selpercatinib 80 MG Oral Tablet [Retevmo]

INDICATIONS AND USAGE RETEVMO ® is a kinase inhibitor indicated for the treatment of: Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test ( 1.1 ) Adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy ( 1.2 ) Adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) ( 1.3 ) Adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options 1 ( 1.4 ) 1 This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). 1.1 RET Fusion-Positive Non-Small Cell Lung Cancer RETEVMO ® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test. 1.2 RET -Mutant Medullary Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy. 1.3 RET Fusion-Positive Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). 1.4 Other RET Fusion-Positive Solid Tumors RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.4 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

DOSAGE AND ADMINISTRATION Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid, or other solid tumors) or specific RET gene mutation (MTC). ( 2.1 , 14 ) Adult and adolescent patients 12 years of age or older : the recommended dosage is based on weight ( 2.3 ): Less than 50 kg: 120 mg orally twice daily 50 kg or greater: 160 mg orally twice daily Pediatric patients 2 to less than 12 years of age: the recommended dosage is based on body surface area ( 2.3 ): 0.33 m 2 to 0.65 m 2 : 40 mg orally three times daily 0.66 m 2 to 1.08 m 2 : 80 mg orally twice daily 1.09 m 2 to 1.52 m 2 : 120 mg orally twice daily ≥1.53 m 2 : 160 mg orally twice daily For patients who cannot swallow, disperse 40 mg RETEVMO tablets and administer orally or via gastrostomy or nasogastric tube ( 2.8 ) Only RETEVMO 40 mg tablets may be used to create the dispersion ( 2.2 ) Reduce RETEVMO dose in patients with severe hepatic impairment. ( 2.7 , 8.7 ) 2.1 Patient Selection Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid cancer, or other solid tumors) or specific RET gene mutation (MTC) in tumor specimens [see Clinical Studies ( 14 )] . Information on FDA-approved test(s) for the detection of RET gene fusions and RET gene mutations is available at: http://www.fda.gov/CompanionDiagnostics. An FDA-approved companion diagnostic test for the detection of RET gene fusions and RET gene mutations in plasma is not available. 2.2 Important Administration Instructions RETEVMO may be taken with or without food unless coadministered with a proton pump inhibitor (PPI) [see Dosage and Administration ( 2.4 ) , Clinical Pharmacology ( 12.3 )] . Swallow the capsule or tablet whole. Do not crush or chew the capsules or tablets. For patients unable to swallow capsules or tablets or who are using a feeding tube, prepare and administer RETEVMO as a dispersion; only RETEVMO 40 mg tablets may be used to create the dispersion [see Dosage and Administration ( 2.8 )] 2.3 Recommended Dosage The recommended dosage of RETEVMO administered as recommended [see Dosage and Administration ( 2.2 )] given until disease progression or unacceptable toxicity is shown in Table 1 : Table 1: Recommended RETEVMO Dosage Population RETEVMO Dosage Adult and adolescent patients 12 years of age or older based on body weight Less than 50 kg 120 mg twice daily 50 kg or greater 160 mg twice daily Pediatric patients 2 to less than 12 years of age based on body surface area 0.33 to 0.65 m 2 40 mg three times daily 0.66 to 1.08 m 2 80 mg twice daily 1.09 to 1.52 m 2 120 mg twice daily ≥1.53 m 2 160 mg twice daily Dosing pediatric patients with body surface area less than 0.33 m 2 is not recommended Missed Dose Do not take a missed dose unless it is more than 6 hours until next scheduled dose. Vomiting If vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose. 2.4 Dosage Modifications for Concomitant Use of Acid-Reducing Agents Avoid concomitant use of a PPI, a histamine-2 (H2) receptor antagonist, or a locally-acting antacid with RETEVMO [see Drug Interactions ( 7.1 )] . If concomitant use cannot be avoided: Take RETEVMO with food when coadministered with a PPI. Take RETEVMO 2 hours before or 10 hours after administration of an H2 receptor antagonist. Take RETEVMO 2 hours before or 2 hours after administration of a locally-acting antacid. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 2 . Table 2: Recommended RETEVMO Dose Reductions for Adverse Reactions Current RETEVMO Dosage Dose Reduction First Second Third 40 mg three times daily 40 mg twice daily 40 mg once daily permanently discontinue 80 mg twice daily 40 mg twice daily 40 mg once daily permanently discontinue 120 mg twice daily 80 mg twice daily 40 mg twice daily 40 mg once daily 160 mg twice daily 120 mg twice daily 80 mg twice daily 40 mg twice daily Permanently discontinue RETEVMO in patients unable to tolerate three dose reductions. The recommended dosage modifications for adverse reactions are provided in Table 3 . Table 3: Recommended RETEVMO Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Hepatotoxicity [see Warnings and Precautions ( 5.1 )] Grade 3 or Grade 4 Withhold RETEVMO and monitor AST/ALT once weekly until resolution to Grade 1 or baseline. Resume at reduced dose by 2 dose levels and monitor AST and ALT once weekly until 4 weeks after reaching dose taken prior to the onset of Grade 3 or 4 increased AST or ALT. Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence. Interstitial Lung Disease/ Pneumonitis [see Warnings and Precautions ( 5.2 )] Grade 2 Withhold RETEVMO until resolution. Resume at a reduced dose. Discontinue RETEVMO for recurrent ILD/pneumonitis. Grade 3 or Grade 4 Discontinue RETEVMO for confirmed ILD/pneumonitis. Hypertension [see Warnings and Precautions ( 5.3 )] Grade 3 Withhold RETEVMO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. Grade 4 Discontinue RETEVMO. QT Interval Prolongation [see Warnings and Precautions ( 5.4 )] Grade 3 Withhold RETEVMO until recovery to baseline or Grade 0 or 1. Resume at a reduced dose or permanently discontinue RETEVMO. Grade 4 Discontinue RETEVMO. Hemorrhagic Events [see Warnings and Precautions ( 5.5 )] Grade 3 or Grade 4 Withhold RETEVMO until recovery to baseline or Grade 0 or 1. Discontinue RETEVMO for severe or life-threatening hemorrhagic events. Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] Grades 1-3 Withhold RETEVMO until resolution of the event. Initiate corticosteroids. Resume at a reduced dose by 3 dose levels while continuing corticosteroids. Increase dose by 1 dose level each week until the dose taken prior to the onset of hypersensitivity is reached, then taper corticosteroids. Discontinue RETEVMO for any severe skin reaction including Stevens Johnson Syndrome. Recurrent Grade 3 or Grade 4 Discontinue RETEVMO. Hypothyroidism [see Warnings and Precautions ( 5.9 )] Grade 3 or Grade 4 Withhold RETEVMO until resolution to Grade 1 or baseline. Discontinue RETEVMO based on severity. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or Grade 4 Withhold RETEVMO until recovery to baseline or Grade 0 or 1. Resume at a reduced dose. 2.6 Dosage Modifications for Concomitant Use of Strong and Moderate CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the RETEVMO dose as recommended in Table 4 . After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume RETEVMO at the dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions ( 7.1 )] . Table 4: Recommended RETEVMO Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors Current RETEVMO Dosage Recommended RETEVMO Dosage Moderate CYP3A Inhibitor Strong CYP3A Inhibitor 40 mg orally three times daily 40 mg orally once daily 40 mg orally once daily 80 mg orally twice daily 40 mg orally twice daily 40 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 40 mg orally twice daily 160 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 2.7 Dosage Modification for Severe Hepatic Impairment Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table 5 [see Use in Specific Populations ( 8.7 )] . Table 5: Recommended RETEVMO Dosage for Severe Hepatic Impairment Current RETEVMO Dosage Recommended RETEVMO Dosage 40 mg orally three times daily

WARNINGS 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% [see Adverse Reactions ( 6.1 )] . 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 [see Dosage and Administration ( 2.5 )] . 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 [see Adverse Reactions ( 6.1 )] . 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 [see Dosage and Administration ( 2.5 )] . 5.4 QT Interval Prolongation RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology ( 12.2 )] . An increase in QTcF interval to >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 [see Adverse Reactions ( 6.1 )] . 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 [see Dosage and Administration ( 2.5 )] . 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 [see Dosage and Administration ( 2.5 )] . 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 [see Adverse Reactions ( 6.1 )] . 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 clin

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC 50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3. Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion positive tumor.