Methadone and Ketoconazole
Desk tier: Serious concern
Mechanism: strong CYP3A4 inhibition of clearance (↑ exposure)
“The concomitant use of methadone hydrochloride tablets with all cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors … could cause potentially fatal respiratory depression”
Why this grade
Methadone HCl tablets label, Boxed Warning (Cytochrome P450 Interaction); 7 DRUG INTERACTIONS
The Methadone HCl tablets label names this interaction in its Boxed Warning: "The concomitant use of methadone hydrochloride tablets with all cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors … could cause potentially fatal respiratory depression" Retrieved from DailyMed 2026-09-27.
Open sourceFDA interaction table
FDA's example-interaction table lists Ketoconazole as a strong CYP3A inhibitor. FDA grades the roles; the severity tier on this row is the desk's rule. Table content current as of 2026-05-29.
Open sourceKetoconazole tablets label, Contraindications
The Ketoconazole tablets label calls this combination contraindicated: "Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine." Retrieved from DailyMed 2026-10-12.
Open sourcePMID 31006110
2019 Clin Pharmacol Ther. 2B6 PM stacks efavirenz. Same isoform as ketamine and methadone.
Open sourceAll pairs for Methadone · Ketoconazole
Enzyme behind this pair: CYP3A4
Educational reference only. Not FDA-cleared. The Prescribing Information governs.
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