OBJECT DRUGS
Opioid Analgesics:
- Alfentanil (Alfenta)
- Codeine
- Fentanyl (Sublimaze, etc.)
- Methadone (Dolophine, etc.)
- Morphine
- Oxycodone (Percocet, etc.)
- Sufentanil (Sufenta)
PRECIPITANT DRUGS
Enzyme Inducers:
- Barbiturates
- Bosentan (Tracleer)
- Carbamazepine (Tegretol, etc.)
- Dabrafenib (Tafinlar)
- Efavirenz (Sustiva)
- Etravirine (Intelence)
- Lumacaftor (Orkambi)
- Nevirapine (Viramune, etc.)
- Oxcarbazepine (Trileptal, etc.)
- Phenytoin (Dilantin, etc.)
- Primidone (Mysoline)
- Rifampin (Rifadin, etc.)
- Rifapentine (Priftin)
- Ritonavir (Norvir)
- St. John's wort
Comment:
Enzyme inducers may increase the elimination of these opioids via CYP3A4 metabolism and other pathways. This may result in reduced analgesic effects and may cause withdrawal symptoms in patients maintained on methadone. For example, rifampin has been shown to markedly reduce oxycodone plasma concentrations. Potent enzyme inducers such as rifampin may have larger effects on these analgesics than other inducers. With codeine, rifampin reduced the conversion of codeine to morphine, but only in those with normal CYP2D6 activity (EMs). Rifampin did not interact with codeine in subjects with little CYP2D6 activity (PMs), but PMs are not likely to have adequate analgesic effects from codeine whether or not they are taking enzyme inducers such as rifampin. Ritonavir may have variable effects on these opioids, depending on the duration of ritonavir therapy and other factors. In one study, ritonavir increased fentanyl plasma concentrations.
Class 3: Assess Risk & Take Action if Necessary
- Consider Alternative: While it would be prudent to use an alternative to the enzyme inducer, suitable alternatives with equivalent therapeutic effects are not available for most enzyme inducers.
- Monitor: Monitor for reduced analgesic effect or evidence of methadone withdrawal (e.g., rhinorrhea, sweating, lacrimation, restlessness, and insomnia). Increase dose of opioid if needed. If the dose of the opioid is increased to compensate for the enzyme inducer, monitor for opioid toxicity if the enzyme inducer is stopped or reduced in dosage. Keep in mind that enzyme induction is usually gradual and may take days to weeks for onset and offset, depending on the specific inducer.