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Rannaprevir is a substrate for P-gp, UGT1A1, and CYP3A.
Potent or moderate CYP3A inducers:
Drugs that are potent or moderate CYP3A inducers may significantly reduce the plasma concentration of rannaprevir, which could result in loss of therapeutic effect and development of drug resistance. The concurrent use of rannaprevir with potent CYP3A inducers is contraindicated during rannaprevir treatment. The concurrent use of rannaprevir with moderate CYP3A inducers is also not recommended.
Concurrent P-gp, UGT1A1, and potent CYP3A inhibitors:
Concurrent use of P-gp, UGT1A1, and potent CYP3A inhibitors may significantly increase the plasma concentration of rannaprevir. The concurrent use of rannaprevir with these inhibitors is not recommended.
Rannaprevir is a moderate inhibitor of CYP3A. Due to the long half-life of rannaprevir after subcutaneous injection, within 9 months following the last subcutaneous administration of rannaprevir, the use of drugs primarily metabolized by CYP3A may lead to increased exposure to these drugs, potentially increasing the risk of adverse reactions.Please refer to the prescribing information for sensitive CYP3A substrates to understand the dosage recommendations when used in combination with moderate CYP3A inhibitors.
The following table provides a list of clinically relevant drug interactions along with recommended preventive or management strategies, although it is not exhaustive. The described drug interactions are based on studies conducted with rufinavir or may occur with rufinavir.
Antiarrhythmic drugs: Digoxin
Effect: Increases digoxin concentrations.
Clinical recommendation: Use with caution and monitor digoxin therapy concentrations.
Anticoagulants: Direct oral anticoagulants (DOACs) such as rivaroxaban, dabigatran, and edoxaban
Effect: Increases DOAC concentrations.
Clinical recommendation: Refer to the prescribing information for DOACs regarding use in combination with moderate CYP3A inhibitors and/or P-gp inhibitors.
Anticonvulsant drugs: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin
Effect: Decreases rufinavir concentrations.
Clinical recommendation: Co-administration may lead to loss of therapeutic effect and development of resistance. The concurrent use of rufinavir with carbamazepine or phenytoin is contraindicated.The concurrent use of rnapavirin with oxcarbazepine or phenobarbital is not recommended in the future. Consider using alternative anticonvulsant medications.
Antiretroviral drugs: Atazanavir/ritonavir, atazanavir/ritonavir plus efavirenz, nevirapine, and telaprevir/ritonavir – Effects: Increase in rnapavirin concentrations (atazanavir/ritonavir, atazanavir/ritonavir) or decrease in rnapavirin concentrations (efavirenz, nevirapine, telaprevir/ritonavir). Clinical recommendations: Concurrent use with efavirenz, nevirapine, or telaprevir/ritonavir may lead to loss of therapeutic effect and development of drug resistance. Concomitant use with atazanavir/ritonavir, atazanavir/ritonavir, efavirenz, nevirapine, or telaprevir/ritonavir is not advised.
Antimycobacterial drugs: Rifubutin, rifampicin, and rifapentine – Effects: Decrease in rnapavirin concentrations. Clinical recommendations: Concurrent use may result in loss of therapeutic effect and development of drug resistance. The concurrent use of rnapavirin with rifampicin is prohibited. The concurrent use of rnapavirin with rifubutin or rifapentine is also not recommended.
Corticosteroids (systemic): Cortisone/hydrocortisone, dexamethasone – Effects: Increase in systemic corticosteroid levels and decrease in rnapavirin concentrations (dexamethasone).Clinical recommendations: Concurrent use with systemic corticosteroids, whose exposure may increase significantly due to CYP3A inhibitors, may increase the risk of Cushing's syndrome and adrenal suppression. Start with the lowest possible dose and titrate carefully, while monitoring safety. The combination with systemic dexamethasone may lead to loss of lenaprevir efficacy and the development of resistance. Alternative corticosteroids other than dexamethasone should be considered, especially for long-term use.
Ergot derivatives: Dihydroergotamine, ergotamine, methylergometrine – Effect: Increase the concentrations of dihydroergotamine, ergotamine, and methylergometrine. Clinical recommendation: Concomitant use of lenaprevir with dihydroergotamine, ergotamine, or methylergometrine is not recommended.
Herbal products: St. John's wort (Hypericum perforatum) – Effect: Reduce the concentration of lenaprevir. Clinical recommendation: Co-administration may result in loss of therapeutic effect and development of resistance. The concurrent use of lenaprevir with St. John's wort is prohibited.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin – Effect: Increase the concentrations of lovastatin and simvastatin. Clinical recommendation: Start lovastatin and simvastatin at the lowest possible doses and titrate carefully, while monitoring safety (e.g., for myopathy).Anesthetic analgesics metabolized by CYP3A: For example, fentanyl and oxycodone. Effect: Increases the concentrations of fentanyl and oxycodone. Clinical recommendations: It is recommended to carefully monitor the therapeutic effects and adverse reactions (including potentially fatal respiratory depression) associated with anesthetic analgesics metabolized by CYP3A when used in combination.
Tramadol: Increases the concentration of tramadol. Clinical recommendations: Dosing of tramadol may need to be reduced when used in combination.
Anesthetic analgesics used for the treatment of opioid dependence: Buprenorphine and methadone. Effects on these drugs are unknown. Clinical recommendations: When starting buprenorphine or methadone in patients taking lenalaprevir, carefully titrate the dose of buprenorphine or methadone to achieve the desired effect; use the lowest possible starting or maintenance dose. If a patient is already taking buprenorphine or methadone, dose adjustments may be necessary. Monitor clinical symptoms and signs.
Opioid receptor antagonists: Naloxol: Increases the concentration of naloxol. Clinical recommendations: Avoid concurrent use with lenalaprevir; if concurrent use is unavoidable, reduce the dose of naloxol and monitor for adverse reactions.Phosphodiesterase-5 (PDE-5) inhibitors: Sildenafil, Tadalafil, Vardenafil
Effect: Increase the concentration of PDE-5 inhibitors.
Clinical recommendations:
For PDE-5 inhibitors used in pulmonary arterial hypertension (PAH): Concomitant use of Ranaprevir and Tadalafil (used for the treatment of PAH) is not recommended.
For PDE-5 inhibitors used in erectile dysfunction: Refer to the dose recommendations in the prescribing information for PDE-5 inhibitors.
Sedatives/hypnotics: Midazolam (oral), Triazolam
Effect: Increase the concentration of midazolam (oral) and triazolam.
Clinical recommendation: Caution should be exercised when midazolam or triazolam is used in combination with Ranaprevir.
Based on drug interaction studies conducted with Ranaprevir, no clinically significant interactions have been observed with the following drugs: Darunavir/Colistimath, Colistimath, Famotidine, Pitavastatin, Rosuvastatin, Tenofovir Alafenamide
FDA，2024.11
