DONEPEZIL HYDROCHLORIDE

Donepezil hydrochloride, USP is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2, 3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H -inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C 24 H 29 NO 3 HCl and a molecular weight of 415.96. Donepezil hydrochloride, USP is a off-white to cream colored powder and is soluble in methylene dichloride. Donepezil hydrochloride USP is available for oral administration in film-coated tablets containing 5, or 10 mg of donepezil hydrochloride, USP. Inactive ingredients are corn starch, lactose monohydrate, low substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose. The film coating contains hypromellose, polyethylene glycol, talc and titanium dioxide. Donepezil hydrochloride, USP complies to test for organic impurities, procedure 2. Donepezil Hydrochloride

Donepezil hydrochloride tablets, USP are 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. Donepezil hydrochloride tablets, USP are an acetycholinesterase 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 tablets should be taken in the evening, just prior to retiring. Donepezil hydrochloride tablets can be taken with or without food. • Mild to Moderate Alzheimer's Disease - 5 mg or 10 mg administered once daily ( 2.1 ) • Moderate to Severe Alzheimer's Disease - 10 mg or 23 mg administered once daily ( 2.2 ) A dose of 10 mg once daily can be administered once patients have been on a daily dose of 5 mg for 4 to 6 weeks. A dose of 23 mg once daily can be administered once patients have been on a dose of 10 mg once daily for at least 3 months ( 2.3 ). 2.1. Mild to Moderate Alzheimer's Disease The dosages of donepezil hydrochloride tablets 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 tablets 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 hydrochloride has been shown to be effective in controlled clinical trials at doses of 10 mg and 23 mg administered once daily. Results of a controlled clinical trial in moderate to severe Alzheimer’s Disease that compared donepezil hydrochloride 23 mg once daily to 10 mg once daily suggest that a 23 mg dose of donepezil hydrochloride provided additional benefit. 2.3. Titration The recommended starting dose of donepezil hydrochloride is 5 mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer's disease indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5 mg dose. In open-label trials using a 6 week titration, the type and frequency of these same adverse events were similar between the 5 mg and 10 mg dose groups. Therefore, because donepezil hydrochloride tablets 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. A dose of 23 mg once daily can be administered once patients have been on a dose of 10 mg once daily for at least 3 months.

Donepezil hydrochloride is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives. ● Patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives ( 4 )

The 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 Jubilant Cadista Pharmaceuticals Inc. at 1-800-313-4623 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1. Clinical Studies Experience Donepezil Hydrochloride Tablets 5 mg/day and 10 mg/day Mild to Moderate Alzheimer's Disease Adverse Events Leading to Discontinuation The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse events 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 events 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 Frequent Adverse Events Leading to Discontinuation from Controlled Clinical Trials by Dose Group Dose Group Placebo 5 mg/day Donepezil Hydrochloride 10 mg/day Donepezil Hydrochloride Patients Randomized 355 350 315 Event/%Discontinuing Nausea 1% 1% 3% Diarrhea 0% <1% 3% Vomiting <1% <1% 2% Most Frequent Adverse Events Seen in Association with the Use of Donepezil Hydrochloride The most common adverse events, 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 events were often of mild intensity and 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 events 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 of 10 mg/day over a 6-week period. The rates of common adverse events 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 events following one and six week titration regimens. Table 2. Comparison of Rates of Adverse Events in Mild to Moderate Patients Titrated to 10 mg/day over 1 and 6 Weeks No titration One week titration Six week titration Adverse Event 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% Adverse Events Reported in Controlled Trials The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 3 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received donepezil hydrochloride and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. In general, adverse events occurred more frequently in female patients and with advancing age. Table 3. Adverse Events Reported in Controlled Clinical Trials in Mild to Moderate Alzheimer's Disease in at Least 2% of Patients Receiving Donepezil Hydrochloride and at a Higher Frequency than Placebo Treated Patients Body System/Adverse Event Placebo (n=355) Donepezil Hydrochloride (n=747) Percent of Patients with any Adverse Event 72 74 Body as a Whole Headache 9 10 Pain, various locations 8 9 Accident 6 7 Fatigue 3 5 Cardiovascular System Syncope 1 2 Digestive System Nausea 6 11 Diarrhea 5 10 Vomiting 3 5 Anorexia 2 4 Hemic and Lymphatic System Ecchymosis 3 4 Metabolic and Nutritional Systems Weight Decrease 1 3 Musculoskeletal System Muscle Cramps 2 6 Arthritis 1 2 Nervous System Insomnia 6 9 Dizziness 6 8 Depression <1 3 Abnormal Dreams 0 3 Somnolence <1 2 Urogenital System Frequent Urination 1 2 Other Adverse Events Observed During Clinical Trials Donepezil hydrochloride has been administered to over 1700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1000 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 1214 days. Treatment emergent signs and symptoms that occurred during three controlled clinical trials and two open-label trials in the United States were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900 patients from these trials who experienced that event while receiving donepezil hydrochloride. All adverse events occurring at least twice are included, except for those already listed in Tables 2 or 3, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100 patients; Infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to donepezil hydrochloride treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States. Body as a Whole: Frequent: influenza, chest pain, toothache; Infrequent: fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, listlessness. Cardiovascular System: Frequent : hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; Infrequent: angina pectoris, postural hypotension, myocardial infarction, AV block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thrombosis. Digestive System: Frequent: fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; Infrequent: eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer. Endocrine System: Infrequent: diabetes mellitus, goiter. Hemic and Lymphatic System: Infrequent: anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia. Metabolic and Nutritional Disorders: Frequent: dehydration; Infrequent: gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase. Musculoskeletal System: Frequent: bone fracture; Infrequent: muscle weakness, muscle fasciculation. Nervous System: Frequent: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia; Infrequent: cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing. Respiratory System: Frequent: dyspnea, sore throat, bronchitis; Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring. Skin and Appendages: Frequent: pruritus, diaphoresis, urticaria; Infrequent: dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer. Special Senses: Frequent: cataract, eye irritation, vision blurred; Infrequent: dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes. Urogenital System: Frequent: urinary incontinence, nocturia; Infrequent: dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis. Severe Alzheimer's Disease Adverse Events Leading to Discontinuation The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse events for the donepezil hydrochloride patients were approximately 12% compared to 7% for placebo patients. The most common adverse events 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 Frequent Adverse Events Seen in Association with the Use of Donepezil Hydrochloride The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice the placebo rate, are largely predicted by donepezil hydrochloride’s cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. Adverse Events Reported in Controlled Trials Table 4 lists adverse events that were reported in at least 2% of patients in placebo-controlled trials who received donepezil hydrochloride and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. Table 4. Adverse Events Reported in Controlled Clinical Trials in Severe Alzheimer's Disease in at Least 2% of Patients Receiving Donepezil Hydrochloride and at a Higher Frequency than Placebo Treated Patients Body System/Adverse Event Placebo (n=392) Donepezil Hydrochloride (n=501) Percent of Patients with any Adverse Event 73 81 Body as a Whole Accident 12 13 Infection 9 11 Headache 3 4 Pain 2 3 Back Pain 2 3 Fever 1 2 Chest Pain <1 2 Cardiovascular System Hypertension 2 3 Hemorrhage 1 2 Syncope 1 2 Digestive System Diarrhea 4 10 Vomiting 4 8 Anorexia 4 8 Nausea 2 6 Hemic and Lymphatic System Ecchymosis 2 5 Metabolic and Nutritional Systems Creatine Phosphokinase Increased 1 3 Dehydration 1 2 Hyperlipemia <1 2 Nervous System Insomnia 4 5 Hostility 2 3 Nervousness 2 3 Hallucinations 1 3 Somnolence 1 2 Dizziness 1 2 Depression 1 2 Confusion 1 2 Emotional Lability 1 2 Personality Disorder 1 2 Skin And Appendages Eczema 2 3 Urogenital System Urinary Incontinence 1 2 Other Adverse Events Observed During Clinical Trials 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. All adverse events occurring at least twice are included, except for those already listed in Table 4, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system using the COSTART dictionary and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100 patients; Infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to donepezil hydrochloride treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies. Body as a Whole: Frequent: abdominal pain, asthenia, fungal infection, flu syndrome; Infrequent: allergic reaction, cellulitis, malaise, sepsis, face edema, hernia. Cardiovascular System: Frequent: hypotension, bradycardia, ECG abnormal, heart failure; Infrequent: myocardial infarction, angina pectoris, atrial fibrillation, congestive heart failure, peripheral vascular disorder, supraventricular extrasystoles, ventricular extrasystoles, cardiomegaly. Digestive System: Frequent: constipation, gastroenteritis, fecal incontinence, dyspepsia; Infrequent: gamma glutamyl transpeptidase increase, gastritis, dysphagia, periodontitis, stomach ulcer, periodontal abscess, flatulence, liver function tests abnormal, eructation, esophagitis, rectal hemorrhage. Endocrine System: Infrequent: diabetes mellitus. Hemic and Lymphatic System: Frequent: anemia; Infrequent : leukocytosis. Metabolic and Nutritional Disorders: Frequent: weight loss, peripheral edema, edema, lactic dehydrogenase increased, alkaline phosphatase increased; Infrequent: hypercholesteremia, hypokalemia, hypoglycemia, weight gain, bilirubinemia, BUN increased, B 12 deficiency anemia, cachexia, creatinine increased, gout, hyponatremia, hypoproteinemia, iron deficiency anemia, SGOT increased, SGPT increased. Musculoskeletal System: Frequent: arthritis; Infrequent: arthrosis, bone fracture, arthralgia, leg cramps, osteoporosis, myalgia. Nervous System: Frequent: agitation, anxiety, tremor, convulsion, wandering, abnormal gait; Infrequent: apathy, vertigo, delusions, abnormal dreams, cerebrovascular accident, increased salivation, ataxia, euphoria, vasodilatation, cerebral hemorrhage, cerebral infarction, cerebral ischemia, dementia, extrapyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia. Respiratory System: Frequent: pharyngitis, pneumonia, cough increased, bronchitis; Infrequent: dyspnea, rhinitis, asthma. Skin and Appendages: Frequent: rash, skin ulcer, pruritus; Infrequent: psoriasis, skin discoloration, herpes zoster, dry skin, sweating, urticaria, vesiculobullous rash. Special Senses: Infrequent: conjunctivitis, glaucoma, abnormal vision, ear pain, lacrimation disorder. Urogenital System: Frequent: urinary tract infection, cystitis, hematuria, glycosuria; Infrequent: vaginitis, dysuria, urinary frequency, albuminuria. Donepezil Hydrochloride Tablets 23 mg/day Moderate to Severe Alzheimer’s Disease 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 Events Leading to Discontinuation The rate of discontinuation from a controlled clinical trial of donepezil hydrochloride 23 mg/day due to adverse events was higher (18.6%) than for the 10 mg/day treatment group (7.9%). The most common adverse events 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 Frequent Adverse Events Leading to Discontinuation from a Controlled Clinical Trial by Treatment Group Dose Group 23 mg/day Donepezil Hydrochloride 10 mg/day Donepezil Hydrochloride Safety Population 963 471 Event/ %Discontinuing Vomiting 3 0 Diarrhea 2 0 Nausea 2 0 Dizziness 1 0 The majority of discontinuations due to adverse events in the 23 mg group occurred during the first month of treatment. Most Frequent Adverse Events Seen in Association with the Use of 23 mg The most common adverse events, defined as those occurring at a frequency of at least 5%, include nausea, diarrhea, vomiting, and anorexia. These adverse events were often of mild to moderate intensity. Adverse Events Reported in Controlled Trials The events cited reflect experience gained under closely monitored conditions of a controlled clinical trial in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 6 lists adverse events that were reported 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 events in patients taking donepezil hydrochloride with or without memantine. Table 6. Adverse Events Reported in a Controlled Clinical Trial in Moderate to Severe Alzheimer’s Disease in at Least 2% of Patients and Higher in the 23 mg/day Group Body System/Adverse Event 23 mg/day Donepezil Hydrochloride 10 mg/day Donepezil Hydrochloride Safety Population 963 471 Percent of Patients with any Adverse Event 74 64 Gastrointestinal disorders Nausea 12 3 Vomiting 9 3 Diarrhea 8 5 General disorders and administration site conditions Fatigue 2 1 Asthenia 2 1 Injury, poisoning and procedural complications Contusion 2 0 Investigations Weight decreased 5 3 Metabolism and nutrition disorders Anorexia 5 2 Nervous system Dizziness 5 3 Headache 4 3 Somnolence 2 1 Psychiatric disorders Insomnia 3 2 Renal and urinary disorders Urinary incontinence 3 1 6.2. Postmarketing Experience Voluntary reports of adverse events temporally associated with donepezil hydrochloride that have been received since market introduction that are not listed above, and for which there are inadequate data to determine the causal relationship with the drug include the following: abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.

• Cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications ( 7. 2). • A synergistic effect may be expected with concomitant administration of succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists ( 7. 3). 7.1 Effects of Other Drugs on the Metabolism of Donepezil Hydrochloride Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro . Whether there is a clinical effect of quinidine is not known. 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 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of donepezil hydrochloride. 7.2 Use with Anticholinergics Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. 7.3 Use with Cholinomimetics and Other Cholinesterase Inhibitors A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.