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Getting Started Recommended Dosing Dosing Modifications

GETTING STARTED

  • Prior to initiating AUGTYRO, discontinue strong and moderate CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor1

Recommended testing for initiation and follow-up1

Test Prior to Initiation Monitoring
Liver function tests including bilirubin Checkmark Icon Every 2 weeks for first month; monthly thereafter and/or as clinically indicated1
Uric acid level Checkmark Icon Periodic monitoring during treatment1
Serum CPK levels N/A Every 2 weeks for first month; periodic monitoring as clinically indicated thereafter1
Interstitial lung disease/pneumonitis N/A Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis1
Test Monitoring
Liver function tests including bilirubin Prior to Initiation Checkmark Icon
Every 2 weeks for first month; monthly thereafter and as clinically indicated1
Uric acid level Prior to Initiation Checkmark Icon
Periodic monitoring during treatment1
Serum CPK levels Prior to Initiation N/A
Every 2 weeks for first month; periodic monitoring as clinically indicated thereafter1
Interstitial lung disease/
pneumonitis		 Prior to Initiation N/A
Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis1

RECOMMENDED DOSING

Recommended dosing of AUGTYRO1

RECOMMENDED ORAL DOSE OF AUGTYRO1*

Days 1-14

160 mg QD
(4 capsules daily)

Day 15 Onward

160 mg BID
(4 capsules, twice daily)

  • Until disease progression or unacceptable toxicity.
Steaming pot icon

AUGTYRO can be taken with or without food1†

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Capsules should be swallowed whole at approximately the same time every day as prescribed1

Crossed out medicine capsule being emptied icon

Contents of the capsule should not be opened, crushed, chewed, or dissolved1

Patient vomiting at toilet icon

If a dose is missed or if a patient vomits at any time after taking a dose, instruct patients to skip the dose and resume at the regularly scheduled time. Two doses should not be taken at the same time1

  • Advise patients not to drink grapefruit juice or eat grapefruit while taking AUGTYRO.1

Dose Modifications

Recommended dosage reductions with AUGTYRO1

Adjustable dosing allows for dose modification if needed for adverse reactions‡

Recommended Dosage Reductions for Adverse Reactions1
Dose Dose Reduction
First Second
160 mg Once Daily 120 mg Once Daily 80 mg Once Daily
160 mg Twice Daily 120 mg Twice Daily 80 mg Twice Daily
Recommended Dosage Reductions for Adverse Reactions1
Dose First Dose Reduction
160 mg Once Daily 120 mg Once Daily
160 mg Twice Daily 120 mg Twice Daily
Dose Second Dose Reduction
160 mg Once Daily 80 mg Once Daily
160 mg Twice Daily 80 mg Twice Daily

Central nervous system effects1

  • If intolerable Grade 2, withhold AUGTYRO until ≤Grade 1 or baseline, then resume at same or reduced dose, as clinically appropriate
  • If Grade 3, withhold AUGTYRO until ≤Grade 1 or baseline, then resume at reduced dose
  • If Grade 4, permanently discontinue AUGTYRO

ILD/pneumonitis1

  • For any grade, withhold AUGTYRO if ILD/pneumonitis is suspected and permanently discontinue if confirmed

Hepatotoxicity1

  • If Grade 3, withhold AUGTYRO until ≤Grade 1 or baseline. Resume at same dose if resolution occurs within 4 weeks, or at reduced dose for recurrent Grade 3 events that resolve within 4 weeks
  • If Grade 4, withhold AUGTYRO until ≤Grade 1 or baseline. Resume at reduced dose if resolution occurs within 4 weeks. Permanently discontinue if AR does not resolve within 4 weeks or if it recurs
  • If ALT or AST >3 times the ULN with concurrent total bilirubin >1.5 times ULN (in absence of cholestasis or hemolysis), permanently discontinue AUGTYRO

CPK Elevation1

  • If CPK elevation >5 times ULN, withhold AUGTYRO until baseline or ≤2.5 times ULN, then resume at same dose
  • If CPK elevation >10 times ULN or second occurrence of CPK elevation of >5 times ULN, withhold AUGTYRO until baseline or ≤2.5 times ULN, then resume at reduced dose

Hyperuricemia1

  • If Grade 3 or 4, withhold AUGTYRO until improvement of signs or symptoms, then resume AUGTYRO at same or reduced dose

Other clinically relevant adverse events1

  • If intolerable Grade 2, Grade 3, or Grade 4 AR, withhold AUGTYRO until ≤Grade 1 or baseline, then resume at same or reduced dose if resolution occurs within 4 weeks. Permanently discontinue if AR does not resolve within 4 weeks, or if recurrent Grade 4
  • Graded per CTCAE v4.03.
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AUGTYRO is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

ALT=alanine transaminase; AR=adverse reaction; AST=aspartate transaminase; CPK=creatinine phosphokinase; CTCAE=Common Terminology Criteria for Adverse Events; ILD=interstitial lung disease; ULN=upper limit of normal.

Reference:

1. AUGTYRO [package insert]. Princeton, NJ. Bristol-Myers Squibb Company.

Prescribing Information Patient Information

IMPORTANT SAFETY INFORMATION

INDICATION

AUGTYROTM (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

Warnings & Precautions

Central Nervous System Adverse Reactions

Among the 351 patients who received AUGTYRO in the TRIDENT-1 study, 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%. Dizziness, including vertigo, occurred in 64% and 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%. 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% 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% 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% 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 351 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.6%] and interstitial lung disease [0.3%]) occurred in 2.9%; Grade 3 ILD/pneumonitis occurred in 1.1%. 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% 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 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 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

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 same or reduced dose upon improvement.

Hyperuricemia

Among the 351 patients treated with AUGTYRO, 18 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.9% 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 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.

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

Among 351 patients who received AUGTYRO for ROS1-positive NSCLC and other solid tumors in the TRIDENT-1 trial, 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%).

In a subset of 264 patients who received AUGTYRO for ROS1-positive NSCLC, the most common (≥20%) adverse reactions were dizziness (63%), dysgeusia (48%), peripheral neuropathy (47%), constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%), cognitive disorders (23%), and muscular weakness (21%).

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 to use an effective nonhormonal contraceptive.

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