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Effects of Co-Administered Drugs on Valproate Clearance: Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of Valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of Valproate. Thus, patients on monotherapy will generally have longer half-life and higher concentrations than patients receiving polytherapy with anti-epilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g. antidepressants, may be expected to have little effect on Valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and betaoxidation.
Because of these changes in Valproate clearance, monitoring of Valproate and concomitant drug concentrations should be increased whenever enzyme-inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on Valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
Drug For Which Potentially Important Interaction: Aspirin: Caution should be observed if Valproate and aspirin are to be co-administered.
Carbapenem Antibiotics: A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (ertapenem, imipenem, meropenem) and may result in loss of seizure control. The mechanism of this interaction is not well understood. 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 [see Interactions with Carbapenem Antibiotics under PRECAUTIONS].
Estrogen-Containing Hormonal Contraceptives: Estrogen containing hormonal contraceptives may increase the clearance of Valproate, which may result in decreased concentration of Valproate and potentially increased seizure frequency. Prescribers should monitor serum Valproate concentrations and clinical response when adding or discontinuing estrogen containing products, preferably during on-off intervals of the hormonal contraceptive cycle.
Felbamate: A decrease in Valproate dosage may be necessary when felbamate therapy is initiated.
Rifampicin: Valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
Protease Inhibitors: Protease inhibitors such as lopinavir, ritonavir decrease Valproate plasma level when coadministered.
Cholestyramine: Cholestyramine may lead to a decrease in plasma level of Valproate when coadministered.
Drugs For Which Either No Interaction or a Likely Clinically Unimportant Interaction: Antacids: Valproate did not reveal any effect on the extent of absorption of Valproate.
Chlorpromazine: Increase plasma levels of Valproate.
Haloperidol: Revealed no significant changes in Valproate through plasma levels.
Cimetidine and Ranitidine: Cimetidine and Ranitidine do not affect the clearance of Valproate.
Effects of Valproate on Other Drugs: Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyl transferases.
The following list provides information about the potential for an influence of Valproate coadministration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs For Which a Potentially Important Valproate Interaction: Amitriptyline/Nortriptyline: Concurrent use of Valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking Valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortripytline in the presence of Valproate.
Carbamazepine/Carbamazepine-10,11-Epoxide: Serum levels of Carbamazepine (CBZ) decreased while that of carbamazepine-10,11-epoxide (CBZ-E) increased by co-administration of Valproate and CBZ to epileptic patients.
Clonazepam: The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures.
Diazepam: Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. The elimination half-life of diazepam remained unchanged upon addition of Valproate.
Ethosuximide: Valproate inhibits the metabolism of Ethosuximide. Patients receiving Valproate and Ethosuximide, especially along with other anticonvulsants should be monitored for alterations in serum concentrations of both drugs.
Lamotrigine: The dose of Lamotrigine should be reduced when co-administered with Valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and Valproate administration. See Lamotrigine package insert for details on Lamotrigine dosing with concomitant Valproate administration.
Phenobarbital: Valproate was found to inhibit the metabolism of phenobarbital. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or Valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Primidone: Primidone is metabolized into a barbiturate and therefore, may also be involved in a similar interaction with Valproate as phenobarbital.
Propofol: A clinically significant interaction between Valproate and propofol may occur leading to an increased blood level of propofol. Therefore, when co-administered with Valproate, the dose of propofol should be reduced.
Phenytoin: Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of Valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Valproic acid serum levels may be increased in case of concomitant use with phenytoin or phenobarbital. Therefore patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemia.
Nimodipine: Concomitant treatment of nimodipine with Valproic acid may increase nimodipine plasma concentration.
Tolbutamide: The unbound fraction of tolbutamide was increased in patients treated with Valproate.
Topiramate and Acetazolamide: Concomitant administration of Valproate and topiramate or acetazolamide has been associated with hyperammonemia with and without encephalopathy. Patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy. Concomitant administration of topiramate with Valproic acid has also been associated with hypothermia in patients who have tolerated either drug alone. Blood ammonia levels should be measured in patients with reported onset of hypothermia [see Hypothermia and Hyperammonemia under PRECAUTIONS].
Warfarin: Valproate increased the unbound fraction of warfarin. The therapeutic relevance of this is unknown. However, coagulation tests should be monitored if divalproex sodium therapy is instituted in patients taking anticoagulants.
Zidovudine: The clearance of zidovudine was decreased after administration of Valproate. The half-life of zidovudine was unaffected.
Quetiapine: Co-administration of Valproate and quetiapine may increase the risk of neutropenia/leucopenia.
Drugs for Which Either No Interaction or a Likely Clinically Unimportant Interaction: Acetaminophen: Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to epileptic patients.
Clozapine: In psychotic patients, no interaction was observed when Valproate was coadministered with clozapine.
Lithium: Co-administration of Valproate (500 mg b.i.d.) and lithium carbonate (300 mg t.i.d.) to normal male volunteers (n=16) had no effect on the steady-state kinetics of Lithium.
Lorazepam: Concomitant administration Valproate and Lorazepam decrease the plasma clearance of Lorazepam.
Olanzapine: Valproate may decrease the Olanzapine plasma concentration.
Rufinamide: Valproic acid may lead to an increase in plasma level of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.
Oral Contraceptive Steroids: Administration of ethinyloestradiol or levonorgestrel on Valproate therapy did not reveal any pharmacokinetic interaction.
