Divalproex Side Effects
Please note - some side effects for Divalproex may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).
Side Effects of Divalproex - for the Consumer
Divalproex Delayed-Release Tablets
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Divalproex Delayed-Release Tablets:
Seek medical attention right away if any of these SEVERE side effects occur when using Divalproex Delayed-Release Tablets:Change in appetite; constipation; diarrhea; dizziness; drowsiness; hair loss; headache; indigestion; nausea; stomach cramps or pain; trouble sleeping; vomiting; weakness; weight changes.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; change in menstrual period; changes in behavior; chest pain; confusion; dark, tarry, or bloody stools; dark urine; difficulty speaking; difficulty urinating or other urination problems; extreme tiredness; fast or irregular heartbeat; hallucinations; hearing loss; involuntary movements of the arms and legs; involuntary movements or chewing movements of face, jaw, mouth, or tongue; joint pain; lack of energy; loss of appetite; loss of coordination; loss of seizure control; memory loss; new or worsening mental or mood changes (eg, aggressiveness, agitation, anxiety, depression, exaggerated feeling of well-being, hostility, impulsiveness, inability to sit still, irritability, panic attacks, restlessness); nosebleed; pounding in the chest; red, swollen, blistered, or peeling skin; severe or persistent nausea, vomiting, or stomach pain; shortness of breath; suicidal thoughts or actions; swelling of the arms or legs; symptoms of infection (eg, fever, chills, sore throat); tremor; unusual bleeding or bruising; unusual weakness; vision changes or blurred vision; yellowing of the skin or eyes.
Divalproex Extended-Release Tablets
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Divalproex Extended-Release Tablets:
Seek medical attention right away if any of these SEVERE side effects occur when using Divalproex Extended-Release Tablets:Change in appetite; constipation; diarrhea; dizziness; drowsiness; hair loss; headache; indigestion; nausea; stomach cramps or pain; trouble sleeping; vomiting; weakness; weight changes.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; change in menstrual period; changes in behavior; chest pain; confusion; dark, tarry, or bloody stools; dark urine; difficulty speaking; difficulty urinating or other urination problems; extreme tiredness; fast or irregular heartbeat; hallucinations; hearing loss; involuntary movements of the arms and legs; involuntary movements or chewing movements of face, jaw, mouth, or tongue; joint pain; lack of energy; loss of appetite; loss of coordination; loss of seizure control; memory loss; new or worsening mental or mood changes (eg, aggressiveness, agitation, anxiety, depression, exaggerated feeling of well-being, hostility, impulsiveness, inability to sit still, irritability, panic attacks, restlessness); nosebleed; pounding in the chest; red, swollen, blistered, or peeling skin; severe or persistent nausea, vomiting, or stomach pain; shortness of breath; suicidal thoughts or actions; swelling of the arms or legs; symptoms of infection (eg, fever, chills, sore throat); tremor; unusual bleeding or bruising; unusual weakness; vision changes or blurred vision; yellowing of the skin or eyes.
Divalproex Sprinkle Capsules
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Divalproex Sprinkle Capsules:
Seek medical attention right away if any of these SEVERE side effects occur when using Divalproex Sprinkle Capsules:Change in appetite; constipation; diarrhea; dizziness; drowsiness; hair loss; headache; indigestion; nausea; stomach cramps or pain; trouble sleeping; vomiting; weakness; weight changes.
TopSevere allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; change in menstrual period; changes in behavior; chest pain; confusion; dark, tarry, or bloody stools; dark urine; difficulty speaking; difficulty urinating or other urination problems; extreme tiredness; fast or irregular heartbeat; fever; general body discomfort; hallucinations; hearing loss; involuntary movements of the arms and legs; involuntary movements or chewing movements of face, jaw, mouth, or tongue; joint pain; lack of energy; loss of appetite; loss of coordination; loss of seizure control; memory loss; new or worsening mental or mood changes (eg, aggressiveness, agitation, anxiety, depression, exaggerated feeling of well-being, hostility, impulsiveness, inability to sit still, irritability, panic attacks, restlessness); nosebleed; pounding in the chest; red, swollen, blistered, or peeling skin; severe or persistent nausea, vomiting, or stomach pain; shortness of breath; suicidal thoughts or actions; swelling of the arms or legs; symptoms of infections (eg, fever, chills, sore throat); tremor; unusual bleeding or bruising; unusual weakness; vision changes or blurred vision; yellowing of the skin or eyes.
Divalproex Side Effects - for the Professional
Divalproex
Mania
The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of Divalproex sodium in the treatment of manic episodes associated with bipolar disorder. The adverse events 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, Divalproex sodium, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Divalproex sodium, and lithium carbonate groups, respectively.
Table 2 summarizes those adverse events reported for patients in these trials where the incidence rate in the Divalproex sodium-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Divalproex sodium-treated group was statistically significantly greater than the placebo group. Vomiting was the only event that was reported by significantly (p ≤ 0.05) more patients receiving Divalproex sodium compared to placebo.
| Adverse Event | Divalproex sodium (n = 89) |
Placebo (n = 97) |
| Nausea | 22% | 15% |
| Somnolence | 19% | 12% |
| Dizziness | 12% | 4% |
| Vomiting | 12% | 3% |
| Asthenia | 10% | 7% |
| Abdominal pain | 9% | 8% |
| Dyspepsia | 9% | 8% |
| Rash | 6% | 3% |
1 The following adverse events occurred at an equal or greater incidence for placebo than for Divalproex sodium: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.
The following additional adverse events were reported by greater than 1% but not more than 5% of the 89 Divalproex sodium-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 erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea.
Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.
Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.
Migraine
Based on two placebo-controlled clinical trials and their long term extension, Divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to Divalproex sodium 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 events reported as the primary reason for discontinuation by ≥ 1% of 248 Divalproex sodium-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 3 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the Divalproex sodium-treated group was greater than 5% and was greater than that for placebo patients.
| Body System Event |
Divalproex sodium |
Placebo |
|
1 The following adverse events occurred in at least 5% of Divalproex sodium-treated patients and at an equal or greater incidence for placebo than for Divalproex sodium: flu syndrome and pharyngitis. |
||
| 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% |
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.
Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Divalproex sodium-treated patients (6%), compared to 1% of placebo-treated patients.
Table 4 lists treatment-emergent adverse events which were reported by ≥ 5% of Divalproex sodium-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 events can be ascribed to Divalproex sodium alone, or the combination of Divalproex sodium and other antiepilepsy drugs.
| Body System/Event | Divalproex sodium (%) (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 events which were reported by ≥ 5% of patients in the high dose Divalproex sodium group, and for which the incidence was greater than in the low dose group, in a controlled trial of Divalproex sodium 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 events can be ascribed to Divalproex sodium alone, or the combination of Divalproex sodium and other antiepilepsy drugs.
| 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 events were reported by greater than 1% but less than 5% of the 358 patients treated with Divalproex sodium 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.
Other Patient Populations
Adverse events 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.
Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.
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.
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. 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.
Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests.
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.
Pancreatic: Acute pancreatitis including fatalities.
Metabolic: Hyperammonemia, 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.
TopSide Effects by Body System
Gastrointestinal
Nausea, vomiting, and indigestion appear less frequently and less severely with divalproex sodium than with valproic acid. These effects may be further attenuated by administering doses with food.
Gastrointestinal side effects related to gastritis are common and include nausea, vomiting, and indigestion, especially with the initiation of therapy and with rapid increases in dose. These effects are generally transient and rarely require the discontinuation of therapy. Life threatening pancreatitis has been reported to occur anywhere from shortly after initial use to occurring after several years of use. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Hyperamylasemia occurs in up to 20% of patients and rarely presents as clinical pancreatitis (usually one to six months after initiation of therapy).
Hepatic
Hepatic side effects including transient dose-dependent elevations of serum transaminases, amylase, and ammonia have been reported to occur in up to 44% of treated patients. Mild elevations in transaminases and amylase may be managed by dose reductions. Dose-related hepatitis, which is occasionally fatal, has also been reported. Some clinicians recommend monitoring liver function tests at baseline, then monthly during the first 6 months of therapy and every 3 months thereafter. Prompt withdrawal of divalproex sodium is recommended if significant hepatic dysfunction occurs.
Risk factors for valproate-associated hepatitis are young age (particularly age less than 2 years old), poor nutritional status, mental retardation, underlying metabolic disease, and concomitant use of other anticonvulsant medications. Characteristic pathological features include microvesicular steatosis.
Nervous system
Nervous system side effects including drowsiness, ataxia, and hand tremor have been reported. Cases of encephalopathy (manifested by stupor, coma, hallucinations or affective changes) and chorea have been reported. Reversible sensorineural hearing loss associated with valproate therapy has been reported rarely. Two cases of extrapyramidal disorders have been reported in association with valproate therapy. A case of pseudotumor cerebri has also been reported.
Divalproex sodium may inhibit urea synthesis resulting in hyperammonemia, which has been associated with encephalopathy, delirium, and ataxia in rare cases.
Loss of seizure control may indicate associated hepatitis.
Hematologic
Some clinicians recommend monitoring complete blood counts (including platelet counts) at baseline, then monthly for three months, and every three months thereafter.
Data from a study of 265 patients strongly suggests a causal relationship between rising plasma valproic acid levels and reduced platelet counts, with additional risk factors including female gender and lower baseline platelet counts.
Hematologic side effects including rare cases of reversible thrombocytopenia associated with antiplatelet antibodies and bone marrow suppression have been reported.
Respiratory
Respiratory side effects including a case of truncal weakness and respiratory failure has been associated with valproate therapy.
Renal
Renal side effects including several case reports which suggested that valproate acid may cause Fanconi's syndrome have been reported. Valproate-induced Fanconi's syndrome has been reported more often in children than in adults.
Cardiovascular
Cardiovascular side effects including vasodilation and peripheral edema have been reported.
Endocrine
Endocrine side effects including a variety of adverse reproductive endocrine disorders have been reported in epileptic women taking valproic acid.
Valproate therapy has been associated with polycystic ovaries, elevated serum testosterone concentrations and menstrual disturbance. One study has suggested that 80% of women treated with valproic acid before the age of 20 have polycystic ovaries or hyperandrogenism.
Dermatologic
Dermatologic side effects including transient alopecia and rare rashes have been reported.
Valproate therapy has been associated with stomatitis and cutaneous leukoclastic vasculitis. A case of psoriasiform eruption has been reported in a patient receiving valproic acid.
Musculoskeletal
Musculoskeletal side effects including a case of osteopenia have been reported.
General
General side effects including hypothermia have been reported.
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