Donepezil hydrochloride tablet, film coated

1 indications and usage

Donepezil hydrochloride tablets, USP are 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)

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Donepezil hydrochloride tablets, USP 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

  • Mild to Moderate Alzheimer's Disease: 5 mg to 10 mg once daily (2.1)
  • Moderate to Severe Alzheimer's Disease: 10 mg once daily (2.2)

3 dosage forms and strengths

  • Tablets: 5 mg and 10 mg (3)

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Donepezil hydrochloride tablets are supplied as film-coated, round tablets containing 5 mg or 10 mg of donepezil hydrochloride.

  • The 5 mg tablets are white to off white, circular, biconvex, film coated tablets debossed with '5' on one side and plain on other side.
  • The 10 mg tablets are peach colored, circular, biconvex, film coated tablets debossed with '10' on one side and plain on other side.

4 contraindications

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

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

5 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 tablets 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)

6 adverse reactions

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 Torrent Pharma Inc. at 1-269-544-2299 or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

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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)]
  • 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)]

7 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).

8 use in specific populations

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

8.1 pregnancy

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 16 times the maximum recommended human dose [MRHD] of 10 mg/day on a mg/m 2basis) and 10 mg/kg/day (approximately 20 times the MRHD on a mg/m 2basis), 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 3 times the MRHD on a mg/m 2basis.

8.3 nursing mothers

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

8.4 pediatric use

The safety and effectiveness of donepezil hydrochloride tablets in children have not been established.

8.5 geriatric use

Alzheimers 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 tablets 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 events reported by patient groups 65 years old and < 65 years old.

10 overdosage

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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 tablets 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 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 is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C 24H 29NO 3HCl 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.

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Donepezil hydrochloride is available for oral administration in film-coated tablets containing 5 or 10 mg of donepezil hydrochloride, USP.

Inactive ingredients in 5 mg and 10 mg tablets are lactose monohydrate, magnesium stearate, maize starch ( Zea mays) and microcrystalline cellulose. The film coating contains hypromellose, polyethylene glycol, talc and titanium dioxide. Additionally, the 10 mg tablet contains ferric oxide red and ferric oxide yellow as coloring agents.

12 clinical pharmacology

12.1 mechanism of action

Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimers 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 to 10 mg given once daily. The rate and extent of absorption of donepezil hydrochloride tablets are not influenced by food.

Donepezil hydrochloride ODT 5 mg and 10 mg are bioequivalent to donepezil hydrochloride 5 mg and 10 mg tablets, respectively.

The elimination half life of donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) is 0.13 to 0.19 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4 to 7 fold, and steady state is reached within 15 days. The steady state volume of distribution is 12 to 16 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha 1- acid glycoprotein (about 21%) over the concentration range of 2 to 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 vitroand 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 (Cl C< 18 mL/min/1.73 m 2) the clearance of donepezil hydrochloride did not differ from 11 age- and sex-matched healthy subjects.

Age

No formal pharmacokinetic study was conducted to examine age-related differences in the pharmacokinetics of donepezil 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 Tablets on the Metabolism of Other Drugs

No in vivoclinical trials have investigated the effect of donepezil hydrochloride tablets on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitrostudies show a low rate of binding to these enzymes (mean K iabout 50 to 130 M), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Based on in vitrostudies, donepezil shows little or no evidence of direct inhibition of CYP2B6, CYP2C8 and CYP2C19 at clinically relevant concentrations.

Whether donepezil hydrochloride tablets have any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of donepezil hydrochloride tablets for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of donepezil hydrochloride tablets on the pharmacokinetics of these drugs were observed.

Effect of Other Drugs on the Metabolism of Donepezil Hydrochloride Tablets

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 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 0 to 24and C max) 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 tablets.

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

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

Drugs Highly Bound to Plasma Proteins

Drug displacement studies have been performed in vitrobetween this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. Donepezil hydrochloride at concentrations of 0.3 to 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 86 times the maximum recommended human dose [MRHD] of 10 mg/day on a mg/m 2basis), or in a 104-week carcinogenicity study in rats at oral doses up to 30 mg/kg/day (approximately 29 times the MRHD on a mg/m 2basis).

Donepezil was negative in a battery of genotoxicity assays ( in vitrobacterial reverse mutation, in vitromouse lymphoma tk, in vitrochromosomal aberration, and in vivomouse micronucleus).

Donepezil had no effect on fertility in rats at oral doses up to 10 mg/kg/day (approximately 10 times the MRHD on a mg/m 2basis) when administered to males and females prior to and during mating and continuing in females through implantation.

13.2 animal toxicology andor 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

How supplied

Product: 68151-3114

NDC: 68151-3114-9 1 TABLET, FILM COATED in a PACKAGE

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 tablets can be taken with or without food.

Advise patients and caregivers that donepezil hydrochloride tablets may cause nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and decreased appetite.

logo

Manufactured by:

TORRENT PHARMACEUTICALS LTD., Indrad-382 721, Dist. Mehsana, INDIA.

For:

TORRENT PHARMA INC., 150 Allen Road, Suite 102, Basking Ridge, NJ 07920

8057807 Revised November 2015

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DONEPEZIL HYDROCHLORIDE TABLETS PATIENT PACKAGE INSERT

Donepezil Hydrochloride (doe-NEP-e-zil HYE-droe-KLOR-ide) Tablets, USP

Rx Only

  • Tablets: 5 mg and 10 mg

Read the Patient Information that comes with donepezil hydrochloride tablets before the patient starts taking them and each time you get a refill. There may be new information. This leaflet does not take the place of talking with the doctor about Alzheimers disease or treatment for it. If you have questions, ask the doctor or pharmacist.

What are donepezil hydrochloride tablets?

Donepezil hydrochloride tablets come as donepezil hydrochloride film-coated tablets in dosage strengths of 5 mg and 10 mg.

Donepezil hydrochloride tablets are a prescription medicine to treat mild, moderate and severe Alzheimers disease. Donepezil hydrochloride tablets can help with mental function and with doing daily tasks. Donepezil hydrochloride tablet 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 tablet does not cure Alzheimers disease. All patients with Alzheimers disease get worse over time, even if they take donepezil hydrochloride tablets.

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

Who should not take donepezil hydrochloride tablets?

The patient should not take donepezil hydrochloride tablets if allergic to any of the ingredients in donepezil hydrochloride tablets or to medicines that contain piperidines. Ask the patients doctor if you are not sure. See the end of this leaflet for a list of ingredients in donepezil hydrochloride tablets.

What should I tell the doctor before the patient takes donepezil hydrochloride tablets?

Tell the doctor about all the patients present or past health problems.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 tablets can harm an unborn baby.
  • Present breast-feeding. It is not known if donepezil hydrochloride passes into breast milk. Donepezil hydrochloride tablets are not for women who are breast-feeding.

Tell the doctor about all the medicines the patient takes,including prescription and non-prescription medicines, vitamins, and herbal products. Donepezil hydrochloride tablets and other medicines may affect each other.

Be particularly sure to tell the doctor if the patient takes 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 the patients medicines are NSAIDs. Taking NSAIDs and donepezil hydrochloride tablets together may make the patient more likely to get stomach ulcers.

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
  • dental surgery or procedures.

Know the medicines that the patient takes. Keep a list of all the patients medicines. Show it to the doctor or pharmacist before the patient starts a new medicine.

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.
  • 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.
  • If the patient takes too much donepezil hydrochloride tablets 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 tablets?

Donepezil hydrochloride tablets 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 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 problems in people with asthma or other lung disease.
  • seizures.
  • difficulty passing urine.

Call the doctor right away if the patient has:

  • fainting.
  • heartburn or stomach pain that is new or wont 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 tablets are:

  • nausea
  • diarrhea
  • not sleeping well
  • vomiting
  • muscle cramps
  • feeling tired
  • not wanting to eat

These side effects may get better after the patient takes donepezil hydrochloride tablets for a while. This is not a complete list of side effects with donepezil hydrochloride tablets. For more information, ask the 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 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F). [see USP Controlled Room Temperature].

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

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.

This leaflet summarizes the most important information about donepezil hydrochloride tablets. If you would like more information talk with the patients doctor. You can ask your pharmacist or doctor for information about donepezil hydrochloride tablets that is written for health professionals. For more information, call 1-269-544-2299.

What are the ingredients in donepezil hydrochloride tablets?

Active ingredient:donepezil hydrochloride, USP

Inactive ingredients:

  • Donepezil hydrochloride 5 mg and 10 mg film-coated tablets:lactose monohydrate, magnesium stearate, maize starch ( Zea mays) and microcrystalline cellulose. The film coating contains hypromellose, polyethylene glycol, talc and titanium dioxide. Additionally, the 10 mg tablet contains ferric oxide red and ferric oxide yellow as coloring agents.

This Medication Guide has been approved by the US Food and Drug Administration.

logo

Manufactured by:

TORRENT PHARMACEUTICALS LTD., Indrad-382 721, Dist. Mehsana, INDIA.

For:

TORRENT PHARMA INC., 150 Allen Road, Suite 102, Basking Ridge, NJ 07920

8057808 Revised November 2015

Ingredients and appearance - Product information

Donepezil hydrochloride tablet, film coated- Donepezil hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 68151-3114
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Donepezil hydrochloride ( UNII: 3O2T2PJ89D)( Donepezil - UNII: 8SSC91326P ) 10 mgin 1

Inactive Ingredients

Ingredient Name Code
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Ferric oxide yellow ( UNII: EX438O2MRT)
Hypromellose 2910 (6 mpa.s) ( UNII: 0WZ8WG20P6)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Polyethylene glycol 6000 ( UNII: 30IQX730WE)
Starch, corn ( UNII: O8232NY3SJ)
Talc ( UNII: 7SEV7J4R1U)
Titanium dioxide ( UNII: 15FIX9V2JP)
Ferric oxide red ( UNII: 1K09F3G675)

Product Characteristics

Color YELLOW (peach colored) Shape ROUND (circular, biconvex)
Size 9 mm Score 1
Imprint Code 10

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 68151-3114-9 1 PACKAGE 2011/05/28

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA090686 USA 2011/05/28

Labeler - Carilion Materials Management( 079239644)

Establishment

Name ID/FEI Business Operations
Carilion Materials Management 079239644 REPACK( 68151-3114)

Donepezil hcl