Donepezil Hydrochloride (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use 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.

7 DRUG INTERACTIONS

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

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risks associated with the use of donepezil hydrochloride 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/m2 basis) and 10 mg/kg/day (approximately 7 times the MRHD on a mg/m2 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/m2 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 and any potential adverse effects on the breastfed infant from donepezil hydrochloride or from the underlying maternal condition.

8.4 Pediatric Use


The safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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 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.

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 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 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.

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]-1H -inden-1-one hydrochloride. Donepezil hydrochloride USP is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24 H29 NO3 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.

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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.

12 CLINICAL PHARMACOLOGY

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.

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