selpercatinib (Rx)

Brand and Other Names:Retevmo
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 40mg
  • 80mg

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

Dosage Modifications

Dose reduction recommendations

  • Weight <50 kg
    • First reduction: 80 mg BID
    • Second reduction: 40 mg BID
    • Third reduction: 40 mg qDay
    • Permanently discontinue if unable to tolerate third dose reduction
  • Weight ≥50 kg
    • First reduction: 120 mg BID
    • Second reduction: 80 mg BID
    • Third reduction: 40 mg BID
    • Permanently discontinue if unable to tolerate third dose reduction

Hepatotoxicity grade 3 or 4

  • Withhold dosing and monitor AST/ALT once weekly until resolution to Grade 1 or baseline
  • Resume at reduced dose by 2 dose levels and monitor AST/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 before Grade 3 or 4 increased AST or ALT after minimum of 4 weeks without recurrence

Hypertension

  • Grade 3: Withhold dosing for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at reduced dose when hypertension controlled
  • Grade 4: Discontinue

QT prolongation

  • Grade 3: Withhold dosing until recovery to baseline or Grade ≤1; resume at reduced dose
  • Grade 4: Discontinue

Hemorrhagic events grade 3 or 4

  • Withhold dosing until recovery to baseline or Grade ≤1
  • Discontinue for severe or life-threatening hemorrhagic events

Hypersensitivity reactions all grades

  • Withhold dosing until resolution; initiate corticosteroids
  • Resume at reduced dose by 3 dose levels while continuing corticosteroids
  • Increase dose by 1 dose level each week until the dose taken prior to hypersensitivity event is reached, then taper corticosteroids

Other adverse effects grade 3 or 4

  • Withhold dosing until recovery to baseline or Grade ≤1
  • Resume at reduced dose

Coadministration with CYP3A inhibitors

  • Avoid coadministration; if unable to avoid, reduce selpercatinib dose
  • After inhibitor has been discontinued for 3-5 elimination half-lives, resume selpercatinib at dose take prior to initiated the CYP3A inhibitor
  • Moderate CYP3A inhibitor
    • If current dose is 120 mg BID, reduce to 80 mg BID
    • If current dose is 160 mg BID, reduce to 120 mg BID
  • Strong CYP3A inhibitor
    • If current dose is 120 mg BID, reduce to 40 mg BID
    • If current dose is 160 mg BID, reduce to 80 mg BID

Renal impairment

  • Mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment required
  • Severe: (CrCl <30 mL/min) or ESRD: Recommended dose not established

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

Acid-reducing agents

Avoid with PPIs, histamine-2 (H2) receptor antagonists, or locally acting antacids

  • If unable to avoid
    • PPIs: Take with food when coadministered
    • H2 receptor antagonist: Take selpercatinib 2 hr before or 10 hr after an H2 antagonist
    • Locally acting antacid: Take selpercatinib 2 hr before or 2 hr after antacid

Dosing Considerations

Select patients for treatment based on presence of RET gene fusion (NSCLC or thyroid cancer) or specific RET gene mutation (MTC) in tumor specimens or plasma

Dosage Forms & Strengths

capsule

  • 40mg
  • 80mg

Medullary Thyroid Cancer

Indicated for advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in children aged ≥12 years who required systemic therapy

<12 years: Safety and efficacy not established

≥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 children aged ≥12 years who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)

<12 years: Safety and efficacy not established

≥12 years

  • <50 kg: 120 mg PO BID
  • ≥50 kg: 160 mg PO BID
  • Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction recommendations

  • Weight <50 kg
    • First reduction: 80 mg BID
    • Second reduction: 40 mg BID
    • Third reduction: 40 mg qDay
    • Permanently discontinue if unable to tolerate third dose reduction
  • Weight ≥50 kg
    • First reduction: 120 mg BID
    • Second reduction: 80 mg BID
    • Third reduction: 40 mg BID
    • Permanently discontinue if unable to tolerate third dose reduction

Hepatotoxicity grade 3 or 4

  • Withhold dosing and monitor AST/ALT once weekly until resolution to Grade 1 or baseline
  • Resume at reduced dose by 2 dose levels and monitor AST/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 before Grade 3 or 4 increased AST or ALT after minimum of 4 weeks without recurrence

Hypertension

  • Grade 3: Withhold dosing for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at reduced dose when hypertension controlled
  • Grade 4: Discontinue

QT prolongation

  • Grade 3: Withhold dosing until recovery to baseline or Grade ≤1; resume at reduced dose
  • Grade 4: Discontinue

Hemorrhagic events grade 3 or 4

  • Withhold dosing until recovery to baseline or Grade ≤1
  • Discontinue for severe or life-threatening hemorrhagic events

Hypersensitivity reactions all grades

  • Withhold dosing until resolution; initiate corticosteroids
  • Resume at reduced dose by 3 dose levels while continuing corticosteroids
  • Increase dose by 1 dose level each week until the dose taken prior to hypersensitivity event is reached, then taper corticosteroids

Other adverse effects grade 3 or 4

  • Withhold dosing until recovery to baseline or Grade ≤1
  • Resume at reduced dose

Coadministration with CYP3A inhibitors

  • Avoid coadministration; if unable to avoid, reduce selpercatinib dose
  • After inhibitor has been discontinued for 3-5 elimination half-lives, resume selpercatinib at dose take prior to initiated the CYP3A inhibitor
  • Moderate CYP3A inhibitor
    • If current dose is 120 mg BID, reduce to 80 mg BID
    • If current dose is 160 mg BID, reduce to 120 mg BID
  • Strong CYP3A inhibitor
    • If current dose is 120 mg BID, reduce to 40 mg BID
    • If current dose is 160 mg BID, reduce to 80 mg BID

Renal impairment

  • Mild-to-moderate (CrCl ≥30 mL/min): No dose adjustment required
  • Severe: (CrCl <30 mL/min) or ESRD: Recommended dose not established

Hepatic impairment

  • Mild or moderate
    • No dose adjustment required
    • Mild defined as: Total bilirubin (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: TB >3-10x ULN with any AST

Acid-reducing agents

Avoid with PPIs, histamine-2 (H2) receptor antagonists, or locally acting antacids

  • If unable to avoid
    • PPIs: Take with food when coadministered
    • H2 receptor antagonist: Take selpercatinib 2 hr before or 10 hr after an H2 antagonist
    • Locally acting antacid: Take selpercatinib 2 hr before or 2 hr after antacid

Dosing Considerations

Select patients for treatment based on presence of RET gene fusion (NSCLC or thyroid cancer) or specific RET gene mutation (MTC) in tumor specimens or plasma

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Interactions

Interaction Checker

and selpercatinib

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10% All Grades

            Increased AST (51%)

            Increased ALT (45%)

            Increased glucose (44%)

            Decreased leukocytes (43%)

            Decreased albumin (42%)

            Decreased calcium (41%)

            Dry mouth (39%)

            Diarrhea (37%)

            Increased creatinine (37%)

            Increased alkaline phosphatase (36%)

            Hypertension (35%)

            Fatigue (35%)

            Edema (33%)

            Decreased platelets (33%)

            Increased total cholesterol (31%)

            Rash (27%)

            Decreased sodium (27%)

            Constipation (25%)

            Decreased magnesium (24%)

            Increased potassium (24%)

            Nausea (23%)

            Abdominal pain (23%)

            Headache (23%)

            Increased bilirubin (23%)

            Decreased glucose (22%)

            Cough (18%)

            Prolonged QT (17%)

            Dyspnea (16%)

            Vomiting (15%)

            Hemorrhage (15%)

            >10% Grades 3 and 4

            Hypertension (18%)

            1-10% Grades 3 and 4

            Increased ALT (9%)

            Increased AST (8%)

            Decreased sodium (7%)

            Prolonged QT (4%)

            Decreased calcium (3.8%)

            Diarrhea (3.4%)

            Decreased platelets (2.7%)

            Dyspnea (2.3%)

            Increased alkaline phosphatase (2.3%)

            Increased glucose (2.2%)

            Fatigue (2%)

            Increased bilirubin (2%)

            Abdominal pain (1.9%)

            Hemorrhage (1.9%)

            Decreased leukocytes (1.6%)

            Headache (1.4%)

            Increased potassium (1.2%)

            Increased creatinine (1%)

            <1% Grades 3 and 4

            Rash (0.7%)

            Decreased albumin (0.7%)

            Decreased glucose (0.7%)

            Constipation (0.6%)

            Nausea (0.6%)

            Decreased magnesium (0.6%)

            Vomiting (0.3%)

            Edema (0.3%)

            Increased total cholesterol (0.1%)

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            Warnings

            Contraindications

            None

            Cautions

            Also see Dosage Modifications for specific instructions on dose reductions for hepatotoxicity, hypertension, hemorrhagic events, hypersensitivity, and drug interactions

            Serious hepatic adverse reactions reported; monitor ALT and AST before initiating, q2Week during first 3 months, then monthly thereafter as clinically indicated; dose adjustment or discontinuation required based on severity

            Hypertension reported; manage with antihypertension medications; monitor blood pressure after 1 week and at least monthly thereafter as clinically indicated

            Monitor patients at significant risk of developing QTc prolongation; assess QT interval, electrolytes, and TSH at baseline and periodically during treatment

            Serious fatal hemorrhagic evens can occur; permanently discontinue with severe of life-threatening hemorrhage

            Hypersensitivity reported; signs and symptoms include fever, rash, and arthralgia or myalgia with concurrent decreased platelets or transaminitis

            Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway; withhold for at least 7 days before elective surgery and do not administer for at least 2 weeks following major surgery and until adequate wound healing

            Based on animal reproductive studies and its mechanism of action, can cause fetal harm

            Drug interaction overview

            • Strong or moderate CYP3A inhibitors or inducers
              • Selpercatinib is predominantly metabolized by CYP3A4
              • Avoid coadministration with strong or moderate CYP3A inhibitors or inducers
              • Adjust selpercatinib dose if unable to avoid use with strong or moderate CYP3A4 inhibitors; see Dosage Modifications
            • Acid-reducing agents
              • Coadministration with acid-reducing agents decreases selpercatinib plasma concentrations, which may reduce efficacy
              • Avoid concomitant use of PPIs, H2 receptor antagonists, and locally acting antacids
              • If unable to avoid, take selpercatinib with food (with a PPI) or modify its administration time (with an H2 receptor antagonist or a locally acting antacid); see Administration
            • QT prolongation
              • Selpercatinib associated with QTc interval prolongation
              • Monitor QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong QT interval
            • CYP2C8 or CYP3A substrates
              • Selpercatinib is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor
              • Avoid coadministration with CYP2C8 or CYP3A substrates where minimal concentration changes may lead to increased adverse reactions
              • If unable to avoid, follow any dose adjustment recommendations for CYP2C8 or CYP3A substrates provided in their product labeling
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            Pregnancy & Lactation

            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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            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

            Absorption

            Absolute bioavailability: 73%

            Peak plasma time: 2 hr

            Peak plasma concentration: 2,980 ng/mL

            AUC: 51,600 ng⋅h/mL

            Steady-state reached: ~7 days

            Distribution

            Vd: 191 L

            Protein bound: 97%

            Metabolism

            Metabolized predominantly by CYP3A4

            Elimination

            Half-life: 32 hr

            Clearance: 6 L/hr

            Excretion: Feces (69% [14% unchanged]); urine (24% [12% unchanged])

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            Administration

            Oral Administration

            May take with or without food unless coadministered with a PPI

            Take with food if administered with a PPI

            Administer weight-based dose BID (~q12hr)

            Swallow capsule whole; do not crush or chew

            Missed dose: Do not take a missed dose unless it is more than 6 hr until next scheduled dose

            Vomited dose: Do not take an additional dose; resume dosing with the next scheduled dose

            Storage

            Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
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            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.