Divalproex Sodium (Page 7 of 14)

6.3 Migraine

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.

Table 5. Adverse Reactions Reported by > 5% of Divalproex Sodium Delayed-Release Tablets -Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1

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) %
Gastrointestinal System
Nausea 31 10
Dyspepsia 13 9
Diarrhea 12 7
Vomiting 11 1
Abdominal Pain 9 4
Increased Appetite 6 4
Nervous System
Asthenia 20 9
Somnolence 17 5
Dizziness 12 6
Tremor 9 0
Other
Weight Gain 8 2
Back Pain 8 6
Alopecia 7 1

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.

Cardiovascular System

Vasodilatation.

Digestive System

Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.

Hemic and Lymphatic System

Ecchymosis.

Metabolic and Nutritional Disorders

Peripheral edema, SGOT increase, and SGPT increase.

Musculoskeletal System

Leg cramps and myalgia.

Nervous System

Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.

Respiratory System

Cough increased, dyspnea, rhinitis, and sinusitis.

Skin and Appendages

Pruritus and rash.

Special Senses

Conjunctivitis, ear disorder, taste perversion, and tinnitus.

Urogenital System

Cystitis, metrorrhagia, and vaginal hemorrhage.

6.4 Postmarketing Experience

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.

Dermatologic

Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.

Psychiatric

Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.

Neurologic

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.

Musculoskeletal

Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.

Hematologic

Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Endocrine

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

Weight gain.

Reproductive

Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.

Genitourinary

Enuresis and urinary tract infection.

Special Senses

Hearing loss.

Other

Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.

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