Augtyro

— THERAPEUTIC CATEGORIES —
  • Respiratory and thoracic cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Augtyro Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Repotrectinib 40mg; caps.

    Pharmacological Class

    Kinase inhibitor.

    How Supplied

    Caps—60, 120

    Storage

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. 

    Manufacturer

    Bristol Myers Squibb

    Generic Availability

    NO

    Mechanism of Action

    Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS1 fusions and mutations.

    Augtyro Indications

    Indications

    Locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

    Augtyro Dosage and Administration

    Prior to Treatment Evaluations

    Patient Selection

    • Select patients based on the presence of ROX1 rearrangement(s) in tumor specimens. An FDA-approved test to detect ROS1 rearrangements for selecting patients for treatment with Augytro is not currently available.

    Important Information Prior to Initiation

    • Discontinue strong and moderate CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor.
    • Evaluate liver function tests including bilirubin and uric acid level.

    Adult

    Confirm presence of ROS1 rearrangement(s) in tumor specimens. Swallow whole. Initially 160mg once daily for 14 days, then increase to 160mg twice daily. Continue until disease progression or unacceptable toxicity. 

    Children

    Not established.

    Hepatic Impairment

    Hepatotoxicity

    • Grade 3: Wtihhold until ≤Grade 1 or baseline. Resume at same dose if resolution occurs within 4 weeks. Resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks.
    • Grade 4: Withhold until ≤Grade 1 or baseline. Resume at reduced dose. Permanently discontinue if adverse reaction does not resolve within 4 weeks or for recurrent Grade 4 events.
    • ALT or AST >3xULN with concurrent total bilirubin >1.5xULN (in the absence of cholestasis or hemolysis): Permanently discontinue.

    Other Modifications

    Central Nervous System Effects

    • Intolerable Grade 2: Withhold until ≤Grade 1 or baseline. Resume at same or reduced dose, as clinically appropriate.
    • Grade 3: Withhold until ≤Grade 1 or baseline. Resume at reduced dose.
    • Grade 4: Permanently discontinue.

    Interstitial Lung Disease (ILD)/Pneumonitis

    • Any Grade: Withhold if ILD/pneumonitis is suspected. Permanently discontinue if ILD/pneumonitis is confirmed.

    Creatine Phosphokinase (CPK) Elevation

    • CPK >5xULN: Withhold until recovery to baseline or to ≤2.5xULN, then resume at same dose.
    • CPK >10xULN or second occurrence of CPK >5xULN: Withhold until recovery to baseline or to ≤2.5xULN, then resume at reduced dose. 

    Hyperuricemia

    • Grade 3 or 4: Withhold until improvement of signs or symptoms. Resume at same or reduced dose.

    Other Clinically Relevant Adverse Reactions

    • Intolerable Grade 2 or Grade 3 or Grade 4: Withhold until ≤Grade 1 or baseline. Resume at same or reduced dose if resolution occurs within 4 weeks. Permanently discontinue if adverse reaction does not resolve within 4 weeks or for recurrent Grade 4 events.

    Administration

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

    Swallow capsules whole. Do not open, chew, or dissolve the capsule prior to swallowing.

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

    Augtyro Contraindications

    Not Applicable

    Augtyro Boxed Warnings

    Not Applicable

    Augtyro Warnings/Precautions

    Warnings/Precautions

    Risk of CNS effects (including dizziness, ataxia, cognitive disorders, mood disorders, sleep disorders), hepatotoxicity; withhold and resume (at same or reduced dose) or permanently discontinue based on severity. Monitor LFTs (including ALT/AST, bilirubin) prior to initiation, every 2 weeks during the first month, then monthly thereafter and as clinically indicated. Monitor for pulmonary symptoms indicative of ILD/pneumonitis; withhold immediately if suspected and permanently discontinue if confirmed. Myalgia with or without CPK elevation. Monitor serum CPK levels every 2 weeks during the first month and as needed if unexplained muscle pain, tenderness, or weakness occurs; initiate supportive care as clinically indicated. Monitor serum uric acid levels prior to initiation and periodically during; initiate treatment with urate-lowering drugs as clinically indicated. Moderate or severe hepatic impairment, severe renal impairment, kidney failure (eGFR-MDRD <30mL/min), patients on dialysis: dosage not established. Embryo-fetal toxicity. Use effective non-hormonal contraception during and for 2 months (females of reproductive potential) or 4 months (males w. female partners) after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for 10 days after the last dose).

    Pregnancy Considerations

    Risk Summary

    • May cause fetal harm when administered to a pregnant woman. There are no available data on Augtyro use in pregnant women.

    Nursing Mother Considerations

    Risk Summary

    • No data on the presence of Augtyro in human milk or its effects on either the breastfed child or on milk production.
    • Discontinue breastfeeding during and for 10 days after the last dose.

    Pediatric Considerations

    Safety and effectiveness in pediatric patients with ROS1-positive NSCLC has not been established.

    Geriatric Considerations

    No clinically meaningful differences in safety and efficacy between patients younger than 65 years of age and patients 65 years of age or older. 

    Renal Impairment Considerations

    Mild or moderate renal impairment: no dosage modification is recommended.

    Severe renal impairment or kidney failure (eGFR-MDRD <30 mL/min) and patients on dialysis: recommended dosage has not been established.

    Hepatic Impairment Considerations

    Mild hepatic impairment (total bilirubin >1 to 1.5xULN or AST >ULN): no dosage modification is recommended.

    Moderate (total bilirubin >1.5 to 3xULN with any AST) or severe (total bilirubin >3xULN with any AST) hepatic impairment: recommended dosage has not been established.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Pregnancy Testing: Verify pregnancy status of females of childbearing potential prior to initiation.
    • Contraception: May cause embryo-fetal harm. Advise females of childbearing potential to use effective nonhormonal contraception during and for 2 months after the last dose. Advise male patients with female partners of childbearing potential to use effective contraception during and for 4 months after the last dose.

    Augtyro Pharmacokinetics

    Absorption

    Absolute bioavailability: 45.7%. Peak repotrectinib concentration occurred at ~2 to 3 hours (after a single oral dose of 40–240 mg under fasted conditions).

    Distribution

    Apparent volume of distribution: 432 L. Plasma protein bound: 95.4%.

    Metabolism

    Hepatic (CYP3A4).

    Elimination

    Fecal (88.8%), renal (4.84%). Mean half-life: ~50.6 hours. Apparent clearance: 15.9 L/h. 

    Augtyro Interactions

    Interactions

    May be potentiated by strong or moderate CYP3A inhibitors (eg, itraconazole); discontinue CYP3A inhibitors for 3–5 elimination half-lives of the CYP3A inhibitor prior to initiating Augtyro. May be potentiated by P-gp inhibitors; avoid. May be antagonized by strong or moderate CYP3A inducers (eg, rifampin); avoid. May antagonize certain CYP3A4 substrates (eg, midazolam); if unavoidable, increase substrate dosage. May reduce the effectiveness of hormonal contraceptives; use nonhormonal methods.

    Augtyro Adverse Reactions

    Adverse Reactions

    Dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, muscular weakness, lab abnormalities; skeletal fractures, hyperuricemia.

    Augtyro Clinical Trials

    Clinical Trials

    The approval was based on data from the open-label, multi-cohort, phase 1/2 TRIDENT-1 trial (ClinicalTrials.gov Identifier: NCT03093116), which evaluated the anti-tumor activity and safety of repotrectinib in patients with advanced solid tumors, including NSCLC. 

    Study participants received repotrectinib 160mg orally once daily for 14 days, and then were increased to 160mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). 

    Among 71 ROS1 TKI-naïve patients, results showed an ORR of 79% (95% CI, 68-88) with 6% of patients achieving complete response and 73% achieving partial response. Median duration of response was 34.1 months (95% CI, 25.6-not evaluable), with 70% of patients having a response lasting at least 12 months.

    Among 56 patients pretreated with 1 prior ROS1 TKI, the ORR was 38% (95% CI, 25-52) with 5% of patients achieving complete response and 32% achieving partial response. Median duration of response was 14.8 months (95% CI, 7.6-not evaluable), with 48% of patients having a response lasting at least 12 months.

    Among patients who had measurable central nervous system (CNS) metastases at baseline, responses in intracranial lesions were observed in 7 of 8 TKI-naïve patients and 5 of 12 of those who were TKI-pretreated.

    Augtyro Note

    Not Applicable

    Augtyro Patient Counseling

    Patient Counseling

    Central Nervous System (CNS) Effects

    • Inform your health care provider if new or worsening CNS symptoms develop. Do not drive or operate hazardous machinery if you are experiencing any CNS adverse reactions.

    Interstitial Lung Disease (ILD)/Pneumonitis

    • Inform your health care provider if new or worsening symptoms develop indicative of ILD/pneumonitis.

    Hepatotoxicity

    • Advise patients of the need to monitor liver function and to immediately report symptosm of hepatotoxicity.

    Myalgia with Creatinine Phosphokinase Elevation

    • Inform your health care provider if muscle pain develops.

    Hyperuricemia

    • Inform your health care provider if signs or symptoms associated with hyperuricemia occur.

    Skeletal Fractures

    • Report any symptoms of bone fractures to your health care provider.

    Embryo-Fetal Toxicity

    • Inform your health care provider of known or suspected pregnancy.
    • Advise females of childbearing potential to use effective nonhormonal contraception during and for 2 months after the last dose.
    • Advise male patients with female partners of childbearing potential to use effective contraception during and for 4 months after the last dose.

    Lactation

    • Do not breastfeed during treatment and for 10 days after the last dose.

    Drug Interactions

    • Inform your health care provider of all concomitant medications.
    • Avoid grapefruit or grapefruit juice during treatment. Hormonal contraceptives may be ineffective during treatment.

    Cost Savings Program

    Bristol Myers Squibb Access Support

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