Interactions : אינטראקציות

4.5.      Interaction with other medicinal products and other forms of interaction
Effects of Orfiril injection on other drugs
Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines
Orfiril injection may potentiate the effect of other psychotropics, such as antipsychotics, monoamine oxidase inhibitors, antidepressants and benzodiazepines. Therefore, clinical monitoring 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
Orfiril injection has no effect on serum lithium levels.

Olanzapine
Valproic acid may decrease the olanzapine plasma concentration.

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.


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 especially when initiating combined therapy with dosage adjustment as necessary.


Phenytoin
Orfiril injection decreases phenytoin total plasma concentration and increases the free form of phenytoin leading to possible overdosage symptoms. Therefore, clinical monitoring is recommended with the free form of phenytoin being measured, when phenytoin plasma levels are determined.

Carbamazepine
Clinical toxicity has been reported when Orfiril injection was administered with carbamazepine as Orfiril injection may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

Lamotrigine
Orfiril injection 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 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
Orfiril injection 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.
Vitamin K-dependent anticoagulants
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproate. The prothrombin time should be closely monitored.

Temozolomide
Co-administration of temozolomide and Orfiril injection may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.

Effects of other drugs on Orfiril injection
Antiepileptics
Antiepileptics with enzyme inducing effects e.g. phenytoin, phenobarbital, carbamazepine, decrease valproate plasma levels. Plasma levels should be monitored, and dosage adjusted accordingly.

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 Orfiril injection decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations.
Orfiril injection dosage should be monitored.
Anti-malaria agents
Mefloquine and chloroquine increases valproate metabolism and therefore epileptic seizures may occur in combined therapy. The dosage of sodium valproate may need adjustment.

Highly protein bound agents
Free valproate levels may be increased in the case of concomitant use with highly protein bound agents e.g. acetylsalicylic acid.

Cimetidine or erythromycin
Valproate 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 imipenem, panipenem 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, co-administration of carbapenem agents in patients stabilized on valproic acid should be avoided (section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.

Colestyramine
Colestyramine may decrease the absorption of valproate.

Rifampicin
Rifampicin may decrease the valproate 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 level 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 (see section 4.4). 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.
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 or mood control) and consider monitoring valproate serum levels as appropriate.
Methotrexate
Some case reports describe a significant decrease in valproate serum levels after methotrexate administration, with occurrence of seizures. Prescribers should monitor clinical response (seizure control) and consider monitoring valproate serum levels as appropriate.
Other interaction
Risk of liver damage
The concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of liver toxicity (see section 4.4). Concomitant use of valproate and multiple anticonvulsant therapy increases the risk of liver damage, especially in young children (see section 4.4).
Concomitant use with cannabidiol increases the incidence of transaminases enzyme elevation. In clinical trials in patients of all ages receiving concomitantly cannabidiol at doses 10 to 25 mg/kg and valproate, ALT increases greater than 3 times the upper limit of normal have been reported in 19% of patients. Appropriate liver monitoring should be exercised when valproate is concomitantly used with other anticonvulsants with potential hepatotoxicity, including cannabidiol, and dose reductions or discontinuation should be considered in case of significant anomalies of liver parameters (see section 4.4).

Newer anti-epileptics (including topiramate and acetazolamide)
Caution is advised when using Orfiril injection in combination with newer antiepileptics whose pharmacodynamics may not be well established.
Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. Careful monitoring of signs and symptoms is advised in particularly at- risk patients such as those with pre-existing encephalopathy.

Pivalate-conjugated medicines
Concomitant administration of valproate and pivalate-conjugated medicines (such as cefditoren pivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) should be avoided due to increased risk of carnitine depletion (see section 4.4 Patients at risk of hypocarnitinaemia). Patients in whom coadministration cannot be avoided should be carefully monitored for signs and symptoms of hypocarnitinaemia.
Quetiapine
Co-administration of Orfiril injection and quetiapine may increase the risk of neutropenia/leucopenia.