Methadone and Nafcillin Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methadone
Nafcillin Injection
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Reduced methadone exposure and an increased risk of opioid withdrawal symptoms
Interaction Deep Dive
Concomitant use of methadone (a CYP3A4 substrate) with CYP3A4 inducers may decrease the plasma concentration of methadone, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone. When using methadone with CYP3A4 inducers, follow patients for signs or symptoms of opioid withdrawal and consider increasing the methadone dosage as needed. Discontinuation of concomitant CYP3A4 inducer in methadone-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Therefore, when discontinuing a CYP3A4 inducer in methadone-treated patients, consider dosage reduction of methadone and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation1234.
Why it happens (mechanism)
Induction of CYP3A4-mediated methadone metabolism
Literature reports
3 reports — tap to read
a) In a pharmacokinetic study in patients receiving methadone maintenance, administration of phenytoin 250 mg twice daily for 1 day followed by 300 mg daily for 3 to 4 days resulted in an approximate 50% reduction in methadone exposure and the development of withdrawal symptoms. When phenytoin was discontinued, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level similar to that prior to the phenytoin administration 1.
b) Twenty-one of 30 patients (70%) on methadone maintenance had withdrawal symptoms after rifAMPin (600 to 900 mg daily) was given. Onset of withdrawal symptoms was from 1 to 33 days after rifAMPin was started. Six of 7 patients with severe withdrawal symptoms had the onset within six days. Methadone plasma levels were measured in six of these patients both on and off rifAMPin. Results showed a 33% to 66% decrease in methadone plasma levels. Peak methadone plasma levels were also found to be consistently lower in patients on rifAMPin after a single dose of methadone. The major metabolite of methadone, pyrrolidine, increased 150% in a 24-hour urinary excretion study in four of the patients 5.
c) In one case withdrawal symptoms were noted 5 days after rifAMPin (450 mg per day) was started in a 24-year-old female maintained on methadone (40 mg per day) 6.
Common questions
Can I take Methadone and Nafcillin Injection together?
Reduced methadone exposure and an increased risk of opioid withdrawal symptoms Always confirm with your pharmacist or prescriber before making any change.
How serious is the Methadone and Nafcillin Injection interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Methadone or Nafcillin Injection need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (6)
- Product Information: DOLOPHINE(R) oral tablets, methadone HCl oral tablets. West-Ward Pharmaceuticals Corp (per FDA), Eatontown, NJ, 2019. DailyMed
- Product Information: DISKETS dispersible tablets, methadone HCl dispersible tablets. Hikma Pharmaceuticals USA Inc (per FDA), Berkeley, NJ, 2023.
- Product Information: METHADOSE oral concentrate, methadone HCl oral concentrate. SpecGx LLC (per FDA), Webster Groves, MO, 2023. DailyMed
- Product Information: Methadone HCl injection, methadone HCl injection. Mylan Institutional LLC (per FDA), Morgantown, WV, 2023. DailyMed
- Kreek MJ, Garfield JW, Gutjahr CL, et al: Rifampin-induced methadone withdrawal. N Engl J Med 1976; 294:1104-1106. PubMed
- Bending MR & Skacel PO: Rifampicin and methadone withdrawal (letter). Lancet 1977; 1:1211. DOI
Keep reading about Methadone
Keep reading about Nafcillin Injection
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