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2.1 Recommended Dosing
Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening.
The dosage of Rivastigmine tartrate capsules shown to be effective in controlled clinical trials in Alzheimer’s disease is 6 mg to 12 mg per day, administered twice a day (daily doses of 3 mg to 6 mg twice a day). There is evidence from the clinical trials that doses at the higher end of this range may be more beneficial.
Initiate treatment with the 1.5 mg twice a day with Rivastigmine tartrate capsules.
After a minimum of 2 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 2 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day).
Parkinson’s Disease Dementia
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 mg to 12 mg per day, administered twice a day (daily doses of 1.5 mg to 6 mg twice a day).
Initiate treatment with the 1.5 mg twice a day with Rivastigmine tartrate capsules.
After a minimum of 4 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 4 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day).
Interruption of Treatment
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 dosing is interrupted for 3 days or fewer, restart treatment with the same or lower dose of Rivastigmine tartrate capsules. If dosing is interrupted for more than 3 days, treatment should be restarted with 1.5 mg twice a day and titrated as described above [see Warnings and Precautions (5.1)].
2.2 Dosing in Specific Populations
Dosing Modifications in Patients with Renal or Hepatic Impairment
Pharmacokinetic studies of oral rivastigmine in patients with moderate to severe renal impairment (glomerular filtration rate [GFR] <50 mL/min) and mild to moderate hepatic impairment (Child-Pugh score 5 to 9) showed reduced clearance of the drug [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)]. Accordingly, such patients may be able to only tolerate lower doses. No data are available on the use of rivastigmine in patients with severe hepatic impairment.
Dosing Modifications in Patients with Low Body Weight
Because rivastigmine blood levels vary with body weight [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)], careful titration and monitoring should be performed in patients with low body weight. In patients with low body weight (less than 50 kg), monitor closely for toxicities (e.g., excessive nausea, vomiting), and consider reducing the dose if such toxicities develop.
2.3 Important Administration Instructions
Rivastigmine tartrate oral solution and Rivastigmine tartrate capsules may be interchanged at equal doses.
2.1 Adult Hypertension
The recommended starting dose of valsartan tablets is 80 mg or 160 mg once daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose. Valsartan tablets may be used over a dose range of 80 mg to 320 mg daily, administered once a day.The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg.No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency. Care should be exercised with dosing of valsartan tablets in patients with hepatic or severe renal impairment.
Valsartan tablets may be administered with other antihypertensive agents.Valsartan tablets may be administered with or without food.
2.2 Pediatric Hypertension 6 to 16 years of age
For children who can swallow tablets, the usual recommended starting dose is 1.3 mg/kg once daily (up to 40 mg total). The dosage should be adjusted according to blood pressure response. Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old.For children who cannot swallow tablets, or children for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths of valsartan tablets , the use of a suspension is recommended. Follow the suspension preparation instructions below (see Preparation of Suspension) to administer valsartan as a suspension. When the suspension is replaced by a tablet, the dose of valsartan may have to be increased. The exposure to valsartan with the suspension is 1.6 times greater than with the tablet.No data are available in pediatric patients either undergoing dialysis orwith a glomerular filtration rate <30 mL/min/1.73 m2[see Pediatric Use (8.4)].valsartan tablets are not recommended for patients <6 years old [see Adverse Reactions (6.1), Clinical Trials (14.1)]. Preparation of Suspension (for 160 mL of a 4 mg/mL suspension) Add 80 mL of Ora-Plus®* oral suspending vehicle to an amber glass bottle containing 8 tablets of Valsartan 80 mg, and shake for a minimum of 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 80 mL of Ora-Sweet SF®* oral sweetening vehicle to the bottle and shake the suspension for at least 10 seconds to disperse the ingredients. The suspension is homogenous and can be stored for either up to 30 days at room temperature (below 30°C/86°F) or up to 75 days at refrigerated conditions (2 to 8°C/35 to 46°F) in the glass bottle with a child-resistant screw-cap closure. Shake the bottle well (at least 10 seconds) prior to dispensing the suspension.*Ora-Sweet SF® and Ora-Plus® are registered trademarks of Paddock Laboratories, Inc.
2.3 Heart Failure
The recommended starting dose of valsartan tablets is 40 mg twice daily. Uptitration to 80 mg and 160 mg twice daily should be done to the highest dose, as tolerated by the patient. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses.
2.1 Important Administration Instructions
Quetiapine fumarate can be taken with or without food.
2.2 Recommended Dosing
The recommended initial dose, titration, dose range and maximum quetiapine fumarate dose for each approved indication is displayed in Table 1. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient [see Clinical Studies (14.1 and 14.2)].
Table 1: Recommended Dosing for Quetiapine Fumarate
1 N/A Not applicable
Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment – Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)].
2.3 Dose Modifications in Elderly Patients
Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions [see Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.
Elderly patients should be started on quetiapine fumarate 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.
2.4 Dose Modifications in Hepatically Impaired Patients
Patients with hepatic impairment should be started on 25 mg/day. The dose should be increased daily in increments of 25 mg/day to 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.
2.5 Dose Modifications when used with CYP3A4 Inhibitors
Quetiapine fumarate dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of quetiapine fumarate should be increased by 6 fold [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)].
2.6 Dose Modifications when used with CYP3A4 Inducers
Quetiapine fumarate dose should be increased up to 5 fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7 to 14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). The dose should be titrated based on the clinical response and tolerability of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine fumarate should be reduced to the original level within 7 to 14 days [see Clinical Pharmacology (12.3) and Drug Interactions (7.1)].
2.7 Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off quetiapine fumarate for more than one week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine fumarate for less than one week, gradual dose escalation may not be required and the maintenance dose may be reinitiated.
2.8 Switching from Antipsychotics
There are no systematically collected data to specifically address switching patients with schizophrenia from antipsychotics to quetiapine fumarate, or concerning concomitant administration with antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients with schizophrenia from depot antipsychotics, if medically appropriate, initiate quetiapine fumarate therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.
Individualize the dosage of metoprolol tablets. Metoprolol tartrate tablets should be taken with or immediately following meals.
The usual initial dosage of metoprolol tartrate tablets is 100 mg daily in single or divided doses, whether used alone or added to a diuretic. Increase the dosage at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. The effective dosage range of metoprolol tartrate tablets is 100 to 450 mg per day. Dosages above 450 mg per day have not been studied. While once daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and larger or more frequent daily doses may be required. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. Beta1 selectivity diminishes as the dose of metoprolol is increased.
The dosage of metoprolol tartrate tablets should be individualized. Metoprolol tartrate tablets should be taken with or immediately following meals.
The usual initial dosage of metoprolol tartrate tablets is 100 mg daily, given in two divided doses. gradually increased at weekly intervals until optimum clinical response has been obtained or there is pronounced slowing of the heart rate.
The effective dosage range of metoprolol tartrate tablets is 100 to 400 mg per day. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, gradually decrease the dosage over a period of 1 to 2 weeks (see WARNINGS).
Early Treatment: During the early phase of definite or suspected acute myocardial infarction, treatment with metoprolol tartrate tablets can be initiated as soon as possible after the patient’s arrival in the hospital. Such treatment should be initiated in a coronary care or similar unit immediately after the patient’s hemodynamic condition has stabilized.
Begin treatment in this early phase should begin with the intravenous administration of three bolus injections of 5 mg of metoprolol tartrate each; the injections should be given at approximately 2 minute intervals. During the intravenous administration of metoprolol, monitor blood pressure, heart rate, and electrocardiogram.
In patients who tolerate the full intravenous dose (15 mg), initiate metoprolol tartrate tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the maintenance dosage is 100 mg twice daily (see Late Treatment below).
Start patients who appear not to tolerate the full intravenous dose on metoprolol tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose or as soon as their clinical condition allows. In patients with severe intolerance, discontinue metoprolol(see WARNINGS).
Late Treatment: Start patients with contraindications to treatment during the early phase of suspected or definite myocardial infarction, patients who appear not to tolerate the full early treatment, and patients in whom the physician wishes to delay therapy for any other reason on metoprolol tartrate tablets, 100 mg twice daily, as soon as their clinical condition allows. Continue therapy for at least 3 months. Although the efficacy of metoprolol beyond 3 months has not been conclusively established, data from studies with other beta-blockers suggest that treatment should be continued for 1 to 3 years.
Pediatric patients: No pediatric studies have been performed. The safety and efficacy of metoprolol in pediatric patients have not been established.
Renal impairment: No dose adjustment of metoprolol is required in patients with renal impairment.
Hepatic impairment: Metoprolol blood levels are likely to increase substantially in patients with hepatic impairment. Therefore, metoprolol should be initiated at low doses with cautious gradual dose titration according to clinical response.
Geriatric patients (>65 years): In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Method of administration:
For oral treatment, the tablets should be swallowed un-chewed with a glass of water. Metoprolol tartrate tablets should always be taken in standardized relation with meals. If the physician asks the patient to take metoprolol tartrate tablets either before breakfast or with breakfast, then the patient should continue taking metoprolol tartrate tablets with the same schedule during the course of therapy.
Meprobamate Tablets USP: The usual adult daily dosage is 1200mg 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).
General Dosing Considerations for Parkinson's Disease and RLS Ropinirole Tablets can be taken with or without food. Patients may be advised that taking Ropinirole Tablets with food may reduce the occurrence of nausea. However, this has not been established in controlled clinical trials. If a significant interruption in therapy with Ropinirole Tablets has occurred, retitration of therapy may be warranted.Geriatric Use Pharmacokinetic studies demonstrated a reduced clearance of ropinirole in the elderly (see CLINICAL PHARMACOLOGY). Dose adjustment is not necessary since the dose is individually titrated to clinical response.Renal Impairment The pharmacokinetics of ropinirole were not altered in patients with moderate renal impairment (see CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is necessary in patients with moderate renal impairment. The use of Ropinirole Tablets in patients with severe renal impairment has not been studied.Hepatic Impairment The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Since patients with hepatic impairment may have higher plasma levels and lower clearance, Ropinirole Tablets should be titrated with caution in these patients.Dosing for Parkinson’s Disease In all clinical studies, dosage was initiated at a subtherapeutic level and gradually titrated to therapeutic response. The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of nausea, dizziness, somnolence, and dyskinesia.The recommended starting dose for Parkinson’s disease is 0.25 mg 3 times daily. Based on individual patient response, dosage should then be titrated with weekly increments as described in Table 5. After week 4, if necessary, daily dosage may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a total dose of 24 mg/day. Doses greater than 24 mg/day have not been tested in clinical trials.Table 5. Ascending-Dose Schedule of Ropinirole Tablets for Parkinson’s DiseaseWeek Dosage Total Daily Dose 1 0.25 mg 3 times daily 0.75 mg 2 0.5 mg 3 times daily 1.5 mg 3 0.75 mg 3 times daily 2.25 mg 4 1 mg 3 times daily 3 mg
When Ropinirole Tablets are administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be decreased gradually as tolerated. L-dopa dosage reduction was allowed during the advanced Parkinson’s disease (with L-dopa) study if dyskinesias or other dopaminergic effects occurred. Overall, reduction of L-dopa dose was sustained in 87% of patients treated with Ropinirole Tablets and in 57% of patients on placebo. On average the L-dopa dose was reduced by 31% in patients treated with Ropinirole Tablets.Ropinirole Tablets for Parkinson’s disease patients should be discontinued gradually over a 7-day period. The frequency of administration should be reduced from 3 times daily to twice daily for 4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of Ropinirole Tablets.Dosing for Restless Legs Syndrome In all clinical trials, the dose for Ropinirole Tablets was initiated at 0.25 mg once daily, 1 to 3 hours before bedtime. Patients were titrated based on clinical response and tolerability. The recommended adult starting dosage for RLS is 0.25 mg once daily, 1 to 3 hours before bedtime. After 2 days, the dosage can be increased to 0.5 mg once daily and to 1 mg once daily at the end of the first week of dosing, then as shown in Table 6 as needed to achieve efficacy. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established. Table 6. Dose Titration Schedule for RLSDay/Week Dosage to be taken once daily, 1 to 3 hours before bedtime Days 1 and 2 0.25 mg Days 3-7 0.5 mg Week 2 1 mg Week 3 1.5 mg Week 4 2 mg Week 5 2.5 mg Week 6 3 mg Week 7 4 mg
In clinical trials of patients being treated for RLS with doses up to 4 mg once daily, Ropinirole Tablets were discontinued without a taper.
Taking theophylline extended-release tablets immediately after a high-fat content meal may result in a somewhat higher Cmax and delayed Tmax and somewhat greater extent of absorption. However, the differences are usually not great and this product may normally be administered without regard to meals (see CLINICAL PHARMACOLOGY, Drug interactions, Drug-Food Interactions ). Theophylline extended-release tablets are recommended for chronic or long-term management and prevention of symptoms, and not for use in treating acute symptoms of asthma and reversible bronchospasm. General considerations: The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400- 1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (see Table V). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady state. Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI). Health care providers should instruct patients and care givers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (seeWARNINGS). If the patient's symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours. Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration. Table V. Dosing initiation and titration (as anhydrous theophylline)* A. Children (6-15 years) and adults (16-60 years) without risk factors for impaired clearance.Titration Step Children < 45 kg Children > 45 kg and adults 1 Starting Dosage 12-14 mg/kg/day up to a maximum of 300 mg/day divided Q12 hrs* 300 mg/day divided Q12 hrs* 2 After 3 days, if tolerated, increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day divided Q12 hrs* 400 mg/day divided Q12 hrs* 3 After 3 more days, if tolerated, increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day divided Q12 hrs* 600 mg/day divided Q12 hrs*
B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: In children 6-15 years of age, the final theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations. In adolescents ≥16 years and adults, including the elderly, the final theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS) or if it is not feasible to monitor serum theophylline concentrations.* Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 8 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose.Table VI. Dosage adjustment guided by serum theophylline concentration.Peak Serum Concentration Dosage Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment. 10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals.¶ If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen. 15-19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated.¶ 20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. 25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage). >30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.
¶ Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present, physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS). Once-Daily Dosing: The slow absorption rate of this preparation may allow once-daily administration in adult non-smokers with appropriate total body clearance and other patients with low dosage requirements. Once-daily dosing should be considered only after the patient has been gradually and satisfactorily titrated to therapeutic levels with q12h dosing. Once-daily dosing should be based on twice the q12h dose and should be initiated at the end of the last q12h dosing interval. The trough concentration (Cmin) obtained following conversion to once-daily dosing may be lower (especially in high clearance patients) and the peak concentration (Cmax) may be higher (especially in low clearance patients) than that obtained with q12h dosing. If symptoms recur, or signs of toxicity appear during the once-daily dosing interval, dosing on the q12h basis should be reinstituted. It is essential that serum theophylline concentrations be monitored before and after transfer to once-daily dosing.Food and posture, along with changes associated with circardien rhythm, may influence the rate of absorption and / or clearance rates of theophylline from extended-release dosage forms administered at night. The exact relationship of these and other factors to nighttime serum concentrations and the clinical significance of such findings require additional study. Therefore, it is not recommended that theophylline extended-release once-daily dosing be administered at night.
Telmisartan And Hydrochlorothiazide 40 Mg12.5 Mg
The usual starting dose of telmisartan is 40 mg once a day; blood pressure response is dose related over the range of 20 to 80 mg.Patients with depletion of intravascular volume should have the condition corrected or telmisartan tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS).Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg once daily.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 telmisartan 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 telmisartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.Telmisartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.Telmisartan and hydrochlorothiazide tablets may be administered with or without food. Replacement TherapyThe combination may be substituted for the titrated components. Dose Titration by Clinical EffectTelmisartan and hydrochlorothiazide tablets are available as tablets containing either telmisartan 40 mg and hydrochlorothiazide 12.5 mg, or telmisartan 80 mg and hydrochlorothiazide 12.5 mg or 25 mg. A patient whose blood pressure is not adequately controlled with telmisartan monotherapy 80 mg (see above) may be switched to telmisartan and hydrochlorothiazide tablets, telmisartan 80 mg/hydrochlorothiazide 12.5 mg once daily, and finally titrated up to 160/25 mg, if necessary.A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide may be switched to telmisartan 80 mg/hydrochlorothiazide 12.5 mg or telmisartan 80 mg/hydrochlorothiazide 25 mg tablets once daily. The clinical response to telmisartan and hydrochlorothiazide tablets should be subsequently evaluated and if blood pressure remains uncontrolled after 2 to 4 weeks of therapy, the dose may be titrated up to 160/25 mg, if necessary. Those patients controlled by 25 mg hydrochlorothiazide but who experience hypokalemia with this regimen, may be switched to telmisartan 80 mg/hydrochlorothiazide 12.5 mg tablets once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. Patients with Renal ImpairmentThe usual regimens of therapy with telmisartan 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 telmisartan and hydrochlorothiazide tablets are not recommended. Patients with Hepatic Impairment Telmisartan and hydrochlorothiazide tablets are not recommended for patients with severe hepatic impairment. Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision using the 40/12.5 mg combination (see PRECAUTIONS).
Donepezil Hydrochloride 5 Mg
Donepezil hydrochloride tablets should be taken in the evening, just prior to retiring.Donepezil hydrochloride tablets can be taken with or without food.
2.1. Mild to Moderate Alzheimer's Disease
The dosages of donepezil hydrochloride shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.
The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of donepezil hydrochloride might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.
2.2. Moderate to Severe Alzheimer's Disease
Donepezil hydrochloridehas been shown to be effective in controlled clinical trials at a dose of 10 mg administered once daily.
The recommended starting dose of donepezil hydrochloride is 5 mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer’s disease indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5 mg dose. In open-label trials using a 6 week titration, the type and frequency of these same adverse events were similar between the 5 mg and 10 mg dose groups. Therefore, because donepezil hydrochloride steady state is achieved about 15 days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks.
Duloxetine Hydrochloride 20 Mg
Duloxetine delayed-release capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Duloxetine delayed-release capsules can be given without regard to meals.
2.1 Initial Treatment
Major Depressive Disorder - Duloxetine delayed-release capsule should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated [see Clinical Studies (14.1)]. Generalized Anxiety Disorder - For most patients, the recommended starting dose for duloxetine delayed-release capsules is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies (14.2)]. Diabetic Peripheral Neuropathic Pain - The recommended dose for duloxetine delayed-release capsules is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered.Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.10), Clinical Pharmacology (12.3)].Chronic Musculoskeletal Pain - The recommended dose for duloxetine delayed-release capsule is 60 mg once daily. Dosing may be started at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)].
2.2 Maintenance/Continuation/Extended Treatment
Major Depressive Disorder - It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with duloxetine delayed-release capsules as monotherapy. Duloxetine delayed-release capsules should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)]. Generalized Anxiety Disorder - It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with duloxetine delayed-release capsules as monotherapy. Duloxetine delayed-release capsules should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.2)]. Diabetic Peripheral Neuropathic Pain - As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of duloxetine delayed-release capsules must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.
Chronic Musculoskeletal Pain - The efficacy of duloxetine delayed-release capsules has not been established in placebo-controlled studies beyond 13 weeks.
2.3 Dosing in Special Populations
Hepatic Insufficiency - It is recommended that duloxetine delayed-release capsules should ordinarily not be administered to patients with any hepatic insufficiency [see Warnings and Precautions (5.13) and Use in Specific Populations (8.9)].Severe Renal Impairment - Duloxetine delayed-release capsule is not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see Warnings and Precautions (5.13) and Use in Specific Populations (8.10)]. Elderly Patients - No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose [see Use in Specific Populations (8.5)].Pregnant Women - There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine delayed-release capsule should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. Nursing Mothers - Because the safety of duloxetine in infants is not known, nursing while on duloxetine hydrochloride is not recommended [see Use in Specific Populations (8.3)].
2.4 Discontinuing duloxetine delayed-release capsules
Symptoms associated with discontinuation of duloxetine delayed-release capsule and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)].
2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI)Intended to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with duloxetine delayed-release capsules.Conversely, at least 5 days should be allowed after stopping duloxetine delayed-release capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].
2.6 Use of Duloxetine delayed-release capsules with Other MAOIs such as Linezolid or Methylene Blue
Do not start duloxetine delayed-release capsule in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].
In some cases, a patient already receiving duloxetine delayed-release capsule therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, duloxetine delayed-release capsule should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with duloxetine delayed-release capsule may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions(5.4)].
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with duloxetine delayed-release capsule is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].
Adults The recommended starting and target dose for aripiprazole is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see CLINICAL STUDIES (14.1)]. Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either aripiprazole 15 mg/day or placebo, and observed for relapse [see CLINICAL STUDIES (14.1)].
Patients should be periodically reassessed to determine the continued need for maintenance treatment.
AdolescentsThe recommended target dose of aripiprazole is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 mg and 30 mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. Aripiprazole can be administered without regard to meals [see CLINICAL STUDIES (14.1)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.Switching from Other Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to aripiprazole or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.
2.2 Bipolar I Disorder
Acute Treatment of Manic and Mixed Episodes
Adults: The recommended starting dose in adults is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with lithium or valproate. Aripiprazole can be given without regard to meals. The recommended target dose of aripiprazole is 15 mg/day, as monotherapy or as adjunctive therapy with lithium or valproate. The dose may be increased to 30 mg/day based on clinical response. The safety of doses above 30 mg/day has not been evaluated in clinical trials.
Pediatrics: The recommended starting dose in pediatric patients (10 to 17 years) as monotherapy is 2 mg/day, with titration to 5 mg/day after 2 days, and a target dose of 10 mg/day after 2 additional days. Recommended dosing as adjunctive therapy to lithium or valproate is the same. Subsequent dose increases, if needed, should be administered in 5 mg/day increments. Aripiprazole can be given without regard to meals[see CLINICAL STUDIES (14.2)].Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
2.7 Dosage Adjustments for Cytochrome P450 Considerations
Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 1). When the coadministered drug is withdrawn from the combination therapy, aripiprazole dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, aripiprazole dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.
Table 1: Dose Adjustments for Aripiprazole in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 InducersFactors Dosage Adjustments for Aripiprazole Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer a quarter of usual dose Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) Double usual dose over 1 to 2 weeks
2.8 Dosing of Oral Solution
The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution [see CLINICAL PHARMACOLOGY (12.3)].
2.9 Dosing of Orally Disintegrating Tablets
The dosing for Aripiprazole Orally Disintegrating Tablets is the same as for the oral tablets [see DOSAGE AND ADMINISTRATION (2.1 and 2.2)].
Dosage must be individualized. The usual starting dose of telmisartan tablets is 40 mg once a day. Blood pressure response is dose-related over the range of 20 to 80 mg [see Clinical Studies (14.1)]. Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. When additional blood pressure reduction beyond that achieved with 80 mg telmisartan is required, a diuretic may be added. No initial dosage adjustment is necessary for elderly patients or patients with renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored. Telmisartan tablets may be administered with other antihypertensive agents.Telmisartan tablets may be administered with or without food.
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