Depakote (divalproex sodium)

Dosage of valproate sodium and divalproex sodium is expressed in terms of valproic acid. Dosage must be carefully and slowly adjusted according to individual requirements and response.

Because of a decrease in clearance of free (unbound) valproic acid and the possibility of increased sensitivity to adverse effects (e.g., somnolence) in geriatric patients, the initial dosage should be reduced. Subsequent dosage should be increased more slowly in geriatric patients. In addition, the manufacturer recommends regular monitoring of fluid and nutritional intake, dehydration, somnolence, and other adverse effects in these individuals. Dosage reduction or discontinuance of valproic acid should be considered in geriatric patients with decreased food or fluid intake and in those with excessive somnolence. The ultimate therapeutic dosage in these patients should be determined on the basis of tolerability and clinical response.

Valproate sodium can be administered orally or by IV infusion and valproic acid and divalproex sodium are administered orally. Valproic acid also has been administered rectally+ by enema or in wax-based suppositories.

Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Cautions: Nervous System Effects and Cautions: Precautions and Contraindications.)

A medication guide explaining the risks and benefits of valproic acid therapy should be distributed to patients receiving valproic acid, valproate sodium, or divalproex sodium.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Cyp1a2 Inducers/Florquinitau F-18

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Florquinitau F-18 is a CYP1A2 substrate. CYP1A2 inducers may decrease the florquinitau F-18 parent fraction in plasma and reduce brain regional signal intensity.(1)

CLINICAL EFFECTS: Concurrent or recent use of CYP1A2 inducers with florquinitau F-18 may interfere with the interpretation of imaging results using fluoroestradiol F-18.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of florquinitau F-18 states use of CYP1A2 inducers should be avoided. Patients should stop CYP1A2 inducers at least 7 days prior to diagnostic testing with florquinitau F-18.(1)

DISCUSSION: Florquinitau F-18 is a CYP1A2 substrate. CYP1A2 inducers may decrease the florquinitau F-18 parent fraction in plasma and reduce brain regional signal intensity.(1) CYP1A2 inducers linked include: aminoglutethimide, asciminib, carbamazepine, fosphenytoin, leflunomide, marijuana smoking, montelukast, moricizine, nelfinavir, olverembatinib, omeprazole, phenobarbital, phenytoin, primidone, rifampin, ritonavir, teriflunomide, and valproic acid.(2,3)

Hdac Inhibitors/Sodium Phenylbutyrate-Taurursodiol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The mechanism of the increased gastrointestinal (GI) adverse effects with concurrent sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine) and other HDAC inhibitors is not known. Phenylbutyrate is a pan-histone deacetylase (HDAC) inhibitor.(1,2)

CLINICAL EFFECTS: Concurrent use of sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine) and another HDAC inhibitor may result in GI adverse effects including nausea and vomiting.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer recommends avoiding use of other HDAC inhibitors in patients taking sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine).(1) The CA manufacturer states sodium phenylbutyrate-taurursodiol should not be coadministered wiht other HDAC inhibitors.(2)

DISCUSSION: Concurrent use of sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine) and another HDAC inhibitor may result in increased GI adverse effects.(1,2) HDAC inhibitors include: belinostat, panobinostat, phenylbutyrate, romidepsin, sodium butyrate, and valproic acid.

Ugt Inhibitors/Lorazepam Extended Release

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of UDP-glucuronosyltransferases (UGT) may inhibit the metabolism of lorazepam.(1)

CLINICAL EFFECTS: Concurrent use of UGT inhibitors may result in increased exposure to and toxicity from lorazepam, including profound sedation, respiratory depression, and coma.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lorazepam extended release capsules states the initiating a UGT inhibitor during therapy with lorazepam extended release capsules should be avoided. If a UGT inhibitor is initiated, discontinue lorazepam extended release capsules and switch patient to a reduced dose of lorazepam tablets during concurrent therapy.(1)

DISCUSSION: In a study in 8 healthy males, pretreatment with valproate (250 mg twice daily for 3 days) decreased the total clearance of a single dose of lorazepam (2 mg intravenously) by 40% in 6 subjects. The formation rate of lorazepam glucuronide was decreased by 55% in these subjects. Lorazepam concentrations were about 2-fold higher for at least 12 hours post-dose during concurrent valproate.(2,4) In a randomized, double-blind, placebo-controlled study in 16 healthy males, concurrent divalproex (500 mg every 12 hours for 12 days) increased the area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of lorazepam (1 mg every 12 hours, Days 6-10) by 20%, 8%, and 31%, respectively. Lorazepam clearance was decreased by 31% during concurrent divalproex.(5) There is one case report of coma following the injection of 6 mg of lorazepam over 24 hours in a patient maintained on valproate (1000 mg). The patient remained in a coma for between 48 and 72 hours.(6) In a study in 9 healthy subjects, pretreatment with probenecid (500 mg every 6 hours) increased the half-life (T1/2) of a single intravenous dose of lorazepam (2 mg) by 130%. Lorazepam clearance was decreased by 45%. There was no change in lorazepam apparent volume of distribution.(2,7) UGT inhibitors linked to this monograph include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, mefenamic acid, nilotinib, pazopanib, probenecid, regorafenib, sorafenib, and valproic acid.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Hdac Inhibitors/Vorinostat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of the increased thrombocytopenia and gastrointestinal bleeding with concurrent vorinostat and other HDAC inhibitors is not known.

CLINICAL EFFECTS: Concurrent use of vorinostat and another HDAC inhibitor may result in severe thrombocytopenia and gastrointestinal bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer recommends close monitoring of patients taking vorinostat with other HDAC inhibitors. The platelet count should be monitored every 2 weeks for the first 2 months.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Concurrent use of vorinostat and another HDAC inhibitor may result in severe thrombocytopenia and gastrointestinal bleeding. The manufacturer recommends monitoring the platelet count every 2 weeks for the first 2 months.(1) HDAC inhibitors include: belinostat, panobinostat, phenylbutyrate, romidepsin, sodium butyrate, and valproic acid.

Selected Anticonvulsants/Selected Barbiturates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Phenobarbital, and perhaps other barbiturates, induce multiple metabolic enzymes including CYP1A2, CYP2C9, CYP2C19, CYP3A4, and glucuronidation (UGT) pathways. Felbamate, oxcarbazepine, and valproic acid are metabolized by one or more of these induced pathways. Valproic acid may inhibit the CYP2C9 mediated metabolism of phenobarbital, and possibly other barbiturates. Felbamate and oxcarbazepine may inhibit the CYP2C19 mediated metabolism of barbiturates.

CLINICAL EFFECTS: Lower felbamate, oxcarbazepine, and valproic acid concentrations may lead to diminished efficacy, e.g loss of seizure control, or new onset/more difficult to control manic episodes. Higher barbiturate concentrations may lead to increased sedation or further CNS depression.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: For patients stabilized on barbiturates, monitor for increased barbiturate levels approximately 4 to 7 days after initiation or after an increase in the dose of felbamate or oxcarbazepine. The US manufacturer of felbamate recommends that the dosage of phenobarbital be reduced by 20-33% when felbamate is initiated. The US manufacturer of extended release oxcarbazepine recommends initiating extended release oxcarbazepine at 900 mg once daily in adults and 12-15 mg/kg once daily (not to exceed 900 mg per day in the first week) in pediatric patients. If a barbiturate is added to a patient stabilized on felbamate or oxcarbazepine, the dose of felbamate or oxcarbazepine may need to be increased. Onset of induction is gradual and may not be maximal for days or weeks. Initiation of barbiturate therapy in a patient already stabilized on valproic acid will lead to a gradual lowering of valproic acid concentrations over approximately 1 to 3 weeks. Valproate concentrations could fall by 50%. Monitor valproate levels and adjust the dose as needed to maintain therapeutic efficacy. Due to valproic acid inhibition of barbiturate metabolism, consider starting barbiturate therapy at a lower than usual dose and increase as tolerated. Closely monitor therapy for needed adjustments in the barbiturate dose in patients maintained on valproate therapy when initiating these agents. Conversely, due to enzyme induction, larger than expected valproic acid doses may be required to achieve therapeutic benefit. Educate the patient regarding possible adverse effects and the need for valproate measurements to assure treatment efficacy. If the barbiturate is discontinued in a patient stabilized on felbamate, oxcarbazepine, and valproic acid therapy, felbamate, oxcarbazepine, and valproic acid concentrations will increase over 1 to 4 weeks. Monitor serum levels and adjust dosages as needed.

DISCUSSION: Prescribing information for oxcarbazepine states that phenobarbital doses of 100 to 150 mg daily decreased the mean concentration of its active metabolite (eslicarbazepine) 25%. In a study in 12 healthy males, administration of felbamate (2400 mg daily) increased phenobarbital levels by 25%. In a study in 24 healthy subjects, administration of felbamate (2400 mg daily) increased phenobarbital (100 mg daily) area-under-curve (AUC) and maximum concentration (Cmax) levels by 22% and 24%, respectively. In clinical trials, patients receiving concurrent phenobarbital were found to have felbamate concentrations that were 29% lower than patients not receiving concurrent phenobarbital. In contrast, a retrospective review of felbamate levels found no effect by barbiturates. In a case report, felbamate was initiated and titrated to 50 mg/kg/day over three weeks. At this time, the patient's phenobarbital dosage was decreased 13% (from 230 mg/daily to 200 mg/day). Despite this, the patient's phenobarbital level increased 42% and the patient developed neurotoxicity. The patient's phenobarbital dosage was further reduced to 35% of the original dosage (to 150 mg daily) and the patient's phenobarbital levels returned to therapeutic range. Valproate metabolites are formed via three major pathways: mitochondrial beta-oxidation (40%), glucuronidation (30-50%), and CYP P-450 (10%). Barbiturates induce several glucuronidation and CYP450 pathways, but not mitochondrial pathways. Manufacturer prescribing for valproic acid states that concomitant primidone or phenobarbital therapy may double valproic acid clearance. An interaction study in health subjects administered valproate 250mg BID for 14 days with a single 60 mg dose of phenobarbital leading to a 50% increase in half-life and a 30% decrease in the clearance of phenobarbital.

Valproate Derivatives/Cannabidiol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve possible additive or synergistic effects on the liver.

CLINICAL EFFECTS: Concurrent use of cannabidiol and valproate derivatives may result in hepatocellular injury.(1)

PREDISPOSING FACTORS: Patients with baseline transaminase levels above the upper limit of normal and/or taking clobazam may be predisposed to elevated transaminase levels with cannabidiol.(1)

PATIENT MANAGEMENT: Consider more frequent monitoring of liver enzymes in patients receiving concurrent cannabidiol and valproate derivatives. If liver enzyme elevations occur, consider dosage adjustment or discontinuation of valproate.(1) Monitor patients for and instruct patients to report symptoms of hepatic dysfunction (unexplained nausea, vomiting, right upper quadrant abdominal pain, fever, itching, fatigue, anorexia, or jaundice and/or dark urine). In symptomatic patients, promptly measure serum transaminases and total bilirubin and interrupt/discontinue cannabidiol therapy.(1) Discontinue cannabidiol in patients with transaminase levels greater than 3 times the upper limit of normal (ULN), or bilirubin levels greater than 2 times the ULN, or sustained transaminase elevations greater than 5 times the ULN.(1)

DISCUSSION: The majority of alanine aminotransferase (ALT) elevations with cannabidiol in clinical trials occurred with concurrent use of valproate. The incidence of ALT elevations greater than 3 times the upper limit of normal (ULN) was 21% in patients taking concurrent valproate compared with 3% in patients taking cannabidiol alone.(1) In a double blind, placebo controlled, clinical trial in patients with Dravet syndrome, an increase in the incidence of ALT elevations greater than 3 times the ULN was observed in 12% of patients taking cannabidiol (10 or 20 mg/kg/day), all patients were concurrently taking valproate.(3) A study in 39 adults and 42 children examined the effects of concurrent cannabidiol and antiepileptic drugs. There were 8 adults and 14 children on concurrent valproate. Elevated liver function tests occurred in 1 adult and 4 children taking concurrent valproate and no patients not on concurrent valproate. There were no effects on valproate levels. (2)

Valproic Acid Derivatives/Pivmecillinam

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Pivalic acid is released after hydrolysis from several prodrugs. In humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination.

CLINICAL EFFECTS: Concurrent use of valproic acid or its derivatives and pivmecillinam may increase the risk of low carnitine levels leading to neurologic deficits with or without encephalopathy. Neurologic deficits may present as changes in state of consciousness and/or cognitive function with lethargy and vomiting.(1-3)

PREDISPOSING FACTORS: Patients with low carnitine levels, significant renal impairment, or decreased muscle mass.

PATIENT MANAGEMENT: The US and UK manufacturers of pivmecillinam state that the use of pivmecillinam and valproic acid and its derivatives should be avoided.(1,2) In patients receiving concurrent valproic acid derivatives and pivmecillinam, monitor for unexplained lethargy, vomiting, and/ or changes in mental status. If these symptoms develop, check the patient's carnitine level and administer exogenous carnitine to increase body stores.(3)

DISCUSSION: There are reports of low carnitine levels caused by the long term (> 6 months) use of these agents resulting in neurological deficits caused by the concurrent use of pivalic acid containing products.(3) The patient improved after carnitine supplementation.

Valproic Acid/Carbapenem Antibiotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Carbapenems may inhibit the absorption of valproic acid from the gastrointestinal tract.(1-3) Meropenem may accelerate the renal excretion of valproate.(4) Carbapenems may increase valproic acid intake by erythrocytes.(5,6) Carbapenems may inhibit the metabolite of valproic acid, valproic acid-glucuronide, from being converted back into the active parent form.(7-9)

CLINICAL EFFECTS: Concurrent use of carbapenems and valproic acid without supplemental antiepileptic therapy is not recommended because it results in rapid, significant reductions in serum levels of valproic acid to non-therapeutic levels which may result in seizures. Dose escalation of valproic acid formulations does not counteract the decrease in serum levels and patients will require additional antiepileptic therapy. The effects may persist for several days beyond discontinuation of the carbapenem.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of carbapenem antibiotics in patients maintained on valproic acid when possible. If concurrent therapy is warranted, patients will require the addition of a supplemental anti-epileptic agent until valproic acid levels return to therapeutic range.

DISCUSSION: In a retrospective review of an 18 month period, charts of 39 patients who received concurrent therapy with valproate and meropenem were examined. A pharmacokinetic interaction was observed in all 39 patients, with an average decrease in valproate levels of 66%. The decrease occurred within 24 hours of the initiation of concurrent therapy. Electroclinical deterioration was seen in 55% of patients.(10) A prospective study evaluated ICU patients given levetiracetam or valproic acid to control seizures. Twenty-four of the 35 patients required meropenem. Each patient that was on valproic acid had valproic acid levels decrease following the addition of meropenum. (13) In a study in 23 healthy male subjects, concurrent doripenem (500 mg every 8 hours) decreased the maximum concentration, (Cmax) area-under-curve (AUC), and minimum concentration (Cmin) of valproic acid by 44.5%, 63% and 77.7%, respectively.(14) There are several case reports of decreased valproic acid levels following the addition of meropenem to therapy.(4,11,12,15-21) Some patients experienced increased seizures.(4 ,11,15,16,20) In some cases, decreased levels persisted despite increased doses of valproic acid.(11,12,15,17,18,21) Others required additional anti-seizure medications during concurrent therapy.(16) Decreased valproic acid levels have also been reported during concurrent ertapenem.(22-25) Seizures were reported in two patients.(22,25) In one patient, valproic acid levels returned to therapeutic levels within three days of discontinuation of ertapenem, despite no change in valproic acid dose.(25) Decreased valproic acid levels have also been reported during concurrent imipenem.(26) A retrospective study evaluated 52 patients given valproic acid and a carbapenem over a five year period. Patients received either ertapenem, imipenem/cilastatin, or meropenem (9, 17, and 26 patients, respectively). The average serum valproic acid concentration before and after carbapenem use was 58.6 +/- 19.2 and 23.7 +/- 16.3 mg/dL, respectively, which represented a decrease of 60% +/- 23% (p<0.001). Valproic acid concentrations were reduced with both intravenous and oral formulations of valproic acid (52% +/- 16% and 61% +/-24%, respectively). Valproic acid serum concentrations were subtherapeutic (<50 mg/L) in 90% of patients during carbapenem concurrent use. Use during ertapenem, imipenem/cilastatin, and meropenem decreased valproic acid concentrations by 72% +/- 17%, 42% +/- 22%, and 67% +/- 19%, respectively.(28) A retrospective study in 54 patients treated with valproic acid for at least three months for seizure control were evaluated for changes in valproic acid with concurrent carbapenem therapy. The mean change in valproic acid levels was 80%, 68%, and 51% in the meropenem, ertapenem, and imipenem group, respectively. During concurrent therapy, 48.1% of patients experienced aggravation of seizures and 25.9% died. Valproic acid levels of those experiencing aggravation of seizures were 17.7 +/- 9.9 mcg/mL versus 17.9 +/- 12.6 mcg/mL in those without aggravation (p=0.944).(29) A retrospective study in 381 neurosurgery inpatients evaluated valproic acid levels with concurrent meropenem therapy. Patients were grouped based on valproic acid dose of 1.2 g/day or 1.6 g/day with and without meropenem. In both 1.2 g/day and 1.6 g/day valproic acid groups, valproic acid levels were decreased after initiation of meropenem (67.3 +/- 4.6 mcg/mL v. 15.3 +/- 1.9 mcg/mL; 78.2% decrease, p<0.001 for 1.2 g/day valproic acid; 67.6 +/- 1.2 mcg/mL v. 18.1 +/- 2.6 mcg/mL; 72.5% decrease, p<0.001 for 1.6 g/day valproic acid. Valproic acid concentrations recovered to levels comparable to valproic acid alone more than seven days after meropenem discontinuation.(30)

Valproic Acid/Lamotrigine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Valproic acid decreases the clearance of lamotrigine.(1)

CLINICAL EFFECTS: Concurrent therapy results in increased levels of lamotrigine, requiring dosage adjustments. Valproic acid levels may also decrease over the first three weeks of therapy. Coadministration of valproic acid may increase the risk of potentially life-threatening lamotrigine-induced rashes.(1)

PREDISPOSING FACTORS: The incidence of lamotrigine-induced rash has been shown to be higher in pediatric patients. Although yet to proven, exceeding the recommended dosage for lamotrigine, exceeding the recommended dose escalation for lamotrigine, or being positive for the HLA-B*1502 allele may also increase the risk for lamotrigine-induced rash.(1)

PATIENT MANAGEMENT: The dosage of lamotrigine should be reduced during concurrent administration of valproic acid. Refer to the current manufacturer's prescribing information for lamotrigine for dosing guidelines for patients receiving concurrent lamotrigine and valproic acid therapy.(1) All patients receiving lamotrigine should be instructed to immediately report the development of a rash of any kind to their physician. The dosage of valproic acid may also need to be adjusted.

DISCUSSION: In clinical trials, 6 of 584 (1%) of patients who received lamotrigine with valproate were hospitalized with rash. Only 4 of 2398 patients who received lamotrigine without valproate were hospitalized. In pediatric patients receiving concurrent valproate, 1.2% experienced a serious rash compared with 0.6% of those not receiving concurrent therapy. (1) In a study in 103 adult patients with epilepsy, 30% of patients receiving concurrent lamotrigine with valproate developed a rash, while only 8% of patients receiving lamotrigine alone developed a rash.(2) In a study in 56 pediatric patients, the addition of lamotrigine to valproate resulted in rash in five patients. When lamotrigine was resumed without concurrent valproate therapy, there was no recurrence of rash.(3) In a study in 18 healthy subjects, the administration of lamotrigine and valproic acid decreased the trough stead-state levels of valproate by 25% over a 3 week period. Valproate levels then stabilized.(4) Valproate increases lamotrigine levels by slightly more than 2-fold.(1)

Valproic Acid/Rifampin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rifampin induces the metabolism of valproic acid.(1)

CLINICAL EFFECTS: Lower valproic acid concentrations may lead to diminished efficacy, e.g. loss of seizure control, increased frequency of migraine headaches, or new onset/more difficult to control manic episodes.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Initiation of rifampin in a patient already stabilized on valproic acid therapy will lead to a lowering of valproic acid concentrations. While induction onset may begin within 3 to 7 days, maximal effects may not be seen for 2 to 3 weeks. Monitor valproate levels and adjust the dose as needed to maintain therapeutic efficacy. When rifampin therapy is discontinued, systemic valproic acid concentrations will increase over a 1 to 3 week period as enzyme induction wanes. Valproic acid dosage may need to be lowered.

DISCUSSION: Valproate metabolites are formed via three major pathways: mitochondrial beta-oxidation (40%), glucuronidation (30-50%), and CYP P-450 (10%). Rifampin induces several glucuronidation and CYP P-450 pathways, but not mitochondrial pathways. A study described in manufacturer prescribing information reports a 40% increase in valproate clearance when rifampin 600 mg daily for 5 days was followed by a single dose of valproate 7 mg/kg.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Slt Anticonvulsants/Hydantoins; Anticonvulsant Barbiturates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Phenobarbital, and perhaps other barbiturates, induce multiple metabolic enzymes including CYP1A2, CYP2C9, CYP2C19, CYP3A4, and glucuronidation (UGT) pathways. Phenytoin, and perhaps other hydantoins, induce multiple metabolic enzymes including CYP2C9, CYP2C19, CYP3A4 and UGT pathways. Felbamate, oxcarbazepine, and valproic acid are metabolized by one or more of these induced pathways. Valproic acid may inhibit the CYP2C9 mediated metabolism of phenobarbital, possibly other barbiturates, and hydantoins. Felbamate and oxcarbazepine may inhibit the CYP2C19 mediated metabolism of phenytoin and barbiturates. Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Lower felbamate, oxcarbazepine, and valproic acid concentrations may lead to diminished efficacy, e.g loss of seizure control, or new onset/more difficult to control manic episodes. Higher barbiturate and/or hydantoin concentrations may lead to increased sedation or further CNS depression.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients stabilized on phenytoin or barbiturates, monitor for increased phenytoin or barbiturate levels approximately 4 to 7 days after initiation or after an increase in the dose of felbamate or oxcarbazepine. The US manufacturer of felbamate recommends that the dosage of phenobarbital and phenytoin be reduced by 20-33% when felbamate is initiated. The US manufacturer of extended release oxcarbazepine recommends initiating extended release oxcarbazepine at 900 mg once daily in adults and 12-15 mg/kg once daily (not to exceed 900 mg per day in the first week) in pediatric patients. If phenytoin or a barbiturate is added to a patient stabilized on felbamate or oxcarbazepine, the dose of felbamate or oxcarbazepine may need to be increased. Onset of induction is gradual and may not be maximal for days or weeks. Initiation of barbiturate or hydantoin therapy in a patient already stabilized on valproic acid will lead to a gradual lowering of valproic acid concentrations over approximately 1 to 3 weeks. Valproate concentrations could fall by 50%. Monitor valproate levels and adjust the dose as needed to maintain therapeutic efficacy. Due to valproic acid inhibition of barbiturate and hydantoin metabolism, consider starting barbiturate or hydantoin therapy at a lower than usual dose and increase as tolerated. Closely monitor therapy for needed adjustments in the barbiturate or hydantoin dose in patients maintained on valproate therapy when initiating these agents. Conversely, due to enzyme induction, larger than expected valproic acid doses may be required to achieve therapeutic benefit. Educate the patient regarding possible adverse effects and the need for valproate measurements to assure treatment efficacy. If the barbiturate or hydantoin is discontinued in a patient stabilized on felbamate, oxcarbazepine, and valproic acid therapy, felbamate, oxcarbazepine, and valproic acid concentrations will increase over 1 to 4 weeks. Monitor serum levels and adjust dosages as needed.

DISCUSSION: In interaction studies, oxcarbazepine dosage > 1200 mg daily increased phenytoin concentrations 30 to 40%; phenytoin doses of 250 to 500mg daily decreased eslicarbazepine or oxcarbazepine concentrations approximately 30%. In a study of lower dosage (900 mg daily) oxcarbazepine and phenytoin, no effects on phenytoin levels were seen. Prescribing information for oxcarbazepine states that phenobarbital doses of 100 to 150 mg daily decreased the mean concentration of its active metabolite (eslicarbazepine) 25%. In a study in 10 patients with epilepsy maintained on phenytoin therapy, phenytoin minimum concentration (Cmin) increased by 24% and 47% following the addition of felbamate at dosages of 1200 mg/day and 1800 mg/day, respectively. Phenytoin dosage reductions of 40% were necessary in 8 of the 10 subjects in order to achieve a felbamate dosage of 3600 mg/day while limiting adverse effects and maintain phenytoin levels. In another clinical trial, decreasing the dosage of phenytoin by 20% at the initiation of felbamate therapy resulted in no significant changes in phenytoin levels. Phenytoin has been shown to almost double the clearance of felbamate, resulting in a 45% decrease in felbamate levels. In a study in 12 healthy males, administration of felbamate (2400 mg daily) increased phenobarbital levels by 25%. In a study in 24 healthy subjects, administration of felbamate (2400 mg daily) increased phenobarbital (100 mg daily) area-under-curve (AUC) and maximum concentration (Cmax) levels by 22% and 24%, respectively. In clinical trials, patients receiving concurrent phenobarbital were found to have felbamate concentrations that were 29% lower than patients not receiving concurrent phenobarbital. In contrast, a retrospective review of felbamate levels found no effect by barbiturates. In a case report, felbamate was initiated and titrated to 50 mg/kg/day over three weeks. At this time, the patient's phenobarbital dosage was decreased 13% (from 230 mg/daily to 200 mg/day). Despite this, the patient's phenobarbital level increased 42% and the patient developed neurotoxicity. The patient's phenobarbital dosage was further reduced to 35% of the original dosage (to 150 mg daily) and the patient's phenobarbital levels returned to therapeutic range. Valproate metabolites are formed via three major pathways: mitochondrial beta-oxidation (40%), glucuronidation (30-50%), and CYP P-450 (10%). Barbiturates induce several glucuronidation and CYP450 pathways, but not mitochondrial pathways. Manufacturer prescribing for valproic acid states that concomitant primidone or phenobarbital therapy may double valproic acid clearance. An interaction study in health subjects administered valproate 250mg BID for 14 days with a single 60 mg dose of phenobarbital leading to a 50% increase in half-life and a 30% decrease in the clearance of phenobarbital. In most patients the active form of phenytoin (the unbound drug) is not significantly changed by valproic acid. Decreased serum phenytoin concentrations have been reported, as have symptoms of phenytoin toxicity. Increases in frequency of seizures have also been reported. Patients receiving phenytoin and valproic acid concurrently tend to have lower serum valproic acid concentrations than patients taking valproic acid alone. Concomitant administration of valproate (400 mg three times a day) with phenytoin (250 mg) in 7 healthy volunteers increased the free fraction of phenytoin by 60%. The total plasma clearance and volume of distrubution of phenytoin increased 30% with concomitant valproate.

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

Valproate Derivatives/Apixaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Valproate derivatives may decrease the efficacy of apixaban.

CLINICAL EFFECTS: Concurrent use of valproate derivatives may result in decreased effectiveness of apixaban.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of valproate derivatives in patients receiving apixaban should be approached with caution. Consider alternative anticonvulsants in patients maintained on apixaban. If concurrent use is warranted, monitor patients closely for decreased response to apixaban.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of valproic acid resulted in an odds ratio (95% CI) of 2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38 (1.37-4.12) compared to controls.(5) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(6)

Valproate Derivatives/Dabigatran

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Valproate derivatives may decrease the efficacy of dabigatran.

CLINICAL EFFECTS: Concurrent use of valproate derivatives may result in decreased effectiveness of dabigatran.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of valproate derivatives in patients receiving dabigatran should be approached with caution. Consider alternative anticonvulsants in patients maintained on dabigatran. If concurrent use is warranted, monitor patients closely for decreased response to dabigatran.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of valproic acid resulted in an odds ratio (95% CI) of 2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38 (1.37-4.12) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5)

Valproate Derivatives/Edoxaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Valproate derivatives may decrease the efficacy of edoxaban.

CLINICAL EFFECTS: Concurrent use of valproate derivatives may result in decreased effectiveness of edoxaban.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of valproate derivatives in patients receiving edoxaban should be approached with caution. Consider alternative anticonvulsants in patients maintained on edoxaban. If concurrent use is warranted, monitor patients closely for decreased response to edoxaban.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of valproic acid resulted in an odds ratio (95% CI) of 2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38 (1.37-4.12) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5)

Valproate Derivatives/Rivaroxaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of the interaction is unknown. Valproate derivatives may decrease the efficacy of rivaroxaban.

CLINICAL EFFECTS: Concurrent use of valproate derivatives may result in decreased effectiveness of rivaroxaban.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of valproate derivatives in patients receiving rivaroxaban should be approached with caution. Consider alternative anticonvulsants in patients maintained on rivaroxaban. If concurrent use is warranted, monitor patients closely for decreased response to rivaroxaban.

DISCUSSION: A nested case-control study of 100,168 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were reviewed for stroke (CVA)/systemic emboli in patients with atrial fibrillation or recurrent thromboembolism in patients with thromboembolism. The primary outcome of CVA/systemic embolism with concurrent use of valproic acid resulted in an odds ratio (95% CI) of 2.58 (1.50-4.45) and a propensity score adjusted odds ratio (95% CI) of 2.38 (1.37-4.12) compared to controls.(4) A population-based retrospective cohort study of 8746 patients on apixaban, dabigatran, edoxaban, or rivaroxaban were evaluated for occurrence of first ischemic stroke with concurrent antiseizure medications. Antiseizure medications that induce CYP3A4 or P-gp were associated with an increased risk of ischemic stroke (annual incidence rate of 5.5% vs 3.9%, adjusted hazard ratio 1.28). The annual incidence rates of ischemic stroke (valproate: 5.1%; levetiracetam: 6.0%; control: 3.9%) and venous thromboembolism (valproate: 3.7%; levetiracetam: 3.8%; control: 3.0%) were higher among valproate and levetiracetam users but were not statistically different from controls.(5) In a case report, a 30-year-old male with a history of deep vein thrombosis (DVT) developed recurrent DVTs on rivaroxaban. The patient was on concurrent valproic acid and lamotrigine for seizures. During concurrent use with valproic acid, rivaroxaban levels were below the 5th percentile. Valproic acid was gradually tapered off and rivaroxaban levels increased significantly.(6)

Valproate/Lorazepam; Mexazolam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valproate may inhibit the metabolism of lorazepam by glucuronidation via UDP-glucuronosyltransferases (UGT).(1-4) One of the active metabolites of mexazolam is lorazepam.

CLINICAL EFFECTS: Concurrent use of valproate or derivatives may increase levels of or clinical effects from lorazepam, including profound sedation, respiratory depression, and coma.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of lorazepam state that the dosage of lorazepam should be reduced by 50% in patients receiving valproate.(1,2)

DISCUSSION: In a study in 8 healthy males, pretreatment with valproate (250 mg twice daily for 3 days) decreased the total clearance of a single dose of lorazepam (2 mg intravenously) by 40% in 6 subjects. The formation rate of lorazepam glucuronide was decreased by 55% in these subjects. Lorazepam concentrations were about 2-fold higher for at least 12 hours post-dose during concurrent valproate.(1,3) In a randomized, double-blind, placebo-controlled study in 16 healthy males, concurrent divalproex (500 mg every 12 hours for 12 days) increased the area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of lorazepam (1 mg every 12 hours, Days 6-10) by 20%, 8%, and 31%, respectively. Lorazepam clearance was decreased by 31% during concurrent divalproex.(4) There is one case report of coma following the injection of 6 mg of lorazepam over 24 hours in a patient maintained on valproate (1000 mg). The patient remained in a coma for between 48 and 72 hours.(5)

Valproate/Methotrexate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Methotrexate may compete with valproate for binding to albumin and displace valproate. Unbound valproate may be rapidly metabolized.(1-3)

CLINICAL EFFECTS: Concurrent use of methotrexate with valproate may decrease the levels and effectiveness of valproate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor valproate levels and clinical response when starting or stopping methotrexate therapy. Valproate dosage adjustments may be necessary.(1)

DISCUSSION: A 6-year-old male with acute lymphoblastic leukemia who developed epileptic symptoms during chemotherapy was maintained on valproate 30 mg/kg/day. Upon receipt of methotrexate-containing chemotherapy (5 gram/m2), the patient developed a focal epileptic attack that became generalized. Serum valproate levels were found to have dropped from 800 mmol/L before methotrexate to 196 mmol/L after methotrexate. Before the next dose of methotrexate, valproate dosage was increased and clonazepam was added. Valproate levels again dropped from 660 mmol/L to 172 mmol/L, but no seizures developed.(2) In another case report, a 21-year-old male who was seizure-free for 5 years on valproic acid 600 mg/day for juvenile Absence Epilepsy started methotrexate 15 mg/week for psoriasis. His absence seizures relapsed and serum valproate levels was found to have dropped from 92 mcg/mL before methotrexate administration to 18 mcg/mL after methotrexate.(3)

Valproate/Rufinamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valproate decreases the clearance of rufinamide.(1-3)

CLINICAL EFFECTS: Concurrent use of valproate may result in elevated levels of and toxicity from rufinamide.(1-3)

PREDISPOSING FACTORS: Greater increases in rufinamide concentrations have been observed in patients with body weights less than 30 kg(1,3) and with higher dosages of valproate.(1-3)

PATIENT MANAGEMENT: The US manufacturers of rufinamide and valproic acid state that if patients are stabilized on rufinamide, valproate should be initiated at a low dose and titrated to an effective dose. Patients maintained on valproate should begin rufinamide at a dosage lower than 400 mg. Pediatric patients taking valproate should begin rufinamide at a dose lower than 10 mg/kg per day.(2) The UK manufacturer of rufinamide recommends that in children from 1 year to less than 4 years of age receiving valproate, rufinamide treatment should be initiated at a dose of 10 mg/kg/day and according to clinical response and tolerability, the dose may be increased by up to 10 mg/kg/day every third day to a maximum target dose of 30 mg/kg/day administered in two equally divided doses separated by approximately 12 hours.(1) The Australian and UK manufacturers of rufinamide recommend that children 4 years of age or older and less than 30 kg receiving valproate should initiate rufinamide treatment at a daily dose of 200 mg. According to clinical response and tolerability, after a minimum of 2 days the dose may be increased by 200 mg/day, to the maximum recommended dose of 600 mg/day.(1,3) The Australian and UK manufacturers of rufinamide recommend that adults, adolescents and children 4 years of age or older and 30 kg or over receiving valproate should initiate rufinamide treatment at a daily dose of 400 mg. According to clinical response and tolerability, the dose may be increased by 400 mg/day increments, as frequently as every other day, up to a maximum recommended dose as defined by weight: - Weight range: 30.0 to 50.0 kg = maximum recommended dose of 1,200 mg/day. - Weight range: 50.1 to 70.0 kg = maximum recommended dose of 1,600 mg/day. - Weight range: 70.1 kg or greater = maximum recommended dose of 2,200 mg/day.(1,3) The UK manufacturer of rufinamide recommends that in patients established on rufinamide treatment a dosage reduction of rufinamide be considered if valproate is initiated.(1)

DISCUSSION: Valproate increases rufinamide by 16% to 70%. The largest effects were seen in children at high doses/concentration of valproate.(1-3) The largest increases were seen in patients weighing less than 30 kg.(1)

Valproic Acid Derivatives/Topiramate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but a pharmacokinetic interaction does not occur.(1-4) Topiramate may contribute to increased ammonia levels by inhibiting carbonic anhydrase and cerebral glutamine.(5) Concurrent use may exacerbate or unmask existing metabolism defects.(1-4)

CLINICAL EFFECTS: Concurrent use of valproic acid or its derivatives and topiramate may increase the risk of hyperammonemia with or without encephalopathy. Hyperammonemic encephalopathy may present as changes in state of consciousness and/or cognitive function with lethargy and vomiting.(1-4) Concurrent use has also resulted in hypothermia.(1)

PREDISPOSING FACTORS: The risk of hyperammonemia with or without encephalopathy may be increased in patients with inborn metabolism errors or decreased hepatic mitochondrial activity.(1-4)

PATIENT MANAGEMENT: In patients receiving concurrent valproic acid derivatives and topiramate, monitor for unexplained lethargy, vomiting, and/ or changes in mental status. If these symptoms develop, check the patient's ammonia level.(1-4) The valproic acid derivative and/or topiramate may need to be discontinued if hyperammonemia develops.(1-3)

DISCUSSION: There have been several reports of hyperammonemia with and without encephalopathy in patients receiving concurrent valproic acid derivatives and topiramate.(1-12) In many of these reports, the patients tolerated the valproic acid derivative alone, but developed hyperammonemia with or without encephalopathy following the addition of topiramate.(1-9) Two clinical trials showed no clinically significant pharmacokinetic interaction between valproic acid and topiramate.(12,13)

Valproic Acid/Amitriptyline; Clomipramine; Nortriptyline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valproic acid may inhibit the metabolism of amitriptyline, clomipramine, and nortriptyline.

CLINICAL EFFECTS: Concurrent use of valproic acid may result in elevated levels of and toxicity from amitriptyline, clomipramine, and nortriptyline.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for signs of toxicity. Monitor tricyclic levels carefully during initiation, titration, and discontinuation of valproic acid. The dosage of the tricyclic antidepressant may need to be adjusted.

DISCUSSION: In a study in 15 healthy subjects, pretreatment with divalproex sodium (500 mg every 12 hours for 9 doses) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of amitriptyline (50 mg) by 31% and 17%, respectively. The AUC and Cmax of nortriptyline increased by 55% and 28%, respectively. The sum of amitriptyline and nortriptyline AUC and Cmax increased by 42% and 19%, respectively.(2) In a study in 20 subjects with depression receiving amitriptyline (125 mg daily), 10 subjects received valpromide (600 mg daily). Amitriptyline and nortriptyline levels increased 50% and 65%, respectively, in subjects receiving concurrent valpromide.(3) There are case reports of encephalopathy and myoclonus,(4) status epilepticus,(5) and increased clomipramine levels(6) have been reported following concurrent administration of valproic acid and clomipramine. In a case report, a patient previous maintained on desipramine and valproic acid developed elevated desipramine levels following the discontinuation of valproic acid.(7) Extrapyramidal symptoms(8) and increased nortriptyline levels(9) have been reported with concurrent nortriptyline and valproic acid.

Valproic Acid/Carbamazepine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valproic acid may displace carbamazepine from protein binding sites and inhibit the metabolism of the active metabolite of carbamazepine. In addition, carbamazepine may increase the metabolism of valproic acid.

CLINICAL EFFECTS: Loss of seizure control due to decreased serum valproic acid concentrations. Toxicity due to increased concentrations of the active metabolite of carbamazepine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum concentrations of both drugs. Adjust the dose of either drug as needed.

DISCUSSION: After discontinuing carbamazepine therapy, valproic acid levels increased in one patient producing pancreatitis. Acute psychosis was reported in another patient 8 days after adding carbamazepine to the patient's valproic acid regimen. Numerous studies have found that carbamazepine can decrease serum valproic acid concentrations. While the effects of valproic acid on carbamazepine levels are variable, serum concentrations of the active metabolite of carbamazepine are increased.

Valproic Acid/Felbamate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Felbamate may inhibit the CYP2C19 metabolism of valproic acid.

CLINICAL EFFECTS: The addition of felbamate may result in elevated levels and toxicity from valproic acid.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of felbamate recommends decreasing the dosage of valproic acid by 20% during the initiation of felbamate therapy.(1)

DISCUSSION: Administration of felbamate to 10 epileptic patients stabilized on valproic acid resulted in a dose related increase in felbamate area-under-curve (AUC) and maximum concentration (Cmax).(2) In a study in 4 subjects with epilepsy receiving valproate, valproate minimum concentration (Cmin) increased by 24% and 52% following the addition of felbamate at dosages of 1200 mg/day an 2400 mg/day, respectively.(1) In a study in 18 healthy subjects receiving valproate (400 mg/day for 21 days) and felbamate (days 8-21 at 1200 mg/day, 2400 mg/day, 3000mg/day, or 3600 mg/day) increased valproate Cmax by 38-72% and AUC by 93-108% (except for the 1200 mg/day dose) depending on felbamate dose. Valproate clearance was reduced by 34-54% depending on felbamate dose.(3) In a study in 10 children on valproic acid with felbamate (mean dose 18.5 mg/kg/day), the Cmin and AUC were increased and the valproic acid clearance was reduced 21%.(4) In a study in 10 subjects with epilepsy stabilized on valproic acid (9.5 - 31.7 mg/kg/day) receiving felbamate (600 mg or 1200 mg twice a day) resulted in an increase in Cmax and AUC of 34-55% and 27-54% and a reduction in clearance of 22-33%.(5)

Valproic Acid/Nimodipine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Valproic acid may inhibit the metabolism of nimodipine.(1)

CLINICAL EFFECTS: Concurrent use of valproic acid may result in increased levels of and toxicity from nimodipine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking valproic acid may required reduced dosages of nimodipine.(1)

DISCUSSION: A study examined nimodipine pharmacokinetics in three groups: normal drug-free controls (n=8), epileptic patients taking enzyme-inducing anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine, n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin, n=1), and epileptic patients taking valproic acid (n=8). In patients taking enzyme-inducing anticonvulsants, nimodipine area-under-curve (AUC), maximum concentration (Cmax), and half-life (T1/2) were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls. In patients taking valproic acid, nimodipine AUC was 54.5% higher than in control patients.(1)

Valproic Acid/Salicylates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Multiple mechanisms appear to be involved. Salicylates may displace valproic acid from plasma protein binding sites. Salicylates may also affect the metabolism of valproate by increasing conjugation and decreasing oxidation of valproic acid.

CLINICAL EFFECTS: Concurrent use of salicylates may increase the unbound fraction of serum valproic acid concentration, resulting in toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent salicylate therapy should be observed for signs of valproic acid toxicity (e.g., ataxia, drowsiness, nystagmus, tremor). The dosage of valproic acid may need to be adjusted.

DISCUSSION: In two studies involving 6 epileptic children taking valproic acid, concurrent aspirin led to an increase in serum valproic acid free fraction and an increased half-life. Renal clearance of free valproic acid was found to decrease.(1,2) In another study involving 5 children, concurrent valproic acid and aspirin resulted in a decrease in free valproic acid clearance although total valproic acid levels did not change significantly.(3) However, one study reported that the concurrent use of valproic acid and aspirin leads to an increased excretion of valproic acid and a decreased total salicylate excretion.(4) In 3 case reports, aspirin given to children taking valproic acid resulted in valproic acid toxicity (tremor, nystagmus, truncal ataxia). There was an increase in free valproic acid levels in two cases, however, a reduction in the free fraction and the total valproic acid levels occurred in the third patient.(5) In another case report, a patient was maintained on divalproex sodium (2500 mg/day) and aspirin (325 mg/day) with a trough valproate level of 24.7 ng/ml and a total valproate level of 64.0 ng/ml. Five days after aspirin was discontinued for a procedure, trough valproate levels fell to 3.9 ng/ml and a total valproate level fell to 36.0 ng/ml with no change in divalproex dosing.(6) In a study in 7 healthy males, concurrent diflunisal (250 mg twice daily) increased the unbound fraction of valproic acid (200 mg twice daily) by 20%. The area-under-curve (AUC) of 3-oxo-valproic acid increased by 35%. There were no effects on diflunisal levels.(7)

Valproic Acid/Sodium Oxybate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.(1)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and valproic acid may result in elevated levels of and increased clinical effects of sodium oxybate, including significant respiratory depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent valproic acid may require lower dosages of sodium oxybate. In patients maintained on sodium oxybate, reduce the dosage of sodium oxybate by 20% if valproic acid is initiated. For patients already taking valproic acid, consider a lower starting dose of sodium oxybate. If valproic acid is discontinued, monitor patient response to sodium oxybate.(1)

DISCUSSION: Administration of valproic acid (1250 mg daily) increased the area-under-curve (AUC) of sodium oxybate (6 g per day dosed as 3 grams given 4 hours apart) by 25%. There was no significant change in sodium oxybate maximum concentration (Cmax).(1)

Valproic Acid/Warfarin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The more active S-isomer of warfarin is primarily metabolized by CYP2C9(1) and valproic acid is an inhibitor of CYP2C9.(2-4) In addition, both drugs are highly protein bound and may compete for albumin binding sites.(4-6)

CLINICAL EFFECTS: Valproic acid may increase warfarin concentrations leading to an increase in INR and risk for bleeding.

PREDISPOSING FACTORS: Patients with normal serum albumin and valproic acid concentrations at the higher end of the therapeutic range, or patients with low serum albumin at any valproic acid concentration are at greater risk for a clinically significant interaction. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor INR response closely in patient maintained on warfarin when initiating, increasing or discontinuing valproic acid. Patients maintained on valproic acid may require lower initial doses of warfarin. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Valproic acid is highly protein bound. At usual therapeutic doses valproic acid is present in high molar concentrations and may saturate albumin binding sites.(4) Further increases in valproic acid dosage lead to a disproportionate increase in free (unbound) valproic acid concentration, increasing the risk for inhibition of CYP2C9 mediated metabolism of warfarin and displacement of warfarin from albumin binding sites. One manufacturer describes an in vitro study in which valproate increased the free fraction of warfarin by up to 32.6%.(5) In a case report, a 71 year-old female patient with glioblastoma multiforme had been maintained on warfarin (5 mg/day on Saturday and Sunday and 2.5 mg/day the other days of the week) with an INR target range of 2-3. Other medications included oral pravastatin 20 mg/day and dexamethasone 2 mg/day. The patient was admitted for complex partial seizures. During transport, she was given intravenous levetiracetam (dose not stated), midazolam 3 mg, and dexamethasone 4 mg. Upon arrival she was given additional 1 gram of intravenous(IV) levetiracetam. Warfarin 2.5mg was administered on the night of admission. Her INR on Day 2 was 3.4 and the warfarin dose was reduced to 0.75 mg due to bleeding concerns. The dose of levetiracetam was increased to 2.5 grams IV twice daily. An IV loading dose of valproic acid of 20 mg/kg (1,100 mg) was administered followed by a maintenance dose of 500 mg IV twice daily (later changed to 250mg every six hours per nasogastric tube). On Day 3, the total valproic acid level was 108 ug/mL (target range: 50-100 ug/mL), free valproic acid level was 20 ug/mL (target range: 4-15 ug/mL), and the INR had increased to 5.5. Eight hours later, the INR had further increased to 7.6. No other hemodynamic or metabolic changes were noted. Valproic acid was stopped, oral vitamin K (dose not stated) was given, and warfarin was held for the following two days. Warfarin was resumed when the INR had decreased to 2.5.(7) In a case report, a 42 year-old female patient was maintained on a regimen of divalproex sodium (1,000 mg/day) and lamotrigine (150 mg/day). She underwent surgery for cardiac valve replacement. Her INR on post-surgery Day 1 was 1.11 and she received warfarin (2.5 mg). On Day 4 her INR had increased to 6.54. Warfarin was held and she was given two units of fresh frozen plasma. Her INR decreased to 3.23. On Day 5, her INR increased to 5.42 without any additional doses of warfarin. Her serum valproate level was 91.7 ug/mL. (therapeutic range: 50-100 ug/mL). Divalproex sodium was held. On Day 6, the INR decreased to 3.27. The divalproex sodium was restarted (250 mg twice daily) on Day 7 and the serum valproate level on Day 8 was 30.2 ug/mL. The patient was discharged on Day 15 with an INR of 1.73, but had INR levels as high as 8.2 associated with epistaxis. Divalproex sodium was discontinued and replaced with another agent two months after surgery.(8)

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• Acute pancreatitis
• Disease of liver
• Hereditary neurometabolic syndromes due to POLG gene mutations
• Ornithine carbamoyltransferase deficiency
• Pregnancy
• Urea cycle disorder

• Carnitine deficiency
• Hyperammonemia
• Organic mental disorder
• Porphyria
• Thrombocytopenic disorder

• Depression
• Hypoalbuminemia
• Suicidal ideation

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More Frequent

• Accidental injury
• Dyspnea
• Nystagmus
• Peripheral edema
• Thrombocytopenic disorder

Less Frequent

• Mood changes

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal spermatozoa morphology
• Accidental fall
• Acute hepatic failure
• Acute intermittent porphyria
• Acute pancreatitis
• Agranulocytosis
• Anaphylaxis
• Anemia
• Angioedema
• Aplastic anemia
• Bloody vomit
• Bradycardia
• Carnitine deficiency
• Cerebral pseudoatrophy
• Cutaneous vasculitis
• Cystitis
• DRESS syndrome
• Encephalopathy
• Eosinophilia
• Erythema multiforme
• Facial edema
• Fracture
• Hearing loss
• Hepatitis
• Hyperammonemia
• Hyperandrogenism
• Hypertension
• Hypofibrinogenemia
• Hypothermia
• Interstitial nephritis
• Jaundice
• Leukopenia
• Lymphadenopathy
• Lymphocytosis
• Macrocytosis
• Male infertility
• Myocarditis
• Nephritis
• Osteoporosis
• Pancytopenia
• Paradoxical convulsion
• Parkinsonism
• Platelet aggregation inhibition
• Polycystic ovarian syndrome
• SIADH syndrome
• Skin photosensitivity
• Stevens-johnson syndrome
• Suicidal ideation
• Tardive dyskinesia
• Toxic epidermal necrolysis

More Frequent

• Acute abdominal pain
• Alopecia
• Anorexia
• Ataxia
• Blurred vision
• Bronchitis
• Constipation
• Depression
• Diarrhea
• Diplopia
• Dizziness
• Drowsy
• Dyspepsia
• Ecchymosis
• Fever
• Flu-like symptoms
• General weakness
• Headache disorder
• Increased appetite
• Infection
• Insomnia
• Irregular menstrual periods
• Memory impairment
• Nausea
• Pharyngitis
• Rhinitis
• Tinnitus
• Tremor
• Vomiting
• Weight gain
• Weight loss

Less Frequent

• Back pain
• Dysgeusia
• Gait abnormality
• Injection site sequelae
• Irritability
• Nervousness
• Vaginitis
• Vasodilation of blood vessels

Rare or Very Rare

• Abnormal hair texture
• Abnormal vaginal bleeding
• Acquired pelger-huet anomaly
• Acute generalized exanthematous pustulosis
• Aggressive behavior
• Agitation
• Altered mental status
• Amenorrhea
• Asthenozoospermia
• Azoospermia
• Behavioral disorders
• Bone pain
• Chest pain
• Conjunctivitis
• Cough
• Cramps in legs
• Disturbance of attention
• Dream disorder
• Dry skin
• Dyschromia
• Dysmenorrhea
• Dysuria
• Epistaxis
• Excitement
• Flatulence
• Galactorrhea not associated with childbirth
• Gynecomastia
• Hair discoloration
• Hirsutism
• Hostility
• Hyperreflexia
• Hypertonia
• Hypokinesia
• Increased urinary frequency
• Indifference
• Maculopapular rash
• Malaise
• Menstrual disorder
• Muscle weakness
• Nail disorders
• Oligospermia
• Osteopenia
• Palpitations
• Panic disorder
• Parotitis
• Personality disorders
• Petechiae
• Seborrhea
• Secondary amenorrhea
• Sinusitis
• Skin pigmentation enhancement
• Skin rash
• Stomatitis
• Symptoms of anxiety
• Tachycardia
• Toxic amblyopia
• Urinary incontinence
• Urinary tract infection
• Vertigo
• Visual changes
• Xerostomia

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Use of valproic acid during pregnancy is associated with an increased risk of neural tube defects (NTDs; e.g., spina bifida) and other major congenital malformations (e.g., craniofacial defects, cardiovascular malformations, malformations involving various body systems). In utero exposure to valproic acid also can cause decreased intelligence quotient (IQ) scores and other adverse cognitive effects in children.

Adverse fetal effects similar to those observed in humans have been observed in developmental toxicity studies in animals. Administration of valproic acid to mice, rats, rabbits, and monkeys during the period of organogenesis resulted in an increased incidence of fetal structural malformations (e.g., skeletal, cardiac, urogenital), intrauterine growth retardation, and embryofetal death. Such effects were observed at clinically relevant dosages of valproic acid. In addition, fetal NTDs were observed in mice following valproic acid administration during critical periods of organogenesis; this teratogenic response correlated with maximum maternal drug concentrations. Behavioral abnormalities (e.g., cognitive, locomotor, and social interaction deficits) and brain histopathologic changes also have been observed in mice and rats following prenatal exposure to clinically relevant dosages of valproic acid.

Valproic acid can cause major congenital malformations in humans, particularly NTDs, and this risk appears to be greatest during the first trimester of pregnancy. Recent data indicate that the risk of major congenital malformations is substantially greater with use of valproic acid than with use of other anticonvulsant agents during pregnancy. To monitor maternal-fetal outcomes of pregnant women exposed to anticonvulsant agents, including valproic acid, the North American Antiepileptic Drug (NAAED) pregnancy registry has been established. Data obtained from the NAAED registry indicate that the rate of major malformations in infants exposed in utero to valproic acid as monotherapy is about fourfold higher than the rate of major malformations in infants exposed to monotherapy with another anticonvulsant agent. Among 149 women in the registry who received valproic acid (average daily dosage of 1 g) for epilepsy during the first trimester of pregnancy, 16 infants were born with a birth defect, including NTDs (3 cases), craniofacial defects, cardiovascular defects, and other malformations involving various body systems. The rate of major malformations in infants exposed to valproic acid was 10.7% compared with a rate of 2.9% among infants born to a control group of women in the registry who received another anticonvulsant drug during the first trimester of pregnancy. The strongest association between maternal use of valproic acid and congenital anomalies is with the development of NTDs (e.g., spina bifida). Use of valproic acid during pregnancy is associated with an approximate 1-2% fetal risk of congenital spinal bifida (based on data from the US Centers for Disease Control and Prevention (CDC)); according to data from the CDC's National Birth Defects Prevention Network, the estimated risk of spina bifida in the general population is about 0.06-0.07%. Evidence suggests that prophylactic use of folic acid prior to conception and during pregnancy decreases the incidence of congenital NTDs in the general population, and folic acid supplementation prior to conception and during pregnancy should be routinely recommended in women receiving valproic acid. It is not known whether folic acid supplementation specifically reduces the risk of NTDs or decreased IQ in the offspring of women receiving valproic acid therapy.

In utero exposure to valproic acid also appears to be associated with an increased risk of adverse cognitive effects in children. Several epidemiologic studies have shown that children born to women who received valproic acid during pregnancy score lower on IQ tests and other cognitive function tests measuring a variety of mental and developmental abilities than those exposed in utero to other anticonvulsant agents or to no anticonvulsant therapy. In one large, prospective, observational cohort study (the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study), children who had been exposed to valproic acid in utero had significantly lower IQ scores at 6 years of age than those exposed in utero to lamotrigine, phenytoin, or carbamazepine monotherapy. After adjustment for potentially confounding factors, IQ scores were on average 8-11 points lower in valproic acid-exposed children compared with those exposed to the other anticonvulsant drugs. These findings of reduced IQ were consistent with those reported in 2 interim analyses that were conducted when the children were 2-3 and 4.5 years of age, although overall IQ scores tended to improve with age. Fetal exposure to valproic acid also was associated with impairments in a range of other cognitive domains (e.g., memory, verbal and nonverbal abilities, executive functions, cognitive fluency and originality); in general, the effects of the drug were dose dependent, with higher dosages associated with worse cognitive outcomes. Other observational studies also have demonstrated poorer cognitive outcomes, including delayed mental development, increased special education needs, and reduced verbal IQ, in cohorts of children exposed in utero to valproic acid compared with other anticonvulsant agents. Despite the methodologic limitations of these studies (e.g., lack of randomization, small sample size), the weight of available evidence currently supports a correlation between prenatal valproic acid exposure and an increased risk of cognitive deficits, including decreased IQ, in children. The long-term effects of prenatal valproic acid exposure on cognitive development have not been established. It is also not known whether these effects occur when fetal exposure is limited with respect to duration or timing (e.g., to the first trimester) during pregnancy. Therefore, the risk for development of adverse cognitive effects in valproic acid-exposed children should be considered at any time during pregnancy. In the NEAD study, a positive association was found between periconceptional use of folic acid and IQ scores; however, this finding should be interpreted with caution because the study was not specifically designed to evaluate this outcome. Folic acid supplementation prior to conception and during pregnancy should be routinely recommended in all women of childbearing age receiving valproic acid to decrease the risk of birth defects.

There also is a possible association between in utero valproic acid exposure and developmental delay, autism, or autism spectrum disorders. Results of a population-based cohort study using national register data from Denmark found that maternal use of valproic acid during pregnancy was associated with an increased risk of autism spectrum disorders and childhood autism in the offspring. The study identified a cohort of children (total of 655,615) born during a 10-year period and followed these children from birth until death, emigration, diagnosis of autism spectrum disorder or childhood autism, or study end. Among 508 children who were identified as having been exposed to valproic acid in utero, the absolute risk of autism spectrum disorder was 4.42% (adjusted hazard ratio of 2.9) and the absolute risk of childhood autism was 2.5% (adjusted hazard ratio of 5.2); the estimated absolute risk of these disorders in the entire population of children studied was 1.53 and 0.48%, respectively, after 14 years of follow-up.

Valproic acid is contraindicated in pregnant women for the prevention of migraine headaches. The drug should not be used in pregnant women with epilepsy or bipolar disorder unless other treatments have failed to provide adequate symptom relief or are otherwise unacceptable; in these cases, the benefits of valproic acid may continue to outweigh its risks. It should be kept in mind that untreated or inadequately treated epilepsy or bipolar disorder during pregnancy increases the risk of complications in both the pregnant woman and her developing fetus.

Because of the risk of major congenital malformations and other adverse pregnancy outcomes (e.g., decreased IQ in offspring) which may occur very early in pregnancy, use of valproic acid should be avoided whenever possible in women of childbearing potential. Alternative therapies to valproic acid should be considered, especially if the drug is being used for the treatment of migraines or other conditions not usually considered life-threatening, in women of childbearing potential. If valproic acid is necessary in a woman of childbearing potential, some experts suggest that the lowest possible dosage be employed. Effective contraception should be used in such women during valproic acid therapy. If pregnancy occurs during therapy, the clinician should be notified immediately; valproic acid should not be discontinued abruptly in a pregnant woman with epilepsy because of the risk of precipitating seizures. In individual cases when the severity and frequency of the seizure disorder are such that discontinuance of therapy does not pose a serious threat to the patient, discontinuance of the drug may be considered prior to and during pregnancy; however, even minor seizures can pose some hazard to the developing embryo or fetus.

In women who are contemplating pregnancy, alternative therapies to valproic acid should be considered; clinicians should review and revise the treatment plan with the patient well before conception. Women who become pregnant while receiving valproic acid should be encouraged to enroll in the NAAED pregnancy registry by calling 888-233-2334; information on the NAAED registry also is available on the website http://www.aedpregnancyregistry.org. Tests to detect neural tube and other malformations using current accepted procedures should be considered a part of routine prenatal care and be offered to all women who become pregnant while receiving valproic acid.

Patients receiving valproic acid may develop clotting abnormalities. A pregnant patient taking multiple anticonvulsant agents, including valproic acid, developed hypofibrinogenemia; the patient then gave birth to an infant with afibrinogenemia, who subsequently died of hemorrhage. If valproic acid is to be used during pregnancy, clotting parameters should be monitored closely.

Cerebral atrophy has been reported in children following prenatal exposure to valproic acid. In addition, fatal cases of hepatic failure in infants exposed to valproic acid in utero have been reported. (See Cautions: Hepatic Effects and see also Cautions: Precautions and Contraindications.)

Valproic acid is distributed into milk; caution is advised when administering the drug to nursing women.

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