Valpros Pedia Drug Interactions

Acetazolamide: When administered concomitantly, valproate and acetazolamide have been associated with encephalopathy and/or hyperammonemia. Careful monitoring for signs and symptoms of hyperammonemic encephalopathy is recommended, especially in patients at-risk such as those with pre-existing encephalopathy.
Aciclovir: Short-term oral aciclovir therapy administered to a child receiving both valproic acid and phenytoin reduced the plasma concentrations of both anticonvulsant drugs to subtherapeutic levels, leading to increased seizure frequency and worsening in electroencephalogram (EEG). Such concomitant therapy should be administered with caution.
Alcohol: Valproate may potentiate the CNS depressant action of alcohol. Concomitant use is not recommended.
Amitriptyline/Nortriptyline: A single oral dose of amitriptyline 50 mg concomitantly given with valproate 500 mg twice a day decreased the plasma clearance of amitriptyline and the net clearance of nortriptyline by 21% and 34%, respectively. The increased amitriptyline levels due to the coadministration with valproate have also been rarely reported in postmarketing studies. However, this interaction has rarely been associated with toxicity.
Monitoring of amitriptyline should be considered in patients concomitantly taking valproate. Lowering the dose of amitriptyline/nortriptyline may also be considered.
Antiepileptics: AEDs with enzyme-inducing effects reduce the plasma concentrations and increase intrinsic clearance of valproic acid. Dosages should be adjusted according to blood levels and clinical response of the patient.
Caution is advised when valproate is used in combination with newer anti-epileptics, whose pharmacodynamics may not be well established.
Anti-malarial agents (e.g., mefloquine, chloroquine): Valproic acid metabolism is increased by anti-malarial agents, which may lead to lower seizure threshold and occurrences of epileptic seizures. The dosage of valproate may be adjusted.
Antiretroviral agents (e.g., ritonavir, lopinavir, zidovudine, lamivudine): Protease inhibitors may reduce valproate plasma level. Severe anemia has been reported with the initiation of valproic acid therapy in a HIV-infected adult patient receiving an antiretroviral regimen consisting of zidovudine, lamivudine, and abacavir. Hepatotoxicity occurred in a HIV-infected adult given with valproic acid concurrently with an antiretroviral therapy containing ritonavir, saquinavir, stavudine, and nevirapine. The administration of valproic acid in a patient receiving fixed combination of lopinavir and ritonavir slightly elevated lopinavir concentrations.
Zidovudine: The coadministration of valproate 250 mg or 500 mg with zidovudine 100 mg both given every 8 hours in patients seropositive for HIV decreased the clearance of zidovudine by 38%, resulting to elevated zidovudine plasma concentration and increased zidovudine toxicity. The half-life of zidovudine was unaffected. Patients receiving both drugs should be closely monitored for zidovudine-related adverse events. Reducing the zidovudine dose may be considered if a significant anemia or other severe adverse events occurred.
Benzodiazepines: Valproate may decrease oxidative hepatic metabolism of some benzodiazepines, leading to increased serum concentrations of benzodiazepine.
Clonazepam: The concurrent use of valproate and clonazepam may induce absence seizures in patients with a history of absence type of seizures.
Diazepam: Valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Valproate 1,500 mg administered daily increased the free fraction of diazepam 10 mg by 90%. In addition, the coadministration decreased the plasma clearance and Vd for free diazepam by 25% and 20%, respectively. Valproate did not affect the elimination half-life of diazepam.
Lorazepam: Valproate 500 mg given twice a day decreased the plasma clearance of lorazepam (1 mg twice a day) by 17%. This decrease is not clinically significant.
Midazolam: Valproate may increase free plasma midazolam levels, potentially leading to an increase in midazolam response.
Carbapenem Antibiotics (e.g., ertapenem, imipenem, meropenem): Patients concurrently receiving carbapenem antibiotics have a 60% to 100% reduction in serum valproic acid concentrations in about 2 days, which is clinically significant. Sub-therapeutic drug levels and to loss of seizure control in epileptic patients or loss of efficacy in non-epileptics may occur. Breakthrough seizures have occurred during the coadministration. The mechanism of this interaction is not well elucidated.
Due to the rapid onset and extent of the serum valproic acid reduction, coadministration of carbapenem should be avoided. If the concurrent treatment is necessary, serum valproic acid concentrations should be frequently monitored upon initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations decreased significantly or if seizure control worsens.
Cholestyramine: Reduced absorption and plasma levels of valproate have been observed with the concurrent use of cholestyramine.
Chlorpromazine: Chlorpromazine inhibited the metabolism of valproate. Chlorpromazine 100 to 300 mg/day administered to schizophrenic patients already receiving valproate 200 mg twice a day resulted to a 15% increase in trough plasma levels of valproate. The increase is considered to be clinically insignificant.
Cimetidine: Cimetidine reduces the hepatic metabolism of valproate, resulting to decreased clearance, increased serum levels, and prolonged half-life of valproate. Serum valproate levels should be monitored when concurrent treatment with cimetidine is initiated or discontinued, or during cimetidine dose adjustments. Valproate dose should be adjusted accordingly.
Clozapine: Caution is advised in the concomitant administration of valproate with clozapine, as competitive protein binding may potentiate an increase in levels of either drugs.
CYP450 Inducers: Drugs that induce hepatic enzymes increased the clearance of valproate. Phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate, resulting to longer half-lives and higher concentrations in patients on monotherapy compared to those receiving polytherapy with other antiepileptic drugs. Monitoring of valproate levels is recommended. The dosage of valproate may need to be increased by 5 to 10 mg/kg/day when used with CYP450 inducers.
CYP450 Inhibitors (e.g., antidepressants): Since CYP450 microsomal-mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and β-oxidation, drugs that inhibit the CYP450 isoenzymes are to be expected to have a little effect in valproate clearance. Monitoring of valproate levels is recommended, and the concentrations of the concomitant drug should be increased whenever enzyme-inducing drugs are introduced or withdrawn.
Drugs affecting hepatic microsomal enzymes: These drugs, particularly those that elevate the levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate and decrease its plasma levels. Monitoring of valproate levels is recommended.
Drugs with extensive protein binding: The coadministration of valproate and drugs with extensive protein binding may alter the serum drug levels.
Aspirin: Aspirin at antipyretic doses (11 to 16 mg/kg) administered in children on valproate therapy decreased the protein binding and inhibited the metabolism of valproate. Valproate free fraction was also increased by 4-fold with the concurrent use of aspirin compared to valproate administered alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of the total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed when valproate is concomitantly administered with aspirin or other drugs affecting coagulation. Reduction in dosage of sodium valproate may be required in patients requiring long-term aspirin therapy.
Carbamazepine/carbamazepine-10,11-Epoxide: In epileptic patients, valproate may displace carbamazepine from protein binding sites and may inhibit its metabolism. Valproate also reduced carbamazepine serum levels by 17% and increased carbamazepine-10,11-epoxide levels by 45%. Valproate may also potentiate the toxic effects of carbamazepine, leading to clinical toxicity.
Carbamazepine induces the hepatic microsomal activity, leading to enhanced metabolism and reduced serum concentrations and half-life of valproate. Discontinuation of carbamazepine following combined treatment with valproate resulted to increased valproate concentrations. Monitoring of serum concentrations of either or both drugs is recommended when either medication is started or discontinued from the existing regimen. Clinical monitoring is also recommended, particularly at the start of combined treatment or discontinuation of one agent, and during dosage adjustments, if appropriate.
Phenobarbital: Valproate inhibits the hepatic metabolism of phenobarbital, resulting to increased phenobarbital plasma concentrations, particularly in children. Valproate 250 mg administered twice a day for 14 days increased the half-life of phenobarbital (60 mg administered as single dose) by 50% and decreased its plasma clearance by 30%. The proportion of phenobarbital excreted unchanged also increased by 50%.
Phenobarbital increased the metabolism of valproic acid, resulting to increased levels of valproic acid metabolite. Thus, patients treated with these medications should be carefully monitored for signs and symptoms of hyperammonemia.
Severe CNS depression with or without significant increases in barbiturate or valproate serum concentrations have occurred. Patients receiving concomitant treatment with valproate and barbiturates should be closely monitored for neurological toxicity, particularly in the first 15 days from the initiation of combined treatment. Serum barbiturate should be obtained, if possible, and the dosage of barbiturate should be immediately decreased, if appropriate or if sedation occurs.
Primidone: Valproate increases the primidone plasma levels, resulting to the exacerbation of adverse effects (e.g., sedation). However, these signs resolve with long-term treatment. Clinical monitoring is recommended, particularly at the initiation of the combined therapy. The dose should be adjusted as necessary.
Phenytoin: Valproate inhibits the hepatic metabolism of phenytoin, resulting to reduced total plasma concentrations and increased in its metabolite levels. Valproate 400 mg administered three times a day is associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent Vd of phenytoin were increased by 30%, while the clearance and apparent Vd of free phenytoin decreased by 25%. An initial fall in total phenytoin levels, with subsequent increase in phenytoin levels has been reported.
Breakthrough seizures have occurred in epileptic patients receiving valproate and phenytoin. The dosage of phenytoin should be adjusted based on the clinical situation. Patients receiving valproate and phenytoin should be monitored for signs and symptoms of hyperammonemia. Clinical monitoring is recommended because of the increased risk for overdose symptoms. The free form should be evaluated when phenytoin plasma levels are determined.
Tolbutamide: In vitro experiments showed that the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients on valproate therapy. The clinical relevance of this displacement is unknown.
Vitamin K-dependent factor anticoagulants: Increased anticoagulant effect was observed due to the displacement of warfarin and other coumarin anticoagulants from their plasma protein binding sites by valproic acid. In an in vitro study, the unbound fraction of warfarin was increased by up to 32.6% in the presence of valproate. Coagulation tests and prothrombin time should be monitored in patients taking valproate with anticoagulants. Caution is recommended when valproate is administered with medications that affect coagulation.
Erythromycin: As a result of decreased hepatic metabolism, erythromycin may increase the plasma levels of valproate.
Estrogen-Containing Hormonal Contraceptives: Estrogen are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in the glucuronidation of valproate. Thus, the clearance of valproate may be increased in the presence of estrogen-containing hormonal contraceptives, which may result to decreased valproate concentrations and potential increase in seizure frequency. Serum valproate concentration and clinical response (seizure control or mood control) must be closely monitored when initiating or discontinuing treatment with estrogen-containing medicines.
Ethosuximide: Valproate inhibits the metabolism of ethosuximide. Compared to ethosuximide 500 mg administered alone, the coadministration of valproate 800 to 1,600 mg/day resulted to a 25% increase in the elimination half-life of ethosuximide and a 15% decrease in its total clearance. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for the change in the serum concentrations of both drugs.
Felbamate: The coadministration of felbamate 1,200 mg/day with valproate in patients with epilepsy increased the mean valproate concentration by 35% (from 86 to 115 mcg/mL). Increasing the dose of felbamate to 2,400 mg/day elevated the mean valproate peak concentration to 133 mcg/mL (another 16% increase). Felbamate may decrease the valproic acid clearance by 22% to 50%, while valproate may reduce the mean clearance of felbamate by up to 16%. Valproate dosage should be monitored when treatment with felbamate is initiated.
Highly protein-bound agents: Free valproic acid plasma levels may be increased in the concomitant use of valproate and highly protein-bound agents (e.g., aspirin).
Lamotrigine: Valproate reduced the lamotrigine metabolism, resulting to increased elimination half-life by 165% and reduced total clearance of lamotrigine by 21%.
This interaction may result to increased lamotrigine toxicity, particularly skin reactions such as rash, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Lamotrigine dose should be reduced, and clinical monitoring is recommended during its coadministration with valproate. Patient receiving combined antiepileptic treatment should be carefully monitored when another agent is started, discontinued, or if the dose is adjusted.
Lithium: Lithium reduced the t_max of valproate, and increased its AUC and C_max by 11% to 12%. Although these pharmacokinetic parameters were statistically significant, these are not considered to be clinically significant.
Monoamine Oxidase Inhibitors (MAOIs), tricyclic antidepressants, and other antipsychotics: Valproate may potentiate the effect of these drugs and may enhance CNS depression and lower seizure threshold. Dosage adjustments may be necessary to control seizures.
Nimodipine: Concomitant administration of sodium valproate increased the plasma concentration of nimodipine by 50%. The nimodipine dose should be decreased in cases of hypotension.
Olanzapine: Valproate 500 mg administered twice a day reduced the C_max and the AUC of olanzapine 5 mg by 15% and 35%, respectively. The risk of certain adverse events of olanzapine (e.g., neutropenia, tremor, dry mouth, increased appetite, weight gain, speech disorder, somnolence) may also increase significantly. No dose adjustment for olanzapine is necessary when it is coadministered with valproate.
Propofol: Valproate may inhibit the metabolism of propofol and increase its blood levels. The usual recommended dose of propofol may be excessive for patients taking oral valproic acid treatment and may produce complications or delay recovery from anesthesia in electroconvulsive therapy (ECT). Reductions in the propofol dose by 26% to 35% have been observed when it is coadministered with valproate. Close monitoring for signs of increased sedation or cardiorespiratory depression should be performed.
Rifampicin: The oral clearance of valproate was increased by 40% when a single dose of valproate (7 mg/kg) was administered 36 hours after 5 nights of daily dosing with rifampicin (600 mg). This may result in decreased valproate blood levels and to lack of therapeutic effect. Adjustments in valproate dosage may be necessary when it is concurrently administered with rifampicin.
Rufinamide: Population pharmacokinetic analysis demonstrated that valproate decreased the clearance of rufinamide, resulting to increased rufinamide concentrations by <16% to 70%, depending on the valproate dose and concentrations. Larger increases were observed in children at high doses or concentrations of valproate. Patients already stabilized on rufinamide should be initiated on valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should be initiated with a rufinamide dose lower than 10 mg/kg/day for children, or 400 mg per day for adults.
Quetiapine: The risk for neutropenia and leukopenia is increased when valproate and quetiapine are used concomitantly.
Selective Serotonin Reuptake Inhibitors (SSRIs): Some evidence suggests that SSRIs inhibit the metabolism of valproate, leading to higher valproate levels.
Temozolomide: Valproate may slightly reduce the clearance of temozolomide.
This interaction is not considered to be clinically relevant.
Topiramate: The coadministration of valproate and topiramate has been associated with hyperammonemia with or without encephalopathy. In addition, their concurrent use has been associated with hypothermia in patients who have tolerated either drug alone. Although not studied, the interaction between valproate and topiramate may exacerbate existing defects or unmask deficiencies in susceptible patients. Blood ammonia levels should be examined in patients in whom the onset of hypothermia has been reported. Careful monitoring of signs and symptoms is advised, especially in patients at risk of, or those with pre-existing encephalopathy. Most manifestations resolved with discontinuation of either drugs.
Tricyclic antidepressants: Valproate may inhibit the metabolism of tricyclic antidepressant.
Clinical monitoring of free antidepressant may be required.
Interactions with Laboratory Test Results: Valproate is partially eliminated in the urine as a ketone-containing metabolite. Therefore, false interpretation of the urine ketone test may occur in patients taking sodium valproate.
Valproate has been associated with altered thyroid function tests. The clinical significance of this interaction is unknown.