AUGTYRO Capsule Ref.[107392] Active ingredients: Repotrectinib

5.1 Central Nervous System Adverse Reactions

AUGTYRO can cause central nervous system adverse reactions.

Among the 351 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 75% with Grade 3 or 4 events occurring in 4% of patients.

Dizziness, including vertigo, occurred in 64% of the 351 patients; Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 6 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 12% required dose reduction of AUGTYRO due to dizziness.

Ataxia, including gait disturbance and balance disorder, occurred in 29% of the 351 patients; Grade 3 ataxia occurred in 0.3% of patients. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 6% of patients, 8% required dose reduction, and one patient (0.3%) permanently discontinued AUGTYRO due to ataxia.

Cognitive disorder, including memory impairment and disturbance in attention, occurred in 23% of the 351 patients. Cognitive disorders included memory impairment (13%), disturbance in attention (11%), and confusional state (2%); Grade 3 cognitive disorders 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, 1.7% required dose reduction, and 0.6% patients permanently discontinued AUGTYRO due to cognitive adverse reactions.

Mood disorders occurred in 6% of the 351 patients. Mood disorders occurring in > 1% of patients included anxiety (2.8%), irritability (1.1%), and depression (1.4%); Grade 4 mood disorders (mania) occurred in 0.3% of patients. Dose interruption was required in 0.3% of patients and 0.3% of patients required a dose reduction due to mood disorders.

Sleep disorders including insomnia and hypersomnia occurred in 15% of the 351 patients. Sleep disorders observed in > 1% of patients were somnolence (8%), insomnia (6%) and hypersomnia (1.1%). Dose interruption was required in 0.9% of patients, and 0.3% of patients required a dose reduction due to sleep disorders.

The incidences of CNS adverse reactions observed were similar in patients with and without CNS metastases.

Advise patients and caregivers of the risk of CNS adverse reactions with AUGTYRO. 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 [see Dosage and Administration (2.5)].

5.2 Interstitial Lung Disease/Pneumonitis

AUGTYRO can cause interstitial lung disease (ILD)/pneumonitis.

Among the 351 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.6%] and interstitial lung disease [0.3%]) occurred in 2.9% of patients; Grade 3 ILD/pneumonitis occurred in 1.1% of patients. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.6% of patients required dose reduction, and 1.1% of patients 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 [see Dosage and Administration (2.5)].

5.3 Hepatotoxicity

AUGTYRO can cause hepatotoxicity.

Among the 351 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 35%, increased aspartate aminotransferase (AST) occurred in 40%, including Grade 3 or 4 increased ALT in 2% and increased AST in 2.6%. 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 1.4% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.6%.

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. Withhold and then resume at the same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on the severity [see Dosage and Administration (2.5)].

5.4 Myalgia with Creatine Phosphokinase Elevation

AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation.

Among the 351 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.6%. 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 the same or reduced dose upon improvement [see Dosage and Administration (2.5)].

5.5 Hyperuricemia

AUGTYRO can cause hyperuricemia.

Among the 351 patients treated with AUGTYRO, 18 patients (5%) experienced hyperuricemia reported as an adverse reaction and 0.9% of patients 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 the same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity [see Dosage and Administration (2.5)].

5.6 Skeletal Fractures

AUGTYRO can cause skeletal fractures.

Among 351 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.6%), feet (0.6%), spine (0.3%), acetabulum (0.3%), sternum (0.3%), and ankles (0.3%). 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.

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.

5.7 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.

Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended 160 mg twice daily dose based on body surface area (BSA).

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 [see Drug Interactions (7.2)]. 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 [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Central Nervous System Adverse Reactions [see Warnings and Precautions (5.1)]
• Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Myalgia with Creatine Phosphokinase Elevation [see Warnings and Precautions (5.4)]
• Hyperuricemia [see Warnings and Precautions (5.5)]
• Skeletal Fractures [see Warnings and Precautions (5.6)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.7)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates reported in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to AUGTYRO as a single agent dosed at 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity in 351 patients with ROS1-positive NSCLC and other solid tumors in the TRIDENT-1 trial. Among 351 patients who received AUGTYRO, 52% were exposed for 6 months or longer and 26% were exposed for greater than 1 year. In this pooled safety population, the most common (>20%) adverse reactions were dizziness (64%), dysgeusia (50%), peripheral neuropathy (47%), constipation (37%), dyspnea (30%), ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea (20%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased gamma glutamyl transferase (13%), decreased lymphocytes (10%), increased urate (10%), decreased neutrophils (8%), decreased hemoglobin (7%), increased creatine phosphokinase (5.8%), decreased phosphate (4.9%), decreased leukocytes (3.8%), increased ALT (3.5%), decreased sodium (3.5%), increased AST (2.9%), increased magnesium (2.9%), increased alkaline phosphatase (2.6%), and increased glucose (2%).

TRIDENT-1

The safety of AUGTYRO was evaluated in 264 patients with ROS1-positive NSCLC in TRIDENT-1 [see Clinical Studies (14.1)]. Eligible patients had an ECOG status of ≤1. Patients with a history of ILD, drug-related pneumonitis, significant, uncontrolled, active cardiovascular disease, or prolonged QTc interval were excluded from enrollment in this trial. Patients received AUGTYRO at a dose of 160 mg orally once daily for the first 14 days, then increased to 160 mg orally twice daily until disease progression or unacceptable toxicity. Among patients who received AUGTYRO, 52% were exposed for at least 6 months, and 27% were exposed for greater than 1 year.

The median age of patients who received AUGTYRO was 56 years (range: 27 to 93); 62% female; 43% White, 49% Asian, 2.7% Black, 0.8% Native Hawaiian or Other Pacific Islander, 0.4% American Indian or Alaska Native, 3.4% race not reported, and 1.1% unknown.

Serious adverse reactions occurred in 33% of patients who received AUGTYRO. Serious adverse reactions in ≥2% of patients included pneumonia (5.7%), dyspnea (3.8%), pleural effusion (3.4%), and hypoxia (3%). Fatal adverse reactions occurred in 4.2% of patients who received AUGTYRO, including death, pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, sudden death, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.

Permanent discontinuation of AUGTYRO was required in 8% of patients due to adverse reactions. The adverse reactions resulting in permanent discontinuation of AUGTYRO in ≥1% of patients were dyspnea, pneumonitis, and muscular weakness.

Dosage interruptions of AUGTYRO due to an adverse reaction occurred in 48% of patients. Adverse reactions that required dosage interruption in ≥5% of patients included CNS toxicity, dyspnea, and muscular weakness.

Dose reductions of AUGTYRO due to an adverse reaction occurred in 35% of patients. Adverse reactions that required dosage reductions in ≥5% of patients included dizziness.

The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased hemoglobin, decreased lymphocytes, decreased leukocytes, increased alanine aminotransferase, decreased neutrophils, increased gamma glutamyl transferase, increased alkaline phosphatase, increased urate, increased magnesium, and decreased phosphate. Table 3 summarizes the adverse reactions in the TRIDENT-1 trial.

Table 3. Adverse Reactions (≥10%) in Patients with ROS1-positive NSCLC Who Received AUGTYRO in TRIDENT-1:

¹ Based on NCI CTCAE v4.03
^a Includes terms dizziness, vertigo, dizziness postural, dizziness exertional, vertigo positional
^b Includes terms dysgeusia, ageusia, anosmia, hypogeusia
^c Includes terms neuralgia, neuropathy peripheral, peripheral sensory neuropathy, dysesthesia, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, hyperesthesia
^d Includes terms ataxia, gait disturbance, balance disorder, cerebellar ataxia
^e Includes terms memory impairment, disturbance in attention, cognitive disorder, confusional state, amnesia, attention deficit hyperactivity disorder, delirium, altered state of consciousness, aphasia, delusion, depressed level of consciousness, hallucination, mental status changes, neurological decompensation
^f Includes terms headache, migraine, tension headache
^g Includes terms dyspnea and dyspnea exertional
^h Includes terms productive cough, cough, and upper-airway cough syndrome
ⁱ Includes terms fatigue and asthenia
^j Includes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema
^k Includes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain
^l Includes terms vision blurred, dry eye, visual impairment, visual field defect, cataract, conjunctivitis, eye pain, photophobia, photosensitivity reaction, visual acuity reduced, vitreous floaters, blepharospasm, color blindness, diplopia, eye hematoma, eye swelling, eyelid disorder, eyelid injury, eyelids pruritus, glaucoma, night blindness, ophthalmic herpes zoster

Clinically relevant adverse reactions in <10% of patients receiving AUGTYRO were pyrexia (8%) and fall (2.7%).

Table 4 summarizes the laboratory abnormalities.

Table 4. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ROS1-positive NSCLC Who Received AUGTYRO in TRIDENT-1:

Abbreviations: AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; GGT: Gamma Glutamyl Transferase; aPTT: Activated Partial Thromboplastin Time; INR: Prothrombin International Normalized Ratio
¹ Based on NCI CTCAE v4.03
² The denominator used to calculate the rate varied from 163 to 261 based on the number of patients with a baseline value and at least one post-treatment value.

7.1 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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

7.2 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 [see Clinical Pharmacology (12.3)], 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 [see Use in Specific Populations (8.1, 8.3)]. Advise females to use an effective nonhormonal contraceptive.

Risk Summary

Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], AUGTYRO can cause fetal harm when administered to a pregnant woman. There are no available data on AUGTYRO use in pregnant women. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.

Animal Data

In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg [approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA]. No embryolethality was observed.

Risk Summary

There are no data on the presence of AUGTYRO in human milk or its effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from AUGTYRO, advise a lactating woman to discontinue breastfeeding during treatment with AUGTYRO and for 10 days after the last dose.

AUGTYRO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of childbearing potential prior to initiating AUGTYRO [see Use in Specific Populations (8.1)].

Contraception

AUGTYRO can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of childbearing potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose. AUGTYRO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)].

Males

Based on genotoxicity findings, advise male patients with female partners of childbearing potential to use effective contraception during treatment with AUGTYRO and for 4 months following the last dose [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of AUGTYRO in pediatric patients with ROS1-positive NSCLC has not been established.

Juvenile Animal Data

Daily oral administration of repotrectinib to juvenile rats for 8 weeks starting on postnatal day 12 (approximately equal to a human pediatric age of a newborn) resulted in toxicities similar to those observed in adult rats, though juvenile animals showed decreased body weight gain at doses ≥1 mg/kg (approximately ≥0.04 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID) and decreased femur lengths at 3 mg/kg (approximately 0.1 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID). Decreased body weight gain and decreased femur lengths persisted following 4 weeks of recovery.

Of the 351 patients who received AUGTYRO, 21% were 65 to 75 years old, and 7% were 75 years of age or older. There were no clinically meaningful differences in safety and efficacy between patients younger than 65 years of age and patients 65 years of age or older.

The recommended dosage of AUGTYRO has not been established in patients with severe renal impairment or kidney failure (eGFR-MDRD <30 mL/min) and patients on dialysis [see Clinical Pharmacology (12.3)].

No dosage modification is recommended for patients with mild or moderate renal impairment (eGFR-MDRD 30 to 90 mL/min).

The recommended dosage of AUGTYRO has not been established in patients with moderate (total bilirubin >1.5 to 3 times upper limit of normal [ULN] with any AST) or severe (total bilirubin >3 times ULN with any AST) hepatic impairment [see Clinical Pharmacology (12.3)].

No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) hepatic impairment.