Valproate Side Effects

Please note - some side effects for Valproate 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 Valproate - for the Consumer

Valproate

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 Valproate:

Change in appetite; constipation; diarrhea; dizziness; drowsiness; hair loss; headache; indigestion; nausea; stomach pain; trouble sleeping; vomiting; weight changes.

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abdominal cramps; abnormal thinking; change in menstrual period; changes in behavior; chest pain; confusion; 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; mental or mood changes; nosebleed; pounding in the chest; severe or persistent nausea, vomiting, or stomach pain; sore throat; suicidal thoughts or actions; swelling of the arms or legs; tremor; unusual bleeding or bruising; unusual weakness; vision changes; yellowing of skin or eyes.

Valproate Syrup

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 Valproate Syrup:

Constipation; diarrhea; dizziness; drowsiness; headache; increased or decreased appetite; mild hair loss; nausea; sore throat; stomach pain or upset; trouble sleeping; vomiting; weight gain.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; behavior changes; blurred vision or other vision changes; change in menstrual period; change in the amount of urine produced; chest pain; confusion; dark urine; fast or irregular heartbeat; fever, chills, or persistent sore throat; general feeling of being unwell; hallucinations; hearing loss; joint or muscle pain or weakness; loss of coordination; memory loss; mental or mood changes (eg, depression, nervousness); pale stools; red, swollen, or blistered skin; ringing in the ears; severe or persistent nausea, vomiting, or loss of appetite; severe or persistent stomach pain or cramps; sluggishness; suicidal thoughts or actions; swelling of the arms or legs; swollen lymph nodes; tremor; trouble speaking or walking; uncontrolled muscle movements; unusual bleeding or bruising; unusual tiredness or weakness; yellowing of the skin or eyes.

Valproate Side Effects - for the Professional

Valproate

The adverse events that can result from Valproate sodium injection use include all of those associated with oral forms of Valproate. The following describes experience specifically with Valproate sodium injection. Valproate sodium injection has been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of 125 to 6000 mg (total daily dose). A total of 2% of patients discontinued treatment with Valproate sodium injection due to adverse events. The most common adverse events leading to discontinuation were 2 cases each of nausea/vomiting and elevated amylase. Other adverse events leading to discontinuation were hallucinations, pneumonia, headache, injection site reaction, and abnormal gait. Dizziness and injection site pain were observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate. The maximum rate of infusion studied was 200 mg/min.

Adverse events reported by at least 0.5% of all subjects/patients in clinical trials of Valproate sodium injection are summarized in Table 1.

In a separate clinical safety trial, 112 patients with epilepsy were given infusions of Valproate injection (up to 15 mg/kg) over 5 to 10 minutes (1.5 to 3 mg/kg/min). The common adverse events (> 2%) were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%), and headache (2.7%). While the incidence of these adverse events was generally higher than in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence (1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache (4.3%), a direct comparison between the incidence of adverse events in the 2 cohorts cannot be made because of differences in patient populations and study designs.

Ammonia levels have not been systematically studied after IV Valproate, so that an estimate of the incidence of hyperammonemia after IV Valproate cannot be provided. Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of Valproate injection.

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 2 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.

Table 3 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.

1Headache 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 using oral therapy.

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 and PRECAUTIONS).

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.

Mania

Although Valproate sodium injection has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse events not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets.

Body as a Whole: Chills, neck pain, neck rigidity.

Cardiovascular System: Hypotension, postural hypotension, vasodilation.

Digestive System: Fecal incontinence, gastroenteritis, glossitis.

Musculoskeletal System: Arthrosis.

Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.

Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.

Special Senses: Conjunctivitis, dry eyes, eye pain.

Urogenital: Dysuria.

Migraine

Although Valproate sodium injection has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse events not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets.

Body as a Whole: Face edema.

Digestive System: Dry mouth, stomatitis.

Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.

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