Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction

Not recommended

Alcohol
Concomitant use with alcohol is not recommended due to enhancement of the sedative effect. This affects the ability to drive and use machinery).

Sodium oxybate
Avoid concomitant use (enhanced effects of sodium oxybate).

HIV-protease inhibitors
Avoid concomitant use (increased risk of prolonged sedation) - see below for zidovudine.
Opioids:
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as Assival with opioids increases the risk of sedation, respiratory depression, coma and death because of additive. CNS depressant effects.
The dosage and duration of concomitant use should be limited (see section 4.4).


Take into account
Centrally acting drugs enhancement of the central depressive effect or sedative effects of diazepam are likely to be intensified by concomitant administration with centrally, acting drugs such as neuroleptics, antipsychotics, anxiolytics/sedatives, , tranquillisers antidepressants, , hypnotics, anti-convulsants, analgesics, narcotic analgesics anaesthetics, barbiturates and sedative antihistamines. The elderly may require special supervision.

Narcotic analgesics
In the case of narcotic analgesics , enhancement of euphoria may also occur leading to an increase in psychic dependence. The elderly require supervision

Anti-epileptic drugs
Pharmacokinetic studies on potential interactions between diazepam and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change, have been reported.
Phenobarbital taken concomitantly may result in an additive CNS effect.
Special care should be taken in adjusting the dose in the initial stages of treatment.
Side effects may be more evident with hydantoins or barbiturates.

Diazepam has been reported to be displaced from protein-binding sites by sodium valproate (increased serum levels: increased risk of drowsiness).

There have also been reports that the metabolic elimination of phenytoin is affected by diazepam.

Other drugs enhancing the sedative effect of diazepam

Cisapride, lofexidine, nabilone, disulfiram and the muscle-relaxants - baclofenand tizanidine. Cisparide may lead to a temporary increase in the sedative effects of orally administered benzodiazepines due to faster absorption.

Compounds that affect hepatic enzymes (particularly cytochrome P450): 
Known inhibitors of hepatic enzymes: e.g cimetidine; isoniazid; erythromycin; omeprazole; esomeprazole fluvoxamine and fluoxetine have been shown to reduce the clearance of benzodiazepines and may potentiate their action.
Itraconazloe, ketoconazole, and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiapine. The effects of benzodiapine may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.
 known inducers of hepatic enzymes e.g. rifampicin) may increases the clearance of benzodiazepines.

Antihypertensives, vasodilators& diuretics:
Enhanced hypotensive effect with ACE inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel. blockers adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics. Enhanced sedative effect with alpha-blockers or moxonidine.

Dopaminergics
Possible antagonism of the effect of levodopa.

Antacids
Concurrent use may delay absorption of diazepam.
Zidovudine
Increased zidovudine clearance by diazepam.

Oestrogen-containing contraceptives
Possible inhibition of hepatic metabolism of diazepam.

Theophylline
Increases metabolism of diazepam which possibly reduces the effect.
Caffeine
Concurrent use may result in reduced sedative and anxiolytic effects of diazepam.

Grapefruit juice
Inhibition of CYP3A4 may increase the plasma concentration of diazepam (possible increased sedation and amnesia). This interaction may be of little significance in healthy individuals, but it not clear is if other factors such as old age or liver cirrhosis increase the risk of adverse effects with concurrent use.