These Highlights Do Not Include All The Information Needed To Use ‎donepezil Hydrochloride Tablets Safely And Effectively. See Full Prescribing Information For donepezil Hydrochloride Tablets.‎

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

Donepezil HCl Oral Tablet 23 MG #30

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.

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 C₂₄H₂₉NO₃HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane.

Donepezil hydrochloride is available for oral administration in film-coated tablets containing 23 mg of donepezil hydrochloride.

Inactive ingredients are carnauba wax, colloidal silicon dioxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone. The film coating contains red and yellow iron oxide, hydroxypropyl methylcellulose, polysorbate, titanium dioxide and triacetin.

USP Dissolution Test pending.

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

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.

The safety and effectiveness of donepezil hydrochloride in pediatric patients have not been established.

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 ³ 65 years old and <65 years old.

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

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)]

• •
  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).

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

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 tablets are 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.

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. 

Donepezil hydrochloride 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.

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.

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.

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

• •
  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).

• •
  Mild to Moderate Alzheimer's Disease: 5 mg to 10 mg administered once ‎daily (2.1)
• •
  Moderate to Severe Alzheimer's Disease: 10 mg to 23 mg administered ‎once daily (2.2)

Donepezil hydrochloride is supplied as reddish, film-coated, round tablets containing 23 mg of donepezil hydrochloride. The strength, in mg (23), is debossed on one side.

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

The following adverse reactions have been identified during post-approval use. 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.

In the controlled clinical trial, among patients in the donepezil hydrochloride 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.

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.

• Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.

Donepezil hydrochloride should be taken in the evening, just prior to retiring. Donepezil hydrochloride can be taken with or without food.

The Donepezil Hydrochloride 23 mg tablet should not be split, crushed, or chewed.

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

Advice 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. Donepezil hydrochloride 23 mg tablets should be swallowed whole without the tablets being split, crushed or chewed.

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

Manufactured by

Dexcel Pharma Technologies Ltd

10 Hakidma St.

Yokneam 2069200,

Israel

Distributed by

Solco Healthcare US, LLC

Cranbury, NJ 08512, USA

16.1 Donepezil Hydrochloride Tablets

Supplied as film-coated, round tablets containing 23 mg of donepezil hydrochloride. The 23 mg tablets are reddish in color. The strength, in mg (23), is debossed on one side.

NDC: 72162-1355-03: 30 tablets in a BOTTLE

NDC: 72162-1355-09: 90 tablets in a BOTTLE

Storage

Store at 20º-25ºC (68º-77ºF), excursions permitted to 15º-30ºC (59º-86ºF) [See USP Controlled Room Temperature].

Repackaged/Relabeled by:

Bryant Ranch Prepack, Inc.

Burbank, CA 91504

Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's disease.

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%).

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 ³ 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.

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.

Donepezil (doe-NEP-e-zil) Hydrochloride Tablets

• •
  Tablets: 23 mg

Read the Patient Information that comes with donepezil hydrochloride before the patient starts taking it 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 Alzheimer's disease or treatment for it. If you have questions, ask the doctor or pharmacist.

What is Donepezil Hydrochloride?

Donepezil Hydrochloride comes as film-coated tablets in dosage strengths of 23 mg.

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 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 patient's 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 patient's 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 can harm an unborn baby.
• •
  Present breast-feeding. It is not known if donepezil hydrochloride passes into breast milk. Donepezil hydrochloride is 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 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 patient's 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 the patient takes donepezil hydrochloride before the patient has:

• •
  surgery
• •
  medical procedures
• •
  dental surgery or procedures

Know the medicines that the patient takes. Keep a list of all the patient's 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 exactly as prescribed by the doctor. Do not stop donepezil hydrochloride or change the dose yourself. Talk with the doctor first.
• •
  Give donepezil hydrochloride one time each day. Donepezil hydrochloride can be taken with or without food.
• •
  If you miss giving the patient a dose of donepezil hydrochloride, just wait. Give only the next dose at the usual time. Do not give 2 doses at the same time.
• •
  If donepezil hydrochloride is missed for 7 days or more, talk with the doctor before starting again.
• •
  If the patient takes 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 the patient faints while taking donepezil hydrochloride.
• •
  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 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 the patient takes Donepezil Hydrochloride for a while. This is not a complete list of side effects with Donepezil Hydrochloride. For more information, ask the doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Solco Healthcare US, LLC at 1-866-257-2597 ‎or FDA at 1-800-FDA-1088.

How should Donepezil Hydrochloride Tablets be stored?

Store donepezil hydrochloride at room temperature between 59° to 86°F (15° to 30°C).

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 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. If you would like more information talk with the patient's doctor. You can ask your pharmacist or doctor for information about donepezil hydrochloride that is written for health professionals.

What are the ingredients in Donepezil Hydrochloride Tablets?

Active ingredient: donepezil hydrochloride

Inactive ingredients:

• •
  Donepezil Hydrochloride 23 mg film-coated tablets: carnauba wax, colloidal silicon dioxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone. The film coating contains red and yellow iron oxide, hydroxypropyl methylcellulose, polysorbate, titanium dioxide and triacetin.

Manufactured by

Dexcel Pharma Technologies Ltd

10 Hakidma St.

Yokneam 2069200,

Israel

Distributed by

Solco Healthcare US, LLC

Cranbury, NJ 08512, USA

Rx Only

Revision August 2016

The recommended starting dosage of donepezil hydrochloride is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage of donepezil hydrochloride 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.

The recommended starting dosage of donepezil hydrochloride is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage of donepezil hydrochloride 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.

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/m² 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/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.

A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.

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

Donepezil HCl Oral Tablet 23 MG #30

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.

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 C₂₄H₂₉NO₃HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane.

Donepezil hydrochloride is available for oral administration in film-coated tablets containing 23 mg of donepezil hydrochloride.

Inactive ingredients are carnauba wax, colloidal silicon dioxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone. The film coating contains red and yellow iron oxide, hydroxypropyl methylcellulose, polysorbate, titanium dioxide and triacetin.

USP Dissolution Test pending.

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

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.

The safety and effectiveness of donepezil hydrochloride in pediatric patients have not been established.

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 ³ 65 years old and <65 years old.

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

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)]

• •
  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).

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

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 tablets are 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.

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. 

Donepezil hydrochloride 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.

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.

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.

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

• •
  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).

• •
  Mild to Moderate Alzheimer's Disease: 5 mg to 10 mg administered once ‎daily (2.1)
• •
  Moderate to Severe Alzheimer's Disease: 10 mg to 23 mg administered ‎once daily (2.2)

Donepezil hydrochloride is supplied as reddish, film-coated, round tablets containing 23 mg of donepezil hydrochloride. The strength, in mg (23), is debossed on one side.

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

The following adverse reactions have been identified during post-approval use. 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.

In the controlled clinical trial, among patients in the donepezil hydrochloride 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.

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.

• Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.

Donepezil hydrochloride should be taken in the evening, just prior to retiring. Donepezil hydrochloride can be taken with or without food.

The Donepezil Hydrochloride 23 mg tablet should not be split, crushed, or chewed.

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

Advice 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. Donepezil hydrochloride 23 mg tablets should be swallowed whole without the tablets being split, crushed or chewed.

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

Manufactured by

Dexcel Pharma Technologies Ltd

10 Hakidma St.

Yokneam 2069200,

Israel

Distributed by

Solco Healthcare US, LLC

Cranbury, NJ 08512, USA

16.1 Donepezil Hydrochloride Tablets

Supplied as film-coated, round tablets containing 23 mg of donepezil hydrochloride. The 23 mg tablets are reddish in color. The strength, in mg (23), is debossed on one side.

NDC: 72162-1355-03: 30 tablets in a BOTTLE

NDC: 72162-1355-09: 90 tablets in a BOTTLE

Storage

Store at 20º-25ºC (68º-77ºF), excursions permitted to 15º-30ºC (59º-86ºF) [See USP Controlled Room Temperature].

Repackaged/Relabeled by:

Bryant Ranch Prepack, Inc.

Burbank, CA 91504

Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's disease.

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%).

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 ³ 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.

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.

Donepezil (doe-NEP-e-zil) Hydrochloride Tablets

• •
  Tablets: 23 mg

Read the Patient Information that comes with donepezil hydrochloride before the patient starts taking it 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 Alzheimer's disease or treatment for it. If you have questions, ask the doctor or pharmacist.

What is Donepezil Hydrochloride?

Donepezil Hydrochloride comes as film-coated tablets in dosage strengths of 23 mg.

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 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 patient's 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 patient's 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 can harm an unborn baby.
• •
  Present breast-feeding. It is not known if donepezil hydrochloride passes into breast milk. Donepezil hydrochloride is 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 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 patient's 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 the patient takes donepezil hydrochloride before the patient has:

• •
  surgery
• •
  medical procedures
• •
  dental surgery or procedures

Know the medicines that the patient takes. Keep a list of all the patient's 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 exactly as prescribed by the doctor. Do not stop donepezil hydrochloride or change the dose yourself. Talk with the doctor first.
• •
  Give donepezil hydrochloride one time each day. Donepezil hydrochloride can be taken with or without food.
• •
  If you miss giving the patient a dose of donepezil hydrochloride, just wait. Give only the next dose at the usual time. Do not give 2 doses at the same time.
• •
  If donepezil hydrochloride is missed for 7 days or more, talk with the doctor before starting again.
• •
  If the patient takes 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 the patient faints while taking donepezil hydrochloride.
• •
  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 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 the patient takes Donepezil Hydrochloride for a while. This is not a complete list of side effects with Donepezil Hydrochloride. For more information, ask the doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Solco Healthcare US, LLC at 1-866-257-2597 ‎or FDA at 1-800-FDA-1088.

How should Donepezil Hydrochloride Tablets be stored?

Store donepezil hydrochloride at room temperature between 59° to 86°F (15° to 30°C).

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 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. If you would like more information talk with the patient's doctor. You can ask your pharmacist or doctor for information about donepezil hydrochloride that is written for health professionals.

What are the ingredients in Donepezil Hydrochloride Tablets?

Active ingredient: donepezil hydrochloride

Inactive ingredients:

• •
  Donepezil Hydrochloride 23 mg film-coated tablets: carnauba wax, colloidal silicon dioxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone. The film coating contains red and yellow iron oxide, hydroxypropyl methylcellulose, polysorbate, titanium dioxide and triacetin.

Manufactured by

Dexcel Pharma Technologies Ltd

10 Hakidma St.

Yokneam 2069200,

Israel

Distributed by

Solco Healthcare US, LLC

Cranbury, NJ 08512, USA

Rx Only

Revision August 2016

The recommended starting dosage of donepezil hydrochloride is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage of donepezil hydrochloride 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.

The recommended starting dosage of donepezil hydrochloride is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage of donepezil hydrochloride 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.

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/m² 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/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.

A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.