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Selpercatinib

Class: Antineoplastic Agents
Chemical Name: 6-(2-hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile
Molecular Formula: C29H31N7O3
CAS Number: 2152628-33-4
Brands: Retevmo

Medically reviewed by Drugs.com on Jul 27, 2020. Written by ASHP.

Introduction

Selpercatinib is a kinase inhibitor antineoplastic agent.

Uses for Selpercatinib

Selpercatinib has the following uses:

Adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC).

Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy

Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Selpercatinib Dosage and Administration

General

Selpercatinib is available in the following dosage form(s) and strength(s):

  • Capsules: 40 mg, 80 mg.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration
  • Select patients for treatment with selpercatinib based on the presence of a RET gene fusion (NSCLC or thyroid) or specific RET gene mutation (MTC).

  • Recommended dosage in pediatric patients 12 years of age or older is based on weight

    Less than 50 kg: 120 mg orally twice daily

    50 kg or greater: 160 mg orally twice daily

  • Administer orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity occurs.

  • Reduce selpercatinib dose in patients with severe hepatic impairment.

  • Consult manufacturer's labeling for recommended dosage modifications for adverse reactions or concomitant use with acid-reducing agents or with strong or moderate CYP3A inhibitors.

Adults

Dosage and Administration
  • Select patients for treatment with selpercatinib based on the presence of a RET gene fusion (NSCLC or thyroid) or specific RET gene mutation (MTC).

  • Recommended dosage in adults is based on weight

    Less than 50 kg: 120 mg orally twice daily

    50 kg or greater: 160 mg orally twice daily

  • Administer orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity occurs.

  • Reduce selpercatinib dose in patients with severe hepatic impairment.

  • Consult manufacturer's labeling for recommended dosage modifications for adverse reactions or concomitant use with acid-reducing agents or with strong or moderate CYP3A inhibitors.

Cautions for Selpercatinib

Contraindications

None.

Warnings/Precautions

Hepatotoxicity

Serious hepatic adverse reactions occurred in 2.6% of patients treated with selpercatinib. Increased AST occurred in 51% of patients, including Grade 3 or 4 events in 8%, and increased ALT occurred in 45% of patients, including Grade 3 or 4 events in 9%. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years).

Monitor ALT and AST prior to initiating selpercatinib, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue selpercatinib based on severity.

Hypertension

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with antihypertension medications.

Do not initiate selpercatinib in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating selpercatinib. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust antihypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue selpercatinib based on severity.

QT Interval Prolongation

Selpercatinib can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients, and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. Selpercatinib 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 selpercatinib and during treatment.

Monitor the QT interval more frequently when selpercatinib is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce dose or permanently discontinue selpercatinib based on severity.

Hemorrhagic Events

Serious, including fatal, hemorrhagic events can occur with selpercatinib. Grade ≥3 hemorrhagic events occurred in 2.3% of patients treated with selpercatinib, including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis.

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

Hypersensitivity

Hypersensitivity occurred in 4.3% of patients receiving selpercatinib, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range: 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash, and arthralgias or myalgias with concurrent decreased platelets or transaminitis.

If hypersensitivity occurs, withhold selpercatinib and begin corticosteroids at a dose of 1 mg/kg. Upon resolution of the event, resume selpercatinib at a reduced dose and increase the dose of selpercatinib by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. Permanently discontinue selpercatinib for recurrent hypersensitivity.

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, selpercatinib has the potential to adversely affect wound healing.

Withhold selpercatinib 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 selpercatinib after resolution of wound healing complications has not been established.

Embryo-fetal Toxicity

Based on data from animal reproduction studies and its mechanism of action, selpercatinib 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 of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with selpercatinib and for at least 1 week after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with selpercatinib and for 1 week after the final dose.

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies, and its mechanism of action, selpercatinib can cause fetal harm when administered to a pregnant woman. There are no available data on selpercatinib use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Animal Data; Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥100 mg/kg (approximately 3.6 times the human exposure based on the area under the curve [AUC] at the clinical dose of 160 mg twice daily) resulted in 100% post-implantation loss. At the dose of 50 mg/kg (approximately equal to the human exposure [AUC] at the clinical dose of 160 mg twice daily), 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax).

Lactation

There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with selpercatinib and for 1 week after the final dose.

Females and Males of Reproductive Potential

Based on animal data, selpercatinib can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily.

Verify pregnancy status in females of reproductive potential prior to initiating selpercatinib.

Advise female patients of reproductive potential to use effective contraception during treatment with selpercatinib and for 1 week after the final dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with selpercatinib and for 1 week after the final dose.

Selpercatinib may impair fertility in females and males of reproductive potential.

Pediatric Use

The safety and effectiveness of selpercatinib have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of selpercatinib for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older. The safety and effectiveness of selpercatinib have not been established in these indications in patients less than 12 years of age.

The safety and effectiveness of selpercatinib have not been established in pediatric patients for other indications.

Animal Toxicity Data: In 4-week general toxicology studies in rats, animals showed signs of physeal hypertrophy and tooth dysplasia at doses resulting in exposures ≥ approximately 3 times the human exposure at the 160 mg twice daily clinical dose. Minipigs also showed signs of minimal to marked increases in physeal thickness at the 15 mg/kg high dose level (approximately 0.3 times the human exposure at the 160 mg twice daily clinical dose). Rats in both the 4- and 13-week toxicology studies had malocclusion and tooth discoloration at the high dose levels (≥1.5 times the human exposure at the 160 mg twice daily clinical dose) that persisted during the recovery period.

Geriatric Use

Of 702 patients who received selpercatinib, 34% (239 patients) were ≥65 years of age and 10% (67 patients) were ≥75 years of age. No overall differences were observed in the safety or effectiveness of selpercatinib between patients who were ≥65 years of age and younger patients.

Renal Impairment

No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [Clcr] ≥30 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (Clcr <30 mL/min) or end-stage renal disease.

Hepatic Impairment

Reduce the dose when administering selpercatinib to patients with severe [total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST] hepatic impairment. No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for selpercatinib-related adverse reactions in patients with hepatic impairment.

Common Adverse Effects

The most common adverse reactions, including laboratory abnormalities, (≥25%) were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take selpercatinib with food (with proton-pump inhibitor) 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.

Actions

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 IC50 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 protein 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.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hepatotoxicity

Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity.

Hypertension

Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings.

QT Prolongation

Advise patients that selpercatinib can cause QTc interval prolongation and to inform their healthcare provider if they have any QTc interval prolongation symptoms, such as syncope.

Hemorrhagic Events

Advise patients that selpercatinib may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding.

Hypersensitivity Reactions

Advise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment.

Risk of Impaired Wound Healing

Advise patients that selpercatinib may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure.

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the possible risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with selpercatinib and for at least 1 week after the final dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with selpercatinib and for at least 1 week after the final dose.

Lactation

Advise women not to breastfeed during treatment with selpercatinib and for 1 week following the final dose.

Infertility

Advise males and females of reproductive potential that selpercatinib may impair fertility.

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John's wort, proton-pump inhibitors, H2-receptor antagonists, and antacids while taking selpercatinib.

If proton-pump inhibitors cannot be avoided, instruct patients to take selpercatinib with food. If H2-receptor antagonists cannot be avoided, instruct patients to take selpercatinib 2 hours before or 10 hours after the H2-receptor antagonist. If locally acting antacids cannot be avoided, instruct patients to take selpercatinib 2 hours before or 2 hours after the locally acting antacid.

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Selpercatinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

40 mg

Retevmo

Eli Lilly and Company

80 mg

Retevmo

Eli Lilly and Company

AHFS Drug Information. © Copyright 2021, Selected Revisions July 27, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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