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Depakote (Divalproex Sodium) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Hepatic failure

Birth defects

Decreased IQ following in utero exposure

Pancreatitis

Thrombocytopenia

Hyperammonemic encephalopathy (5.10, 5.11)

Multi-organ hypersensitivity reactions

Somnolence in the elderly

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.

Information on pediatric adverse reactions is presented in section 8.

Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote ER in the treatment of manic episodes associated with bipolar disorder.

Table 3 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote ER-treated group was greater than 5% and greater than the placebo incidence.

Table 3. Adverse Reactions Reported by > 5% of Depakote-Treated Patients During Placebo-Controlled Trials of Acute Mania 1
Adverse Event Depakote ER
(n=338)
Placebo
(n=263)
Somnolence 26% 14%
Dyspepsia 23% 11%
Nausea 19% 13%
Vomiting 13% 5%
Diarrhea 12% 8%
Dizziness 12% 7%
Pain 11% 10%
Abdominal pain 10% 5%
Accidental injury 6% 5%
Asthenia 6% 5%
Pharyngitis 6% 5%
1. The following adverse reactions/event occurred at an equal or greater incidence for placebo than for Depakote ER: headache

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

Body as a Whole: Back Pain, Flu Syndrome, Infection, Infection Fungal

Cardiovascular System: Hypertension

Digestive System: Constipation, Dry Mouth, Flatulence

Hemic and Lymphatic System: Ecchymosis

Metabolic and Nutritional Disorders: Peripheral Edema

Musculoskeletal System: Myalgia

Nervous System: Abnormal Gait, Hypertonia, Tremor

Respiratory System: Rhinitis

Skin and Appendages: Pruritus, Rash

Special Senses: Conjunctivitis

Urogenital System: Urinary Tract Infection, Vaginitis

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 4 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 4. Adverse Reactions Reported by ≥ 5% of Patients Treated with Valproate During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Event 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 5 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 5. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures 1
Body System/Event 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 event 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 6 includes those adverse reactions reported for patients in the placebo-controlled trial where the incidence rate in the Depakote ER-treated group was greater than 5% and was greater than that for placebo patients.

Table 6. Adverse Reactions Reported by >5% of Depakote ER-Treated Patients During the Migraine Placebo-Controlled Trial with a Greater Incidence than Patients Taking Placebo 1
Body System
Event
Depakote ER
(n=122)
Placebo
(n=115)
Gastrointestinal System
     Nausea 15% 9%
     Dyspepsia 7% 4%
     Diarrhea 7% 3%
     Vomiting 7% 2%
     Abdominal Pain 7% 5%
Nervous System
     Somnolence 7% 2%
Other
     Infection 15% 14%
1. The following adverse reactions occurred in greater than 5% of Depakote ER-treated patients and at a greater incidence for placebo than for Depakote ER: asthenia and flu syndrome.

The following additional adverse reactions were reported by greater than 1% but not more than 5% of Depakote ER-treated patients and with a greater incidence than placebo in the placebo-controlled clinical trial for migraine prophylaxis:

Body as a Whole: Accidental injury, viral infection.

Digestive System: Increased appetite, tooth disorder.

Metabolic and Nutritional Disorders: Edema, weight gain.

Nervous System: Abnormal gait, dizziness, hypertonia, insomnia, nervousness, tremor, vertigo.

Respiratory System: Pharyngitis, rhinitis.

Skin and Appendages: Rash.

Special Senses: Tinnitus.

Table 7 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the valproate-treated group was greater than 5% and was greater than that for placebo patients.

Table 7. Adverse Reactions Reported by > 5% of Valproate-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence than Patients Taking Placebo 1
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 greater than 5% of Depakote-treated patients and at a 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 valproate-treated patients in the controlled clinical trials:

Body as a Whole: Chest pain.

Cardiovascular System: Vasodilatation.

Digestive System: Constipation, dry mouth, flatulence, and stomatitis.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Peripheral edema.

Musculoskeletal System: Leg cramps.

Nervous System: Abnormal dreams, confusion, paresthesia, speech disorder, and thinking abnormalities.

Respiratory System: Dyspnea, and sinusitis.

Skin and Appendages: Pruritus.

Urogenital System: Metrorrhagia.

Other Patient Populations

Mania

The following adverse reactions not listed previously were reported by greater than 1% of Depakote-treated patients and with a greater incidence than placebo in placebo-controlled trials of manic episodes associated with bipolar disorder:

Body as a Whole: Chills, chills and fever, drug level increased, neck rigidity.

Cardiovascular System: Arrhythmia, hypotension, postural hypotension.

Digestive System: Dysphagia, fecal incontinence, gastroenteritis, glossitis, gum hemorrhage, mouth ulceration.

Hemic and Lymphatic System: Anemia, bleeding time increased, leucopenia.

Metabolic and Nutritional Disorders: Hypoproteinemia.

Musculoskeletal System: Arthrosis.

Nervous System: Agitation, catatonic reaction, dysarthria, hallucinations, hypokinesia, psychosis, reflexes increased, sleep disorder, tardive dyskinesia.

Respiratory System: Hiccup.

Skin and Appendages: Discoid lupus erythematosus, erythema nodosum, furunculosis, maculopapular rash, seborrhea, sweating, vesiculobullous rash.

Special Senses: Conjunctivitis, dry eyes, eye disorder, eye pain, photophobia, taste perversion.

Urogenital System: Cystitis, menstrual disorder.

Epilepsy

Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system.

Gastrointestinal

The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients.

CNS Effects

Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions ].

There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of valproate products. In some cases the patients recovered with permanent sequelae [see Warnings and Precautions ]. Cerebral atrophy has been reported in children exposed to valproate in utero [see Use in Specific Populations ].

Dermatologic

Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions ].

Psychiatric

Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.

Musculoskeletal

Weakness.

Hematologic

Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions and Drug Interactions (7) ]. Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Hepatic

Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions ].

Endocrine

Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions ].

There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.

Pancreatic

Acute pancreatitis including fatalities [see Warnings and Precautions ].

Metabolic

Hyperammonemia [see Warnings and Precautions (5.10, 5.11) ], hyponatremia, and inappropriate ADH secretion.

There have been rare reports of Fanconi's syndrome occurring chiefly in children.

Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.

Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.

Genitourinary

Enuresis and urinary tract infection.

Special Senses

Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.

Other

Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia [see Warnings and Precautions ].

There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy.



REPORTS OF SUSPECTED DEPAKOTE SIDE EFFECTS / ADVERSE REACTIONS

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

Possible Depakote side effects / adverse reactions in 43 year old male

Reported by a health professional (non-physician/pharmacist) from United Kingdom on 2011-10-03

Patient: 43 year old male

Reactions: Overdose, Metabolic Acidosis, Hyperammonaemic Encephalopathy, Hypocalcaemia, Hypernatraemia, Thrombocytopenia

Adverse event resulted in: hospitalization

Suspect drug(s):
Ibuprofen

Depakote
    Indication: Epilepsy



Possible Depakote side effects / adverse reactions in 7 year old male

Reported by a consumer/non-health professional from United States on 2011-10-03

Patient: 7 year old male

Reactions: Adverse Reaction

Adverse event resulted in: hospitalization

Suspect drug(s):
Depakote
    Dosage: unknown dose was increased
    Administration route: Oral
    Indication: Affective Disorder
    End date: 2011-09-01

Depakote
    Dosage: unknown dose
    Administration route: Oral
    Indication: Attention Deficit/hyperactivity Disorder
    Start date: 2011-09-01
    End date: 2011-09-01



Possible Depakote side effects / adverse reactions in 43 year old male

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

Patient: 43 year old male

Reactions: Metabolic Acidosis, Overdose, Hyperammonaemic Encephalopathy, Hypocalcaemia, Hypernatraemia, Thrombocytopenia

Adverse event resulted in: hospitalization

Suspect drug(s):
Depakote
    Indication: Epilepsy

Ibuprofen



See index of all Depakote side effect reports >>

Drug label data at the top of this Page last updated: 2014-03-28

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