SAFETY PROFILE

Adverse reaction profile with AUGTYRO in the TRIDENT-1 study1

The pooled safety population included 426 patients who were exposed to AUGTYRO1

Serious adverse reactions occurred in 35% of patients who received AUGTYRO. Serious adverse reactions reported in ≥2% of patients included pneumonia, dyspnea, pleural effusion, and hypoxia. Fatal adverse reactions were reported in 3.5% of patients who received AUGTYRO, including pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.1

Adverse Reaction1*
(≥10%) in patients taking AUGTYRO		 AUGTYRO (N=426)
ALL GRADES % GRADE 3 OR 4 % 
Nervous System Disorders    
     Dizzinessa 65 2.8
     Dysgeusiab 54 0
     Peripheral neuropathyc 49 1.4
     Ataxiad 28 0.5
     Cognitive impairmente 25 0.9
     Headachef 19 0
Gastrointestinal Disorders    
     Constipation 38 0.2
     Nausea 20 0.7
     Diarrhea 14 0.7
     Vomiting 12 1.2
Respiratory, Thoracic, and Mediastinal Disorders    
     Dyspneag 30 6
     Coughh 18 0.2
     Pneumoniai 11 6
General Disorders    
     Fatiguej 30 1.2
     Edemak 15 0.5
     Decreased appetite 11 0.2
Musculoskeletal and Connective Tissue Disorders    
     Muscular weakness 20 2
     Myalgial 13 0.7
Metabolism and Nutritional    
     Increased weight 16 3
Eye Disorders    
     Vision disordersm 12 0.5
* 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 and coordination abnormal.
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 pneumonia, pneumonia aspiration, lower respiratory tract infection, pneumonia viral, pneumonia bacterial, lower respiratory tract infection bacterial, pneumonia klebsiella.
j Includes terms fatigue and asthenia.
k Includes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema.
l Includes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain.
m 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.

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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).

CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; NSCLC=non-small cell lung cancer; ROS1=proto-oncogene C-Ros1, receptor tyrosine kinase.

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


IMPORTANT SAFETY INFORMATION

SUMMARY OF WARNINGS AND PRECAUTIONS

AUGTYRO was assessed in 426 patients with ROS1+ NSCLC and other solid tumors in the TRIDENT-1 pivotal study and is associated with the following warnings and precautions: central nervous system (CNS) adverse reactions, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase (CPK) elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity.

INDICATION

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

IMPORTANT SAFETY INFORMATION

Warnings and 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.
  • Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5%. 
  • 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.
  • 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.
  • 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%). 
  • 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

  • ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%.
  • 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

  • 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%.
  • 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. Myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Concurrent increased CPK within a 7-day window was observed in 3.7% of patients.
  • 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

  • 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

  • Fractures occurred in 2.3% of patients and 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.
  • 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 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

  • Avoid concomitant use with P-gp inhibitors, strong or moderate CYP3A inducers, and strong or moderate CYP3A inhibitors. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating 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 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 Full U.S. Full Prescribing Information for AUGTYRO.

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3600-US-2400348   04/25