2.1     Dosing and Administration

The recommended dose of ZYKADIA is 750 mg orally once daily until disease progression or unacceptable toxicity. Administer ZYKADIA on an empty stomach (i.e., do not administer within 2 hours of a meal) [see Clinical Pharmacology (12.3)].

A recommended dose has not been determined for patients with moderate to severe hepatic impairment [see Use in Specific Populations (8.6)].

If a dose of ZYKADIA is missed, make up that dose unless the next dose is due within 12 hours.

If vomiting occurs during the course of treatment, do not administer an additional dose and continue with the next scheduled dose of ZYKADIA.

2.2     Dose Modifications for Adverse Reactions

Recommendations for dose modifications of ZYKADIA for adverse reactions are provided in Table 1.

Approximately 58% of patients initiating treatment at the recommended dose required at least one dose reduction and the median time to first dose reduction was 7 weeks.

Discontinue ZYKADIA for patients unable to tolerate 300 mg daily.

2.3     Dose Modification for Strong CYP3A4 Inhibitors

Avoid concurrent use of strong CYP3A inhibitors during treatment with ZYKADIA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the ZYKADIA dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ZYKADIA dose that was taken prior to initiating the strong CYP3A4 inhibitor.

5.1     Severe or Persistent Gastrointestinal Toxicity

Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients treated with ZYKADIA in Study 1. Dose modification due to diarrhea, nausea, vomiting, or abdominal pain occurred in 38% of patients.

Monitor and manage patients using standards of care, including anti-diarrheals, anti-emetics, or fluid replacement, as indicated. Based on the severity of the adverse drug reaction, withhold ZYKADIA with resumption at a reduced dose as described in Table 1 [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2     Hepatotoxicity

Drug-induced hepatotoxicity occurred in patients treated with ZYKADIA. Elevations in alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN) occurred in 27% of 255 patients in Study 1. One patient (0.4%) required permanent discontinuation due to elevated transaminases, and jaundice. Concurrent elevations in ALT greater than 3 times the ULN and total bilirubin greater than 2 times the ULN, with normal alkaline phosphatase, occurred in less than 1% of patients in clinical studies.

Monitor with liver laboratory tests including ALT, aspartate aminotransferase (AST), and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on the severity of the adverse drug reaction, withhold ZYKADIA with resumption at a reduced dose, or permanently discontinue ZYKADIA as described in Table 1 [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.3     Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, or fatal ILD/pneumonitis can occur in patients treated with ZYKADIA. In Study 1, pneumonitis was reported in 4% of 255 patients treated with ZYKADIA. CTCAE Grade 3 or 4 ILD/pneumonitis was reported in 3% of patients, and fatal ILD/pneumonitis was reported in 1 patient (0.4%) in Study 1. One percent (1%) of patients discontinued ZYKADIA in Study 1 due to ILD/pneumonitis.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.4     QT Interval Prolongation

QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmias (e.g., Torsade de pointes) or sudden death, occurred in patients treated with ZYKADIA in clinical trials. Three percent (3%) of 255 patients experienced a QTc interval increase over baseline greater than 60 msec in Study 1. Across the development program of ZYKADIA, one of 304 patients (less than 1%) treated with ZYKADIA doses ranging from 50 to 750 mg was found to have a QTc greater than 500 msec and 3% of patients had an increase from baseline QTc greater than 60 msec. A pharmacokinetic analysis suggested that ZYKADIA causes concentration-dependent increases in the QTc interval.

When possible, avoid use of ZYKADIA in patients with congenital long QT syndrome. Conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Withhold ZYKADIA in patients who develop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec, then resume ZYKADIA at a reduced dose as described in Table 1. Permanently discontinue ZYKADIA in patients who develop QTc interval prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)].

5.5     Hyperglycemia

Hyperglycemia can occur in patients receiving ZYKADIA. In Study 1, CTCAE Grade 3–4 hyperglycemia, based on laboratory values, occurred in 13% of 255 patients. There was a 6-fold increase in the risk of CTCAE Grade 3–4 hyperglycemia in patients with diabetes or glucose intolerance and a 2-fold increase in patients taking corticosteroids.

Monitor fasting serum glucose prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Initiate or optimize anti-hyperglycemic medications as indicated. Based on the severity of the adverse drug reaction, withhold ZYKADIA until hyperglycemia is adequately controlled, then resume ZYKADIA at a reduced dose as described in Table 1. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ZYKADIA [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.6     Bradycardia

Bradycardia can occur in patients receiving ZYKADIA. In Study 1, sinus bradycardia, defined as a heart rate of less than 50 beats per minute, was noted as a new finding in 1% of 255 patients. Bradycardia was reported as an adverse drug reaction in 3% of patients in Study 1.

Avoid using ZYKADIA in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold ZYKADIA until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, eva luate the use of concomitant medications, and adjust the dose of ZYKADIA. Permanently discontinue ZYKADIA for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with a concomitant medication known to cause bradycardia or hypotension, withhold ZYKADIA until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if the concomitant medication can be adjusted or discontinued, resume ZYKADIA at a reduced dose as described in Table 1 upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.7     Pancreatitis

Pancreatitis, including one fatality, has been reported in less than 1% of patients receiving ZYKADIA in clinical trials. CTCAE Grade 3-4 elevations of lipase and/or amylase occurred in 15% of patients receiving ZYKADIA in Study 1. Monitor lipase and amylase prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Based on the severity of the laboratory abnormalities, withhold ZYKADIA with resumption at a reduced dose as described in Table 1 [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.8     Embryofetal Toxicity

Based on its mechanism of action, ZYKADIA may cause fetal harm when administered to a pregnant woman. In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures below the recommended human dose of 750 mg daily caused increases in skeletal anomalies in rats and rabbits. Apprise women of reproductive potential of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ZYKADIA and for at least 2 weeks following completion of therapy [see Use in Specific Populations (8.7)].