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adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions in clinical studies of donepezil hydrochloride tablets are nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience The rates of discontinuation from controlled clinical trials of donepezil hydrochloride tablets due to adverse events for the donepezil hydrochloride tablets 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 events 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 Frequent Adverse Events Leading to Discontinuation from Controlled Clinical Trials by Dose Group Dose Group Placebo 5 mg/day Donepezil Hydrochloride Tablets 10 mg/day Donepezil Hydrochloride Tablets Patients Randomized 355 350 315 Event/%Discontinuing Nausea 1% 1% 3% Diarrhea 0% <1% 3% Vomiting <1% <1% 2% The most common adverse events, 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 tablet’s cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia. These adverse events were often of mild intensity and transient, resolving during continued donepezil hydrochloride tablets treatment without the need for dose modification. There is evidence to suggest that the frequency of these common adverse events 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 of 10 mg/day over a 6-week period. The rates of common adverse events 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 events following one and six week titration regimens. No titration One week titration Six week titration Adverse Event Placebo (n=315) 5 mg/day (n=311) 10 mg/day (n=315) 10 mg/day (n=269) Nausea 6% 5% 19% 6% Diarrhea 5% 8% 15% 9% Insomnia 6% 6% 14% 6% Fatigue 3% 4% 8% 3% Vomiting 3% 3% 8% 5% Muscle cramps 2% 6% 8% 3% Anorexia 2% 3% 7% 3% The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 3 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received donepezil hydrochloride tablets and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride tablets than with placebo. Body System/Adverse Event Placebo (n=355) Donepezil hydrochloride tablets (n=747) Percent of Patients with any Adverse Event 72 74 Body as a Whole Headache 9 10 Pain, various locations 8 9 Accident 6 7 Fatigue 3 5 Cardiovascular System Syncope 1 2 Digestive System Nausea 6 11 Diarrhea 5 10 Vomiting 3 5 Anorexia 2 4 Hemic and Lymphatic System Ecchymosis 3 4 Metabolic and Nutritional Systems Weight Decrease 1 3 Musculoskeletal System Muscle Cramps 2 6 Arthritis 1 2 Nervous System Insomnia 6 9 Dizziness 6 8 Depression <1 3 Abnormal Dreams 0 3 Somnolence <1 2 Urogenital System Frequent Urination 1 2 Donepezil hydrochloride tablets have been administered to over 1700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1000 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 1214 days. Treatment emergent signs and symptoms that occurred during three controlled clinical trials and two open-label trials in the United States were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900 patients from these trials who experienced that event while receiving donepezil hydrochloride tablets. All adverse events occurring at least twice are included, except for those already listed in Tables 2 or 3, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100 patients; Infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to donepezil hydrochloride tablets treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States. Body as a Whole: Frequent : influenza, chest pain, toothache; Infrequent : fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, listlessness. Cardiovascular System: Frequent: hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; Infrequent: angina pectoris, postural hypotension, myocardial infarction, AV block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thrombosis. Digestive System: Frequent : fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; Infrequent: eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer. Endocrine System: Infrequent: diabetes mellitus, goiter. Hemic and Lymphatic System: Infrequent: anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia. Metabolic and Nutritional Disorders: Frequent: dehydration; Infrequent : gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase. Musculoskeletal System: Frequent: bone fracture; Infrequent : muscle weakness, muscle fasciculation. Nervous System: Frequent: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia; Infrequent: cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing. Respiratory System: Frequent: dyspnea, sore throat, bronchitis; Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring. Skin and Appendages: Frequent: pruritus, diaphoresis, urticaria; Infrequent: dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer. Special Senses: Frequent: cataract, eye irritation, vision blurred; Infrequent: dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes. Urogenital System: Frequent: urinary incontinence, nocturia; Infrequent: dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis. The rates of discontinuation from controlled clinical trials of donepezil hydrochloride tablets due to adverse events for the donepezil hydrochloride tablets patients were approximately 12% compared to 7% for placebo patients. The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride tablets patients and at twice the incidence seen in placebo patients, were anorexia (2% vs 1% placebo), nausea (2% vs <1% placebo), diarrhea (2% vs 0% placebo) and urinary tract infection (2% vs 1% placebo). The rates of discontinuation from controlled clinical trials of donepezil hydrochloride tablets due to adverse events for the donepezil hydrochloride tablets patients were approximately 12% compared to 7% for placebo patients. The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride tablets patients and at twice the incidence seen in placebo patients, were anorexia (2% vs 1% placebo), nausea (2% vs <1% placebo), diarrhea (2% vs 0% placebo) and urinary tract infection (2% vs 1% placebo). Table 4 lists adverse events that were reported in at least 2% of patients in placebo-controlled trials who received donepezil hydrochloride tablets and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride tablets than with placebo. Body System/Adverse Event Placebo (n=392) Donepezil hydrochloride tablets (n=501) Percent of Patients with any Adverse Event 73 81 Body as a Whole Accident 12 13 Infection 9 11 Headache 3 4 Pain 2 3 Back Pain 2 3 Fever 1 2 Chest Pain <1 2 Cardiovascular System Hypertension 2 3 Hemorrhage 1 2 Syncope 1 2 Digestive System Diarrhea 4 10 Vomiting 4 8 Anorexia 4 8 Nausea 2 6 Hemic and Lymphatic System Ecchymosis 2 5 Metabolic and Nutritional Systems Creatine Phosphokinas Increased 1 3 Dehydration 1 2 Hyperlipemia <1 2 Nervous System Insomnia 4 5 Hostility 2 3 Nervousness 2 3 Hallucinations 1 3 Somnolence 1 3 Dizziness 1 2 Depression 1 2 Confusion 1 2 Emotional Lability 1 2 Personality Disorder 1 2 Skin And Appendages Eczema 2 3 Urogenital System Urinary Incontinence 1 2 Donepezil hydrochloride tablets 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, one of which had an open label extension. All adverse events occurring at least twice are included, except for those already listed in Table 4, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system using the COSTART dictionary and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100 patients; Infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to donepezil hydrochloride tablets treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole: Frequent: abdominal pain, asthenia, fungal infection, flu syndrome; Infrequent: allergic reaction, cellulitis, malaise, sepsis, face edema, hernia. Cardiovascular System: Frequent: hypotension, bradycardia, ECG abnormal, heart failure; Infrequent: myocardial infarction, angina pectoris, atrial fibrillation, congestive heart failure, peripheral vascular disorder, supraventricular extrasystoles, ventricular extrasystoles, cardiomegaly. Digestive System: Frequent: constipation, gastroenteritis, fecal incontinence, dyspepsia; Infrequent: gamma glutamyl transpeptidase increase, gastritis, dysphagia, periodontitis, stomach ulcer, periodontal abscess, flatulence, liver function tests abnormal, eructation, esophagitis, rectal hemorrhage. Endocrine System: Infrequent: diabetes mellitus. Hemic and Lymphatic System: Frequent: anemia; Infrequent: leukocytosis. Metabolic and Nutritional Disorders: Frequent: weight loss, peripheral edema, edema, lactic dehydrogenase increased, alkaline phosphatase increased; Infrequent hypercholesteremia, hypokalemia, hypoglycemia, weight gain, bilirubinemia, BUN increased, B 12 deficiency anemia, cachexia, creatinine increased, gout, hyponatremia, hypoproteinemia, iron deficiency anemia, SGOT increased, SGPT increased. Musculoskeletal System: Frequent: arthritis; Infrequent: arthrosis, bone fracture, arthralgia, leg cramps, osteoporosis, myalgia. Nervous System: Frequent: agitation, anxiety, tremor, convulsion, wandering, abnormal gait; Infrequent: apathy, vertigo, delusions, abnormal dreams, cerebrovascular accident, increased salivation, ataxia, euphoria, vasodilatation, cerebral hemorrhage, cerebral infarction, cerebral ischemia, dementia, extrapyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia. Respiratory System: Frequent: pharyngitis, pneumonia, cough increased, bronchitis; Infrequent: dyspnea, rhinitis, asthma. Skin and Appendages: Frequent: rash, skin ulcer, pruritus; Infrequent: psoriasis, skin discoloration, herpes zoster, dry skin, sweating, urticaria, vesiculobullous rash. Special Senses: Infrequent: conjunctivitis, glaucoma, abnormal vision, ear pain, lacrimation disorder. Urogenital System: Frequent: urinary tract infection, cystitis, hematuria, glycosuria; Infrequent: vaginitis, dysuria, urinary frequency, albuminuria. 6.2 Postmarketing Experience Voluntary reports of adverse events temporally associated with donepezil hydrochloride tablets that have been received since market introduction that are not listed above, and for which there are inadequate data to determine the causal relationship with the drug include the following: abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.