These highlights do not include all the information needed to use donepezil hydrochloride orally disintegrating tablets safely and effectively. See full prescribing information for donepezil hydrochloride orally disintegrating tablets.
Initial U.S. Approval: 1996
INDICATIONS AND USAGE
Donepezil hydrochloride orally disintegrating tablets are 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 (1.0).
DOSAGE AND ADMINISTRATION
Mild to Moderate Alzheimer’s disease – 5 mg or 10 mg administered once daily (2.1)
Severe Alzheimer’s disease - 10 mg administered once daily (2.2)
A dose of 10 mg once daily can be administered once patients have been on a daily dose of 5 mg for 4 to 6 weeks. (2.3)
DOSAGE FORMS AND STRENGTHS
Orally Disintegrating Tablets(ODT): 5 mg and 10 mg (3)
CONTRAINDICATIONS
Patients with 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).
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
The 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 Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 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 (7.3).
A synergistic effect may be expected with concomitant administration of succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists (7.4).
USE IN SPECIFIC POPULATIONS
Based on animal data, donepezil hydrochloride may cause fetal harm (8.1).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
Revised: 05/2011
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FULL PRESCRIBING INFORMATION: CONTENTS*
*Sections or subsections omitted from the full prescribing information are not listed
1. INDICATIONS AND USAGE
2. DOSAGE AND ADMINISTRATION
2.1 Mild to Moderate Alzheimer’s Disease
2.2 Severe Alzheimer’s Disease
2.3 Titration
3. DOSAGE FORMS AND 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 Genitourinary Conditions
5.6 Neurological Conditions
5.7 Pulmonary Conditions
6. ADVERSE REACTIONS
6.1 Clinical Studies Experience
6.2 Postmarketing Experience
7. DRUG INTERACTIONS
7.1 Effects of Donepezil Hydrochloride on the Metabolism of Other Drugs
7.2 Effects of Other Drugs on the Metabolism of Donepezil Hydrochloride
7.3 Use with Anticholinergics
7.4 Use with Cholinomimetics and Other Cholinesterase Inhibitors
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
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 Severe Alzheimer’s disease
16. HOW SUPPLIED/STORAGE AND HANDLING
17. PATIENT COUNSELING INFORMATION
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FULL PRESCRIBING INFORMATION
1. INDICATIONS AND USAGE
Donepezil hydrochloride orally disintegrating tablets are indicated for the treatment of dementia of the Alzheimer’s type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease.
2. DOSAGE AND ADMINISTRATION
Donepezil hydrochloride orally disintegrating tablets should be taken in the evening, just prior to retiring.
Allow donepezil hydrochloride orally disintegrating tablets to dissolve on the tongue and follow with water.
2.1 Mild to Moderate Alzheimer’s Disease
The dosages of donepezil hydrochloride shown to be effective in controlled clinical trials are 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 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.
2.2 Severe Alzheimer’s Disease
Donepezil hydrochloride has been shown to be effective in controlled clinical trials at a dose of 10 mg administered once daily.
2.3 Titration
The recommended starting dose of donepezil hydrochloride 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 hydrochloride 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.
3. DOSAGE FORMS AND STRENGTHS
Donepezil hydrochloride orally disintegrating tablets are supplied as round tablets containing 5 mg or 10 mg of donepezil hydrochloride.
The 5 mg orally disintegrating tablets are white to off-white, biconvex, uncoated tablets engraved with ‘ZF 14’on one side and plain on other side.
The 10 mg orally disintegrating tablets are white to off-white, biconvex, uncoated tablets engraved with ‘ZF 15’on one side and plain on other side.
4. CONTRAINDICATIONS
Donepezil hydrochloride orally disintegrating tablets are 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.
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 hydrochloride, patients should be observed closely at the initiation of treatment and after dose increases.
5.4 Peptic Ulcer Disease and GI Bleeding
Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of donepezil hydrochloride in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
5.5 Genitourinary Conditions
Although not observed in clinical trials of donepezil hydrochloride, cholinomimetics may cause bladder outflow obstruction.
5.6 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.
5.7 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
6.1 Clinical Studies Experience
Mild to Moderate Alzheimer’s Disease
Adverse Events Leading to Discontinuation
The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse events for the donepezil hydrochloride 5 mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day was higher at 13%.
The most common adverse 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 1Most Frequent Adverse Events Leading to Discontinuation from Controlled Clinical Trials by Dose Group
DoseGroup
Placebo
5mg/day
10mg/day
DonepezilHydrochloride
DonepezilHydrochloride
PatientsRandomized Event/%Discontinuing
355
350
315
Nausea
1%
1%
3%
Diarrhea
0%
<1%
3%
Vomiting
<1%
<1%
2%
Most Frequent Adverse Events Seen in Association with the Use of Donepezil Hydrochloride
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 hydrochloride’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 hydrochloride 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 ModeratePatients Titrated to 10 mg/day over 1 and 6 Weeks
Notitration
Oneweek titration
Sixweek titration
AdverseEvent
Placebo
5mg/day
10mg/day
10mg/day
(n=315)
(n=311)
(n=315)
(n=269)
Nausea
6%
5%
19%
6%
Diarrhea
5%
8%
15%
9%
Insomnia
6%
6%
14%
6%
Fatigue
3%
4%
8%
3%
Vomiting
3%
3%
8%
5%
Musclecramps
2%
6%
8%
3%
Anorexia
2%
3%
7%
3%
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 hydrochloride and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride 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 ModerateAlzheimer’s Disease in at Least 2% of Patients Receiving Donepezil Hydrochlorideand at a Higher Frequency than Placebo Treated Patients
BodySystem/AdverseEvent
Placebo
DonepezilHydrochloride
(n=355)
(n=747)
PercentofPatientswithanyAdverseEvent
72
74
BodyasaWhole
Headache
9
10
Pain,variouslocations
8
9
Accident
6
7
Fatigue
3
5
CardiovascularSystem
Syncope
1
2
DigestiveSystem
Nausea
6
11
Diarrhea
5
10
Vomiting
3
5
Anorexia
2
4
HemicandLymphaticSystem
Ecchymosis
3
4
MetabolicandNutritionalSystems
WeightDecrease
1
3
MusculoskeletalSystem
MuscleCramps
2
6
Arthritis
1
2
NervousSystem
Insomnia
6
9
Dizziness
6
8
Depression
<1
3
AbnormalDreams
0
3
Somnolence
<1
2
UrogenitalSystem
FrequentUrination
1
2
Other Adverse Events Observed During Clinical Trials
Donepezil hydrochloride has been administered to over 1700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1000 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 1214 days.
Treatment emergent signs and symptoms that occurred during three controlled clinical trials and two open-label trials in the United States were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900 patients from these trials who experienced that event while receiving donepezil hydrochloride. All adverse events occurring at least twice are included, except for those already listed in Tables 2 or 3, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100 patients; Infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to donepezil hydrochloride treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States.
The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse events for the donepezil hydrochloride patients were approximately 12% compared to 7% for placebo patients. The most common adverse events 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 Frequent Adverse Events Seen in Association with the Use of Donepezil Hydrochloride
The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice or more the placebo rate, are largely predicted by donepezil hydrochloride’s cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification.
Adverse Events Reported in Controlled Trials
Table 4 lists adverse events that were reported in at least 2% of patients in placebo-controlled trials who received donepezil hydrochloride and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo.
Table 4Adverse Events Reported in Controlled Clinical Trials in Severe Alzheimer’s Disease in at Least 2% of Patients Receiving Donepezil Hydrochloride and at a Higher Frequency than Placebo-Treated Patients
BodySystem/AdverseEvent
Placebo
DonepezilHydrochloride
(n=392)
(n=501)
PercentofPatientswithanyAdverseEvent
73
81
BodyasaWhole
Accident
12
13
Infection
9
11
Headache
3
4
Pain
2
3
BackPain
2
3
Fever
1
2
ChestPain
<1
2
CardiovascularSystem
Hypertension
2
3
Hemorrhage
1
2
Syncope
1
2
DigestiveSystem
Diarrhea
4
10
Vomiting
4
8
Anorexia
4
8
Nausea
2
6
HemicandLymphaticSystem
Ecchymosis
2
5
MetabolicandNutritionalSystems
CreatinePhosphokinaseIncreased
1
3
Dehydration
1
2
Hyperlipemia
<1
2
NervousSystem
Insomnia
4
5
Hostility
2
3
Nervousness
2
3
Hallucinations
1
3
Somnolence
1
2
Dizziness
1
2
Depression
1
2
Confusion
1
2
EmotionalLability
1
2
PersonalityDisorder
1
2
SkinAndAppendages
Eczema
2
3
UrogenitalSystem
UrinaryIncontinence
1
2
Other Adverse Events Observed During Clinical Trials
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. All adverse events occurring at least twice are included, except for those already listed in Table 4, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system using the COSTART dictionary and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100 patients; Infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to donepezil hydrochloride treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies.
