Rossi S (Ed.) (2008). Australian Medicines Handbook 2008 (Electronic edition). Adelaide: Australian Medicines Handbook.

Benzodiazepines

Benzodiazepines cause CNS and respiratory depression; administration with other drugs* which also have these effects increases the risk of these effects; reduce benzodiazepine dose if appropriate and monitor clinically.

Antiepileptic use

Pharmacokinetic interactions between antiepileptic drugs are variable and unpredictable. They can increase or decrease drug concentrations, and either increase risk of toxicity or reduce seizure control.

Monitor clinically when adding or withdrawing an antiepileptic drug in a patient already receiving another antiepileptic drug. Concentration monitoring may be useful for some drugs. Adjust dosage as required.

Use with drugs which lower seizure threshold cautiously, if at all, see Table B-2 Drugs which may cause seizures. Some drugs* may be contraindicated.

cimetidine + benzodiazepines

Cimetidine may increase concentration of alprazolam, clobazam, diazepam, midazolam, nitrazepam and triazolam with possible increase in adverse effects; use alternative H₂ antagonist (eg ranitidine) or an alternative benzodiazepine (eg lorazepam, oxazepam or temazepam) or monitor clinical effects and decrease dosage of benzodiazepine if necessary.

clozapine + benzodiazepines

theophylline + benzodiazepines

Theophylline may reduce sedative effects of benzodiazepines; monitor for clinical effect and increase benzodiazepine dose if necessary.

Alprazolam

Drugs that inhibit CYP3A4 may inhibit alprazolam's metabolism, enhance sedative effect and may cause respiratory depression; monitor clinical effect and reduce alprazolam dose if necessary or consider using an alternative benzodiazepine (eg lorazepam, oxazepam or temazepam). See Table B-1 Some inducers, inhibitors & substrates of CYP450 enzymes. Some combinations* may be contraindicated by the manufacturers.

delavirdine + alprazolam

Delavirdine is likely to reduce alprazolam's metabolism; may increase sedation or cause respiratory depression; preferably avoid combination; use an alternative benzodiazepine or reduce alprazolam dose and monitor clinical effects; adjust alprazolam dose as needed. (Manufacturer of delavirdine contraindicates combination.)

fluoxetine + alprazolam

Fluoxetine may inhibit metabolism of alprazolam and may enhance sedation and other adverse effects; consider an alternative SSRI or benzodiazepine, eg lorazepam or oxazepam, or reduce alprazolam dose and monitor clinical effects; adjust alprazolam dose if necessary.

fluvoxamine + alprazolam

Fluvoxamine may inhibit metabolism of alprazolam; may enhance sedation and other adverse effects; consider an alternative SSRI or benzodiazepine, eg lorazepam or oxazepam, or consider halving the initial alprazolam dose and monitor clinical effects; adjust alprazolam dose if necessary.

itraconazole + alprazolam

Itraconazole inhibits metabolism of alprazolam; may enhance sedation and cause respiratory depression; avoid combination or reduce alprazolam dose and monitor clinical effects; adjust alprazolam dose if necessary.

ketoconazole + alprazolam

Ketoconazole inhibits metabolism of alprazolam; may enhance sedation and cause respiratory depression; avoid combination or reduce alprazolam dose and monitor clinical effects; adjust alprazolam dose if necessary.

protease inhibitors + alprazolam

Ritonavir inhibits alprazolam's metabolism, increasing its sedative effect (respiratory depression may result); other PIs are likely to behave similarly. (Interaction with ritonavir is complex as induction of metabolism over time may offset the short term inhibition so the net effect is hard to predict.) Avoid combinations or reduce alprazolam dose and monitor clinical effects; adjust alprazolam dose if necessary. Manufacturer of indinavir contraindicates combination.

St John's wort + alprazolam

St John's wort increases metabolism of alprazolam, decreasing its concentration and therapeutic effect; avoid combination or monitor for withdrawal symptoms or decreased efficacy and increase alprazolam dose if necessary.

Diazepam

fluconazole + diazepam

Fluconazole may inhibit diazepam's metabolism, increasing the risk of adverse effects; monitor for adverse effects and decrease diazepam dose if necessary.

phenytoin + diazepam

rifampicin + diazepam

Rifampicin may substantially increase the metabolism of diazepam, decreasing its concentration and clinical effect; may need to increase diazepam dose or use alternative benzodiazepine, eg temazepam.

voriconazole + diazepam

Voriconazole may inhibit diazepam's metabolism, increasing the risk of adverse effects; monitor for adverse effects and decrease diazepam dose if necessary.

Midazolam

See also General anaesthetics

Drugs that inhibit CYP3A4, see Table B-1 Some inducers, inhibitors & substrates of CYP450 enzymes, may inhibit metabolism of midazolam:

may prolong its sedative and respiratory depressant effects; midazolam should not be thought a short acting agent in these circumstances (may result in an inability to drive for some hours after a single dose)
reduce midazolam dose and monitor clinical effects, adjusting its dose or increasing the dosing interval if necessary; or if appropriate, consider using an alternative benzodiazepine, eg lorazepam
some combinations* may be contraindicated by the manufacturers.

aprepitant + midazolam

Aprepitant may increase midazolam concentration significantly, prolonging its sedative and respiratory depressant effects; consider using an alternative benzodiazepine or reducing the midazolam dose.

azoles + midazolam

Azole antifungals inhibit metabolism of midazolam, prolonging its sedative and respiratory depressant effects (this effect may be substantial).
Fluconazole, avoid combination or reduce midazolam dose (probably by at least half) and monitor clinical effect.
Itraconazole, reduce midazolam dose (possibly to one-quarter) and monitor clinical effect (combination with oral midazolam contraindicated by manufacturer).
Ketoconazole, avoid combination or reduce midazolam dose (possibly to one-quarter) and monitor clinical effect (combination with oral midazolam contraindicated by manufacturer).
Posaconazole, avoid combination.
Voriconazole, avoid combination with oral midazolam; reduce IV midazolam dose, monitor for midazolam's adverse effects and adjust dose further if necessary.

carbamazepine + midazolam

Carbamazepine may increase midazolam's metabolism and decrease its effects; use alternative benzodiazepine (see Midazolam) or increase midazolam dose if needed.

clarithromycin + midazolam

Clarithromycin may inhibit midazolam's metabolism prolonging its sedative and respiratory depressant effects; reduce midazolam dose and monitor clinical effect, adjusting midazolam dose if necessary, or use an alternative benzodiazepine (see Midazolam).

delavirdine + midazolam

Delavirdine is likely to reduce midazolam's metabolism; combination may result in prolonged sedation or respiratory depression; avoid combination if possible (may use single dose midazolam for procedural sedation with caution). Manufacturer of delavirdine contraindicates combination.

diltiazem + midazolam

Diltiazem inhibits metabolism of midazolam prolonging its sedative and respiratory depressant effects; reduce midazolam dose (possibly by at least half) and monitor clinical effects.

efavirenz + midazolam

Efavirenz is likely to reduce midazolam's metabolism, resulting in prolonged sedation or respiratory depression; avoid combination if possible (may use single dose midazolam for procedural sedation with caution). Manufacturer of efavirenz contraindicates combination.

erythromycin + midazolam

Erythromycin inhibits metabolism of midazolam prolonging its sedative and respiratory depressant effects; avoid combination or give quarter to a half usual midazolam dose and monitor clinical effect. An alternative benzodiazepine may be appropriate (see Midazolam).

phenytoin + midazolam

Phenytoin may increase midazolam metabolism, decreasing its therapeutic effects; avoid combination or increase midazolam dose if needed. An alternative benzodiazepine may be appropriate (see Midazolam).

protease inhibitors + midazolam

Saquinavir inhibits metabolism of midazolam (the other PIs are likely to behave in the same way); combination may result in prolonged sedation or respiratory depression (midazolam concentration expected to be higher after oral midazolam). Avoid combination or reduce midazolam dose and monitor closely (may use single dose midazolam for procedural sedation with caution).

rifampicin + midazolam

Rifampicin may substantially increase the metabolism of midazolam, decreasing its concentration and clinical effect; as the effect is so great avoid combination and use an alternative benzodiazepine (see Midazolam).

St John's wort + midazolam

St John's wort increases metabolism of midazolam, decreasing its concentration and therapeutic effect; avoid combination or monitor for decreased efficacy and increase midazolam dose if necessary.

verapamil + midazolam

Verapamil inhibits metabolism of midazolam prolonging its sedative and respiratory depressant effects; reduce midazolam dose (possibly by at least half) and monitor clinical effect.

Nitrazepam

rifampicin + nitrazepam

Rifampicin may substantially increase the metabolism of nitrazepam, decreasing its concentration and clinical effect; may need to increase nitrazepam dose or use an alternative benzodiazepine, eg temazepam.

Triazolam

Drugs that inhibit CYP3A4, see Table B-1 Some inducers, inhibitors & substrates of CYP450 enzymes, may inhibit metabolism of triazolam prolonging its sedative and respiratory depressant effects; monitor clinically and reduce triazolam dose if necessary. Consider using an alternative benzodiazepine, eg lorazepam, oxazepam or temazepam. Some combinations* may be contraindicated by the manufacturers.

clarithromycin + triazolam

Clarithromycin inhibits the metabolism of triazolam and may increase its sedative and respiratory depressant effects; avoid combination or give quarter to a half usual triazolam dose and monitor clinical effect.

delavirdine + triazolam

Delavirdine is likely to reduce triazolam's metabolism; combination may result in prolonged sedation or respiratory depression; avoid combination (combination contraindicated by manufacturer). An alternative benzodiazepine may be appropriate (see Triazolam).

diltiazem + triazolam

Diltiazem inhibits metabolism of triazolam, prolonging its sedative and respiratory depressant effects; avoid combination or reduce triazolam dose and monitor clinically. An alternative benzodiazepine may be appropriate (see Triazolam).

efavirenz + triazolam

Efavirenz is likely to reduce triazolam's metabolism; combination may result in prolonged sedation or respiratory depression; avoid combination (combination contraindicated by manufacturer). An alternative benzodiazepine may be appropriate (see Triazolam).

erythromycin + triazolam

Erythromycin inhibits the metabolism of triazolam and may significantly increase its therapeutic and adverse effects; avoid combination or give quarter to a half usual triazolam dose and monitor clinical effects. An alternative benzodiazepine may be appropriate (see Triazolam).

fluconazole + triazolam

Fluconazole reduces triazolam metabolism increasing sedation and adverse effects; avoid combination or reduce triazolam dose (probably by about half) and monitor clinical effects.

itraconazole + triazolam

Itraconazole inhibits metabolism of triazolam prolonging its sedative and respiratory depressant effects; avoid combination or reduce triazolam dose to one-quarter and monitor clinical effects (combination contraindicated by manufacturer).

ketoconazole + triazolam

Ketoconazole reduces triazolam's metabolism and increases sedation and adverse effects; avoid combination or reduce triazolam dose to one-quarter and monitor clinically (combination contraindicated by manufacturer).

protease inhibitors + triazolam

Ritonavir reduces triazolam's metabolism; combination may result in prolonged sedation or respiratory depression; other PIs are likely to behave similarly. (Interaction with ritonavir is complex as induction of metabolism over time may offset short term inhibition so that the net effect is hard to predict.) Avoid any combination or reduce triazolam dose and monitor closely. Manufacturers of PIs contraindicate combinations.

rifampicin + triazolam

Rifampicin may substantially increase the metabolism of triazolam, decreasing its concentration and clinical effect; as the effect is so great avoid combination and use an alternative benzodiazepine (see Triazolam).

* Check the relevant drug monograph(s) to see whether these effects are likely to occur

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