Repotrectinib (Monograph)

Brand name: Augtyro
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a potent and selective inhibitor of multiple receptor tyrosine kinases including tropomyosin receptor tyrosine kinase (TRK) A, TRKB, TRKC, and proto-oncogene tyrosine-protein kinase ROS-1.

Uses for Repotrectinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of locally advanced or metastatic NSCLC in adult patients with tumors positive for c-ros oncogene-1 (ROS-1) (designated an orphan drug by FDA for this use). Guidelines from the American Society of Clinical Oncology (ASCO) recommend repotrectinib among first-line therapies for treatment of ROS-1-positive NSCLC; ASCO also recommends repotrectinib as a second-line treatment option in patients previously treated with another ROS-1 tyrosine kinase inhibitor.

Solid Tumors with Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion

Treatment of solid tumors harboring an NTRKfusion (without a known acquired mutation for resistance) in adult and pediatric patients ≥12 years of age who have locally advanced or metastatic disease or may experience severe morbidity following surgical resection, and whose disease progressed following prior therapy or have no satisfactory alternative treatment option (designated an orphan drug by FDA for these cancers). 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.

International experts recommend consideration of selective tropomyosin receptor kinase (TRK) inhibitors (e.g., larotrectinib, entrectinib) for the treatment of adults and pediatric patients with various TRK fusion-positive cancers, generally in the setting of unresectable/metastatic disease, disease that has progressed on other therapies, or disease in patients who are not eligible for other therapies.

Repotrectinib Dosage and Administration

General

Pretreatment Screening

Confirm the presence of ROS-1 rearrangement(s) in tumor specimens prior to initiating repotrectinib therapy for the treatment of locally advanced or NSCLC.
Confirm the presence ofNTRK 1/2/3 rearrangements in tumor specimens prior to initiating repotrectinib therapy for the treatment of solid tumors.
Assess serum uric acid levels prior to initiating repotrectinib.
Perform liver function tests (including AST, ALT, and bilirubin) prior to initiating repotrectinib.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor patients for new or worsening pulmonary symptoms indicative of interstitial lung disease/pneumonitis.
Monitor liver function tests (including ALT, AST, and bilirubin) every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated.
Monitor serum CPK levels every 2 weeks during the first month of treatment, during therapy, and as needed in patients reporting unexplained muscle pain, tenderness, or weakness.
Monitor serum uric acid levels periodically during treatment.

Other General Considerations

Discontinue strong and moderate CYP3A inhibitors for 3–5 elimination half-lives of the CYP3A inhibitor prior to initiating repotrectinib.

Administration

Oral Administration

Available as capsules containing 40 or 160 mg of the drug.

Administer at approximately the same time each day, with or without food.

Swallow capsules whole; do not open, chew, crush, or dissolve the capsules prior to swallowing. Do not take any capsules that are broken, cracked, or damaged.

If a dose is missed or if vomiting occurs at any time after taking a dose, skip the dose and resume repotrectinib at its regularly scheduled time.

Dosage

Select patients for the treatment of locally advanced or metastatic NSCLC with repotrectinib based on the presence of ROS-1 rearrangement(s) in tumor specimens; an FDA-approved test to detect ROS-1 rearrangements is currently unavailable.

Select patients for the treatment of solid tumors with repotrectinib based on the presence of NTRK1/2/3 rearrangements in tumor specimens; an FDA-approved test to detect NTRK1/2/3 rearrangements is currently unavailable. Consider treatment with repotrectinib without confirmation of NTRK rearrangements in tumor specimens in patients with secretory breast cancer or mammary analogue secretory cancer.

Pediatric Patients

Solid Tumors

Oral

Pediatric patients ≥12 years of age: 160 mg orally once daily for 14 days, then increase to 160 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Adults

Non-small Cell Lung Cancer

Oral

160 mg orally once daily for 14 days, then increase to 160 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Solid Tumors

Oral

160 mg orally once daily for 14 days, then increase to 160 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

<C> Dosage Modification for Toxicity

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of repotrectinib may be necessary if adverse effects occur.

Consult Table 1 for recommended repotrectinib dosage reductions for adverse reactions.

Consult Table 2 for recommended dosage adjustments for adverse reactions based on severity.

Table 1. Recommended Repotrectinib Dosage Reductions for Adverse Reactions.1
Dosage	First Dosage Reduction	Second Dosage Reduction
160 mg once daily	120 mg once daily	80 mg once daily
160 mg twice daily	120 mg twice daily	80 mg twice daily

Table 2. Recommended Repotrectinib Dosage Adjustments for Adverse Reactions.1
Adverse Reaction	Severity	Recommended Dosage Adjustment
CNS effects	Intolerable grade 2	Withhold until recovery to grade 1 or less or return to baseline Resume at the same or reduced dosage, as clinically appropriate
CNS effects	Grade 3	Withhold until recovery to grade 1 or less or return to baseline Resume at reduced dosage
CNS effects	Grade 4	Permanently discontinue
Interstitial lung disease (ILD)/pneumonitis	Any grade	Withhold if ILD/pneumonitis is suspected Permanently discontinue if ILD/pneumonitis is confirmed
Hepatotoxicity	Grade 3	Withhold until recovery to grade 1 or less or baseline Resume at same dosage if resolution occurs within 4 weeks Resume at a reduced dose for recurrent grade 3 events that resolve within 4 weeks
Hepatotoxicity	Grade 4	Withhold until recovery to grade 1 or less or return to baseline Resume at reduced dose Permanently discontinue if hepatotoxicity does not resolve within 4 weeks Permanently discontinue for recurrent grade 4 events
Hepatotoxicity	ALT or AST >3 times ULN with concurrent total bilirubin >1.5 times ULN (in the absence of cholestasis or hemolysis)	Permanently discontinue
CPK elevation	CPK elevation >5 times ULN	Withhold until recovery to baseline or to ≤2.5 times ULN, then resume at same dosage
CPK elevation	CPK elevation >10 times ULN or second occurrence of CPK elevation >5 times ULN	Withhold until recovery to baseline or to ≤2.5 times ULN, then resume at reduced dosage
Hyperuricemia	Grade 3 or grade 4	Withhold until improvement of signs or symptoms Resume at same or reduced dosage
Other clinically important adverse reactions	Intolerable grade 2, grade 3, or grade 4	Withhold until recovery to grade 1 or less or return to baseline Resume at same or reduced dosage if resolution occurs within 4 weeks Permanently discontinue if adverse reaction does not resolve within 4 weeks Permanently discontinue for recurrent grade 4 events

Special Populations

Hepatic Impairment

No dosage modification required for patients with mild (total bilirubin >1–1.5 times ULN or AST greater than ULN) hepatic impairment.

Recommended dosage not established in patients with moderate (total bilirubin >1.5–3 times ULN with any AST) or severe (total bilirubin >3 times ULN with any AST) hepatic impairment.

Renal Impairment

No dosage modification required for patients with mild or moderate renal impairment (eGFR 30–90 mL/minute).

Recommended dosage not established in patients with severe renal impairment or kidney failure (eGFR <30 mL/minute) and patients on dialysis.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Repotrectinib

Contraindications

None.

Warnings/Precautions

CNS Adverse Reactions

Broad spectrum of CNS adverse reactions reported, such as dizziness (e.g., vertigo), ataxia (e.g., gait disturbance, balance disorder), cognitive disorders (e.g., memory impairment, disturbance in attention, confusional state), mood disorders (e.g., anxiety), and sleep disorders (e.g., insomnia, hypersomnia). Observed incidences similar in patients with and without CNS metastases.

Advise patients and caregivers of the risk of CNS adverse reactions. Advise patients not to drive or operate machinery if they are experiencing CNS adverse reactions. If CNS adverse reactions occur, withhold repotrectinib and then resume at same or reduced dosage upon improvement, or permanently discontinue based on severity.

Interstitial Lung Disease/Pneumonitis

Interstitial lung disease (ILD)/pneumonitis reported.

Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. If ILD/pneumonitis suspected, immediately withhold repotrectinib. If ILD/pneumonitis confirmed, permanently discontinue repotrectinib.

Hepatotoxicity

Hepatotoxicity (e.g., elevations in ALT/AST, hyperbilirubinemia) reported.

Monitor liver function tests, including ALT, AST, and bilirubin, prior to initiating repotrectinib, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. If hepatotoxicity occurs, withhold and then resume repotrectinib at the same or reduced dosage upon improvement, or permanently discontinue repotrectinib based on severity.

Myalgia with Elevation in CPK

Myalgia with or without CPK elevation reported.

Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during therapy. Monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. If myalgia occurs, withhold and then resume repotrectinib at the same or reduced dosage upon improvement, based on severity.

Hyperuricemia

Hyperuricemia reported.

Monitor serum uric acid levels prior to initiating repotrectinib and periodically during treatment. Initiate urate-lowering therapy as clinically indicated. If hyperuricemia occurs, withhold and then resume repotrectinib at the same or reduced dosage upon improvement, or permanently discontinue repotrectinib based on severity.

Skeletal Fractures

Skeletal fractures reported. Fractures involved the ribs, feet, spine, acetabulum, sternum, and ankles; some fractures occurred at sites of disease and prior radiation therapy. No data available on the effects of repotrectinib on healing of known fractures and risk of future fractures.

Fractures requiring dosage interruption reported in pediatric patients.

Promptly evaluate patients with signs or symptoms of fractures (e.g., pain, changes in mobility, deformity).

Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm based on data in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal reproduction studies, and mechanism of action of repotrectinib. Fetal malformations demonstrated in animals.

Verify pregnancy status in females of reproductive potential prior to initiating repotrectinib. Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for 2 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Specific Populations

Pregnancy

May cause fetal harm based on data in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and mechanism of action of repotrectinib.

Human data on repotrectinib use during pregnancy not available. Fetal malformations demonstrated in animals.

Apprise pregnant women of the potential hazard to a fetus.

Lactation

Unknown whether distributes into human milk, or affects milk production or the breast-feeding infant.

Advise lactating women to discontinue breast-feeding during treatment and for 10 days after the last dose.

Females and Males of Reproductive Potential

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

Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for 2 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Pediatric Use

Safety and effectiveness established in pediatric patients ≥12 years of age for the treatment of locally advanced or metastatic neurotrophic tyrosine receptor kinase(NTRK)-positive solid tumors. Safety and effectiveness not established in pediatric patients <12 years of age with NTRKgene fusion-positive solid tumors.

Safety and effectiveness not established in pediatric patients with ROS-1-positive non-small cell lung cancer (NSCLC).

Geriatric Use

No clinically important differences in repotrectinib efficacy or safety observed between geriatric (≥65 years of age) and younger patients.

Hepatic Impairment

No clinically important differences in repotrectinib pharmacokinetics observed based on mild hepatic impairment (total bilirubin >1–1.5 times ULN or AST greater than ULN). Effect of moderate (total bilirubin >1.5–3 times ULN with any AST) or severe (total bilirubin >3 times ULN with any AST) hepatic impairment on repotrectinib pharmacokinetics unknown or not fully characterized.

Renal Impairment

No clinically important differences in repotrectinib pharmacokinetics observed based on mild to moderate renal impairment (eGFR 30–<90 mL/minute). Effect of severe renal impairment, kidney failure (eGFR <30 mL/minute), or dialysis on repotrectinib pharmacokinetics unknown or not fully characterized.

Common Adverse Effects

Common adverse effects (incidence ≥20%); dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, nausea.

Drug Interactions

Primarily metabolized by CYP3A4.

In vitro, induces CYP3A4, CYP2B6, CYP2C8, CYP2C19, and CYP2C9; does not induce CYP1A2.

Inhibits CYP3A4/5 (GI tract) and uridine diphosphate-glucuronosyl transferase (UGT) 1A1. Also inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and multidrug and toxin extrusion 2 (MATE2)-K.

Substrate of P-gp.

Drugs Affecting Hepatic Microsomal Enzymes

Strong and Moderate CYP3A Inhibitors

May increase repotrectinib exposure and consequently increase adverse reactions related to repotrectinib.

Avoid concomitant use. Discontinue CYP3A inhibitors for 3–5 elimination half-lives of the CYP3A inhibitor prior to initiating repotrectinib.

Strong and Moderate CYP3A Inducers

May decrease repotrectinib plasma concentrations and consequently decrease repotrectinib efficacy.

Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Certain CYP3A4 Substrates

Decreased plasma concentrations of CYP3A4 substrates, resulting in reduced efficacy of these substrates.

Avoid concomitant use with CYP3A substrates where minimal concentration changes can cause reduced efficacy, unless otherwise recommended in the prescribing information for the CYP3A substrate. If concomitant use unavoidable, increase dosage of the CYP3A4 substrate in accordance with approved product labeling.

Drugs Affecting the P-glycoprotein Transport System

Concomitant use with P-gp inhibitor may increase repotrectinib exposure and consequently increase adverse reactions related to repotrectinib.

Avoid concomitant use with P-gp inhibitors.

Specific Drugs

Drug	Interaction	Comments
Hormonal contraceptives (e.g., estrogen, progestin)	Decreased exposure of progestin or estrogen could reduce effectiveness of hormonal contraceptives	Avoid concomitant use; advise females of reproductive potential to use an effective nonhormonal contraceptive
Itraconazole (strong CYP3A and P-gp inhibitor)	Repotrectinib AUC and peak plasma concentration increased by 5.9- and 1.7-fold, respectively	Avoid concomitant use; discontinue itraconazole for 3–5 elimination half-lives prior to initiating repotrectinib
Midazolam (CYP3A substrate)	Midazolam AUC and peak plasma concentration decreased by 69 and 48%, respectively	Avoid concomitant use with CYP3A substrates where minimal concentration changes can cause reduced efficacy, unless otherwise recommended in the prescribing information for the substrate
Rifampin (strong CYP3A and P-gp inducer)	Repotrectinib AUC and peak plasma concentration decreased by 92 and 79%, respectively	Avoid concomitant use

Repotrectinib Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability: 45.7%.

Peak plasma concentrations occurred at approximately 2–3 hours after single oral dose of 40–240 mg under fasted conditions.

AUC and peak plasma concentration increase approximately dose-proportional (but less than linear with estimated slopes of 0.70 and 0.78, respectively) over single dose range of 40–240 mg.

Steady state achieved within 14 days of daily administration of 160 mg. Steady-state pharmacokinetics time-dependent with autoinduction of CYP3A4.

Food

No clinically important differences in repotrectinib pharmacokinetics observed following administration of a high-fat meal (approximately 800–1000 calories, 50% fat).

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

95.4% (in vitro).

Blood-to-plasma ratio: 0.56 (in vitro).

Elimination

Metabolism

Principally metabolized by CYP3A4 followed by secondary glucuronidation.

Elimination Route

Following single, radiolabeled, oral dose (160 mg), 4.84% (0.56% unchanged) recovered in urine and 88.8% (50.6% unchanged) in feces.

Elimination is time-dependent due to autoinduction of CYP3A4.

Half-life

Mean terminal half-life approximately 60.7 hours following a single dose.

Steady-state terminal half-life approximately 40.3 hours.

Special Populations

No clinically important differences in pharmacokinetics observed based on age (12—93 years), sex, or race (white, Asian, Black).

Stability

Storage

Oral

Capsules

20–25°C; excursions permitted to 15–30°C.

Actions

Inhibits multiple receptor tyrosine kinases including tropomyosin receptor kinases (TRK) A, TRKB, TRKC, and proto-oncogene tyrosine-protein kinase ROS-1.
ROS-1 and TRK fusion proteins can produce hyperactivation of downstream signaling pathways, leading to cell proliferation and tumorigenic potential.
Exhibited anti-tumor activity in cultured cells expressing ROS-1 fusions and any of several mutations.
Inhibited cell proliferation in cultured cells expressing NTRK fusions and any of several mutations.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients to swallow repotrectinib capsules whole with or without food.
Instruct patients that if they miss a dose of repotrectinib, or vomit at any time after taking a dose, to skip that dose and take the next dose of repotrectinib at the next scheduled time.
Advise patients to inform their clinician if they experience new or worsening CNS symptoms (e.g., dizziness, vertigo, ataxia, changes in mood, cognitive disorders). Instruct patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions.
Advise patients to inform their clinician if they experience new or worsening pulmonary symptoms indicative of interstitial lung disease or pneumonitis.
Advise patients to immediately report symptoms of hepatotoxicity to their clinician. Inform patients of the need for laboratory tests to monitor liver function.
Advise patients to inform their clinician if they experience muscle pain.
Advise patients to inform their clinician if they experience signs or symptoms associated with hyperuricemia.
Advise patients of the risk of bone fractures with repotrectinib and to report symptoms to their clinician.
Advise women to inform their clinician of a known or suspected pregnancy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise patients that hormonal contraceptives can be ineffective while taking repotrectinib. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with repotrectinib and for 2 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with repotrectinib and for 4 months after the final dose.
Advise females not to breast-feed during treatment with repotrectinib and for 10 days after the final dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses. Advise patients to avoid grapefruit or grapefruit juice while taking repotrectinib.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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.

Repotrectinib is only available through specialty pharmacies; visit the Augtyro website ([Web]) for more information on access to repotrectinib.