0.9% sodium chloride has not been evaluated. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever the solution and container permit. If diluted, use immediately.

Sodium ferric gluconate complex in sucrose injection treatment may be repeated if iron deficiency reoccurs.

2.1 Adult Dosage and Administration

The recommended dosage of sodium ferric gluconate complex in sucrose injection for the repletion treatment of iron deficiency in hemodialysis patients is 10 mL of sodium ferric gluconate complex in sucrose injection (125 mg of elemental iron). Sodium ferric gluconate complex in sucrose injection may be diluted in 100 mL of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session. Sodium ferric gluconate complex in sucrose injection may also be administered undiluted as a slow intravenous injection (at a rate of up to 12.5 mg/min) per dialysis session. For repletion treatment most patients may require a cumulative dose of 1000 mg of elemental iron administered over 8 dialysis sessions. Sodium ferric gluconate complex in sucrose injection has been administered at sequential dialysis sessions by infusion or by slow intravenous injection during the dialysis session itself.

Data from sodium ferric gluconate complex in sucrose injection postmarketing spontaneous reports indicate that individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events [see Adverse Reactions (6.2)].

2.2 Pediatric Dosage and Administration

The recommended pediatric dosage of sodium ferric gluconate complex in sucrose injection for the repletion treatment of iron deficiency in hemodialysis patients is 0.12 mL/kg sodium ferric gluconate complex in sucrose injection (1.5 mg/kg of elemental iron) diluted in 25 mL 0.9% sodium chloride and administered by intravenous infusion over 1 hour per dialysis session. The maximum dosage should not exceed 125 mg per dose.
Hydrochlorothiazide

Hydrochlorothiazide

For Control of Hypertension: The adult initial dose of hydrochlorothiazide 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.
Metformin Hydrochloride...

Metformin Hydrochloride

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Metformin Hydrochloride Extended-Release Tablets or any other pharmacologic agent. Dosage of Metformin Hydrochloride Extended-Release Tablets must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose. The maximum recommended daily dose of Metformin Hydrochloride Extended-Release Tablets in adults is 2500 mg.

Metformin Hydrochloride Extended-Release Tablets should be taken with a full glass of water once daily with the evening meal. Metformin Hydrochloride Extended-Release Tablets should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of theminimumdose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to Metformin Hydrochloride Extended-Release Tablets and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Metformin Hydrochloride Extended-Release Tablets, either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.

Short-term administration of Metformin Hydrochloride Extended-Release Tablets, may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Recommended Dosing Schedule

The usual starting dose of Metformin Hydrochloride Extended-Release Tablets is 1000 mg taken with a full glass of water once daily with the evening meal, although 500mg may be utilized when clinically appropriate. Dosage increases should be made in increments of 500mg weekly, up to a maximum of 2500 mg once daily with the evening meal (see CLINICAL PHARMACOLOGY, Clinical Studies).

In randomized trials, patients currently treated with immediate-release metformin were switched to Metformin Hydrochloride Extended-Release Tablets. Results of this trial suggest that patients receiving immediate-release metformin treatment may be safely switched to Metformin Hydrochloride Extended-Release Tablets once daily at the same total daily dose, up to 2500 mg once daily. Following a switch from immediate release metformin to Metformin Hydrochloride Extended-Release Tablets, glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY, Clinical Studies).

Pediatrics – There is no pediatric information available for Metformin Hydrochloride Extended-Release Tablets.

Transfer From Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to Metformin Hydrochloride Extended-Release Tablets, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

Concomitant Metformin Hydrochloride Extended-Release Tablets and Oral Sulfonylurea Therapy in Adult Patients

If patients have not responded to four weeks of the maximum dose of Metformin Hydrochloride Extended-Release Tablets monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Metformin Hydrochloride Extended-Release Tablets at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (also known as glibenclamide). With concomitant Metformin Hydrochloride Extended-Release Tablets and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant Metformin Hydrochloride Extended-Release Tablets and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken (see Package Insert of the respective sulfonylurea).

If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of Metformin Hydrochloride Extended-Release Tablets and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without Metformin Hydrochloride Extended-Release Tablets.

Concomitant Metformin Hydrochloride Extended-Release Tablets and Insulin Therapy in Adult Patients

The current insulin dose should be continued upon initiation of Metformin Hydrochloride Extended-Release Tablets therapy. Metformin Hydrochloride Extended-Release Tablets therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Metformin Hydrochloride Extended-Release Tablets should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose for Metformin Hydrochloride Extended-Release Tablet is 2500 mg. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Metformin Hydrochloride Extended-Release Tablets. Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations

Metformin Hydrochloride Extended-Release Tablets are not recommended for use in pregnancy, and is not recommended in patients below the age of 17 years.

The initial and maintenance dosing of Metformin Hydrochloride Extended-Release Tablets should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Metformin Hydrochloride Extended-Release Tablets.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly (see WARNINGS).
Oxycodone Hydrochloride...

Oxycodone Hydrochloride And Ibuprofen

Carefully consider the potential benefits and risks of oxycodone hydrochloride and ibuprofen tablets and other treatment options before deciding to use oxycodone hydrochloride and ibuprofen 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 oxycodone hydrochloride and ibuprofen tablets, the dose and frequency should be adjusted to suit an individual patient’s needs.”

For the management of acute moderate to severe pain, the recommended dose of oxycodone hydrochloride and ibuprofen is one tablet given orally. Dosage should not exceed 4 tablets in a 24-hour period and should not exceed 7 days.
Oxandrolone

Oxandrolone

Therapy with anabolic steroids is adjunctive to and not a replacement for conventional therapy. The duration of therapy with oxandrolone will depend on the response of the patient and the possible appearance of adverse reactions. Therapy should be intermittent.

Adults: The response of individuals to anabolic steroids varies. The daily adult dosage is 2.5 mg to 20 mg given in 2 to 4 divided doses. The desired response may be achieved with as little as 2.5 mg or as much as 20 mg daily. A course of therapy of 2 to 4 weeks is usually adequate. This may be repeated intermittently as indicated.

Children: For children the total daily dosage of oxandrolone is ≤0.1 mg per kilogram body weight or ≤0.045 mg per pound of body weight. This may be repeated intermittently as indicated.

Geriatric Use: Recommended dose for geriatric patients is 5 mg bid.
Valproic Acid Solution

Valproic Acid Solution

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

Complex Partial Seizures:

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy):

Valproic acid has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 μg/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 μg/mL in females and 135 μg/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 μg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of valproic acid therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy:

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

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

Simple and Complex Absence Seizures:

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

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

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

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

The following table is a guide for the initial daily dose of valproic acid (15 mg/kg/day):

Weight
(Kg) (Lb)
Total

Daily
Dose (mg)
Number of Teaspoonfuls
of Oral Solution Dose 1 Dose 2 Dose 3 10 - 24.9 22 - 54.9 250 0 0 1 25 - 39.9 55 - 87.9 500 1 0 1 40 - 59.9 88 - 131.9 750 1 1 1 60 - 74.9 132 - 164.9 1,000 1 1 2 75 - 89.9 165 - 197.9 1,250 2 1 2
General Dosing Advice

Dosing in Elderly Patients

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

Dose-Related Adverse Events

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

G.I. Irritation

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

Ammonium Lactate Lotion

Shake well. Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician.
Ropinirole Hydrochlorid...

Ropinirole Hydrochloride

2.1 General Dosing Considerations
Ropinirole extended-release tablets are taken once daily, with or without food. Taking ropinirole extended-release tablets with food may reduce the occurrence of nausea; this has not been established in controlled clinical trials [see Clinical Pharmacology (12.3)]. Tablets must be swallowed whole and must not be chewed, crushed, or divided. If a significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted.
2.2 Dosing for Parkinson’s Disease

The starting dose is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at 1-week or longer intervals as appropriate, depending on therapeutic response and tolerability, up to a maximally recommended dose of 24 mg/day.

In clinical trials, dosage was initiated at 2 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 24 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 1 week or longer after each dose increment. Caution should be exercised during dose titration because too rapid a rate of titration may lead to dose selection that may not provide additional benefit, but that may increase the risk of adverse reactions [see Clinical Studies (14.2)]. Due to the flexible dosing design used in clinical studies, specific dose response information could not be determined.

When ropinirole extended-release tablets are administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be decreased gradually as tolerated. In the placebo-controlled advanced Parkinson's disease study, the L-dopa dose was reduced once patients reached a dose of ropinirole extended-release tablets of 8 mg/day. Overall, L-dopa dose reduction was sustained in 93% of patients treated with ropinirole extended-release tablets and in 72% of patients on placebo. On average the L-dopa dose was reduced by 34% in patients treated with ropinirole extended-release tablets [see Clinical Studies (14)]. Ropinirole extended-release tablets should be discontinued gradually over a 7–day period.

2.3 Switching From Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets

Patients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets. The initial dose of ropinirole extended-release tablets should most closely match the total daily dose of the immediate-release formulation of ropinirole tablets, as shown in Table 1.
Table 1. Conversion from Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets Immediate-Release Ropinirole Tablets Total Daily Dose (mg) Ropinirole Extended- Release Tablets Total Daily Dose (mg) 0.75 to 2.25 2 3 to 4.5 4 6 6 7.5 to 9 8 12 12 15 to 18 16 21 20 24 24
Following conversion to ropinirole extended-release tablets, the dose may be adjusted depending on therapeutic response and tolerability [see Dosage and Administration (2.2)].
Ammonium Lactate

Ammonium Lactate

Apply to the affected areas and rub in thoroughly. Use twice daily or as directed by a physician.
Triamterene And Hydroch...

Triamterene And Hydrochlorothiazide

Note: 37.5 mg/25 mg= 37.5 mg triamterene and 25 mg hydrochlorothiazide 75 mg/50 mg= 75 mg triamterene and 50 mg hydrochlorothiazide

The usual dosage of triamterene and hydrochlorothiazide as a tablet is 37.5 mg/25 mg or 75 mg/50 mg daily, given as a single dose, with appropriate monitoring of serum potassium (see WARNINGS). There is no experience with the use of more than 75 mg/50 mg daily of triamterene and hydrochlorothiazide. Clinical experience with the administration of 37.5 mg/25 mg of triamterene and hydrochlorothiazide twice daily in divided doses (rather than as a single dose) suggests an increased risk of electrolyte imbalance and renal dysfunction.

Patients receiving 50 mg of hydrochlorothiazide who become hypokalemic may be transferred to this 75 mg/50 mg product directly. Patients receiving 25 mg hydrochlorothiazide who become hypokalemic may be transferred to a 37.5 mg/25 mg product directly.

In patients requiring hydrochlorothiazide therapy and in whom hypokalemia cannot be risked, therapy may be initiated with 37.5 mg/25 mg of triamterene and hydrochlorothiazide. If an optimal blood pressure response is not obtained with 37.5 mg/25 mg triamterene and hydrochlorothiazide, the dose should be increased to 75 mg/50 mg daily as a single dose. If blood pressure still is not controlled, another antihypertensive agent may be added (see PRECAUTIONS: Drug Interactions).

Clinical studies have shown that patients taking less bioavailable formulations of triamterene and hydrochlorothiazide in daily doses of 25 mg to 50 mg hydrochlorothiazide and 50 mg to 100 mg of triamterene may be safely changed to 37.5 mg/25 mg of triamterene and hydrochlorothiazide daily. All patients changed from less bioavailable formulations to triamterene and hydrochlorothiazide tablets should be monitored clinically and for serum potassium after the transfer.
Meprobamate

Meprobamate

Meprobamate Tablets USP: The usual adult daily dosage is 1200 mg to 1600 mg, in three or four divided doses; a daily dosage above 2400 mg is not recommended. The usual daily dosage for children ages six to twelve years is 200 mg to 600 mg, in two or three divided doses.

Not recommended for children under age 6 (see Usage in Children).
Estradiol

Estradiol

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Patients should be started at the lowest dose for the indication.

1. For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible.

Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. The usual initial dosage range is 1 to 2 mg daily of estradiol adjusted as necessary to control presenting symptoms. The minimal effective dose for maintenance therapy should be determined by titration. Administration should be cyclic (e.g., 3 weeks on and 1 week off).

2. For treatment of female hypoestrogenism due to hypogonadism, castration or primary ovarian failure.

Treatment is usually initiated with a dose of 1 to 2 mg daily of estradiol, adjusted as necessary to control presenting symptoms; the minimal effective dose for maintenance therapy should be determined by titration.

3. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease.

Suggested dosage is 10 mg three times daily for a period of at least three months.

4. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only.

Suggested dosage is 1 to 2 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.

5. For prevention of osteoporosis.

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.

The lowest effective dose of estradiol tablets has not been determined.
Estropipate

Estropipate

When estrogen is prescribed for a woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (See BOXED WARNINGS and WARNINGS.) For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Attempts to discontinue or taper medication should be made at 3month to 6-month intervals. Usual dosage ranges:Vasomotor symptoms—One estropipate 0.75 mg tablet to two estropipate 3 mg tablets per day. The lowest dose that will control symptoms should be chosen. If the patient has not menstruated within the last two months or more, cyclic administration is started arbitrarily. If the patient is menstruating, cyclic administration is started on day 5 of bleeding.Vulval and vaginal atrophy—One estropipate 0.75 mg tablet to two estropipate 3 mg tablets daily, depending upon the tissue response of the individual patient. The lowest dose that will control symptoms should be chosen. Administer cyclically.

For treatment of female hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. Usual dosage ranges:Female hypogonadism—A daily dose of one estropipate 1.5 mg tablet to three estropipate 3 mg tablets may be given for the first three weeks of a theoretical cycle, followed by a rest period of eight to ten days. The lowest dose that will control symptoms should be chosen. If bleeding does not occur by the end of this period, the same dosage schedule is repeated. The number of courses of estrogen therapy necessary to produce bleeding may vary depending on the responsiveness of the endometrium. If satisfactory withdrawal bleeding does not occur, an oral progestogen may be given in addition to estrogen during the third week of the cycle.Female castration or primary ovarian failure—A daily dose of one estropipate 1.5 mg tablet to three estropipate 3 mg tablets may be given for the first three weeks of a theoretical cycle, followed by a rest period of eight to ten days. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control.Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.

For prevention of osteoporosis. A daily dose of one estropipate 0.75 mg tablet for 25 days of a 31-day cycle per month.
Tacrolimus

Tacrolimus

NOTE: Anaphylactic reactions have occurred with injectables containing castor oil derivatives. See WARNINGS.

Tacrolimus capsules
Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations Patient Population Recommended Initial Oral Dosagea Observed Whole Blood Trough Concentrations a) Note: two divided doses, q12h b) In a second smaller study, the initial dose of tacrolimus was 0.15 to 0.2 mg/kg/day and observed tacrolimus concentrations were 6 to 16 ng/mL during month 1 to 3 and 5 to 12 ng/mL during month 4 to 12 (see CLINICAL STUDIES). Adult kidney transplant patients In combination with azathioprine 0.2 mg/kg/day month 1 to 3: 7 to 20 ng/mL month 4 to 12: 5 to 15 ng/mL In combination with MMF/IL-2 receptor antagonistb 0.1 mg/kg/day month 1 to 12: 4 to 11 ng/mL Adult liver transplant patients 0.10 to 0.15 mg/kg/day month 1 to 12: 5 to 20 ng/mL Pediatric liver transplant patients 0.15 to 0.20 mg/kg/day month 1 to 12: 5 to 20 ng/mL
Liver Transplantation

It is recommended that patients initiate oral therapy with tacrolimus capsules if possible. If IV therapy is necessary, conversion from IV to oral tacrolimus is recommended as soon as oral therapy can be tolerated. This usually occurs within 2 to 3 days. The initial dose of tacrolimus should be administered no sooner than 6 hours after transplantation. In a patient receiving an IV infusion, the first dose of oral therapy should be given 8 to 12 hours after discontinuing the IV infusion. The recommended starting oral dose of tacrolimus capsules is 0.10 to 0.15 mg/kg/day administered in two divided daily doses every 12 hours. Coadministered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. (See Drugs that May Alter Tacrolimus Concentrations).

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

Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Liver Transplantation below.

Kidney Transplantation

The recommended starting oral dose of tacrolimus (administered every 12 hours in two divided doses) is 0.2 mg/kg/day when used in combination with azathioprine or 0.1 mg/kg/day when used in combination with MMF and IL-2 receptor antagonist (see CLINICAL STUDIES). The initial dose of tacrolimus may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered (as indicated for example by a serum creatinine ≤ 4 mg/dL). Black patients may require higher doses to achieve comparable blood concentrations. Dosage and typical tacrolimus whole blood trough concentrations are shown in the table above; blood concentration details are described in Blood Concentration Monitoring: Kidney Transplantation below.

The data in kidney transplant patients indicate that the Black patients required a higher dose to attain comparable trough concentrations compared to Caucasian patients.
Time After Transplant Caucasian n=114 Black n=56 Dose (mg/kg) Trough Concentrations (ng/mL) Dose (mg/kg) Trough Concentrations (ng/mL) Day 7 0.18 12.0 0.23 10.9 Month 1 0.17 12.8 0.26 12.9 Month 6 0.14 11.8 0.24 11.5 Month 12 0.13 10.1 0.19 11.0
Pediatric Patients

Pediatric liver transplantation patients without pre-existing renal or hepatic dysfunction have required and tolerated higher doses than adults to achieve similar blood concentrations. Therefore, it is recommended that therapy be initiated in pediatric patients at a starting IV dose of 0.03 to 0.05 mg/kg/day and a starting oral dose of 0.15 to 0.20 mg/kg/day. Dose adjustments may be required. Experience in pediatric kidney transplantation patients is limited.

Patients with Hepatic or Renal Dysfunction

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

Due to the potential for nephrotoxicity, patients with renal or hepatic impairment should receive doses at the lowest value of the recommended IV and oral dosing ranges. Further reductions in dose below these ranges may be required. Tacrolimus therapy usually should be delayed up to 48 hours or longer in patients with post-operative oliguria.

Conversion from One Immunosuppressive Regimen to Another

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

Blood Concentration Monitoring

Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies.

Two methods have been used for the assay of tacrolimus, a microparticle enzyme immunoassay (MEIA) and ELISA. Both methods have the same monoclonal antibody for tacrolimus. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anti-coagulant. Heparin anti-coagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; if samples are to be kept longer they should be deep frozen at -20° C for up to 12 months.

Liver Transplantation

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from Phase II and III studies of liver transplant patients have shown an increasing incidence of adverse events with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients often are maintained at the low end of this target range.

Data from the U.S. clinical trial show that tacrolimus whole blood concentrations, as measured by ELISA, were most variable during the first week post-transplantation. After this early period, the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.

Therapeutic Drug Monitoring, 1995, Volume 17, Number 6 contains a consensus document and several position papers regarding the therapeutic monitoring of tacrolimus from the 1995 International Consensus Conference on Immunosuppressive Drugs. Refer to these manuscripts for further discussions of tacrolimus monitoring.

Kidney Transplantation

Data from a Phase 3 study of tacrolimus in conjunction with azathioprine indicate that trough concentrations of tacrolimus in whole blood, as measured by IMx®** were most variable during the first week of dosing. During the first three months of that trial, 80% of the patients maintained trough concentrations between 7 to 20 ng/mL, and then between 5 to 15 ng/mL, through 1 year.

In a separate clinical trial of tacrolimus in conjunction with MMF and daclizumab, approximately 80% of patients maintained tacrolimus whole blood concentrations between 4 to 11 ng/mL through 1 year post-transplant.

In another clinical trial of tacrolimus in conjunction with MMF and basiliximab, approximately 80% of patients maintained tacrolimus whole trough blood concentrations between 6 to 16 ng/mL during month 1 to 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

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

Propranolol Hydrochloride

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 the 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 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.
Sodium Ferric Gluconate...

Sodium Ferric Gluconate Complex In Sucrose

The dosage of sodium ferric gluconate complex in sucrose injection is expressed in terms of mg of elemental iron. Each 5 mL sterile, single-use vial contains 62.5 mg of elemental iron (12.5 mg/mL).

Do not mix sodium ferric gluconate complex in sucrose injection with other medications, or add to parenteral nutrition solutions for intravenous infusion. The compatibility of sodium ferric gluconate complex in sucrose injection with intravenous infusion vehicles other than 0.9% sodium chloride has not been evaluated. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever the solution and container permit. If diluted, use immediately.

Sodium ferric gluconate complex in sucrose injection treatment may be repeated if iron deficiency reoccurs.

2.1 Adult Dosage and Administration

The recommended dosage of sodium ferric gluconate complex in sucrose injection for the repletion treatment of iron deficiency in hemodialysis patients is 10 mL of sodium ferric gluconate complex in sucrose injection (125 mg of elemental iron). Sodium ferric gluconate complex in sucrose injection may be diluted in 100 mL of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session. Sodium ferric gluconate complex in sucrose injection may also be administered undiluted as a slow intravenous injection (at a rate of up to 12.5 mg/min) per dialysis session. For repletion treatment most patients may require a cumulative dose of 1000 mg of elemental iron administered over 8 dialysis sessions. Sodium ferric gluconate complex in sucrose injection has been administered at sequential dialysis sessions by infusion or by slow intravenous injection during the dialysis session itself.

Data from sodium ferric gluconate complex in sucrose injection postmarketing spontaneous reports indicate that individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events [see Adverse Reactions (6.2)].

2.2 Pediatric Dosage and Administration

The recommended pediatric dosage of sodium ferric gluconate complex in sucrose injection for the repletion treatment of iron deficiency in hemodialysis patients is 0.12 mL/kg sodium ferric gluconate complex in sucrose injection (1.5 mg/kg of elemental iron) diluted in 25 mL 0.9% sodium chloride and administered by intravenous infusion over 1 hour per dialysis session. The maximum dosage should not exceed 125 mg per dose.
Neomycin And Polymyxin ...

Neomycin And Polymyxin B Sulfates Irrigant

This preparation is specifically designed for use with “three-way” catheters or with other catheter systems permitting continuous irrigation of the urinary bladder. The usual irrigation dose is one 1-mL ampule a day for up to 10 days.

Using strict aseptic techniques, the contents of one 1-mL ampule of Neomycin and Polymyxin B Sulfates Solution for Irrigation should be added to a 1,000-mL container of isotonic saline solution. This container should then be connected to the inflow lumen of the “three-way” catheter which has been inserted with full aseptic precautions; use of a sterile lubricant is recommended during insertion of the catheter. The outflow lumen should be connected, via a sterile disposable plastic tube, to a disposable plastic collection bag. Stringent procedures, such as taping the inflow and outflow junction at the catheter, should be observed when necessary to insure the junctional integrity of the system.

For most patients, the inflow rate of the 1,000-mL saline solution of neomycin and polymyxin B should be adjusted to a slow drip to deliver about 1,000 mL every 24 hours. If the patient’s urine output exceeds 2 liters per day, it is recommended that the inflow rate be adjusted to deliver 2,000 mL of the solution in a 24 hour period.

It is important that the rinse of the bladder be continuous; the inflow or rinse solution should not be interrupted for more than a few minutes.

Preparation of the irrigation solution should be performed with strict aseptic techniques. The prepared solution should be stored at 4° C, and should be used within 48 hours following preparation to reduce the risk of contamination with resistant microorganisms.
Armodafinil

Armodafinil

Obstructive Sleep Apnea (OSA) and Narcolepsy

The recommended dose of armodafinil tablets for patients with OSA or narcolepsy is 150 mg or 250 mg given as a single dose in the morning. In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit beyond that of the 150 mg/day dose (See CLINICAL PHARMACOLOGY and CLINICAL TRIALS).

Shift Work Disorder (SWD)

The recommended dose of armodafinil tablets for patients with SWD is 150 mg given daily approximately 1 hour prior to the start of their work shift.

Dosage adjustment should be considered for concomitant medications that are substrates for CYP3A4/5, such as steroidal contraceptives, triazolam, and cyclosporine (See PRECAUTIONS, Drug Interactions).

Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, and phenytoin may have prolonged elimination upon coadministration with armodafinil tablets and may require dosage reduction and monitoring for toxicity (See PRECAUTIONS, Drug Interactions).

In patients with severe hepatic impairment, armodafinil tablets should be administered at a reduced dose (See CLINICAL PHARMACOLOGY and PRECAUTIONS).

There is inadequate information to determine safety and efficacy of dosing in patients with severe renal impairment (See CLINICAL PHARMACOLOGY and PRECAUTIONS).

In elderly patients, elimination of armodafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should be given to the use of lower doses in this population (See CLINICAL PHARMACOLOGY and PRECAUTIONS).
Atorvastatin Calcium

Atorvastatin Calcium

2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)

The recommended starting dose of atorvastatin calcium tablets is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin calcium tablets is 10 to 80 mg once daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP Guidelines). After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.

2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10–17 years of age)

The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [see current NCEP Pediatric Panel Guidelines, Clinical Pharmacology (12), and Indications and Usage (1.2)]. Adjustments should be made at intervals of 4 weeks or more.

2.3 Homozygous Familial Hypercholesterolemia

The dosage of atorvastatin calcium tablets in patients with homozygous FH is 10 to 80 mg daily. Atorvastatin calcium tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

2.4 Concomitant Lipid-Lowering Therapy

Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7)].

2.5 Dosage in Patients With Renal Impairment

Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions, Skeletal Muscle (5.1), Clinical Pharmacology, Pharmacokinetics (12.3)].

2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors

In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium tablets and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is employed. In patients with HIV taking nelfinavir, therapy with atorvastatin calcium tablets should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is employed [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7)].
Quinidine Sulfate

Quinidine Sulfate

Treatment of P. falciparum malaria

Quinidine sulfate tablets are used in one of the approved regimens for the treatment of life-threatening P. falciparum malaria. The central component of the regimen is Quinidine Gluconate Injection, and the regimen is described in the package insert of Quinidine Gluconate Injection.

Conversion of atrial fibrillation/flutter to sinus rhythm

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Patients with symptomatic atrial fibrillation/flutter should be treated with quinidine sulfate only after ventricular rate control (e.g., with digitalis or ß-blockers) has failed to provide satisfactory control of symptoms.

Adequate trials have not identified an optimal regimen of quinidine sulfate for conversion of atrial fibrillation/flutter to sinus rhythm. In one reported regimen, the patient first receives two tablets (400 mg; 332 mg of quinidine base) of quinidine sulfate every six hours. If this regimen has not resulted in conversion after 4 or 5 doses, then the dose is cautiously increased. If, at any point during administration, the QRS complex widens to 130% of its pre-treatment duration; the QTC interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension, then quinidine sulfate is discontinued, and other means of conversion (e.g., direct-current cardioversion) are considered.

Reduction of frequency of release into atrial fibrillation/flutter

In a patient with a history of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy with quinidine sulfate should be an increase in the average time between episodes. In most patients, the tachyarrhythmia will recur during therapy with quinidine sulfate, and a single recurrence should not be interpreted as therapeutic failure.

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available. Monitoring should be continued for two or three days after initiation of the regimen on which the patient will be discharged.

Therapy with quinidine sulfate should be begun with 200 mg (equivalent to 166 mg of quinidine base) every six hours. If this regimen is well tolerated, if the serum quinidine level is still well within the laboratory’s therapeutic range, and if the average time between arrhythmic episodes has not been satisfactorily increased, then the dose may be cautiously raised. The total daily dosage should be reduced if the QRS complex widens to 130% of its pre-treatment duration; the QTC interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension.

Suppression of ventricular arrhythmias

Dosing regimens for the use of quinidine sulfate in suppressing life-threatening ventricular arrhythmias have not been adequately studied. Described regimens have generally been similar to the regimen described just above for the prophylaxis of symptomatic atrial fibrillation/flutter. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.
Fentanyl – Novapl...

Fentanyl – Novaplus

2.1 Proper Patient Selection

Abuse PotentialAssess patients for their clinical risks for opioid abuse or addiction prior to prescribing fentanyl transdermal system [see Warnings and Precautions (5.1)].

Opioid ToleranceOpioid tolerance to an opioid of comparable potency must be established before prescribing fentanyl transdermal system [see Warnings and Precautions (5.2)].

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

2.2 Dosing

Conversion to Fentanyl Transdermal System in Opioid-Tolerant Patients

The recommended starting dose when converting from other opioids to fentanyl transdermal system is intended to minimize the potential for overdosing patients with the first dose. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with fentanyl transdermal system [see Warnings and Precautions (5.2)].

In selecting an initial fentanyl transdermal system dose, take the following factors into account:
the daily dose, potency, and characteristics of the opioid the patient has been taking previously (e.g., whether it is a pure agonist or mixed agonist-antagonist); the reliability of the relative potency estimates used to calculate the fentanyl transdermal system dose needed (potency estimates may vary with the route of administration); the degree of opioid tolerance; the general condition and medical status of the patient.
To convert adult and pediatric patients from oral or parenteral opioids to fentanyl transdermal system, use Table 1. Do not use Table 1 to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent.
TABLE 11: DOSE CONVERSION GUIDELINES Current Analgesic Daily Dosage (mg/day) Oral morphine 60-134 135-224 225-314 315-404 Intramuscular orIntravenous morphine 10-22 23-37 38-52 53-67 Oral oxycodone 30-67 67.5-112 112.5-157 157.5-202 Oral codeine 150-447 Oral hydromorphone 8-17 17.1-28 28.1-39 39.1-51 Intravenous Hydromorphone 1.5-3.4 3.5-5.6 5.7-7.9 8-10 Intramuscular meperidine 75-165 166-278 279-390 391-503 Oral methadone 20-44 45-74 75-104 105-134 ↓ ↓ ↓ ↓ RecommendedFentanyl TransdermalSystem Dose 25 mcg/hour 50 mcg/hour 75 mcg/hour 100 mcg/hour
Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the conversion methodology outlined above with Table 2.

1 Table 1 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.3)].

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the following methodology:
Calculate the previous 24-hour analgesic requirement. Convert this amount to the equianalgesic oral morphine dose using a reliable reference.Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose and the corresponding fentanyl transdermal system dose. Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than 3 days after the initial dose and every 6 days thereafter) until analgesic efficacy is attained. Do not use Table 2 to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent. TABLE 21: RECOMMENDED INITIAL FENTANYL TRANSDERMAL SYSTEM DOSE BASED UPON DAILY ORAL MORPHINE DOSE Oral 24-hourMorphine(mg/day) Fentanyl Transdermal SystemDose(mcg/hour) 60-134 25 135-224 50 225-314 75 315-404 100 405-494 125 495-584 150 585-674 175 675-764 200 765-854 225 855-944 250 945-1034 275 1035-1124 300
NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion tofentanyl transdermal system.

1 Table 2 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table 2 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.3)].

For delivery rates in excess of 100 mcg/hour, multiple systems may be used.

Hepatic ImpairmentAvoid the use of fentanyl transdermal system in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions (5.12), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Renal ImpairmentAvoid the use of fentanyl transdermal system in patients with severe renal impairment. In patients with mild to moderate renal impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions (5.13), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.3 Titration and Maintenance of Therapy

Once therapy is initiated, assess pain intensity and opioid adverse reactions frequently, especially respiratory depression [see Warnings and Precautions (5.2)]. Routinely monitor all patients for signs of misuse, abuse and addiction [see Warnings and Precautions (5.1)].

The initial fentanyl transdermal system dose may be increased after 3 days based on the daily dose of supplemental opioid analgesics required by the patient on the second or third day of the initial application.

It may take up to 6 days for fentanyl levels to reach equilibrium on a new dose [see Clinical Pharmacology (12.3)]. Therefore, evaluate patients for further titration after no less than two 3-day applications before any further increase in dosage is made.

Base dosage increments on the daily dosage of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12 mcg/hour increase in fentanyl transdermal system dose.

The majority of patients are adequately maintained with fentanyl transdermal system administered every 72 hours. Some patients may not achieve adequate analgesia using this dosing interval and may require systems to be applied at 48 hours rather than at 72 hours, only if adequate pain control cannot be achieved using a 72-hour regimen. An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen. Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended.

Discontinuation of Fentanyl Transdermal SystemTo convert patients to another opioid, remove fentanyl transdermal system and titrate the dose of the new analgesic based upon the patient’s report of pain until adequate analgesia has been attained. Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations. Withdrawal symptoms are possible in some patients after conversion or dose adjustment [see Warnings and Precautions (5.15)].

Do not use Tables 1 and 2 to convert from fentanyl transdermal system to other therapies to avoid overestimating the dose of the new agent potentially resulting in overdose of the new analgesic and death.

When discontinuing fentanyl transdermal system and not converting to another opioid, use a gradual downward titration, such as halving the dose every 6 days, in order to reduce the possibility of withdrawal symptoms [see Warnings and Precautions (5.15)]. It is not known at what dose level fentanyl transdermal system may be discontinued without producing the signs and symptoms of opioid withdrawal.

2.4 Administration of Fentanyl Transdermal System

Fentanyl transdermal system patches are for transdermal use, only.

Proper handling of fentanyl transdermal system is advised in order to prevent adverse reactions, including death, associated with accidental secondary exposure to fentanyl transdermal system [see Warnings and Precautions (5.3)].

Application and Handling Instructions
Patients should apply fentanyl transdermal system to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site may be clipped (not shaved) prior to system application. If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application. Patients should apply fentanyl transdermal system immediately upon removal from the sealed package. The patch must not be altered (e.g., cut) in any way prior to application. fentanyl transdermal system should not be used if the pouch seal is broken or if the patch is cut or damaged. The transdermal system is pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges. Each fentanyl transdermal system patch may be worn continuously for 72 hours. The next patch is applied to a different skin site after removal of the previous transdermal system. If problems with adhesion of the fentanyl transdermal system patch occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with a transparent adhesive film dressing. If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site. Patients (or caregivers who apply fentanyl transdermal system) should wash their hands immediately with soap and water after applying fentanyl transdermal system. Contact with unwashed or unclothed application sites can result in secondary exposure to fentanyl transdermal system and should be avoided. Examples of accidental exposure include transfer of a fentanyl transdermal system patch from an adult’s body to a child while hugging, sharing the same bed as the patient, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while applying or removing the patch. Instruct patients, family members, and caregivers to keep patches in a secure location out of the reach of children and of others for whom fentanyl transdermal system was not prescribed.
Avoidance of HeatInstruct patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see Warnings and Precautions (5.9)].

2.5 Disposal Instructions

Proper disposal of fentanyl transdermal system is advised in order to prevent adverse reactions, including death, associated with accidental secondary exposure to fentanyl transdermal system [see Warnings and Precautions (5.3)].

Patients should dispose of used patches by folding the adhesive side of the patch to itself, then flush the patch down the toilet immediately upon removal.

Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed. Unused patches should be removed from their pouches, fold so that the adhesive side of the patch adheres to itself, and flush down the toilet.
Irbesartan

Irbesartan

Irbesartan tablets may be administered with other antihypertensive agents and with or without food.

Hypertension

The recommended initial dose of irbesartan tablets is 150 mg once daily. Patients requiring further reduction in blood pressure should be titrated to 300 mg once daily.

A low dose of a diuretic may be added, if blood pressure is not controlled by irbesartan tablets alone. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY: Clinical Studies). Patients not adequately treated by the maximum dose of 300 mg once daily are unlikely to derive additional benefit from a higher dose or twice-daily dosing.

No dosage adjustment is necessary in elderly patients, or in patients with hepatic impairment or mild to severe renal impairment.

Nephropathy in Type 2 Diabetic Patients

The recommended target maintenance dose is 300 mg once daily. There are no data on the clinical effects of lower doses of irbesartan tablets on diabetic nephropathy (see CLINICAL PHARMACOLOGY: Clinical Studies).

Volume- and Salt-Depleted Patients

A lower initial dose of irbesartan tablets (75 mg) is recommended in patients with depletion of intravascular volume or salt (e.g., patients treated vigorously with diuretics or on hemodialysis) (see WARNINGS: Hypotension in Volume- or Salt-Depleted Patients).
Hydroxyzine Pamoate

Hydroxyzine Pamoate

For symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested: in adults, 50 mg to 100 mg q.i.d.; children under 6 years, 50 mg daily in divided doses; and over 6 years, 50 mg 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: in adults, 25 mg t.i.d. or q.i.d.; children under 6 years, 50 mg daily in divided doses; and over 6 years, 50 mg to 100 mg daily in divided doses.

As a sedative when used as a premedication and following general anesthesia: 50 mg to 100 mg in adults, and 0.6 mg/kg in children. When treatment is initiated by the intramuscular route of administration, subsequent doses may be administered orally.

As with all medications, the dosage should be adjusted according to the patient's response to therapy.
Irbesartan And Hydrochl...

Irbesartan And Hydrochlorothiazide

2.1 General Considerations

The side effects of irbesartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. [See Adverse Reactions (6).]

Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose.

Irbesartan and hydrochlorothiazide tablets may be administered with or without food.

Irbesartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.

Renal impairment. The usual regimens of therapy with irbesartan and hydrochlorothiazide tablets may be followed as long as the patient's creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so irbesartan and hydrochlorothiazide tablets are not recommended.

Hepatic impairment. No dosage adjustment is necessary in patients with hepatic impairment.

2.2 Add-On Therapy

In patients not controlled on monotherapy with irbesartan or hydrochlorothiazide, the recommended doses of irbesartan and hydrochlorothiazide tablets, in order of increasing mean effect, are (irbesartan-hydrochlorothiazide) 150 mg/12.5 mg, 300 mg/12.5 mg, and 300 mg/25 mg. The largest incremental effect will likely be in the transition from monotherapy to 150 mg/12.5 mg. [See Clinical Studies (14.2).]

2.3 Replacement Therapy

Irbesartan and hydrochlorothiazide tablets may be substituted for the titrated components.

2.4 Initial Therapy

The usual starting dose is irbesartan and hydrochlorothiazide tablet 150 mg/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of 300 mg/25 mg once daily as needed to control blood pressure [see Clinical Studies (14.2)]. Irbesartan and hydrochlorothiazide tablets are not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2)].
Albuterol Sulfate Solut...

Albuterol Sulfate Solution

The usual starting dosage for patients 2 to 12 years of age is 1.25 mg or 0.63 mg of albuterol sulfate inhalation solution administered 3 or 4 times daily, as needed, by nebulization. More frequent administration is not recommended.

To administer 1.25 mg or 0.63 mg of albuterol, use the entire contents of one unit-dose vial [3 mL of 0.042% (1.25 mg) or 0.021% (0.63 mg) inhalation solution] by nebulization. Adjust nebulizer flow rate to deliver albuterol sulfate over 5 to 15 minutes.

The use of albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimum benefit from regular use of the inhalation solution.

Patients 6 to 12 years of age with more severe asthma (baseline FEV1 less than 60% predicted), weight >40 kg, or patients 11 to 12 years of age may achieve a better initial response with the 1.25 mg dose.

Albuterol sulfate inhalation solution has not been studied in the setting of acute attacks of bronchospasm. A 2.5 mg dose of albuterol provided by a higher concentration product (2.5 mg albuterol per 3 mL) may be more appropriate for treating acute exacerbations, particularly in children 6 years old and above.

If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of seriously worsening asthma which would require reassessment of therapy.

The drug compatibility (physical and chemical), clinical efficacy and safety of albuterol sulfate inhalation solution, when mixed with other drugs in a nebulizer have not been established.

The safety and efficacy of albuterol sulfate inhalation solution have been established in clinical trials when administered using the Pari LC Plus™ nebulizer and Pari PRONEB™ compressor. The safety and efficacy of albuterol sulfate inhalation solution when administered with other nebulizer systems have not been established.

Albuterol sulfate inhalation solution should be administered via jet nebulizer connected to an air compressor with adequate air flow, equipped with a mouthpiece or suitable face mask.
Valacyclovir Hydrochlor...

Valacyclovir Hydrochloride

Valacyclovir hydrochloride tablets may be given without regard to meals.
      Labeling describing use of valacyclovir HCL in pediatric patients for whom a solid dosage form is not appropriate is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that information is not approved for this valacyclovir HCL tablet product.

2.1       Adult Dosing Recommendations

      Cold Sores (Herpes Labialis): The recommended dosage of valacyclovir hydrochloride tablets for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).

      Genital Herpes: Initial Episode: The recommended dosage of valacyclovir hydrochloride tablets for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.

      Recurrent Episodes: The recommended dosage of valacyclovir hydrochloride tablets for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode.

      Suppressive Therapy: The recommended dosage of valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily.

      In HIV-infected patients with a CD4+ cell count ≥100 cells/mm3, the recommended dosage of valacyclovir hydrochloride tablets for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily.

      Reduction of Transmission: The recommended dosage of valacyclovir hydrochloride tablets for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner.

      Herpes Zoster: The recommended dosage of valacyclovir hydrochloride tablets for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of herpes zoster and is most effective when started within 48 hours of the onset of rash.

2.2       Pediatric Dosing Recommendations

      Cold Sores (Herpes Labialis): The recommended dosage of valacyclovir hydrochloride tablets for the treatment of cold sores in pediatric patients ≥12 years of age is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning).

      Labeling describing additional dosing of valacyclovir HCL for pediatric patients with chickenpox is approved for GlaxoSmithKline’s Valtrex®* Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of that additional dosing information is not approved for this valacyclovir HCL tablet product.

2.4       Patients With Renal Impairment

            Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not available for the use of valacyclovir hydrochloride tablets in pediatric patients with a creatinine clearance <50 mL/min/1.73 m2.
Table 1. Valacyclovir Hydrochloride Tablets Dosage Recommendations for Adults With Renal Impairment    Normal Dosage Regimen Creatinine Clearance (mL/min) Indications (Creatinine Clearance ≥ 50 mL/min) 30 to 49 10 to 29 <10 Cold sores (Herpes labialis) Do not exceed 1 day of treatment. Two 2 gramdoses taken12 hours apart Two 1 gramdoses taken12 hours apart Two 500 mg doses taken 12 hours apart 500 mg singledose Genital herpes: Initial Episode 1 gram every12 hours no reduction 1 gram every24 hours 500 mg every24 hours Genital herpes: Recurrent episode 500 mg every12 hours no reduction 500 mg every24 hours 500 mg every24 hours Genital herpes: Suppressive therapy       Immunocompetent 1 gram every no reduction 500 mg every 500 mg every       patients 24 hours 24 hours 24 hours             Alternate dose for 500 mg every no reduction 500 mg every 500 mg every       immunocompetent 24 hours 48 hours 48 hours       patients with ≤ 9       recurrences/year       HIV-Infected patients 500 mg every no reduction 500 mg every 500 mg every 12 hours 24 hours 24 hours Herpes zoster 1 gram every8 hours 1 gram every12 hours 1 gram every24 hours 500 mg every24 hours
      Hemodialysis: Patients requiring hemodialysis should receive the recommended dose of valacyclovir hydrochloride tablets after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of valacyclovir hydrochloride tablets is approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session.

      Peritoneal Dialysis: There is no information specific to administration of valacyclovir hydrochloride tablets in patients receiving peritoneal dialysis. The effect of chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with end-stage renal disease (ESRD) not receiving hemodialysis. Therefore, supplemental doses of valacyclovir hydrochloride tablets should not be required following CAPD or CAVHD.
Albuterol Sulfate Solut...

Albuterol Sulfate Solution

Adults and Children 2 to 12 Years of Age:

The usual dosage for adults and for children weighing at least 15 kg is 2.5 mg of albuterol (one vial) administered three to four times daily by nebulization. Children weighing < 15 kg who require < 2.5 mg/dose (i.e., less than a full vial) should use albuterol inhalation solution, 0.5% instead of albuterol inhalation solution, 0.083%. More frequent administration or higher doses are not recommended. To administer 2.5 mg of albuterol, administer the entire contents of one sterile unit dose vial (3 mL of 0.083% inhalation solution) by nebulization. The flow rate is regulated to suit the particular nebulizer so that albuterol inhalation solution will be delivered over approximately 5 to 15 minutes.

The use of albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimum benefit from regular use of the inhalation solution.

If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of seriously worsening asthma that would require reassessment of therapy.
Atenolol And Chlorthali...

Atenolol And Chlorthalidone

DOSAGE MUST BE INDIVIDUALIZED (SEE INDICATIONS AND USAGE): Chlorthalidone is usually given at a dose of 25 mg daily; the usual initial dose of atenolol is 50 mg daily. Therefore, the initial dose should be one atenolol and chlorthalidone 50 mg-25 mg tablet given once a day. If an optimal response is not achieved, the dosage should be increased to one atenolol and chlorthalidone 100 mg-25 mg tablet given once a day.

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.

Since atenolol is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73 m2 (normal range is 100-150 mL/min/1.73 m2); therefore, the following maximum dosages are recommended for patients with renal impairment.
Creatinine Clearance Atenolol Elimination (mL/min/1.73 m2) Half-life (hrs) Maximum Dosage 15-35 16-27 50 mg daily <15 >27 50 mg every other day
Lisinopril And Hydrochl...

Lisinopril And Hydrochlorothiazide

Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10-80 mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5-50 mg per day. In clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates generally increased with increasing dose of either component.

The side effects (see WARNINGS) of lisinopril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of lisinopril and hydrochlorothiazide may be associated with either or both dose-independent or dose-dependent side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

Dose Titration Guided by Clinical Effect:A patient whose blood pressure is not adequately controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to lisinopril/HCTZ 10/12.5 mg or lisinopril/HCTZ 20/12.5 mg, depending on current monotherapy dose. Further increases of either or both components should depend on clinical response with blood pressure measured at the interdosing interval to ensure that there is an adequate antihypertensive effect at that time. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed. After addition of the diuretic it may be possible to reduce the dose of lisinopril. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen may achieve similar or greater blood-pressure control without electrolyte disturbance if they are switched to lisinopril/HCTZ 10/12.5 mg.

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

If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril 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).

Concomitant administration of lisinopril and hydrochlorothiazide with potassium supplements, potassium salt substitutes or potassium-sparing diuretics may lead to increases of serum potassium (See PRECAUTIONS).

Replacement Therapy: The combination may be substituted for the titrated individual components.

Use in Renal Impairment: Regimens of therapy with lisinopril/HCTZ need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.7 m2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so lisinopril/HCTZ is not recommended (See WARNINGS, Anaphylactoid Reactions During Membrane Exposure).
Glipizide And Metformin...

Glipizide And Metformin Hydrochloride

General Considerations

Dosage of glipizide and metformin hydrochloride tablets USP must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glipizide/2000 mg metformin. Glipizide and metformin hydrochloride tablets USP should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glipizide), reduce GI side effects (largely due to metformin), and permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.

With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to glipizide and metformin hydrochloride tablets USP and to identify the minimum effective dose for the patient. Thereafter, HbA1c should be measured at intervals of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease FPG, PPG, and HbA1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA1c, which is a better indicator of long-term glycemic control than FPG alone.

No studies have been performed specifically examining the safety and efficacy of switching to glipizide and metformin hydrochloride tablet therapy in patients taking concomitant glipizide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring.

Glipizide and Metformin Hydrochloride Tablets USP in Patients With Inadequate Glycemic Control on Diet and Exercise Alone

For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of glipizide and metformin hydrochloride tablets USP is 2.5 mg/250 mg once a day with a meal. For patients whose FPG is 280 mg/dL to 320 mg/dL a starting dose of glipizide and metformin hydrochloride tablets USP, 2.5 mg/500 mg twice daily should be considered. The efficacy of glipizide and metformin hydrochloride tablets USP in patients whose FPG exceeds 320 mg/dL has not been established. Dosage increases to achieve adequate glycemic control should be made in increments of 1 tablet per day every 2 weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg glipizide and metformin hydrochloride tablets USP per day given in divided doses. In clinical trials of glipizide and metformin hydrochloride tablets USP as initial therapy, there was no experience with total daily doses > 10 mg/2000 mg per day.

Glipizide and Metformin Hydrochloride Tablets USP in Patients With Inadequate Glycemic Control on a Sulfonylurea and/or Metformin

For patients not adequately controlled on either glipizide (or another sulfonylurea) or metformin alone, the recommended starting dose of glipizide and metformin hydrochloride tablets USP is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of glipizide and metformin hydrochloride tablets USP should not exceed the daily doses of glipizide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

Patients previously treated with combination therapy of glipizide (or another sulfonylurea) plus metformin may be switched to glipizide and metformin hydrochloride tablets USP, 2.5 mg/500 mg or 5 mg/500 mg; the starting dose should not exceed the daily dose of glipizide (or equivalent dose of another sulfonylurea) and metformin already being taken. The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of glipizide and metformin hydrochloride tablets USP should be titrated as described above to achieve adequate control of blood glucose.

Specific Patient Populations

Glipizide and metformin hydrochloride tablets USP are not recommended for use during pregnancy or for use in pediatric patients. The initial and maintenance dosing of glipizide and metformin hydrochloride tablets USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of glipizide and metformin hydrochloride tablets USP to avoid the risk of hypoglycemia. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see WARNINGS).
Losartan Potassium

Losartan Potassium

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 USP 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 3-6 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 Populations and Pharmacodynamics and Clinical Effects, and 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, Pharmacokinetics, 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™1 and Ora-Sweet SF™1 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.
1 Ora-Plus TM and Ora-Sweet SF TM are trademarks of Paddock Laboratories, Inc.
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 tablets may be administered with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones and glucosidase inhibitors).
Levalbuterol Hydrochlor...

Levalbuterol Hydrochloride Solution

Children 6–11 years old: The recommended dosage of Levalbuterol HCl Inhalation Solution for patients 6–11 years old is 0.31 mg administered three times a day, by nebulization. Routine dosing should not exceed 0.63 mg three times a day.

Adults and Adolescents ≥ 12 years old: The recommended starting dosage of Levalbuterol HCl Inhalation Solution for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.

Patients 12 years of age and older with more severe asthma or patients who do not respond adequately to a dose of 0.63 mg of Levalbuterol HCl Inhalation Solution may benefit from a dosage of 1.25 mg three times a day.

Patients receiving the highest dose of Levalbuterol HCl Inhalation Solution should be monitored closely for adverse systemic effects, and the risks of such effects should be balanced against the potential for improved efficacy.

The use of Levalbuterol HCl Inhalation Solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time, most patients gain optimal benefit from regular use of the inhalation solution.

If a previously effective dosage regimen fails to provide the expected relief, medical advice should be sought immediately, since this is often a sign of seriously worsening asthma that would require reassessment of therapy.

The drug compatibility (physical and chemical), efficacy, and safety of Levalbuterol HCl Inhalation Solution when mixed with other drugs in a nebulizer have not been established.

The safety and efficacy of Levalbuterol HCl Inhalation Solution have been established in clinical trials when administered using the PARI LC Jet™ and PARI LC Plus™ nebulizers, and the PARI Master® Dura-Neb® 2000 and Dura-Neb® 3000 compressors. The safety and efficacy of Levalbuterol HCl Inhalation Solution when administered using other nebulizer systems have not been established.
Sulfasalazine

Sulfasalazine

The dosage of sulfasalazine tablets should be adjusted to each individual’s response and tolerance.

Initial Therapy:

Adults: 3 to 4 g daily in evenly divided doses with dosage intervals not exceeding eight hours. In some cases, it is advisable to initiate therapy with a smaller dosage, e.g., 1 to 2 g daily, to reduce possible gastrointestinal intolerance. If daily doses exceeding 4 g are required to achieve desired effects, the increased risk of toxicity should be kept in mind.

Children, six years of age and older: 40 to 60 mg/kg body weight in each 24-hour period, divided into 3 to 6 doses.

Maintenance Therapy:

Adults: 2 g daily.

Children, six years of age and older: 30 mg/kg body weight in each 24-hour period, divided into 4 doses.

The response of acute ulcerative colitis to sulfasalazine tablets can be evaluated by clinical criteria, including the presence of fever, weight changes, and degree and frequency of diarrhea and bleeding, as well as by sigmoidoscopy and the evaluation of biopsy samples. It is often necessary to continue medication even when clinical symptoms, including diarrhea, have been controlled. When endoscopic examination confirms satisfactory improvement, the dosage of sulfasalazine should be reduced to a maintenance level. If diarrhea recurs, the dosage should be increased to previously effective levels. If symptoms of gastric intolerance (anorexia, nausea, vomiting, etc.) occur after the first few doses of sulfasalazine, they are probably due to increased serum levels of total sulfapyridine and may be alleviated by halving the daily dose of sulfasalazine and subsequently increasing it gradually over several days. If gastric intolerance continues, the drug should be stopped for 5 to 7 days, then reintroduced at a lower daily dose.

Some patients may be sensitive to treatment with sulfasalazine. Various desensitization-like regimens have been reported to be effective in 34 of 53 patients, 4 7 of 8 patients, 5 and 19 of 20 patients. 6 These regimens suggest starting with a total daily dose of 50 to 250 mg sulfasalazine initially, and doubling it every 4 to 7 days until the desired therapeutic level is achieved. If the symptoms of sensitivity recur, sulfasalazine should be discontinued.

Desensitization should not be attempted in patients who have a history of agranulocytosis, or who have experienced an anaphylactoid reaction while previously receiving sulfasalazine.
Zolpidem Tartrate

Zolpidem Tartrate

The dose of zolpidem tartrate extended-release tablets should be individualized.

2.1 Dosage in adults

The recommended dose of zolpidem tartrate extended-release tablets for adults is 12.5 mg once daily immediately before bedtime. The total zolpidem tartrate extended-release tablets dose should not exceed 12.5 mg per day.

2.2 Special populations

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normals. The recommended dose of zolpidem tartrate extended-release tablets in both of these patient populations is 6.25 mg once daily immediately before bedtime [see Warnings and Precautions (5.6)].

2.3 Use with CNS depressants

Dosage adjustments may be necessary when zolpidem tartrate extended-release tablets are combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.5)].

2.4 Administration

Zolpidem tartrate extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of zolpidem tartrate extended-release tablets may be slowed by ingestion with or immediately after a meal.
Budesonide Inhalation

Budesonide Inhalation

The recommended starting dose and highest recommended dose of budesonide inhalation suspension, based on prior asthma therapy, are listed in the following table.
Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators alone 0.5 mg total daily dose administeredtwice daily in divided doses 0.5 mg total daily dose Inhaled Corticosteroids 0.5 mg total daily dose administeredtwice daily in divided doses 1 mg total daily dose Oral Corticosteroids 1 mg total daily dose administeredas 0.5 mg twice daily 1 mg total daily dose
2.1 Dosing Recommendations

Dosing recommendations based on previous therapy are as follows:
Bronchodilators alone: 0.25 mg twice daily Inhaled corticosteroids: 0.25 mg twice daily up to 0.5 mg twice daily Oral corticosteroids: 0.5 mg twice daily
In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved.

2.2 Directions for Use

Budesonide inhalation suspension should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of budesonide inhalation suspension and, therefore, are NOT recommended.

The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed. Budesonide inhalation suspension should be administered separately in the nebulizer [see Patient Counseling Information, Administration with a jet nebulizer (17.1)].

A Pari-LC-Jet Plus Nebulizer (with face mask or mouthpiece) connected to a Pari Master compressor was used to deliver budesonide inhalation suspension to each patient in 3 U.S. controlled clinical studies. The safety and efficacy of budesonide inhalation suspension delivered by other nebulizers and compressors have not been established.
Ipratropium Bromide Sol...

Ipratropium Bromide Solution

The usual dosage of ipratropium bromide inhalation solution is 500 mcg (1 Unit-Dose Vial) administered three to four times a day by oral nebulization, with doses 6 to 8 hours apart. Ipratropium bromide inhalation solution unit-dose vials contain 500 mcg ipratropium bromide, USP anhydrous in 2.5 mL normal saline. Ipratropium bromide inhalation solution can be mixed in the nebulizer with albuterol or metaproterenol if used within one hour. Drug stability and safety of Ipratropium Bromide Inhalation Solution when mixed with other drugs in a nebulizer have not been established.
Nortriptyline Hydrochlo...

Nortriptyline Hydrochloride

Nortriptyline hydrochloride is not recommended for children.

Nortriptyline hydrochloride is administered orally. Lower than usual dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients than for hospitalized patients who will be under close supervision. The physician should initiate dosage at a low level and increase it gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission.

If a patient develops minor side effects, the dosage should be reduced. The drug should be discontinued promptly if adverse effects of a serious nature or allergic manifestations occur.

Usual Adult Dose - 25 mg three or four times daily; dosage should begin at a low level and be increased as required. As an alternate regimen, the total daily dosage may be given once a day. When doses above 100 mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150 ng/mL. Doses above 150 mg/day are not recommended.

Elderly and Adolescent Patients - 30 to 50 mg/day, in divided doses, or the total daily dosage may be given once a day.

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

Use of Nortriptyline Hydrochloride With Other MAOIs, Such as Linezolid or Methylene Blue Do not start nortriptyline hydrochloride in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).

In some cases, a patient already receiving nortriptyline hydrochloride therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, nortriptyline hydrochloride should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with nortriptyline hydrochloride may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).

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

Ipratropium Bromide And Albuterol Sulfate Solution

The recommended dose of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution is one 3 mL vial administered 4 times per day via nebulization with up to 2 additional 3 mL doses allowed per day, if needed. Safety and efficacy of additional doses or increased frequency of administration of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution beyond these guidelines has not been studied and the safety and efficacy of extra doses of albuterol sulfate or ipratropium bromide in addition to the recommended doses of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution have not been studied.

The use of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution can be continued as medically indicated to control recurring bouts of bronchospasm. If a previously effective regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of worsening COPD, which would require reassessment of therapy.

A Pari-LC-Plus™ nebulizer (with face mask or mouthpiece) connected to a PRONEB™ compressor was used to deliver Ipratropium Bromide and Albuterol Sulfate Inhalation Solution to each patient in one U.S. clinical study. The safety and efficacy of Ipratropium Bromide and Albuterol Sulfate Inhalation Solution delivered by other nebulizers and compressors have not been established.

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.
Ipratropium Bromide And...

Ipratropium Bromide And Albuterol Sulfate Solution

The recommended dose of ipratropium bromide and albuterol sulfate inhalation solution is one 3 mL vial administered 4 times per day via nebulization with up to 2 additional 3 mL doses allowed per day, if needed. Safety and efficacy of additional doses or increased frequency of administration of ipratropium bromide and albuterol sulfate inhalation solution beyond these guidelines has not been studied and the safety and efficacy of extra doses of albuterol sulfate or ipratropium bromide in addition to the recommended doses of ipratropium bromide and albuterol sulfate inhalation solution have not been studied.The use of ipratropium bromide and albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. If a previously effective regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of worsening COPD, which would require reassessment of therapy.A Pari-LC-Plus™ nebulizer (with face mask or mouthpiece) connected to a PRONEB™ compressor was used to deliver ipratropium bromide and albuterol sulfate inhalation solution to each patient in one U.S. clinical study. The safety and efficacy of ipratropium bromide and albuterol sulfate inhalation solution delivered by other nebulizers and compressors have not been established.Ipratropium bromide and albuterol sulfate inhalation solution should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.
Cyclobenzaprine Hydroch...

Cyclobenzaprine Hydrochloride

For most patients, the recommended dose of cyclobenzaprine HCl is 5 mg three times a day. Based on individual patient response, the dose may be increased to either 7.5 mg or 10 mg three times a day. Use of cyclobenzaprine HCl for periods longer than two or three weeks is not recommended. (See INDICATIONS AND USAGE.)

Less frequent dosing should be considered for hepatically impaired or elderly patients (see PRECAUTIONS, Impaired Hepatic Function, and Use in the Elderly).
Valsartan And Hydrochlo...

Valsartan And Hydrochlorothiazide

2.1 General Considerations

The usual starting dose is valsartan and hydrochlorothiazide tablets 160 mg/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 320 mg/25 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.2)]. Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose.

2.2 Add-On Therapy

A patient whose blood pressure is not adequately controlled with valsartan (or another ARB) alone or hydrochlorothiazide alone may be switched to combination therapy with valsartan and hydrochlorothiazide tablets.

A patient who experiences dose-limiting adverse reactions on either component alone may be switched to valsartan and hydrochlorothiazide tablets containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to valsartan and hydrochlorothiazide tablets should be subsequently evaluated and if blood pressure remains uncontrolled after 3 to 4 weeks of therapy, the dose may be titrated up to a maximum of 320 mg/25 mg.

2.3 Replacement Therapy

Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components.

2.4 Initial Therapy

Valsartan and hydrochlorothiazide tablets are not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2)].

2.5 Use with Other Antihypertensive Drugs

Valsartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.
Hydroxychloroquine Sulf...

Hydroxychloroquine Sulfate

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

Carisoprodol

The recommended dose of carisoprodol tablets is 350 mg three times a day and at bedtime. The recommended maximum duration of carisoprodol tablets use is up to two or three weeks.
Propafenone Hcl

Propafenone Hcl

The dose of propafenone hydrochloride tablets must be individually titrated on the basis of response and tolerance. Initiate therapy with propafenone hydrochloride tablets 150 mg given every eight hours (450 mg/day). Dosage may be increased at a minimum of 3 to 4 day intervals to 225 mg every 8 hours (675 mg/day). If additional therapeutic effect is needed, the dose of propafenone hydrochloride tablets may be increased to 300 mg every 8 hours (900 mg/day). The usefulness and safety of dosages exceeding 900 mg per day have not been established.

In patients with hepatic impairment or thosewith significant widening of the QRS complex or second or third degree AV block, consider reducing the dose.

As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of propafenone hydrochloride tablets should be increased more gradually during the initial phase of treatment.

The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proarrhythmia and other adverse events. Therefore, avoid simultaneous use of propafenone hydrochloride with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions (5.4) and Drug Interactions (7.1)].
Ciclopirox Shampoo

Ciclopirox Shampoo

Ciclopirox Shampoo 1% is not for ophthalmic, oral, or intravaginal use.

Wet hair and apply approximately 1 teaspoon (5 mL) of Ciclopirox Shampoo 1% to the scalp. Up to 2 teaspoons (10 mL) may be used for long hair. Lather and leave on hair and scalp for 3 minutes. A timer may be used. Avoid contact with eyes. Rinse off. Treatment should be repeated twice per week for 4 weeks, with a minimum of 3 days between applications.

If a patient with seborrheic dermatitis shows no clinical improvement after 4 weeks of treatment with Ciclopirox Shampoo 1%, the diagnosis should be reviewed.
Oxycodone And Acetamino...

Oxycodone And Acetaminophen

Dosage should be adjusted according to the severity of the pain and the response of the patient. It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids. If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule. Oxycodone and acetaminophen tablets are given orally.

Oxycodone and acetaminophen tablets 5 mg/325 mg; Oxycodone and acetaminophen tablets 7.5 mg/500 mg; Oxycodone and acetaminophen tablets 10 mg/650 mg The usual adult dosage is one tablet every 6 hours as needed for pain. The total daily dose of acetaminophen should not exceed 4 grams.

Oxycodone and acetaminophen tablets 7.5 mg/325 mg; Oxycodone and acetaminophen tablets 10 mg/325 mg The usual adult dosage is one tablet every 6 hours as needed for pain. The total daily dose of acetaminophen should not exceed 4 grams.
Strength Maximal Daily Dose Oxycodone and Acetaminophen Tablets 5 mg/325 mg 12 tablets Oxycodone and Acetaminophen Tablets 7.5 mg/325 mg 8 tablets Oxycodone and Acetaminophen Tablets 7.5 mg/500 mg 8 tablets Oxycodone and Acetaminophen Tablets 10 mg/325 mg 6 tablets Oxycodone and Acetaminophen Tablets 10 mg/650 mg 6 tablets
Cessation of Therapy

In patients treated with oxycodone and acetaminophen tablets for more than a few weeks who no longer require therapy, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient.
Ibandronate Sodium

Ibandronate Sodium

2.1 Dosage Information

The dose of ibandronate sodium is one 150 mg tablet taken once monthly on the same date each month.

2.2 Important Administration Instructions

Instruct Patients to do the following:
Take ibandronate sodium tablets at least 60 minutes before the first food or drink (other than water) of the day or before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, (see Drug Interactions [7.1]). Avoid the use of water with supplements including mineral water because they may have a higher concentration of calcium. Swallow ibandronate sodium tablets whole with a full glass of plain water (6 to 8 oz) while standing or sitting in an upright position to reduce the potential for esophageal irritation. Avoid lying down for 60 minutes after taking ibandronate sodium tablets (see Warnings and Precautions [5.1]). Do not chew or suck the tablet because of a potential for oropharyngeal ulceration. Do not eat, drink anything except plain water, or take other medications for at least 60 minutes after taking ibandronate sodium tablets.
2.3 Recommendations for Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Avoid the use of calcium supplements within 60 minutes of ibandronate sodium tablets administration because coadministration of ibandronate sodium tablets and calcium may interfere with the absorption of ibandronate sodium (see Drug Interactions [7.1] ).

2.4 Administration Instructions for Missed Once-Monthly Doses

If the once-monthly dose is missed, instruct patients to do the following:
If the next scheduled ibandronate sodium tablets day is more than 7 days away, take one ibandronate sodium 150 mg tablet in the morning following the date that it is remembered. If the next scheduled ibandronate sodium tablets day is only 1 to 7 days away, wait until the subsequent month’s scheduled ibandronate sodium tablets day to take their tablet.
For subsequent monthly doses for both of the above scenarios, instruct patients to return to their original schedule by taking one ibandronate sodium 150 mg tablet every month on their previous chosen day.
Oxycodone And Acetamino...

Oxycodone And Acetaminophen

Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to oxycodone can develop with continued use and that the incidence of untoward effects is dose related. This product is inappropriate even in high doses for severe or intractable pain.

Oxycodone and acetaminophen capsules are given orally. The usual adult dosage is one capsule every 6 hours as needed for pain.
Buspirone Hcl

Buspirone Hcl

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

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

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

Phenadoz

Promethazine HCl Rectal Suppositories, USP are contraindicated for children under 2 years of age (see WARNINGS- Use in Pediatric Patients).

Phenadoz Suppositories are for rectal administration only.

Allergy

The average dose is 25 mg taken before retiring; however, 12.5 mg may be taken before meals and on retiring, if necessary. Single 25-mg doses at bedtime or 6.25 to 12.5 mg taken three times daily will usually suffice. After initiation of treatment in children or adults, dosage should be adjusted to the smallest amount adequate to relieve symptoms. The administration of promethazine hydrochloride in 25-mg doses will control minor transfusion reactions of an allergic nature.

Motion Sickness

The average adult dose is 25 mg taken twice daily. The initial dose should be taken one-half to one hour before anticipated travel and be repeated 8 to 12 hours later, if necessary. On succeeding days of travel, it is recommended that 25 mg be given on arising and again before the evening meal. For children, Phenadoz Suppositories, 12.5 to 25 mg, twice daily, may be administered.

Nausea and Vomiting

Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see WARNINGS- Use in Pediatric Patients).

The average effective dose of Phenadoz for the active therapy of nausea and vomiting in children or adults is 25 mg. 12.5- to 25-mg doses may be repeated, as necessary, at 4 to 6 hour intervals.

For nausea and vomiting in children, the usual dose is 0.5 mg per pound of body weight, and the dose should be adjusted to the age and weight of the patient and the severity of the condition being treated.

For prophylaxis of nausea and vomiting, as during surgery and the postoperative period, the average dose is 25 mg repeated at 4- to 6-hour intervals, as necessary.

Sedation

This product relieves apprehension and induces a quiet sleep from which the patient can be easily aroused. Administration of 12.5 to 25 mg Phenadoz by rectal suppository at bedtime will provide sedation in children. Adults usually require 25 to 50 mg for nighttime, presurgical, or obstetrical sedation.

Pre- and Postoperative Use

Phenadoz in 12.5- to 25-mg doses for children and 50-mg doses for adults the night before surgery relieves apprehension and produces a quiet sleep.

For preoperative medication children require doses of 0.5 mg per pound of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug. Usual adult dosage is 50 mg Phenadoz with an appropriately reduced dose of narcotic or barbiturate and the required amount of a belladonna alkaloid.

Postoperative sedation and adjunctive use with analgesics may be obtained by the administration of 12.5 to 25 mg in children and 25-to 50-mg doses in adults.

Phenadoz Rectal Suppositories are not recommended for children under 2 years of age.
Progesterone

Progesterone

Prevention of Endometrial Hyperplasia

Progesterone Capsules should be given as a single daily dose at bedtime, 200 mg orally for 12 days sequentially per 28-day cycle, to a postmenopausal woman with a uterus who is receiving daily conjugated estrogens tablets.

Treatment of Secondary Amenorrhea

Progesterone Capsules may be given as a single daily dose of 400 mg at bedtime for 10 days.

Some women may experience difficulty swallowing Progesterone Capsules. For these women, Progesterone Capsules should be taken with a glass of water while in the standing position.
Mirtazapine

Mirtazapine

Initial Treatment

The recommended starting dose for mirtazapine orally disintegrating tablets is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In the controlled clinical trials establishing the efficacy of mirtazapine in the treatment of major depressive disorder, the effective dose range was generally 15 to 45 mg/day. While the relationship between dose and satisfactory response in the treatment of major depressive disorder for mirtazapine has not been adequately explored, patients not responding to the initial 15-mg dose may benefit from dose increases up to a maximum of 45 mg/day. Mirtazapine has an elimination half-life of approximately 20 to 40 hours; therefore, dose changes should not be made at intervals of less than 1 to 2 weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose.

Administration of Mirtazapine Orally Disintegrating Tablets

Patients should be instructed to open tablet blister pack with dry hands and place the tablet on the tongue. The tablet should be used immediately after removal from its blister; once removed, it cannot be stored. Mirtazapine orally disintegrating tablets will disintegrate rapidly on the tongue and can be swallowed with saliva. No water is needed for taking the tablet. Patients should not attempt to split the tablet.

Elderly and Patients with Renal or Hepatic Impairment

The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment (see PRECAUTIONS and CLINICAL PHARMACOLOGY).

Maintenance/Extended 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. Systematic evaluation of mirtazapine tablets has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8 to 12 weeks of initial treatment at a dose of 15 to 45 mg/day (see CLINICAL PHARMACOLOGY). Based on these limited data, it is unknown whether or not the dose of mirtazapine 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.

Switching Patients To or From a Monoamine Oxidase Inhibitor

Concomitant use of mirtazapine orally disintegrating tablets with MAOIs is contraindicated. At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with mirtazapine orally disintegrating tablets. In addition, at least 14 days should be allowed after stopping mirtazapine orally disintegrating tablets before starting an MAOI.

Discontinuation of Mirtazapine Treatment

Symptoms associated with the discontinuation or dose reduction of mirtazapine orally disintegrating tablets have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction. A gradual reduction in the dose over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see PRECAUTIONS and ADVERSE REACTIONS).
Glipizide Er

Glipizide Er

There is no fixed dosage regimen for the management of diabetes mellitus with glipizide extended-release tablets or any other hypoglycemic agent. Glycemic control should be monitored with hemoglobin A1C and/or blood-glucose levels to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Home blood-glucose monitoring may also provide useful information to the patient and physician. Short-term administration of glipizide extended-release tablets may be sufficient during periods of transient loss of control in patients usually controlled on diet.

In general, glipizide extended-release tablets should be given with breakfast.

Recommended Dosing: The usual starting dose of glipizide extended-release tablets as initial therapy is 5 mg per day, given with breakfast. Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose.

Dosage adjustment should be based on laboratory measures of glycemic control. While fasting blood-glucose levels generally reach steady-state following initiation or change in glipizide extended-release tablet dosage, a single fasting glucose determination may not accurately reflect the response to therapy. In most cases, hemoglobin A1C level measured at three month intervals is the preferred means of monitoring response to therapy.

Hemoglobin A1C should be measured as glipizide extended-release tablet therapy is initiated and repeated approximately three months later. If the result of this test suggests that glycemic control over the preceding three months was inadequate, the glipizide extended-release tablet dose may be increased. Subsequent dosage adjustments should be made on the basis of hemoglobin A1C levels measured at three month intervals. If no improvement is seen after three months of therapy with a higher dose, the previous dose should be resumed. Decisions which utilize fasting blood glucose to adjust glipizide extended-release tablet therapy should be based on at least two or more similar, consecutive values obtained seven days or more after the previous dose adjustment.

Most patients will be controlled with 5 mg to 10 mg taken once daily. However, some patients may require up to the maximum recommended daily dose of 20 mg. While the glycemic control of selected patients may improve with doses which exceed 10 mg, clinical studies conducted to date have not demonstrated an additional group average reduction of hemoglobin A1C beyond what was achieved with the 10 mg dose.

Based on the results of a randomized crossover study, patients receiving immediate release glipizide may be switched safely to glipizide extended-release tablets once-a-day at the nearest equivalent total daily dose. Patients receiving immediate release glipizide also may be titrated to the appropriate dose of glipizide extended-release tablets starting with 5 mg once daily. The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment.

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

Combination Use: When adding other blood-glucose-lowering agents to glipizide extended-release tablets for combination therapy, the agent should be initiated at the lowest recommended dose, and patients should be observed carefully for hypoglycemia. Refer to the product information supplied with the oral agent for additional information.

When adding glipizide extended-release tablets to other blood-glucose-lowering agents, glipizide extended-release tablets can be initiated at 5 mg. Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose. Titration should be based on clinical judgment.

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

Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many patients with stable type 2 diabetes receiving insulin may be transferred safely to treatment with glipizide extended-release tablets. When transferring patients from insulin to glipizide extended-release tablets, the following general guidelines should be considered:

For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide extended-release tablet therapy may begin at usual dosages. Several days should elapse between titration steps.

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

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

Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide extended-release tablets. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide extended-release tablets due to potential overlapping of drug effect.
Pentazocine Hcl And Ace...

Pentazocine Hcl And Acetaminophen

Adult

The usual adult dose is 1 tablet every 4 hours as needed for pain relief, up to a maximum of 6 tablets per day.

Discontinuation

Due to the potential for withdrawal symptoms associated with abrupt discontinuation, consideration should be given to tapering patients off pentazocine and acetaminophen tablets after prolonged periods of treatment with pentazocine and acetaminophen tablets (See PRECAUTIONS , Drug Abuse and Dependence).
Clomiphene Citrate

Clomiphene Citrate

General Considerations

The workup and treatment of candidates for clomiphene citrate tablets USP therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene citrate tablets USP only after careful diagnostic evaluation (see INDICATIONS AND USAGE). The plan of therapy should be outlined in advance. Impediments to achieving the goal of therapy must be excluded or adequately treated before beginning clomiphene citrate tablets USP. The therapeutic objective should be balanced with potential risks and discussed with the patient and others involved in the achievement of a pregnancy.

Ovulation most often occurs from 5 to 10 days after a course of clomiphene citrate tablets USP. Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time.

Recommended Dosage

Treatment of the selected patient should begin with a low dose, 50 mg daily (1 tablet) for 5 days. The dose should be increased only in those patients who do not ovulate in response to cyclic 50 mg clomiphene citrate tablets USP. A low dosage or duration of treatment course is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, such as in patients with polycystic ovary syndrome (see WARNINGS; Ovarian Hyperstimulation Syndrome).

The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle.

If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs prior to therapy, the regimen of 50 mg daily for 5 days should be started on or about the 5th day of the cycle. Therapy may be started at any time in the patient who has had no recent uterine bleeding. When ovulation occurs at this dosage, there is no advantage to increasing the dose in subsequent cycles of treatment.

If ovulation does not appear to occur after the first course of therapy, a second course of 100 mg daily (two 50 mg tablets given as a single daily dose) for 5 days should be given. This course may be started as early as 30 days after the previous one after precautions are taken to exclude the presence of pregnancy. Increasing the dosage or duration of therapy beyond 100 mg/day for 5 days is not recommended.

The majority of patients who are going to ovulate will do so after the first course of therapy. If ovulation does not occur after three courses of therapy, further treatment with clomiphene citrate tablets USP is not recommended and the patient should be reevaluated. If three ovulatory responses occur, but pregnancy has not been achieved, further treatment is not recommended. If menses does not occur after an ovulatory response, the patient should be reevaluated. Long-term cyclic therapy is not recommended beyond a total of about 6 cycles (see PRECAUTIONS).
Glipizide

Glipizide

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

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

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

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

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

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

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

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

For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide therapy may begin at usual dosages. Several days should elapse between glipizide titration steps.

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

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

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

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

Lisinopril

Hypertension

Initial Therapy: In patients with uncomplicated essential hypertension not on diuretic therapy, the recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 20 to 40 mg per day administered in a single daily dose. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. Doses up to 80 mg have been used but do not appear to give greater effect. If blood pressure is not controlled with lisinopril alone, a low dose of a diuretic may be added. Hydrochlorothiazide, 12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.

Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of lisinopril. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with lisinopril tablet to reduce the likelihood of hypotension (See WARNINGS). The dosage of lisinopril should be adjusted according to blood pressure response. If the patient's blood pressure is not controlled with lisinopril alone, diuretic therapy may be resumed as described above.

If the diuretic cannot be discontinued, an initial dose of 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).

Concomitant administration of lisinopril with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (See PRECAUTIONS).

Dosage Adjustment in Renal Impairment: The usual dose of lisinopril (10 mg) is recommended for patients with creatinine clearance > 30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance ≥ 10 mL/min ≤ 30 mL/min (serum creatinine ≥ 3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance < 10 mL/min (usually on hemodialysis) the recommended initial dose is 2.5 mg. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.
Renal Status Creatinine ClearancemL/min Initial Dosemg/day *See WARNINGS, Anaphylactoid Reactions During Membrane Exposure. * * Dosage or dosing interval should be adjusted depending on the blood pressure response. Normal Renal Function to Mild Impairment >30 10 Moderate to Severe Impairment ≥10 ≤30 5 Dialysis Patients* < 10 2.5* *
Heart Failure

Lisinopril tablets are indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended starting dose is 5 mg once a day. When initiating treatment with lisinopril in patients with heart failure, the initial dose should be administered under medical observation, especially in those patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension (See WARNINGS and PRECAUTIONS, Drug Interactions). The appearance of hypotension after the initial dose of lisinopril does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

The usual effective dosage range is 5 to 40 mg per day administered as a single daily dose. The dose of lisinopril can be increased by increments of no greater than 10 mg, at intervals of no less than 2 weeks to the highest tolerated dose, up to a maximum of 40 mg daily. Dose adjustment should be based on the clinical response of individual patients.

Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia: In patients with heart failure who have hyponatremia (serum sodium < 130 mEq/L) or moderate to severe renal impairment (creatinine clearance ≤ 30 mL/min or serum creatinine > 3 mg/dL), therapy with lisinopril should be initiated at a dose of 2.5 mg once a day under close medical supervision (See WARNINGS and PRECAUTIONS, Drug Interactions).

Acute Myocardial Infarction

In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, the first dose of lisinopril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg of lisinopril once daily. Dosing should continue for six weeks. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers.

Patients with a low systolic blood pressure (≤ 120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of lisinopril tablet (See WARNINGS). If hypotension occurs (systolic blood pressure ≤ 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure < 90 mmHg for more than 1 hour) lisinopril tablet should be withdrawn. For patients who develop symptoms of heart failure, see DOSAGE AND ADMINISTRATION, Heart Failure.

Dosage Adjustment in Patients With Myocardial Infarction with Renal Impairment: In acute myocardial infarction, treatment with lisinopril tablets should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosing adjustments in myocardial infarction patients with severe renal impairment has been performed.

Use in Elderly

In general, the clinical response was similar in younger and older patients given similar doses of lisinopril. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients, so that dosage adjustments should be made with particular caution.

Pediatric Hypertensive Patients ≥ 6 years of age

The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects).

Lisinopril is not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m2 (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects and PRECAUTIONS).
Amlodipine Besylate And...

Amlodipine Besylate And Benazepril Hydrochloride

2.1 General Considerations

The recommended initial dose of amlodipine besylate and benazepril hydrochloride capsules is one capsule of amlodipine 2.5 mg/benazepril 10 mg orally once daily.

It is usually appropriate to begin therapy with amlodipine besylate and benazepril hydrochloride capsules only after a patient has either (a) failed to achieve the desired antihypertensive effect with amlodipine or benazepril monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema.

The antihypertensive effect of amlodipine besylate and benazepril hydrochloride capsules is largely attained within 2 weeks. If blood pressure remains uncontrolled, the dose may be titrated up to amlodipine 10 mg/benazepril 40 mg once daily. The dosing should be individualized and adjusted according to the patient’s clinical response.

Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5 to 10 mg while benazepril is effective in doses of 10 to 80 mg. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5 to 10 mg and benazepril doses of 10 to 40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups.

2.2 Dosage Adjustment in Renal Impairment

Renal Impairment: Amlodipine besylate and benazepril hydrochloride capsules is not recommended in patients with creatinine clearance ≤ 30 mL/min. No dose adjustment of amlodipine besylate and benazepril hydrochloride capsules is required in patients creatinine clearance >30 mL/min (serum creatinine roughly ≤3 mg/dL or 265 μmol/L). [see Warnings and Precautions (5.7), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.3 Replacement Therapy

Amlodipine besylate and benazepril hydrochloride capsules may be substituted for the titrated components.
Hydromorphone Hydrochlo...

Hydromorphone Hydrochloride

2.1      Initial Dosing

To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, hydromorphone hydrochloride extended-release tablets are only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning hydromorphone hydrochloride extended-release tablets therapy. As hydromorphone hydrochloride extended-release tablets are only for use in opioid-tolerant patients, do not begin any patient on hydromorphone hydrochloride extended-release tablets as the first opioid.

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Initiate the dosing regimen for each patient individually, taking into account the patient"s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with hydromorphone hydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Hydromorphone hydrochloride extended-release tablets must be taken whole. Crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].

Conversion from Other Oral Hydromorphone Formulations to Hydromorphone Hydrochloride Extended-release TabletsPatients receiving oral immediate-release hydromorphone may be converted to hydromorphone hydrochloride extended-release tablets by administering a starting dose equivalent to the patient’s total daily oral hydromorphone dose, taken once daily.

Conversion from Other Oral Opioids to Hydromorphone Hydrochloride Extended-release TabeltsDiscontinue all other around-the-clock opioid drugs when hydromorphone hydrochloride extended-release tablets therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral hydromorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydromorphone requirements, which could result in adverse reactions.

In a hydromorphone hydrochloride extended-release tablets clinical trial with an open-label titration period, patients were converted from their prior opioid to hydromorphone hydrochloride extended-release tablets using the Table 1 as a guide for the initial hydromorphone hydrochloride extended-release tablets dose. The recommended starting dose of hydromorphone hydrochloride extended-release tablets is 50% of the calculated estimate of daily hydromorphone requirement. Calculate the estimated daily hydromorphone requirement using Table 1.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to hydromorphone hydrochloride extended-release tablets. The table cannot be used to convert from hydromorphone hydrochloride extended-release tablets to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. Table 1. Conversion Factors to Hydromorphone Hydrochloride Extended-release Tablets
Prior Oral Opioid

Approximate OralConversion Factor

Hydromorphone

1

Codeine

0.06

Hydrocodone

0.4

Methadone

0.6

Morphine

0.2

Oxycodone

0.4

Oxymorphone

0.6

To calculate the estimated hydromorphone hydrochloride extended-release tablets dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydromorphone daily dose. For patients on a regimen of more than one opioid, calculate the approximate oral hydromorphone dose for each opioid and sum the totals to obtain the approximate total hydromorphone daily dose. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablets strength(s) available. Example conversion from a single opioid to hydromorphone hydrochloride extended-release tablets:

Step 1: Sum the total daily dose of the opioid
30 mg of oxycodone 2 times daily = 60 mg total daily dose of oxycodone
Step 2: Calculate the approximate equivalent dose of oral hydromorphone based on the total daily dose of the current opioid using Table 1
60 mg total daily dose of oxycodone x Conversion Factor of 0.4 = 24 mg of oral hydromorphone daily
Step 3: Calculate the approximate starting dose of hydromorphone hydrochloride extended-release tablets to be given every 24 hours, which is 50% of the calculated oral hydromorphone dose. Round down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablet strengths available.
50% of 24 mg results in an initial dose of 12 mg of hydromorphone hydrochloride extended-release tablets once daily Adjust individually for each patient
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to hydromorphone hydrochloride extended-release tablets.

Conversion from Transdermal Fentanyl to Hydromorphone Hydrochloride Extended-release TabletsEighteen hours following the removal of the transdermal fentanyl patch, hydromorphone hydrochloride extended-release tablets treatment can be initiated. To calculate the 24-hour hydromorphone hydrochloride extended-release tablets dose, use a conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of hydromorphone hydrochloride extended-release tablets. Then reduce the hydromorphone hydrochloride extended-release tablets dose by 50%.

For example:         Step 1: Identify the dose of transdermal fentanyl.
75 mg of transdermal fentanyl
Step 2: Use the conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of hydromorphone hydrochloride extended-release tablets.
75 mg of transdermal fentanyl : 36 mg total daily dose of hydromorphone hydrochloride extended-release tablets
Step 3: Calculate the approximate starting dose of hydromorphone hydrochloride extended-release tablets to be given every 24 hours, which is 50% of the converted dose. Round down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablet strengths available.
50% of 36 mg results in an initial dose of 18 mg, which would be rounded down to 16 mg of hydromorphone hydrochloride extended-release tablets once daily Adjust individually for each patient
Conversion from Methadone to Hydromorphone Hydrochloride Extended-release TabletsClose monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

2.2       Titration and Maintenance of Therapy

Individually titrate hydromorphone hydrochloride extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving hydromorphone hydrochloride extended-release tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.

Plasma levels of hydromorphone hydrochloride extended-release tablets are sustained for 18 to 24 hours. Dosage adjustments of hydromorphone hydrochloride extended-release tablets may be made in increments of 4-8 mg every 3 to 4 days as needed to achieve adequate analgesia.

Patients who experience breakthrough pain may require a dose increase of hydromorphone hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the hydromorphone hydrochloride extended-release tablets dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3       Discontinuation of Hydromorphone Hydrochloride Extended-release Tablets

When a patient no longer requires therapy with hydromorphone hydrochloride extended-release tablets, taper doses gradually, by 25% to 50% every 2 or 3 days down to a dose of 8 mg before discontinuation of therapy, to prevent signs and symptoms of withdrawal in the opioid-tolerant patient.

To dispose of unused hydromorphone hydrochloride extended-release tablets flush all remaining tablets down the toilet or remit to authorities at a certified drug take-back program.

2.4       Hepatic Impairment

Start patients with moderate hepatic impairment on 25% of the hydromorphone hydrochloride extended-release tablets dose that would be prescribed for patients with normal hepatic function. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with hydromorphone hydrochloride extended-release tablets and during dose titration. Use of alternate analgesics is recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

2.5       Renal Impairment

Start patients with moderate renal impairment on 50% and patients with severe renal impairment on 25% of the hydromorphone hydrochloride extended-release tablets dose that would be prescribed for patients with normal renal function. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with hydromorphone hydrochloride extended-release tablets and during dose titration. As hydromorphone hydrochloride extended-release tablets are only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Use in Specific Populations (8.7)].

2.6       Administration of Hydromorphone Hydrochloride Extended-release Tablets

Instruct patients to swallow hydromorphone hydrochloride extended-release tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5.2)].

2.1      Initial Dosing

To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, hydromorphone hydrochloride extended-release tablets are only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning hydromorphone hydrochloride extended-release tablets therapy. As hydromorphone hydrochloride extended-release tablets are only for use in opioid-tolerant patients, do not begin any patient on hydromorphone hydrochloride extended-release tablets as the first opioid.

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Initiate the dosing regimen for each patient individually, taking into account the patient"s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with hydromorphone hydrochloride extended-release tablets [see Warnings and Precautions (5.2)].

Hydromorphone hydrochloride extended-release tablets must be taken whole. Crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].

Conversion from Other Oral Hydromorphone Formulations to Hydromorphone Hydrochloride Extended-release TabletsPatients receiving oral immediate-release hydromorphone may be converted to hydromorphone hydrochloride extended-release tablets by administering a starting dose equivalent to the patient’s total daily oral hydromorphone dose, taken once daily.

Conversion from Other Oral Opioids to Hydromorphone Hydrochloride Extended-release TabeltsDiscontinue all other around-the-clock opioid drugs when hydromorphone hydrochloride extended-release tablets therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient’s 24-hour oral hydromorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydromorphone requirements, which could result in adverse reactions.

In a hydromorphone hydrochloride extended-release tablets clinical trial with an open-label titration period, patients were converted from their prior opioid to hydromorphone hydrochloride extended-release tablets using the Table 1 as a guide for the initial hydromorphone hydrochloride extended-release tablets dose. The recommended starting dose of hydromorphone hydrochloride extended-release tablets is 50% of the calculated estimate of daily hydromorphone requirement. Calculate the estimated daily hydromorphone requirement using Table 1.

Consider the following when using the information in Table 1:
This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to hydromorphone hydrochloride extended-release tablets. The table cannot be used to convert from hydromorphone hydrochloride extended-release tablets to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. Table 1. Conversion Factors to Hydromorphone Hydrochloride Extended-release Tablets
Prior Oral Opioid

Approximate OralConversion Factor

Hydromorphone

1

Codeine

0.06

Hydrocodone

0.4

Methadone

0.6

Morphine

0.2

Oxycodone

0.4

Oxymorphone

0.6

To calculate the estimated hydromorphone hydrochloride extended-release tablets dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydromorphone daily dose. For patients on a regimen of more than one opioid, calculate the approximate oral hydromorphone dose for each opioid and sum the totals to obtain the approximate total hydromorphone daily dose. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablets strength(s) available. Example conversion from a single opioid to hydromorphone hydrochloride extended-release tablets:

Step 1: Sum the total daily dose of the opioid
30 mg of oxycodone 2 times daily = 60 mg total daily dose of oxycodone
Step 2: Calculate the approximate equivalent dose of oral hydromorphone based on the total daily dose of the current opioid using Table 1
60 mg total daily dose of oxycodone x Conversion Factor of 0.4 = 24 mg of oral hydromorphone daily
Step 3: Calculate the approximate starting dose of hydromorphone hydrochloride extended-release tablets to be given every 24 hours, which is 50% of the calculated oral hydromorphone dose. Round down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablet strengths available.
50% of 24 mg results in an initial dose of 12 mg of hydromorphone hydrochloride extended-release tablets once daily Adjust individually for each patient
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to hydromorphone hydrochloride extended-release tablets.

Conversion from Transdermal Fentanyl to Hydromorphone Hydrochloride Extended-release TabletsEighteen hours following the removal of the transdermal fentanyl patch, hydromorphone hydrochloride extended-release tablets treatment can be initiated. To calculate the 24-hour hydromorphone hydrochloride extended-release tablets dose, use a conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of hydromorphone hydrochloride extended-release tablets. Then reduce the hydromorphone hydrochloride extended-release tablets dose by 50%.

For example:         Step 1: Identify the dose of transdermal fentanyl.
75 mg of transdermal fentanyl
Step 2: Use the conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of hydromorphone hydrochloride extended-release tablets.
75 mg of transdermal fentanyl : 36 mg total daily dose of hydromorphone hydrochloride extended-release tablets
Step 3: Calculate the approximate starting dose of hydromorphone hydrochloride extended-release tablets to be given every 24 hours, which is 50% of the converted dose. Round down, if necessary, to the appropriate hydromorphone hydrochloride extended-release tablet strengths available.
50% of 36 mg results in an initial dose of 18 mg, which would be rounded down to 16 mg of hydromorphone hydrochloride extended-release tablets once daily Adjust individually for each patient
Conversion from Methadone to Hydromorphone Hydrochloride Extended-release TabletsClose monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.
Verapamil Hydrochloride...

Verapamil Hydrochloride

The dose of verapamil must be individualized by titration. The usefulness and safety of dosages exceeding 480 mg/day have not been established; therefore, this daily dosage should not be exceeded. Since the half-life of verapamil increases during chronic dosing, maximum response may be delayed.

Angina:

Clinical trials show that the usual dose is 80 mg to 120 mg three times a day. However, 40 mg three times a day may be warranted in patients who may have an increased response to verapamil (e.g., decreased hepatic function, elderly, etc.). Upward titration should be based on therapeutic efficacy and safety evaluated approximately eight hours after dosing. Dosage may be increased at daily (e.g., patients with unstable angina) or weekly intervals until optimum clinical response is obtained.

Arrhythmias:

The dosage in digitalized patients with chronic atrial fibrillation (see PRECAUTIONS) ranges from 240 to 320 mg/day in divided (three times a day or four times a day) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (three times a day or four times a day) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy.

Essential hypertension:

Dose should be individualized by titration. The usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/day). Daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. The antihypertensive effects of verapamil are evident within the first week of therapy. Upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval.

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