SELPERCATINIB Drug Interactions: What You Need to Know

INTERACTIONS Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). ( 2.4 , 7.1 ) Strong and Moderate CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. ( 2.6 , 7.1 ) Strong and Moderate CYP3A Inducers: Avoid coadministration. ( 7.1 ) CYP2C8 and CYP3A Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. ( 7.2 ) Certain P-gp and BCRP Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. ( 7.2 )

7.1 Effects of Other Drugs on RETEVMO Acid-Reducing Agents Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may reduce RETEVMO anti-tumor activity. Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> . Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 ), Warning and Precautions ( 5.4 )]</span> . Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may reduce RETEVMO anti-tumor activity. Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.

7.2 Effects of RETEVMO on Other Drugs CYP2C8 and CYP3A Substrates RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. Certain P-gp and BCRP Substrates RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.

7.3 Drugs that Prolong QT Interval RETEVMO is associated with QTc interval prolongation <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.2 )]</span> . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

None. None. ( 4 )

AND PRECAUTIONS Hepatotoxicity : Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.1 )

Interstitial Lung

Disease (ILD)/Pneumonitis : Monitor for new or worsening pulmonary symptoms. Withhold, reduce the dose or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.2 ) Hypertension: Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating RETEVMO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.3 ) QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.4 )

Hemorrhagic

Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage. ( 2.5 , 5.5 ) Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at a reduced dose and increase dose by 1 dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. ( 2.5 , 5.6 )

Tumor Lysis

Syndrome: Closely monitor patients at risk and treat as clinically indicated. ( 5.7 ) Risk of Impaired Wound Healing: Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established. ( 5.8 ) Hypothyroidism: Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Withhold until clinically stable or permanently discontinue based on severity. ( 5.9 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the possible risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 )

Slipped Capital Femoral Epiphysis/Slipped

Upper Femoral Epiphysis (SCFE/SUFE) in Pediatric Patients: Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate ( 5.11 , 6.1 )

5.1 Hepatotoxicity Serious hepatic adverse reactions occurred in 3% of patients treated with RETEVMO. Increased AST occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 55% of patients, including Grade 3 or 4 events in 12% <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . The median time to first onset for increased AST was 6 weeks (range: 1 day to 3.4 years) and increased ALT was 5.8 weeks (range: 1 day to 2.5 years). Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 1.8% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.3% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce the dose or permanently discontinue RETEVMO based on severity of confirmed ILD [ see Dosage and Administration ( 2.5 ) ].

5.3 Hypertension Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.4 QT Interval Prolongation RETEVMO can cause concentration-dependent QT interval prolongation <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . An increase in QTcF interval to &gt;500 ms was measured in 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% of patients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating RETEVMO and during treatment. Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on the severity <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.5 Hemorrhagic Events Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥3 hemorrhagic events occurred in 3.1% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage (n = 1), and hemoptysis (n=1). Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.6 Hypersensitivity RETEVMO can cause hypersensitivity, including severe skin reactions such as Stevens Johnson Syndrome. All grade hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 in 1.9%. The median time to onset was 1.9 weeks (range: 5 days to 2 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis.

Stevens Johnsons

Syndrome has been observed in the post-marketing setting [see Adverse Reactions ( 6.2 )] . Discontinue RETEVMO in patients with Stevens Johnson Syndrome. If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration ( 2.5 )] . Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.

5.7 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

5.8 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, RETEVMO has the potential to adversely affect wound healing. Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established.

5.9 Hypothyroidism RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 13% of patients treated with RETEVMO; all reactions were Grade 1 or 2. Hypothyroidism occurred in 13% of patients (50/373) with thyroid cancer and 13% of patients (53/423) with other solid tumors including NSCLC <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.10 Embryo-Fetal Toxicity Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (2.8% of 36 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .