Selcaxen Capsule

Non-small Cell Lung Cancer, Medullary Thyroid Cancer, Thyroid Cancer, Other RET Fusion-Positive Solid Tumors

Adult Oral Non-small Cell Lung Cancer Indicated for metastatic RET fusion-positive non-small cell lung cancer (NSCLC) <50 kg: 120 mg PO BID >50 kg: 160 mg PO BID Continue until disease progression or unacceptable toxicity Medullary Thyroid Cancer Indicated for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in patients who required systemic therapy <50 kg: 120 mg PO BID >50 kg: 160 mg PO BID Continue until disease progression or unacceptable toxicity Thyroid Cancer Indicated for advanced or metastatic RET fusion-positive thyroid cancer in patients who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) <50 kg: 120 mg PO BID >50 kg: 160 mg PO BID Continue until disease progression or unacceptable toxicity Other RET Fusion-Positive Solid Tumors Indicated for locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options <50 kg: 120 mg PO BID >50 kg: 160 mg PO BID Continue until disease progression or unacceptable toxicity

Oral Medullary Thyroid Cancer Indicated for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in adolescents and children aged >2 years who required systemic therapy <2 years: Safety and efficacy not established 2 years to <12 years Dosing based on body surface area (BSA) BSA <0.33 m2: Not recommended BSA 0.33-0.65 m2: 40 mg PO TID BSA 0.66-1.08 m2: 80 mg PO BID BSA 1.09-1.52 m2: 120 mg PO BID BSA >1.53 m2: 160 mg PO BID >12 years <50 kg: 120 mg PO BID >50 kg: 160 mg PO BID Continue until disease progression or unacceptable toxicity Thyroid Cancer Indicated for advanced or metastatic RET fusion-positive thyroid cancer in adolescents and children aged ?2 years who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) <2 years: Safety and efficacy not established 2 years to <12 years Dosing based on body surface area (BSA) BSA <0.33 m2: Not recommended BSA 0.33-0.65 m2: 40 mg PO TID BSA 0.66-1.08 m2: 80 mg PO BID BSA 1.09-1.52 m2: 120 mg PO BID BSA >1.53 m2: 160 mg PO BID >12 years <50 kg: 120 mg PO BID >50 kg: 160 mg PO BID Continue until disease progression or unacceptable toxicity Other RET Fusion-Positive Solid Tumors Indicated for locally advanced or metastatic solid tumors with a RET gene fusion in adolescents and children aged ?2 years that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options <2 years: Safety and efficacy not established 2 years to <12 years Dosing based on body surface area (BSA) BSA <0.33 m2: Not recommended BSA 0.33-0.65 m2: 40 mg PO TID BSA 0.66-1.08 m2: 80 mg PO BID BSA 1.09-1.52 m2: 120 mg PO BID BSA >1.53 m2: 160 mg PO BID >12 years <50 kg: 120 mg PO BID >50 kg: 160 mg PO BID Continue until disease progression or unacceptable toxicity

Renal impairment Mild-to-severe (CrCl >15 mL/min): No dose adjustment required ESRD: Recommended dose not established

No overall differences were observed in the safety or effectiveness of Selpercatinib between patients who were >65 years of age and younger patients.

Hepatic impairment Mild or moderate No dose adjustment required Mild defined as: TB <ULN with AST >ULN OR TB >1-1.5x ULN with any AST Moderate defined as: TB >1.5-3x ULN with any AST Severe If current dose is 120 mg or 160 mg BID, reduce to 80 mg BID Severe defined as: Total biliruvin (TB) >3-10x ULN with any AST

May take with or without food unless coadministered with a PPI Take with food if administered with a PPI Swallow capsule/tablet whole; do not crush or chew Do not administer capsules to pediatric patients who are unable to swallow a capsule

Hepatotoxicity Can cause hepatotoxicity, including increased AST/ALT Median time to onset for increased AST/ALT: ∼6 weeks Evaluate AST/ALT prior to therapy, every 2 weeks for 3 months, then monthly thereafter and as clinically indicated during therapy Withhold, dose reduce, or permanently discontinue as recommended based on severity Interstitial Lung Disease (ILD)/pneumonitis Can cause severe, life-threatening, or fatal ILD/pneumonitis Monitor patients for pulmonary symptoms or symptoms of ILD (eg, dyspnea, cough, fever) Promptly evaluate and withhold therapy for acute or worsening of respiratory symptoms Withhold, dose reduce, or permanently discontinue as recommended based on severity Hypertension Do not use in patients with uncontrolled hypertension; optimize blood pressure control prior to initiating therapy Manage treatment-emergent hypertension with antihypertension medications; initiate or adjust antihypertensive therapy as appropriate Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated Withhold, dose reduce, or permanently discontinue as recommended based on severity QT interval prolongation Can cause concentration-dependent QT interval prolongation Monitor patients at significant risk of developing QT prolongation (eg, long QT syndromes, bradyarrhythmias, and severe/uncontrolled heart failure) Assess QT interval, electrolytes, and TSH prior to and periodically during therapy; adjust monitoring frequency based on risk factors (eg, diarrhea) Correct electrolyte imbalances (eg, hypokalemia, hypomagnesemia, hypocalcemia) prior to and during therapy Monitor the QT interval more often when concomitantly taking strong or moderate CYP3A inhibitors or drugs known to prolong QTc interval Withhold, dose reduce, or permanently discontinue as recommended based on severity Hemorrhagic events Can cause serious or fatal hemorrhagic events (eg, cerebral hemorrhage) Permanently discontinue if severe or life-threatening hemorrhage

Not Classi Pregnancy Based on findings from animal studies and its mechanism of action, can cause fetal harm when administered to pregnant females Data are not available regarding use in pregnant females Verify pregnancy status in females of reproductive potential before initiating Advise patients of potential risk Animal studies Administration to pregnant rats during organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg BID Contraception Use effective contraception during treatment and for 1 week after final dose in females of reproductive potential and in males with female partners of reproductive potential Fertility May impair fertility in females and males of reproductive potential Lactation Data are not available on the presence of selpercatinib or its metabolites in human milk or on their effects on breastfed children or milk production Advise women not to breastfeed during treatment and for 1 week after the final dose

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

>50% All grades Increased ALT (53-81%) Increased AST (47-77%) Calcium decreased (53-59%) Albumin decreased (11-56%) Glucose increased (53%) Lymphocytes decreased (41-53%) Platelets decreased (28-53%) Neutrophils decreased (25-53%) Bilirubin increased (30-52%) >10-50% All grades Edema (33-49%) Hypertension (41-48%) Diarrhea (26-47%) Increased creatinine (23-47%) Fatigue (28-46%) Dry mouth (32-43%) Sodium decreased (20-42%) Increased alkaline phosphatase (35-40%) Increased total cholesterol (35%) Glucose decreased (34%) Abdominal pain (18-34%) Potassium increased (17-34%) Rash (19-33%) Constipation (16-33%) Magnesium decreased (9-33%) Nausea (10-31%) Hemoglobin decreased (18-28%) Headache (14-28%) Musculoskeletal pain (25%) Cough (24%) Dyspnea (22%) Hemorrhage (13-22%) Vomiting (8-22%) Prolonged QT interval (14-21%) Arthralgia (21%) COVID-19 (19%) Stomatitis (14-18%) Decreased appetite (12-17%) Erectile dysfunction (16%) Pyrexia (12-13%) Hypothyroidism (9-13%) Urinary tract infection (8-12%) Pneumonia (<11%) Grade 3 or 4 Increased ALT (12-21%) Hypertension (19-20%) Lymphocytes decreased (8-20%) Neutrophils decreased (2-14%) Increased AST (5-11%) Sodium decreased (3.2-11%) 1-10% All grades Dizziness (8%) Potassium decreased (8%) Hypersensitivity (<6%) Interstitial lung disease/pneumonitis (<4.4%) Chylothorax (<2%) Chylous ascites (<2%) Grade 3 or 4 Prolonged QT interval (4.7-9%) Increased creatinine (2.4-6%) Increased alkaline phosphatase (1.3-6%) Calcium decreased (1.9-5.7%) Diarrhea (1.3-5%) Fatigue (3.2-4.1%) Hemoglobin decreased (2.1-3.5%) Magnesium decreased (3.3%) Platelets decreased (1.1-3.2%) Dyspnea (3.1%) Glucose increased (2.8%) Bilirubin increased (1.1-2.8%) Potassium increased (1.3-2.7%) Hemorrhage (2.6%) Abdominal pain (<2.5%) Edema (<2.5%) Albumin decreased (1.1-2.3%) Rash (<1.9%) Vomiting (1.8%) Increased total cholesterol (1.7%) Headache (<1.4%) Nausea (1-1.1%) Glucose decreased (1%) Pyrexia (<1%)

Selpercatinib is a kinase inhibitor of wild-type rearranged during transfection (RET) and multiple mutated RET isoforms, as well as vascular endothelial growth factor receptors (VEGFR1, VEGFR3) Genomic alterations in RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth RET fusion cancers and RET-mutant MTC are primarily dependent on this single activated kinase for their proliferation and survival; this dependency, often referred to as "oncogene addiction," renders such tumors highly susceptible to small molecule inhibitors targeting RET

Selcaxen 40 mg Capsule manufactured by Everest Pharmaceuticals Ltd.. Its generic name is Selpercatinib.