Interactions : אינטראקציות

4.5    Interactions with other medicinal products and other forms of interaction

Opioids
The simultaneous use of sedatives such as benzodiazepines or other related medicinal products such as Assival Teva 10 mg/2 ml solution for injection with opioids increases the risk of sedation, respiratory depression, coma and death due to an additive depressive effect on the CNS. The dosage and duration of any simultaneous use should be limited (see section 4.4).

The oxidative breakdown of diazepam into N-desmethyldiazepam, 3-hydroxydiazepam (temazepam) and oxazepam is catalyzed by Cytochrome-P450-isoenzymes CYP2C19 and CYP3A. In vitro studies have shown that hydroxylation is mainly mediated by CYP3A, whereas both isoenzymes CYP3A and CYP2C19 are involved in the N- demethylation. These in vitro observations were confirmed by findings from in vivo studies with subjects.

Concomitantly used medicinal products, containing active substances that are also substrates of CYP3A and/or CYP2C19 can therefore alter the pharmacokinetics of diazepam. Thus, known CYP3A or CYP2C19 inhibitors such as cimetidine, omeprazole, disulfiram, ketoconazole, fluvoxamine and fluoxetine can lead to deep and prolonged sedation.

In case of concomitant use of diazepam with the following medicinal products, mutual enhancement of the sedative, respiratory and hemodynamic effects is possible: - Sedatives, hypnotics, narcotic analgesics, anesthetics
- Neuroleptics
- Antiepileptics
- Anxiolytics
- Sedating antihistamines
- Antidepressants, lithium preparations
- 4-hydroxybutanoic acid (sodium oxybate)
- HIV protease inhibitors

This applies, in particular, to simultaneous alcohol consumption, which can change and enhance the effects of diazepam in an unpredictable manner.

Moreover, combination with narcotic analgesics can cause an intensification of the euphoric effect and thus to accelerated development of dependency.

In case of simultaneous administration of muscle relaxants, the relaxant effect is enhanced, especially in elderly patients and with higher doses (risk of falls ).

In smokers, the elimination of diazepam can be accelerated.

Theophylline in low doses removes the sedation caused by diazepam.
Diazepam can inhibit the action of levodopa.

In rare cases, diazepam can inhibit the metabolism of phenytoin and enhance its effect.
phenobarbital and phenytoin can accelerate the metabolism of diazepam.

Because of the slow elimination of diazepam, possible interactions are to be expected even after discontinuation of diazepam treatment.

In patients on long-term therapy with other medicinal products, such as centrally acting antihypertensives, β-blockers, anticoagulants and cardiac glycosides, the nature and extent of the interactions are not reliably predictable. The treating physician should verify the existence of long-term treatments prior to the administration of diazepam.
Therefore, particular caution is required if the preparation is used concomitantly, especially at the beginning of the treatment.