Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).
Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the divalproex sodium delayed-release tablets -treated group was greater than 5% and was greater than that for placebo patients.
1 The following adverse reactions occurred in at least 5% of divalproex sodium delayed-release tablets -treated patients and at an equal or greater incidence for placebo than for divalproex sodium delayed-release tablets: flu syndrome and pharyngitis.
|Body System Reaction||Divalproex Sodium Delayed-Release Tablets (N = 202) %||Placebo (N = 81) %|
The following additional adverse reactions were reported by greater than 1% but not more than 5 % of the 202 divalproex sodium delayed-release tablets-treated patients in the controlled clinical trials:
Body as a Whole
Chest pain, chills, face edema, fever and malaise.
Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.
Hemic and Lymphatic System
Metabolic and Nutritional Disorders
Peripheral edema, SGOT increase, and SGPT increase.
Leg cramps and myalgia.
Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.
Cough increased, dyspnea, rhinitis, and sinusitis.
Skin and Appendages
Pruritus and rash.
Conjunctivitis, ear disorder, taste perversion, and tinnitus.
Cystitis, metrorrhagia, and vaginal hemorrhage.
The following adverse reactions have been identified during post approval use of divalproex sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.
Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.
Paradoxical convulsion, parkinsonism
There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.
There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or fully after valproate discontinuation.
Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.
Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.
There have been rare reports of Fanconi’s syndrome occurring chiefly in children.
Metabolism and nutrition
Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.
Enuresis and urinary tract infection.
Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.
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