Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

Rivotril can be administered concurrently with one or more other anti-epileptic medicines, in which case the dosage of each medicine must be adjusted to achieve the optimum effect.
Interactions have been reported between some benzodiazepines and other anticonvulsants, with changes in the serum concentration of the benzodiazepine or anticonvulsant. It is recommended that patients be observed for altered responses when benzodiazepines and anticonvulsants are prescribed together, and that serum level monitoring of the other anticonvulsant is performed more frequently.

Pharmacokinetic Interactions
The anti-epileptic medicines phenytoin, phenobarbitone, carbamazepine, lamotrigine and valproate may increase the clearance of clonazepam, thereby decreasing the plasma concentrations of the latter during combined treatment.

Phenytoin

The effect of clonazepam on phenytoin plasma levels is not clear as the latter may increase or decrease according to study reports depending on dosing and patient factors.

Carbamazepine

Levels may be lowered by clonazepam.Rivotril itself does not appear to induce the enzymes responsible for its own metabolism. The enzymes involved in the metabolism of Rivotril have 
not been clearly identified but include CYP3A4. Inhibitors of CYP3A4 (e.g., fluconazole) may impair the metabolism of Rivotril and lead to exaggerated concentrations and effects.

The selective serotonin reuptake inhibitors (SSRIs) sertraline and fluoxetine do not significantly affect the pharmacokinetics of clonazepam when administered concomitantly.

Pharmacodynamic Interactions
Benzodiazepines, including Rivotril, produce additive CNS depressant effects when co- administered with other medications which themselves produce CNS depression e.g. other anticonvulsant (anti-epileptic) agents, lithium, barbiturates, sedatives, tricyclic antidepressants, non-selective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines, narcotic analgesics and anaesthetics. This is especially true in the presence of alcohol (see section 4.4 Special warnings and precautions for use).

Rivotril undergoes oxidative metabolism and, consequently, may interact with disulfiram or cimetidine resulting in increased plasma levels of Rivotril. Patients should be observed closely for evidence of enhanced benzodiazepine response during concomitant treatment with either disulfiram or cimetidine; some patients may require a reduction in benzodiazepine dosage.

The anticholinergic effects of atropine and similar medicines, antihistamines and antidepressants may be potentiated.
Minor EEG changes, usually low voltage fast activity, of no known clinical significance, has been reported with benzodiazepine administration.
Some specific interactions noted with clonazepam are:

Alcohol

Epileptic patients should not under any circumstances consume alcohol while being treated with Rivotril, since alcohol may alter the effect of the medicine, reduce the efficacy of treatment or produce unexpected side effects (see section 4.4 Special warnings and precautions for use).

Sodium valproate - reports of sodium valproate causing petit mal status epilepticus with clonazepam exist.