Donepezil Hydrochloride

1 INDICATIONS AND USAGE Donepezil hydrochloride tablets 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 are 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 ).

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 tablets 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 tablets 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.

2.1 Dosing in Mild to Moderate Alzheimer’s Disease The recommended starting dosage of donepezil hydrochloride tablets 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 tablets 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.

3 DOSAGE FORMS AND STRENGTHS Donepezil hydrochloride tablets, USP are supplied as film-coated, round tablets containing either 5 mg or 10 mg of donepezil hydrochloride USP. • The 5 mg tablets are white to off white, round, biconvex, film-coated tablets debossed with ‘ML 89’ on one side and plain on the other side. • The 10 mg tablets are yellow, round, biconvex, film-coated tablets debossed with ‘ML 88’ on one side and plain on the other side. Donepezil hydrochloride 23 mg tablets are supplied as film-coated, round tablets containing 23 mg of donepezil hydrochloride USP. • The 23 mg tablets are red, round, biconvex, film-coated tablets debossed with “C 26” on one side, and plain on the other side. Donepezil hydrochloride orally disintegrating tablets, USP are supplied as round tablets containing either 5 mg or 10 mg of donepezil hydrochloride USP. • The 5 mg orally disintegrating tablets are yellow, circular, flat face, beveled edge uncoated tablets debossed with “CL 31” on one side and plain on the other side. • The 10 mg orally disintegrating tablets are yellow, circular, flat face, beveled edge uncoated tablets debossed with “CL 32” on one side and plain on the other side. Tablets: 5 mg,10 mg, and 23 mg ( 3 ) Orally Disintegrating Tablets (ODT) : 5 mg and 10 mg ( 3 )

4 CONTRAINDICATIONS • Known hypersensitivity to donepezil hydrochloride or to piperidine derivatives ( 4 ) Donepezil hydrochloride tablets are contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.

6 ADVERSE REACTIONS 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)] Most common adverse reactions in clinical studies of Donepezil Hydrochloride Tablets are nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Cadila Pharmaceuticals Limited at 1-202-355-9785 (fax 1-202-355-9784) or FDA at 1-800-FDA-1088 or www .fda.gov/medwatch . 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 Tablets has been administered to over 1,700 individuals during clinical trials worldwide. Approximately 1,200 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 Tablets due to adverse reactions for the Donepezil Hydrochloride Tablets 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 escalation 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 Tablets (n=350) % 10 mg/day Donepezil Hydrochloride Tablets (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 Tablet'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 Tablets 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 of 10 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 w …

7 DRUG INTERACTIONS • Cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications ( 7.1 ) • A synergistic effect may be expected with concomitant administration of succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists ( 7.2 ) 7.1 Use with Anticholinergics Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. 7.2 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.

7.1 Use with Anticholinergics Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.

7.2 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.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, donepezil hydrochloride tablets may cause fetal harm ( 8.1 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of donepezi hydrochloride tablets in pregnant women. In animal studies, developmental toxicity was not observed when donepezil was administered to pregnant rats and rabbits during organogenesis, but administration to rats during the latter part of pregnancy and throughout lactation resulted in increased stillbirths and decreased offspring survival at clinically relevant doses [see Data]. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. The background risks of major birth defects and miscarriage for the indicated population are unknown. Data Animal Data Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] of 23 mg/day on a mg/m 2 basis) and 10 mg/kg/day (approximately 7 times the MRHD on a mg/m 2 basis), respectively. Oral administration of donepezil (1, 3, 10 mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an increase in stillbirths and reduced offspring survival through postpartum day 4 at the highest dose. The no-effect dose of 3 mg/kg/day is approximately equal to the MRHD on a mg/m 2 basis. 8.2 Lactation Risk Summary There are no data on the presence of donepezil or its metabolites in human milk, the effects on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for donepezil hydrochloride tablets and any potential adverse effects on the breastfed infant from donepezil hydrochloride tablets or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Alzheimer’s disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the clinical studies with donepezil hydrochloride tablets was 73 years; 80% of these patients were between 65 and 84 years old, and 49% of patients were at or above the age of 75. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically significant differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 years old. 8.6 Lower Weight Individuals In the controlled clinical trial, among patients in the donepezil hydrochloride tablets 23 mg treatment group, those patients weighing < 55 kg reported more nausea, vomiting, and decreased weight than patients weighing 55 kg or more. There were more withdrawals due to adverse reactions as well. This finding may be related to higher plasma exposure associated with lower weight.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of donepezi hydrochloride tablets in pregnant women. In animal studies, developmental toxicity was not observed when donepezil was administered to pregnant rats and rabbits during organogenesis, but administration to rats during the latter part of pregnancy and throughout lactation resulted in increased stillbirths and decreased offspring survival at clinically relevant doses [see Data]. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. The background risks of major birth defects and miscarriage for the indicated population are unknown. Data Animal Data Oral administration of donepezil to pregnant rats and rabbits during the period of organog …

12.1. Mechanism of Action Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer’s disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.

11 DESCRIPTION Donepezil hydrochloride, USP are 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 USP 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 white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile, and practically insoluble in ethyl acetate and in n-hexane. Donepezil hydrochloride USP is available for oral administration in film-coated tablets containing 5, 10, or 23 mg of donepezil hydrochloride. Inactive ingredients in 5 mg and 10 mg tablets are lactose monohydrate, pregelatinised starch, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate. The film coating contains talc, polyethylene glycol, hypromellose and titanium dioxide. Additionally, the 10 mg tablet contains yellow iron oxide (synthetic) as a coloring agent. Inactive ingredients in 23 mg tablets include hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and hypromellose. The film coating includes ferric oxide red, hypromellose, polyethylene glycol 8000, talc and titanium dioxide. USP Dissolution Test pending. Donepezil hydrochloride orally disintegrating tablets USP are available for oral administration. Each donepezil hydrochloride orally disintegrating tablets contains 5 or 10 mg of donepezil hydrochloride USP. Inactive ingredients are mannitol, crospovidone, sucralose, sodium chloride, ferric oxide yellow and magnesium stearate. str

10 OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for donepezil hydrochloride tablets overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride tablets and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation, and lower body surface temperature.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Donepezil Hydrochloride Tablets Supplied as film-coated, round tablets containing either 5 mg, 10 mg or 23 mg donepezil hydrochloride USP. Donepezil Hydrochloride 5 mg and 10 mg Tablets, USP The 5 mg tablets are white to off white, round, biconvex, film-coated tablets debossed with 'ML 89' on one side and plain on the other side. Bottles of 30 NDC 33342-027-07 Bottles of 90 NDC 33342-027-10 Bottles of 500 NDC 33342-027-15 Bottle of 1000 NDC 33342-027-44 Unit Dose Blister Package 50 (5x10) NDC 33342-027-31 Unit Dose Blister Package 100 (10x10) NDC 33342-027-12 The 10 mg tablets are yellow, round, biconvex, film-coated tablets debossed with 'ML 88' on one side and plain on the other side. Bottles of 30 NDC 33342-028-07 Bottles of 90 NDC 33342-028-10 Bottles of 500 NDC 33342-028-15 Bottle of 1000 NDC 33342-028-44 Unit Dose Blister Package 50 (5x10) NDC 33342-028-31 Unit Dose Blister Package 100 (10x10) NDC 33342-028-12 Donepezil Hydrochloride 23 mg Tablets The 23 mg tablets are red, round, biconvex, film-coated tablets debossed with "C 26" on one side and plain on the other side. Bottles of 30 NDC 33342-061-07 Bottles of 90 NDC 33342-061-10 Unit Dose Blister Package 100 (10 x 10) NDC 33342-061-12 16.2 Donepezil Hydrochloride Orally Disintegrating Tablets,USP Supplied as round tablets containing either 5 mg or 10 mg of donepezil hydrochloride USP. The 5 mg orally disintegrating tablets are yellow coloured, circular, flat face beveled edge uncoated tablets debossed with "CL 31" on one side and plain on the other side. Unit Dose Blister Package 30 (3x10) NDC 33342-029-06 Unit Dose Blister Package 100 (10x10) NDC 33342-029-12 Unit Dose Blister Package 28 (4x7) NDC 33342-029-60 Container Pack of 30's NDC 33342-029-07 The 10 mg orally disintegrating tablets are yellow, circular, flat face beveled edge uncoated tablets debossed with "CL 32" on one side and plain on the other side. Unit Dose Blister Package 30 (3x10) NDC 33342-030-06 Unit Dose Blister Package 100 (10x10) NDC 33342-030-12 Unit Dose Blister Package 28 (4x7) NDC 33342-030-60 Container Pack of 30's NDC 33342-030-07 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].