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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hepatotoxicity: Hepatotoxicity, including drug-induced liver injury and fatal adverse reactions, can occur. 88% of patients experienced increased AST, including 10% Grade 3/4. 85% of patients experienced increased ALT, including 13% Grade 3/4. Fatal liver events occurred in 0.6% of patients. Median time to first onset of AST or ALT elevation was 15 days (range: 3 days to 20.8 months).

Increased AST or ALT each led to dose interruption in 7% of patients and dose reduction in 5% and 9% of patients, respectively. Permanent discontinuation was caused by increased AST, ALT, or bilirubin each in 0.3% and by hepatotoxicity in 0.6% of patients.

Concurrent elevations in AST or ALT ≥3 times the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in 0.6% of patients.

Monitor liver function tests (AST, ALT, and bilirubin) prior to treatment, every 2 weeks during the first 2 months, and then monthly thereafter as clinically indicated. Test more frequently if transaminase elevations occur. Advise patients to immediately report symptoms of hepatotoxicity. Based on severity and resolution, withhold, then resume at a reduced dose or permanently discontinue.

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, or fatal ILD or pneumonitis can occur. ILD/pneumonitis occurred in 2.3% of patients, including 1.1% Grade 3/4. One fatal ILD case occurred at the 400 mg daily dose. Median time to first onset of ILD/pneumonitis was 3.8 months (range: 12 days to 11.8 months).

ILD/pneumonitis led to dose interruption in 1.1% of patients, dose reduction in 0.6% of patients, and permanent discontinuation in 0.6% of patients.

Monitor patients for new or worsening pulmonary symptoms. Advise patients to report symptoms. If ILD/pneumonitis is suspected, immediately withhold; based on severity and resolution, resume at same or reduced dose, or permanently discontinue.

QTc Interval Prolongation: QTc interval prolongation can occur, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. IBTROZI prolongs the QTc interval in a concentration-dependent manner.

In patients who received IBTROZI and underwent at least one post baseline ECG, QTcF increase of >60 msec compared to baseline and QTcF >500 msec occurred in 13% and 2.6% of patients, respectively. 3.4% of patients experienced Grade ≥3. Median time from first dose of IBTROZI to onset of ECG QT prolongation was 22 days (range: 1 day to 38.7 months). Dose interruption and dose reduction each occurred in 2.8% of patients.

Monitor ECGs and electrolytes prior to start of therapy, and then periodically thereafter as clinically indicated. Adjust frequency based on risk factors such as known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and concomitant medications.

Significant QTc interval prolongation may occur when IBTROZI is taken with food, strong and moderate CYP3A inhibitors, and/or drugs with a known potential to prolong QTc. Administer IBTROZI on an empty stomach. Avoid concomitant use with strong and moderate CYP3A inhibitors and/or drugs with a known potential to prolong QTc.

Advise patients to immediately report any symptoms of QT interval prolongation. Based on severity and resolution, withhold, then resume at same or reduced dose, or permanently discontinue.

Hyperuricemia: Hyperuricemia can occur and was reported in 14% of patients, with 16% of these requiring urate-lowering medication without pre-existing gout or hyperuricemia. 0.3% of patients experienced Grade ≥3. Median time to first onset was 2.1 months (range: 7 days to 35.8 months). Dose interruption occurred in 0.3% of patients.

Monitor serum uric acid levels prior to initiating and periodically during treatment. Initiate urate-lowering medications as clinically indicated. Advise patients to report symptoms. Based upon severity and resolution, withhold, then resume at same or reduced dose, or permanently discontinue.

Myalgia with Creatine Phosphokinase (CPK) Elevation: Myalgia with or without CPK elevation can occur. Myalgia occurred in 10% of patients. Median time to first onset was 11 days (range: 2 days to 10 months).

Concurrent myalgia with increased CPK within a 7-day time period occurred in 0.9% of patients. Dose interruption occurred in 0.3% of patients with myalgia and concurrent CPK elevation.

Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during treatment every 2 weeks during the first month, and then as clinically indicated. Based on severity, withhold, then resume at same or reduced dose upon improvement.

Skeletal Fractures: IBTROZI can increase the risk of fractures. ROS1 inhibitors as a class have been associated with skeletal fractures. 3.4% of patients experienced fractures, including 1.4% Grade 3. Some fractures occurred in the setting of a fall or other predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. Median time to first onset of fracture was 10.7 months (range: 26 days to 29.1 months). Dose interruption occurred in 0.3% of patients.

Advise patients to immediately report symptoms. Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures.

There are no data on the effects of IBTROZI on healing of known fractures and risk of future fractures.

Embryo-Fetal Toxicity: Based on literature, animal studies, and its mechanism of action, IBTROZI can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating IBTROZI. Advise females to inform their healthcare provider of a known or suspected pregnancy.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential and male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks following the last dose.

ADVERSE REACTIONS

Among patients who received IBTROZI, the most frequently reported adverse reactions (≥20%) were diarrhea (64%), nausea (47%), vomiting (43%), dizziness (22%), rash (22%), constipation (21%), and fatigue (20%).

The most frequently reported Grade 3/4 laboratory abnormalities (≥5%) were increased ALT (13%), increased AST (10%), decreased neutrophils (5%), and increased creatine phosphokinase (5%).

DRUG INTERACTIONS

• Strong and Moderate CYP3A Inhibitors: Avoid concomitant use.
• Strong and Moderate CYP3A Inducers: Avoid concomitant use.
• Gastric Acid Reducing Agents: Avoid concomitant use with PPIs and H2 receptor antagonists. If an acid-reducing agent cannot be avoided, administer locally acting antacids at least 2 hours before or 2 hours after taking IBTROZI.
• Drugs that Prolong the QTc Interval: Avoid concomitant use. If concomitant use cannot be avoided, adjust the frequency of monitoring as recommended. Withhold IBTROZI if the QTc interval is >500 msec or the change from baseline is >60 msec.

OTHER CONSIDERATIONS

• Pregnancy: Please see important information in Warnings and Precautions under Embryo-Fetal Toxicity.
• Lactation: Advise women not to breastfeed during treatment and for 3 weeks after the last dose.
• Effect on Fertility: Based on findings in animals, IBTROZI may impair fertility in males and females. The effects on animal fertility were reversible.
• Pediatric Use: The safety and effectiveness of IBTROZI in pediatric patients has not been established.
• Photosensitivity: IBTROZI can cause photosensitivity. Advise patients to minimize sun exposure and to use sun protection, including broad-spectrum sunscreen, during treatment and for at least 5 days after discontinuation.

Please see accompanying full Prescribing Information.