JIDEYTRO Film-coated tablet Ref.[116775] Active ingredients:

5.1 Central Nervous System Adverse Reactions

JIDEYTRO can cause central nervous system adverse reactions.

In the pooled safety population 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 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 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 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 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 Dosage and Administration (2.3)].

5.4 Skeletal Fractures

JIDEYTRO can increase the risk of skeletal fractures.

In the pooled safety population 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 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 Dosage and Administration (2.3)].

5.6 Pancreatic Toxicity

JIDEYTRO can cause pancreatic toxicity.

In the pooled safety population 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 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 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 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)]
• QTc Interval Prolongation [see Warnings and Precautions (5.2)]
• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)]
• Skeletal Fractures [see Warnings and Precautions (5.4)]
• Myalgia with Creatine Phosphokinase Elevation [see Warnings and Precautions (5.5)]
• Pancreatic Toxicity [see Warnings and Precautions (5.6)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed 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 JIDEYTRO in 446 patients with ROS1-positive NSCLC (n=432) and other solid tumors (n=14) who received JIDEYTRO at a dose of 100 mg orally once daily until disease progression or unacceptable toxicity in ARROS-1 [see Clinical Studies (14.1)]. Among 446 patients who received JIDEYTRO, 44% were exposed for 6 months or longer and 14% were exposed for greater than one year. In this pooled safety population, the most common (≥15%) adverse reactions included: edema (38%), peripheral neuropathy (25%), constipation (17%), fatigue (16%), dyspnea (15%). The most common Grade 3 or 4 laboratory abnormalities (≥2%), were increased lipase (8%), increased creatine phosphokinase (CPK) (4%), increased triglycerides (3.5%), decreased lymphocytes (2.7%), and decreased hemoglobin (2.3%).

Previously Treated ROS1-positive NSCLC

The safety of JIDEYTRO was evaluated in ARROS-1 [see Clinical Studies (14.1)]. Patients received JIDEYTRO 100 mg orally once daily until disease progression or unacceptable toxicity. Among the 432 patients who received JIDEYTRO, 44% were exposed to JIDEYTRO for 6 months or longer, and 15% were exposed for greater than 1 year.

The median age of patients who received JIDEYTRO was 58 years (range: 26 to 87); 62% female; 41% White, 41% Asian, 3.7% Black or African American, 0.2% American Indian or Alaska Native, 14% other races, multiple races or race unknown, and 4.6% of patients were of Hispanic or Latino ethnicity.

Serious adverse reactions occurred in 22% of patients who received JIDEYTRO. Serious adverse reactions in ≥2% of patients included pneumonia (6%) and dyspnea (2.5%). Fatal adverse reactions occurred in 2.3% of patients who received JIDEYTRO, including pneumonia (0.5%), cerebrovascular accident (0.2%), COVID-19 (0.2%), dyspnea (0.2%), infectious pleural effusion (0.2%), influenza (0.2%), myocardial infarction (0.2%), myocarditis (0.2%), and respiratory failure (0.2%).

Permanent discontinuation of JIDEYTRO due to an adverse reaction occurred in 2.3% of patients. Adverse reactions resulting in permanent discontinuation of JIDEYTRO occurring in ≥2 patients were pneumonia (0.7%) and pneumonitis (0.5%).

Dosage interruptions of JIDEYTRO due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥1% of patients included pneumonia (4.6%), increased creatine phosphokinase level (3.0%), peripheral neuropathy (1.9%), peripheral edema (1.6%), COVID-19 (1.4%), and dyspnea and elevated alanine aminotransferase level (each in 1.2%).

Dose reductions of JIDEYTRO due to an adverse reaction occurred in 10% of patients. Adverse reactions which required dosage reduction in ≥1% of patients included peripheral edema (1.9%) and peripheral neuropathy (1.2%).

Table 3 summarizes the adverse reactions that occurred in the ARROS-1 trial.

Table 3. Adverse Reactions (≥10%) in Patients with ROS1-Positive NSCLC Who Received JIDEYTRO in ARROS-1:

¹ Based on NCI CTCAE v5.0
^* Grouped term

Clinically relevant adverse reactions in <10% of patients receiving JIDEYTRO were cognitive disorders, psychiatric disorders, stomatitis, ataxia, ILD/pneumonitis, QTc prolongation, pancreatitis, and ankle fracture.

Table 4 summarizes the laboratory abnormalities in ARROS-1.

Table 4. Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ROS1-Positive NSCLC Who Received JIDEYTRO in ARROS-1:

¹ Based on NCI CTCAE v5.0
² The denominator used to calculate the rate varied from 37 to 429 based on the number of patients with a baseline value and at least one post-baseline treatment value.

7.1 Effect of Other Drugs on JIDEYTRO

Strong and Moderate CYP3A Inhibitors

Avoid concomitant use of JIDEYTRO with a strong or moderate CYP3A inhibitor.

Zidesamtinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor increases zidesamtinib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of JIDEYTRO adverse reactions.

Strong and Moderate CYP3A Inducers

Avoid concomitant use of JIDEYTRO with strong or moderate CYP3A inducers.

Concomitant use of JIDEYTRO with a strong or moderate CYP3A inducer may decrease zidesamtinib exposure [see Clinical Pharmacology (12.3)], which may decrease the effectiveness of JIDEYTRO.

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)], JIDEYTRO can cause etal harm when administered to a pregnant woman. There are no available data on JIDEYTRO use in pregnant women to inform a drug-associated risk. 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 AUC (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, pregnant rats received oral doses of 3, 8, or 30 mg/kg/day of zidesamtinib during the period of organogenesis (gestation day 6 to 17). Zidesamtinib caused decreased fetal body weight, visceral malformations (absent kidneys and ureter), and an increase in the incidence of skeletal variations, including misshapen sternebra and cervical arch and incomplete ossification of the sternebra and thoracic centrum at 3 mg/kg/day (approximately 1.4 times the human exposure at the recommended dose based on AUC). Zidesamtinib resulted in complete litter resorption (post-implantation loss) at doses ≥8 mg/kg/day (approximately ≥3.5 times the human exposure at the recommended dose based on AUC).

Risk Summary

There are no data on the presence of zidesamtinib or its metabolites in human milk or their effects on a breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with JIDEYTRO and for 1 week after the last dose.

JIDEYTRO 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 reproductive potential prior to initiating JIDEYTRO [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with JIDEYTRO and for 6 months after the last dose.

Males

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 Nonclinical Toxicology (13.1)].

Infertility

Based on findings from animal studies, JIDEYTRO may impair fertility in males and females. The effects on male fertility were reversible. The reversibility of the effect on fertility in females is unknown [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of JIDEYTRO in pediatric patients has not been established.

Juvenile Animal Data

Daily oral administration of zidesamtinib to juvenile rats from postnatal day 7 to 28 (approximately equal to a human pediatric age of a neonate to child) resulted in ocular toxicity, including hemorrhage, corneal ulcers, rupture, and vision loss at 8 mg/kg/day (approximately 2.4 times the human exposure based on AUC at the recommended dose).

Of the 446 patients who received JIDEYTRO, 22% were 65 to 74 years old, and 8% 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 effect of severe renal impairment (eGFR <30 mL/min) or dialysis on zidesamtinib pharmacokinetics is unknown.

No dosage modification is recommended for patients with eGFR 30 to 90 mL/min [see Clinical Pharmacology (12.3)].

The effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) on the zidesamtinib pharmacokinetics is unknown.

No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) or moderate (total bilirubin >1.5 to 3 times ULN with any AST) hepatic impairment [see Clinical Pharmacology (12.3)].