Composition:

Each film coated tablet contains

5mg Donepezil hydrochloride (equivalent to 4.56mg of Donepezil free base)

or 10mg Donepezil hydrochloride (equivalent to 9.12mg of Donepezil free base)

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.

Pharmacokinetics:

Following oral dosing, peak plasma concentration is achieved for Donepezil 10 mg tablets in approximately 3 hours. Peak plasma concentrations were about 2-fold higher for Donepezil 23 mg tablets than Donepezil 10 mg

tablets.

Donepezil ODT 5 mg and 10 mg are bioequivalent to Donepezil 5 mg and 10 mg tablets, respectively.

The elimination half- life of donepezil is about 70 hours.

Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha - acid glycoprotein (about 21%) over the concentration range of 2-1000 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.

Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation.

Indications:

Donepezil 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.

Dosage and administration

• Mild to Moderate Alzheimer’s Disease:

The recommended starting dosage of Donepezil is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage 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.

• Moderate to Severe Alzheimer’s Disease:

The recommended starting dosage of Donepezil is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage 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.

• Administration Information:

Donepezil should be taken in the evening, just prior to retiring. Donepezil can be taken with or without food.

• Children:

Donepezil Hydrochloride 1mg/1ml Oral Solution is not recommended for use in children and adolescents below 18 years of age.

Contraindications:

Donepezil is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.

Warnings and precautions

• Anesthesia: Donepezil, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
• Cardiovascular Conditions: Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of Donepezil.
• Nausea and Vomiting: Donepezil, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea, and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. Although in most cases, these effects have been transient, sometimes lasting one to three weeks, and have resolved during continued use of Donepezil, patients should be observed closely at the initiation of treatment and after dose increases.
• Peptic Ulcer Disease and GI Bleeding:

Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent

nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of Donepezil in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

• Weight Loss: Weight loss was reported as an adverse reaction in 4.7% of patients assigned to Donepezil in a dose of 23 mg/day compared to 2.5% of patients assigned to 10 mg/day. 4.9% of patients taking 10 mg/day were found to have weight loss of ≥ 7% at the end of the study.
• Genitourinary Conditions: Although not observed in clinical trials of Donepezil, cholinomimetics may cause bladder outflow obstruction.
• Neurological Conditions : Seizures

Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer’s disease.

• Pulmonary Conditions: Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

Adverse reactions:

Nausea,Vomiting, Diarrhea, Insomnia, Fatigue, Muscle cramps, Anorexia, Headache, Pain, Dizziness, Ecchymosis, Abnormal Dreams,Depression,Weight Loss ,Arthritis ,Frequent Urination ,Somnolence, Syncope, Hallucinations ,Hostility ,Increase in Creatine Phosphokinase , Nervousness ,Fever ,Chest Pain  ,Confusion ,Dehydration , Emotional Lability ,Hemorrhage, Hyperlipemia , Personality Disorder ,Urinary Incontinence.    

Drug Interactions:

Use with Anticholinergics:

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

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.

Pregnancy:

There are no adequate data on the developmental risks associated with the use of Donepezil 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 .

Lactation:

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 and any potential adverse effects on the breastfed infant from Donepezil or from the underlying maternal condition.

Pediatric Use:

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

Geriatric Use:

Alzheimer’s disease is a disorder occurring primarily in individuals over 55 years of age.

There were no clinically significant differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 years old.

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 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 and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).