Discussion Questions for Aricept Ad: General 1. What is your overall impression of the direct-to-consumer TV ad for Aricept? 2. Based on your knowledge and information from the Aricept PI, are there any claims or presentations that you find false or misleading? Specific 3. What is your overall impression regarding the efficacy of Aricept after watching the TV ad? a. Did the Alzheimer’s patient’s behavior change after he discussed Aricept treatment with the doctor? b. How would you describe the magnitude of this change? c. Is this improvement consistent with the clinical trials results as described in the Aricept PI? 3 PHA 3030 – U.S. Health Care Systems & Policy Group Assignment – Evaluation of DTC Prescription Drug Promotion Ad “Convincing people they are sick and need a drug is a multi-billion dollar industry. In 2015, Big Pharma dropped a record breaking $5.4 billion on direct-to-consumer (DTC) ads, according to Kantar Media. And it paid off for Big Pharma. The same year, Americans spent a record $457 billion on prescription drugs. The U.S. and New Zealand are the only countries where DTC is legal. Americans also pay more for drugs and devices than any other country” (dw-big-pharma-marketing.pdf). According the FDA, prescription drug advertising must: • Be accurate • Balance the risk and benefit information • Be consistent with the prescribing information approved by FDA • Only include information that is supported by strong evidence Each group will be assigned a prescription drug promotion ad and case study to evaluate for possible false or misleading claims. An evaluation guide and grading rubric is provided below. The assignment will be presented in a PowerPoint presentation (4 slide maximum) and will be graded based on the extent to which all questions on the evaluation guide are addressed. Grading Rubric for Group Assignment Overall impression of ad 35 points Claims or presentations that are false or 35 points misleading Impression of the actual efficacy of the drug 35 points Discussion of risk/benefit information 35 points Information supporting evidence of efficacy 35 points Participation in presentation 35 points Total 210 points NDA 20-690/S-026 NDA 21-720/S-003 Page 3 ARICEPT® (Donepezil Hydrochloride Tablets) ARICEPT® ODT (Donepezil Hydrochloride) Orally Disintegrating Tablets DESCRIPTION ARICEPT® (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. ARICEPT® is available for oral administration in film-coated tablets containing 5 or 10 mg of donepezil hydrochloride. Inactive ingredients are lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate. The film coating contains talc, polyethylene glycol, hypromellose and titanium dioxide. Additionally, the 10 mg tablet contains yellow iron oxide (synthetic) as a coloring agent. ARICEPT® ODT tablets are available for oral administration. Each ARICEPT® ODT tablet contains 5 or 10 mg of donepezil hydrochloride. Inactive ingredients are carrageenan, mannitol, colloidal silicon dioxide and polyvinyl alcohol. Additionally, the 10 mg tablet contains ferric oxide (yellow) as a coloring agent. NDA 20-690/S-026 NDA 21-720/S-003 Page 4 CLINICAL PHARMACOLOGY 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. Clinical Trial Data The effectiveness of ARICEPT® as a treatment for Alzheimer’s Disease is demonstrated by the results of randomized, double-blind, placebo-controlled clinical investigations in patients with mild to moderate Alzheimer’s Disease, and in patients with severe Alzheimer’s Disease. Mild-Moderate Alzheimer’s Disease The effectiveness of ARICEPT® as a treatment for mild to moderate Alzheimer’s Disease is demonstrated by the results of two randomized, double-blind, placebocontrolled clinical investigations in patients with Alzheimer’s Disease (diagnosed by NINCDS and DSM III-R criteria, Mini-Mental State Examination ≥ 10 and ≤ 26 and Clinical Dementia Rating of 1 or 2). The mean age of patients participating in ARICEPT® 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%. Study Outcome Measures: In each study, the effectiveness of treatment with ARICEPT® was evaluated using a dual outcome assessment strategy. The ability of ARICEPT® to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), a multiitem instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s Disease patients. The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher. The patients recruited as participants in each study had mean scores on the Alzheimer’s Disease Assessment Scale (ADAS-cog) of approximately 26 units, with a range from 4 to 61. Experience gained in longitudinal studies of ambulatory patients NDA 20-690/S-026 NDA 21-720/S-003 Page 5 with mild to moderate Alzheimer’s Disease suggest that they gain 6 to 12 units a year on the ADAS-cog. However, lesser degrees of change are seen in patients with very mild or very advanced disease because the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in ARICEPT® trials was approximately 2 to 4 units per year. The ability of ARICEPT® to produce an overall clinical effect was assessed using a Clinician’s Interview Based Impression of Change that required the use of caregiver information, the CIBIC plus. The CIBIC plus is not a single instrument and is not a standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC plus evaluations from other clinical trials. The CIBIC plus used in ARICEPT® trials was a semi-structured instrument that was intended to examine four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “markedly improved,” to a score of 4, indicating “no change” to a score of 7, indicating “markedly worse.” The CIBIC plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods. Thirty-Week Study In a study of 30 weeks duration, 473 patients were randomized to receive single daily doses of placebo, 5 mg/day or 10 mg/day of ARICEPT®. The 30-week study was divided into a 24-week double-blind active treatment phase followed by a 6-week singleblind placebo washout period. The study was designed to compare 5 mg/day or 10 mg/day fixed doses of ARICEPT® to placebo. However, to reduce the likelihood of cholinergic effects, the 10 mg/day treatment was started following an initial 7-day treatment with 5 mg/day doses. Effects on the ADAS-cog: Figure 1 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 30 weeks of the study. After 24 weeks of treatment, the mean differences in the ADAS-cog change scores for ARICEPT® treated patients compared to the patients on placebo were 2.8 and 3.1 units for the 5 mg/day and 10 mg/day treatments, respectively. These differences were statistically significant. While the treatment effect size may appear to be slightly greater for the 10 mg/day treatment, there was no statistically significant difference between the two active treatments. Following 6 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT® treatment groups were indistinguishable from those patients who had NDA 20-690/S-026 NDA 21-720/S-003 Page 6 received only placebo for 30 weeks. This suggests that the beneficial effects of ARICEPT® abate over 6 weeks following discontinuation of treatment and do not represent a change in the underlying disease. There was no evidence of a rebound effect 6 weeks after abrupt discontinuation of therapy. Figure 2 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained the measure of improvement in ADAS-cog score shown on the X axis. Three change scores, (7-point and 4-point reductions from baseline or no change in score) have been identified for illustrative purposes and the percent of patients in each group achieving that result is shown in the inset table. The curves demonstrate that both patients assigned to placebo and ARICEPT® have a wide range of responses, but that the active treatment groups are more likely to show the greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo, respectively. NDA 20-690/S-026 NDA 21-720/S-003 Page 7 Effects on the CIBIC plus: Figure 3 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 24 weeks of treatment. The mean drug-placebo differences for these groups of patients were 0.35 units and 0.39 units for 5 mg/day and 10 mg/day of ARICEPT®, respectively. These differences were statistically significant. There was no statistically significant difference between the two active treatments. NDA 20-690/S-026 NDA 21-720/S-003 Page 8 Fifteen-Week Study In a study of 15 weeks duration, patients were randomized to receive single daily doses of placebo or either 5 mg/day or 10 mg/day of ARICEPT® for 12 weeks, followed by a 3week placebo washout period. As in the 30-week study, to avoid acute cholinergic effects, the 10 mg/day treatment followed an initial 7-day treatment with 5 mg/day doses. Effects on the ADAS-Cog: Figure 4 illustrates the time course of the change from baseline in ADAS-cog scores for all three dose groups over the 15 weeks of the study. After 12 weeks of treatment, the differences in mean ADAS-cog change scores for the ARICEPT® treated patients compared to the patients on placebo were 2.7 and 3.0 units each, for the 5 and 10 mg/day ARICEPT®treatment groups respectively. These differences were statistically significant. The effect size for the 10 mg/day group may appear to be slightly larger than that for 5 mg/day. However, the differences between active treatments were not statistically significant. Following 3 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT® treatment groups increased, indicating that discontinuation of ARICEPT® resulted in a loss of its treatment effect. The duration of this placebo washout period was not sufficient to characterize the rate of loss of the treatment effect, but, the 30week study (see above) demonstrated that treatment effects associated with the use of ARICEPT® abate within 6 weeks of treatment discontinuation. NDA 20-690/S-026 NDA 21-720/S-003 Page 9 Figure 5 illustrates the cumulative percentages of patients from each of the three treatment groups who attained the measure of improvement in ADAS-cog score shown on the X axis. The same three change scores, (7-point and 4-point reductions from baseline or no change in score) as selected for the 30-week study have been used for this illustration. The percentages of patients achieving those results are shown in the inset table. As observed in the 30-week study, the curves demonstrate that patients assigned to either placebo or to ARICEPT® have a wide range of responses, but that the ARICEPT® treated patients are more likely to show the greater improvements in cognitive performance. Effects on the CIBIC plus: Figure 6 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 12 weeks of treatment. The differences in mean scores for ARICEPT® treated patients compared to the patients on placebo at Week 12 were 0.36 and 0.38 units for the 5 mg/day and 10 mg/day treatment groups, respectively. These differences were statistically significant. NDA 20-690/S-026 NDA 21-720/S-003 Page 10 In both studies, patient age, sex and race were not found to predict the clinical outcome of ARICEPT® treatment. Severe Alzheimer’s Disease Swedish 24-Week Study The effectiveness of ARICEPT® as a treatment for severe Alzheimer’s Disease is demonstrated by the results of a randomized, double-blind, placebo-controlled clinical study conducted in Sweden (24-Week Study) in patients with probable or possible Alzheimer’s Disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1-10. Two hundred and forty eight (248) patients with severe Alzheimer’s disease were randomized to ARICEPT® or placebo. For patients randomized to ARICEPT®, treatment was initiated at 5 mg once daily for 28-days and then increased to 10 mg once daily. At the end of the 24-week treatment period, 90.5% of the ARICEPT® treated patients were receiving the 10 mg dose. The mean age of patients was 84.9 years with a range of 59 to 99. Approximately 77 % of patients were women and 23 % were men. Almost all patients were Caucasian. Probable AD was diagnosed in the majority of the patients (83.6% of ARICEPT®-treated patients and 84.2% of placebotreated patients). Study Outcome Measures: The effectiveness of treatment with ARICEPT® was determined using a dual outcome assessment strategy that evaluated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment. This study showed that patients on ARICEPT® experienced significant improvement on both measures compared to placebo. NDA 20-690/S-026 NDA 21-720/S-003 Page 11 The ability of ARICEPT® to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment. Daily function was assessed using the Modified Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer’s Disease (ADCS-ADL-severe). The ADCS-ADL-severe is derived from the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory, which is a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss. The ADCS-ADL-severe is a subset of 19 items, including ratings of the patient’s ability to eat, dress, bathe, use the telephone, get around (or travel), and perform other activities of daily living; it has been validated for the assessment of patients with moderate to severe dementia. The ADCSADL-severe has a scoring range of 0 to 54 with the lower scores indicating greater functional impairment. The investigator performs the inventory by interviewing a caregiver, in this study a nurse staff member, familiar with the functioning of the patient. Effects on the SIB: Figure 7 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the SIB change scores for ARICEPT® -treated patients compared to patients on placebo was 5.9 units. ARICEPT treatment was statistically significantly superior to placebo. NDA 20-690/S-026 NDA 21-720/S-003 Page 12 Figure 8 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to ARICEPT® and to placebo have a wide range of responses, the curves show that the ARICEPT® group is more likely to show a greater improvement in cognitive performance. NDA 20-690/S-026 NDA 21-720/S-003 Page 13 Figure 8. Cumulative percentage of patients completing 24 weeks of double-blind treatment with particular changes from baseline in SIB scores. NDA 20-690/S-026 NDA 21-720/S-003 Page 14 Effects on the ADCS-ADL-severe: Figure 9 illustrates the time course for the change from baseline in ADCS-ADL-severe scores for patients in the two treatment groups over the 24 weeks of the study. After 24 weeks of treatment, the mean difference in the ADCS-ADL-severe change scores for ARICEPT® treated patients compared to patients on placebo was 1.8 units. ARICEPT treatment was statistically significantly superior to placebo. Figure 10 shows the cumulative percentages of patients from each treatment group with specified changes from baseline ADCS-ADL-severe scores. While both patients assigned to ARICEPT®and placebo have a wide range of responses, the curves demonstrate that the ARICEPT®group is more likely to show a smaller decline or an improvement. NDA 20-690/S-026 NDA 21-720/S-003 Page 15 Figure 10. Cumulative percentage of patients completing 24 weeks of doubleblind treatment with particular changes from baseline in ADCS-ADL-severe scores. Japanese 24-Week Study In a study of 24 weeks duration, conducted in Japan, 325 patients with severe Alzheimer’s Disease were randomized to doses of 5 mg/day or 10 mg/day of donepezil, administered once daily, or placebo. Patients randomized to treatment with donepezil were to achieve their assigned doses by titration, beginning at 3 mg/day, and extending over a maximum of 6 weeks. 248 patients completed the study with similar proportions of patients completing the study in each treatment group. The primary efficacy measures for this study were the SIB and CIBIC plus. At 24 weeks of treatment, statistically significant treatment differences were observed between the 10 mg/day dose of donepezil and placebo on both the SIB and CIBIC plus. The 5 mg/day dose of donepezil showed a statistically significant superiority to placebo on the SIB, but not on the CIBIC plus. Clinical Pharmacokinetics ARICEPT® ODT is bioequivalent to ARICEPT® Tablets. Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1-10 mg given once daily. NDA 20-690/S-026 NDA 21-720/S-003 Page 16 Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption of ARICEPT® Tablets. A food effect study has not been conducted with ARICEPT® ODT; however, the effect of food with ARICEPT® ODT is expected to be minimal. ARICEPT® ODT can be taken without regard to meals. The elimination half life of donepezil is about 70 hours and the mean apparent plasma clearance (Cl/F) is 0.13 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 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. Special Populations: Hepatic Disease: In a study of 10 patients with stable alcoholic cirrhosis, the clearance of ARICEPT® 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 (ClCr < 18 mL/min/1.73 m2) the clearance of ARICEPT® 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 ARICEPT®. However, mean plasma ARICEPT® concentrations measured during therapeutic drug monitoring of elderly patients with Alzheimer’s Disease are comparable to those observed in young healthy volunteers. Gender and Race: No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of ARICEPT®. However, retrospective pharmacokinetic analysis indicates that gender and race (Japanese and Caucasians) did not affect the clearance of ARICEPT®. NDA 20-690/S-026 NDA 21-720/S-003 Page 17 Drug-Drug Interactions Drugs Highly Bound to Plasma Proteins: Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. ARICEPT® at concentrations of 0.3-10 μg/mL did not affect the binding of furosemide (5 μg/mL), digoxin (2 ng/mL), and warfarin (3 μg/mL) to human albumin. Similarly, the binding of ARICEPT® to human albumin was not affected by furosemide, digoxin and warfarin. Effect of ARICEPT® on the Metabolism of Other Drugs: No in vivo clinical trials have investigated the effect of ARICEPT® on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Whether ARICEPT® has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of ARICEPT® for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of ARICEPT® on the pharmacokinetics of these drugs were observed. Effect of Other Drugs on the Metabolism of ARICEPT® : Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. In a 7day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown. Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT®. Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT® is not significantly affected by concurrent administration of digoxin or cimetidine. INDICATIONS AND USAGE ARICEPT® is indicated for the treatment of dementia of the Alzheimer’s type. Efficacy has been demonstrated in patients with mild to moderate Alzheimer’s Disease, as well as in patients with severe Alzheimer’s Disease. CONTRAINDICATIONS ARICEPT® is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives. NDA 20-690/S-026 NDA 21-720/S-003 Page 18 WARNINGS Anesthesia: ARICEPT®, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 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 ARICEPT®. Gastrointestinal Conditions: 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 antiinflammatory drugs (NSAIDS). Clinical studies of ARICEPT® have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. ARICEPT®, 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. In most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of ARICEPT®. Genitourinary: Although not observed in clinical trials of ARICEPT®, cholinomimetics may cause bladder outflow obstruction. 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. 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. PRECAUTIONS Drug-Drug Interactions (see Clinical Pharmacology: Clinical Pharmacokinetics: Drugdrug Interactions) Effect of ARICEPT® on the Metabolism of Other Drugs: No in vivo clinical trials have investigated the effect of ARICEPT® on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies NDA 20-690/S-026 NDA 21-720/S-003 Page 19 show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Whether ARICEPT® has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of ARICEPT® for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of ARICEPT® on the pharmacokinetics of these drugs were observed. Effect of Other Drugs on the Metabolism of ARICEPT®: Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. In a 7day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown. Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT®. Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT® is not significantly affected by concurrent administration of digoxin or cimetidine. Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil hydrochloride conducted in CD-1 mice at doses up to 180 mg/kg/day (approximately 90 times the maximum recommended human dose on a mg/m2 basis), or in a 104-week carcinogenicity study in Sprague-Dawley rats at doses up to 30mg/kg/day (approximately 30 times the maximum recommended human dose on a mg/m2 basis). Donepezil was not mutagenic in the Ames reverse mutation assay in bacteria, or in a mouse lymphoma forward mutation assay in vitro. In the chromosome aberration test in cultures of Chinese hamster lung (CHL) cells, some clastogenic effects were observed. Donepezil was not clastogenic in the in vivo mouse micronucleus test and was not genotoxic in an in vivo unscheduled DNA synthesis assay in rats. NDA 20-690/S-026 NDA 21-720/S-003 Page 20 Donepezil had no effect on fertility in rats at doses up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2 basis). Pregnancy Pregnancy Category C: Teratology studies conducted in pregnant rats at doses up to 16 mg/kg/day (approximately 13 times the maximum recommended human dose on a mg/m2 basis) and in pregnant rabbits at doses up to 10 mg/kg/day (approximately 16 times the maximum recommended human dose on a mg/m2 basis) did not disclose any evidence for a teratogenic potential of donepezil. However, in a study in which pregnant rats were given up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2 basis) from day 17 of gestation through day 20 postpartum, there was a slight increase in still births and a slight decrease in pup survival through day 4 postpartum at this dose; the next lower dose tested was 3 mg/kg/day. There are no adequate or well-controlled studies in pregnant women. ARICEPT® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether donepezil is excreted in human breast milk. ARICEPT® has no indication for use in nursing mothers. Pediatric Use There are no adequate and well-controlled trials to document the safety and efficacy of ARICEPT® in any illness occurring in children. Geriatric Use 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 ARICEPT® 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. ADVERSE REACTIONS Mild To Moderate Alzheimer’s Disease Adverse Events Leading to Discontinuation The rates of discontinuation from controlled clinical trials of ARICEPT® due to adverse events for the ARICEPT® 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%. NDA 20-690/S-026 NDA 21-720/S-003 Page 21 The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of patients and at twice the incidence seen in placebo patients, are shown in Table 1. Table 1. Most Frequent Adverse Events Leading to Withdrawal from Controlled Clinical Trials by Dose Group Dose Group Placebo 5 mg/day 10 mg/day ® ARICEPT ARICEPT® 355 350 315 Patients Randomized Event/%Discontinuing Nausea 1% 1% 3% Diarrhea 0%
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