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Divalproex ER

Class
Anticonvulsants
Subclass
Valeric acid derivatives
Generic name
Divalproex sodium ER
Brand names
Depakote ER®
Common formulations
Tablet
See also
Divalproex DR (Depakote®)
Dosage and administration
Adults patients
Treatment
Absence seizures • Simple or complex
•
Start at: 15 mg/kg PO daily
•
Maintenance: 15-60 mg/kg PO daily
•
Maximum: 60 mg/kg per day
Taper dose gradually, increase at one week intervals by 5 to 10 mg/kg/day. If satisfactory clinical response has not been achieved, can dose to plasma levels of accepted therapeutic range (50-100 mcg/mL).
Epilepsy • Complex partial seizures
•
Start at: 10-15 mg/kg PO daily
•
Maintenance: 10-60 mg/kg PO daily
•
Maximum: 60 mg/kg per day
Taper dose gradually, increase at one week intervals by 5 to 10 mg/kg/day. If satisfactory clinical response has not been achieved, can dose to plasma levels of accepted therapeutic range (50-100 mcg/mL).
Generalized tonic-clonic seizures • Off-label
•
Start at: 250 mg PO daily
•
Maintenance: 1,000-2,000 mg PO daily
Titrate over 2 to 4 weeks as tolerated to 1,000 mg/day, generally target serum levels of maintain serum levels of 50 to 100 mg/L. May further increase up to 2,000 mg/day if needed.
Juvenile myoclonic epilepsy • Off-label
•
Start at: 300 mg PO daily
•
Maintenance: 1,200 mg PO daily
•
Maximum: 2,400 mg per day
Titrate every 2 weeks to target dose of 1,200 mg by week 8.
Adjunctive treatment
Adjunctive treatment for seizures • Complex partial seizures, simple
•
Start at: 10-15 mg/kg PO daily for 1 week
•
Maintenance: 10-60 mg/kg PO daily
•
Maximum: 60 mg/kg per day
Monitor valproate plasma level. Taper dose gradually, increase at one week intervals by 5 to 10 mg/kg/day. If satisfactory clinical response has not been achieved, can dose to plasma levels of accepted therapeutic range (50-100 mcg/mL).
Prevention
Prevention of migraine attacks
•
Start at: 500 mg PO daily for 1 week
•
Maintenance: 500-1,000 mg PO daily
Other off-label uses
•
Treatment of diabetic neuropathy
•
Adjunctive treatment for alcohol withdrawal syndrome
•
Prevention of headache episodes in patients with chronic tension-type headache
Indications for use
Labeled indications
Adults
•
Treatment of absence seizures (simple or complex)
•
Treatment of bipolar disorder (manic episodes)
•
Treatment of epilepsy (complex partial seizures)
•
Adjunctive treatment for epilepsy (complex partial seizures)
•
Adjunctive treatment for seizures (complex partial seizures, simple)
•
Prevention of migraine attacks
Off-label indications
Adults
•
Treatment of diabetic neuropathy
•
Treatment of generalized tonic-clonic seizures
•
Treatment of juvenile myoclonic epilepsy
•
Adjunctive treatment for alcohol withdrawal syndrome
•
Prevention of headache episodes in patients with chronic tension-type headache
Safety risks
Boxed warnings
Exacerbation of acute pancreatitis
Hepatotoxicity
Contraindications
Hypersensitivity to divalproex sodium or its components
In women of childbearing age who are not using effective contraception; increased risk of birth defects, malformations and fetal harm, including decreased IQ following in utero exposure
Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG)
Liver disease
Urea cycle disorders
Warnings and precautions
Decreased platelet count
•
Use caution in all patients. Take CBCs and coagulation test before initiating therapy and at periodic intervals.
DRESS syndrome
•
Use caution in all patients. Divalproex may cause Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions.
Encephalopathy, hyperammonemia, hypothermia
•
Use caution in patients with concomitant administration of topiramate.
Seizure
•
Use caution in concurrent use of carbepenems, as it may decrease concentrations serum valproate, which could lead to decreased control of seizures.
Somnolence
•
Use caution in the elderly.
Suicidal ideation
•
Use caution in all patients, suicidal ideation may persist throughout treatment course.
Teratogenesis
•
Maintain a high level of suspicion of increased birth defects, malformations and fetal harm, including decreased IQ following in utero exposure.
Specific populations
Hepatic impairment
Any severity
•
Do not use.
Pregnancy and breastfeeding
Pregnancy
All trimesters
•
Avoid use. Evidence of fetal harm in humans. Contraindicated for use of migraine prophylaxis, but can consider for treatment of bipolar and epilepsy if patient has failed all other therapeutic options. If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the mother, then these parameters should also be monitored in the neonate.
Breastfeeding
Use with caution during breastfeeding.
•
Acceptable for use during breastfeeding.
Low excretion in breastmilk (5-25%).
Very low levels in breastfed infants (< 5%).
May potentially cause adverse effects in breastfed infants.
Adverse reactions
Very common > 10%
•
↓ platelet count, abdominal pain, asthenia, diarrhea, diplopia, dizziness, drowsiness, dyspepsia, insomnia, loss of appetite, nausea, oligomenorrhea, vomiting
Common 1-10%
•
Agitation, amblyopia, arthropathy, ataxia, conjunctivitis, dysarthria, dysgeusia, ecchymosis, erythema nodosum, exacerbation of arrhythmia, hirsutism, hyperreflexia, hypertension, hypertonia, hypotension, ↑ liver enzymes, influenza virus infection, maculopapular rash, nystagmus, oral ulcers, orthostatic hypotension, pancreatitis, peripheral edema, peripheral vasodilation, petechiae, pharyngitis, amenorrhea, amnesia, anxiety, back pain, blurred vision, chest pain, chills, confusion, constipation, cough, depression, dry mouth, dysmenorrhea, dyspnea, dysuria, emotional lability, eye pain, fever, flatulence, hair loss, headache, hearing loss, hematemesis, hiccups, itching, malaise, menstrual irregularity, muscle cramps, muscle weakness, myalgia, nosebleed, otalgia, palpitations, photophobia, skin rash, tinnitus, tremor, urinary incontinence, vaginal bleeding, vertigo, weight gain, rhinitis, sinus tachycardia, skin bullae, stomatitis, tardive dyskinesia, vaginitis, xerophthalmia
Uncommon < 1%
•
Hyperhidrosis, euphoria, hypoesthesia, vesicular rash
Unknown frequency
•
Agranulocytosis, aplastic anemia, asterixis, azoospermia, bone fracture, bradycardia, breast enlargement, cognitive impairment, coma, DRESS syndrome, ↓ WBC count, ↓ blood neutrophil count, ↓ serum sodium, encephalopathy, erythema multiforme, fanconi syndrome, folate deficiency, gastritis, hyperactivity, hypothyroidism, ↑ blood ammonia, ↑ blood lymphocyte count, interstitial nephritis, jaundice, lethargy, macrocytosis, osteopenia, osteoporosis, pancytopenia, photosensitivity of skin, ↑bleeding time, pseudoparkinsonism, psychosis, pure red cell aplasia, arthralgia, bone pain, galactorrhea, hair discoloration, hallucinations, hostility, irritability, suicidal ideation, visual disturbances, weakness, weight loss, syndrome of inappropriate antidiuretic hormone secretion, Stevens-Johnson syndrome, teratogenesis, toxic epidermal necrolysis, vasculitis, vitamin D deficiency
Interactions
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