Zidesamtinib

5 WARNINGS AND PRECAUTIONS Central Nervous System (CNS) Adverse Reactions (AR): Can cause CNS AR including dizziness, ataxia, cognitive and psychiatric disorders. Based on severity, withhold JIDEYTRO and resume at same or reduced dose, or permanently discontinue. ( 5.1 ) QTc Interval Prolongation: Can cause QTc prolongation. Evaluate ECGs and electrolytes prior to administration of JIDEYTRO and monitor periodically during treatment. Based on severity, withhold JIDEYTRO and resume at the same or reduced dose, or permanently discontinue. ( 5.2 ) Interstitial Lung Disease (ILD)/pneumonitis: Can cause ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold in patients with suspected ILD/pneumonitis. Based on severity, withhold JIDEYTRO and resume at the same or reduced dose, or permanently discontinue. ( 5.3 ) Skeletal Fractures : Can cause skeletal fractures. Promptly evaluate patients with signs or symptoms of fractures. ( 5.4 ) Myalgia with Creatine Phosphokinase (CPK) Elevation: Can cause CPK elevation. Advise patients to report unexplained muscle pain or tenderness. Monitor serum CPK levels during treatment. Based on severity, withhold JIDEYTRO and resume at same or reduced dose upon recovery to baseline. ( 5.5 ) Pancreatic Toxicity: Evaluate amylase and lipase prior to administration of JIDEYTRO and monitor periodically during treatment. Withhold, dose reduce or permanently discontinue JIDEYTRO based on severity. ( 5.6 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 ) 5.1 Central Nervous System Adverse Reactions JIDEYTRO can cause central nervous system adverse reactions. In the pooled safety population [see Adverse Reactions ( 6.1) ] , a broad spectrum of central nervous system (CNS) adverse reactions, including dizziness, ataxia, cognitive and psychiatric disorders, occurred in 25% of patients who received JIDEYTRO; of these, 2.5% were Grade 3 or 4. One patient (0.2%) with brain metastases experienced a Grade 3 seizure. Dizziness, including vertigo, presyncope and positional dizziness occurred in 12% of patients who received JIDEYTRO; of these 0.2% were Grade 3. The median time to onset of dizziness was 22 days (range: 1 day to 9 months). Dosage interruption of JIDEYTRO for dizziness was required in 0.4% of patients, and 0.7% of patients required dose reduction. Ataxia, including gait disturbance and balance disorder, occurred in 2% of patients who received JIDEYTRO and were all Grade 1 or 2. The median time to onset of ataxia was 64 days (range: 6 days to 2.5 years). Cognitive impairment occurred in 9% of patients who received JIDEYTRO, of these 1.6% were Grade 3 or 4. Cognitive impairment included memory impairment (3.1%), cognitive disorder (1.6%), hallucination (1.1%), delirium (1.1%), aphasia (0.9%), amnesia (0.7%), confusional state (0.7%), anterograde amnesia (0.2%), disturbance in attention (0.4%), slow speech (0.2%). The median time to onset of cognitive impairment was 43 days (range: 4 days to 1.9 years). Dose interruption of JIDEYTRO for cognitive impairment was required in 1.3% of patients. Psychiatric disorders occurred in 6% of patients who received JIDEYTRO, of these 0.7% were Grade 3 or 4. Psychiatric disorders included anxiety (3.1%), depression (1.3%), agitation (0.7%), affect lability (0.4%), irritability (0.4%), abnormal behavior (0.2%), depressed mood (0.2%), personality change (0.2%), psychotic disorder (0.2%), and suicidal ideation (0.2%). The median time to onset of psychiatric disorders was 57 days (range: 1 day to 10 months). Dosage interruption of JIDEYTRO for psychiatric disorders was required in 0.9% of patients. Advise patients and caregivers of the risk of CNS adverse reactions with JIDEYTRO. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination such as operating machinery or driving a motor vehicle if they are experiencing CNS reactions. Monitor patients for CNS adverse reactions and suicidal thoughts and behaviors during treatment with JIDEYTRO. Withhold and then resume at the same or reduced dose upon improvement or permanently discontinue JIDEYTRO based on severity [see Dosage and Administration ( 2.3 )] . 5.2 QTc Interval Prolongation JIDEYTRO can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. JIDEYTRO has not been studied in patients with a history of QTcF >450 msec on more than one assessment prior to initiation. In the pooled safety population [see Adverse Reactions ( 6.1 )], of the 435 patients who underwent at least one post baseline electrocardiogram (ECG) assessment, 2% experienced an increase in QTcF of >60 msec compared to baseline after receiving JIDEYTRO and 0.2% increase in QTcF to >500 msec. The median time from the first dose of JIDEYTRO to the onset of QTc prolongation was 15 days (range: 1 day to approximately 1 month). QTc prolongation led to dose interruption in 0.4% of patients who received JIDEYTRO. Evaluate ECGs and electrolytes prior to administration of JIDEYTRO and monitor periodically during treatment. Adjust the frequency of monitoring based on risk factors such as known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and concomitant medications associated with QTc interval prolongation. Withhold, then resume at the same or reduced dose, or permanently discontinue JIDEYTRO based on severity [see Dosage and Administration ( 2.3 )] . 5.3 Interstitial Lung Disease/Pneumonitis JIDEYTRO can cause severe or life-threatening interstitial lung disease (ILD) or pneumonitis. In the pooled safety population [see Adverse Reactions ( 6.1 )] , interstitial lung disease (ILD)/pneumonitis occurred in 1.8% of patients treated with JIDEYTRO, including Grade 3 or 4 in 0.4%. The median time to first onset of ILD/pneumonitis was 4.5 months (range: 8 days to 11 months). ILD/pneumonitis led to dose interruption of JIDEYTRO in 0.7% of patients. ILD/pneumonitis required dose reduction in 0.2% of patients and permanent discontinuation of JIDEYTRO in 0.4% of patients. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold JIDEYTRO in patients with suspected ILD/pneumonitis, then upon recovery resume at the same or reduced dose or permanently discontinue based on severity [see Dosage and Administration ( 2.3 )]. 5.4 Skeletal Fractures JIDEYTRO can increase the risk of skeletal fractures. In the pooled safety population [see Adverse Reactions ( 6.1 )] , 5 patients (1.1%) experienced skeletal fractures, and Grade 3 ankle fractures occurred in two patients (0.4%) who received JIDEYTRO. Some fractures occurred in the setting of an accidental fall or other predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. The median time to fracture was 48 days (range: 32 days to approximately 6 months). JIDEYTRO was interrupted in 0.4% of patients for fractures. 5.5 Myalgia with Creatine Phosphokinase Elevation JIDEYTRO can cause myalgia with creatine phosphokinase (CPK) elevation. In the pooled safety population [see Adverse Reactions ( 6.1 )] , myalgia occurred in 13% of patients who received JIDEYTRO. Based on laboratory values, concurrent myalgia with increased CPK occurred in 2.1% of patients. The median time to onset of myalgia for these patients with CPK elevation was 2 months (range: 8 days to 6 months). Advise patients to report unexplained muscle pain or tenderness. Monitor serum CPK levels prior to administration of JIDEYTRO and every 2 weeks during the first month of treatment and then every 1 to 2 months and as clinically indicated in patients reporting unexplained muscle pain or tenderness. Withhold, then resume at the same or reduced dose, or permanently discontinue JIDEYTRO based on severity [see Dosage and Administration ( 2.3 )]. 5.6 Pancreatic Toxicity JIDEYTRO can cause pancreatic toxicity. In the pooled safety population [see Adverse Reactions ( 6.1 )] , among the subgroup of patients who underwent pancreatic lab testing, increased amylase occurred in 22% and increased lipase occurred in 25% of patients treated with JIDEYTRO. Grade 3 increased lipase occurred in 8% of these patients. Grade 3 lipase elevation resulted in JIDEYTRO dose reduction in one patient. The median time-to-onset of Grade 3 increased lipase was 143 days (range: 28 to 249 days). In the pooled safety population [see Adverse Reactions ( 6.1 )] , Grade 3 pancreatitis occurred in one patient (0.2%) treated with JIDEYTRO. Evaluate amylase and lipase prior to administration of JIDEYTRO and monitor periodically during treatment. Based on the severity of the adverse reaction, temporarily withhold, reduce the dose, or permanently discontinue JIDEYTRO [see Dosage and Administration ( 2.3 )] . 5.7 Embryo-Fetal Toxicity Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor kinase (TRK) signaling, findings from animal studies and its mechanism of action, JIDEYTRO can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of zidesamtinib to pregnant rats during the period of organogenesis resulted in embryo-fetal mortality, alterations to growth, and structural abnormalities at maternal exposures approximately equivalent to the human exposure at the recommended dose based on area under the curve (AUC). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with JIDEYTRO and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with JIDEYTRO and for 3 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

4 CONTRAINDICATIONS None. None.