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Donepezil Hydrochloride Tablet

Donepezil Hydrochloride Orally Disintegrating Tablet (ODT)

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Donepezil hydrochloride is a reversible inhibitor of the enzyme acetylcholinesterase.

Donepezil hydrochloride is known chemically as (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1Hinden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl and a molecular weight of 415.96.

Donepezil hydrochloride 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 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, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, 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 ethylcellulose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and methacrylic acid copolymer, Type C. The film coating includes ferric oxide, hypromellose 2910, polyethylene glycol 8000, talc and titanium dioxide.

Donepezil ODT tablets are available for oral administration. Each donepezil ODT tablet contains 5 or 10 mg of donepezil hydrochloride. Inactive ingredients are carrageenan, mannitol, colloidal silicon dioxide and polyvinyl alcohol. Additionally, the 10 mg tablet contains ferric oxide (yellow) as a coloring agent.

2. INDICATIONS AND USAGE

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.

3. DOSAGE AND ADMINISTRATION

Donepezil should be taken in the evening, just prior to retiring.

Donepezil can be taken with or without food and should be swallowed whole with water. Donepezil should not be split or crushed.

The 23 mg tablet should not be crushed or chewed because this may increase its rate of absorption.

Allow donepezil ODT tablet to dissolve on the tongue and follow with water.

3.1 Mild to Moderate Alzheimer’s Disease

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 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.

3.2 Moderate to Severe Alzheimer’s Disease

Donepezil 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 23 mg once daily to 10 mg once daily suggest that a 23 mg dose of donepezil provided additional benefit.

3.3. Titration

The recommended starting dose of donepezil 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 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.

4. CONTRAINDICATIONS

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

5. 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

6.2 Nursing Mothers

It is not known whether donepezil is excreted in human breast milk. Caution should be exercised when donepezil is administered to a nursing woman.

6.3 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

6.4 Geriatric Use

Alzheimer’s disease is a disorder occurring primarily in individuals over 55 years of age. 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 events reported by patient groups ≥ 65 years old and < 65 years old.

6.5 Lower Weight Individuals

In the controlled clinical trial, among patients in the donepezil 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 events as well. This finding may be related to higher plasma exposure associated with lower weight.

7. WARNINGS AND PRECAUTIONS

7.1 Anesthesia

Donepezil, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

7.2 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.

7.3. 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, and more frequently with the 23 mg dose than with the 10 mg dose. Specifically, in a controlled trial that compared a dose of 23 mg/day to 10 mg/day in patients who had been treated with donepezil 10 mg/day for at least three months, the incidence of nausea in the 23 mg group was markedly greater than in the patients who continued on 10 mg/day (11.8% vs 3.4%, respectively), and the incidence of vomiting in the 23 mg group was markedly greater than in the 10 mg group (9.2% vs 2.5%, respectively). The percent of patients who discontinued treatment due to vomiting in the 23 mg group was markedly higher than in the 10 mg group (2.9% vs 0.4%, respectively).

Although in most cases, these effects have been mild and 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.

7.4. 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 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. Results of a controlled clinical study with 23 mg/day showed an increase, relative to 10 mg/day, in the incidence of peptic ulcer disease (0.4% vs. 0.2%) and gastrointestinal bleeding from any site (1.1% vs. 0.6%).

7.5. Weight Loss

Weight loss was reported as an adverse event in 4.7% of patients assigned to donepezil in a dose of23 mg/day compared to 2.5% of patients assigned to 10 mg/day. Compared to their baseline weights, 8.4% of patients taking 23 mg/day were found to have a weight decrease of ≥ 7% by the end of the study, while 4.9% of patients taking 10 mg/day were found to have weight loss of ≥ 7% at the end of the study.

7.6 Genitourinary

Although not observed in clinical trials of donepezil, cholinomimetics may cause bladder outflow obstruction.

7.7 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.

7.8 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.

8. ADVERSE REACTIONS

8.1. Clinical Studies Experience

Donepezil 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 due to adverse events for the donepezil 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 Withdrawal from Controlled Clinical Trials by Dose Group

Most Frequent Adverse Events Seen in Association with the Use of Donepezil

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’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 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

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 and for which the rate of occurrence was greater for patients treated with donepezil 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 and at a Higher Frequency than Placebo Treated Patients

Donepezil 23 mg/day

Moderate to Severe Alzheimer’s Disease

Donepezil 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 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 4.

Table 4. Most Frequent Adverse Events Leading to Discontinuation from a Controlled Clinical Trial by Treatment Group

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 5 lists adverse events that were reported in at least 2% of patients who received 23 mg/day of donepezil and at a higher frequency than those receiving 10 mg/day of donepezil 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 with or without memantine.

Table 5. 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

8.2 Postmarketing Experience

Voluntary reports of adverse events temporally associated with donepezil 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.

9. 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).

10. DRUG INTERACTIONS

Drugs Highly Bound to Plasma Proteins: Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. Donepezil at concentrations of 0.3–10 μg/mL did not affect the binding of furosemide (5 μg/mL), digoxin (2 ng/mL), and warfarin (3 μg/mL) to human albumin. Similarly, the binding of donepezil to human albumin was not affected by furosemide, digoxin and warfarin.

Effect of Donepezil on the Metabolism of Other Drugs: No in vivo clinical trials have investigated the effect of donepezil on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50–130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference.

Whether donepezil has any potential for enzyme induction is not known.

Formal pharmacokinetic studies evaluated the potential of donepezil for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of donepezil on the pharmacokinetics of these drugs were observed.

Effect of Other Drugs on the Metabolism of Donepezil: 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 once daily) increased mean donepezil (5 mg once daily) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.

Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of donepezil.

Formal pharmacokinetic studies demonstrated that the metabolism of donepezil is not significantly affected by concurrent administration of digoxin or cimetidine.

11. PHARMACOKINETICS

Donepezil ODT is bioequivalent to donepezil tablets. Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1-10 mg given once daily. Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption of donepezil tablets. A food effect study has not been conducted with donepezil ODT; however, the effect of food with donepezil ODT is expected to be minimal. Donepezil ODT can be taken without regard to meals.

The elimination half life of donepezil is about 70 hours and the mean apparent plasma clearance (Cl/F) is 0.13 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4-7 fold and steady state is reached within 15 days. The steady state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1 - 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, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug.

Special Populations:

Hepatic Disease: In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil was decreased by 20% relative to 10 healthy age and sex matched subjects.

Renal Disease: In a study of 11 patients with moderate to severe renal impairment (ClCr < 18 mL/min/1.73 m2) the clearance of donepezil did not differ from 11 age and sex matched healthy subjects.

Age: No formal pharmacokinetic study was conducted to examine age related differences in the pharmacokinetics of donepezil. However, mean plasma donepezil concentrations measured during therapeutic drug monitoring of elderly patients with Alzheimer’s Disease are comparable to those observed in young healthy volunteers.

Gender and Race: No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of donepezil. However, retrospective pharmacokinetic analysis indicates that gender and race (Japanese and Caucasians) did not affect the clearance of donepezil.

12. HOW SUPPLIED/STORAGE AND HANDLING

12.1 How Available:

a) Brand names: ARICEPT, by EISAI MEDCL RES.

ARICEPT ODT, by EISAI MEDCL RES.

b) Generic drugs: DONEPEZIL HYDROCHLORIDE, by various manufacturers.

ARICEPT 23 mg tablet equivalent: No generic drug is available.

12.2 How Supplied:

12.2.1. ARICEPT Tablets

Supplied as film-coated, round tablets containing 5 mg, 10 mg, or 23 mg of donepezil hydrochloride.

The 5 mg tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side.

Bottles of 30 (NDC# 62856-245-30)

Bottles of 90 (NDC# 62856-245-90)

Bottles of 1000 (NDC# 62856-245-11)

Unit Dose Blister Package 100 (10x10) (NDC# 62856-245-41)

The 10 mg tablets are yellow. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side.

Bottles of 30 (NDC# 62856-246-30)

Bottles of 90 (NDC# 62856-246-90)

Bottles of 1000 (NDC# 62856-246-11)

Unit Dose Blister Package 100 (10x10) (NDC# 62856-246-41)

The 23 mg tablets are reddish in color. The strength, in mg (23), is debossed on one side and ARICEPT is debossed on the other side.

Bottles of 30 (NDC# 62856-247-30)

Bottles of 90 (NDC# 62856-247-90)

12.2.2 ARICEPT ODT

Supplied as round tablets containing either 5 mg or 10 mg of donepezil hydrochloride.

The 5 mg orally disintegrating tablets are white. The strength, in mg (5), is embossed on one side and ARICEPT is embossed on the other side.

5 mg (White) Unit Dose Blister Package 30 (10x3) (NDC# 62856-831-30)

The 10 mg orally disintegrating tablets are yellow. The strength, in mg (10), is embossed on one side and ARICEPT is embossed on the other side.

10 mg (Yellow) Unit Dose Blister Package 30 (10x3) (NDC# 62856-832-30)

3) Storage: Store at controlled room temperature, 15°C to 30°C (59°F to 86°F).

Rx only

Rev 05/12