Table 1.
Drug-Drug Interactions to Watch Out for When Treating Invasive Aspergillosis
| Coadministered Drug | Effect on Drug Levels | Effect on Antifungal | Potential Clinical Effects | DDI Severity Ranking |
Management Strategies* |
|---|---|---|---|---|---|
| Posaconazole (strong CYP3A4 inhibitor; P-gp inhibitor and substrate) | |||||
| Venetoclax | ↑ Venetoclax (AUC: 90-144%) | No significant change | Hematologic toxicity, GI toxicity, tumor lysis syndrome | Major | CLL/SLL at steady state dose: reduce venetoclax to 70-100 mg/day; AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 70-100 mg/day starting on day 4 |
| Ibrutinib | ↑ Ibrutinib (3- to 10- fold increase in exposure) | No significant change | Hematologic toxicity, bleeding, infection | Major | If coadministered with posaconazole oral suspension 200 mg t.i.d. or 400 mg b.i.d. or posaconazole delayed release tablets or i.v. once daily, reduce ibrutinib to or 140 mg/day p.o. for chronic GVHD. |
| Ruxolitinib | ↑ Ruxolitinib | No significant change | Thrombocytopenia, anemia, elevated liver enzymes, diarrhea | Major | No initial dose adjustments necessary for patients with GVHD. |
| Bortezomib | ↑ Bortezomib | No significant change | Myelosuppression, peripheral neuropathy, GI toxicity | Moderate | Use with caution; monitor bortezomib toxicity. |
| Idelalisib | ↑ Idelalisib (AUC: 1.8-fold) | No significant change | Myelosuppression, infection, elevated liver enzymes, enterocolitis | Major | No recommendation for dose adjustment. |
| Duvelisib | ↑ Duvelisib (AUC: 2-fold) | No significant change | Myelosuppression, infection, elevated liver enzymes, enterocolitis | Major | Reduce duvelisib dose to 15 mg p.o. b.i.d. |
| Tacrolimus | ↑ Tacrolimus (Cmax2-fold; AUC: 4.5-fold) | No significant change | Nephrotoxicity, neurotoxicity, hyperkalemia, electrolyte abnormalities | Major | Dosage reduction of tacrolimus is recommended. |
| Sirolimus | ↑ Sirolimus (Cmax: 572%; AUC: 788%) | No significant change | Hypertension, peripheral edema, hepatotox- icity, impaired wound healing, ILD | Severe | Dosage reduction of sirolimus is recommended. |
| Cyclosporine | ↑ Cyclosporine | No significant change | Nephrotoxicity, hepatotoxicity, neurotoxicity, hypertension | Major | Dosage reduction of cyclosporine is recommended. |
| Voriconazole (strong CYP3A4 and CYP2C9 inhibitor; CYP2C19 inhibitor; CYP2C19, CYP2C9, and CYP3A4 substrate) | |||||
| Venetoclax | ↑ Venetoclax (AUC: 90-690%) | No significant change | Hematologic toxicity, GI toxicity, tumor lysis syndrome | Major | See posaconazole for details. |
| Ibrutinib | ↑ Ibrutinib (Cmax: 6.7-fold; AUC: 5.7-fold) | No significant change | Hematologic toxicity, bleeding, infection | Major | If coadministered with voriconazole 200 mg p.o. b.i.d, reduce ibrutinib dose to 140 mg/day p.o. for B cell malignancy or 280 mg/day p.o. for chronic GVHD. |
| Ruxolitinib | ↑ Ruxolitinib | No significant change | Thrombocytopenia, anemia, elevated liver enzyme, diarrhea | Major | See posaconazole for details. |
| Bortezomib | ↑ Bortezomib | No significant change | Myelosuppression, peripheral neuropathy, GI toxicity | Moderate | Use with caution; monitor bortezomib for toxicity. No recommendation for dosage adjustment. |
| Idelalisib | ↑ Idelalisib | ↑ Voriconazole | Myelosuppression, infection, elevated liver enzymes, enterocolitis | Major | Avoid coadministration. No recommendation for dosage adjustment. |
| Duvelisib | ↑ Duvelisib (AUC: 1.8-fold) | No significant change | Myelosuppression, infection, elevated liver enzymes, enterocolitis | Major | Reduce duvelisib dose to 15 mg p.o. b.i.d. |
| Tacrolimus | ↑ Tacrolimus (Cp: 2-fold; AUC: 3-fold) | No significant change | Nephrotoxicity, neurotoxicity, hyperkalemia, electrolyte abnormalities | Major | Dosage reduction of tacrolimus is recommended. |
| Sirolimus | ↑ Sirolimus (Cp: 7-fold; AUC: 11-fold) | No significant change | Hypertension, peripheral edema, hepatotoxicity, impaired wound healing, ILD | Severe | Dosage reduction of sirolimus is recommended. |
| Cyclosporine | ↑ Cyclosporine | No significant change | Nephrotoxicity, hepatotoxicity, neurotoxicity, hypertension | Major | Dosage reduction of cyclosporine is recommended. |
| Itraconazole (strong CYP3A4 inhibitor, P-gp and BCRP inhibitor, and CYP3A4, P-gp substrate) | |||||
| Venetoclax | ↑ Venetoclax (AUC: 90-690%) | No significant change | Hematologic toxicity, GI toxicity, tumor lysis syndrome | Major | See posaconazole for details. |
| Coadministered Drug | Effect on Drug Levels | Effect on Antifungal | Potential Clinical Effects | DDI Severity Ranking | Management Strategies* |
| Ibrutinib | ↑ Ibrutinib | No significant change | Hematologic toxicity, bleeding, infection | Major | No recommendation for dosage adjustment. |
| Ruxolitinib | ↑ Ruxolitinib | No significant change | Thrombocytopenia, anemia, elevated liver enzymes, diarrhea | Major | See posaconazole for details. |
| Bortezomib | ↑ Bortezomib | No significant change | Myelosuppression, peripheral neuropathy, GI toxicity | Moderate | Use with caution; monitor for bortezomib toxicity. No recommendation for dosage adjustment. |
| Idelalisib | ↑ Idelalisib (AUC: 1.8-fold) | ↑ Voriconazole | Myelosuppression, infection, elevated liver enzymes, enterocolitis | Major | Avoid coadministration. No recommendation for dosage adjustment. |
| Duvelisib | ↑ Duvelisib (AUC: 2-fold) | No significant change | Myelosuppression, infection, elevated liver enzymes, enterocolitis | Major | Reduce duvelisib dose to 15 mg p.o. b.i.d. |
| Tacrolimus | ↑ Tacrolimus | No significant change | Nephrotoxicity, neurotoxicity, hyperkalemia, electrolyte abnormalities | Moderate | Dosage reduction of tacrolimus is recommended. |
| Sirolimus | ↑ Sirolimus | Hypertension, peripheral edema, hepatotoxicity, impaired wound healing, ILD | Major | Dosage reduction of sirolimus is recommended. | |
| Cyclosporine | ↑ Cyclosporine | No significant change | Nephrotoxicity, hepatotoxicity, neurotoxicity, hypertension | Major | Dosage reduction of cyclosporine is recommended. |
| Isavuconazole (moderate CYP3A4 inhibitor; CYP3A4 and UGT substrate | |||||
| Venetoclax | ↑ Venetoclax (AUC: 78%) | No significant change | Hematologic toxicity, GI toxicity, tumor lysis syndrome | Major | Reduce venetoclax by at least 50%. Monitor for venetoclax toxicity. |
| Nilotinib | N/A | N/A | N/A | Minor | |
| Dasatinib | N/A | N/A | N/A | Minor | |
| Ponatinib | N/A | N/A | N/A | Minor | |
| Bosutinib | ↑ Bosutinib (Cmax: 1.5-fold; AUC 2-fold) | Myelosuppression, GI toxicity | Major | No recommendation for dosage adjustment. | |
| Ibrutinib | ↑ Ibrutinib (Cmax: 3.4-fold; AUC: 3-fold) | No significant change | Hematologic toxicity, bleeding, infection | Major | Reduce ibrutinib dose to 280 mg/day for treatment of B cell malignancies. Initiate ibrutinib at the recommended dose of 420 mg/day p.o. for the treatment of chronic GVHD. |
| Ruxolitinib | ↑ Ruxolitinib (Cmax: 8%; AUC: 27%) | No significant change | Thrombocytopenia, anemia, elevated liver enzyme, diarrhea | Moderate | No dosage adjustment necessary; monitor for ruxolitinib toxicity. |
| Bortezomib | ↑ Bortezomib | No significant change | Myelosuppression, peripheral neuropathy, GI toxicity | Moderate | Use with caution; monitor for bortezomib toxicity. No recommendation for dosage adjustment. |
| Idelalisib | No significant change | ↑ Isavuconazole (AUC: 5-fold) | Myelosuppression, infection, elevated liver enzymes, enterocolitis | Severe | Concurrent use is contraindicated. Consider alternative therapy. |
| Duvelisib | ↑ Duvelisib | ↑ Isavuconazole | Myelosuppression, infection, elevated liver enzymes, enterocolitis | Moderate | Monitor for increased toxicity of duvelisib and isavuconazonium during coadministration. |
| Tacrolimus | ↑ Tacrolimus (AUC: 125%) | No significant change | Nephrotoxicity, neurotoxicity, hyperkalemia, electrolyte abnormalities | Moderate | Dosage reduction of tacrolimus may be considered. |
| Sirolimus | ↑ Sirolimus (AUC: 84%) | No significant change | Hypertension, peripheral edema, hepatotoxicity, impaired wound healing, ILD | Moderate | Dosage reduction of sirolimus may be considered. |
| Cyclosporine | ↑ Cyclosporine (AUC: 29%) | No significant change | Nephrotoxicity, hepatotoxicity, neurotoxicity, hypertension | Moderate | Dosage reduction of cyclosporine may be considered. |
| Mycophenolate mofetil | ↑ Mycophenolate mofetil | No significant change | Diarrhea, leukopenia, hyperglycemia | Moderate | |
| Caspofungin | |||||
| Tacrolimus | ↓ Tacrolimus | No significant change | Reduction in tacrolimus efficacy | Major | Monitor tacrolimus levels. Consider a 25% increase in tacrolimus dose. |
| Sirolimus | ↓ Sirolimus | No significant change | Reduction in sirolimus efficacy | Major | Monitor cyclosporine levels. Consider a 25% increase in sirolimus dose. |
| Coadministered Drug | Effect on Drug Levels | Effect on Antifungal | Potential Clinical Effects | DDI Severity Ranking | Management Strategies* |
| Cyclosporine | No significant change | ↑ caspofungin (AUC: 35%) | Hepatotoxicity | Major | Monitor liver function tests. |
| Micafungin | |||||
| Tacrolimus | N/A | N/A | N/A | Minor | |
| Sirolimus | ↑ Sirolimus (Cmax: no effect; AUC: 21%) | No significant change | Hypertension, peripheral edema, hepatotoxicity, impaired wound healing, ILD | Moderate | |
| Cyclosporine | N/A | N/A | N/A | Minor | |
| Itraconazole | ↑ Itraconazole (Cmax: 11%; AUC: 22%) | No significant change | Hepatotoxicity | Moderate | Monitor liver function tests and itraconazole levels. |
DDI, drug-drug interactions; AUC, area under the curve; Cmax, maximum plasma concentration; Cp, concentration in plasma; GI, gastrointestinal; CLL, chronic lymphoblastic leukemia; SLL, small lymphocytic lymphoma; AML, acute myelogenous leukemia; ILD, interstitial lung disease; N/A, non-applicable.
*
Consultation with a transplantation pharmacist is strongly recommended to determine an appropriate preemptive dosage reduction.