Drug Interactions between buprenorphine and ivacaftor / lumacaftor

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of buprenorphine, which is partially metabolized (approximately 30%) by the isoenzyme. The interaction appears to be dependent, in part, on the route of administration of buprenorphine. When administered transdermally, buprenorphine peak plasma concentration (Cmax) and systemic exposure (AUC) were not significantly affected by ketoconazole, a potent CYP450 3A4 inhibitor. However, it was reported in another study that ketoconazole increased the Cmax and AUC of buprenorphine (route unspecified) by approximately 70% and 50%, respectively, and to a lesser extent, of the metabolite norbuprenorphine. The interaction has also been reported with atazanavir/ritonavir. A case series describes three patients who experienced excessive opiate effects of buprenorphine during concomitant antiretroviral therapy with atazanavir, ritonavir, and various nucleoside reverse transcriptase inhibitors. Two of the patients had been on their antiretroviral regimen for several months and reported doped-up feeling, dizziness, and feeling high following initiation of buprenorphine 8 mg/day. The dosage was reduced to 8 mg every other day. One was maintained on this dosage while the other had dosage increased up to 12 mg/day, whereupon he developed hypersomnolence but managed to maintain that dosage. The third patient had been inducted with buprenorphine and titrated to a stable dose of 14 mg/day for two days prior to beginning antiretroviral therapy. The next day, the patient complained of daytime somnolence and decreased mental functioning. His buprenorphine dosage was decreased to 8 mg/day, and he developed tolerance to the sedative effects within 7 days.

MANAGEMENT: Caution is advised if buprenorphine is prescribed with CYP450 3A4 inhibitors. Induction with buprenorphine should begin at a reduced dosage, and dosage escalation should occur more slowly to allow for assessment of opiate effects and development of patient tolerance. In patients who are already stabilized on buprenorphine, pharmacologic response and vital signs should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the buprenorphine dosage adjusted as necessary. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities. Patients should seek medical attention if potential signs and symptoms of toxicity occur such as dizziness, confusion, fainting, extreme sedation, bradycardia, slow or difficult breathing, and shortness of breath.

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of buprenorphine, which is primarily metabolized by the isoenzyme. Reduced efficacy or withdrawal symptoms may occur in patients maintained on buprenorphine. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Pharmacologic response to buprenorphine should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the buprenorphine dosage adjusted as necessary. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The prescribing information for the concomitant CYP450 3A4 inducers should be consulted for specific recommendations.