ADDITIONAL DOSING INFORMATION FOR ADULTS WITH PREVIOUSLY TREATED cGVHD
IMBRUVICA® Dose Modifications for CYP3A Inhibitors in adults with cGVHD*
| Coadministered Drug | Recommended IMBRUVICA® Dose |
|---|---|
| Moderate CYP3A inhibitor† | 420 mg once daily Modify dose as recommended per Section 2.2 of the full Prescribing Information |
Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily | 280 mg once daily Modify dose as recommended per Section 2.2 of the full Prescribing Information |
Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily | 140 mg once daily Interrupt dose as recommended per Section 2.2 of the full Prescribing Information |
Other strong CYP3A inhibitors‡ | Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for 7 days or less), interrupt IMBRUVICA® |
*Please note that dose modifications for use with CYP3A inhibitors for patients with cGVHD differ from those with B-cell malignancies.
After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA® per Sections 2.1 and 7.1 of full Prescribing Information.1
- Avoid grapefruit and Seville oranges during IMBRUVICA® treatment, as these contain strong or moderate inhibitors of CYP3A1
The coadministration of IMBRUVICA® with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid coadministration with strong CYP3A inducers.
†Examples of moderate CYP3A inhibitors include: aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, grapefruit juice, imatinib, isavuconazole, tofisopam, verapamil.
‡Examples of strong CYP3A inhibitors include: cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and ombitasvir (and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, telithromycin, troleandomycin, voriconazole.
§Examples of strong CYP3A inducers include: apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, St. John’s wort.
These examples are a guide and not considered a comprehensive list of all possible drugs that may fit these categories.
cGVHD=chronic graft versus host disease, CYP3A=cytochrome P450, family 3, subfamily A.
The recommended dose is:
- 140 mg daily for patients 12 years of age and older with total bilirubin level >1.5 to 3 x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome).
- 80 mg/m2 daily for patients 1 to less than 12 years of age with total bilirubin level >1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
Avoid the use of IMBRUVICA® in these patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
cGVHD=chronic graft versus host disease.
Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA® increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA® without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA®. Monitor for signs and symptoms of bleeding.
Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
cGVHD=chronic graft versus host disease, CYP3A=cytochrome P450, family 3, subfamily A.
CYP3A inhibitors and inducers1,2
IMBRUVICA® Dose Modifications for CYP3A Inhibitors in adults with cGVHD*
| Coadministered Drug | Recommended IMBRUVICA® Dose |
|---|---|
| Moderate CYP3A inhibitor† | 420 mg once daily Modify dose as recommended per Section 2.2 of the full Prescribing Information |
Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily | 280 mg once daily Modify dose as recommended per Section 2.2 of the full Prescribing Information |
Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily | 140 mg once daily Interrupt dose as recommended per Section 2.2 of the full Prescribing Information |
Other strong CYP3A inhibitors‡ | Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for 7 days or less), interrupt IMBRUVICA® |
*Please note that dose modifications for use with CYP3A inhibitors for patients with cGVHD differ from those with B-cell malignancies.
After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA® per Sections 2.1 and 7.1 of full Prescribing Information.1
- Avoid grapefruit and Seville oranges during IMBRUVICA® treatment, as these contain strong or moderate inhibitors of CYP3A1
The coadministration of IMBRUVICA® with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid coadministration with strong CYP3A inducers.
†Examples of moderate CYP3A inhibitors include: aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, grapefruit juice, imatinib, isavuconazole, tofisopam, verapamil.
‡Examples of strong CYP3A inhibitors include: cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and ombitasvir (and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, telithromycin, troleandomycin, voriconazole.
§Examples of strong CYP3A inducers include: apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, St. John’s wort.
These examples are a guide and not considered a comprehensive list of all possible drugs that may fit these categories.
cGVHD=chronic graft versus host disease, CYP3A=cytochrome P450, family 3, subfamily A.
Hepatic impairment1
The recommended dose is:
- 140 mg daily for patients 12 years of age and older with total bilirubin level >1.5 to 3 x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome).
- 80 mg/m2 daily for patients 1 to less than 12 years of age with total bilirubin level >1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
Avoid the use of IMBRUVICA® in these patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
cGVHD=chronic graft versus host disease.
Hemorrhage1
Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA® increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA® without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA®. Monitor for signs and symptoms of bleeding.
Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
cGVHD=chronic graft versus host disease, CYP3A=cytochrome P450, family 3, subfamily A.
References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed January 23, 2023.