Selpercatinib (Systemic)

Brand names: Retevmo
Drug class: Antineoplastic Agents

Usage of Selpercatinib (Systemic)

RET Fusion-Positive Non-small Cell Lung Cancer (NSCLC)

Treatment of locally advanced or metastatic NSCLC with a rearranged during transfection (RET) gene fusion in adults. Select patients for therapy based on the presence of RET gene fusion as detected by an FDA-approved test.

Designated an orphan drug by FDA for the treatment of this cancer.

RET-Mutant Medullary Thyroid Cancer

Treatment of advanced or metastatic RET-mutant medullary thyroid cancer in adults and pediatric patients ≥12 years of age who require systemic therapy. Select patients for therapy based on the presence of RET mutation as detected by an FDA-approved test.

Accelerated approval based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in cOnfirmatory studies.

Designated an orphan drug by FDA for the treatment of this cancer.

RET Fusion-Positive Thyroid Cancer

Treatment of advanced or metastatic RET gene fusion-positive metastatic thyroid cancer in adults and pediatric patients ≥12 years of age who require systemic therapy and who are also refractory to radioactive iodine (iodine-131) therapy (for whom such therapy is appropriate). Select patients for therapy based on the presence of RET gene fusion as detected by an FDA-approved test.

Accelerated approval based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Designated an orphan drug by FDA for the treatment of this cancer.

Other RET Fusion-Positive Solid Tumors

Treatment of adults with locally advanced or metastatic solid tumors with a RETgene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. Select patients for therapy based on the presence of RET gene fusion.

Accelerated approval based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Designated an orphan drug by FDA for the treatment of this type of cancer.

Relate drugs

How to use Selpercatinib (Systemic)

General

Pretreatment Screening

  • Confirm presence of a RET gene fusion (NSCLC, thyroid cancer, or other solid tumors) or specific RET gene mutation (medullary thyroid cancer).
  • Assess serum ALT and AST concentrations.
  • Assess blood pressure. Do not initiate selpercatinib therapy in patients with uncontrolled hypertension.
  • Assess risk for developing QTc interval prolongation. Assess QT interval, electrolyte concentrations, and thyroid stimulating hormone (TSH) concentrations at baseline. Correct electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia) prior to initiation of and during selpercatinib therapy.
  • Assess patient for risk of tumor lysis syndrome (e.g., high tumor burden, rapidly growing tumors, renal dysfunction, dehydration) and consider appropriate prophylaxis (e.g., adequate hydration).
  • Assess thryoid function.
  • Verify pregnancy status in females of reproductive potential.

    • Patient Monitoring

  • Assess serum ALT and AST concentrations every 2 weeks for the first 3 months of therapy, monthly thereafter, and as clinically indicated.
  • Monitor blood pressure 1 week following initiation of selpercatinib therapy, at least monthly thereafter, and as clinically indicated.
  • Skeletal and tooth abnormalities observed in immature animals receiving selpercatinib; monitor growth plates in adolescents with open growth plates.
  • Assess QT interval periodically during therapy; adjust frequency of monitoring based upon risk factors (i.e., diarrhea, concomitant use of drugs known to prolong the QTc interval or potent or moderate CYP3A inhibitors).
  • Assess electrolyte and TSH concentrations periodically during therapy; adjust frequency of monitoring based upon risk factors (including diarrhea).
  • Closely monitor patients at risk for tumor lysis syndrome (e.g., high tumor burden, rapidly growing tumors, renal dysfunction, dehydration).
  • Monitor patients for pulmonary symptoms (e.g., dyspnea, cough, and fever) that may indicate interstitial lung disease/pneumonitis.
  • Monitor thyroid function periodically during treatment.

    • Dispensing and Administration

  • Based on the Institute for Safe Medication Practices (ISMP), selpercatinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

    • Administration

    Oral Administration

    Administer orally twice daily (approximately every 12 hours) without regard to meals, unless administered with drugs affecting gastric acidity (i.e., proton-pump inhibitors, histamine H2-receptor antagonists, antacids).

    If concomitant use with a proton-pump inhibitor cannot be avoided, administer selpercatinib with food. If concomitant use with a histamine H2-receptor antagonist cannot be avoided, administer selpercatinib 2 hours before or 10 hours after administration of the histamine H2-receptor antagonist. If concomitant use with an antacid cannot be avoided, administer selpercatinib 2 hours before or 2 hours after administration of the antacid.

    Swallow capsules whole; do not crush or chew capsules.

    Dosage

    Pediatric Patients

    RET-Mutant Medullary Thyroid Cancer and RET Fusion-Positive Thyroid Cancer Oral

    Pediatric patients ≥12 years of age weighing ≥50 kg: 160 mg twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity occurs.

    Pediatric patients ≥12 years of age weighing <50 kg: 120 mg twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity occurs.

    Dosage Modification

    Follow recommendations for dosage modification in adults.

    Adults

    RET Fusion-Positive NSCLC Oral

    Body weight ≥50 kg: 160 mg twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity occurs.

    Body weight <50 kg: 120 mg twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity occurs.

    RET-Mutant Medullary Thyroid Cancer and RET Fusion-Positive Thyroid Cancer Oral

    Body weight ≥50 kg: 160 mg twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity occurs.

    Body weight <50 kg: 120 mg twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity occurs.

    Other RET Fusion-Positive Solid Tumors Administration Oral

    Body weight ≥50 kg: 160 mg twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity occurs.

    Body weight <50 kg: 120 mg twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity occurs.

    Dosage Modification for Toxicity

    Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of drug may be necessary. When dosage reduction is required, reduce dosage of selpercatinib as described in Table 1.

    Table 1. Dosage Reduction for Selpercatinib Toxicity.1

    Dose Reduction level

    Adults and Pediatric Patients ≥12 Years of Age Weighing ≥50 kg

    Adults and Pediatric Patients ≥12 Years of Age Weighing <50 kg

    First

    120 mg twice daily

    80 mg twice daily

    Second

    80 mg twice daily

    40 mg twice daily

    Third

    40 mg twice daily

    40 mg once daily

    Fourth

    Permanently discontinue selpercatinib

    Permanently discontinue selpercatinib

    If an adverse reaction occurs, modify dosage accordingly .

    Table 2. Dosage Modification for Selpercatinib Toxicity1

    Adverse Reaction and Severity

    Modification

    Hepatotoxicity (Grade 3 or 4)

    Withhold therapy and monitor AST and ALT concentrations once weekly

    When the toxicity resolves to baseline or grade 1, resume at a dosage reduced 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 (ILD)/Pneumonitis (Grade 2)

    Withhold therapy until resolution, then resume at a reduced dose. Discontinue therapy for recurrent ILD/pneumonitis.

    Interstitial Lung Disease (ILD)/Pneumonitis (Grade 3 or 4)

    Discontinue therapy for confirmed ILD/pneumonitis.

    Hypertension (Grade 3)

    Withhold therapy if grade 3 hypertension occurs despite optimal antihypertensive therapy

    When hypertension is controlled, resume at reduced dosage

    Hypertension (Grade 4)

    Discontinue therapy

    Prolongation of QT Interval (Grade 3)

    Withhold therapy; when toxicity improves to baseline or grade 1 or less, resume at reduced dosage

    Prolongation of QT Interval (Grade 4)

    Discontinue therapy

    Hemorrhagic Events (Grade 3 or 4)

    Withhold therapy until toxicity improves to baseline or grade 1 or less

    If severe or life-threatening hemorrhagic events occur, permanently discontinue therapy

    Hypersensitivity Reactions (All grades)

    Withhold therapy and initiate corticosteroid therapy

    When the reaction has resolved, resume at a dosage reduced by 3 dose levels and then increase dosage by 1 dose level in 1-week intervals until the dosage used prior to onset of the reaction is reached

    Taper corticosteroid therapy when dosage returns to dosage used prior to onset of the reaction

    If hypersensitivity reactions recur, permanently discontinue therapy

    Growth Plate Abnormality (Any grade)

    Consider interrupting or discontinuing therapy based on severity and individual risk-benefit assessment in adolescent patients.

    Hypothyroidism (Grade 3 or 4)

    Withhold therapy until toxicity improves to baseline or grade 1. Discontinue therapy based on severity.

    Other toxicity (Grade 3 or 4)

    Withhold therapy until toxicity improves to baseline or grade 1 or less; resume at reduced dosage

    Concomitant use of CYP3A Inhibitors:Avoid concomitant use with moderate or potent inhibitors of CYP3A; if concomitant use cannot be avoided, reduce dosage of selpercatinib (see Table 3). When concomitant use of the moderate or potent CYP3A inhibitor is discontinued, return selpercatinib dosage (after 3–5 elimination half-lives of the CYP3A inhibitor) to dosage used prior to initiation of moderate or potent CYP3A inhibitor.

    Table 3: Recommended Dosage Reduction for Concomitant Use with Moderate or Potent CYP3A Inhibitors1

    Current Dosage

    Recommended Dosage when Used Concomitantly with a Moderate CYP3A Inhibitor

    Recommended Dosage when Used Concomitantly with a Potent CYP3A Inhibitor

    120 mg twice daily

    80 mg twice daily

    40 mg twice daily

    160 mg twice daily

    120 mg twice daily

    80 mg twice daily

    Special Populations

    Hepatic Impairment

    Severe hepatic impairment (total bilirubin concentration >3–10 times the ULN and any AST concentration): Reduce selpercatinib dosage to 80 mg twice daily.

    Mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration >1–1.5 times the ULN with any AST concentration) or moderate hepatic impairment (total bilirubin concentration >1.5–3 times the ULN with any AST concentration): No dosage adjustment necessary.

    Renal Impairment

    Mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 15–89 mL/minute): No dosage adjustment recommended.

    Geriatric Patients

    No special dosage recommendations at this time.

    Warnings

    Contraindications

  • None.

    • Warnings/Precautions

    Sensitivity Reactions

    Hypersensitivity

    Hypersensitivity, including grade 3 reactions, reported. Median time to onset of hypersensitivity is 1.9 weeks.

    If hypersensitivity occurs, interrupt selpercatinib therapy until reaction resolves and initiate corticosteroid therapy (1 mg/kg of prednisone [or equivalent]). Upon resolution of the reaction, resume selpercatinib therapy at a reduced dosage and gradually increase to dosage used prior to onset of the hypersensitivity reaction, then taper corticosteroid dosage. Permanently discontinue selpercatinib therapy for recurrent hypersensitivity.

    Hepatotoxicity

    Serious hepatic adverse reactions reported. Median time to onset of increased AST or ALT concentrations was approximately 6 or 5.8 weeks, respectively.

    Monitor ALT and AST concentrations prior to initiating selpercatinib, every 2 weeks during the first 3 months of therapy, monthly thereafter, and as clinically indicated. If hepatotoxicity occurs, interruption of drug therapy, dosage reduction, or permanent discontinuance of therapy may be necessary.

    Interstitial Lung Disease/Pneumonitis

    Serious, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis has been reported.

    Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold selpercatinib and promptly evaluate for ILD in any patient who presents with acute or worsening of respiratory symptoms (e.g., dyspnea, cough, and fever). Withhold, reduce dose, or permanently discontinue therapy based on severity of confirmed ILD.

    Hypertension

    Hypertension, including grade 3 and 4 hypertension, reported. Treatment-emergent hypertension commonly managed with antihypertensive therapy.

    Do not initiate selpercatinib in patients with uncontrolled hypertension. Assess BP prior to initiation of therapy, and monitor after 1 week of therapy, at least monthly thereafter, and as clinically indicated. Initiate antihypertensive therapy or adjust as appropriate to control BP during therapy. If hypertension occurs, interruption of drug therapy, dosage reduction, or permanent discontinuance of therapy may be necessary.

    Prolongation of QT Interval

    Selpercatinib causes concentration-Dependent QT interval prolongation; the drug has not been studied in patients with clinically important active cardiovascular disease or recent myocardial infarction.

    Monitor patients who are at substantial risk of developing QTc interval prolongation, including patients with known long QT syndromes, clinically important bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolyte concentrations, and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors (e.g., diarrhea). Correct electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia) prior to initiation and during therapy.

    Monitor QT interval more frequently when selpercatinib is concomitantly administered with moderate or potent CYP3A inhibitors or drugs known to prolong QTc interval. If QT interval prolongation occurs, interruption of drug therapy, dosage reduction, or permanent discontinuance of therapy may be necessary.

    Hemorrhagic Events

    Serious, including fatal, hemorrhagic events reported.

    Permanently discontinue therapy in patients with severe or life-threatening hemorrhage. If grade 3 or 4 hemorrhagic event occurs, temporarily interrupt selpercatinib therapy until the hemorrhagic event improves to baseline or grade 1.

    Tumor Lysis Syndrome

    Tumor lysis syndrome reported in patients with medullary thyroid carcinoma receiving selpercatinib.

    Closely monitor patients at risk for tumor lysis syndrome (e.g., those with rapidly growing tumors, high tumor burden, renal dysfunction, dehydration). Consider appropriate prophylaxis (e.g., adequate hydration). If tumor lysis syndrome occurs, treat patients as clinically indicated.

    Wound Healing Complications

    Inhibitors of vascular endothelial growth factor (VEGF) signaling pathway, such as selpercatinib, may impair wound healing.

    Withhold selpercatinib therapy for ≥7 days prior to elective surgery. Do not administer selpercatinib for ≥2 weeks following major surgery and until adequate wound healing has occurred. Safety of resuming selpercatinib therapy following resolution of wound healing complications not established.

    Hypothyroidism

    Hypothyroidism reported; all reported reactions were grade 1 or 2.

    Monitor thyroid function before treatment with selpercatinib and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold until clinically stable or permanently discontinue based on severity.

    Fetal/Neonatal Morbidity and Mortality

    May cause fetal harm. Embryofetal toxicity (i.e., postimplantation loss, early resorption, decreased fetal body weight) and teratogenicity (i.e., short tail, small snout, localized edema of the neck and thorax) observed in pregnant rats.

    Verify pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Females of reproductive potential should use effective methods of contraception while receiving selpercatinib and for ≥1 week after the final dose. Advise males who are partners of such females to use effective methods of contraception while receiving the drug and for ≥1 week after the final dose. If used during pregnancy, apprise patient of the potential fetal hazard.

    Impairment of Fertility

    Results of animal studies suggest selpercatinib may impair male and female fertility.

    Specific Populations

    Pregnancy

    May cause fetal harm.

    Verify pregnancy status prior to initiating therapy. Avoid pregnancy during therapy.

    Lactation

    Not known whether selpercatinib or its metabolites are distributed into milk, affect milk production, or affect nursing infants. Women should not breast-feed during therapy and for 1 week following the final dose.

    Pediatric Use

    Safety and efficacy not established for treatment of metastatic RET fusion-positive NSCLC.

    Safety and efficacy in pediatric patients ≥12 years of age with RET fusion-positive thyroid cancer and RET mutation-positive medullary thyroid cancer supported by extrapolation of data from clinical studies evaluating selpercatinib in adults and pharmacokinetic and safety data in pediatric patients ≥12 years of age.

    Skeletal (i.e., physeal hypertrophy) abnormalities that were not reversible observed in immature animals (equivalent to a human child to late adolescent) receiving selpercatinib. Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length, and with reduction in bone mineral density. Other abnormalities noted in animal studies include reversible hypocellularity of bone marrow in males and reversible alterations of dentin composition.

    Monitor growth plates in adolescents with open growth plates. If growth plate abnormalities occur, consider interrupting or discontinuing therapy based on severity of the abnormality and individual risk-benefit assessment.

    In pediatric patients 6 months to 21 years of age enrolled in a clinical trial evaluating selpercatinib in advanced solid or primary CNS tumors† [off-label] harboring an activating RET aberration (LOXO-RET-18036; NCT03899792), growth plate monitoring, dental examinations, and physical development (i.e., Tanner staging) were assessed.

    Geriatric Use

    No overall differences in safety relative to younger adults observed.

    Hepatic Impairment

    Mild hepatic impairment (not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration >1–1.5 times the ULN with any AST concentration): AUC of selpercatinib increased by 7%; no dosage adjustment needed.

    Moderate hepatic impairment (total bilirubin concentration >1.5–3 times the ULN with any AST concentration): AUC of selpercatinib increased by 32%; no dosage adjustment needed.

    Severe hepatic impairment (total bilirubin concentration >3–10 times the ULN and any AST concentration): AUC of selpercatinib increased by 77%; reduce selpercatinib dosage to 80 mg twice daily.

    Renal Impairment

    Mild, moderate, or severe renal impairment (eGFR of 15–89 mL/minute) do not substantially affect pharmacokinetics of selpercatinib; no dosage adjustment needed.

    Pharmacokinetics of selpercatinib not established in patients with end-stage renal disease.

    Common Adverse Effects

    Adverse reactions reported in ≥25% of patients receiving selpercatinib: edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, headache.

    What other drugs will affect Selpercatinib (Systemic)

    Principally metabolized by CYP isoenzyme 3A4.

    Moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. In vitro, does not inhibit or induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 2D6 at clinically important concentrations.

    In vitro, substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate for organic anion transporter (OAT) 1 or 3, organic cation transporter (OCT) 1 or 2, organic anion transporting polypeptide (OATP) 1B1 or 1B3, and multidrug and toxin extrusion (MATE) 1 or 2K. In vitro, inhibits MATE1, P-gp, and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, bile salt export pump (BSEP), and MATE2K.

    Drugs Affecting Hepatic Microsomal Enzymes

    Potent CYP3A inhibitors: Possible increased selpercatinib plasma concentrations and potentially increased risk of selpercatinib toxicity. Avoid concomitant use. If concomitant use of a potent CYP3A inhibitor cannot be avoided in patients receiving selpercatinib 120 mg twice daily, reduce dosage of selpercatinib to 40 mg twice daily. If concomitant use of a potent CYP3A inhibitor cannot be avoided in patients receiving selpercatinib 160 mg twice daily, reduce dosage of selpercatinib to 80 mg twice daily. When concomitant use of the potent CYP3A inhibitor is discontinued, return selpercatinib dosage (after 3–5 elimination half-lives of the CYP3A inhibitor) to dosage used prior to initiation of the potent CYP3A inhibitor.

    Moderate CYP3A inhibitors: Possible increased selpercatinib plasma concentrations and potentially increased risk of selpercatinib toxicity. Avoid concomitant use. If concomitant use of a moderate CYP3A inhibitor cannot be avoided in patients receiving selpercatinib 120 mg twice daily, reduce dosage of selpercatinib to 80 mg twice daily. If concomitant use of a moderate CYP3A inhibitor cannot be avoided in patients receiving selpercatinib 160 mg twice daily, reduce dosage of selpercatinib to 120 mg twice daily. When concomitant use of the moderate CYP3A inhibitor is discontinued, return selpercatinib dosage (after 3–5 elimination half-lives of the CYP3A inhibitor) to dosage used prior to initiation of the moderate CYP3A inhibitor.

    Moderate or potent CYP3A inducers: Possible decreased selpercatinib concentrations and reduced selpercatinib efficacy. Avoid concomitant use.

    Drugs Metabolized by Hepatic Microsomal Enzymes

    CYP2C8 and 3A substrates: Possible increased systemic exposure to the CYP2C8 or 3A substrate and increased risk of adverse effects of the substrate drug. Avoid concomitant use with CYP2C8 or CYP3A substrates that have a narrow therapeutic index. If concomitant use cannot be avoided, adjust dosage of CYP2C8 or 3A substrate as appropriate.

    P-gp Inhibitor Substrates

    Possible increased systemic exposure and increased incidence of adverse reactions related to these substrate drugs. Avoid concomitant use with P-gp substrates that have a narrow therapeutic index. If concomitant use cannot be avoided, follow recommendations for P-gp substrates provided in their approved product labeling.

    Drugs Affecting Gastric Acidity

    Concomitant use with drugs that reduce gastric acidity may result in decreased systemic exposure of selpercatinib and reduced selpercatinib efficacy.

    Proton-pump Inhibitors: Possible decreased systemic exposure of selpercatinib; however, concomitant administration with omeprazole in a fed state does not significantly change systemic exposure of selpercatinib. Avoid concomitant use. If concomitant use cannot be avoided, administer selpercatinib with food.

    Histamine H2-receptor Antagonist: No clinically important changes in pharmacokinetics of selpercatinib. Avoid concomitant use. If concomitant use cannot be avoided, administer selpercatinib 2 hours before or 10 hours after administration of the histamine H2-receptor antagonist.

    Antacids: Avoid concomitant use. If concomitant use cannot be avoided, administer selpercatinib 2 hours before or 2 hours after administration of the antacid.

    Drugs that Prolong the QT Interval

    If a drug known to prolong the QT interval must be used concomitantly with selpercatinib, monitor ECG more frequently.

    Specific Drugs

    Drug

    Interaction

    Comments

    Antacids

    Possible decreased systemic exposure of selpercatinib and reduced selpercatinib efficacy

    Avoid concomitant use; if concomitant use with an antacid cannot be avoided, administer selpercatinib 2 hours before or 2 hours after administration of the antacid

    Antifungals, azoles (e.g., fluconazole, itraconazole)

    Fluconazole: AUC and peak plasma concentration of selpercatinib predicted to increase by 60–99 and 46–76%, respectively

    Itraconazole: AUC and peak plasma concentration of selpercatinib increased by 133 and 30%, respectively

    Avoid concomitant use; if concomitant use cannot be avoided, adjust selpercatinib dosage

    Potent CYP3A inhibitors (e.g., itraconazole): In patients receiving selpercatinib 120 or 160 mg twice daily, reduce dosage of selpercatinib to 40 or 80 mg twice daily, respectively; when concomitant use of the potent CYP3A inhibitor is discontinued, return selpercatinib dosage (after 3–5 elimination half-lives of the CYP3A inhibitor) to dosage used prior to initiation of the potent CYP3A inhibitor

    Moderate CYP3A inhibitors (e.g., fluconazole): In patients receiving selpercatinib 120 or 160 mg twice daily, reduce dosage of selpercatinib to 80 or 120 mg twice daily, respectively; when concomitant use of the moderate CYP3A inhibitor is discontinued, return selpercatinib dosage (after 3–5 elimination half-lives of the CYP3A inhibitor) to dosage used prior to initiation of the moderate CYP3A inhibitor

    Bosentan

    AUC and peak plasma concentration of selpercatinib expected to decrease by 40–70 and 34–57%, respectively

    Avoid concomitant use

    Calcium-channel blocking agents (e.g., diltiazem, verapamil)

    Diltiazem and verapamil: AUC and peak plasma concentration of selpercatinib expected to increase by 60–99 and 46–76%, respectively

    Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of selpercatinib in patients receiving selpercatinib 120 or 160 mg twice daily to 80 or 120 mg twice daily, respectively; when concomitant use of diltiazem or verapamil is discontinued, return selpercatinib dosage (after 3–5 elimination half-lives of diltiazem or verapamil) to dosage used prior to initiation of the diltiazem or verapamil

    Dabigatran

    AUC and peak plasma concentration of dabigatran expected to increase by 38% and 43%, respectively

    Efavirenz

    AUC and peak plasma concentration of selpercatinib expected to decrease by 40–70 and 34–57%, respectively

    Avoid concomitant use

    Histamine H2-receptor antagonists

    Possible decreased systemic exposure of selpercatinib and reduced selpercatinib efficacy

    No clinically important effect on selpercatinib pharmacokinetics when ranitidine (not commercially available in the US) was administered 10 hours before or 2 hours after the selpercatinib dose in a fasted state

    Avoid concomitant use; if concomitant use cannot be avoided, selpercatinib should be taken 2 hours before or 10 hours after administration of the histamine H2-receptor antagonists

    Metformin

    No clinically important effect on blood glucose concentrations

    Midazolam

    AUC and peak plasma concentration of midazolam increased by 54 and 39%, respectively

    Avoid concomitant use with CYP2C8 or CYP3A substrates that have a narrow therapeutic index; if concomitant use cannot be avoided, adjust dosage of CYP2C8 or 3A substrate as appropriate

    Modafinil

    AUC and peak plasma concentration of selpercatinib predicted to decrease by 33 and 26%, respectively

    Avoid concomitant use

    Proton-pump inhibitors (e.g., omeprazole)

    Possible decreased systemic exposure of selpercatinib and reduced selpercatinib efficacy

    In a fasted state, omeprazole decreased AUC and peak plasma concentration of selpercatinib by 69 and 88%, respectively

    With a high-fat meal, omeprazole increased AUC of selpercatinib by 2% and decreased peak plasma concentration of selpercatinib by 49%

    With a low-fat meal, omeprazole decreased peak plasma concentration of selpercatinib by 22% with no effect on AUC

    Avoid concomitant use; if concomitant use cannot be avoided, administer selpercatinib with food

    Repaglinide

    AUC and peak plasma concentration of repaglinide increased by 188 and 91%, respectively

    Avoid concomitant use with CYP2C8 or CYP3A substrates that have a narrow therapeutic index; if concomitant use cannot be avoided, adjust dosage of CYP2C8 or 3A substrate as appropriate

    Rifampin

    Concomitant administration of repeated doses of rifampin decreased AUC and peak plasma concentration of selpercatinib by 87 and 70%, respectively.

    Concomitant administration of a single dose of rifampin did not result in clinically important changes in pharmacokinetics of selpercatinib

    Avoid concomitant use

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