DONEPEZIL HYDROCHLORIDE - donepezil hydrochloride tablet, film coated
Macleods Pharmaceuticals Limited
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Donepezil Hydrochloride Tablets USP safely and effectively. See full prescribing information for Donepezil Hydrochloride Tablets USP.
Donepezil Hydrochloride Tablets USP Initial U.S. Approval: 1996 RECENT MAJOR CHANGESNone
INDICATIONS AND USAGEDonepezil hydrochloride USP 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 (1.0).
DOSAGE AND ADMINISTRATIONDOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSThe most common adverse reactions in clinical studies of donepezil hydrochloride tablets 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 INTERACTIONSUSE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION. Revised: 01/2013 |
Donepezil hydrochloride tablets should be taken in the evening just before retiring.
The dosages of donepezil hydrochloride shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.
The recommended starting dose of donepezil hydrochloride is 5mg 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.
Donepezil hydrochloride is supplied as film-coated, round tablets containing either 5 mg or 10 mg of donepezil hydrochloride.
The 5 mg tablets are white to off white, round shaped, biconvex, film-coated tablets debossed with ‘ML 89’ on one side and plain on the other side.
The 10 mg tablets are yellow, round shaped, biconvex, film-coated tablets debossed with ‘ML 88’ on one side and plain on the other side.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 10mg/day dose than with the 5mg/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.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).
Table 1. Most Frequent Adverse Events Leading to Withdrawal from Controlled Clinical Trials by Dose Group |
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Dose Group |
Placebo |
5 mg/day Donepezil hydrochloride |
10 mg/day Donepezil hydrochloride |
Patients Randomized
|
355 |
350 |
315 |
Event/%Discontinuing
|
|
|
|
Nausea |
1% |
1% |
3% |
Diarrhea
|
0% |
< 1% |
3% |
Vomiting |
<1% |
< 1% |
2% |
Table 2. Comparison of rates of adverse events in mild to moderate patients titrated to 10 mg/day over 1 and 6 weeks |
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|
No titration |
One week titration |
Six week titration |
|
Adverse Event
|
Placebo (n=315) |
5 mg/day (n=311) |
10 mg/day (n=315) |
10 mg/day (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% |
Muscle cramps |
2% |
6% |
8% |
3% |
Anorexia |
2% |
3% |
7% |
3% |
Table 3. Adverse Events Reported in Controlled Clinical Trials in Mild to Moderate Alzheimer's Disease in at Least 2% of Patients Receiving donepezil hydrochloride and at a Higher Frequency than Placebo treated Patients |
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Body System/Adverse Event
|
Placebo (n=355) |
Donepezil hydrochloride (n=747) |
Percent of Patients with any Adverse Event
|
72 |
74 |
Body as a Whole
| | |
Headache |
9 |
10 |
Pain, various locations |
8 |
9 |
Accident |
6 |
7 |
Fatigue |
3 |
5 |
Cardiovascular System
| | |
Syncope |
1 |
2 |
Digestive System
| | |
Nausea |
6 |
11 |
Diarrhea |
5 |
10 |
Vomiting |
3 |
5 |
Anorexia |
2 |
4 |
Hemic and Lymphatic System
| | |
Ecchymosis |
3 |
4 |
Metabolic and Nutritional Systems
| | |
Weight Decrease |
1 |
3 |
Musculoskeletal System
| | |
Muscle Cramps |
2 |
6 |
Arthritis |
1 |
2 |
Nervous System
| | |
Insomnia |
6 |
9 |
Dizziness |
6 |
8 |
Depression |
<1 |
3 |
Abnormal Dreams |
0 |
3 |
Somnolence |
<1 |
2 |
Urogenital System
| | |
Frequent Urination |
1 |
2 |
Adverse Events Leading to Discontinuation
Most Frequent Adverse Clinical Events Seen in Association with the Use of donepezil hydrochloride
Adverse Events Reported in Controlled Trials
Table 4. Adverse 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 |
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Body System/Adverse Event |
Placebo (n=392) |
Donepezil hydrochloride (n=501) |
Percent of Patients with any Adverse Event
|
73 |
81 |
Body as a Whole
| | |
Accident |
12 |
13 |
Infection |
9 |
11 |
Headache |
3 |
4 |
Pain |
2 |
3 |
Back Pain |
2 |
3 |
Fever |
1 |
2 |
Chest Pain |
<1 |
2 |
Cardiovascular System
| | |
Hypertension |
2 |
3 |
Hemorrhage |
1 |
2 |
Syncope |
1 |
2 |
Digestive System
| | |
Diarrhea |
4 |
10 |
Vomiting |
4 |
8 |
Anorexia |
4 |
8 |
Nausea |
2 |
6 |
Hemic and Lymphatic System | | |
Ecchymosis |
2 |
5 |
Metabolic and Nutritional Systems
| | |
Creatine Phosphokinase Increased |
1 |
3 |
Dehydration |
1 |
2 |
Hyperlipemia |
<1 |
2 |
Nervous System
| | |
Insomnia |
4 |
5 |
Hostility |
2 |
3 |
Nervousness |
2 |
3 |
Hallucinations |
1 |
3 |
Somnolence |
1 |
2 |
Dizziness |
1 |
2 |
Depression |
1 |
2 |
Confusion |
1 |
2 |
Emotional Lability |
1 |
2 |
Personality Disorder |
1 |
2 |
Skin And Appendages
| | |
Eczema |
2 |
3 |
Urogenital System
| | |
Urinary Incontinence |
1 |
2 |
Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] of 23 mg/day on a mg/m2 basis) and 10 mg/kg/day (approximately 7 times the MRHD on a mg/m2 basis), respectively. Oral administration of donepezil (1, 3, 10 mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an increase in stillbirths and reduced offspring survival through postpartum day 4 at the highest dose. The no-effect dose of 3 mg/kg/day is approximately equal to the MRHD on a mg/m2 basis.
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
A small effect of CYP2D6 inhibitors was identified in a population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer’s disease. Donepezil clearance was reduced by approximately 17% in patients taking 10 or 23 mg in combination with a known CYP2D6 inhibitor. This result is consistent with the conclusion that CYP2D6 is a minor metabolic pathway of donepezil.
Formal pharmacokinetic studies demonstrated that the metabolism of donepezil hydrochloride is not significantly affected by concurrent administration of digoxin or cimetidine.
An in vitro study showed that donepezil was not a substrate of P-glycoprotein.
No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil hydrochloride conducted in mice at oral doses up to 180 mg/kg/day or in a 104-week carcinogenicity study in rats at doses up to 30 mg/kg/day (approximately 13 times the MRHD on a mg/m2 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/m2 basis) when administered to males and females prior to and during mating and continuing in females through implantation.
Bottles of 30 (NDC 33342-027-07 )
Bottles of 90 (NDC 33342-027-10 )
Blister Pack of 50 (5x10) (NDC 33342-027-31 )
Bottles of 30 (NDC 33342-028-07 )
Bottles of 90 (NDC 33342-028-10 )
Blister Pack of 50 (5x10) (NDC 33342-028-31 )
PATIENT PACKAGE INSERT
Donepezil hydrochloride tablets USP
What are donepezil hydrochloride tablets?
Donepezil hydrochloride tablets come as film-coated tablets in dosage strengths of 5mg and 10mg.
Donepezil hydrochloride is a prescription medicine to treat mild, moderate and severe Alzheimer's disease (up to 10mg). Donepezil hydrochloride tablets can help in 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
Who should not take donepezil hydrochloride tablets?
Tell the doctor about all the patient’s present or past health problems.
Include:
· Any heart problems including problems with irregular, slow, or fast heartbeats
· Asthama 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.
Donepezil hydrochloride tablets taken with certain medicines used for anesthesia may cause side effects. Tell the responsible doctor or dentist that the patient takes donepezil hydrochloride tablets before the patient has:
· surgery
· medical procedures
How should the patient take donepezil hydrochloride tablets?
· Give donepezil hydrochloride tablets exactly as prescribed by the doctor. Do not stop donepezil hydrochloride tablets or change the dose yourself. Talk with the doctor first.
· Give donepezil hydrochloride tablets one time each day. Donepezil hydrochloride tablets can be taken with or without food.
· Donepezil hydrochloride Tablets should be swallowed whole without the tablets being broken or crushed.
· If you miss giving the patient a dose of donepezil hydrochloride tablets, just wait. Give only the next dose at the usual time. Do not give 2 doses at the same time.
· If donepezil hydrochloride tablets are missed for 7 days or more, talk with the doctor before starting again.
What are the possible side effects of donepezil hydrochloride tablets?
· slow heartbeat and fainting. This happens more often in people with heart problems. Call the doctor right away if the patient faints while taking donepezil hydrochloride tablets.
· more stomach acid: This raises the chance of ulcers and bleeding.. The risk is higher for patients who had ulcers, or take aspirin or other NSAIDs.
· worsening of lung problem in people with asthma or other lung diseases.
· siezures.
Call the doctor right awayif the patient has:
· 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 movement or stools that look like black tar.
· new or worse asthma or breathing problem.
· seizures.
The most common side effects of donepezil hydrochloride tablets are:
· nausea
· diarrhea
· not sleeping well
· vomiting
· muscle cramps
· feeling tired
How should Donepezil hydrochloride tablets be stored?
General information about donepezil hydrochloride tablets
Medicines are sometimes prescribed for conditions that are not mentioned in this Patient Information Leaflet. Do not use donepezil hydrochloride tablets for a condition for which it was not prescribed. Do not give donepezil hydrochloride tablets to people other than the patient, even if they have the same symptoms as the patient, as it may harm them.
· Donepezil hydrochloride 5mg and 10mg 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 10mg tablet contains yellow iron oxide (synthetic) as a coloring agent.
Macleods Pharma USA, INC,.
Plainsboro, NJ 08536
Manufactured by:
Macleods Pharmaceutical Ltd.
Baddi, Himachal Pradesh, India.
Rx only
Rx only
30 TABLETS
Donepezil Hydrochloride Tablets USP
NDC 33342-027-10
Rx only
90 TABLETS
Donepezil Hydrochloride Tablets USP
NDC 33342-028-07
Rx only
30 TABLETS
Label Donepezil Hydrochloride Tablets USP
DONEPEZIL HYDROCHLORIDE
donepezil hydrochloride tablet, film coated |
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DONEPEZIL HYDROCHLORIDE
donepezil hydrochloride tablet, film coated |
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Labeler - Macleods Pharmaceuticals Limited (862128535) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
Macleods Pharmaceuticals Limited | 676369519 | ANALYSIS(33342-027, 33342-028), LABEL(33342-027, 33342-028), MANUFACTURE(33342-027, 33342-028), PACK(33342-027, 33342-028) |