adverse reactions
ADVERSE REACTIONS The experience described in this section derives from studies in patients with Alzheimer’s disease and vascular dementia. Adverse Events Leading to Discontinuation: In placebo-controlled trials in which dementia patients received doses of memantine hydrochloride up to 20 mg/day, the likelihood of discontinuation because of an adverse event was the same in the memantine hydrochloride group as in the placebo group. No individual adverse event was associated with the discontinuation of treatment in 1% or more of memantine hydrochloride-treated patients and at a rate greater than placebo. Adverse Events Reported in Controlled Trials: The reported adverse events in memantine hydrochloride trials reflect experience gained under closely monitored conditions in a highly selected patient population. In actual practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior and the types of patients treated may differ. Table 1 lists treatment-emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled dementia trials and for which the rate of occurrence was greater for patients treated with memantine hydrochloride than for those treated with placebo. No adverse event occurred at a frequency of at least 5% and twice the placebo rate. Table 1: Adverse Events Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving Memantine Hydrochloride and at a Higher Frequency than Placebo-treated Patients. Body System Adverse Event Placebo (N = 922) % Memantine hydrochloride (N = 940) % Body as a Whole Fatigue 1 2 Pain 1 3 Cardiovascular System Hypertension 2 4 Central and Peripheral Nervous System Dizziness 5 7 Headache 3 6 Gastrointestinal System Constipation 3 5 Vomiting 2 3 Musculoskeletal System Back pain 2 3 Psychiatric Disorders Confusion 5 6 Somnolence 2 3 Hallucination 2 3 Respiratory System Coughing 3 4 Dyspnea 1 2 Other adverse events occurring with an incidence of at least 2% in memantine hydrochloride-treated patients but at a greater or equal rate on placebo were agitation, fall, inflicted injury, urinary incontinence, diarrhea, bronchitis, insomnia, urinary tract infection, influenza-like symptoms, abnormal gait, depression, upper respiratory tract infection, anxiety, peripheral edema, nausea, anorexia, and arthralgia. The overall profile of adverse events and the incidence rates for individual adverse events in the subpopulation of patients with moderate to severe Alzheimer’s disease were not different from the profile and incidence rates described above for the overall dementia population. Vital Sign Changes: Memantine hydrochloride and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, diastolic blood pressure, and weight) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. There were no clinically important changes in vital signs in patients treated with memantine hydrochloride. A comparison of supine and standing vital sign measures for memantine hydrochloride and placebo in elderly normal subjects indicated that memantine hydrochloride treatment is not associated with orthostatic changes. Laboratory Changes: Memantine hydrochloride and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with memantine hydrochloride treatment. ECG Changes: Memantine hydrochloride and placebo groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in ECG parameters associated with memantine hydrochloride treatment. Other Adverse Events Observed During Clinical Trials Memantine hydrochloride has been administered to approximately 1350 patients with dementia, of whom more than 1200 received the maximum recommended dose of 20 mg/day. Patients received memantine hydrochloride treatment for periods of up to 884 days, with 862 patients receiving at least 24 weeks of treatment and 387 patients receiving 48 weeks or more of treatment. Treatment emergent signs and symptoms that occurred during 8 controlled clinical trials and 4 open-label trials 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 WHO terminology, and event frequencies were calculated across all studies. All adverse events occurring in at least two patients are included, except for those already listed in Table 1 , WHO terms too general to be informative, minor symptoms or events unlikely to be drug-caused, e.g., because they are common in the study population. 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 memantine hydrochloride treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole: Frequent: syncope. Infrequent: hypothermia, allergic reaction. Cardiovascular System: Frequent: cardiac failure. Infrequent: angina pectoris, bradycardia, myocardial infarction, thrombophlebitis, atrial fibrillation, hypotension, cardiac arrest, postural hypotension, pulmonary embolism, pulmonary edema. Central and Peripheral Nervous System: Frequent: transient ischemic attack, cerebrovascular accident, vertigo, ataxia, hypokinesia. Infrequent: paresthesia, convulsions, extrapyramidal disorder, hypertonia, tremor, aphasia, hypoesthesia, abnormal coordination, hemiplegia, hyperkinesia, involuntary muscle contractions, stupor, cerebral hemorrhage, neuralgia, ptosis, neuropathy. Gastrointestinal System: Infrequent: gastroenteritis, diverticulitis, gastrointestinal hemorrhage, melena, esophageal ulceration. Hemic and Lymphatic Disorders: Frequent: anemia. Infrequent: leukopenia. Metabolic and Nutritional Disorders: Frequent: increased alkaline phosphatase, decreased weight. Infrequent: dehydration, hyponatremia, aggravated diabetes mellitus. Psychiatric Disorders: Frequent: aggressive reaction. Infrequent: delusion, personality disorder, emotional lability, nervousness, sleep disorder, libido increased, psychosis, amnesia, apathy, paranoid reaction, thinking abnormal, crying abnormal, appetite increased, paroniria, delirium, depersonalization, neurosis, suicide attempt. Respiratory System: Frequent: pneumonia. Infrequent: apnea, asthma, hemoptysis. Skin and Appendages: Frequent: rash. Infrequent: skin ulceration, pruritus, cellulitis, eczema, dermatitis, erythematous rash, alopecia, urticaria. Special Senses: Frequent: cataract, conjunctivitis. Infrequent: macula lutea degeneration, decreased visual acuity, decreased hearing, tinnitus, blepharitis, blurred vision, corneal opacity, glaucoma, conjunctival hemorrhage, eye pain, retinal hemorrhage, xerophthalmia, diplopia, abnormal lacrimation, myopia, retinal detachment. Urinary System: Frequent: frequent micturition. Infrequent: dysuria, hematuria, urinary retention. Events Reported Subsequent to the Marketing of Memantine Hydrochloride, both U.S. and Ex-U.S. Although no causal relationship to memantine treatment has been found, the following adverse events have been reported to be temporally associated with memantine treatment and are not described elsewhere in labeling: atrioventricular block, bone fracture, carpal tunnel syndrome, cerebral infarction, chest pain, claudication, colitis, dyskinesia, dysphagia, gastritis, gastroesophageal reflux, grand mal convulsions, intracranial hemorrhage, hepatic failure, hyperlipidemia, hypoglycemia, ileus, impotence, malaise, neuroleptic malignant syndrome, acute pancreatitis, aspiration pneumonia, acute renal failure, prolonged QT interval, restlessness, Stevens-Johnson syndrome, sudden death, supraventricular tachycardia, tachycardia, tardive dyskinesia, and thrombocytopenia.