July 29, 2016
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Depakote




Depakote Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Depakote

Last reviewed on RxList 1/29/2016

Depakote (divalproex sodium) is a stable coordination compound comprised of sodium valproate and valproic acid used to treat manic episodes associated with bipolar disorder, epilepsy, and migraine headaches. Generic Depakote (termed divalproex sodium) is available under several other names. Side effects of Depakote include drowsiness, weakness, nausea, vomiting, stomach upset, diarrhea, constipation, mood swings, changes in menstrual periods, enlarged breasts, weight changes, agitation, tremor (shaking), vision changes, unusual or unpleasant taste in your mouth, and hair loss.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Depakote FDA Prescribing Information: Side Effects
(Adverse Reactions)

SIDE EFFECTS

The following serious adverse reactions are described below and elsewhere in the labeling:

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively.

Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo.

Table 2: Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo- Controlled Trials of Acute Mania1

Adverse Reaction Depakote
(n = 89)
Placebo
(n = 97)
Nausea 22% 15%
Somnolence 19% 12%
Dizziness 12% 4%
Vomiting 12% 3%
Accidental Injury 11% 5%
Asthenia 10% 7%
Abdominal pain 9% 8%
Dyspepsia 9% 8%
Rash 6% 3%
1 The following adverse reactions occurred at an equal or greater incidence for placebo than for Depakote: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials:

Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.

Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation.

Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Edema, peripheral edema.

Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.

Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.

Respiratory System: Dyspnea, rhinitis.

Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea.

Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.

Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.

Epilepsy

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo-treated patients.

Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.

Table 3: Adverse Reactions Reported by ≥ 5% of Patients Treated with Depakote During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures

Body System/Reaction Depakote (%)
(n = 77)
Placebo (%)
(n = 70)
Body as a Whole
  Headache 31 21
  Asthenia 27 7
  Fever 6 4
Gastrointestinal System
  Nausea 48 14
  Vomiting 27 7
  Abdominal Pain 23 6
  Diarrhea 13 6
  Anorexia 12 0
  Dyspepsia 8 4
  Constipation 5 1
Nervous System
  Somnolence 27 11
  Tremor 25 6
  Dizziness 25 13
  Diplopia 16 9
  Amblyopia/Blurred Vision 12 9
  Ataxia 8 1
  Nystagmus 8 1
  Emotional Lability 6 4
  Thinking Abnormal 6 0
  Amnesia 5 1
Respiratory System
  Flu Syndrome 12 9
  Infection 12 6
  Bronchitis 5 1
  Rhinitis 5 4
Other
  Alopecia 6 1
  Weight Loss 6 0

Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.

Table 4: Adverse Reactions Reported by ≥ 5% of Patients in the High Dos e Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1

Body System/Reaction High Dose (%)
(n = 131)
Low Dose (%)
(n =134)
Body as a Whole
  Asthenia 21 10
Digestive System
  Nausea 34 26
  Diarrhea 23 19
  Vomiting 23 15
  Abdominal Pain 12 9
  Anorexia 11 4
  Dyspepsia 11 10
Hemic/Lymphatic System
  Thrombocytopenia 24 1
  Ecchymosis 5 4
Metabolic/Nutritional
  Weight Gain 9 4
  Peripheral Edema 8 3
Nervous System
  Tremor 57 19
  Somnolence 30 18
  Dizziness 18 13
  Insomnia 15 9
  Nervousness 11 7
  Amnesia 7 4
  Nystagmus 7 1
  Depression 5 4
Respiratory System
  Infection 20 13
  Pharyngitis 8 2
  Dyspnea 5 1
Skin and Appendages
  Alopecia 24 13
Special Senses
  Amblyopia/Blurred Vision 8 4
  Tinnitus 7 1
1 Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group.

The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures:

Body as a Whole: Back pain, chest pain, malaise.

Cardiovascular System: Tachycardia, hypertension, palpitation.

Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.

Hemic and Lymphatic System: Petechia.

Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.

Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.

Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.

Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.

Skin and Appendages: Rash, pruritus, dry skin.

Special Senses: Taste perversion, abnormal vision, deafness, otitis media.

Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.

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 Depakote-treated group was greater than 5% and was greater than that for placebo patients.

Table 5: Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1

Body System Reaction Depakote
(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%
1 The following adverse reactions occurred in at least 5% of Depakote-treated patients and at an equal or greater incidence for placebo than for Depakote: flu syndrome and pharyngitis.

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-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.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Depakote. 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, and Stevens-Johnson syndrome.

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

Neurologic: 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.

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

Hematologic: Relative lymphocytosis, macrocytosis, leucopenia, 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.

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.

Read the entire FDA prescribing information for Depakote (Depakote Divalproex Sodium Tablets)

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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