DONEPEZIL HYDROCHLORIDE - donepezil hydrochloride tablet, film coated DONEPEZIL HYDROCHLORIDE - donepezil hydrochloride tablet

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Active ingredient:
DONEPEZIL HYDROCHLORIDE (UNII: 3O2T2PJ89D) (DONEPEZIL - UNII:8SSC91326P)
Available from:
Macleods Pharmaceuticals Limited
INN (International Name):
DONEPEZIL HYDROCHLORIDE
Composition:
DONEPEZIL HYDROCHLORIDE 5 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Donepezil hydrochloride 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. Donepezil hydrochloride is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives. 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 de
Product summary:
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. 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 The 23 mg tablets are red, round, biconvex, film-coated tablets debossed with "C 26" on one side and plain on the other side. 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. 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. 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].
Authorization status:
Abbreviated New Drug Application
Authorization number:
33342-027-07, 33342-027-10, 33342-027-12, 33342-027-15, 33342-027-31, 33342-027-44, 33342-028-07, 33342-028-10, 33342-028-12, 33342-028-15, 33342-028-31, 33342-028-44, 33342-029-06, 33342-029-07, 33342-029-12, 33342-029-60, 33342-030-06, 33342-030-07, 33342-030-12, 33342-030-60, 33342-061-07, 33342-061-10, 33342-061-12

DONEPEZIL HYDROCHLORIDE - donepezil hydrochloride tablet, film coated

DONEPEZIL HYDROCHLORIDE - donepezil hydrochloride tablet, orally disintegrating

Macleods Pharmaceuticals Limited

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use DONEPEZIL HYDROCHLORIDE

TABLETS and DONEPEZIL HYDROCHLORIDE ORALLY DISINTEGRATING TABLETS safely and effectively.

See full prescribing information for DONEPEZIL HYDROCHLORIDE TABLETS and DONEPEZIL

HYDROCHLORIDE ORALLY DISINTEGRATING TABLETS.

DONEPEZIL HYDROCHLORIDE tablets for oral use

DONEPEZIL HYDROCHLORIDE orally disintegrating tablets

Initial U.S. Approval: 1996

RECENT MAJOR CHANGES

None

INDICATIONS AND USAGE

Donepezil hydrochloride is 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)

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)

DOSAGE FORMS AND STRENGTHS

Tablets: 5mg,10mg and 23 mg (3)

Orally Disintegrating Tablets : 5 mg and 10 mg (3)

CONTRAINDICATIONS

Known hypersensitivity to donepezil hydrochloride or to piperidine derivatives (4)

WARNINGS AND PRECAUTIONS

Cholinesterase inhibitors are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia (5.1)

Cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes manifesting as

bradycardia or heart block (5.2)

Donepezil hydrochloride can cause vomiting. Patients should be observed closely at initiation of treatment and after

dose increases (5.3)

Patients should be monitored closely for symptoms of active or occult gastrointestinal (GI) bleeding, especially those at

increased risk for developing ulcers (5.4)

The use of donepezil hydrochloride tablets in a dose of 23 mg once daily is associated with weight loss (5.5)

Cholinomimetics may cause bladder outflow obstructions (5.6)

Cholinomimetics are believed to have some potential to cause generalized convulsions (5.7)

Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary

disease (5.8)

ADVERSE REACTIONS

Most common adverse reactions in clinical studies of donepezil hydrochloride are nausea, diarrhea, insomnia, vomiting,

muscle cramps, fatigue, and anorexia (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or FDA

at 1-800-FDA-1088 or www.fda.gov/medwatch.

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)

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, donepezil hydrochloride may cause fetal harm (8.1)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosing in Mild to Moderate Alzheimer's Disease

2.2 Dosing in Moderate to Severe Alzheimer's Disease

2.3 Administration Information

3 DOSAGE FORMSAND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Anesthesia

5.2 Cardiovascular Conditions

5.3 Nausea and Vomiting

5.4 Peptic Ulcer Disease and GI Bleeding

5.5 Weight Loss

5.6 Genitourinary Conditions

5.7 Neurological Conditions: Seizures

5.8 Pulmonary Conditions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Use with Anticholinergics

7.2 Use with Cholinomimetics and Other Cholinesterase Inhibitors

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Lower Weight Individuals

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Mild to Moderate Alzheimer's disease

14.2 Moderate to Severe Alzheimer's Disease

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Donepezil Hyrochloride Tablets

16.2 Donepezil Hydrochloride Orally Disintegrating Tablets

17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Donepezil hydrochloride 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.

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. 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.

Allow donepezil hydrochloride orally disintegrating tablets to dissolve on the tongue and follow with

water.

3 DOSAGE FORMSAND 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.

4 CONTRAINDICATIONS

Donepezil hydrochloride is contraindicated in patients with known hypersensitivity to donepezil

hydrochloride or to piperidine derivatives.

5 WARNINGS AND PRECAUTIONS

5.1 Anesthesia

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, 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 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.

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%).

5.5 Weight Loss

Weight loss was reported as an adverse reaction in 4.7% of patients assigned to donepezil

hydrochloride in a dose of 23 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.

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 Reactions Leading to Discontinuation

The rates of discontinuation from controlled clinical trials of Donepezil hydrochloride 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 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

Advers e

Reaction

Placebo

(n=355) %

5 mg/day Donepezil

Hydrochloride

(n=350) %

10 mg/day Donepezil

Hydrochloride (n=315)

%

Nausea

Diarrhea

<1

Vomiting

<1

<1

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

cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and

anorexia. These adverse reactions 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

Advers e

Reaction

Placebo

(n=315) %

5 mg/day

(n=311) %

10 mg/day

(n=315) %

10 mg/day

(n=269) %

Nausea

Diarrhea

Insomnia

Fatigue

Vomiting

Muscle cramps

Anorexia

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 Reaction

Placebo

(n=355) %

Donepezil Hydrochloride

(n=747) %

Percent of Patients with any

Adverse Reaction

72

74

Nausea

Diarrhea

Headache

Insomnia

Pain, various locations

Dizziness

Accident

Muscle Cramps

Fatigue

Vomiting

Anorexia

Ecchymosis

Abnormal Dreams

Depression

<1

Weight Loss

Arthritis

Frequent Urination

Somnolence

<1

Syncope

Severe Alzheimer’s Disease (donepezil hydrochloride tablets 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 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 Reactions in Pooled Controlled Clinical Trials in Severe

Alzheimer’s Disease

Body System/Adverse Reaction

Placebo (n=392)

%

Donepezil Hydrochloride

(n=501) %

Percent of Patients with any

Adverse Reaction

73

81

Accident

Infection

Diarrhea

Anorexia

Vomiting

Nausea

Insomnia

Ecchymosis

Headache

Hypertension

Pain

Back Pain

Eczema

Hallucinations

Hostility

Increase in Creatine

Phosphokinase

Nervousness

Fever

Chest Pain

<1

Confusion

Dehydration

Depression

Dizziness

Emotional Lability

Hemorrhage

Hyperlipemia

<1

Personality Disorder

Somnolence

Syncope

Urinary Incontinence

Moderate to Severe Alzheimer’s Disease (Donepezil Hydrochloride Tablets 23 mg/day)

Donepezil hydrochloride tablets 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 Reactions Leading to Discontinuation

The rate of discontinuation from a controlled clinical trial of donepezil hydrochloride tablets 23 mg/day

due to adverse reactions was higher (19%) than for the 10 mg/day treatment group (8%). The most

common adverse reactions 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 5.

Table

5.

Most

Common

Adverse

Reactions

Leading

to

Discontinuation

in

Patients

with

Moderate

to

Severe

Alzheimer’s Disease

Advers e

Reaction

23 mg/day

Donepezil

Hydrochlori

de (n=963) %

10 mg/day Donepezil

Hydrochloride

(n=471) %

Vomiting

Diarrhea

Nausea

Dizziness

The majority of discontinuations due to adverse reactions in the 23 mg group occurred during the first

month of treatment.

Most Common Adverse Reactions with Donepezil Hydrochloride Tablets 23 mg/day

The most common adverse reactions, defined as those occurring at a frequency of at least 5%, include

nausea, diarrhea, vomiting, and anorexia.

Table 6 lists adverse reactions that occurred in at least 2% of patients who received 23 mg/day of

donepezil hydrochloride and at a higher frequency than those receiving 10 mg/day of donepezil

hydrochloride in a controlled clinical trial that compared the two doses. In this study, there were no

important differences in the type of adverse reactions in patients taking donepezil hydrochloride with or

without memantine.

Table 6. Adverse Reactions in a Controlled Clinical Trial in Moderate to

Severe Alzheimer’s Disease

Adverse Reaction

23 mg/day Donepezil

Hydrochloride

(n=963) %

10 mg/day

Donepezil

Hydrochloride

(n=471) %

Percent of Patients with any

Adverse Reaction

Nausea

Vomiting

Diarrhea

Anorexia

Dizziness

Weight Loss

Headache

Insomnia

Urinary incontinence

Asthenia

Contusion

Fatigue

Somnolence

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

Pregnancy Category C

There are no adequate or well-controlled studies in pregnant women. Donepezil hydrochloride tablets

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/m basis) and 10 mg/kg/day (approximately 7

times the MRHD on a mg/m 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 basis.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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/m basis) and 10 mg/kg/day (approximately 7

times the MRHD on a mg/m 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 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 is 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 C2 H NO 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 tablets, USP are 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, propylene 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 contain 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.

12.3 Pharmacokinetics

Pharmacokinetics of donepezil are linear over a dose range of 1-10 mg given once daily. The rate and

extent of absorption of donepezil hydrochloride is not influenced by food.

Based on population pharmacokinetic analysis of plasma donepezil concentrations measured in patients

with Alzheimer’s disease, following oral dosing, peak plasma concentration is achieved for donepezil

hydrochloride 23 mg tablets in approximately 8 hours, compared with 3 hours for donepezil

hydrochloride 10 mg tablets. Peak plasma concentrations were about 2-fold higher for donepezil

hydrochloride 23 mg tablets than donepezil hydrochloride 10 mg tablets.

Donepezil hydrochloride orally disintegrating tablets 5 mg and 10 mg are bioequivalent to donepezil

hydrochloride 5 mg and 10 mg tablets, respectively. A food effect study has not been conducted with

donepezil hydrochloride orally disintegrating tablets; however, the effect of food with donepezil

hydrochloride orally disintegrating tablets is expected to be minimal. Donepezil hydrochloride orally

disintegrating tablets 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 0.13-0.19 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 12-16 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. Examination of the effect of CYP2D6 genotype in Alzheimer’s patients showed

differences in clearance values among CYP2D6 genotype subgroups. When compared to the extensive

metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24%

faster clearance.

Hepatic Disease

In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil hydrochloride 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 (ClC < 18 mL/min/1.73 m2) the

clearance of donepezil hydrochloride did not differ from 11 age-and sex-matched healthy subjects.

No formal pharmacokinetic study was conducted to examine age-related differences in the

pharmacokinetics of donepezil hydrochloride. Population pharmacokinetic analysis suggested that the

clearance of donepezil in patients decreases with increasing age. When compared with 65-year old,

subjects, 90-year old subjects have a 17% decrease in clearance, while 40-year old subjects have a

33% increase in clearance. The effect of age on donepezil clearance may not be clinically significant.

Gender and Race

No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the

disposition of donepezil hydrochloride. However, retrospective pharmacokinetic analysis and

population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with

Alzheimer’s disease indicates that gender and race (Japanese and Caucasians) did not affect the

clearance of donepezil hydrochloride to an important degree.

Body Weight

There was a relationship noted between body weight and clearance. Over the range of body weight

from 50 kg to 110 kg, clearance increased from 7.77 L/h to 14.04 L/h, with a value of 10 L/hr for 70 kg

individuals.

Drug Interactions

Effect of donepezil hydrochloride on the Metabolism of Other Drugs

No in vivo clinical trials have investigated the effect of donepezil hydrochloride 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. Based on in vitro studies, donepezil shows little or no evidence of direct inhibition of

CYP2B6, CYP2C8, and CYP2C19 at clinically relevant concentrations.

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

pharmacokinetic studies evaluated the potential of donepezil hydrochloride for interaction with

theophylline, cimetidine, warfarin, digoxin, and ketoconazole. No effects of donepezil hydrochloride

on the pharmacokinetics of these drugs were observed.

Effect of Other Drugs on the Metabolism of donepezil hydrochloride

Ketoconazole and quinidine, strong inhibitors of CYP450 3A and 2D6, respectively, inhibit donepezil

metabolism in vitro. Whether there is a clinical effect of quinidine is not known. Population

pharmacokinetic analysis showed that in the presence of concomitant CYP2D6 inhibitors donepezil

AUC was increased by approximately 17% to 20% in Alzheimer’s disease patients taking donepezil

hydrochloride tablets 10 and 23 mg. This represented an average effect of weak, moderate, and strong

CYP2D6 inhibitors. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.)

increased mean donepezil (5 mg q.d.) concentrations (AUC

and C

) by 36%. The clinical

relevance of this increase in concentration is unknown.

Inducers of CYP 3A (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could

increase the rate of elimination of donepezil hydrochloride.

Formal pharmacokinetic studies demonstrated that the metabolisms of donepezil hydrochloride are not

significantly affected by concurrent administration of digoxin or cimetidine.

An in vitro study showed that donepezil was not a substrate of P-glycoprotein.

0-24

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 hydrochloride at concentrations of

0.3-10 micrograms/mL did not affect the binding of furosemide (5 micrograms/mL), digoxin (2 ng/mL),

and warfarin (3 micrograms/mL) to human albumin. Similarly, the binding of donepezil hydrochloride to

human albumin was not affected by furosemide, digoxin, and warfarin.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

No evidence of carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil

conducted in mice at oral doses up to 180 mg/kg/day (approximately 40 times the maximum

recommended human dose [MRHD] of 23 mg/day on a mg/m basis),or in a 104-week carcinogenicity

study in rats at oral doses up to 30 mg/kg/day (approximately 13 times the MRHD on a mg/m basis).

Donepezil was negative in a battery of genotoxicity assays (in vitro bacterial reverse mutation, in vitro

mouse lymphoma tk, in vitro chromosomal aberration, and in vivo mouse micronucleus).

Donepezil had no effect on fertility in rats at oral doses up to 10 mg/kg/day (approximately 4 times the

MRHD on a mg/m basis) when administered to males and females prior to and during mating and

continuing in females through implantation.

13.2 Animal Toxicology and/or Pharmacology

In an acute dose neurotoxicity study in female rats, oral administration of donepezil and memantine in

combination resulted in increased incidence, severity, and distribution of neurodegeneration compared

with memantine alone. The no-effect levels of the combination were associated with clinically relevant

plasma donepezil and memantine levels.

The relevance of this finding to humans is unknown.

14 CLINICAL STUDIES

14.1 Mild to Moderate Alzheimer's disease

The effectiveness of donepezil hydrochloride as a treatment for mild to moderate Alzheimer’s disease

is demonstrated by the results of two randomized, double-blind, placebo-controlled clinical

investigations in patients with Alzheimer’s disease (diagnosed by NINCDS and DSM III-R criteria,

Mini-Mental State Examination ≥ 10 and ≤ 26 and Clinical Dementia Rating of 1 or 2). The mean age of

patients participating in donepezil hydrochloride trials was 73 years with a range of 50 to 94.

Approximately 62% of patients were women and 38% were men. The racial distribution was white

95%, black 3%, and other races 2%.

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 hydrochloride 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.

Study Outcome Measures

In each study, the effectiveness of treatment with donepezil hydrochloride was evaluated using a dual

outcome assessment strategy.

The ability of donepezil hydrochloride to improve cognitive performance was assessed with the

cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), a multi-item instrument

that has been extensively validated in longitudinal cohorts of Alzheimer’s disease patients. The ADAS-

cog examines selected aspects of cognitive performance including elements of memory, orientation,

attention, reasoning, language, and praxis. The ADAS-cog scoring range is from 0 to 70, with higher

scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it

is not unusual for non-demented adults to score slightly higher.

The patients recruited as participants in each study had mean scores on the ADAS-cog of approximately

26 points, with a range from 4 to 61. Experience based on longitudinal studies of ambulatory patients

with mild to moderate Alzheimer’s disease suggest that scores on the ADAS-cog increase (worsen) by

6-12 points per year. However, smaller changes may be seen in patients with very mild or very

advanced disease since the ADAS-cog is not uniformly sensitive to change over the course of the

disease. The annualized rate of decline in the placebo patients participating in donepezil hydrochloride

trials was approximately 2 to 4 points per year.

The ability of donepezil hydrochloride to produce an overall clinical effect was assessed using a

Clinician’s Interview-Based Impression of Change that required the use of caregiver information, the

CIBIC-plus. The CIBIC-plus is not a single instrument and is not a standardized instrument like the

ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each

different in terms of depth and structure.

As such, results from a CIBIC-plus reflect clinical experience from the trial or trials in which it was

used and cannot be compared directly with the results of CIBIC-plus evaluations from other clinical

trials. The CIBIC-plus used in donepezil hydrochloride trials was a semi-structured instrument that was

intended to examine four major areas of patient function: General, Cognitive, Behavioral, and Activities

of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an

interview with the patient, in combination with information supplied by a caregiver familiar with the

behavior of the patient over the interval rated. The CIBIC-plus is scored as a seven-point categorical

rating, ranging from a score of 1, indicating “markedly improved,” to a score of 4, indicating “no

change” to a score of 7, indicating “markedly worse.” The CIBIC-plus has not been systematically

compared directly to assessments not using information from caregivers (CIBIC) or other global

methods.

Thirty-Week Study

In a study of 30 weeks duration, 473 patients were randomized to receive single daily doses of placebo,

5 mg/day or 10 mg/day of donepezil hydrochloride. The 30-week study was divided into a 24-week

double-blind active treatment phase followed by a 6-week single-blind placebo washout period. The

study was designed to compare 5 mg/day or 10 mg/day fixed doses of donepezil hydrochloride to

placebo. However, to reduce the likelihood of cholinergic effects, the 10 mg/day treatment was started

following an initial 7-day treatment with 5 mg/day doses.

Effects on the ADAS-cog

Figure 1 illustrates the time course for the change from baseline in ADAS-cog scores for all three

dose groups over the 30 weeks of the study. After 24 weeks of treatment, the mean differences in the

ADAS-cog change scores for donepezil hydrochloride treated patients compared to the patients on

placebo were 2.8 and 3.1 points for the 5 mg/day and 10 mg/day treatments, respectively. These

differences were statistically significant. While the treatment effect size may appear to be slightly

greater for the 10 mg/day treatment, there was no statistically significant difference between the two

active treatments.

Following 6 weeks of placebo washout, scores on the ADAS-cog for both the donepezil

hydrochloride treatment groups were indistinguishable from those patients who had received only

placebo for 30 weeks. This suggests that the beneficial effects of donepezil hydrochloride abate over

6 weeks following discontinuation of treatment and do not represent a change in the underlying disease.

There was no evidence of a rebound effect 6 weeks after abrupt discontinuation of therapy.

Figure 1. Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing 24

Weeks of Treatment.

Figure 2 illustrates the cumulative percentages of patients from each of the three treatment groups who

had attained the measure of improvement in ADAS-cog score shown on the X axis. Three change

scores (7-point and 4-point reductions from baseline or no change in score) have been identified for

illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset

table.

The curves demonstrate that both patients assigned to placebo and donepezil hydrochloride have a wide

range of responses, but that the active treatment groups are more likely to show greater improvements.

A curve for an effective treatment would be shifted to the left of the curve for placebo, while an

ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for

placebo.

Figure 2. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment with

Specified Changes from Baseline ADAS-cog Scores. The Percentages of Randomized Patients who

Completed the Study were: Placebo 80%, 5 mg/day 85%, and 10 mg/day 68%.

Effects on the CIBIC-plus

Figure 3 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients assigned

to each of the three treatment groups who completed 24 weeks of treatment. The mean drug-placebo

differences for these groups of patients were 0.35 points and 0.39 points for 5 mg/day and 10 mg/day of

donepezil hydrochloride, respectively. These differences were statistically significant. There was no

statistically significant difference between the two active treatments.

Figure 3. Frequency Distribution of CIBIC-plus Scores at Week 24.

Fifteen-Week Study

In a study of 15 weeks duration, patients were randomized to receive single daily doses of placebo or

either 5 mg/day or 10 mg/day of donepezil hydrochloride for 12 weeks, followed by a 3-week placebo

washout period. As in the 30-week study, to avoid acute cholinergic effects, the 10 mg/day treatment

followed an initial 7-day treatment with 5 mg/day doses.

Effects on the ADAS-cog

Figure 4 illustrates the time course of the change from baseline in ADAS-cog scores for all three dose

groups over the 15 weeks of the study. After 12 weeks of treatment, the differences in mean ADAS-cog

change scores for the donepezil hydrochloride treated patients compared to the patients on placebo

were 2.7 and 3.0 points each, for the 5 and 10 mg/day donepezil hydrochloride treatment groups,

respectively. These differences were statistically significant. The effect size for the 10 mg/day group

may appear to be slightly larger than that for 5 mg/day. However, the differences between active

treatments were not statistically significant.

Figure 4. Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing the

15-week Study.

Following 3 weeks of placebo washout, scores on the ADAS-cog for both the donepezil

hydrochloride treatment groups increased, indicating that discontinuation of donepezil hydrochloride

resulted in a loss of its treatment effect. The duration of this placebo washout period was not sufficient

to characterize the rate of loss of the treatment effect, but the 30-week study (see above) demonstrated

that treatment effects associated with the use of donepezil hydrochloride abate within 6 weeks of

treatment discontinuation.

Figure 5 illustrates the cumulative percentages of patients from each of the three treatment groups who

attained the measure of improvement in ADAS-cog score shown on the X axis. The same three change

scores (7-point and 4-point reductions from baseline or no change in score) as selected for the 30-week

study have been used for this illustration. The percentages of patients achieving those results are shown

in the inset table.

As observed in the 30-week study, the curves demonstrate that patients assigned to either placebo or to

donepezil hydrochloride have a wide range of responses, but that the donepezil hydrochloride treated

patients are more likely to show greater improvements in cognitive performance.

Figure 5. Cumulative Percentage of Patients with Specified Changes from Baseline ADAS-cog Scores.

The Percentages of Randomized Patients Within Each Treatment Group Who Completed the Study

Were: Placebo 93%, 5 mg/day 90%, and 10 mg/day 82%.

Effects on the CIBIC-plus

Figure 6 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients assigned

to each of the three treatment groups who completed 12 weeks of treatment. The differences in mean

scores for donepezil hydrochloride treated patients compared to the patients on placebo at Week 12

were 0.36 and 0.38 points for the 5 mg/day and 10 mg/day treatment groups, respectively. These

differences were statistically significant.

Figure 6. Frequency Distribution of CIBIC-plus Scores at Week 12.

In both studies, patient age, sex, and race were not found to predict the clinical outcome of donepezil

hydrochloride treatment.

14.2 Moderate to Severe Alzheimer's Disease

The effectiveness of donepezil hydrochloride in the treatment of patients with moderate to severe

Alzheimer’s disease was established in studies employing doses of 10 mg/day and 23 mg/day. Results

of a controlled clinical trial in moderate to severe Alzheimer’s Disease that compared donepezil

hydrochloride tablets 23 mg once daily to 10 mg once daily suggest that a 23 mg dose of donepezil

hydrochloride provided additional benefit.

Swedish 6 Month Study (10 mg/day)

The effectiveness of donepezil hydrochloride as a treatment for severe Alzheimer’s disease is

demonstrated by the results of a randomized, double-blind, placebo-controlled clinical study conducted

in Sweden (6 month study) in patients with probable or possible Alzheimer’s disease diagnosed by

NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1-10. Two hundred and forty eight (248)

patients with severe Alzheimer’s disease were randomized to donepezil hydrochloride or placebo. For

patients randomized to donepezil hydrochloride, treatment was initiated at 5 mg once daily for 28 days

and then increased to 10 mg once daily. At the end of the 6 month treatment period, 90.5% of the

donepezil hydrochloride tablets treated patients were receiving the 10 mg/day dose. The mean age of

patients was 84.9 years, with a range of 59 to 99. Approximately 77% of patients were women, and 23%

were men. Almost all patients were Caucasian. Probable Alzheimer’s disease was diagnosed in the

majority of the patients (83.6% of donepezil hydrochloride treated patients and 84.2% of placebo

treated patients).

Study Outcome Measures

The effectiveness of treatment with donepezil hydrochloride was determined using a dual outcome

assessment strategy that evaluated cognitive function using an instrument designed for more impaired

patients and overall function through caregiver-rated assessment. This study showed that patients on

donepezil hydrochloride experienced significant improvement on both measures compared to placebo.

The ability of donepezil hydrochloride to improve cognitive performance was assessed with the

Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation

of cognitive function in patients with moderate to severe dementia. The SIB evaluates selective aspects

of cognitive performance, including elements of memory, language, orientation, attention, praxis,

visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with

lower scores indicating greater cognitive impairment.

Daily function was assessed using the Modified Alzheimer’s Disease Cooperative Study Activities of

Daily Living Inventory for Severe Alzheimer’s Disease (ADCS-ADL-severe). The ADCS-ADL-

severe is derived from the Alzheimer’s Disease Cooperative Study Activities of Daily Living

Inventory, which is a comprehensive battery of ADL questions used to measure the functional

capabilities of patients. Each ADL item is rated from the highest level of independent performance to

complete loss. The ADCS-ADL-severe is a subset of 19 items, including ratings of the patient’s ability

to eat, dress, bathe, use the telephone, get around (or travel), and perform other activities of daily living;

it has been validated for the assessment of patients with moderate to severe dementia. The ADCS-ADL-

severe has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment.

The investigator performs the inventory by interviewing a caregiver, in this study a nurse staff member,

familiar with the functioning of the patient.

Effects on the SIB

Figure 7 shows the time course for the change from baseline in SIB score for the two treatment groups

over the 6 months of the study. At 6 months of treatment, the mean difference in the SIB change scores

for donepezil hydrochloride treated patients compared to patients on placebo was 5.9 points. Donepezil

hydrochloride treatment was statistically significantly superior to placebo.

Figure 7. Time Course of the Change from Baseline in SIB Score for Patients Completing 6 Months of

Treatment.

Figure 8 illustrates the cumulative percentages of patients from each of the two treatment groups who

attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to

donepezil hydrochloride and to placebo have a wide range of responses, the curves show that the

donepezil hydrochloride group is more likely to show a greater improvement in cognitive performance.

Figure 8. Cumulative Percentage of Patients Completing 6 Months of Double-blind Treatment with

Particular Changes from Baseline in SIB Scores.

Figure 9. Time Course of the Change from Baseline in ADCS-ADL-Severe Score for Patients

Completing 6 Months of Treatment.

Effects on the ADCS-ADL-severe

Figure 9 illustrates the time course for the change from baseline in ADCS-ADL-severe scores for

patients in the two treatment groups over the 6 months of the study. After 6 months of treatment, the mean

difference in the ADCS-ADL-severe change scores for donepezil hydrochloride treated patients

compared to patients on placebo was 1.8 points. Donepezil hydrochloride treatment was statistically

significantly superior to placebo.

Figure 10 shows the cumulative percentages of patients from each treatment group with specified

changes from baseline ADCS-ADL-severe scores. While both patients assigned to donepezil

hydrochloride and placebo have a wide range of responses, the curves demonstrate that the donepezil

hydrochloride group is more likely to show a smaller decline or an improvement.

Figure 10. Cumulative Percentage of Patients Completing 6 Months of Double-blind Treatment with

Particular Changes from Baseline in ADCS-ADL-Severe Scores.

Japanese 24-Week Study (10 mg/day)

In a study of 24 weeks duration conducted in Japan, 325 patients with severe Alzheimer’s disease were

randomized to doses of 5 mg/day or 10 mg/day of donepezil, administered once daily, or placebo.

Patients randomized to treatment with donepezil were to achieve their assigned doses by titration,

beginning at 3 mg/day, and extending over a maximum of 6 weeks. Two hundred and forty eight (248)

patients completed the study, with similar proportions of patients completing the study in each treatment

group. The primary efficacy measures for this study were the SIB and CIBIC-plus.

At 24 weeks of treatment, statistically significant treatment differences were observed between the 10

mg/day dose of donepezil and placebo on both the SIB and CIBIC-plus. The 5 mg/day dose of donepezil

showed a statistically significant superiority to placebo on the SIB, but not on the CIBIC-plus.

Study of 23 mg/day

The effectiveness of donepezil hydrochloride tablets 23 mg/day as a treatment for moderate to severe

Alzheimer’s disease has been demonstrated by the results of a randomized, double-blind, controlled

clinical investigation in patients with moderate to severe Alzheimer’s disease. The controlled clinical

study was conducted globally in patients with probable Alzheimer’s disease diagnosed by NINCDS-

ADRDA and DSM-IV criteria, MMSE: range of 0-20. Patients were required to have been on a stable

ADRDA and DSM-IV criteria, MMSE: range of 0-20. Patients were required to have been on a stable

dose of donepezil hydrochloride tablets 10 mg/day for at least 3 months prior to screening. One

thousand four hundred and thirty four (1434) patients with moderate to severe Alzheimer’s disease were

randomized to 23 mg/day or 10 mg/day. The mean age of patients was 73.8 years, with a range of 47 to

90. Approximately 63% of patients were women, and 37% were men. Approximately 36% of the

patients were taking memantine throughout the study.

Study Outcome Measures

The effectiveness of treatment with 23 mg/day was determined using a dual outcome assessment

strategy that evaluated cognitive function using an instrument designed for more impaired patients and

overall function through caregiver-rated assessment.

The ability of 23 mg/day to improve cognitive performance was assessed with the Severe Impairment

Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation of cognitive

function in patients with moderate to severe dementia. The SIB evaluates selective aspects of cognitive

performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability,

construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores

indicating greater cognitive impairment.

The ability of 23 mg/day to produce an overall clinical effect was assessed using a Clinician’s

Interview-Based Impression of Change that incorporated the use of caregiver information, the CIBIC-

plus. The CIBIC-plus used in this trial was a semi-structured instrument that examines four major areas

of patient function: General, Cognitive, Behavioral, and Activities of Daily Living. It represents the

assessment of a skilled clinician based upon his/her observations at an interview with the patient, in

combination with information supplied by a caregiver familiar with the behavior of the patient over the

interval rated. The CIBIC-plus is scored as a seven-point categorical rating, ranging from a score of 1,

indicating “markedly improved,” to a score of 4, indicating “no change” to a score of 7, indicating

“markedly worse.”

Effects on the SIB

Figure 11 shows the time course for the change from baseline in SIB score for the two treatment

groups over the 24 weeks of the study. At 24 weeks of treatment, the LS mean difference in the SIB

change scores for 23 mg/day-treated patients compared to patients treated with 10 mg was 2.2 units (p =

0.0001). The dose of 23 mg/day was statistically significantly superior to the dose of 10 mg/day.

Figure 11. Time-course of the Change from Baseline in SIB Score for Patients Completing 24 Weeks

of Treatment.

Figure 12 illustrates the cumulative percentages of patients from each of the two treatment groups who

attained the measure of improvement in SIB score shown on the Xaxis. While patients assigned both to

23 mg/day and to 10 mg/day have a wide range of responses, the curves show that the 23 mg-group is

more likely to show a greater improvement in cognitive performance. When such curves are shifted to

the left, this indicates a greater percentage of patients responding to treatment on the SIB.

Figure 12. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment with

Specified Changes from Baseline SIB Scores.

Effects on the CIBIC-plus

Figure 13 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients at the

end of 24 weeks of treatment. The mean difference between the 23 mg/day and 10 mg/day treatment

groups was 0.06 units. This difference was not statistically significant.

Figure 13. Frequency Distribution of CIBIC-plus Scores at Week 24.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Donepezil Hyrochloride 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) NDC33342-028-31

Unit Dose Blister Package 100 (10x10) NDC33342-028-12

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

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].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Instruct patients and caregivers to take donepezil hydrochloride tablets only once per day, as

prescribed.

Instruct patients and caregivers that donepezil hydrochloride can be taken with or without food.

Donepezil hydrochloride 23 mg tablets should be swallowed whole without the tablets being split,

crushed or chewed. Donepezil hydrochloride orally disintegrating tablets should not be swallowed

whole, but be allowed to dissolve on the tongue and followed with water.

Advise patients and caregivers that donepezil hydrochloride may cause nausea, diarrhea, insomnia,

vomiting, muscle cramps, fatigue, and decreased appetite.

Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.

PM01370907

PATIENT PACKAGE INSERT

Donepezil Hydrochloride Tablets

(doe-NEP-e-zil HYE-droe-KLOR-ide)

Tablets USP: 5 mg and 10 mg and 23 mg

Tablets: 23 mg

Donepezil Hydrochloride Orally Disintegrating Tablets (doe-NEP-e-zil HYE-droe-KLOR-ide)

orally disintegrating tablets, USP: 5 mg and 10 mg

Read this Patient Information that comes with donepezil hydrochloride before you start taking it and

each time you get a refill. There may be new information. This leaflet does not take the place of talking

with your doctor about Alzheimer’s disease or treatment for it. If you have questions, ask the doctor or

pharmacist.

What is donepezil hydrochloride?

Donepezil hydrochloride comes as donepezil hydrochloride film-coated tablets in dosage strengths of

5 mg, 10 mg, and 23 mg, and as Donepezil Hydrochloride Orally Disintegrating Tablets ( 5 mg and 10

mg). Except where indicated, all the information about donepezil hydrochloride in this leaflet also

applies to donepezil hydrochloride orally disintegrating tablets.

Donepezil hydrochloride is a prescription medicine to treat mild, moderate, and severe Alzheimer’s

disease. Donepezil hydrochloride can help with mental function and with doing daily tasks. Donepezil

hydrochloride does not work the same in all people. Some people may:

Seem much better

Get better in small ways or stay the same

Get worse over time but slower than expected

Not change and then get worse as expected

Donepezil hydrochloride does not cure Alzheimer’s disease. All patients with Alzheimer’s disease get

worse over time, even if they take donepezil hydrochloride.

Donepezil hydrochloride has not been approved as a treatment for any medical condition in children.

Who should not take donepezil hydrochloride?

Do not take donepezil hydrochloride if you are allergic to any of the ingredients in donepezil

hydrochloride or to medicines that contain piperidines. Ask your doctor if you are not sure. See the end

of this leaflet for a list of ingredients in donepezil hydrochloride.

What should I tell my doctor before taking donepezil hydrochloride?

Tell the doctor about all of your present or past health problems and conditions. Include:

Any heart problems including problems with irregular, slow, or fast heartbeats

Asthma or lung problems

A seizure

Stomach ulcers

Difficulty passing urine

Liver or kidney problems

Trouble swallowing tablets

Present pregnancy or plans to become pregnant. It is not known if donepezil hydrochloride can harm an

unborn baby.

Present breast-feeding. It is not known if donepezil hydrochloride passes into breast milk. Talk to your

doctor about the best way to feed your baby if you take donepezil hydrochloride.

Tell your doctor about all the medicines you take, including prescription and non-prescription

medicines, vitamins, and herbal products. Donepezil hydrochloride and other medicines may affect each

other.

Be particularly sure to tell the doctor if you take aspirin or medicines called nonsteroidal anti-

inflammatory drugs (NSAIDs). There are many NSAID medicines, both prescription and non-

prescription. Ask the doctor or pharmacist if you are not sure if any of your medicines are NSAIDs.

Taking NSAIDs and donepezil hydrochloride together may make the patient more likely to get stomach

ulcers.

Donepezil hydrochloride taken with certain medicines used for anesthesia may cause side effects. Tell

the responsible doctor or dentist that you take donepezil hydrochloride before you have:

surgery

medical procedures

dental surgery or procedures.

Know the medicines that you take. Keep a list of all your medicines. Show it to your doctor or

pharmacist before you start a new medicine.

How should the patient take donepezil hydrochloride?

Take donepezil hydrochloride exactly as prescribed by the doctor. Do not stop donepezil

hydrochloride or change the dose yourself. Talk with your doctor first.

Take donepezil hydrochloride one time each day. Donepezil hydrochloride can be taken with or

without food.

Donepezil hydrochloride 23 mg tablets should be swallowed whole. Do not split, crush, or chew the

tablets.

Donepezil hydrochloride orally disintegrating tablets melts on the tongue. You should drink some

water after the tablet melts.

If you miss a dose of donepezil hydrochloride, just wait. Take only the next dose at the usual time. Do

not take 2 doses at the same time.

If donepezil hydrochloride are missed for 7 days or more, talk your doctor before starting again.

If you take too much donepezil hydrochloride at one time, call the doctor or poison control center, or

go to the emergency room right away.

What are the possible side effects of donepezil hydrochloride?

Donepezil hydrochloride may cause the following serious side effects:

slow heartbeat and fainting. This happens more often in people with heart problems. Call the doctor

right away if you feel faint or lightheaded while taking donepezil hydrochloride.

more stomach acid. This raises the chance of ulcers and bleeding, especially when taking donepezil

hydrochloride tablets 23 mg. The risk is higher for people who have had ulcers, or take aspirin or

other NSAIDs.

worsening of lung problems in people with asthma or other lung disease.

seizures.

difficulty passing urine.

Call your doctor right away if you have:

fainting.

heartburn or stomach pain that is new or won’t go away.

nausea or vomiting, blood in the vomit, dark vomit that looks like coffee grounds.

bowel movements or stools that look like black tar.

new or worse asthma or breathing problems.

seizures.

difficulty passing urine.

The most common side effects of donepezil hydrochloride are:

nausea

diarrhea

not sleeping well

vomiting

muscle cramps

feeling tired

not wanting to eat

These side effects may get better after you take donepezil hydrochloride for a while. This is not a

complete list of side effects with donepezil hydrochloride. For more information, ask your doctor

or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-

800-FDA-1088.

How should donepezil hydrochloride tablets be stored?

Store donepezil hydrochloride tablets at 20° to 25° C (68° to 77° F); excursions permitted to 15° C to

30° C (59° F to 86°F).

Keep donepezil hydrochloride tablets and all medicines out of the reach of children.

General information about donepezil hydrochloride

Medicines are sometimes prescribed for conditions that are not mentioned in this Patient Information

Leaflet. Do not use donepezil hydrochloride for a condition for which it was not prescribed. Do not

give donepezil hydrochloride to other people, even if they have the same symptoms or conditions. It

may harm them.

This leaflet summarizes the most important information about donepezil hydrochloride. If you would

like more information talk with the patient’s doctor. You can ask your pharmacist or doctor for

information about donepezil hydrochloride tablets that is written for health professionals. For more

information call 1-888-943-3210.

What are the ingredients in donepezil hydrochloride tablets?

Active ingredient: donepezil hydrochloride

Inactive ingredients:

Donepezil hydrochloride tablets 5 mg and 10 mg film-coated tablets: 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.

Donepezil hydrochloride 23 mg film-coated tablets: hydroxypropyl cellulose, lactose monohydrate,

magnesium stearate and hypromellose. The reddish color film coating includes ferric oxide red,

hypromellose, polyethylene glycol 8000, talc and titanium dioxide.

Donepezil hydrochloride orally disintegrating tablets 5 mg and 10 mg: mannitol, crospovidone,

sucralose, sodium chloride, ferric oxide yellow and magnesium stearate.

Manufactured for:

Macleods Pharma USA, INC,

Plainsboro, NJ 08536

Manufactured by:

Macleods Pharmaceutical Ltd.

Baddi, Himachal Pradesh, India.

March 2019

PM01370907

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-5 mg 30 Tablets

NDC 33342-027-07

Rx only

30 TABLETS

Donepezil Hydrochloride Tablets USP

5 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-5 mg 90 Tablets

NDC 33342-027-10

Rx only

90 TABLETS

Donepezil Hydrochloride Tablets USP

5 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-5 mg 500 Tablets

NDC 33342-027-15

Rx only

500 TABLETS

Label Donepezil Hydrochloride Tablets USP

5 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-10 mg 30 Tablets

NDC 33342-028-07

Rx only

30 TABLETS

Label Donepezil Hydrochloride Tablets USP

10 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-10 mg 30 Tablets

NDC 33342-028-15

Rx only

500 TABLETS

Label Donepezil Hydrochloride Tablets USP

10 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-23 mg 30 Tablets

NDC 33342-061-07

Rx only

30 TABLETS

Label Donepezil Hydrochloride Tablets USP

23 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-23 mg 90 Tablets

NDC 33342-061-10

Rx only

90 TABLETS

Label Donepezil Hydrochloride Tablets USP

23 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-23 mg 90 Tablets

NDC 33342-061-12

Rx only

10X10 TABLETS

Label Donepezil Hydrochloride Tablets USP

23 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-ODT 5 mg 30 Tablets

NDC 33342-029-07

Rx only

30 TABLETS

Label Donepezil Hydrochloride Orally Disintegrating Tablets USP

5 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-ODT 5 mg 28 Tablets

NDC 33342-029-60

Rx only

4X7 TABLETS

Label Donepezil Hydrochloride Orally Disintegrating Tablets USP

5 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-ODT 10 mg 30 Tablets

NDC 33342-030-07

Rx only

30 TABLETS

Label Donepezil Hydrochloride Orally Disintegrating Tablets USP

10 mg

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-ODT 10 mg 28 Tablets

NDC 33342-030-60

Rx only

4X7 TABLETS

Label Donepezil Hydrochloride Orally Disintegrating Tablets USP

10 mg

DONEPEZIL HYDROCHLORIDE

donepezil hydrochloride tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:33342-0 27

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DO NEPEZIL HYDRO CHLO RIDE (UNII: 3O2T2PJ8 9 D) (DONEPEZIL -

UNII:8 SSC9 1326 P)

DONEPEZIL

HYDROCHLORIDE

5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

STARCH, CO RN (UNII: O8 232NY3SJ)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

TALC (UNII: 7SEV7J4R1U)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

WHITE (white to o ff white)

S core

no sco re

S hap e

ROUND (bico nvex)

S iz e

Flavor

Imprint Code

ML;8 9

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:33342-0 27-0 7 30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /17/20 12

2

NDC:33342-0 27-10

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /17/20 12

3

NDC:33342-0 27-31

5 in 1 CARTON

0 8 /17/20 12

3

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

4

NDC:33342-0 27-12

10 in 1 CARTON

0 8 /17/20 12

4

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

5

NDC:33342-0 27-44

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/0 6 /20 14

6

NDC:33342-0 27-15

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/0 6 /20 14

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 1146

0 8 /17/20 12

DONEPEZIL HYDROCHLORIDE

donepezil hydrochloride tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:33342-0 28

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DO NEPEZIL HYDRO CHLO RIDE (UNII: 3O2T2PJ8 9 D) (DONEPEZIL -

UNII:8 SSC9 1326 P)

DONEPEZIL

HYDROCHLORIDE

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

STARCH, CO RN (UNII: O8 232NY3SJ)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

TALC (UNII: 7SEV7J4R1U)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

Product Characteristics

Color

YELLOW

S core

no sco re

S hap e

ROUND (bico nvex)

S iz e

8 mm

Flavor

Imprint Code

ML;8 8

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:33342-0 28 -0 7 30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /17/20 12

2

NDC:33342-0 28 -10

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /17/20 12

3

NDC:33342-0 28 -31

5 in 1 CARTON

0 8 /17/20 12

3

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

4

NDC:33342-0 28 -12

10 in 1 CARTON

0 8 /17/20 12

4

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

5

NDC:33342-0 28 -44

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/0 6 /20 14

6

NDC:33342-0 28 -15

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/0 6 /20 14

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 1146

0 8 /17/20 12

DONEPEZIL HYDROCHLORIDE

donepezil hydrochloride tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:33342-0 6 1

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DO NEPEZIL HYDRO CHLO RIDE (UNII: 3O2T2PJ8 9 D) (DONEPEZIL -

UNII:8 SSC9 1326 P)

DONEPEZIL

HYDROCHLORIDE

23 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYDRO XYPRO PYL CELLULO SE, UNSPECIFIED (UNII: 9 XZ8 H6 N6 OH)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

RED (red)

S core

no sco re

S hap e

ROUND (ro und,bico nvex)

S iz e

8 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:33342-0 6 1-0 7 30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/23/20 14

2

NDC:33342-0 6 1-10

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 1/23/20 14

3

NDC:33342-0 6 1-12

10 in 1 CARTON

0 1/23/20 14

3

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 26 31

0 1/23/20 14

DONEPEZIL HYDROCHLORIDE

donepezil hydrochloride tablet, orally disintegrating

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:33342-0 29

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DO NEPEZIL HYDRO CHLO RIDE (UNII: 3O2T2PJ8 9 D) (DONEPEZIL -

UNII:8 SSC9 1326 P)

DONEPEZIL

HYDROCHLORIDE

5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MANNITO L (UNII: 3OWL53L36 A)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

SUCRALO SE (UNII: 9 6 K6 UQ3ZD4)

SO DIUM CHLO RIDE (UNII: 451W47IQ8 X)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

Product Characteristics

Color

YELLOW (yello w)

S core

no sco re

S hap e

ROUND (circular,flat face beveled edge)

S iz e

Flavor

Imprint Code

CL;31

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:33342-0 29 -0 6

3 in 1 CARTON

12/14/20 12

1

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

2

NDC:33342-0 29 -12

10 in 1 CARTON

12/14/20 12

2

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

3

NDC:33342-0 29 -6 0

4 in 1 CARTON

12/14/20 12

3

7 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

4

NDC:33342-0 29 -0 7

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/14/20 12

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 178 7

12/14/20 12

DONEPEZIL HYDROCHLORIDE

donepezil hydrochloride tablet, orally disintegrating

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:33342-0 30

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DO NEPEZIL HYDRO CHLO RIDE (UNII: 3O2T2PJ8 9 D) (DONEPEZIL -

UNII:8 SSC9 1326 P)

DONEPEZIL

HYDROCHLORIDE

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MANNITO L (UNII: 3OWL53L36 A)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

SUCRALO SE (UNII: 9 6 K6 UQ3ZD4)

SO DIUM CHLO RIDE (UNII: 451W47IQ8 X)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

Product Characteristics

Color

YELLOW (yello w)

S core

no sco re

S hap e

ROUND (circular,flat face beveled edge)

S iz e

8 mm

Flavor

Imprint Code

CL;32

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:33342-0 30 -0 6

3 in 1 CARTON

12/14/20 12

1

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

2

NDC:33342-0 30 -12

10 in 1 CARTON

12/14/20 12

2

10 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

3

NDC:33342-0 30 -6 0

4 in 1 CARTON

12/14/20 12

3

7 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

4

NDC:33342-0 30 -0 7

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/14/20 12

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 178 7

12/14/20 12

Labeler -

Macleods Pharmaceuticals Limited (862128535)

Establishment

Macleods Pharmaceuticals Limited

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Ma c le o ds

Pha rma c e utic a ls

Limite d

6 76 36 9 519

ANALYSIS(33342-0 27, 33342-0 28 , 33342-0 29 , 33342-0 30 , 33342-0 6 1) , LABEL(33342-0 27,

33342-0 28 , 33342-0 29 , 33342-0 30 , 33342-0 6 1) , MANUFACTURE(33342-0 27, 33342-0 28 ,

33342-0 29 , 33342-0 30 , 33342-0 6 1) , PACK(33342-0 27, 33342-0 28 , 33342-0 29 , 33342-0 30 ,

33342-0 6 1)

Revised: 8/2019

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