In SPRINT Phase II study Layer 1, adverse reactions reported at an incidence ≥40% in pediatric patients were: vomiting, rash, abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, fever, acneiform rash, stomatitis, headache, paronychia, and pruritus.
Selumetinib Drug Interactions
Selumetinib is primarily metabolized by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP2C19, 1A2, 2C9, 2E1, and 3A5 isoenzymes. Selumetinib is also glucuronidated via UGT1A1 and UGT1A3. The metabolism of selumetinib to the active metabolite N-desmethyl selumetinib is mediated by CYP2C19 and CYP1A2, with contributions from CYP2C9 and CYP2A6. N-desmethyl selumetinib is metabolized via the same pathways as selumetinib.
In vitro studies indicate that selumetinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, or 2E1 isoenzymes. It does not induce CYP3A4, 1A2, or 2B6 isoenzymes.
It does not inhibit the breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K transporters. It is a substrate of BCRP and P-gp transporters.
Drugs Affecting Hepatic Microsomal Enzymes
1. Moderate or strong CYP3A4 inhibitors: Coadministration may increase selumetinib systemic exposure (AUC), increasing the risk of selumetinib adverse reactions. Avoid concomitant use. If concomitant use cannot be avoided, reduce the selumetinib dose from 25 mg/m² twice daily to 20 mg/m² twice daily; for patients currently receiving selumetinib 20 mg/m² twice daily, reduce the dose to 15 mg/m² twice daily. For specific dose reductions, see the "Dose Adjustment with Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes" section above. If the moderate or strong CYP3A4 inhibitor or fluconazole is discontinued, resume the selumetinib dose to that used before the inhibitor or fluconazole after 3 terminal half-lives of the inhibitor or fluconazole have elapsed.
2. Moderate or strong CYP3A4 inducers: May decrease selumetinib systemic exposure (AUC), reducing selumetinib efficacy. Avoid concomitant use.
Specific Drug Interactions with Selumetinib
1. Azole antifungals (e.g., fluconazole, itraconazole):
Fluconazole: Increased selumetinib AUC and peak concentration (by 53% and 26%, respectively).
Itraconazole: Increased selumetinib AUC and peak concentration (by 49% and 19%, respectively).
Management: If concomitant use cannot be avoided, reduce selumetinib dose (see above). Resume original dose after discontinuation of the inhibitor.
2. Antiplatelet agents: Increased bleeding risk. Monitor for bleeding, assess INR or prothrombin time more frequently. Adjust antiplatelet dose as appropriate.
3. Efavirenz: Expected to decrease selumetinib AUC and peak concentration (by 38% and 22%, respectively). Avoid concomitant use.
4. Erythromycin: Expected to increase selumetinib AUC and peak concentration (by 41% and 23%, respectively). Management: If concomitant use cannot be avoided, reduce selumetinib dose (see above). Resume original dose after discontinuation of the inhibitor.
5. Rifampin: Decreased selumetinib AUC and peak concentration (by 51% and 26%, respectively). Avoid concomitant use.
6. Vitamin E: If total daily vitamin E intake (including the amount of vitamin E in selumetinib capsules) exceeds the recommended or safe daily limit, bleeding risk is increased. Management: Do not supplement with vitamin E during selumetinib treatment if the total daily vitamin E intake (including the vitamin E from selumetinib capsules) would exceed the recommended or safe daily limit.
7. Warfarin: Increased bleeding risk. Monitor for bleeding, assess INR or prothrombin time more frequently. Adjust warfarin dose as appropriate.
