AUGTYRO^™ (repotrectinib)

Indication(s) Important Safety Information U.S. Full Prescribing Information

INDICATIONS

AUGTYRO^™ is indicated for the treatment of:

• adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC)
• adult and pediatric patients 12 years of age and older with solid tumors that:
  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion,
  • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and
  • have progressed following treatment or have no satisfactory alternative therapy
  • This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Warnings & Precautions

Central Nervous System Adverse Reactions

• Among the 426 patients who received AUGTYRO in Study TRIDENT-1, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients with Grade 3 or 4 events occurring in 4.5%.
• Dizziness, including vertigo, occurred in 65%; Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 7 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 11% required dose reduction of AUGTYRO due to dizziness.
• Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 5% of patients, 8% required dose reduction and one patient (0.2%) permanently discontinued AUGTYRO due to ataxia.
• Cognitive impairment, including memory impairment and disturbance in attention, occurred in 25% of patients. Cognitive impairment included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); Grade 3 cognitive impairment occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 2.1% required dose reduction and 0.5% permanently discontinued AUGTYRO due to cognitive adverse reactions.
• Mood disorders occurred in 6% of patients. Mood disorders occurring in >1% of patients included anxiety (2.6%); Grade 4 mood disorders (mania) occurred in 0.2% of patients. Dose interruption was required in 0.2% of patients and 0.2% required a dose reduction due to mood disorders.
• Sleep disorders including insomnia and hypersomnia occurred in 18% of patients. Sleep disorders observed in >1% of patients were somnolence (9%), insomnia (6%) and hypersomnia (1.6%). Dose interruption was required in 0.7% of patients, and 0.2% required a dose reduction due to sleep disorders.
• The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases.
• Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.

Interstitial Lung Disease (ILD)/Pneumonitis

• Among the 426 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.5% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis.
• Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed.

Hepatotoxicity

• Among the 426 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 38%, increased aspartate aminotransferase (AST) occurred in 41%, including Grade 3 or 4 increased ALT in 3.3% and increased AST in 2.9%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.2% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.5%.
• Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and then as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity.

Myalgia with Creatine Phosphokinase (CPK) Elevation

• AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation. Among the 426 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation.
• Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and 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. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement.

Hyperuricemia

• Among the 426 patients treated with AUGTYRO, 21 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.7% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.
• Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.

Skeletal Fractures

• Among 426 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.5%), feet (0.5%), spine (0.2%), acetabulum (0.2%), sternum (0.2%), and ankles (0.2%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients.
• Of 26 evaluable patients in an ongoing open-label study in pediatric patients, fractures occurred in one 12-year-old patient (ankle/foot) and one 10-year-old patient (stress fracture). AUGTYRO was interrupted in both patients. AUGTYRO is not approved for use in pediatric patients less than 12 years of age.
• Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures.

Embryo-Fetal Toxicity

• Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.
• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective.
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose.

Adverse Reactions

• The safety of AUGTYRO was evaluated in 426 patients in TRIDENT-1. The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.

Drug Interactions

Effects of Other Drugs on AUGTYRO

Strong and Moderate CYP3A Inhibitors

• Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO.

P-gp Inhibitors

• Avoid concomitant use with P‑gp inhibitors. Concomitant use of AUGTYRO with a P‑gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO.

Strong and Moderate CYP3A Inducers

• Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO.

Effects of AUGTYRO on other Drugs

Certain CYP3A4 Substrates

• Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.
• Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates.

Contraceptives

• Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.
• Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females of childbearing potential to use an effective nonhormonal contraceptive.

Please see U.S. Full Prescribing Information for AUGTYRO.