DONEPEZIL HYDROCHLORIDE — donepezil hydrochloride tablet, film coated
Graviti Pharmaceuticals Private Limited
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.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing in Mild to Moderate Alzheimer’s Disease
The recommended starting dosage of donepezil hydrochloride tablets are 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 are 5 mg administered once per day in the evening, just prior to retiring. 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.
2.3 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.
3 DOSAGE FORMS AND STRENGTHS
Donepezil hydrochloride tablets, USP are supplied as film-coated, round tablets containing 5 mg or 10 mg of donepezil hydrochloride.
The 5 mg tablets are white, debossed with “OE” on one side and “645” on the other side.
The 10 mg tablets are yellow, debossed with “OE” on one side and “648” on the other side.
Donepezil hydrochloride is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.
5 WARNINGS AND PRECAUTIONS
Donepezil hydrochloride, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
5.2 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 hydrochloride.
5.3 Nausea and Vomiting
Donepezil hydrochloride, 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 hydrochloride, patients should be observed closely at the initiation of treatment and after dose increases.
5.4 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 hydrochloride 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.
5.6 Genitourinary Conditions
Although not observed in clinical trials of donepezil hydrochloride, cholinomimetics may cause bladder outflow obstruction.
5.7 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.
5.8 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.
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)]
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 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 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 HCl (n=350) %||10 mg/day donepezil HCl (n=315) %|
The most common adversereactions, 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 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 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 week titration||Six week titration|
|Adverse Reactions||Placebo (n=315) %||5 mg/day (n=311) %||1 0 mg/day (n=315) %||10 mg/day (n=269) %|
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 Reactions||Placebo (n=355) %||Donepezil Hydrochloride (n=747) %|
|Percent of Patients with any Adverse Reactions||72||74|
|Pain, various locations||8||9|
Severe Alzheimer’s Disease (Donepezil Hydrochloride 5 mg/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 in Pooled Controlled Clinical Trials in Severe Alzheimer’s Disease|
|Body System/Adverse Reaction||Placebo (n=392) %||Donepezil HCl (n=501) %|
|Percent of Patients with any Adverse Reaction||73||81|
|Increased in Creatine Phosphokinase||1||3|
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