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  • CLASSES

    Anticonvulsants, Valproic Acid and derivatives
    Mood Stabilizers
    Other Anti-migraine Drugs

    BOXED WARNING

    Carnitine deficiency, hepatic disease, hepatotoxicity, hypoalbuminemia, organic brain syndrome

    Valproic acid and its analogs are hepatotoxic and are contraindicated in patients with hepatic disease or significant hepatic dysfunction. Use with extreme caution in patients with a prior history of hepatic disease. Hepatotoxicity, including hepatic failure, has been fatal and may more commonly occur in the first 6 months of treatment. Because carnitine deficiency may promote hepatotoxicity, valproate should be avoided in patients with inborn errors of carnitine metabolism. Liver function tests (LFTs) should be performed before therapy and at frequent intervals for patients at risk, especially during the first 6 months of therapy. Clinicians should not completely rely on serum biochemistry since these LFTs may not always be abnormal, but should also consider the results of a detailed medical history and physical examination. In some instances, hepatotoxicity progressed even after the drug was discontinued. Patients with organic brain syndrome, congenital metabolic disorders, severe seizures or a severe seizure disorder accompanied by mental retardation, on multiple anticonvulsants, and pediatric patients less than 2 years of age may be at highest risk for hepatotoxicity. Valproic acid also should be dosed carefully in patients with hypoalbuminemia because protein binding is reduced, which can increase the likelihood for drug-induced toxicity. There is an increased risk of valproate-induced acute hepatic failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase gamma (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproic acid and its analogs are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and pediatric patients under 2 years of age who are clinically suspected of having a mitochondrial disorder. POLG mutation screening should be performed in accordance with current clinical practice.

    Pancreatitis

    Cases of life-threatening pancreatitis have been reported in both pediatric and adult patients receiving valproic acid or its analogs. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after re-challenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

    Contraception requirements, pregnancy, reproductive risk

    Valproic acid and its analogs are contraindicated for use during pregnancy when the drug is being used for migraine prophylaxis. Valproic acid is not appropriate for migraine prophylaxis during pregnancy, as use is not considered necessary to prevent permanent injury or death. For the treatment of epilepsy and manic episodes associated with bipolar disorder, valproic acid valproate products should only be prescribed during pregnancy for these conditions if other alternative medications are not acceptable or not effective for treating the condition. Valproic acid and its derivatives are associated with reproductive risk. In utero exposure to valproate can cause major congenital malformations, including neural tube defects (e.g., spina bifida), craniofacial defects, cardiovascular malformations, hypospadias, and limb malformations. Some of the malformations are fatal. Additionally, fetal exposure may cause decreased IQ scores, cerebral atrophy, developmental delay, and autism and/or autism spectrum disorders. The strongest association is with maternal valproic acid use and neural tube defects, particularly when the drug is taken during the first trimester. It is unknown whether folic acid reduces the risk of neural tube defects in pregnant women receiving valproic acid; however, routine folic acid intake should be implemented during pregnancy regardless of therapy with the drug because studies in the general population show that folic acid intake prior to conception and during early pregnancy reduces the risk of neural tube defects. About 1 in 1,500 babies is born with a neural tube defect in the U.S. The risk of neural tube defects in babies born to mothers treated with valproate during the first 12 weeks of pregnancy is 1 in 20 babies. The CDC has estimated the risk for spina bifida in children exposed to valproic acid during gestation to be approximately 1% to 2% versus 0.14% to 0.2% in the general population. Data collected from the North American Antiepileptic Drug Pregnancy Registry suggest a 4-fold increased incidence of congenital malformations with valproic acid monotherapy during the first trimester compared to all other antiepileptic drug (AED) monotherapies as a group. Results from a prospective, multi-center, long-term, observational study of fetal death and malformations during in utero exposure to phenytoin, carbamazepine, lamotrigine, or valproate indicate that valproate poses the greatest risk for serious adverse outcomes. Enrollment was limited to pregnant women receiving monotherapy with one of the four agents for epilepsy. The outcomes of 333 infants were analyzed. The total percentages of serious adverse outcomes (fetal death or congenital malformations) were as follows: lamotrigine 1%, carbamazepine 8.2%, phenytoin 10.7%, and valproate 20.3%. Fetal deaths occurred in 3.6% of the carbamazepine and phenytoin groups, 2.9% of the valproate group, and no deaths occurred with lamotrigine. Congenital malformations were reported as follows: lamotrigine 1%, carbamazepine 4.5%, phenytoin 7.1%, and valproate 17.4%. Congenital malformations in the valproate group included brachycephaly, coarctation of the aorta, hypoplastic right heart, atrial septal defect, hydronephrosis, undescended testes, hypospadias, cleft palate, dysplastic ribs, two thumbs on right hand and a third nipple, and pulmonary stenosis. Valproate demonstrated a dose-dependent effect for adverse outcomes. In May 2013, the FDA notified healthcare professionals of an increased risk of lower cognitive test scores in children exposed to valproate and related products (valproic acid and divalproex sodium) during pregnancy. The data come from the Neurodevelopmental Effects of Antiepileptic Drugs epidemiologic study in which cognitive tests were performed on children exposed to monotherapy with antiepileptic drugs in utero. At age 6, the average IQ difference between children exposed to valproic acid and those exposed to either carbamazepine, lamotrigine, or phenytoin varied between 8 to 11 points. The long-term effects on cognitive development after exposure to valproate during pregnancy are not known. The occurrence of these effects if exposure to valproate is limited to less than the full duration of pregnancy, such as only to the first trimester, is also unknown. In a population-based cohort study (n = 655,615) with long-term follow-up of children with or without prenatal exposure to valproate, a significantly increased risk of autism was observed. In this cohort, 5,437 children were identified with autism spectrum disorder and 2,067 with childhood autism. The absolute risk of autism spectrum disorder or childhood autism was 1.53% and 0.48%, respectively. Of the 508 children with in utero exposure to valproate, the absolute risk was 4.42% for autism spectrum disorder and 2.5% for childhood autism. The therapeutic benefit of valproic acid in women of childbearing age should be carefully weighed against the risk for injury to the fetus, particularly during the first trimester of pregnancy. If the patient is taking the drug to prevent major seizures, the medical necessity of continuing valproic acid versus changing to an alternate agent should be assessed if the woman is planning to become pregnant. Determinations should be made on an individual basis, since seizures resulting from a change in therapy may pose more of a threat to both the mother and the fetus than continued therapy with valproic acid. Women of child-bearing potential should be carefully counseled on the possible fetal risks of valproic acid treatment for any indication during pregnancy, instructed in the contraception requirements and use of effective contraception, and informed of the importance of reporting a pregnancy to their health care provider as soon as possible. It is advisable to conduct tests for detection of neural tube and other defects as part of prenatal care in pregnant women receiving the drug. Women who took valproate during pregnancy should be instructed to inform their child's pediatrician of the exposure. Other adverse effects which have occurred during pregnancy include a woman with low fibrinogen taking multiple anticonvulsants whose infant died from hemorrhage secondary to afibrinogenemia; valproate products are known to cause dose-related thrombocytopenia. The manufacturer recommends careful periodic monitoring of complete blood counts (CBC) and clotting parameters if valproate must be used during pregnancy. Physicians are advised to recommend that pregnant patients receiving valproic acid enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    DEA CLASS

    Rx

    DESCRIPTION

    Anticonvulsant available orally (valproic acid, divalproex, valproate) and IV (valproate)
    Useful for absence, myoclonic, partial and tonic-clonic seizures; treats bipolar disorder and agitation secondary to dementia; delayed-release and extended-release formulations approved for migraine prophylaxis
    Close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended

    COMMON BRAND NAMES

    Depacon, Depakene, Depakote, Depakote ER

    HOW SUPPLIED

    Depacon/Valproate Sodium Intravenous Inj Sol: 1mL, 100mg
    Depakene/Valproic Acid Oral Cap: 250mg
    Depakene/Valproic Acid Oral Sol: 5mL, 250mg
    Depakote ER/Divalproex Sodium Oral Tab ER: 250mg, 500mg
    Depakote/Divalproex Sodium Oral Cap DR Pellets: 125mg
    Depakote/Divalproex Sodium Oral Tab DR: 125mg, 250mg, 500mg

    DOSAGE & INDICATIONS

    For the monotherapy or adjunct treatment of simple absence seizures, complex absence seizures, or complex partial seizures, and adjunctively for other seizure types that include absence or partial complex seizures (e.g., tonic-clonic seizures, myoclonic seizures).
    Oral dosage (delayed-release divalproex (Depakote) or delayed-release valproic acid (Stavzor))
    Adults, Adolescents, and Children 10 years and older

    Initially, 10 mg/kg/day to 15 mg/kg/day PO for complex partial seizures and 15 mg/kg/day PO for simple or complex absence seizures. The drug should be administered in divided doses if the total daily dose exceeds 250 mg. Increase by 5 mg/kg/day to 10 mg/kg/day at weekly intervals as tolerated and necessary. The maximum daily recommended dose is 60 mg/kg/day. For most patients, optimal clinical response is achieved at doses below 60 mg/kg/day. In general, use a reduced initial dosage and slower dose titration in geriatric adults. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The final therapeutic dose should be achieved on the basis of tolerability and clinical response. For patients who do not respond, measure plasma concentrations to determine whether they are within the usually accepted range (50 mcg/mL to 100 mcg/mL). When converting to divalproex or valproic acid monotherapy from other anticonvulsants, the dosage of the concomitant antiepilepsy drug(s) can usually be reduced by 25% every 2 weeks. This reduction can begin at the initiation of valproic acid/divalproex sodium therapy, or delayed for 1 to 2 weeks if necessary to avoid rebound seizures.

    Children 2 to 9 years†

    Valproate has been administered to children as young as 2 years, but data on appropriate dosage based on age are limited. Younger children, especially those receiving concomitant enzyme-inducing anticonvulsants, may need larger maintenance doses to attain target total and unbound serum valproic acid concentrations compared to adults. Children 3 months to 10 years of age have a 50% higher clearance of valproic acid expressed on weight (mL/min/kg) than adults. Use valproate with close clinical monitoring and caution.

    Oral dosage (valproic acid; i.e., Depakene)
    Adults, Adolescents, and Children 10 years and older

    Initially, 10 mg/kg/day to 15 mg/kg/day PO for complex partial seizures and 15 mg/kg/day PO for simple or complex absence seizures. The drug should be administered in divided doses if the total daily dose exceeds 250 mg. Increase by 5 mg/kg/day to 10 mg/kg/day at weekly intervals according to response and tolerability. The maximum daily recommended dose is 60 mg/kg/day. For most patients, optimal clinical response is achieved at doses below 60 mg/kg/day. WEIGHT-BASED GUIDE FOR TREATMENT INITIATION: 10 kg to 24.9 kg = 250 mg once daily; 25 kg to 39.9 kg = 250 mg twice daily; 40 kg to 59.9 kg = 250 mg three times daily; 60 kg to 74.9 kg = 250 mg in the morning, 250 mg in the afternoon, and 500 mg in the evening; 75 kg to 89.9 kg = 500 mg in the morning, 250 mg in the afternoon, and 500 mg in the evening. In general, use a reduced initial dosage and slower dose titration in geriatric adults. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. For patients who do not respond, measure plasma concentrations to determine whether they are within the usually accepted range (50 mcg/mL to 100 mcg/mL). When converting to valproic acid monotherapy from other anticonvulsants, the dosage of the concomitant antiepilepsy drug(s) can usually be reduced by 25% every 2 weeks. This reduction can begin at the initiation of valproic acid therapy, or delayed for 1 to 2 weeks if necessary to avoid rebound seizures.

    Children 2 to 9 years†

    Valproic acid has been administered to children as young as 2 years, but data on appropriate dosage based on age are limited. Younger children, especially those receiving concomitant enzyme-inducing anticonvulsants, may need larger maintenance doses to attain target total and unbound serum valproic acid concentrations compared to adults. Children 3 months to 10 years of age have a 50% higher clearance of valproic acid expressed on weight (mL/min/kg) than adults. Use valproic acid with close clinical monitoring and caution.

    Oral dosage (extended-release divalproex; i.e., Depakote ER)
    Adults, Adolescents, and Children 10 years and older

    Initially, 10 mg/kg/day to 15 mg/kg/day PO once daily for complex partial seizures and 15 mg/kg/day PO once daily for simple or complex absence seizures. Increase by 5 mg/kg/day to 10 mg/kg/day at weekly intervals as tolerated/necessary. The maximum daily recommended dose is 60 mg/kg/day. For most patients, optimal clinical response is achieved at doses below 60 mg/kg/day. In general, use a reduced initial dosage and slower dose titration in geriatric adults. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The final therapeutic dose should be achieved on the basis of tolerability and clinical response. For patients who do not respond, measure plasma concentrations to determine whether they are within the usually accepted range (50 mcg/mL to 100 mcg/mL). Little data exist regarding safety and efficacy of doses above 60 mg/kg/day. When converting from divalproex delayed-release tablets (Depakote) to divalproex extended-release tablets (Depakote ER), the dosage of Depakote ER should be given once daily at a dose 8% to 20% higher than the total daily dose of Depakote. Based on strength, if the Depakote dose cannot be directly converted to Depakote ER, consider increasing the Depakote total daily dose to the next higher dosage before converting to a daily dose of Depakote ER. When converting to Depakote ER monotherapy from other anticonvulsants, the dosage of the concomitant antiepilepsy drug(s) can usually be reduced by 25% every 2 weeks. This reduction can begin at the initiation of Depakote ER therapy, or can be delayed for 1 to 2 weeks if necessary to avoid rebound seizures. As with other divalproex products, doses should be individualized. If a patient requires smaller dose adjustments than that available with Depakote ER, other oral formulations should be used instead.

    Intravenous dosage (valproate sodium injection; e.g., Depacon)
    Adults, Adolescents, and Children 10 years and older

    When initiating valproate sodium as monotherapy or adjunctive therapy, give 10 mg/kg/day to 15 mg/kg/day IV. The dosage may be increased by 5 mg/kg/day to 10 mg/kg/day at weekly intervals as needed and tolerated until seizures are controlled or side effects preclude further increases. If the total daily dose exceeds 250 mg, valproate sodium should be administered in divided doses. The maximum daily recommended dose is 60 mg/kg/day. For most patients, optimal clinical response is achieved at doses below 60 mg/kg/day. In general, use a reduced initial dosage and slower dose titration in geriatric adults. CONVERSION FROM ORAL TO INTRAVENOUS THERAPY: In patients with an established oral valproic acid or divalproex regimen, give the normal oral daily dosage by the IV route with the same frequency as the oral products. In clinical trials, the daily IV dosage was administered in divided doses every 6 hours. Less frequent administration may require closer monitoring of valproate serum trough levels and clinical monitoring. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The final therapeutic dose should be achieved on the basis of tolerability and clinical response. For patients who do not respond, measure plasma concentrations to determine whether they are within the usually accepted range (50 mcg/mL to 100 mcg/mL). Little data exist regarding safety and efficacy of doses above 60 mg/kg/day. Use of intravenous valproate sodium for periods of more than 14 days has not been studied. When converting to valproate sodium monotherapy from other anticonvulsants, the dosage of the concomitant antiepilepsy drug(s) can usually be reduced by 25% every 2 weeks. This reduction can begin at the initiation of valproate sodium therapy, or delayed for 1 to 2 weeks if necessary to avoid rebound seizures.

    Children 2 to 9 years†

    Valproate sodium has been administered IV to children as young as 2 years, but data on appropriate dosage based on age are limited. Younger children, especially those receiving concomitant enzyme-inducing anticonvulsant drugs, may need larger maintenance doses to attain target total and unbound serum valproic acid concentrations compared to adults. Use valproic acid with close clinical monitoring and caution.

    For the treatment of acute mania associated with bipolar disorder, with or without psychotic features.
    Oral dosage (delayed-release divalproex (Depakote) or delayed-release valproic acid (Stavzor))
    Adults

    Initially, 750 mg/day PO, administered in divided doses. The dosage should then be increased as rapidly as possible to the lowest effective dose that produces the desired clinical effect or the desired serum concentrations. The maximum recommended dosage is 60 mg/kg/day. Although not approved by the FDA, an alternative dosing strategy for divalproex in the treatment of mania has been studied. A loading dose is implemented to attain therapeutic valproic acid levels more quickly. An initial dosage of 20 mg/kg/day PO in divided doses has been shown to produce a clinically significant response within 3 days in some cases. Alternatively, an initial loading dose of 30 mg/kg/day for 2 days, followed by 20 mg/kg/day was also shown to be safe and effective. Divalproex sodium has been shown to be superior to placebo and equivalent to lithium in the treatment of acute mania. In these studies, dosing was initiated at 250 mg of divalproex sodium PO three times daily 30 minutes after meals and titrated upwards to achieve a trough serum concentration of 50 mcg/mL to 100 mcg/mL in one study or a trough serum concentration not greater than 150 mcg/mL in another study. In a comparative study of lithium vs. divalproex monotherapy in rapid-cycling bipolar adults, the mean dose of divalproex was 1,571 mg PO daily (range 750 mg to 2,750 mg), and the mean valproate serum concentration was 77 mcg/mL. However, the rates of relapse into any mood episode for those given lithium versus divalproex were 56% and 50%, respectively. Data from divalproex clinical trials longer than 3 weeks in length are not available for guidance in long-term treatment of bipolar mania. However, it is generally agreed that extension of treatment with frequent monitoring is desirable, both for prevention and maintenance of manic episodes.

    Adolescents† and Children†

    Safety and efficacy have not been fully established. Large, well controlled clinical trials evaluating divalproex sodium monotherapy as treatment for pediatric bipolar disorder are lacking. In one small (n = 34; mean age 12.3 years), open label study divalproex sodium was given for a mixed disorder at 15 mg/kg/day to 20 mg/kg/day PO, with an initial dose of 250 mg to 500 mg PO on day 1 and increased to full dose over 1 week. Serum levels of divalproex were measured 5 days after reaching a dose that was considered tolerable and optimal, repeated at day 14 and then monthly. Dose increments were guided by tolerability, trough serum levels (50 mcg/mL to 120 mcg/mL) and clinical progress. Significant improvements from baseline were seen in the primary outcome measures (Young Mania Rating Scale and the Child Depression Rating Scale-Revised). Although large trials are lacking, clinical pediatric guideline algorithms include a recommendation of divalproex as one choice for first line monotherapy (Stage 1) treatment of nonpsychotic bipolar disorder I (manic or mixed) in children 6 years to 17 years of age. Other first line agents include: lithium, carbamazepine, olanzapine, quetiapine, and risperidone. Both the clinical experience of the provider and the side effect profile of the medication for a given child must guide initial monotherapy selection. Recommendations for divalproex in the algorithm met both the Level B and C requirements (level B data consist of adult randomized clinical trial; level C data consist of open child/adolescent trials and retrospective analysis). The panel recommended a minimum of 4 to 6 weeks at therapeutic blood levels and/or adequate dose to assess initial response. In children with psychosis, combination therapy with a mood stabilizer, such as divalproex, and an atypical antipsychotic is suggested. Additional recommendations based on response to initial monotherapy and augmentation strategies can be found within the guideline and accompanying algorithms.

    Oral dosage (extended-release divalproex; i.e., Depakote ER)
    Adults

    Initially, 25 mg/kg/day PO given once daily. Increase dose as rapidly as possible to achieve the desired clinical effect or range of plasma concentrations. Consider a reduced initial dosage and slower dose titration in geriatric adults. The maximum recommended dosage is 60 mg/kg/day PO. In one clinical trial, the Depakote ER dose was initiated at 25 mg/kg/day and increased by 500 mg/day PO on Day 3. The dose was then adjusted to clinical response with a trough plasma concentration between 85 mcg/mL and 125 mcg/mL. Depakote ER was significantly more effective than placebo in reduction of the Mania Rating Scale (MRS) total score. If a patient requires smaller doses than available with divalproex ER, other oral formulations can be used. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The final therapeutic dose should be achieved on the basis of tolerability and clinical response.

    For migraine prophylaxis.
    Oral dosage (delayed-release divalproex (Depakote) or delayed-release valproic acid (Stavzor))
    Adults 65 years of age and younger

    Initially, 250 mg PO twice daily. Titrate as needed up to a maximum of 500 mg PO twice daily. Higher doses do not appear to improve efficacy. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The final therapeutic dose should be achieved on the basis of tolerability and clinical response. There is insufficient information available to determine the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65 years of age. In a clinical study, adults (mean age 45 years) were randomized to either divalproex or placebo. Divalproex was initially administered as 250 mg PO once daily and titrated upwards over a 4-week period until the trough valproic acid serum concentration was 70 mcg/mL to 120 mcg/mL. Divalproex was then administered at a constant dose for another 8 weeks. At the end of the study, patients receiving divalproex had a lower rate of migraine frequency and a lower rate of symptom severity relative to the placebo group.

    Oral dosage (extended-release divalproex; i.e., Depakote ER)
    Adults 65 years of age and younger

    Initially, 500 mg PO once daily for 1 week, thereafter increasing to 1,000 mg PO once daily. Do not exceed 1,000 mg/day. As with other divalproex products, doses of the extended-release tablets should be individualized and dose adjustment may be necessary. If a patient requires smaller dose adjustments than that available with Depakote ER, the delayed-release tablets should be used instead. If a patient requires smaller doses than that available with Depakote ER, the delayed-release tablets should be used instead. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The final therapeutic dose should be achieved on the basis of tolerability and clinical response. There is insufficient information available to determine the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65 years of age.

    For the treatment of refractory status epilepticus†.
    NOTE: Valproate has been used for emergency treatment of seizures where other agents have failed, or, when other medications are not readily available or when phenytoin is contraindicated.
    Rectal dosage† (valproic acid, rectal dosage not commercially available in US)
    Adults

    400—600 mg PR either as an enema or in a wax base suppository.

    Children

    20 mg/kg/dose PR.

    Intravenous dosage
    Adults

    Controlled, randomized, double blind studies are not yet available; optimal regimens have not been defined. In one study, an IV loading dose of 20 mg/kg IV at a rate of 40 mg/min, was effective in terminating status epilepticus (SE) in 88% of patients receiving the drug. In another study, 102 patients received IV sodium valproate for emergent seizures (n=35 for SE), with a greater than 86% efficacy rate; most (74%) of the 102 patients received an IV bolus between 15 and 16 mg/kg , given within 5—10 min, followed by a continuous infusion (flow control pump) of a 0.5—4 mg/kg/h maintenance dosage ranging from 2 h to 10 days.

    For the treatment of persistent singultus (hiccups)†.
    Oral dosage (delayed-release divalproex (Depakote), valproic acid (Depakene), or delayed-release valproic acid (Stavzor))
    Adults

    A dose of 15 mg/kg/day PO has been used. In general, use a reduced initial dosage and slower dose titration in geriatric patients. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The final therapeutic dose should be achieved on the basis of tolerability and clinical response.

    For the treatment of severe behavioral disturbances, such as agitation†.
    For severe behavioral disturbances† (e.g., aggression, agitation†, explosive temper) occurring with attention-deficit hyperactivity disorder (ADHD)†.
    Oral dosage (delayed-release divalproex; i.e., Depakote)
    Adolescents and Children 6 years and older

    One study in children (age 10 years and older) found that divalproex titrated between 750 mg/day and 1,500 mg/day PO was effective in treating explosive temper and mood lability in disruptive youths with ADHD and other behavioral disorders. In another study, children 6 to 13 years old (n = 27) with ADHD, who remained with significant aggression despite stimulant monotherapy, were randomized to receive divalproex extended-release PO once daily. Titration began with 250 mg PO once each evening and was adjusted as needed by 250 mg increments to attain a dose of approximately 20 mg/kg/dose PO once daily by the end of week 2. Further dose adjustments followed a protocol based upon tolerability, behavioral response, and serum drug levels. The authors reported that the addition of divalproex increased the likelihood that aggression will remit vs. placebo (p< 0.05, CI=1.16 to 46.23). Larger trials are needed to confirm results due to the small study size.

    For the symptomatic treatment of acquired pendular nystagmus†.
    Oral dosage (delayed-release divalproex (Depakote), valproic acid (Depakene), or delayed-release valproic acid (Stavzor))
    Adults

    10 mg/kg/day to 60 mg/kg/day PO. It is advisable to individualize the dosage based upon clinical response and tolerability.

    For the treatment of painful diabetic neuropathy†.
    Oral dosage (delayed-release divalproex (Depakote), valproic acid (Depakene), or delayed-release valproic acid (Stavzor))
    Adults

    Initially, 250 mg PO twice daily for 1 week. Then may increase to 500 mg PO twice daily. Then, titrate to the lowest effective dose that produces the desired clinical effect. Suggested Max: 1,200 mg/day PO, given in divided doses. The American Academy of Neurology guidelines classify sodium valproate and related agents as probably effective for the treatment of painful diabetic neuropathy.

    Oral dosage (extended-release divalproex; i.e., Depakote ER)
    Adults

    Initially, 500 mg PO once daily for 1 week. Thereafter dose may be increased to 1,000 mg PO once daily. Titrate to the lowest effective dose that produces the desired clinical effect. Suggested Max: 1,000 mg/day PO, given once daily. The American Academy of Neurology guidelines classify sodium valproate and related agents as probably effective for the treatment of painful diabetic neuropathy.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    60 mg/kg/day PO or IV for the treatment of seizures; 1000 mg/day PO for migraine prophylaxis; 60 mg/kg/day PO for bipolar mania.

    Elderly

    60 mg/kg/day PO or IV for the treatment of seizures; 1000 mg/day PO for migraine prophylaxis; 60 mg/kg/day PO for bipolar mania.

    Adolescents

    >= 16 years: 60 mg/kg/day PO or IV for the treatment of seizure; 1000 mg/day PO for migraine prophylaxis; not recommended for bipolar mania.
    < 16 years: 60 mg/kg/day PO or IV for the treatment of seizure. Use in migraine prophylaxis or bipolar mania not established.

    Children

    >= 10 years: 60 mg/kg/day PO or IV for the treatment of seizure. Use in migraine prophylaxis or bipolar mania not established.
    2—9 years: Maximum dosages are not well established; use of Depakote ER not recommended; not recommended for bipolar mania.
    < 2 years: Data indicate this population is more at risk for fatal hepatotoxicity from valproic acid/divalproex sodium. Use is not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Because of the severe hepatotoxicity that may occur with valproic acid, avoid use in those with active hepatic disease/impairment. Drug clearance may be decreased by 50% in cirrhosis. Because liver dysfunction associated with valproic acid is likely dose-related, titrate dose slowly in susceptible patients. Periodic liver function tests should be performed. Discontinue if significant hepatic dysfunction is suspected or confirmed.

    Renal Impairment

    In patients with severe renal impairment or renal failure, uremia can cause an increase in the free fraction of the drug, resulting in possible toxicity. Also, unbound valproic acid in the blood may be cleared more rapidly than bound drug. Close monitoring of valproic acid serum concentrations may be warranted to ensure adequate dosage, ensure efficacy and limit toxicity.

    ADMINISTRATION

    A MedGuide will be available that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications.

    Oral Administration

    Valproic acid, valproate sodium, and divalproex sodium are administered orally.
    Although the same total daily dosage is used when switching formulations, higher peak levels may be achieved with different divalproex formulations compared to equivalent doses of valproic acid.
    If the total daily dosage exceeds 250 mg, the daily dosage should be administered in divided doses.

    Oral Solid Formulations

    Valproic acid capsules, immediate-release (Depakene)
    In order to prevent local irritation to the mouth and throat, capsules should be swallowed whole and not chewed or crushed.
    Patients should be closely monitored during the transition from brand to generic products. Rarely, breakthrough seizures have been reported.
    May be administered with food to minimize GI irritation.
     
    Divalproex sodium (Depakote Sprinkle Capsules)
    Sprinkle capsules may be swallowed intact. Alternatively, the capsule contents may be sprinkled on a small amount (roughly 5 ml) of semisolid food (e.g., applesauce, pudding) immediately before swallowing. Do not chew the sprinkle and food mixture. Drinking water after taking the preparation will ensure the entire dose has been swallowed. If any of the contents are spilled while opening the capsule, begin with a new capsule and portion of food.
    Use any food-drug mixture immediately after preparation; do not store for future use.
    Dosage is expressed in terms of valproic acid.
     
    Divalproex sodium (Depakote delayed-release Tablets)
    May be administered with food to minimize GI irritation.
    Tablets are enteric-coated and should be swallowed whole. Do not cut, chew, or crush.
    Dosage is expressed in terms of valproic acid.
     
    Divalproex sodium (Depakote ER Tablets)
    NOTE: Depakote ER tablets are not bioequivalent to Depakote delayed-release tablets.
    May be administered with food to minimize GI irritation.
    Tablets should be swallowed whole. Do not cut, chew, or crush.
    Dosage is expressed in terms of valproic acid.

    Oral Liquid Formulations

    Valproate sodium (Depakene Syrup)
    Do not mix oral solution with carbonated beverages because valproic acid will be liberated and may cause an unpleasant taste as well as local irritation to the mouth and throat.
    May be administered with food to minimize GI irritation.
    Dosage is expressed in terms of valproic acid.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Valproate sodium is administered intravenously.
    The total daily dose and frequency of oral and IV dosages are equivalent. Note that clinical studies comparing the oral and IV products were conducted using a six hour dosing frequency for each product. If the total daily dose exceeds 250 mg, the IV dosage should be given in a divided regimen.
    Serum valproic acid concentrations should be monitored and dosage adjustments made if necessary.
    Patients receiving doses near the maximum recommended daily dose of 60 mg/kg/day IV, particularly those not receiving enzyme-inducing drugs, should be monitored more closely.
     
    Intravenous dosage preparation
    Use aseptic technique to prepare dosage.
    Dilute prescribed dose with at least 50 ml of a compatible sterile diluent for IV administration. Compatible diluents include D5W, NS, and Lactated Ringer's injection.
     
    Intravenous infusion administration
    Administer dosage as an IV infusion over 60 minutes. The recommended infusion rate is generally 20 mg/min. Faster infusion rates of valproate sodium (Depacon) have been studied in a separate clinical safety trial; 112 patients with epilepsy were given infusions of up to 15 mg/kg IV over 5 to 10 minutes (1.5—3 mg/kg/min). Patients generally tolerated the more rapid infusions well; however, the incidence of adverse events may be higher than with the standard infusion rate (see Adverse Reactions). The efficacy of faster infusion rates versus the standard rate has not been determined. Use of the standard infusion rate is recommended unless the faster infusion rate is deemed medically necessary.

    Rectal Administration

    NOTE: Valproic acid is not approved by the FDA for rectal administration.
    Valproic acid syrup may be diluted 1:1 with water for use as a retention enema.

    STORAGE

    Depacon:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Depakene:
    - Avoid excessive humidity
    - Protect from light
    - Protect from moisture
    - Store at room temperature (between 59 to 86 degrees F)
    Depakote:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Depakote ER:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Stavzor:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Valproic acid and its analogs are partially eliminated in the urine as a keto-metabolite. This may lead to false interpretation of the urine ketone test. In addition, there have been reports of altered thyroid function tests associated with these drugs. The clinical significance of these laboratory interferences is unknown.

    Encephalopathy

    Valproic acid and its analogs are contraindicated in patients with known urea cycle disorders (UCD). Patients with UCD have a genetic enzyme defect leading to an impaired ability to produce urea. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with known or suspected UCD. Clinical signs of UCD include hyperammonemia, encephalopathy, and respiratory alkalosis. Patients who develop signs and symptoms consistent with UCD should be promptly evaluated with discontinuation of valproate therapy. Refer to the manufacturers labeling for additional information detailing patient evaluation of UCD prior to initiation of these drugs. Concomitant administration of topiramate and valproic acid has also been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone.

    Serious rash

    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking valproic acid and its analogs. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, serious rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Other serious hypersensitivity or rashes have been reported, including anaphylaxis, erythema multiforme, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome (SJS). If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established.

    Mitochondrial disease

    Valproic acid and its analogs are contraindicated in patients known to have a mitochondrial disease caused by mutations in mitochondrial DNA polymerase gamma (POLG; e.g., Alpers-Huttenlocher Syndrome) and pediatric patients less than 2 years of age who are suspected of having a POLG-related disorder. The risk of valproate-induced acute liver toxicity, hepatic failure, and death is increased in patients with hereditary neurometabolic syndromes caused by this mutation. Most of the reported cases of hepatic failure in patients with these syndromes have been identified in children and adolescents. POLG mutation screening should be performed in accordance with current clinical practice. POLG-related disorders should be suspected in patients with a family history or symptoms suggestive of a POLG-related disorder (e.g., unexplained encephalopathy, refractory epilepsy (focal, myoclonic), developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura). The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. In patients more than 2 years of age clinically suspected of having a hereditary mitochondrial disease, only use valproic acid if other anticonvulsants have failed and with close monitoring for the development of acute liver injury.

    Carnitine deficiency, hepatic disease, hepatotoxicity, hypoalbuminemia, organic brain syndrome

    Valproic acid and its analogs are hepatotoxic and are contraindicated in patients with hepatic disease or significant hepatic dysfunction. Use with extreme caution in patients with a prior history of hepatic disease. Hepatotoxicity, including hepatic failure, has been fatal and may more commonly occur in the first 6 months of treatment. Because carnitine deficiency may promote hepatotoxicity, valproate should be avoided in patients with inborn errors of carnitine metabolism. Liver function tests (LFTs) should be performed before therapy and at frequent intervals for patients at risk, especially during the first 6 months of therapy. Clinicians should not completely rely on serum biochemistry since these LFTs may not always be abnormal, but should also consider the results of a detailed medical history and physical examination. In some instances, hepatotoxicity progressed even after the drug was discontinued. Patients with organic brain syndrome, congenital metabolic disorders, severe seizures or a severe seizure disorder accompanied by mental retardation, on multiple anticonvulsants, and pediatric patients less than 2 years of age may be at highest risk for hepatotoxicity. Valproic acid also should be dosed carefully in patients with hypoalbuminemia because protein binding is reduced, which can increase the likelihood for drug-induced toxicity. There is an increased risk of valproate-induced acute hepatic failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase gamma (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproic acid and its analogs are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and pediatric patients under 2 years of age who are clinically suspected of having a mitochondrial disorder. POLG mutation screening should be performed in accordance with current clinical practice.

    Pancreatitis

    Cases of life-threatening pancreatitis have been reported in both pediatric and adult patients receiving valproic acid or its analogs. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after re-challenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

    Children, infants, neonates

    Valproic acid is not FDA-approved for the treatment of bipolar disorder in children, although some clinical pediatric guideline algorithms include a recommendation for use of divalproex in children as young as 6 years of age. Safety and efficacy of valproic acid for epilepsy is not established in pediatric patients less than 10 years of age, and use for migraine prophylaxis has not been established in those less than 16 years of age. Children less than 2 years of age (including infants and neonates) have an increased risk of developing fatal hepatotoxicity when given valproic acid or its analogs for the treatment of epilepsy; when used in this patient population, valproate should be used as the sole agent and with extreme caution. As children get older, the risk of fatal hepatotoxicity decreases considerably. Liver-function tests (LFTs) should be performed before therapy and at frequent intervals for patients at risk, especially during the first 6 months of therapy. Pediatric patients with organic brain syndrome, congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, and on multiple anticonvulsants are most at risk from hepatotoxicity. Hepatotoxicity of this type usually occurs during the first 6 months of therapy. Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. Children 3 months to 10 years of age have a 50% higher clearance of valproic acid expressed on weight (i.e., mL/minute/kg) than adults. Variability in the free fraction of valproic acid limits the usefulness of therapeutic drug monitoring; therefore interpretation of valproic acid concentrations in pediatric patients should take into account factors that affect hepatic metabolism and protein binding.

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Bleeding, coagulopathy, surgery, thrombocytopenia

    Valproic acid and its analogs are associated with dose-related thrombocytopenia. Valproate use has also been associated with decreases in other cell lines and myelodysplasia. Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters (e.g., coagulopathy due to low fibrinogen), complete blood counts (CBC) and coagulation tests are recommended before initiating valproic acid therapy and at periodic intervals. It is recommended that patients receiving valproate be monitored for CBC and coagulation parameters prior to planned surgery and if a woman is pregnant. Evidence of bleeding, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.

    Renal failure, renal impairment

    Valproic acid should be used with caution in patients with severe renal impairment or renal failure, because uremia can cause increased free fraction of drug, resulting in possible toxicity. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (CrCl less than 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no specific dosage adjustment appears to be necessary in patients with renal failure who are receiving dialysis.

    Human immunodeficiency virus (HIV) infection

    In vitro studies suggest valproate and its analogs stimulate the replication of the HIV and cytomegalovirus (CMV) viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in patients with human immunodeficiency virus (HIV) infection receiving valproate or when following CMV-infected patients clinically.

    Driving or operating machinery, ethanol ingestion

    Valproic acid can cause dizziness and drowsiness. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether valproic acid adversely affects their mental and/or motor performance. Valproate products may produce CNS depression, especially when combined with another CNS depressant, such as with ethanol ingestion.

    Colostomy, diarrhea, ileostomy

    There have been rare reports of medication residue in the stool associated with some oral solid formulations of valproic acid, divalproex sodium. Some reports have been in patients with anatomic (e.g., ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. Other reports have occurred in patients with diarrhea. Check plasma valproate levels in patients who experience medication residue in the stool, and monitor the patient's clinical condition. Consider alternative treatment if clinically indicated.

    Head trauma

    Valproate should not be used in patients with acute head trauma for the prophylaxis of post-traumatic seizures. In a study comparing intravenous valproate and phenytoin in such patients, the incidence of death was found to be higher in the valproate groups (13%) compared to the phenytoin group (8.5%). Although the study was not placebo-controlled and many of the patients were critically ill with multiple severe injuries, FDA-approved labeling advises against the use of valproate for this indication until further information is available.

    Abrupt discontinuation

    Unless severe adverse reactions warrant, abrupt discontinuation of valproic acid therapy should not be undertaken in patients with seizure disorders. Antiepileptic drugs should be withdrawn gradually to minimize the potential of increased seizure frequency. If adverse reactions are of such severity that valproic acid must be discontinued, the practitioner must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to drug withdrawal seizures or even status epilepticus.

    Contraception requirements, pregnancy, reproductive risk

    Valproic acid and its analogs are contraindicated for use during pregnancy when the drug is being used for migraine prophylaxis. Valproic acid is not appropriate for migraine prophylaxis during pregnancy, as use is not considered necessary to prevent permanent injury or death. For the treatment of epilepsy and manic episodes associated with bipolar disorder, valproic acid valproate products should only be prescribed during pregnancy for these conditions if other alternative medications are not acceptable or not effective for treating the condition. Valproic acid and its derivatives are associated with reproductive risk. In utero exposure to valproate can cause major congenital malformations, including neural tube defects (e.g., spina bifida), craniofacial defects, cardiovascular malformations, hypospadias, and limb malformations. Some of the malformations are fatal. Additionally, fetal exposure may cause decreased IQ scores, cerebral atrophy, developmental delay, and autism and/or autism spectrum disorders. The strongest association is with maternal valproic acid use and neural tube defects, particularly when the drug is taken during the first trimester. It is unknown whether folic acid reduces the risk of neural tube defects in pregnant women receiving valproic acid; however, routine folic acid intake should be implemented during pregnancy regardless of therapy with the drug because studies in the general population show that folic acid intake prior to conception and during early pregnancy reduces the risk of neural tube defects. About 1 in 1,500 babies is born with a neural tube defect in the U.S. The risk of neural tube defects in babies born to mothers treated with valproate during the first 12 weeks of pregnancy is 1 in 20 babies. The CDC has estimated the risk for spina bifida in children exposed to valproic acid during gestation to be approximately 1% to 2% versus 0.14% to 0.2% in the general population. Data collected from the North American Antiepileptic Drug Pregnancy Registry suggest a 4-fold increased incidence of congenital malformations with valproic acid monotherapy during the first trimester compared to all other antiepileptic drug (AED) monotherapies as a group. Results from a prospective, multi-center, long-term, observational study of fetal death and malformations during in utero exposure to phenytoin, carbamazepine, lamotrigine, or valproate indicate that valproate poses the greatest risk for serious adverse outcomes. Enrollment was limited to pregnant women receiving monotherapy with one of the four agents for epilepsy. The outcomes of 333 infants were analyzed. The total percentages of serious adverse outcomes (fetal death or congenital malformations) were as follows: lamotrigine 1%, carbamazepine 8.2%, phenytoin 10.7%, and valproate 20.3%. Fetal deaths occurred in 3.6% of the carbamazepine and phenytoin groups, 2.9% of the valproate group, and no deaths occurred with lamotrigine. Congenital malformations were reported as follows: lamotrigine 1%, carbamazepine 4.5%, phenytoin 7.1%, and valproate 17.4%. Congenital malformations in the valproate group included brachycephaly, coarctation of the aorta, hypoplastic right heart, atrial septal defect, hydronephrosis, undescended testes, hypospadias, cleft palate, dysplastic ribs, two thumbs on right hand and a third nipple, and pulmonary stenosis. Valproate demonstrated a dose-dependent effect for adverse outcomes. In May 2013, the FDA notified healthcare professionals of an increased risk of lower cognitive test scores in children exposed to valproate and related products (valproic acid and divalproex sodium) during pregnancy. The data come from the Neurodevelopmental Effects of Antiepileptic Drugs epidemiologic study in which cognitive tests were performed on children exposed to monotherapy with antiepileptic drugs in utero. At age 6, the average IQ difference between children exposed to valproic acid and those exposed to either carbamazepine, lamotrigine, or phenytoin varied between 8 to 11 points. The long-term effects on cognitive development after exposure to valproate during pregnancy are not known. The occurrence of these effects if exposure to valproate is limited to less than the full duration of pregnancy, such as only to the first trimester, is also unknown. In a population-based cohort study (n = 655,615) with long-term follow-up of children with or without prenatal exposure to valproate, a significantly increased risk of autism was observed. In this cohort, 5,437 children were identified with autism spectrum disorder and 2,067 with childhood autism. The absolute risk of autism spectrum disorder or childhood autism was 1.53% and 0.48%, respectively. Of the 508 children with in utero exposure to valproate, the absolute risk was 4.42% for autism spectrum disorder and 2.5% for childhood autism. The therapeutic benefit of valproic acid in women of childbearing age should be carefully weighed against the risk for injury to the fetus, particularly during the first trimester of pregnancy. If the patient is taking the drug to prevent major seizures, the medical necessity of continuing valproic acid versus changing to an alternate agent should be assessed if the woman is planning to become pregnant. Determinations should be made on an individual basis, since seizures resulting from a change in therapy may pose more of a threat to both the mother and the fetus than continued therapy with valproic acid. Women of child-bearing potential should be carefully counseled on the possible fetal risks of valproic acid treatment for any indication during pregnancy, instructed in the contraception requirements and use of effective contraception, and informed of the importance of reporting a pregnancy to their health care provider as soon as possible. It is advisable to conduct tests for detection of neural tube and other defects as part of prenatal care in pregnant women receiving the drug. Women who took valproate during pregnancy should be instructed to inform their child's pediatrician of the exposure. Other adverse effects which have occurred during pregnancy include a woman with low fibrinogen taking multiple anticonvulsants whose infant died from hemorrhage secondary to afibrinogenemia; valproate products are known to cause dose-related thrombocytopenia. The manufacturer recommends careful periodic monitoring of complete blood counts (CBC) and clotting parameters if valproate must be used during pregnancy. Physicians are advised to recommend that pregnant patients receiving valproic acid enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    Breast-feeding

    Valproic acid and its analogs are excreted in human milk. Caution should be exercised when valproate is administered to a lactating woman. Valproic acid is excreted into breast milk with reported concentrations of 1% to 10% that of serum concentrations. One case of thrombocytopenia and anemia has been reported in a 3 month old breast-fed infant whose mother was receiving valproic acid 1,200 mg/day as monotherapy for epilepsy. The thrombocytopenia and anemia resolved approximately a month after the mother discontinued breast-feeding. The infant's serum valproic acid concentration was 6.6 mcg/mL. If use is necessary to the mother, consideration could be given to monitoring infant exposure by measuring infant serum concentrations. Monitor the infant clinically for bleeding, possible liver toxicity, or excessive somnolence. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Geriatric patients (particularly those more than 68 years of age) are more likely to have reduced valproic acid clearance and higher serum concentrations of free valproic acid and thus the geriatric patient may require initial dosing reductions or close monitoring of serum concentrations. A significantly higher proportion of elderly patients with dementia receiving valproate had somnolence and discontinuation due to somnolence when compared to placebo. In elderly patients, valproic acid/divalproex dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events which are more commonly seen in elderly patients. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. No patients older than 65 years old were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were more than 65 years of age. A higher percentage of these elderly patients reported accidental injury, infection, pain, somnolence, and tremor. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among the elderly. No particular safety concerns were noted in clinical trials of valproate among the elderly patients (n = 21) in clinical trials pre-approval. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If valproic acid or divalproex must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). The need for indefinite continuation in treating any condition should be based on confirmation of the condition and its potential cause(s). Periodic assessment of drug concentrations and evaluation of symptoms should be used to adjust doses. Significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    ADVERSE REACTIONS

    Severe

    hematemesis / Delayed / 1.1-5.0
    pancreatitis / Delayed / 1.1-5.0
    tardive dyskinesia / Delayed / 1.1-5.0
    lupus-like symptoms / Delayed / 1.1-5.0
    hearing loss / Delayed / 1.1-5.0
    erythema nodosum / Delayed / 1.0
    arrhythmia exacerbation / Early / 1.0
    suicidal ideation / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    porphyria / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    coma / Early / Incidence not known
    vasculitis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    afibrinogenemia / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    bone fractures / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    Fanconi syndrome / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known

    Moderate

    thrombocytopenia / Delayed / 1.0-27.0
    peripheral edema / Delayed / 1.1-8.0
    nystagmus / Delayed / 1.0-7.0
    confusion / Early / 1.1-5.0
    amnesia / Delayed / 1.1-5.0
    depression / Delayed / 1.1-5.0
    glossitis / Early / 1.1-5.0
    constipation / Delayed / 1.1-5.0
    stomatitis / Delayed / 1.1-5.0
    fecal incontinence / Early / 1.1-5.0
    elevated hepatic enzymes / Delayed / 1.1-5.0
    hypertonia / Delayed / 1.1-5.0
    ataxia / Delayed / 1.1-5.0
    dysarthria / Delayed / 1.1-5.0
    hyperreflexia / Delayed / 1.1-5.0
    furunculosis / Delayed / 1.1-5.0
    palpitations / Early / 1.1-5.0
    orthostatic hypotension / Delayed / 1.1-5.0
    chest pain (unspecified) / Early / 1.1-5.0
    peripheral vasodilation / Rapid / 0.9-5.0
    sinus tachycardia / Rapid / 1.1-5.0
    hypertension / Early / 1.1-5.0
    hypotension / Rapid / 1.1-5.0
    vaginal bleeding / Delayed / 1.1-5.0
    myasthenia / Delayed / 1.1-5.0
    dyspnea / Early / 1.0-5.0
    blurred vision / Early / 1.1-5.0
    amblyopia / Delayed / 1.1-5.0
    conjunctivitis / Delayed / 1.1-5.0
    cystitis / Delayed / 1.1-5.0
    urinary incontinence / Early / 1.1-5.0
    vaginitis / Delayed / 1.1-5.0
    dysuria / Early / 1.1-5.0
    edema / Delayed / 1.1-5.0
    euphoria / Early / 0-0.9
    dysphagia / Delayed / 1.0
    oral ulceration / Delayed / 1.0
    bullous rash / Early / 1.0
    photophobia / Early / 1.0
    hostility / Early / Incidence not known
    psychosis / Early / Incidence not known
    hallucinations / Early / Incidence not known
    gastritis / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperammonemia / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    anemia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    lymphocytosis / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    impaired cognition / Early / Incidence not known
    pseudoparkinsonism / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    infusion-related reactions / Rapid / Incidence not known
    infertility / Delayed / Incidence not known
    vitamin D deficiency / Delayed / Incidence not known
    folate deficiency / Delayed / Incidence not known

    Mild

    nausea / Early / 3.2-34.0
    drowsiness / Early / 1.1-26.0
    diarrhea / Early / 0.9-23.0
    vomiting / Early / 1.3-23.0
    dyspepsia / Early / 7.0-23.0
    asthenia / Delayed / 6.0-20.0
    diplopia / Early / 16.0-16.0
    insomnia / Early / 1.1-15.0
    oligomenorrhea / Delayed / 14.0-14.0
    abdominal pain / Early / 1.1-12.0
    dizziness / Early / 1.1-12.0
    anorexia / Delayed / 1.1-11.0
    weight gain / Delayed / 1.1-9.0
    tremor / Early / 1.1-9.0
    back pain / Delayed / 1.1-8.0
    pharyngitis / Delayed / 0.6-8.0
    alopecia / Delayed / 1.1-7.0
    amenorrhea / Delayed / 1.1-7.0
    appetite stimulation / Delayed / 1.1-6.0
    rash / Early / 1.1-6.0
    emotional lability / Early / 1.1-5.0
    agitation / Early / 1.1-5.0
    anxiety / Delayed / 1.1-5.0
    dysgeusia / Early / 1.1-5.0
    eructation / Early / 1.1-5.0
    flatulence / Early / 1.1-5.0
    xerostomia / Early / 1.1-5.0
    ecchymosis / Delayed / 1.1-5.0
    petechiae / Delayed / 1.1-5.0
    paresthesias / Delayed / 0.9-5.0
    vertigo / Early / 1.1-5.0
    pruritus / Rapid / 1.1-5.0
    seborrhea / Delayed / 1.1-5.0
    xerosis / Delayed / 1.1-5.0
    maculopapular rash / Early / 1.1-5.0
    dysmenorrhea / Delayed / 1.1-5.0
    menstrual irregularity / Delayed / 1.1-5.0
    muscle cramps / Delayed / 1.1-5.0
    myalgia / Early / 1.1-5.0
    arthropathy / Delayed / 1.1-5.0
    fever / Early / 1.1-5.0
    epistaxis / Delayed / 1.1-5.0
    influenza / Delayed / 1.1-5.0
    cough / Delayed / 1.1-5.0
    infection / Delayed / 1.1-5.0
    rhinitis / Early / 1.1-5.0
    sinusitis / Delayed / 1.1-5.0
    otalgia / Early / 1.1-5.0
    ocular pain / Early / 1.1-5.0
    tinnitus / Delayed / 1.0-5.0
    xerophthalmia / Early / 1.1-5.0
    increased urinary frequency / Early / 1.1-5.0
    malaise / Early / 1.1-5.0
    headache / Early / 4.3-4.3
    hirsutism / Delayed / 3.0-3.0
    injection site reaction / Rapid / 2.4-2.6
    hyperhidrosis / Delayed / 0.9-0.9
    hypoesthesia / Delayed / 0.6-0.6
    vesicular rash / Delayed / 1.0
    chills / Rapid / 1.0
    hiccups / Early / 1.0
    hyperactivity / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    hypothermia / Delayed / Incidence not known
    lethargy / Early / Incidence not known
    macrocytosis / Delayed / Incidence not known
    asterixis / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    hair discoloration / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    weakness / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Concomitant administration of valproic acid and oral zidovudine may result in increase in the area under the concentration-time curve of zidovudine and a decrease in the AUC of its glucuronide metabolite. This interaction does not appear to be clinically significant unless the patient is experiencing hematologic toxicities. The dose of zidovudine may be reduced in patients who are experiencing pronounced anemia while receiving chronic coadministration of zidovudine and valproic acid.
    Acetaminophen; Butalbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Tramadol: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL 2 may affect CNS function significantly.Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psyhcotropic activity, such as valproic acid. Also, Aldesleukin may alter hepatic function, and this effect can be additive with other drugs that might cause hepatotoxicity. Use with caution.
    Alfentanil: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
    Aluminum Hydroxide: (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide.
    Aluminum Hydroxide; Magnesium Carbonate: (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide.
    Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Antacids containing magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation. (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Antacids containing magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation. (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide.
    Aluminum Hydroxide; Magnesium Trisilicate: (Minor) Antacids containing the combination of magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation while taking valproic acid and aluminum hydroxide.
    Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. In addition, administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers who received valproate orally (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare post-marketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received; but, concurrent use has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline; a reduction in the dose of amitriptyline may be required.
    Amitriptyline; Chlordiazepoxide: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. In addition, administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers who received valproate orally (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare post-marketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received; but, concurrent use has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline; a reduction in the dose of amitriptyline may be required.
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Telmisartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amobarbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like amobarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered.
    Amphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue the amphetamine.
    Amphetamine; Dextroamphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue the amphetamine.
    Amphetamines: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue the amphetamine.
    Apalutamide: (Moderate) Monitor valproic acid concentrations and watch for decreased efficacy if coadministration with apalutamide is necessary. Valproic acid is a CYP2C9 substrate as well as a substrate of UGT1A4 and 2B7. Apalutamide is a weak CYP2C9 inducer and may also be a UGT inducer.
    Aprepitant, Fosaprepitant: (Minor) Use caution if valproic acid, divalproex sodium and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of valproic acid. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Valproic acid is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant. Valproic acid is also a weak in vitro CYP3A4 inhibitor / inducer, and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    Aripiprazole: (Minor) When administered with valproic acid the Cmax of aripiprazole is decreased by 25%. This interaction does not appear to cause clinically relevant effects and therefore no dosage adjustments are required.
    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butalbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Atazanavir: (Major) Caution is warranted when atazanavir is administered with valproic acid as there is a potential for elevated valproic acid concentrations and altered concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. In addition valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; atazanavir is a CYP3A4 substrate.
    Atazanavir; Cobicistat: (Major) Caution is warranted when atazanavir is administered with valproic acid as there is a potential for elevated valproic acid concentrations and altered concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. In addition valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; atazanavir is a CYP3A4 substrate. (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Valproic acid inhibits phenobarbital metabolism, and most likely the metabolism of other barbiturates. Valproic acid decreases the plasma and metabolic clearance of phenobarbital. Phenobarbital renal clearance is not affected by valproic acid. Lower doses of phenobarbital may be necessary if valproic acid is added. One study showed that phenobarbital concentrations increased by 51% in adults and 112% in children when valproic acid was added, thus, the age of the patient should be considered when managing this drug interaction. Also, CNS depression can be additive even without elevations of phenobarbital concentrations. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased when appropriate.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Valproic acid inhibits phenobarbital metabolism, and most likely the metabolism of other barbiturates. Valproic acid decreases the plasma and metabolic clearance of phenobarbital. Phenobarbital renal clearance is not affected by valproic acid. Lower doses of phenobarbital may be necessary if valproic acid is added. One study showed that phenobarbital concentrations increased by 51% in adults and 112% in children when valproic acid was added, thus, the age of the patient should be considered when managing this drug interaction. Also, CNS depression can be additive even without elevations of phenobarbital concentrations. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased when appropriate.
    Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Benzphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue the amphetamine.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupropion: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Bupropion; Naltrexone: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Butabarbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like butabarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Calcium Carbonate: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation.
    Calcium Carbonate; Magnesium Hydroxide: (Minor) Antacids containing magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation. (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation.
    Calcium Carbonate; Risedronate: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation.
    Calcium Carbonate; Simethicone: (Minor) Antacids may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation.
    Cannabidiol: (Major) Consider discontinuation or dose reduction of valproate and/or cannabidiol during coadministration. Coadministration may increase the incidence of liver enzyme elevations. Additionally, both drugs are CNS depressants and additive sedation and somnolence may occur.
    Capecitabine: (Moderate) Use caution if coadministration of capecitabine with valproic acid, divalproex sodium is necessary, and monitor for an increase in valproic acid-related adverse reactions. Valproic acid is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Carbamazepine: (Major) Carbamazepine induces hepatic microsomal enzyme activity and can increase the clearance of valproic acid (or divalproex) and decrease valproic acid serum concentrations, an interaction that is clinically significant in practice and may result in reduction in valproic acid efficacy. Clearance of valproic acid may double. Valproic acid may also decrease the metabolism of the active metabolite of carbamazepine, carbamazepine10,11-epoxide, by inhibition of epoxide hydrolase, which is the enzyme responsible for converting carbamazepine10,11-epoxide to an inactive end metabolite. Carbamazepine10,11-epoxide is more hepatotoxic than the parent drug and can be especially problematic for children, causing vomiting and tiredness. Carbamazepine-10,11-epoxide serum concentrations have been elevated by 45% when coadministered with valproate. Careful monitoring of both valproic acid and carbamazepine serum concentrations, along with the patient's clinical response may be necessary when one agent is added to the other.
    Carbapenems: (Major) Concomitant use of carbapenems (doripenem, ertapenem, imipenem, meropenem) and valproic acid is not recommended. If the drugs are coadministered and serum valproic acid concentrations cannot be maintained or if seizures occur, alternative antibacterial or anticonvulsant therapy should be considered. Carbapenems can reduce serum concentrations of valproic acid to subtherapeutic levels when the two drugs are administered together. The exact mechanism of this interaction is not known, however, based on in vitro and animal data, inhibition of valproic acid glucuronide hydrolysis is a suggested mechanism. A retrospective study evaluated the interaction between meropenem and valproate and reported an average reduction of 66% in plasma valproate concentrations. The study also reported that electroclinical deterioration was present in 55% of patients. Case studies have reported ertapenem causing decreases in valproic acid and divalproex serum concentrations when ertapenem was added to their regimen; discontinuation of ertapenem resulted in increased valproic acid concentrations. Doripenem has been shown to reduce the valproic acid AUC by 63% when coadminstered in healthy volunteers.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cholestyramine: (Major) One small study in 6 healthy volunteers suggested that cholestyramine can impair the oral bioavailability of valproic acid, divalproex sodium. Concurrent administration reduced valproic acid plasma concentrations by a mean of 14%, however, intersubject variability was large. Separating the dosing of valproic acid, divalproex sodium and cholestyramine by 3 hours may lessen the interaction.
    Citalopram: (Minor) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with valproic acid, a weak CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors.
    Clarithromycin: (Minor) Postmarketing reports of interactions with coadministration of clarithromycin and valproic acid have been noted. The clarithromycin manufacturer recommends caution if coadministered.
    Clomipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently.
    Clonazepam: (Moderate) Although concomitant use of clonazepam and valproic acid has been reported to produce absence status, this combination also has been used successfully in treating refractory seizures in children. This combination should be used only when the benefits outweigh the risks.
    Clozapine: (Moderate) Until more data become available, it is advisable to monitor for effectiveness of clozapine as well as evidence of side effects during concurrent use of valproic acid. One study documented an average decrease in clozapine concentrations of 41% during combined use, while others report minor increases in clozapine serum concentrations. The mechanism by which this apparent pharmacokinetic interaction occurs is not clear, since valproic acid is not an established inhibitor or inducer of the primary CYP isoenzymes responsible for clozapine metabolism, and the protein binding characteristics of the two agents differ. No adverse outcomes were reported in association with these studies; however, further investigation is needed to establish clinical relevance. In a separate case, one patient experienced sedation, confusion, disorientation, and slurred speech when clozapine was added to a regimen of valproic acid and lithium; discontinuation of valproic acid with subsequent re-initiation produced similar symptoms. The authors suggest the CNS properties of valproic acid and clozapine as one possible explanation; however, the exact cause of the reaction cannot be determined with the available information. Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, have occurred when clozapine was coadministered with valproic acid or divalproex sodium. Although clozapine is associated with a well-established risk of seizures, the benefits and risks of continuing clozapine with anticonvulsant therapy must be considered in a patient whose psychiatric sypmtoms have improved substantially while taking clozapine. Clinicians should also monitor for weight gain and sedation during combination therapy with clozapine and valproic acid. In addition, the risk for adverse hematologic effects such as neutropenia may theoretically be increased during concomitant use of these agents.
    Cobicistat: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and valproic acid, divalproex sodium is necessary, use caution and monitor for decreased efficacy of cobimetinib as well as increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and valproic acid is a both a weak in vitro inhibitor and inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Additionally, in healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers or inhibitors; exposure to cobimetinib may be affected unpredictably if coadministered with valproic acid.
    Codeine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Promethazine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of valproic acid. To minimize potential for interactions, consider administering oral anticonvulsants such as valproic acid or divalproex sodium at least 1 hour before or at least 4 hours after colesevelam.
    Conjugated Estrogens: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Conjugated Estrogens; Bazedoxifene: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Cyclophosphamide: (Minor) Use caution if cyclophosphamide is used concomitantly with valproic acid, divalproex sodium, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Valproic acid is a moderate CYP2C9 inhibitor, a weak CYP2C19 inhibitor, and a weak inducer/inhibitor of CYP3A4; conversion of cyclophosphamide to its active or toxic metabolites may be affected. It is not yet clear what effects CYP2C9, 2C19, or 3A4 inhibitors, or CYP450 inducers, have on the activation and/or toxicity of cyclophosphamide.
    Darunavir: (Major) Caution is warranted when darunavir is administered with valproic acid as there is a potential for altered concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; darunavir is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. (Major) Caution is warranted when darunavir is administered with valproic acid as there is a potential for altered concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; darunavir is a CYP3A4 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. (Major) Caution is warranted when darunavir is administered with valproic acid as there is a potential for altered concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; darunavir is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of valproic acid with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered valproic acid plasma concentrations and decreased concentrations of dasabuvir, ombitasvir, paritaprevir, and ritonavir. Valproic acid is an inducer of the drug transporter P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp, while ritonavir, paritaprevir, and dasabuvir (minor) are partially metabolized by CYP3A4. In addition, in a case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. Caution and close monitoring are advised if these drugs are administered together. (Major) In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp.
    Desipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently.
    Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as valproic acid, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dextroamphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue the amphetamine.
    Diazepam: (Minor) The administration of valproic acid to patients receiving diazepam can cause an increase in diazepam serum concentrations. If therapeutic effect is altered in patients receiving these medications, an alternative anticonvulsant should be instituted.
    Dienogest; Estradiol valerate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Doripenem: (Major) Concomitant use of carbapenems (doripenem, ertapenem, imipenem, meropenem) and valproic acid is not recommended. If the drugs are coadministered and serum valproic acid concentrations cannot be maintained or if seizures occur, alternative antibacterial or anticonvulsant therapy should be considered. Carbapenems can reduce serum concentrations of valproic acid to subtherapeutic levels when the two drugs are administered together. The exact mechanism of this interaction is not known, however, based on in vitro and animal data, inhibition of valproic acid glucuronide hydrolysis is a suggested mechanism. A retrospective study evaluated the interaction between meropenem and valproate and reported an average reduction of 66% in plasma valproate concentrations. The study also reported that electroclinical deterioration was present in 55% of patients. Case studies have reported ertapenem causing decreases in valproic acid and divalproex serum concentrations when ertapenem was added to their regimen; discontinuation of ertapenem resulted in increased valproic acid concentrations. Doripenem has been shown to reduce the valproic acid AUC by 63% when coadminstered in healthy volunteers.
    Doxepin: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Increased concentrations of doxepin are also possible. Valproic acid inhibits CYP2C9; doxepin is a CYP2C9 substrate. Monitor patients closley when taking doxepin with valproic acid; the dose of doxepin may need to be reduced.
    Doxorubicin: (Major) In vitro, valproic acid, divalproex soidum is a mild CYP3A4 and P-glycoprotein (P-gp) inducer; it is also a mild CYP3A4 inhibitor. Doxorubicin is a major substrate of CYP2D6, CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of valproic acid and doxorubicin if possible. If not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with valproic acid, divalproex sodium is necessary, and monitor for changes in the efficacy or adverse effect profile of dronabinol (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate. Valproic acid is a moderate inhibitor of CYP2C9 as well as a weak inhibitor and inducer (in vitro) of CYP3A4. Concomitant use may result in altered plasma concentrations of dronabinol.
    Drospirenone; Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) High doses of folate may cause decreased serum concentrations of valproic acid, divalproex sodium resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with valproic acid. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity. (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Elbasvir; Grazoprevir: (Major) If possible, avoid concurrent administration of elbasvir with valproic acid, divalproex sodium. Use of these drugs together may cause changes in the plasma concentrations of elbasvir, which could result in decreased virologic response or adverse reactions (i.e., hepatotoxicity). Valproic acid is an inhibitor and inducer of CYP3A; elbasvir is a substrate of CYP3A. (Major) If possible, avoid concurrent administration of grazoprevir with valproic acid, divalproex sodium. Use of these drugs together may cause changes in the plasma concentrations of grazoprevir, which could result in decreased virologic response or adverse reactions (i.e., hepatotoxicity). Valproic acid is an inhibitor and inducer of CYP3A; grazoprevir is a substrate of CYP3A.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of valproic acid and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of valproic acid and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. Valproic acid is a weak CYP3A4 inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration with CYP3A4 inhibitors, such as valproic acid, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Enzalutamide: (Moderate) Monitor valproic acid concentrations and watch for decreased efficacy if coadministration with enzalutamide is necessary. Valproic acid is a CYP2C9 substrate and enzalutamide is a moderate CYP2C9 inducer.
    Ertapenem: (Major) Concomitant use of carbapenems (doripenem, ertapenem, imipenem, meropenem) and valproic acid is not recommended. If the drugs are coadministered and serum valproic acid concentrations cannot be maintained or if seizures occur, alternative antibacterial or anticonvulsant therapy should be considered. Carbapenems can reduce serum concentrations of valproic acid to subtherapeutic levels when the two drugs are administered together. The exact mechanism of this interaction is not known, however, based on in vitro and animal data, inhibition of valproic acid glucuronide hydrolysis is a suggested mechanism. A retrospective study evaluated the interaction between meropenem and valproate and reported an average reduction of 66% in plasma valproate concentrations. The study also reported that electroclinical deterioration was present in 55% of patients. Case studies have reported ertapenem causing decreases in valproic acid and divalproex serum concentrations when ertapenem was added to their regimen; discontinuation of ertapenem resulted in increased valproic acid concentrations. Doripenem has been shown to reduce the valproic acid AUC by 63% when coadminstered in healthy volunteers.
    Esterified Estrogens: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Esterified Estrogens; Methyltestosterone: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Estropipate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethanol: (Moderate) Concomitant use of ethanol or other CNS depressants with valproic acid can cause additive CNS depression.
    Ethinyl Estradiol: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Desogestrel: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) High doses of folate may cause decreased serum concentrations of valproic acid, divalproex sodium resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with valproic acid. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity. (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Norethindrone: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Norgestimate: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethinyl Estradiol; Norgestrel: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Ethosuximide: (Moderate) Valproate inhibits the metabolism of ethosuximide and may lead to elevated serum concentrations of ethosuximide. Additionally, concurrent administration of valproic acid, divalproex sodium and ethosuximide may result in lowered valproic acid serum concentrations. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs due to complicated pharmacokinetic drug interactions.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide, VP-16 when coadministered with valproic acid, divalproex sodium, as concomitant use is associated with increased etoposide clearance and reduced efficacy. Valproic acid is a weak in vitro inducer of CYP3A4 and P-gp, as well as a weak CYP3A4 inhibitor; etoposide is a CYP3A4 and P-gp substrate. Increased etoposide-related adverse effects are also possible.
    Felbamate: (Moderate) Felbamate has been shown to increase valproic acid serum concentrations, however the magnitude of this effect varies. Felbamate may interfere with valproic acid metabolism and should be administered cautiously to patients receiving valproic acid.
    Fentanyl: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Folic Acid, Vitamin B9: (Moderate) High doses of folate may cause decreased serum concentrations of valproic acid, divalproex sodium resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with valproic acid. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with valproic acid, divalproex sodium. Valproic acid is an inhibitor of CYP2C9, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with valproic acid, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Major) Caution is advised when administering fosamprenavir with valproic acid, divalproex sodium as there is a potential for altered fosamprenavir plasma concentrations. Valproic acid is an inducer of P-glycoprotein (P-gp) and a mild inducer and inhibitor of CYP3A4. Fosamprenavir is a substrate both CYP3A4 and P-gp.
    Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like valproic acid. Monitor serum glucose concentrations if glimepiride is coadministered with valproic acid. Dosage adjustments may be necessary.
    Glimepiride; Pioglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like valproic acid. Monitor serum glucose concentrations if glimepiride is coadministered with valproic acid. Dosage adjustments may be necessary.
    Glimepiride; Rosiglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like valproic acid. Monitor serum glucose concentrations if glimepiride is coadministered with valproic acid. Dosage adjustments may be necessary.
    Glycerol Phenylbutyrate: (Moderate) Valproic acid may induce elevated blood ammonia concentrations. Use caution and monitor ammonia concentrations closely if co-administration of valproic acid and glycerol phenylbutyrate is necessary.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Haloperidol: (Major) Concomitant use of other CNS depressants, such as haloperidol, with valproic acid can cause additive CNS depression. Haloperidol, used concomitantly with valproic acid, can increase CNS depression and also can lower the seizure threshold, requiring change in the valproic acid dose.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydantoins: (Major) Phenytoin and valproic acid should be used together with caution. Valproic acid can displace phenytoin from protein-binding sites and inhibit its metabolism. Phenytoin can accelerate the metabolism of valproic acid. Phenytoin toxicity can occur if valproic acid is added to phenytoin. Loss of seizure control can occur as a result of lower valproic acid levels, although this would seem unlikely during the addition of a second anticonvulsant. Because this interaction is complex, serum concentrations of both agents should be monitored closely, and the patient should be observed for loss of seizure control or the occurrence of phenytoin toxicity. Similar interactions may occur with fosphenytoin or ethotoin.
    Hydrocodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking valproic acid. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydromorphone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as valproic acid. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Imipenem; Cilastatin: (Major) Concomitant use of carbapenems (doripenem, ertapenem, imipenem, meropenem) and valproic acid is not recommended. If the drugs are coadministered and serum valproic acid concentrations cannot be maintained or if seizures occur, alternative antibacterial or anticonvulsant therapy should be considered. Carbapenems can reduce serum concentrations of valproic acid to subtherapeutic levels when the two drugs are administered together. The exact mechanism of this interaction is not known, however, based on in vitro and animal data, inhibition of valproic acid glucuronide hydrolysis is a suggested mechanism. A retrospective study evaluated the interaction between meropenem and valproate and reported an average reduction of 66% in plasma valproate concentrations. The study also reported that electroclinical deterioration was present in 55% of patients. Case studies have reported ertapenem causing decreases in valproic acid and divalproex serum concentrations when ertapenem was added to their regimen; discontinuation of ertapenem resulted in increased valproic acid concentrations. Doripenem has been shown to reduce the valproic acid AUC by 63% when coadminstered in healthy volunteers.
    Imipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently.
    Isoniazid, INH: (Major) Concomitant use of isoniazid with valproic acid may result in increased serum concentrations of valproic acid and increase the risk for serious adverse reactions, such as hepatoxicity. Several case reports demonstrated elevated valproic acid concentrations and hepatotoxicity when isoniazid was added to previously stabilized valproic acid therapy. Monitor serum valproic acid concentrations during coadministration; appropriate dosage adjustments of vaproic acid should be made.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concomitant use of isoniazid with valproic acid may result in increased serum concentrations of valproic acid and increase the risk for serious adverse reactions, such as hepatoxicity. Several case reports demonstrated elevated valproic acid concentrations and hepatotoxicity when isoniazid was added to previously stabilized valproic acid therapy. Monitor serum valproic acid concentrations during coadministration; appropriate dosage adjustments of vaproic acid should be made. (Major) The oral clearance of valproate may be increased in patients receiving valproic acid and rifampin concurrently. Valproate dosage adjustments may be necessary.
    Isoniazid, INH; Rifampin: (Major) Concomitant use of isoniazid with valproic acid may result in increased serum concentrations of valproic acid and increase the risk for serious adverse reactions, such as hepatoxicity. Several case reports demonstrated elevated valproic acid concentrations and hepatotoxicity when isoniazid was added to previously stabilized valproic acid therapy. Monitor serum valproic acid concentrations during coadministration; appropriate dosage adjustments of vaproic acid should be made. (Major) The oral clearance of valproate may be increased in patients receiving valproic acid and rifampin concurrently. Valproate dosage adjustments may be necessary.
    Kava Kava, Piper methysticum: (Major) The German Commission E warns that any substances that act on the CNS, including anticonvulsants, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with CNS-active agents that undergo oxidative metabolism via these CYP isozymes are also possible. Persons taking an anticonvulsant should discuss the use of herbal supplements with their health care professional prior to consuming them.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g.,valproic acid), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Concomitant administration of valproic acid and oral zidovudine may result in increase in the area under the concentration-time curve of zidovudine and a decrease in the AUC of its glucuronide metabolite. This interaction does not appear to be clinically significant unless the patient is experiencing hematologic toxicities. The dose of zidovudine may be reduced in patients who are experiencing pronounced anemia while receiving chronic coadministration of zidovudine and valproic acid.
    Lamotrigine: (Major) Coadministration of valproic acid with lamotrigine can decrease the elimination of lamotrigine. Valproic acid more than doubles the elimination half-life of lamotrigine in both pediatric and adult patients. In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate coadministration (a 165% increase). The decrease in apparent clearance of lamotrigine may occur via inhibition of lamotrigine metabolism through competition for liver glucuronidation sites. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. In any patient receiving valproic acid, lamotrigine must be initiated at a reduced dosage that is less than half the dose used in patients not receiving valproic acid. In controlled clinical trials, lamotrigine had no appreciable effect on plasma valproic acid concentrations when added to existing valproic acid therapies. If valproic acid therapy is discontinued, lamotrigine doses may need to be adjusted upward. The inhibitory effects of valproic acid on lamotrigine elimination may offset the actions of other anticonvulsants with known hepatic enzyme-inducing properties on lamotrigine clearance.
    Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like valproic acid, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
    Lesinurad: (Major) Lesinurad should not be administered with valproic acid, divalproex sodium. In vitro studies suggest inhibitors of epoxide hydrolase, such as valproic acid, may interfere with the metabolism of lesinurad.
    Lesinurad; Allopurinol: (Major) Lesinurad should not be administered with valproic acid, divalproex sodium. In vitro studies suggest inhibitors of epoxide hydrolase, such as valproic acid, may interfere with the metabolism of lesinurad.
    Levomefolate: (Moderate) High doses of folate may cause decreased serum concentrations of valproic acid, divalproex sodium resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with valproic acid. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
    Levorphanol: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lisdexamfetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue the amphetamine.
    Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anticonvulsants. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be altered when administered concurrently with valproic acid, divalproex sodium, an inducer/inhibitor of CYP3A4 and a mild inducer of P-gp. If these drugs are used together, monitor for reduced efficacy and loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be altered when administered concurrently with valproic acid, divalproex sodium, an inducer/inhibitor of CYP3A4 and a mild inducer of P-gp. If these drugs are used together, monitor for reduced efficacy and loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp.
    Lorazepam: (Moderate) Valproic acid, divalproex sodium has been reported to increase lorazepam peak plasma concentrations and the AUC by 8% and 20%, respectively. In this study, concurrent valproic therapy did not alter sedation scores. This interaction is attributed to inhibition of hepatic glucuronidation of lorazepam by valproate.
    Loxapine: (Major) Loxapine, used concomitantly with valproic acid, can increase CNS depression and also can lower the seizure threshold, requiring change in the dosage of valproic acid.
    Magnesium Hydroxide: (Minor) Antacids containing magnesium and aluminum hydroxide have been shown to increase valproic acid AUC by an average of 12%. Although this finding is of marginal clinical significance, patients should be monitored for adverse effects in this situation.
    Maprotiline: (Major) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Maraviroc: (Minor) Use caution and closely monitor for decreased efficacy and/or increased adverse effects with the coadministration of maraviroc and valproic acid as altered maraviroc concentrations may occur. Maraviroc is a substrate of CYP3A and P-glycoprotein (P-gp); valproic acid is a weak CYP3A4 inhibitor/inducer, as well as a weak P-gp inducer. The effects of P-gp on the concentrations of maraviroc are unknown, although a decrease in concentrations and thus, decreased efficacy, are possible.
    Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Meperidine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Meperidine; Promethazine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Mephobarbital: (Moderate) Valproic acid inhibits hepatic metabolism of phenobarbital, the major metabolite of mephobarbital, decreasing the plasma clearance of phenobarbital. Lower doses of mephobarbital, may be necessary if valproic acid is added.
    Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Meropenem: (Major) Concomitant use of carbapenems (doripenem, ertapenem, imipenem, meropenem) and valproic acid is not recommended. If the drugs are coadministered and serum valproic acid concentrations cannot be maintained or if seizures occur, alternative antibacterial or anticonvulsant therapy should be considered. Carbapenems can reduce serum concentrations of valproic acid to subtherapeutic levels when the two drugs are administered together. The exact mechanism of this interaction is not known, however, based on in vitro and animal data, inhibition of valproic acid glucuronide hydrolysis is a suggested mechanism. A retrospective study evaluated the interaction between meropenem and valproate and reported an average reduction of 66% in plasma valproate concentrations. The study also reported that electroclinical deterioration was present in 55% of patients. Case studies have reported ertapenem causing decreases in valproic acid and divalproex serum concentrations when ertapenem was added to their regimen; discontinuation of ertapenem resulted in increased valproic acid concentrations. Doripenem has been shown to reduce the valproic acid AUC by 63% when coadminstered in healthy volunteers.
    Meropenem; Vaborbactam: (Major) Concomitant use of carbapenems (doripenem, ertapenem, imipenem, meropenem) and valproic acid is not recommended. If the drugs are coadministered and serum valproic acid concentrations cannot be maintained or if seizures occur, alternative antibacterial or anticonvulsant therapy should be considered. Carbapenems can reduce serum concentrations of valproic acid to subtherapeutic levels when the two drugs are administered together. The exact mechanism of this interaction is not known, however, based on in vitro and animal data, inhibition of valproic acid glucuronide hydrolysis is a suggested mechanism. A retrospective study evaluated the interaction between meropenem and valproate and reported an average reduction of 66% in plasma valproate concentrations. The study also reported that electroclinical deterioration was present in 55% of patients. Case studies have reported ertapenem causing decreases in valproic acid and divalproex serum concentrations when ertapenem was added to their regimen; discontinuation of ertapenem resulted in increased valproic acid concentrations. Doripenem has been shown to reduce the valproic acid AUC by 63% when coadminstered in healthy volunteers.
    Mestranol; Norethindrone: (Moderate) Monitor serum valproic acid concentrations and patient clinical response when adding or discontinuing estrogen-containing therapy. Estrogen may increase the clearance of valproic acid, possibly leading to decreased efficacy of valproic acid and increased seizure frequency.
    Methadone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Methamphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue the amphetamine.
    Methohexital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like methohexital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Methsuximide: (Moderate) Concurrent administration of valproic acid, divalproex sodium and methsuximide may result in lowered valproic acid serum concentrations. Pre-morning-dose valproic acid serum concentrations were measured in 17 patients who had either started or stopped taking methsuximide, but whose dose of valproate and other medication remained unchanged. For all patients, the mean valproic acid concentration while not taking methsuximide was 81.9 +/- 5.3 mg/L and while taking methsuximide was 55.7 +/- 4.3 mg/L, a significant difference. In 8 patients who stopped taking methsuximide the mean serum concentration increased from 49.8 +/- 7.5 mg/L to 71.7 +/- 8.5 mg/L. It may be necessary to increase the valproate dose when methsuximide is added to avoid loss of therapeutic effect. Conversely, reduction of the valproate dose may be needed when methsuximide therapy stops, to avoid valproate toxicity
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Monoamine oxidase inhibitors: (Moderate) Concomitant use of CNS depressants with valproic acid can cause additive CNS depression. MAOIs, used concomitantly with valproic acid, can increase CNS depression and also can lower the seizure threshold,
    Morphine: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Nimodipine: (Moderate) Limited data suggest that nimodipine may potentiate the effects of valproic acid. In epileptic patients taking valproic acid, there is a 50% increase in the AUC of nimodipine. Patients receiving valproic acid, divalproex sodium and nimodipine concomitantly should be monitored closely for valproic acid or nimodipine-related side effects. Doses should be adjusted accordingly.
    Nonsteroidal antiinflammatory drugs: (Moderate) Due to the high protein binding of NSAIDs, they could displace other highly protein-bound drugs such as valproic acid, divalproex sodium from albumin binding sites in the blood leading to an increase in valproic acid free drug concentrations. In such cases, a patient may experience valproic acid toxicity even if the total drug concentration is within the therapeutic range.
    Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. In addition, nortriptyline is the active metabolite of amitriptyline. Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers who received valproate orally (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Monitor patients taking nortriptyline carefully when valproic acid is used concurrently; a reduction in the dose of nortriptyline may be required.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of valproic acid with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered valproic acid plasma concentrations and decreased concentrations of dasabuvir, ombitasvir, paritaprevir, and ritonavir. Valproic acid is an inducer of the drug transporter P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp, while ritonavir, paritaprevir, and dasabuvir (minor) are partially metabolized by CYP3A4. In addition, in a case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. Caution and close monitoring are advised if these drugs are administered together. (Major) In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp.
    Omeprazole; Sodium Bicarbonate: (Minor) Sodium bicarbonate may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation.
    Oritavancin: (Moderate) Valproic acid is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated valproic acid plasma concentrations. If these drugs are administered concurrently, monitor patients for signs of valproic acid toxicity, such as diarrhea, bruising, tremor, changes in mood or behavior, yellowing of skin or eyes, unusual tiredness or weakness, or severe stomach pain with nausea and vomiting.
    Oxycodone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Oxymorphone: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Paliperidone: (Moderate) Coadministration of a single 12 mg oral dose of paliperidone with divalproex sodium extended-release tablets (1,000 mg once daily) resulted in an increase in Cmax and AUC of paliperidone of about 50%. The clinical significance, if any, is unknown; however, a decrease in oral paliperidone dosage may be necessary in select patients after initiation of valproic acid, valproate, or divalproex sodium. A clinically meaningful pharmacokinetic interaction between injectable paliperidone (Invega Sustenna or Invega Trinza) and valproate, valproic acid, or divalproex sodium is not expected. Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment is needed for valproate or derivatives when coadministered with injectable forms of paliperidone.
    Pemoline: (Major) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents. Dosage adjustments of anticonvulsants may be necessary during simultaneous use of these drugs.
    Pentobarbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like pentobarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Perphenazine; Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. In addition, administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers who received valproate orally (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare post-marketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received; but, concurrent use has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline; a reduction in the dose of amitriptyline may be required.
    Phenobarbital: (Moderate) Valproic acid inhibits phenobarbital metabolism, and most likely the metabolism of other barbiturates. Valproic acid decreases the plasma and metabolic clearance of phenobarbital. Phenobarbital renal clearance is not affected by valproic acid. Lower doses of phenobarbital may be necessary if valproic acid is added. One study showed that phenobarbital concentrations increased by 51% in adults and 112% in children when valproic acid was added, thus, the age of the patient should be considered when managing this drug interaction. Also, CNS depression can be additive even without elevations of phenobarbital concentrations. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased when appropriate.
    Phenothiazines: (Moderate) The phenothiazines, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the phenothiazine or the anticonvulsant.
    Phentermine; Topiramate: (Major) Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In addition, concomitant administration of topiramate and valproic acid has been associated with hypothermia with or without hyperammonemia in patients who have tolerated either drug alone. Assessment of blood ammonia levels may be advisable in patients presenting with symptoms of hypothermia. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as valproic acid, may also increase the risk of bleeding; monitor patients appropriately. In several case reports, children with localized epilepsy have presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate. Previously, the children tolerated valproic acid with other antiepileptic drugs. Children presented with elevated serum ammonia, normal or elevated LFTs, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted to normal along with clinical improvement following withdrawal of valproate. The possible mechanism is topiramate-induced aggravation of all the known complications of valproic acid monotherapy; it is not due to a pharmacokinetic interaction. This condition is reversible with cessation of either valproic acid or topiramate.
    Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Primidone: (Moderate) Valproic acid inhibits phenobarbital metabolism, and most likely the metabolism of other barbiturates. Since primidone is metabolized to phenobarbital, similar precautions should be observed if this agent is used concurrently with valproic acid. Valproic acid decreases the plasma and metabolic clearance of phenobarbital. Phenobarbital renal clearance is not affected by valproic acid. Lower doses of phenobarbital may be necessary if valproic acid is added. One study showed that phenobarbital concentrations increased by 51% in adults and 112% in children when valproic acid was added, thus, the age of the patient should be considered when managing this drug interaction. Also, CNS depression can be additive even without elevations of phenobarbital concentrations. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased when appropriate.
    Propofol: (Major) Concomitant use of valproate and propofol may result in elevated blood concentrations of propofol. If used together, reduce the dose of propofol and monitor patients closely for signs of increased sedation or cardiorespiratory depression.
    Protriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently.
    Quetiapine: (Minor) The combined use of valproic acid, divalproex sodium and quetiapine could lead to increased sedation.
    Remifentanil: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Rifampin: (Major) The oral clearance of valproate may be increased in patients receiving valproic acid and rifampin concurrently. Valproate dosage adjustments may be necessary.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and valproic acid. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Risperidone: (Minor) Coadministration of risperidone and valproate may result in a minor increase in peak plasma concentrations of valproic acid; however, dosage adjustments of valproic acid are not recommended. In one evaluation, concomitant administration of risperidone 4 mg/day and valproate 1,000 mg/day resulted in a 20% increase in valproate peak plasma concentration (Cmax) and there was no effect on the pre-dose or average plasma concentrations and exposure (AUC) of valproate. The mechanism of this interaction is not known.
    Ritonavir: (Major) In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp.
    Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Rufinamide: (Major) A population pharmacokinetic analysis showed no effect on valproate concentrations and an increase of less than 16 to 70% in rufinamide concentrations during concurrent use. Adult patients currently stabilized on valproic acid or divalproex should initiate rufinamide therapy at a dosage lower than 400 mg/day, and pediatric patients stabilized on valproate therapy should begin rufinamide at a dose lower than 10 mg/kg/day. Similarly, patients stabilized on rufinamide before being prescribed valproate should initiate valproate therapy at a low dose followed by careful titration.
    Salicylates: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly.
    Secobarbital: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like secobarbital, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Silodosin: (Major) KMD-3213G, the primary metabolite of silodosin, is formed from direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UBT2B7). In theory, coadministration of silodosin with UBT2B7 inhibitors such as valproic acid may increase silodosin plasma concentrations.
    Sodium Benzoate; Sodium Phenylacetate: (Major) Valproic acid may inhibit N-acetylglutamate synthase, which is the essential cofactor for carbamyl phosphate synthetase in the urea cycle. The clinician should pay careful attention to patients with urea cycle deficiencies who are receiving valproic acid because their plasma ammonia concentrations could rise significantly. Discontinuation of valproate therapy may be necessary.
    Sodium Bicarbonate: (Minor) Sodium bicarbonate may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation.
    Sodium Oxybate: (Major) In one evaluation, concurrent administration of sodium oxybate and valproic acid, divalproex sodium resulted in a 25% mean increase in systemic exposure of sodium oxybate, as well as a greater impairment on some attention and memory tests than with either drug alone. The manufacturer of sodium oxybate recommends a minimum 20% dose reduction of sodium oxybate if valproic acid, valproate, or divalproex sodium treatment is initiated. Similarly, a lower starting dose of sodium oxybate is recommended when initiating the drug in a patient currently receiving valproic acid, valproate, or divalproex. Patients should be closely monitored; further dose adjustments may be necessary. Patients should be warned to assess the cognitive effects of the combination prior to performing potentially hazardous tasks.
    Sodium Phenylbutyrate: (Severe) Valproic acid and its analogs are contraindicated in patients with urea cycle disorders, including those being treated with sodium phenylbutyrate. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with known or suspected urea cycle disorders. Do not administer valproic acid to a patient who is being treated with sodium phenylbutyrate.
    Sofosbuvir; Velpatasvir: (Minor) Theoretically, taking velpatasvir with valproic acid may reduce the plasma concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy. Caution is advised if these drugs are administered together. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); valproic acid is a weak P-gp inducer. Velpatasvir is also a substrate for CYP3A4; valproic acid is a weak inducer/inhibitor of CYP34.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of voxilaprevir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as valproic acid. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Minor) Theoretically, taking velpatasvir with valproic acid may reduce the plasma concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy. Caution is advised if these drugs are administered together. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); valproic acid is a weak P-gp inducer. Velpatasvir is also a substrate for CYP3A4; valproic acid is a weak inducer/inhibitor of CYP34.
    Sufentanil: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) The risk for developing leukopenia and/or thrombocytopenia can be increased if other bone marrow depressants are used with sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. Megaloblastic anemia can occur when sulfamethoxazole; trimethoprim, SMX-TMP is used in patients who are taking other folate antagonists. These agents include: valproic acid, divalproex sodium. If these agents are used concomitantly, close observation of blood counts is warranted. (Minor) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of divalproex or valproic acid.
    Tapentadol: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Teduglutide: (Moderate) Teduglutide may increase absorption of valproic acid, divalproex sodium because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of valproic acid is recommended.
    Telotristat Ethyl: (Minor) Use caution if valproic acid is coadministered with telotristat ethyl, and monitor for a decrease in the efficacy of telotristat ethyl. Telotristat, the active metabolite of telotristat ethyl, is a substrate of P-glycoprotein (P-gp) and valproic acid is a weak P-gp inducer in vitro. Exposure to telotristat ethyl may decrease.
    Temozolomide: (Moderate) Valproic acid decreases the oral clearance of temozolomide. The clinical implication of this effect is not known.
    Tenofovir Alafenamide: (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering valproic acid. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9; valproic acid is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as valproic acid, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Thiopental: (Moderate) Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates, like thiopental, would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly.
    Thiothixene: (Major) Thiothixene, when used concomitantly with various anticonvulsants, such as valproic acid, can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when thiothixene is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the neuroleptic or the anticonvulsant.
    Tiagabine: (Moderate) Tiagabine causes a slight decrease (about 10%) in steady state valproic acid concentrations. The addition of tiagabine to patients taking valproic acid chronically has no effect on tiagabine pharmacokinetics. However, valproic acid has been shown to decrease tiagabine protein binding in vitro from 96.3% to 94.8%, resulting in a 40% increase in free tiagabine concentration; the clinical significance of this finding is not known. Because dosing recommendations for tiagabine were based on use in patients taking enzyme-inducing drugs, patients receiving valproic acid monotherapy may require lower doses or slower dose titration of tiagabine.
    Tipranavir: (Major) Coadministration of tipranavir and valproic acid, divalproex sodium may result in decreased valproic acid concentrations. Monitor valproic acid concentrations and efficacy.
    Tolbutamide: (Minor) Unbound tolbutamide may increase when given to patients receiving valproate. The mechanism may be due to tolbutamide protein displacement by valproate. The clinical relevance of this interaction is unknown.
    Topiramate: (Major) Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In addition, concomitant administration of topiramate and valproic acid has been associated with hypothermia with or without hyperammonemia in patients who have tolerated either drug alone. Assessment of blood ammonia levels may be advisable in patients presenting with symptoms of hypothermia. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as valproic acid, may also increase the risk of bleeding; monitor patients appropriately. In several case reports, children with localized epilepsy have presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate. Previously, the children tolerated valproic acid with other antiepileptic drugs. Children presented with elevated serum ammonia, normal or elevated LFTs, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted to normal along with clinical improvement following withdrawal of valproate. The possible mechanism is topiramate-induced aggravation of all the known complications of valproic acid monotherapy; it is not due to a pharmacokinetic interaction. This condition is reversible with cessation of either valproic acid or topiramate.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and valproic acid, divalproex sodium is necessary, due to the risk of altered trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, valproic acid is weak inhibitor and inducer of CYP3A. There are no specific recommendations for concomitant use of weak CYP3A inhibitors or inducers with trabectedin. If concomitant use is necessary, monitor the patient closely for chemotherapeutic efficacy and adverse effects.
    Tramadol: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Trimethoprim: (Minor) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of divalproex or valproic acid.
    Trimipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently.
    Vincristine Liposomal: (Moderate) In vitro, Valproic Acid, Divalproex Sodium is a mild CYP3A4 inhibitor and inducer, as well as a mild P-glycoprotein (P-gp) inducer; vincristine is a substrate of both CYP3A and P-gp. Theoretically, concentrations of vincristine may be affected by coadministration. Monitor patients for changes in vincristine efficacy and toxicity if these drugs are used together.
    Vincristine: (Moderate) In vitro, Valproic Acid, Divalproex Sodium is a mild CYP3A4 inhibitor and inducer, as well as a mild P-glycoprotein (P-gp) inducer; vincristine is a substrate of both CYP3A and P-gp. Theoretically, concentrations of vincristine may be affected by coadministration. Monitor patients for changes in vincristine efficacy and toxicity if these drugs are used together.
    Voriconazole: (Moderate) Voriconazole is an inhibitor of the cytochrome P450 2C19 and 2C9 isoenzymes and interactions are possible with drugs that are substrates of these enzymes, like valproic acid. Increased valproic acid plasma levels may occur.
    Vorinostat: (Major) Severe thrombocytopenia and GI bleeding have been reported during concomitant administration of vorinostat and valproic acid. Monitor platelet counts every 2 weeks for the first 2 months of vorinostat therapy, and then monthly or as clinically indicated.
    Warfarin: (Moderate) Concurrent administration of highly protein-bound agents may displace warfarin from its binding sites leading to increased anticoagulation. In an in-vitro study valproic acid, divalproex sodium (valproate) increased the unbound fraction of warfarin by 33%. The therapeutic relevance of this interaction is uncertain; however, it would be prudent to monitor coagulation tests more closely when valproate therapy is introduced or stopped.
    Zidovudine, ZDV: (Minor) Concomitant administration of valproic acid and oral zidovudine may result in increase in the area under the concentration-time curve of zidovudine and a decrease in the AUC of its glucuronide metabolite. This interaction does not appear to be clinically significant unless the patient is experiencing hematologic toxicities. The dose of zidovudine may be reduced in patients who are experiencing pronounced anemia while receiving chronic coadministration of zidovudine and valproic acid.
    Zolpidem: (Moderate) A probable interaction between zolpidem and valproic acid resulted in somnambulism (sleep walking) in one case report. A 47 year old patient with a history of bipolar disorder was receiving citalopram (40 mg once daily) and zolpidem (5 mg at bedtime). Manic symptoms developed during treatment and he received valproic acid. Somnambulism developed 2 days after the valproic acid was initiated. The sleep walking stopped after the valproic acid was discontinued and with a rechallenge the symptoms reappeared. It is not known if this interaction is of a pharmacokinetic or pharmacodynamic nature. Somnambulism has also been reported as a rare side effect of zolpidem when used without interacting medications; however this patient did not experience sleep walking with zolpidem monotherapy or with valproic acid monotherapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Valproic acid and its analogs are contraindicated for use during pregnancy when the drug is being used for migraine prophylaxis. Valproic acid is not appropriate for migraine prophylaxis during pregnancy, as use is not considered necessary to prevent permanent injury or death. For the treatment of epilepsy and manic episodes associated with bipolar disorder, valproic acid valproate products should only be prescribed during pregnancy for these conditions if other alternative medications are not acceptable or not effective for treating the condition. Valproic acid and its derivatives are associated with reproductive risk. In utero exposure to valproate can cause major congenital malformations, including neural tube defects (e.g., spina bifida), craniofacial defects, cardiovascular malformations, hypospadias, and limb malformations. Some of the malformations are fatal. Additionally, fetal exposure may cause decreased IQ scores, cerebral atrophy, developmental delay, and autism and/or autism spectrum disorders. The strongest association is with maternal valproic acid use and neural tube defects, particularly when the drug is taken during the first trimester. It is unknown whether folic acid reduces the risk of neural tube defects in pregnant women receiving valproic acid; however, routine folic acid intake should be implemented during pregnancy regardless of therapy with the drug because studies in the general population show that folic acid intake prior to conception and during early pregnancy reduces the risk of neural tube defects. About 1 in 1,500 babies is born with a neural tube defect in the U.S. The risk of neural tube defects in babies born to mothers treated with valproate during the first 12 weeks of pregnancy is 1 in 20 babies. The CDC has estimated the risk for spina bifida in children exposed to valproic acid during gestation to be approximately 1% to 2% versus 0.14% to 0.2% in the general population. Data collected from the North American Antiepileptic Drug Pregnancy Registry suggest a 4-fold increased incidence of congenital malformations with valproic acid monotherapy during the first trimester compared to all other antiepileptic drug (AED) monotherapies as a group. Results from a prospective, multi-center, long-term, observational study of fetal death and malformations during in utero exposure to phenytoin, carbamazepine, lamotrigine, or valproate indicate that valproate poses the greatest risk for serious adverse outcomes. Enrollment was limited to pregnant women receiving monotherapy with one of the four agents for epilepsy. The outcomes of 333 infants were analyzed. The total percentages of serious adverse outcomes (fetal death or congenital malformations) were as follows: lamotrigine 1%, carbamazepine 8.2%, phenytoin 10.7%, and valproate 20.3%. Fetal deaths occurred in 3.6% of the carbamazepine and phenytoin groups, 2.9% of the valproate group, and no deaths occurred with lamotrigine. Congenital malformations were reported as follows: lamotrigine 1%, carbamazepine 4.5%, phenytoin 7.1%, and valproate 17.4%. Congenital malformations in the valproate group included brachycephaly, coarctation of the aorta, hypoplastic right heart, atrial septal defect, hydronephrosis, undescended testes, hypospadias, cleft palate, dysplastic ribs, two thumbs on right hand and a third nipple, and pulmonary stenosis. Valproate demonstrated a dose-dependent effect for adverse outcomes. In May 2013, the FDA notified healthcare professionals of an increased risk of lower cognitive test scores in children exposed to valproate and related products (valproic acid and divalproex sodium) during pregnancy. The data come from the Neurodevelopmental Effects of Antiepileptic Drugs epidemiologic study in which cognitive tests were performed on children exposed to monotherapy with antiepileptic drugs in utero. At age 6, the average IQ difference between children exposed to valproic acid and those exposed to either carbamazepine, lamotrigine, or phenytoin varied between 8 to 11 points. The long-term effects on cognitive development after exposure to valproate during pregnancy are not known. The occurrence of these effects if exposure to valproate is limited to less than the full duration of pregnancy, such as only to the first trimester, is also unknown. In a population-based cohort study (n = 655,615) with long-term follow-up of children with or without prenatal exposure to valproate, a significantly increased risk of autism was observed. In this cohort, 5,437 children were identified with autism spectrum disorder and 2,067 with childhood autism. The absolute risk of autism spectrum disorder or childhood autism was 1.53% and 0.48%, respectively. Of the 508 children with in utero exposure to valproate, the absolute risk was 4.42% for autism spectrum disorder and 2.5% for childhood autism. The therapeutic benefit of valproic acid in women of childbearing age should be carefully weighed against the risk for injury to the fetus, particularly during the first trimester of pregnancy. If the patient is taking the drug to prevent major seizures, the medical necessity of continuing valproic acid versus changing to an alternate agent should be assessed if the woman is planning to become pregnant. Determinations should be made on an individual basis, since seizures resulting from a change in therapy may pose more of a threat to both the mother and the fetus than continued therapy with valproic acid. Women of child-bearing potential should be carefully counseled on the possible fetal risks of valproic acid treatment for any indication during pregnancy, instructed in the contraception requirements and use of effective contraception, and informed of the importance of reporting a pregnancy to their health care provider as soon as possible. It is advisable to conduct tests for detection of neural tube and other defects as part of prenatal care in pregnant women receiving the drug. Women who took valproate during pregnancy should be instructed to inform their child's pediatrician of the exposure. Other adverse effects which have occurred during pregnancy include a woman with low fibrinogen taking multiple anticonvulsants whose infant died from hemorrhage secondary to afibrinogenemia; valproate products are known to cause dose-related thrombocytopenia. The manufacturer recommends careful periodic monitoring of complete blood counts (CBC) and clotting parameters if valproate must be used during pregnancy. Physicians are advised to recommend that pregnant patients receiving valproic acid enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    MECHANISM OF ACTION

    Mechanism of Action: Although the exact mechanism of action is unclear, it is believed that valproic acid increases brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS. It may inhibit enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. These explanations do not, however, account for therapeutic effects seen in animal models in the absence of an accompanying increase in GABA levels. Valproic acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.

    PHARMACOKINETICS

    Valproic acid and divalproex sodium are administered orally and valproate sodium is administered intravenously. Protein binding of valproate is concentration dependent. The free fraction of the drug increases at higher concentrations; approximately 90% is bound at a concentration of 40 mcg/mL and 80% is bound at a concentration of 130 mcg/mL. Mean Vd for total valproate is 11 L/1.73 m2; mean Vd for unbound valproate is 92 L/1.73 m2. Valproate distributes into the cerebrospinal fluid at concentrations similar to unbound (free) plasma concentrations (i.e., 10% to 20% of the total concentration). Valproate is metabolized extensively via hepatic glucuronidation (30% to 50% of an adult monotherapy dose) and mitochondrial beta-oxidation (40% of the dose). Smaller amounts (10% to 20% of the dose) are eliminated by other oxidative mechanisms (cytochrome-catalyzed terminal desaturation and hydroxylation, mainly mediated by CYP2C9). Less than 3% of the dose is excreted unchanged in the urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable protein binding. The pharmacokinetics of unbound drug are linear. Mean plasma clearance for total and unbound valproate is 0.56 L/hour/1.73 m2 and 4.6 L/hour/1.73 m2, respectively. Mean terminal half-life of valproate during adult monotherapy is 9 to 16 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: UGT, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP3A4, P-gp
    Biotransformation of valproate primarily occurs via glucuronidation conjugation, mediated by uridine diphosphate glucuronosyltransferase (UGT) and mitochondrial beta-oxidation. However, cytochrome-catalyzed metabolism of valproate accounts for approximately 10% to 20% of the administered dose. CYP2C9 is responsible for the majority (75% to 80%) of valproate terminal desaturation and hydroxylation; CYP2A6 and CYP2B6 contribute to the remainder of these reactions. Studies have indicated that genetic polymorphisms of CYP2C9, CYP2A6, CYP2B6, and CYP2C19 are significant factors for valproate pharmacokinetic variability. In addition, valproate is an inhibitor of epoxide hydrase and glucuronosyltransferases (UGT). It inhibits CYP2C9 competitively, and it is a weak inhibitor of CYP3A4 and CYP2C19. Induction of CYP3A4 and P-gp by valproate has been demonstrated in a human hepatocyte study. Drugs that affect hepatic enzyme expression, particularly those that elevate concentrations of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital can double the valproate clearance. Hence, patients on valproate monotherapy have longer half-lives and higher plasma concentrations when compared to those on anticonvulsant polytherapy. In contrast, because cytochrome P450-mediated oxidation is a minor secondary pathway (compared to glucuronidation and beta-oxidation), cytochrome P450 inhibitors (e.g., antidepressants) have little effect on valproate clearance.

    Oral Route

    Following oral administration of valproic acid, divalproex, or valproate sodium, bioavailability is nearly 100%. Absorption of valproate sodium from the syrup is rapid. Orally administered valproate sodium is rapidly converted to valproic acid in the stomach. Food can delay the rate, but not the extent, of absorption. Magnesium-aluminum antacids can increase valproic acid AUC by 12%. Bioavailability is the same for valproic acid and divalproex sodium. Depakote ER is not bioequivalent to divalproex delayed-release tablets, even when administered at the same daily dosage. After multiple dosing, Depakote ER given once daily has been shown to produce concentration fluctuations that are 10% to 20% lower than that of regular divalproex delayed-release tablets given twice daily, three times daily, or four times daily. Divalproex sodium passes through the stomach into the upper small intestine, where the enteric coating allows release and dissociation into valproate, which is then absorbed. Peak plasma concentrations are achieved within 1 to 4 hours following oral administration of the sodium salt or immediate-release valproic acid, within 3 to 5 hours for divalproex delayed-release, and within 4 to 17 hours following divalproex extended-release tablets. A pharmacokinetic study comparing delayed-release valproic acid to delayed-release divalproex demonstrated similar plasma concentration-time profiles under fasted conditions; however, the median tmax values were 2 hours and 3.5 hours, respectively. Full therapeutic effects require several days of therapy.