Donepezil Hydrochloride

1 INDICATIONS AND USAGE Donepezil hydrochloride tablet is an acetylcholinesterase inhibitor indicated for the treatment of dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer's Disease ( 1 ). Donepezil hydrochloride tablet is indicated for the treatment of dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer's disease.

2 DOSAGE AND ADMINISTRATION Mild to Moderate Alzheimer's Disease: 5 mg to 10 mg once daily ( 2.1 ) Moderate to Severe Alzheimer's Disease: 10 mg to 23 mg once daily ( 2.2 ) 2.1 Dosing in Mild to Moderate Alzheimer’s Disease The recommended starting dosage of donepezil hydrochloride tablet is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage of donepezil hydrochloride tablets in patients with mild to moderate Alzheimer's disease is 10 mg per day. A dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks. 2.2 Dosing in Moderate to Severe Alzheimer’s Disease The recommended starting dosage of donepezil hydrochloride tablet is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage of donepezil hydrochloride tablets in patients with moderate to severe Alzheimer's disease is 23 mg per day. 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. A dose of 23 mg per day should not be administered until patients have been on a daily dose of 10 mg for at least 3 months. 2.3 Administration Information Donepezil hydrochloride tablets should be taken in the evening, just prior to retiring. Donepezil hydrochloride tablets can be taken with or without food. The donepezil hydrochloride 23 mg tablet should not be split, crushed, or chewed.

6 ADVERSE REACTIONS Most common adverse reactions in clinical studies of donepezil hydrochloride are nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/ medwatch . The following serious adverse reactions are described below and elsewhere in the labeling: Cardiovascular Conditions [ see Warnings and Precautions ( 5.2 ) ]. Nausea and Vomiting [ see Warnings and Precautions ( 5.3 ) ]. Peptic Ulcer Disease and GI Bleeding [ see Warnings and Precautions ( 5.4 ) ]. Weight Loss [ see Warnings and Precautions ( 5.5 ) ]. Genitourinary Conditions [ see Warnings and Precautions ( 5.6 ) ]. Neurological Conditions: Seizures [ see Warnings and Precautions ( 5.7 ) ]. Pulmonary Conditions [ see Warnings and Precautions ( 5.8 ) ]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Donepezil hydrochloride has been administered to over 1,700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1,000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months, and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1,214 days. Mild to Moderate Alzheimer's Disease Adverse Reactions Leading to Discontinuation: The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride 5 mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day was higher at 13%. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of patients and at twice or more the incidence seen in placebo patients, are shown in Table 1. Table 1 . Most Common Adverse Reactions Leading to Discontinuation in Patients with Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo ( n = 355 ) % 5 mg / day Donepezil Hydrochloride ( n = 350 ) % 10 mg / day Donepezil Hydrochloride ( n = 315 ) % Nausea 1 1 3 Diarrhea 0 <1 3 Vomiting <1 <1 2 Most Common Adverse Reactions: The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by donepezil hydrochloride's cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. There is evidence to suggest that the frequency of these common adverse reactions may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15- and 30-week studies. These patients were titrated to a dose of10 mg/day over a 6-week period. The rates of common adverse reactions were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day. See Table 2 for a comparison of the most common adverse reactions following one and six week titration regimens. Table 2 . Comparison of Rates of Adverse Reactions in Mild to Moderate Patients Titrated to 10 mg / day over 1 and 6 Weeks No titration One week titration Six week titration Adverse Reaction Placebo ( n = 315 ) % 5 mg / day ( n = 311 ) % 10 mg / day ( n = 315 ) % 10 mg / day ( n = 269 ) % Nausea 6 5 19 6 Diarrhea 5 8 15 9 Insomnia 6 6 14 6 Fatigue 3 4 8 3 Vomiting 3 3 8 5 Muscle cramps 2 6 8 3 Anorexia 2 3 7 3 Table 3 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received either donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. In general, adverse reactions occurred more frequently in female patients and with advancing age. Table 3 . Adverse Reactions in Pooled Placebo - Controlled Clinical Trials in Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo ( n = 355 ) % Donepezil Hydrochloride ( n = 747 ) % Percent of Patients with any Adverse Reaction 72 74 Nausea 6 11 Diarrhea 5 10 Headache 9 10 Insomnia 6 9 Pain, various locations 8 9 Dizziness 6 8 Accident 6 7 Muscle Cramps 2 6 Fatigue 3 5 Vomiting 3 5 Anorexia 2 4 Ecchymosis 3 4 Abnormal Dreams 0 3 Depression <1 3 Weight Loss 1 3 Arthritis 1 2 Frequent Urination 1 2 Somnolence <1 2 Syncope 1 2 Severe Alzheimer's Disease (Donepezil Hydrochloride 5mg/day and 10 mg/day) Donepezil hydrochloride has been administered to over 600 patients with severe Alzheimer's disease during clinical trials of at least 6 months duration, including three double-blind, placebo-controlled trials, two of which had an open label extension. Adverse Reactions Leading to Discontinuation: The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride patients were approximately 12% compared to 7% for placebo patients. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride patients and at twice or more the incidence seen in placebo, were anorexia (2% vs. 1% placebo), nausea (2% vs. <1% placebo), diarrhea (2% vs. 0% placebo), and urinary tract infection (2% vs. 1% placebo). Most Common Adverse Reactions: The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice or more the placebo rate, are largely predicted by donepezil hydrochloride's cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. Table 4 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. Table 4 . Adverse Reactions in Pooled Controlled Clinical Trials in Severe Alzheimer’s Disease Body System / Adverse Reaction Placebo ( n = 392 ) % Donepezil Hydrochloride ( n = 501 ) % Percent of Patients with any Adverse Reaction 73 81 Accident 12 13 Infection 9 11 Diarrhea 4 10 Anorexia 4 8 Vomiting 4 8 Nausea 2 6 Insomnia 4 5 Ecchymosis 2 5 Headache 3 4 Hypertension 2 3 Pain 2 3 Back Pain 2 3 Eczema 2 3 Hallucinations 1 3 Hostility 2 3 Increase in Creatine Phosphokinase 1 3 Nervousness 2 3 Fever 1 2 Chest Pain <1 2 Confusion 1 2 Dehydration 1 2 Depression 1 2 Dizziness 1 2 Emotional Lability 1 2 Hemorrhage 1 2 Hyperlipemia <1 2 Personality Disorder 1 2 Somnolence 1 2 Syncope 1 2 Urinary Incontinence 1 2 Moderate to Severe Alzheimer's Disease Tablets (Donepezil Hydochloride 23 mg/day) Donepezil hydrochloride 23 mg/day has been administered to over 1300 individuals globally in clinical trials. Approximately 1050 of these patients have been treated for at least three months and more than 950 patients have been treated for at least six months. The range of patient exposure was from 1 to over 500 days. Adverse Reactions Leading to Discontinuation: The rate of discontinuation from a controlled clinical trial of donepezil hydrochloride 23 mg/day due to adverse reactions was higher (19%) than for the 10 mg/day treatment group (8%). The most common adverse reactions leading to discontinuation, defined as those occurring in at least 1% of patients and greater than those occurring with 10 mg/day are shown in Table 5. Table 5. Most Common Adverse Reactions Leading to Discontinuation in Patients with Moderate to Severe Alzheimer's Disease Adverse Reaction 23 mg/day Donepezil Hydrochloride (n=963) % 10 mg/day Donepezil Hydrochloride (n=471) % Vomiting 3 0 Diarrhea 2 0 Nausea 2 0 Dizziness 1 0 The majority of discontinuations due to adverse reactions in the 23 mg group occurred during the first month of treatment. Most Common Adverse Reactions with Donepezil Hydrochloride Tablets 23 mg/day: The most common adverse reactions, defined as those occurring at a frequency of at least 5%, include nausea, diarrhea, vomiting, and anorexia. Table 6 lists adverse reactions that occurred in at least 2% of patients who received 23 mg/day of donepezil hydrochloride and at a higher frequency than those receiving 10 mg/day of donepezil hydrochloride in a controlled clinical trial that compared the two doses. In this study, there were no important differences in the type of adverse reactions in patients taking donepezil hydrochloride with or without memantine. $notablefooter $nofootnote Table 6. Adverse Reactions in a Controlled Clinical Trial in Moderate to Severe Alzheimer's Disease Adverse Reaction 23 mg/day Donepezil Hydrochloride (n=963) % 10 mg/day Donepezil Hydrochloride (n=471) % Percent of Patients with any Adverse Reaction 74 64 Nausea 12 3 Vomiting 9 3 Diarrhea 8 5 Anorexia 5 2 Dizziness 5 3 Weight Loss 5 3 Headache 4 3 Insomnia 3 2 Urinary Incontinence 3 1 Asthenia 2 1 Contusion 2 0 Fatigue 2 1 Somnolence 2 1 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of donepezil hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Abdominal pain, agitation, aggression, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, rash, rhabdomyolysis, QTc prolongation, and torsade de pointes.

12.3 Pharmacokinetics Pharmacokinetics of donepezil are linear over a dose range of 1 to 10 mg given once daily. The rate and extent of absorption of donepezil hydrochloride tablets are not influenced by food. Based on population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer's disease, following oral dosing, peak plasma concentration is achieved for donepezil hydrochloride 23 mg tablets in approximately 8 hours, compared with 3 hours for donepezil hydrochloride 10 mg tablets. Peak plasma concentrations were about 2-fold higher for donepezil hydrochloride 23 mg tablets than donepezil hydrochloride 10 mg tablets. The elimination half life of donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) is 0.13 to 0.19 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4 to 7 fold, and steady state is reached within 15 days. The steady state volume of distribution is 12 to 16 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha 1 - acid glycoprotein (about 21%) over the concentration range of 2 to 1000 ng/mL. Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14 C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug. Examination of the effect of CYP2D6 genotype in Alzheimer's patients showed differences in clearance values among CYP2D6 genotype subgroups. When compared to the extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24% faster clearance. Hepatic Disease In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil hydrochloride was decreased by 20% relative to 10 healthy age-and sex-matched subjects. Renal Disease In a study of 11 patients with moderate to severe renal impairment (Cl C < 18 mL/min/1.73 m 2 ) the clearance of donepezil hydrochloride did not differ from 11 age- and sex-matched healthy subjects. Age No formal pharmacokinetic study was conducted to examine age-related differences in the pharmacokinetics of donepezil hydrochloride. Population pharmacokinetic analysis suggested that the clearance of donepezil in patients decreases with increasing age. When compared with 65-year old subjects, 90-year old subjects have a 17% decrease in clearance, while 40 - year old subjects have a 33% increase in clearance. The effect of age on donepezil clearance may not be clinically significant. Gender and Race No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of donepezil hydrochloride. However, retrospective pharmacokinetic analysis and population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer's disease indicates that gender and race (Japanese and Caucasians) did not affect the clearance of donepezil hydrochloride to an important degree. Body Weight There was a relationship noted between body weight and clearance. Over the range of body weight from 50 kg to 110 kg, clearance increased from 7.77 L/h to 14.04 L/h, with a value of 10 L/hr for 70 kg individuals. Drug Interactions Effect of Donepezil Hydrochloride on the Metabolism of Other Drugs: No in vivo clinical trials have investigated the effect of donepezil hydrochloride on the clearance of drugs metabolized by CYP3A4 (e.g., cisapride, terfenadine) or by CYP2D6 (e.g., imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean K i about 50 to 130 µM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Based on in vitro studies, donepezil shows little or no evidence of direct inhibition of CYP2B6, CYP2C8, and CYP2C19 at clinically relevant concentrations. Whether donepezil hydrochloride has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of donepezil hydrochloride for interaction with theophylline, cimetidine, warfarin, digoxin, and ketoconazole. No effects of donepezil hydrochloride on the pharmacokinetics of these drugs were observed. Effect of Other Drugs on the Metabolism of Donepezil Hydrochloride: Ketoconazole and quinidine, strong inhibitors of CYP450 3A and 2D6, respectively, inhibit donepezil metabolism in vitro . Whether there is a clinical effect of quinidine is not known. Population pharmacokinetic analysis showed that in the presence of concomitant CYP2D6 inhibitors donepezil AUC was increased by approximately 17% to 20% in Alzheimer's disease patients taking donepezil hydrochloride 10 and 23 mg. This represented an average effect of weak, moderate, and strong CYP2D6 inhibitors. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.) increased mean donepezil (5 mg q.d.) concentrations (AUC 0-24 and C max ) by 36%. The clinical relevance of this increase in concentration is unknown. Inducers of CYP 3A (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of donepezil hydrochloride. Formal pharmacokinetic studies demonstrated that the metabolism of donepezil hydrochloride is not significantly affected by concurrent administration of digoxin or cimetidine. An in vitro study showed that donepezil was not a substrate of P-glycoprotein. Drugs Highly Bound to Plasma Proteins: Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. Donepezil hydrochloride at concentrations of 0.3 to 10 micrograms/mL did not affect the binding of furosemide (5 micrograms/mL), digoxin (2 ng/mL), and warfarin (3 micrograms/mL) to human albumin. Similarly, the binding of donepezil hydrochloride to human albumin was not affected by furosemide, digoxin, and warfarin.