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Selpercatinib

Brand name: Retevmo
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- Rearranged During Transfection
- RET Inhibitor
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

Medically reviewed by Drugs.com on Dec 13, 2021. Written by ASHP.

Introduction

Antineoplastic agent; inhibitor of multiple receptor tyrosine kinases, including wild-type and mutated rearranged during transfection (RET) isoforms.

Uses for Selpercatinib

Non-small Cell Lung Cancer

Treatment of metastatic RET fusion-positive NSCLC.

Accelerated approval based on objective 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.

Medullary Thyroid Cancer

Treatment of advanced or metastatic RET-mutant medullary thyroid cancer in patients requiring systemic therapy.

Accelerated approval based on objective 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.

Thyroid Cancer

Treatment of advanced or metastatic RET fusion-positive medullary thyroid cancer.

Treatment of advanced or metastatic RET fusion-positive thyroid cancer in patients requiring systemic therapy who are also refractory to radioactive iodine (iodine-131) therapy (for whom such therapy is appropriate).

Accelerated approval based on objective 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.

Selpercatinib Dosage and Administration

General

Pretreatment Screening

  • In patients with medullary thyroid cancer, confirm presence of specific RET mutations in tumor specimens or plasma.

  • In patients with NSCLC or thyroid cancer, confirm presence of a RET gene fusion in tumor specimens or plasma.

  • Assess serum ALT and AST concentrations.

  • Assess BP. 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).

  • 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 BP 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).

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

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

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.

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.

Dosage Modification

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

(Initial Dosage = 160 mg twice daily)

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

(Initial Dosage = 120 mg twice daily)

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 (see Table 2).

Table 2. Dosage Modification for Selpercatinib Toxicity1

Adverse Reaction and Severity

Modification

Hepatotoxicity

Modification

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 (see Table 1)

If the toxicity does not recur for ≥2 weeks, increase dosage by 1 dose level and then increase to dosage used prior to treatment interruption if the toxicity does not recur for ≥ 4 weeks

Continue monitoring AST and ALT concentrations once weekly until the dosage that was used prior to treatment interruption has been reached for 4 weeks

Hypertension

Modification

Grade 3

Withhold therapy if grade 3 hypertension occurs despite optimal antihypertensive therapy

When hypertension is controlled, resume at reduced dosage (see Table 1)

Grade 4

Discontinue therapy

Prolongation of QT Interval

Modification

Grade 3

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

Grade 4

Discontinue therapy

Hemorrhagic Events

Modification

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

Modification

All grades

Withhold therapy and initiate corticosteroid therapy

When the reaction has resolved, resume at a dosage reduced by 3 dose levels (see Table 1) 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

Modification

Any grade

Consider interrupting or discontinuing therapy based on severity and individual risk-benefit assessment

Other Toxicity

Modification

Grade 3 or 4

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

Concomitant Use with 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

Moderate CYP3A Inhibitor

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.

Cautions for Selpercatinib

Contraindications

  • None.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Hypersensitivity, including grade 3 reactions, reported. Median time to onset of hypersensitivity is 1.7 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 4 weeks.

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.

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.

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) and tooth abnormalities (i.e., malocclusion, tooth discoloration, tooth dysplasia) observed in immature animals receiving selpercatinib. 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: Elevated concentrations of aminotransferases (i.e., ALT, AST), elevated concentrations of serum glucose, decreased leukocyte counts, decreased albumin, decreased calcium concentrations, dry mouth, diarrhea, elevated concentrations of Scr, elevated concentrations of alkaline phosphatase, hypertension, fatigue, edema, decreased platelet counts, increased total cholesterol, rash, decreased sodium concentrations, constipation.

Interactions for Selpercatinib

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.

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

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

Selpercatinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and systemic exposure increase in a slightly more than dose-proportional manner over a dosage range of 20 mg once daily to 240 mg twice daily.

Peak plasma concentration attained in a median of 2 hours.

Steady-state concentrations achieved after approximately 7 days of twice-daily dosing with 3.4-fold accumulation.

Mean absolute oral bioavailability is 73%.

Food

Co-administration with a high-fat, high-calorie meal (approximately 900 calories) has no clinically meaningful effect on pharmacokinetics of selpercatinib in healthy individuals.

Special Populations

Mild, moderate, or severe hepatic impairment increases AUC of selpercatinib by 7, 32, or 77%, respectively, compared with individuals with normal hepatic function.

Mild, moderate, and severe renal impairment (eGFR 15–89 mL/min) do not affect pharmacokinetics. Pharmacokinetics not established in patients with end-stage renal disease.

Apparent volume of distribution and clearance increase with increasing body weight (27–177 kg).

Distribution

Extent

Not known whether selpercatinib or its metabolites are distributed into milk.

Plasma Protein Binding

96% bound to plasma proteins (independent of selpercatinib concentration).

Elimination

Metabolism

Principally metabolized by CYP3A4.

Elimination Route

Eliminated in feces (69% [14% as unchanged drug]) and urine (24% [12% as unchanged drug]).

Half-life

32 hours.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

  • An inhibitor of multiple tyrosine kinases, including wild-type and mutated RET isoforms.

  • Inhibits both wild-type RET and several mutated RET isoforms (e.g., RET-V804L, RET-V804M, RET-A883F, RET-S904F, RET-M918T) in enzyme assays.

  • Also inhibits vascular endothelial growth factor receptor (VEGFR) 3 or fibroblast growth factor receptor (FGFR) 1 and FGFR2 at concentrations approximately 60- or 8-fold, respectively, higher than the inhibitory concentration for RET.

Advice to Patients

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

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

  • 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.

  • 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.

  • 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.

  • Advise patients to contact their healthcare provider promptly to report any signs and symptoms of tumor lysis syndrome.

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

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

  • 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.

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

  • Advise women not to breast-feed during treatment with selpercatinib and for 1 week following the final dose.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription, OTC drugs, vitamins, and herbal products, as well as any concomitant illnesses. Inform patients to avoid St. John's wort, proton-pump inhibitors, histamine H2-receptor antagonists, and antacids while taking selpercatinib. If proton-pump inhibitors cannot be avoided, instruct patients to take selpercatinib with food. If histamine H2-receptor antagonists cannot be avoided, instruct patients to take selpercatinib 2 hours before or 10 hours after the H2-receptor antagonist. If antacids cannot be avoided, instruct patients to take selpercatinib 2 hours before or 2 hours after the locally acting antacid.

  • Importance of informing patients of other important precautionary information.

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.

Obtain selpercatinib only through designated specialty pharmacies and distributors. Contact manufacturer for additional information.

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 DI Essentials™. © Copyright 2022, Selected Revisions December 13, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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