ZYKADIA™

Ceritinib is a white to almost white or light yellow or light brown powder with a pKa of 9.7 and 4.1.

ZYKADIA is supplied as printed hard-gelatin capsules containing 150 mg of ceritinib and the following inactive ingredients: colloidal anhydrous silica, L-hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and hard gelatin capsule shells. The capsule shell is composed of gelatin, indiogotine, and titanium dioxide.

Ceritinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. Ceritinib exhibited dose-dependent anti-tumor activity in mice bearing EML4-ALK-positive NSCLC xenografts with demonstrated resistance to crizotinib, at concentrations within a clinically relevant range.

This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies - package insert]. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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USE IN SPECIFIC POPULATIONS
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Pregnancy
Pregnancy Category D
Risk Summary
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 caused increases in skeletal anomalies in rats and rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data
In an embryo-fetal development study in which pregnant rats were administered daily doses of ceritinib during organogenesis, dose-related skeletal anomalies were observed at doses as low as 50 mg/kg (less than 0.5-fold the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations.

In pregnant rabbits administered ceritinib daily during organogenesis, dose-related skeletal anomalies, including incomplete ossification, were observed at doses equal to or greater than 2 mg/kg/day (approximately 0.015-fold the human exposure by AUC at the recommended dose). A low incidence of visceral anomalies, including absent or malpositioned gallbladder and retroesophageal subclavian cardiac artery, was observed at doses equal to or greater than 10 mg/kg/day (approximately 0.13-fold the human exposure by AUC at the recommended dose). Maternal toxicity and abortion occurred in rabbits at doses of 35 mg/kg or greater. In addition, embryolethality was observed in rabbits at a dose of 50 mg/kg.

Nursing Mothers
It is not known whether ceritinib or its metabolites are present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from ceritinib, advise mothers to discontinue nursing.

Pediatric Use
The safety and effectiveness of ZYKADIA in pediatric patients have not been established.

Geriatric Use
Clinical studies of ZYKADIA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 255 patients in Study 1 who received ZYKADIA at the recommended dose, 40 (16%) were 65 years or older.

Hepatic Impairment
As ceritinib is eliminated primarily via the liver, patients with hepatic impairment may have increased exposure. Dose adjustment is not recommended for patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin greater than 1.0 to 1.5 times ULN and any AST) based on results of the population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. A recommended dose has not been determined for patients with moderate to severe hepatic impairment.

Females and Males of Reproductive Potential
Contraception
Based on its mechanism of action, ZYKADIA may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ZYKADIA and for at least 2 weeks following completion of therapy.

1.  Severe or Persistent Gastrointestinal Toxicity: Dose modification due to diarrhea, nausea, vomiting or abdominal pain occurred in 38% of patients. Withhold if not responsive to anti-emetics or anti-diarrheals, then dose reduce ZYKADIA.
2. Hepatotoxicity: ZYKADIA can cause hepatotoxicity. Monitor liver laboratory tests at least monthly. Withhold then dose reduce, or permanently discontinue ZYKADIA.
3. Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 4% of patients. Permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis.
4. QT Interval Prolongation: ZYKADIA can cause QTc interval prolongation. Monitor electrocardiograms 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 then dose reduce, or permanently discontinue ZYKADIA.
5. Hyperglycemia: ZYKADIA can cause hyperglycemia. Monitor glucose and initiate or optimize anti-hyperglycemic medications as indicated. Withhold then dose reduce, or permanently discontinue ZYKADIA.
6. Bradycardia: ZYKADIA can cause bradycardia. Monitor heart rate and blood pressure regularly. Withhold then dose reduce, or permanently discontinue ZYKADIA.
7. Embryofetal Toxicity: ZYKADIA may cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
CYP3A Inhibitors and Inducers: Avoid concurrent use of ZYKADIA with strong CYP3A inhibitors or inducers. If concurrent use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ZYKADIA.
CYP3A and CYP2C9 Substrates: Avoid concurrent use of ZYKADIA with CYP3A or CYP2C9 substrates with narrow therapeutic indices.

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

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

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

Dose Modifications for Adverse Reactions
Recommendations for dose modifications of ZYKADIA for adverse reactions are provided in Table 1.

Approximately 60% 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.

Table 1: ZYKADIA Dose Interruption, Reduction, or Discontinuation Recommendations

Dose Modification for Strong CYP3A4 Inhibitors
Avoid concurrent use of strong CYP3A inhibitors during treatment with ZYKADIA [see Drug Interactions  and Clinical Pharmacology - package insert].

If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the ZYKADIA dose by approximately one-third, rounded to the nearest 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.

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].