Sepadx Selpercatinib Capsules

I. Drug Name

Generic Name: Selpercatinib Capsules / Selpercatinib

English Name: Selpercatinib Capsules

Brand Names: Retevmo, Sepadx

Dosage Form: Oral Capsules

Specification: 40 mg per capsule; 120 capsules per box

Manufacturer: Laos Daxiong Pharmaceutical Co., Ltd.

Regulatory Approval Number: 10L 1031/23

II. Pharmacological Actions

Pharmacological Classification: Receptor Tyrosine Kinase RET (Rearranged during Transfection) Inhibitor

Mechanism of Action: Selpercatinib is a potent, highly selective, orally bioavailable small-molecule RET kinase inhibitor.

RET gene fusions (e.g., with genes such as KIF5B or CCDC6) or point mutations (e.g., M918T) are key drivers in the pathogenesis and progression of various tumors, leading to the constitutive activation of the RET signaling pathway, which promotes cancer cell proliferation and survival.

By highly selectively inhibiting RET, Selpercatinib blocks its aberrantly activated signaling pathways, thereby inhibiting tumor growth and inducing cancer cell apoptosis.

Its selectivity for RET is significantly higher than that of other multi-targeted kinase inhibitors; consequently, it may offer superior efficacy and lower off-target toxicity.

III. Indications

Selpercatinib is indicated for the treatment of adult and pediatric patients aged ≥12 years with the following RET gene abnormalities:

1. Non-Small Cell Lung Cancer (NSCLC):

Adult patients with metastatic RET fusion-positive NSCLC.

Adult patients with advanced or metastatic RET fusion-positive NSCLC who require systemic therapy.

2. Thyroid Cancer:

Adult and pediatric patients aged ≥12 years with advanced or metastatic RET-mutant Medullary Thyroid Carcinoma (MTC) who require systemic therapy.

Adult and pediatric patients aged ≥12 years with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if applicable).

IV. Dosage and Administration

Recommended Dosage (based on body weight):

Body weight < 50 kg: 120 mg, orally, twice daily (approximately every 12 hours). Body weight ≥ 50 kg: 160 mg, twice daily (approximately every 12 hours), orally.

Administration Instructions:

Swallow capsules whole; do not chew or crush the capsules.

May be taken with or without food.

If a dose is missed by more than 6 hours, skip the missed dose and take the next dose at the regularly scheduled time. Do not take a double dose to make up for a missed dose.

If vomiting occurs after taking the medication, do not take a replacement dose; wait until the next scheduled time to take the regular dose.

V. Contraindications

Patients with a history of severe hypersensitivity to selpercatinib or to any of the excipients.

VI. Warnings and Precautions

1. Hepatotoxicity:

Selpercatinib may cause severe, life-threatening hepatotoxicity.

Monitor ALT (alanine aminotransferase) and AST (aspartate aminotransferase) levels prior to initiating treatment, every 2 weeks during the first 3 months of treatment, and monthly thereafter.

Depending on the severity of the hepatotoxicity, withhold, reduce the dose, or permanently discontinue the drug.

2. Hypertension:

Hypertension, including hypertensive crisis, may occur.

Blood pressure control should be optimized prior to initiating treatment.

Monitor blood pressure regularly during treatment. For patients who develop hypertension, adjust or initiate antihypertensive therapy. Depending on the severity, withhold, reduce the dose, or permanently discontinue the drug.

3. QT Interval Prolongation:

Selpercatinib may cause concentration-dependent prolongation of the QTc interval, increasing the risk of Torsades de Pointes.

Monitor ECGs and electrolytes (e.g., potassium, calcium, magnesium) prior to initiating treatment and periodically during treatment.

Monitor patients at risk for QTc interval prolongation more frequently. Depending on the severity of the QTc interval prolongation, withhold, reduce the dose, or permanently discontinue the drug.

4. Hemorrhagic Events:

Severe, including fatal, hemorrhagic events may occur.

Permanently discontinue selpercatinib in patients who experience severe or life-threatening hemorrhage.

5. Hypersensitivity Reactions:

Severe hypersensitivity reactions may occur, manifesting as fever, rash, arthritis, etc. Depending on the severity, suspend the medication and administer corticosteroid therapy; upon recovery, either reduce the dosage or permanently discontinue the drug.

6. Embryo-Fetal Toxicity:

Based on data from animal studies, use during pregnancy may cause harm to the fetus.

Females of reproductive potential should use effective contraception during treatment and for at least 1 week after the last dose.

Male patients engaging in sexual contact with pregnant women or females of reproductive potential should use condoms during treatment and for at least 1 week after the last dose.

VII. Adverse Reactions

Very Common (>10%) Serious and/or Major Adverse Reactions:

Laboratory Abnormalities: Increased ALT, increased AST, increased blood glucose, leukopenia, decreased serum albumin, increased serum creatinine, thrombocytopenia, increased total cholesterol, decreased blood calcium, decreased blood sodium, increased alkaline phosphatase. 

General Disorders: Fatigue, edema (e.g., peripheral edema). 

Gastrointestinal: Dry mouth, diarrhea, abdominal pain, constipation, nausea. 

Cardiovascular: Hypertension, QT interval prolongation.

Common but Serious Adverse Reactions:

Hepatic injury, severe hemorrhage, hypersensitivity reactions, hypertensive crisis.

VIII. Drug Interactions

Strong CYP3A Inhibitors (e.g., clarithromycin, itraconazole, ritonavir):

Co-administration significantly increases the plasma concentration of selpercatinib, thereby increasing the risk of adverse reactions. 

Co-administration should be avoided. If co-administration cannot be avoided, monitor closely for adverse reactions and consider reducing the dosage of selpercatinib.

Strong CYP3A Inducers (e.g., rifampin, carbamazepine, St. John's wort):

Co-administration significantly decreases the plasma concentration of selpercatinib, which may lead to a loss of therapeutic efficacy. 

Co-administration should be avoided.

CYP2C8 and CYP3A Substrates:

Selpercatinib may inhibit CYP2C8 and CYP3A, thereby increasing the plasma concentrations of drugs metabolized by these enzymes (e.g., repaglinide, midazolam) and increasing the risk of their associated adverse reactions. Close monitoring is required during concomitant use, and a dose reduction of these substrate medications should be considered.

P-gp and BCRP Substrates:

Selpercatinib may inhibit P-gp and BCRP transporters, thereby increasing the plasma concentrations of these substrate medications (e.g., digoxin, methotrexate).

Close monitoring is required during concomitant use, and a dose reduction of these substrate medications should be considered.

IX. Use in Specific Populations

Pregnancy: May cause fetal harm. Advise pregnant women of the potential risk to the fetus.

Lactation: It is not known whether selpercatinib is excreted in human milk. Given the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after the last dose.

Pediatric Use: Approved for use in pediatric patients aged ≥12 years with RET-mutant MTC and RET fusion-positive thyroid cancer.

Geriatric Use: No overall differences in safety were observed between patients aged 65 years and older and younger patients.

Hepatic/Renal Impairment:

Hepatic Impairment: For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, a dose reduction of approximately 40% is recommended (follow physician's instructions). Data are limited for patients with severe (Child-Pugh C) hepatic impairment; use with caution. 

Renal Impairment: No dose adjustment is required for patients with mild to moderate renal impairment (eGFR 30–89 mL/min/1.73 m²). Data are limited for patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or those requiring dialysis; use with caution.

X. Overdosage

Symptoms: Expected to be an exacerbation of adverse reactions.

Management: There is no specific antidote. General supportive measures should be instituted, including close monitoring of vital signs and ECG, and symptomatic treatment.

XI. Clinical Pharmacology

Pharmacokinetics: Selpercatinib is rapidly absorbed following oral administration, reaching peak plasma concentrations in approximately 2 hours. A high-fat, high-calorie meal slightly increases its exposure. It is primarily metabolized in the body via CYP3A4. Feces constitute its primary route of excretion.

XII. Patient Counseling Information

1.  **Genetic Testing:** Understand that RET gene testing must be performed prior to initiating treatment.

2.  **Adherence to Prescribing Instructions:** Take the medication strictly according to the weight-based dosage and the schedule prescribed by the physician.

3.  **Regular Monitoring:** Understand the importance of regular monitoring of liver function, blood pressure, ECG, and electrolytes.

4.  **Signs of Bleeding:** Immediately report any abnormal bleeding or bruising.

5.  **Hypersensitivity Reactions:** Report symptoms such as fever, rash, or joint pain.

6.  **Contraception Requirements:** Patients of reproductive potential must understand and adhere to the required contraceptive measures.

7.  **Disclosure of Medication History:** Inform your physician of all other medications you are currently taking.