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Aricept (Donepezil Hydrochloride) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

Clinical Studies Experience

ARICEPT 5 mg/day and 10 mg/day

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%.

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
ARICEPT
10 mg/day
ARICEPT
Patients Randomized 355 350 315
Event/%Discontinuing
   Nausea 1% 1% 3%
   Diarrhea 0% <1% 3%
   Vomiting <1% <1% 2%

Most Frequent Adverse Events Seen in Association with the Use of ARICEPT

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 ARICEPT'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 ARICEPT 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.

Table 2. Comparison of Rates of Adverse Events in Mild to Moderate Patients Titrated to 10 mg/day over 1 and 6 Weeks
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%

Adverse Events Reported in Controlled Trials

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 ARICEPT and for which the rate of occurrence was greater for patients treated with ARICEPT than with placebo. In general, adverse events occurred more frequently in female patients and with advancing age.

Table 3. Adverse Events Reported in Controlled Clinical Trials in Mild to Moderate Alzheimer's Disease in at Least 2% of Patients Receiving ARICEPT and at a Higher Frequency than Placebo Treated Patients
Body System/Adverse Event Placebo
(n=355)
ARICEPT
(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

Other Adverse Events Observed During Clinical Trials

ARICEPT has 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 ARICEPT. 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 ARICEPT 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.


Severe 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 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 ARICEPT 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 Frequent Adverse Events Seen in Association with the Use of ARICEPT

The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving ARICEPT and at twice or more the placebo rate, are largely predicted by ARICEPT's cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT treatment without the need for dose modification.


Adverse Events Reported in Controlled Trials

Table 4 lists adverse events that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT and for which the rate of occurrence was greater for patients treated with ARICEPT than with placebo.

Table 4. Adverse Events Reported in Controlled Clinical Trials in Severe Alzheimer's Disease in at Least 2% of Patients Receiving ARICEPT and at a Higher Frequency than Placebo Treated Patients
Body System/Adverse Event Placebo
(n=392)
ARICEPT
(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 Phosphokinase 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 2
   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

Other Adverse Events Observed During Clinical Trials

ARICEPT 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. 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 ARICEPT 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, B12 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.


ARICEPT 23 mg/day

Moderate to Severe Alzheimer's Disease

ARICEPT 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 Events Leading to Discontinuation

The rate of discontinuation from a controlled clinical trial of ARICEPT 23 mg/day due to adverse events was higher (18.6%) than for the 10 mg/day treatment group (7.9%). The most common adverse events leading to discontinuation, defined as those occurring in at least 1% of patients and greater than those occurring with 10 mg/day are shown in Table 5.

Table 5. Most Frequent Adverse Events Leading to Discontinuation from a Controlled Clinical Trial by Treatment Group
Dose Group 23 mg/day
ARICEPT
10 mg/day
ARICEPT
Safety Population 963 471
Event/%Discontinuing
   Vomiting 3 0
   Diarrhea 2 0
   Nausea 2 0
   Dizziness 1 0

The majority of discontinuations due to adverse events in the 23 mg group occurred during the first month of treatment.


Most Frequent Adverse Events Seen in Association with the Use of 23 mg

The most common adverse events, defined as those occurring at a frequency of at least 5%, include nausea, diarrhea, vomiting, and anorexia. These adverse events were often of mild to moderate intensity.


Adverse Events Reported in Controlled Trials

The events cited reflect experience gained under closely monitored conditions of a controlled clinical trial 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 6 lists adverse events that were reported in at least 2% of patients who received 23 mg/day of ARICEPT and at a higher frequency than those receiving 10 mg/day of ARICEPT in a controlled clinical trial that compared the two doses. In this study, there were no important differences in the type of adverse events in patients taking ARICEPT with or without memantine.

Table 6. Adverse Events Reported in a Controlled Clinical Trial in Moderate to Severe Alzheimer's Disease in at Least 2% of Patients and Higher in the 23 mg/day Group
Body System/Adverse Event 23 mg/day
ARICEPT
10 mg/day
ARICEPT
Safety Population 963 471
Percent of Patients with any Adverse Event 74 64
Gastrointestinal disorders
   Nausea 12 3
   Vomiting 9 3
   Diarrhea 8 5
General disorders and administration site conditions
   Fatigue 2 1
   Asthenia 2 1
Injury, poisoning and procedural complications
   Contusion 2 0
Investigations
   Weight decreased 5 3
Metabolism and nutrition disorders
   Anorexia 5 2
Nervous system
   Dizziness 5 3
   Headache 4 3
   Somnolence 2 1
Psychiatric disorders
   Insomnia 3 2
Renal and urinary disorders
   Urinary incontinence 3 1

Postmarketing Experience

Voluntary reports of adverse events temporally associated with ARICEPT 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.



REPORTS OF SUSPECTED ARICEPT SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Aricept. The information is not vetted and should not be considered as verified clinical evidence.

Possible Aricept side effects / adverse reactions in 74 year old male

Reported by a health professional (non-physician/pharmacist) from Germany on 2011-10-05

Patient: 74 year old male

Reactions: Refusal of Treatment by Patient, Rhabdomyolysis

Suspect drug(s):
Memantine
    Dosage: 20 mg (20 mg, 1 in 1 d), oral
    Administration route: Oral
    Indication: Dementia Alzheimer's Type
    Start date: 2011-07-12
    End date: 2011-08-11

Memantine
    Dosage: 5 mg (5 mg, 1 in 1 d), oral; increased dose, oral
    Administration route: Oral
    Indication: Dementia Alzheimer's Type
    Start date: 2011-06-21
    End date: 2011-06-01

Memantine
    Dosage: 5 mg (5 mg, 1 in 1 d), oral; increased dose, oral
    Administration route: Oral
    Indication: Dementia Alzheimer's Type
    Start date: 2011-06-01
    End date: 2011-07-11

Lyrica
    Dosage: 300 mg (150 mg, 2 in 1 d), oral
    Administration route: Oral
    Indication: Pain
    Start date: 2011-08-01
    End date: 2011-08-11

Gramalil (Tiapride Hydrochloride)
    Dosage: 25 mg (25 mg, 1 in 1 d),oral
    Administration route: Oral
    Indication: Dementia Alzheimer's Type
    Start date: 2011-04-25
    End date: 2011-08-12

Aricept
    Dosage: 5 mg (5 mg, 1 in 1 d), oral
    Administration route: Oral
    Indication: Dementia Alzheimer's Type
    Start date: 2011-01-31
    End date: 2011-08-11

Other drugs received by patient: Yoku-KAN-SAN (Herbal Extract Nos) (Herbal Extract Nos); Methycobal (Mecobalamin) (Mecobalamin)



Possible Aricept side effects / adverse reactions in 85 year old female

Reported by a physician from Japan on 2011-10-05

Patient: 85 year old female

Reactions: Epilepsy, Tremor

Adverse event resulted in: hospitalization

Suspect drug(s):
Aromasin
    Dosage: 25 mg, 1x/day
    Administration route: Oral
    Indication: Breast Cancer

Aricept
    Dosage: 10 mg, 1x/day
    Administration route: Oral
    Start date: 2011-08-04
    End date: 2011-09-08

Aricept
    Dosage: 5 mg, 1x/day
    Administration route: Oral
    Start date: 2011-06-16
    End date: 2011-08-03

Lansoprazole
    Dosage: 15 mg, 1x/day
    Administration route: Oral
    Indication: Gastrooesophageal Reflux Disease
    End date: 2011-09-08

Aricept
    Dosage: 3 mg, 1x/day
    Administration route: Oral
    Indication: Dementia Alzheimer's Type
    Start date: 2011-06-02
    End date: 2011-06-15

Other drugs received by patient: Candesartan Cilexetil; Depas



Possible Aricept side effects / adverse reactions in 64 year old female

Reported by a physician from Germany on 2011-10-10

Patient: 64 year old female weighing 60.0 kg (132.0 pounds)

Reactions: Hyperchromic Anaemia

Suspect drug(s):
Aricept
    Dosage: unk

Venlafaxine HCL
    Dosage: 300 mg daily
    Administration route: Oral
    Indication: Depression
    Start date: 2006-01-01



See index of all Aricept side effect reports >>

Drug label data at the top of this Page last updated: 2012-04-26

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