Donepezil for Dementia

INDICATIONS AND USAGE Memantine and donepezil hydrochlorides extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type in patients stabilized on 10 mg of donepezil hydrochloride once daily. Memantine and donepezil hydrochlorides extended-release capsules are a combination of memantine hydrochloride, an NMDA receptor antagonist, and donepezil hydrochloride, an acetylcholinesterase inhibitor, indicated for the treatment of moderate to severe dementia of the Alzheimer’s type in patients stabilized on 10 mg of donepezil hydrochloride once daily. ( 1 )

DOSAGE AND ADMINISTRATION • For patients on donepezil hydrochloride 10 mg only, the recommended starting dose of memantine and donepezil hydrochlorides extended-release capsules is 7 mg/10 mg, taken once daily in the evening. The dose should be increased in 7 mg increment to the recommended maintenance dose of 28 mg /10 mg. the minimum recommended interval between dose increases is one week. ( 2.1 ) • Patients on memantine hydrochloride (10 mg twice daily or 28 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily can be switched to memantine and donepezil hydrochlorides extended-release capsules 28 mg/10 mg, taken once daily in the evening ( 2.1 ) • Memantine and donepezil hydrochlorides extended-release capsules can be taken with or without food, whole or sprinkled on applesauce; do not divide, chew, or crush ( 2.2 ) • Severe renal impairment: the recommended maintenance dose for memantine and donepezil hydrochlorides extended-release capsules is 14 mg/10 mg once daily in the evening. ( 2.3 ) 2.1 Recommended Dosing The recommended dose of memantine and donepezil hydrochlorides extended-release capsules is 28 mg/10 mg once daily. For patients stabilized on donepezil and not currently on memantine: For patients stabilized on donepezil hydrochloride 10 mg and not currently on memantine hydrochloride, the recommended starting dose of memantine and donepezil hydrochlorides extended-release capsules is 7 mg/10 mg, taken once a day in the evening. The dose should be increased in 7 mg increments of the memantine hydrochloride component to the recommended maintenance dose of 28 mg/10 mg once daily. The minimum recommended interval between dose increases is one week. The dose should only be increased if the previous dose has been well tolerated. The maximum dose is 28 mg /10 mg once daily. For patients stabilized on both donepezil and memantine: Patients stabilized on memantine hydrochloride (10 mg twice daily or 28 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily can be switched to memantine and donepezil hydrochlorides extended-release capsules 28 mg/10 mg, taken once a day in the evening. Patients should start memantine and donepezil hydrochlorides extended-release capsules the day following the last dose of memantine hydrochloride and donepezil hydrochloride administered separately. If a patient misses a single dose of memantine and donepezil hydrochlorides extended-release capsules, the next dose should be taken as scheduled, without doubling up the dose. 2.2 Administration Information Memantine and donepezil hydrochlorides extended-release capsules can be taken with or without food. Memantine and donepezil hydrochlorides extended-release capsules can be taken intact or may be opened, sprinkled on applesauce, and swallowed without chewing. The entire contents of each memantine and donepezil hydrochlorides extended-release capsules should be consumed; the dose should not be divided. Except when opened and sprinkled on applesauce, as described above, memantine and donepezil hydrochlorides extended-release capsules should be swallowed whole. Memantine and donepezil hydrochlorides extended-release capsules should not be divided, chewed, or crushed. 2.3 Dosing in Patients with Severe Renal Impairment For patients stabilized on donepezil and not currently on memantine: For patients with severe renal impairment (creatinine clearance 5-29 mL/min, based on the Cockcroft-Gault equation) stabilized on donepezil hydrochloride 10 mg once daily and not currently on memantine hydrochloride, the recommended starting dose of memantine and donepezil hydrochlorides extended-release capsules is 7 mg/10 mg taken once a day in the evening. The dose should be increased to the recommended maintenance dose of 14 mg/10 mg once daily in the evening after a minimum of one week [ see Use in Specific Populations (8.6) ]. For patients stabilized on both donepezil and memantine: Patients with severe renal impairment, stabilized on memantine hydrochloride (5 mg twice daily or 14 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily, can be switched to memantine and donepezil hydrochlorides extended-release capsules 14 mg/10 mg, taken once daily in the evening.

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 ) 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 ) 5.1 Anesthesia Donepezil hydrochloride tablets, as a cholinesterase inhibitor, are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 5.2 Cardiovascular Conditions Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of donepezil hydrochloride tablets. 5.3 Nausea and Vomiting Donepezil hydrochloride tablets, as a predictable consequence of its pharmacological properties, have 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 tablets, patients should be observed closely at the initiation of treatment and after dose increases. 5.4 Peptic Ulcer Disease and GI Bleeding Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of donepezil hydrochloride tablets in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Results of a controlled clinical study with 23 mg/day showed an increase, relative to 10 mg/day, in the incidence of peptic ulcer disease (0.4% vs. 0.2%) and gastrointestinal bleeding from any site (1.1% vs. 0.6%). 5.5 Weight Loss Weight loss was reported as an adverse reaction in 4.7% of patients assigned to donepezil hydrochloride tablets in a dose of 23 mg/day compared to 2.5% of patients assigned to 10 mg/day. Compared to their baseline weights, 8.4% of patients taking 23 mg/day were found to have a weight decrease of ≥ 7% by the end of the study, while 4.9% of patients taking 10 mg/day were found to have weight loss of ≥ 7% at the end of the study. 5.6 Genitourinary Conditions Although not observed in clinical trials of donepezil hydrochloride tablets, cholinomimetics may cause bladder outflow obstruction. 5.7 Neurological Conditions: Seizures Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer’s disease. 5.8 Pulmonary Conditions Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. 5.1 Anesthesia Donepezil hydrochloride tablets, as a cholinesterase inhibitor, are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 5.2 Cardiovascular Conditions Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of donepezil hydrochloride tablets. 5.3 Nausea and Vomiting Donepezil hydrochloride tablets, as a predictable consequence of its pharmacological properties, have 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 tablets, patients should be observed closely at the initiation of treatment and after dose increases. 5.4 Peptic Ulcer Disease and GI Bleeding Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of donepezil hydrochloride tablets in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Results of a controlled clinical study with 23 mg/day showed an increase, relative to 10 mg/day, in the incidence of peptic ulcer disease (0.4% vs. 0.2%) and gastrointestinal bleeding from any site (1.1% vs. 0.6%). 5.5 Weight Loss Weight loss was reported as an adverse reaction in 4.7% of patients assigned to donepezil hydrochloride tablets in a dose of 23 mg/day compared to 2.5% of patients assigned to 10 mg/day. Compared to their baseline weights, 8.4% of patients taking 23 mg/day were found to have a weight decrease of ≥ 7% by the end of the study, while 4.9% of patients taking 10 mg/day were found to have weight loss of ≥ 7% at the end of the study. 5.6 Genitourinary Conditions Although not observed in clinical trials of donepezil hydrochloride tablets, cholinomimetics may cause bladder outflow obstruction. 5.7

DRUG INTERACTIONS • Combined use with NMDA antagonists: use with caution. ( 7.2 ) • Memantine and donepezil hydrochlorides extended-release capsules may interfere with anticholinergic medications. ( 7.4 ) • Concomitant administration of succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists may lead to synergistic effect. ( 7.5 ) 7.1 Use of Memantine with Drugs That Make the Urine Alkaline The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse reactions. Urine pH is altered by diet, drugs (e.g., carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions. 7.2 Use of Memantine with Other N-methyl-D-aspartate (NMDA) Antagonists The combined use of memantine hydrochloride with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution. 7.3 Effect of Other Drugs on the Metabolism of Donepezil Inhibitors of CYP3A4 (e.g., ketoconazole) and CYP2D6 (e.g., quinidine), inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. Inducers of CYP3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of donepezil. 7.4 Use of Donepezil with Anticholinergics Because of their mechanism of action, cholinesterase inhibitors, including donepezil hydrochloride, have the potential to interfere with the activity of anticholinergic medications. 7.5 Use of Donepezil with Cholinomimetics and Other Cholinesterase Inhibitors A synergistic effect may be expected when cholinesterase inhibitors, including donepezil hydrochloride, are given concurrently with succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists such as bethanechol.

ADVERSE REACTIONS Most common adverse reactions in clinical studies of donepezil hydrochloride are nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/ medwatch . The following serious adverse reactions are described below and elsewhere in the labeling: Cardiovascular Conditions [ see Warnings and Precautions ( 5.2 ) ]. Nausea and Vomiting [ see Warnings and Precautions ( 5.3 ) ]. Peptic Ulcer Disease and GI Bleeding [ see Warnings and Precautions ( 5.4 ) ]. Weight Loss [ see Warnings and Precautions ( 5.5 ) ]. Genitourinary Conditions [ see Warnings and Precautions ( 5.6 ) ]. Neurological Conditions: Seizures [ see Warnings and Precautions ( 5.7 ) ]. Pulmonary Conditions [ see Warnings and Precautions ( 5.8 ) ]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Donepezil hydrochloride has been administered to over 1,700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1,000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months, and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1,214 days. Mild to Moderate Alzheimer's Disease Adverse Reactions Leading to Discontinuation: The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride 5 mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day was higher at 13%. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of patients and at twice or more the incidence seen in placebo patients, are shown in Table 1. Table 1 . Most Common Adverse Reactions Leading to Discontinuation in Patients with Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo ( n = 355 ) % 5 mg / day Donepezil Hydrochloride ( n = 350 ) % 10 mg / day Donepezil Hydrochloride ( n = 315 ) % Nausea 1 1 3 Diarrhea 0 <1 3 Vomiting <1 <1 2 Most Common Adverse Reactions: The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by donepezil hydrochloride's cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. There is evidence to suggest that the frequency of these common adverse reactions may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15- and 30-week studies. These patients were titrated to a dose of10 mg/day over a 6-week period. The rates of common adverse reactions were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day. See Table 2 for a comparison of the most common adverse reactions following one and six week titration regimens. Table 2 . Comparison of Rates of Adverse Reactions in Mild to Moderate Patients Titrated to 10 mg / day over 1 and 6 Weeks No titration One week titration Six week titration Adverse Reaction 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 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received either donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. In general, adverse reactions occurred more frequently in female patients and with advancing age. Table 3 . Adverse Reactions in Pooled Placebo - Controlled Clinical Trials in Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo ( n = 355 ) % Donepezil Hydrochloride ( n = 747 ) % Percent of Patients with any Adverse Reaction 72 74 Nausea 6 11 Diarrhea 5 10 Headache 9 10 Insomnia 6 9 Pain, various locations 8 9 Dizziness 6 8 Accident 6 7 Muscle Cramps 2 6 Fatigue 3 5 Vomiting 3 5 Anorexia 2 4 Ecchymosis 3 4 Abnormal Dreams 0 3 Depression <1 3 Weight Loss 1 3 Arthritis 1 2 Frequent Urination 1 2 Somnolence <1 2 Syncope 1 2 Severe Alzheimer's Disease (Donepezil Hydrochloride 5mg/day and 10 mg/day) Donepezil hydrochloride has been administered to over 600 patients with severe Alzheimer's disease during clinical trials of at least 6 months duration, including three double-blind, placebo-controlled trials, two of which had an open label extension. Adverse Reactions Leading to Discontinuation: The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride patients were approximately 12% compared to 7% for placebo patients. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride patients and at twice or more the incidence seen in placebo, were anorexia (2% vs. 1% placebo), nausea (2% vs. <1% placebo), diarrhea (2% vs. 0% placebo), and urinary tract infection (2% vs. 1% placebo). Most Common Adverse Reactions: The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice or more the placebo rate, are largely predicted by donepezil hydrochloride's cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. Table 4 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. Table 4 . Adverse Reactions in Pooled Controlled Clinical Trials in Severe Alzheimer’s Disease Body System / Adverse Reaction Placebo ( n = 392 ) % Donepezil Hydrochloride ( n = 501 ) % Percent of Patients with any Adverse Reaction 73 81 Accident 12 13 Infection 9 11 Diarrhea 4 10 Anorexia 4 8 Vomiting 4 8 Nausea 2 6 Insomnia 4 5 Ecchymosis 2 5 Headache 3 4 Hypertension 2 3 Pain 2 3 Back Pain 2 3 Eczema 2 3 Hallucinations 1 3 Hostility 2 3 Increase in Creatine Phosphokinase 1 3 Nervousness 2 3 Fever 1 2 Chest Pain <1 2 Confusion 1 2 Dehydration 1 2 Depression 1 2 Dizziness 1 2 Emotional Lability 1 2 Hemorrhage 1 2 Hyperlipemia <1 2 Personality Disorder 1 2 Somnolence 1 2 Syncope 1 2 Urinary Incontinence 1 2 Moderate to Severe Alzheimer's Disease Tablets (Donepezil Hydochloride 23 mg/day) Donepezil hydrochloride 23 mg/day has been administered to over 1300 individuals globally in clinical trials. Approximately 1050 of these patients have been treated for at least three months and more than 950 patients have been treated for at least six months. The range of patient exposure was from 1 to over 500 days. Adverse Reactions