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Effects of Epilim on other drugs: Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines: Epilim may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of other psychotropics should be adjusted when appropriate.
In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy 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.
Lithium: Epilim has no effect on serum lithium levels.
Olanzapine: Valproic acid may decrease the olanzapine plasma concentration.
Phenobarbital: Epilim increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. 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.
Primidone: Epilim increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long-term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Phenytoin: Epilim decreases phenytoin total plasma concentration. Moreover, Epilim increases phenytoin free form with possible overdosage symptoms (valproic acid 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.
Carbamazepine: Clinical toxicity has been reported when Epilim was administered with carbamazepine as Epilim may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Lamotrigine: Epilim reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly twofold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.
Felbamate: Valproic acid may decrease the felbamate mean clearance by up to 16%.
Rufinamide: Valproic acid may lead to an increase in plasma levels 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.
Propofol: Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.
Zidovudine: Epilim may raise zidovudine plasma concentration leading to increased zidovudine toxicity.
Nimodipine: In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension.
Temozolomide: Co-administration of temozolomide and Epilim may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Effects of Other Drugs on Epilim: Anti-epileptics: Anti-epileptics with enzyme-inducing effects (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to blood levels in case of combined therapy.
Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin or phenobarbital. Therefore, patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.
On the other hand, combination of felbamate and Epilim decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations. Epilim dosage should be monitored.
Anti-malarial agents: Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore, epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of Epilim may need adjustment.
Highly protein bound agents: In case of concomitant use of Epilim and highly protein bound agents (eg, aspirin), free valproic acid plasma levels may be increased.
Vitamin K-dependent factor anticoagulants: The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.
Cimetidine or erythromycin: Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
Carbapenem antibiotics such as panipenem, imipenem and meropenem: Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60%-100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, coadministration of carbapenem agents in patients stabilised on valproic acid should be avoided (see Precautions). If treatment with these antibiotics cannot be avoided close monitoring of valproic acid blood levels should be performed.
Rifampicin: Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
Protease inhibitors: Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma levels when co-administered.
Cholestyramine: Cholestyramine may lead to decrease in plasma level of valproate when co-administered.
Oestrogen-containing products, including oestrogen-containing hormonal contraceptives: Oestrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase the clearance of valproate, which would result in
decreased serum concentration of valproate and potentially decreased valproate efficacy. Consider monitoring of valproate serum levels.
On the opposite, valproate has no enzyme-inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.
Other Interactions: Newer anti-epileptics (including topiramate and acetazolamide): Caution is advised when using Epilim in combination with newer anti-epileptics whose pharmacodynamics may not be well established.
Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring of signs and symptoms is advised in particularly at risk patients such as those with preexisting encephalopathy.
Quetiapine: Co-administration of Epilim and quetiapine may increase the risk of neutropenia/leucopenia.
Epilim IV: Metamizole: Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy. Prescribers should monitor clinical response (seizure control) and consider monitoring valproate serum levels as appropriate.
