MIDOSTAURIN Drug Interactions: What You Need to Know

INTERACTIONS Strong CYP3A4 Inhibitors : Strong CYP3A4 inhibitors may increase exposure to midostaurin and its active metabolites. Consider alternative therapies that do not strongly inhibit CYP3A4 or monitor for increased risk of adverse reactions. ( 7.1 ) Strong CYP3A4 Inducers : Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and its active metabolites. ( 7.1 ) CYP2B6, BCRP, OATP1B1 Substrates : Dose adjustments for coadministered CYP2B6, BCRP, and OATP1B1 substrates may be necessary with RYDAPT. ( 7.2 )

7.1 Effect of Other Drugs on RYDAPT Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on RYDAPT.

Table

6: Drug Interactions with RYDAPT That Affect Midostaurin Strong CYP3A Inhibitors a The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength). b The induction potency of St. John’s wort may vary widely based on preparation.

Clinical Impact

Coadministration of RYDAPT with strong CYP3A inhibitors may increase midostaurin concentrations. The increase in midostaurin concentrations may be pronounced if strong CYP3A inhibitors are administered during the first week of RYDAPT administration [see Clinical Pharmacology (12.3)]. Increased midostaurin concentrations may increase the risk of toxicity. Prevention or Management Consider alternative therapies that do not strongly inhibit CYP3A activity. Alternatively, with coadministration of RYDAPT and strong CYP3A inhibitors, monitor patients for increased risk of adverse reactions, especially during the first week of consecutive RYDAPT administration in advanced SM population, and during first week of RYDAPT administration in each cycle of chemotherapy in AML population.

Examples

Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juice a , idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole Strong CYP3A Inducers Clinical Impact Coadministration of RYDAPT with strong CYP3A inducers may decrease midostaurin concentrations [see Clinical Pharmacology (12.3)]. Decreased midostaurin concentrations may reduce efficacy. Prevention or Management Avoid coadministration of RYDAPT with strong CYP3A4 inducers.

Examples

Carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort b

7.2 Effect of RYDAPT on Other Drugs CYP2B6 Substrates RYDAPT decreased the systemic exposure of a sensitive CYP2B6 substrate <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> . Dose adjustments for the coadministered CYP2B6 substrate may be necessary with RYDAPT. Substrates of Transporters Coadministration of RYDAPT increased the exposure of a breast cancer resistance protein (BCRP) and organic anion transporter polypeptide (OATP)1B1 substrate <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> . Dose adjustments for the coadministered BCRP or OATP1B1 substrates may be necessary with RYDAPT.

RYDAPT is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients [see Description (11)]. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Adverse Reactions (6.1)]. Hypersensitivity to midostaurin or any of the excipients. ( 4 )

AND PRECAUTIONS Embryo-Fetal Toxicity : RYDAPT may cause fetal harm when administered to a pregnant woman. Advise of the potential risk to a fetus. ( 5.1 , 8.1 )

Pulmonary

Toxicity : Monitor for symptoms of interstitial lung disease or pneumonitis. Discontinue RYDAPT in patients with signs or symptoms of pulmonary toxicity. Fatal cases have occurred. ( 5.2 )

5.1 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal reproduction studies, RYDAPT may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating RYDAPT therapy. Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)]</span> .

5.2 Pulmonary Toxicity Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with RYDAPT as monotherapy or with chemotherapy. Monitor patients for pulmonary symptoms. Discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.

5.3 Risk of Prolonged Severe Neutropenia and Thrombocytopenia in Pediatric Patients Treated With Combination Chemotherapy Prolonged Grade 4 neutropenia and thrombocytopenia occurred in two pediatric patients with AML who received an unapproved formulation of midostaurin in combination with chemotherapy, including anthracyclines, fludarabine, and cytarabine; these two patients were coadministered an azole antifungal (a strong CYP3A4 inhibitor), which may increase midostaurin concentrations and subsequently, the risk of toxicity <span class="opacity-50 text-xs">[see Drug Interactions (7.1), Use in Specific Populations (8.4)]</span> . The safety and effectiveness of RYDAPT in pediatric patients have not been established.