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Drug Interactions between Dolophine and nevirapine

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

methadone nevirapine

Applies to: Dolophine (methadone) and nevirapine

MONITOR: Coadministration with the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz or nevirapine may decrease the plasma concentrations of methadone. The mechanism is NNRTI induction of methadone metabolism via CYP450 3A4. In 11 patients on stable methadone maintenance therapy, initiation of antiretroviral therapy containing efavirenz (600 mg once a day) resulted in decreases in mean methadone peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of 48% and 57%, respectively, compared to baseline. Nine patients developed symptoms consistent with methadone withdrawal an average of 8 to 10 days after start of efavirenz, which required a 22% mean increase in methadone dosage. In a similar study using nevirapine (200 mg once daily for 2 weeks followed by 200 mg twice daily), the reduction in mean methadone Cmax and AUC was 36% and 52%, respectively, in 8 patients stabilized on methadone treatment. Withdrawal symptoms occurred in six patients 8 to 10 days after start of nevirapine, and methadone dosage was subsequently increased an average of 16%. Dosage increases of up to 100% and eventual discontinuation of NNRTI therapy have been cited in some case reports.

MANAGEMENT: Caution is advised if efavirenz or nevirapine is prescribed to patients treated with methadone. Pharmacologic response to methadone should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of NNRTI therapy in patients who are stabilized on their methadone regimen. Following cessation of NNRTI therapy, it takes approximately 2 to 3 weeks for enzyme activity to return to pre-induction levels. Thus, if NNRTI therapy is discontinued due to adverse events or antiretroviral failure, methadone dosage should be gradually reduced over 2 to 3 weeks to pre-NNRTI levels. For patients treated with efavirenz, clinicians must also bear in mind that neurological adverse effects such as dizziness, headache, insomnia, vivid dreams, nightmares, and agitation may occur in up to 25% of patients shortly (within the first several days) after starting efavirenz. These symptoms may be self-limiting and should be clinically differentiated from symptoms of methadone withdrawal so as to avoid unnecessary increases in methadone dosage and the risk of toxicity.

References

  1. Heelon MW, Meade LB (1999) "Methadone withdrawal when starting an antiretroviral regimen including nevirapine." Pharmacotherapy, 19, p. 471-2
  2. Altice FL, Friedland GH, Cooney EL (1999) "Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone." AIDS, 13, p. 957-62
  3. Otero MJ, Fuertes A, Sanchez R, Luna G (1999) "Nevirapine-induced withdrawal symptoms in HIV patients on methadone maintenance programme: an alert." AIDS, 13, p. 1004-5
  4. Pinzani V, Faucherre V, Peyriere H, Blayac JP (2000) "Methadone withdrawal symptoms with nevirapine and efavirenz." Ann Pharmacother, 34, p. 405-7
  5. Marzolini C, Troillet N, Telenti A, Baumann P, Decosterd LA, Eap CB (2000) "Efavirenz decreases methadone blood concentrations." Aids, 14, p. 1291-2
  6. Clarke SM, Mulcahy FM, Reynolds HE, Gibbons SE, Barry MG, Back DJ (2001) "The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz." Br J Clin Pharmacol, 51, p. 213-7
  7. Clarke SM, Mulcahy FM, Tjia J, et al. (2001) "Pharmacokinetic Interactions of Nevirapine and Methadone and Guidelines for Use of Nevirapine to Treat Injection Drug Users." Clin Infect Dis, 33
  8. Back D, Gibbons S, Khoo S (2003) "Pharmacokinetic drug interactions with nevirapine." J Acquir Immune Defic Syndr, 34 Suppl 1, S8-14
View all 8 references

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Drug and food interactions

Moderate

methadone food

Applies to: Dolophine (methadone)

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of methadone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 8 study subjects stabilized on methadone maintenance treatment, ingestion of regular strength grapefruit juice (200 mL one-half hour before and 200 mL simultaneously with the daily methadone dose) for five days resulted in an approximately 17% mean increase in methadone peak plasma concentration (Cmax) and systemic exposure (AUC) and a 14% mean decrease in apparent clearance for both the R(+) and S(-) enantiomers. Grapefruit juice did not affect the time to peak level (Tmax), terminal half-life, or apparent volume of distribution of methadone. No signs or symptoms of methadone toxicity or changes in intensity of withdrawal symptoms were reported in the study.

MANAGEMENT: Given the interindividual variability in the pharmacokinetics of methadone, a more significant interaction with grapefruit juice in certain patients cannot be ruled out. Patients treated with methadone should preferably avoid or limit the consumption of grapefruit juice, particularly during the induction of maintenance treatment.

References

  1. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, Beaune P, Menez JF (1996) "Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes." Chem Res Toxicol, 9, p. 365-73
  2. Oda Y, Kharasch ED (2001) "Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation." J Pharmacol Exp Ther, 298, p. 1021-32
  3. Benmebarek M, Devaud C, Gex-Fabry M, et al. (2004) "Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone." Clin Pharmacol Ther, 76, p. 55-63
  4. Foster DJ, Somogyi AA, Bochner F (1999) "Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4." Br J Clin Pharmacol, 47, p. 403-12
View all 4 references

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Moderate

methadone food

Applies to: Dolophine (methadone)

GENERALLY AVOID: Ethanol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

MANAGEMENT: Concomitant use of opioid analgesics with ethanol should be avoided.

References

  1. Linnoila M, Hakkinen S (1974) "Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving." Clin Pharmacol Ther, 15, p. 368-73
  2. Sturner WQ, Garriott JC (1973) "Deaths involving propoxyphene: a study of 41 cases over a two-year period." JAMA, 223, p. 1125-30
  3. Girre C, Hirschhorn M, Bertaux L, et al. (1991) "Enhancement of propoxyphene bioavailability by ethanol: relation to psychomotor and cognitive function in healthy volunteers." Eur J Clin Pharmacol, 41, p. 147-52
  4. Levine B, Saady J, Fierro M, Valentour J (1984) "A hydromorphone and ethanol fatality." J Forensic Sci, 29, p. 655-9
  5. Sellers EM, Hamilton CA, Kaplan HL, Degani NC, Foltz RL (1985) "Pharmacokinetic interaction of propoxyphene with ethanol." Br J Clin Pharmacol, 19, p. 398-401
  6. Carson DJ (1977) "Fatal dextropropoxyphene poisoning in Northern Ireland. Review of 30 cases." Lancet, 1, p. 894-7
  7. Rosser WW (1980) "The interaction of propoxyphene with other drugs." Can Med Assoc J, 122, p. 149-50
  8. Edwards C, Gard PR, Handley SL, Hunter M, Whittington RM (1982) "Distalgesic and ethanol-impaired function." Lancet, 2, p. 384
  9. Kiplinger GF, Sokol G, Rodda BE (1974) "Effect of combined alcohol and propoxyphene on human performance." Arch Int Pharmacodyn Ther, 212, p. 175-80
View all 9 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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