Valpros/Valpros i-IV Drug Interactions

Valpros: Alcohol: Valproate may potentiate the CNS depressant activity of alcohol. Concomitant use is not recommended.
Antiepileptic drugs (e.g., phenytoin, carbamazepine, phenobarbital, lamotrigine, primidone, felbamate): Several AEDs often used in conjunction with valproate have the ability to increase the intrinsic clearance of valproate, presumably by enzymatic induction of metabolism.
Valproate may displace carbamazepine from protein binding sites and may inhibit the metabolism of both carbamazepine and its metabolites, potentiating the toxic effects of carbamazepine. Clinical monitoring is recommended particularly at the beginning of combined therapy, with dosage adjustment when necessary.
Valproate reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended and lamotrigine dosage should be decreased as appropriate.
Valproate may block the metabolism of barbiturates resulting in increased phenobarbital plasma levels, which particularly in children, may be associated with sedation.
Concomitant use of phenobarbital and sodium valproate + valproic acid can cause CNS depression without significant elevation of serum level of either drug. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Concomitant use of phenytoin and sodium valproate + valproic acid may lead to breakthrough seizures. Most reports have noted a decrease in total plasma phenytoin concentration, however, increases in total phenytoin levels have been reported. An initial fall in total phenytoin levels with subsequent increase in phenytoin levels has also been reported. Furthermore, a decrease in total serum phenytoin with an increase in the free versus protein bound phenytoin levels has been reported with possible overdose symptoms (valproate displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended. When phenytoin plasma levels are determined, the free form should be evaluated. The dosage of phenytoin may require adjustment when given concomitantly with valproate as required by the clinical situation.
Valproate increases primidone plasma levels with exacerbation of its adverse effects (e.g., sedation); these signs cease with long-term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Valproate may decrease felbamate mean clearance by up to 16%. On the other hand, combination of felbamate and sodium valproate + valproic acid decreases valproate clearance by 22% to 50% and consequently increase the valproate plasma concentrations. Valproate dosage should be monitored when given in combination with felbamate.
Anticoagulants: The concomitant use of sodium valproate with drugs that exhibit extensive protein binding (e.g., aspirin, warfarin) may result in alteration of serum drug levels.
The effect of valproate on anticoagulants is unknown. Caution is recommended when administering anticoagulants and other products which have anticoagulant properties.
Concomitant use of sodium valproate + valproic acid and aspirin may result in displacement of valproate from protein binding sites, resulting in a rise in free levels of valproate. In addition, aspirin appears to inhibit the metabolism of valproate. Caution is advised when aspirin is given concomitantly with sodium valproate + valproic acid. Patients requiring long-term aspirin therapy may require a reduction in sodium valproate + valproic acid dose.
Carbapenem antibiotics (e.g., panipenem, meropenem, imipenem): Decreases in blood levels of valproate have been reported when it is co-administered with carbapenem agents resulting in a 60 to 100% decrease in valproate levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, concomitant use of carbapenem agents in patients stabilized on valproate should be avoided. If treatment with these antibiotics cannot be avoided, close monitoring of valproate blood levels should be done.
Cimetidine or Erythromycin: Concomitant use may increase valproate serum levels (as a result of reduced hepatic metabolism).
Cholestyramine: May decrease the absorption of valproate.
Ethosuximide: Valproate may inhibit ethosuximide metabolism, particularly in the presence of other anticonvulsants. Patients receiving this combination should be monitored clinically.
Mefloquinone and chloroquine: These drugs increase valproate metabolism and may lower the seizure threshold; therefore, epileptic seizures may occur in cases of combined therapy.
Dose adjustment of sodium valproate + valproic acid may be necessary.
Psychotropic agents [e.g., monoamine oxidase inhibitors (MAOIs), antipsychotics (e.g., clozapine, haloperidol, olanzapine, quetiapine), antidepressants (e.g., fluoxetine), and benzodiazepines (e.g., clonazepam, diazepam, lorazepam, midazolam)]: Valproate may potentiate the effects of psychotropic agents; therefore, clinical monitoring is advised and the dose of these drugs should be reduced accordingly.
Concomitant use of clozapine and sodium valproate + valproic acid may potentiate an increase in clozapine or valproate levels.
A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate revealed no significant changes in valproate trough plasma levels.
Concomitant use of olanzapine and sodium valproate + valproic acid may result in significant increase in the risk of adverse events associated with olanzapine e.g., neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder, and somnolence.
Concomitant use of sodium valproate + valproic acid and quetiapine may increase the risk of neutropenia/leukopenia.
Fluoxetine may inhibit the metabolism of sodium valproate + valproic acid as it does with TCAs, carbamazepine, and diazepam.
The concomitant use of sodium valproate + valproic acid and clonazepam may produce absence status.
Valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Monitoring of free diazepam levels may be necessary if the patient becomes sedated.
Concomitant use of sodium valproate + valproic acid and lorazepam results in decreased lorazepam plasma clearance.
Concomitant use of sodium valproate + valproic acid results in increased free plasma midazolam leading to an increase in of the midazolam response.
Lithium: Sodium valproate + valproic acid has no effect on serum lithium levels.
Rifampicin: Rifampicin may decrease valproate blood levels resulting in a lack of therapeutic effect. Therefore, sodium valproate + valproic acid dosage adjustment may be necessary when it is co-administered with rifampicin.
Temozolomide: Concomitant use with sodium valproate + valproic acid may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Tolbutamide: In vitro studies showed that the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with sodium valproate + valproic acid. The clinical relevance of this displacement is unknown.
Topiramate: Concomitant use with sodium valproate + valproic acid has been associated with encephalopathy and/or hyperammonemia. Patients treated with these drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy.
Tricyclic Antidepressants (TCAs) (e.g., chlorpromazine, amitriptyline/nortriptyline): Valproate may inhibit the metabolism of TCAs. Clinical monitoring of free antidepressant levels may be necessary.
Chlorpromazine may inhibit the metabolism of sodium valproate + valproic acid.
Concomitant use of amitriptyline and sodium valproate + valproic acid resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Concomitant use of these drugs has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking sodium valproate + valproic acid concomitantly with amitriptyline. Lowering the amitriptyline/nortriptyline dose in the presence of sodium valproate + valproic acid should be considered.
Vitamin K-dependent factor anticoagulant: The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased after displacement from plasma protein binding sites by valproate. The prothrombin time should be closely monitored.
Zidovudine: Sodium valproate + valproic acid may increase zidovudine plasma concentrations leading to increased zidovudine toxicity.
Antacids: Concomitant use with sodium valproate + valproic acid did not reveal any effect on the extent of valproate absorption.
Paracetamol: Concomitant use with sodium valproate + valproic acid had no effect on the pharmacokinetics of paracetamol.
Oral contraceptives steroids: Concomitant use with sodium valproate + valproic acid did not reveal any pharmacokinetic interaction.
Other Interactions: Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. Altered thyroid function tests associated with valproate has also been reported.
In vitro studies suggest that valproate stimulates the replication of the human immunodeficiency virus (HIV) and cytomegalovirus (CMV) viruses under certain experimental conditions. The clinical consequence, if any, is not known. In addition, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be taken into consideration when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV
infected patients clinically.
There have been reports of altered thyroid function test results associated with valproate. The clinical significant of this is unknown.
Valpros i-IV: Alcohol: Valproate may potentiate the CNS depressant activity of alcohol.
Aspirin: Concomitant use of sodium valproate and aspirin may result in displacement of valproate from protein binding sites, resulting in an increased free valproate concentration. Also, aspirin appears to inhibit the metabolism of valproate.
Caution is advised when patients on sodium valproate are prescribed with aspirin. Likewise, patients requiring long-term aspirin therapy may require a reduction in dosage of sodium valproate.
Vitamin K-dependent factor anticoagulants (e.g., coumarin, warfarin): Close monitoring of prothrombin time should be done in case of concomitant use of vitamin K-dependent factor anticoagulants with sodium valproate since valproate may possibly enhance the anticoagulant effect of these drugs.
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased after displacement from the plasma protein binding site by valproate. Prothrombin time should be closely monitored.
Carbapenem antibiotics (e.g., ertapenem, imipinem, meropenem): Decreases in blood levels of valproic acid have been reported when it is coadministered with carbapenem agents resulting in a 60 to 100% decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, coadministration of carbapenem agents in patients stabilized on valproic acid should be avoided. If treatment with these antibiotics cannot be avoided, serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates.
Rifampicin: May decrease the valproate blood levels resulting in a lack of therapeutic effect. Valproate dosage adjustment may be necessary when it is coadministered with rifampicin.
Antidepressants [e.g., monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs)]: These may have the potential to inhibit the metabolism of valproate via the cytochrome P450 system. However, within normal therapeutic doses, any significant interaction is not expected. Antidepressants can lower the seizure threshold of non-stabilized epileptic patients, and so careful and regular monitoring of their condition is indicated.
Fluoxetine may inhibit the metabolism of valproate as it does with TCAs, carbamazepine and diazepam.
Clozapine: Caution is advised during concomitant use as competitive protein binding may potentiate an increase in clozapine or valproate levels.
Chlorpromazine: May inhibit the metabolism of valproate.
Olanzapine: Adding olanzapine to valproate may significantly increase the risk of certain adverse events associated with olanzapine (e.g., neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder, and somnolence).
Carbamazepine: Valproate may displace carbamazepine from protein binding sites and may inhibit the metabolism of both carbamazepine and its metabolite carbamazepine 10, 11 epoxide and consequently potentiate carbamazepine toxicity. Clinical monitoring is recommended particularly at the beginning of combined therapy, with dosage adjustment when appropriate.
Felbamate: May increase valproate serum concentrations. Valproate dosage should be monitored when given in conjunction with felbamate. Valproate may decrease felbamate mean clearance by up to 16%.
Lamotrigine: Sodium valproate reduces lamotrigine metabolism and increases its mean half-life by nearly two-fold. This interaction may lead to increased lamotrigine toxicity, in particular, serious skin rashes. Clinical monitoring is recommended and lamotrigine dosage should be decreased as appropriate.
Phenobarbital: Sodium valproate increases phenobarbital plasma concentrations and sedation may occur, particularly in children. Clinical monitoring is recommended throughout the first 15 days of combined treatment with an immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital levels when appropriate.
There is evidence of severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity.
Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone: Sodium valproate increases primidone plasma levels causing an exacerbation of side effects (e.g., sedation); these signs cease with long-term treatment. Clinical monitoring is recommended particularly when initiating combined therapy with dosage adjustment as necessary.
Phenytoin: Phenytoin total plasma levels are decreased by sodium valproate; the free form of phenytoin is increased leading to possible overdosage symptoms. Thus, clinical monitoring is recommended with the free form of phenytoin being measured.
There have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin in patients with epilepsy. The dosage of phenytoin should be adjusted as required by the clinical situation.
Topiramate: Concomitant use of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant use of these drugs has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported. In patients taking valproate and topiramate, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
Clonazepam: The concomitant use of sodium valproate and clonazepam may induce absence status in patients with a history of absence type seizures.
Diazepam: Sodium valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Monitoring of free diazepam levels may be necessary if the patient becomes sedated.
Lorazepam: Concomitant use with sodium valproate may cause a decrease in lorazepam plasma clearance.
Zidovudine: In patients who were seropositive for human immunodeficiency virus (HIV), the clearance of zidovudine was decreased by 38% after administration of valproate; the half-life of zidovudine was unaffected.
Temozolomide: Concomitant use of temozolomide and sodium valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Mefloquine and chloroquine: Increase valproate metabolism and thus epileptic seizures may occur with combined therapy. The dosage of sodium valproate may need adjustment.
Cimetidine or erythromycin: Valproate plasma levels may be increased when used concomitantly with cimetidine or erythromycin as a result of reduced hepatic metabolism.
Cholestyramine: May decrease the absorption of valproate.
Ethosuximide: There is evidence that sodium valproate may inhibit ethosuximide metabolism, particularly in the presence of other anticonvulsants. Patients receiving this combination should be monitored clinically.
Oral contraceptive: Sodium valproate usually has no enzyme-inducing effect; thus, sodium valproate injection does not reduce the efficacy of oestroprogestative agents in women receiving hormonal contraception, including oral contraceptive pill.
Interference with clinical laboratory and other tests: Sodium valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies. This may give false positive in the urine testing of possible diabetics.
There have been reports of altered thyroid function test results associated with sodium valproate. The clinical significance of this is unknown.