Depakene Side Effects

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

Depakene

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 Depakene:

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.

Depakene 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 Depakene 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.

Depakene Side Effects - for the Professional

Depakene

Epilepsy

The data described in the following section were obtained using DEPAKOTE (divalproex sodium) tablets.

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, DEPAKOTE was generally well tolerated with most adverse events 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 2 lists treatment-emergent adverse events which were reported by ≥ 5% of DEPAKOTE-treated patients and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive therapy for the 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 DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.

Table 3 lists treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose DEPAKOTE 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 events can be ascribed to DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.

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

Back pain, chest pain, malaise.

Tachycardia, hypertension, palpitation.

Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.

Petechia.

SGOT increased, SGPT increased.

Myalgia, twitching, arthralgia, leg cramps, myasthenia.

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

Sinusitis, cough increased, pneumonia, epistaxis.

Rash, pruritus, dry skin.

Taste perversion, abnormal vision, deafness, otitis media.

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.

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.

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.

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.

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

Weakness.

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.

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.

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.

Acute pancreatitis, including fatalities.

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.

Enuresis and urinary tract infection.

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.

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

Mania

Although Depakene 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 DEPAKOTE tablets.

Chills, neck pain, neck rigidity.

Hypotension, postural hypotension, vasodilation.

Fecal incontinence, gastroenteritis, glossitis.

Arthrosis.

Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.

Furunculosis, maculopapular rash, seborrhea.

Conjunctivitis, dry eyes, eye pain.

Dysuria.

Migraine

Although Depakene has not been evaluated for safety and efficacy in the treatment of prophylaxis 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 DEPAKOTE tablets.

Face edema.

Dry mouth, stomatitis.

Cystitis, metrorrhagia, and vaginal hemorrhage.

Side Effects by Body System

Gastrointestinal

Gastrointestinal side effects have been reported frequently and include nausea, vomiting, and indigestion (in up to 16% of patients), especially with initiation of therapy and rapid increases in dose. Life threatening pancreatitis has been reported to occur anywhere from shortly after initial use to after several years of use. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Hyperamylasemia has occurred in up to 20% of patients and has rarely presented as clinical pancreatitis (usually one to six months after initiation of therapy).

Severe nausea, emesis, and anorexia may be due to valproate-induced hyperammonemia or hepatitis. Adverse gastrointestinal effects may be attenuated by administering doses with food. Increased appetite and weight gain occur in approximately one half of treated patients.

Hepatic

Hepatic side effects including transient dose-dependent elevations of serum transaminases, amylase, and ammonia have been reported in up to 44% of treated patients. 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 valproic acid is recommended if significant hepatic dysfunction occurs.

Risk factors for valproic acid-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.

Mild elevations in transaminases and amylase may be managed by dose reductions.

Nervous system

Neurologic 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 also been reported. Valproate may inhibit urea synthesis resulting in hyperammonemia, which has been associated with encephalopathy, delirium, and ataxia in rare cases. Reversible sensorineural hearing loss associated with valproic acid has been reported rarely. Two cases of extrapyramidal disorders have been reported in association with valproic acid therapy. A case of truncal weakness and respiratory failure has also been associated with valproic acid therapy.

A clinical observational study has reported that valproic acid is associated with cognitive decline in HIV-infected individuals.

Loss of seizure control may indicate associated hepatitis.

Hematologic

Hematologic side effects including rare cases of reversible thrombocytopenia associated with antiplatelet antibodies and bone marrow suppression have been reported.

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.

Dermatologic

Valproic acid has been associated with stomatitis and cutaneous leukoclastic vasculitis. A case of psoriasiform eruption has been reported in a patient receiving valproic acid.

The mechanism of valproic acid induced alopecia is believed to be telogen shedding. This is believed to appear within three months of the initiation of valproic acid therapy. Alopecia does not appear to be dose related. Limited data have reported that supplements with a zinc and selenium-containing vitamin may be useful in the prevention of valproic acid associated alopecia.

Dermatologic side effects including transient alopecia (2.6% to 12%), thinning of the hair, hair color changes, hair texture changes, and rare rashes have been reported. Valproic acid has been implicated in producing Stevens-Johnson syndrome and toxic epidermal necrolysis.

Cardiovascular

Cardiovascular side effects including peripheral edema have been reported rarely.

Renal

Valproate-induced Fanconi's syndrome has been reported more often in children than in adults.

Renal side effects including several cases of Fanconi's syndrome have been reported.

Endocrine

Valproate therapy has been associated with polycystic ovaries, elevated serum testosterone concentrations and menstrual disturbances. One study has suggested that 80% of women treated with valproic acid before the age of 20 have polycystic ovaries or hyperandrogenism.

Endocrine side effects including a variety of adverse reproductive endocrine disorders have been reported in epileptic women taking valproic acid.

Respiratory

Respiratory side effects including a case of eosinophilic pleural effusion have been reported.

Immunologic

Immunologic side effects have been reported including a case of bone marrow suppression in a girl who received high dose valproic acid.

Other

Other side effects including a case of valproate-withdrawal induced migraine has been reported.

Musculoskeletal

Musculoskeletal side effects including decreased bone mass and increased bone turnover have been reported.

Hypersensitivity

Hypersensitivity side effects including a case of hypersensitivity syndrome have been reported.

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