Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Combinations that require specific consideration:
Hepatic injury, including a fatal case, have been reported in patients treated with temozolomide (TMZ) and levetiracetam (LEV) concomitantly.
Some of the reactions occurred in patients with underlying hepatic disease or taking concomitant medications known to have the potential for hepatic injury.

A suggested mechanism for the interaction is the inhibition of O-6-methylguanine-DNA methyltransferase (MGMT) by LEV causing accumulation of TMZ in the circulation resulting in potential increase in the risk of hepatic injury.
Before treatment initiation with LEV and TMZ combination:

Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating the combination including the potential for fatal hepatic failure.

During Treatment with LEV and TMZ combination:

Liver function tests should be performed regularly during treatment (see section 4.4).
For patients with liver function abnormalities, physicians should assess the benefit/risk of continuing treatment.

In case of development of signs and symptoms of liver dysfunction or active liver disease, treatment with this combination should be suspended pending the outcome of the benefit/risk evaluation.


Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.
A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dosage adjustment is not required.

Probenecid
Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low.


Methotrexate
Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

Oral contraceptives and other pharmacokinetics interactions
Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified.
Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.

Laxatives
There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.

Food and alcohol
The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.
No data on the interaction of levetiracetam with alcohol are available.