Ceritinib
FDA Drug Information • Also known as: Zykadia
- Brand Names
- Zykadia
- Drug Class
- Kinase Inhibitor [EPC]
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Ceritinib is a kinase inhibitor for oral administration. The molecular formula for ceritinib is C 28 H 36 N 5 O 3 ClS. The molecular weight is 558.14 g/mol. Ceritinib is described chemically as 5-Chloro-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine. The chemical structure of ceritinib is shown below: Ceritinib is a white to almost white or light yellow powder. ZYKADIA is supplied as printed hard-gelatin capsules containing 150 mg of ceritinib and the following inactive ingredients: colloidal silicon dioxide, hard gelatin capsule shells, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The capsule shell is composed of FD&C Blue # 2, gelatin, and titanium dioxide. ZYKADIA is supplied as film-coated tablets containing 150 mg of ceritinib and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose and povidone. The tablet coating contains FD&C Blue # 2 aluminum lake, hypromellose, polyethylene glycol 4000, talc, and titanium dioxide. The chemical structure of ceritinib.
What Is Ceritinib Used For?
1 INDICATIONS AND USAGE ZYKADIA ® is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test [see Dosage and Administration (2.1)] . ZYKADIA is a kinase inhibitor indicated for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. ( 1 , 2.1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Recommended Dosage: 450 mg orally once daily with food. ( 2.2 ) 2.1 Patient Selection Select patients for treatment of metastatic NSCLC with ZYKADIA based on the presence of ALK positivity in tumor specimens [see Clinical Studies (14.1)] . Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. 2. 2 Recommended Dosage The recommended dosage of ZYKADIA is 450 mg orally once daily with food until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)] . 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. 3 Dosage Modifications for Adverse Reactions Table 1: Recommended ZYKADIA Dose Reductions Dose Reduction Recommended Dosage First-dose reduction 300 mg taken orally once daily with food Second-dose reduction 150 mg taken orally once daily with food Discontinue ZYKADIA for patients unable to tolerate 150 mg taken orally once daily with food. Dosage modifications for selected adverse reactions of ZYKADIA are provided in Table 2. If dose reduction is required due to an adverse reaction not listed in Table 2, then reduce the daily dose of ZYKADIA by 150 mg. Table 2: Recommended ZYKADIA Dosage Modifications for Adverse Reactions Adverse Reaction ZYKADIA Dose Modification Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)] Severe or intolerable nausea, vomiting, or diarrhea despite optimal antiemetic or anti-diarrheal therapy Withhold until improved, then resume ZYKADIA at the next lower dosage. Hepatotoxicity [see Warnings and Precautions (5.2)] ALT or AST elevation greater than 5 times ULN with total bilirubin elevation less than or equal to 2 times ULN Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume ZYKADIA at the next lower dosage. ALT or AST elevation greater than 3 times ULN with total bilirubin elevation greater than 2 times ULN in the absence of cholestasis or hemolysis Permanently discontinue ZYKADIA. Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)] Any Grade treatment-related ILD/pneumonitis Permanently discontinue ZYKADIA. QT Interval Prolongation [see Warnings and Precautions (5.4)] QTc interval greater than 500 msec on at least 2 separate ECGs Withhold until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume ZYKADIA at the next lower dosage. QTc interval prolongation in combination with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Permanently discontinue ZYKADIA. Hyperglycemia [see Warnings and Precautions (5.5)] Persistent hyperglycemia greater than 250 mg/dL despite optimal anti-hyperglycemic therapy Withhold...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)] QT Interval Prolongation [see Warnings and Precautions (5.4)] Hyperglycemia [see Warnings and Precautions (5.5)] Bradycardia [see Warnings and Precautions (5.6)] Pancreatitis [see Warnings and Precautions (5.7)] The most common adverse reactions (incidence of ≥ 25%) in patients treated with ZYKADIA 450 mg with food are diarrhea, nausea, abdominal pain, vomiting, and fatigue; and with ZYKADIA 750 mg under fasted conditions are diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, and weight loss. ( 6 ) 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. 6.1 Clinical Trials Experience 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 data in the Warnings and Precautions section reflect exposure to ZYKADIA 750 mg once daily under fasted conditions in 925 patients with ALK-positive NSCLC across seven clinical studies, including ASCEND-4 and ASCEND-1, described below, a randomized active-controlled study, two single arm studies, and two dose-escalation studies. The majority of patients enrolled in these studies had received prior treatment with chemotherapy and/or crizotinib for NSCLC. Among these 925 patients, the most common adverse reactions (≥ 25% incidence) were diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, and weight loss. Approximately 45% of patients initiating treatment with ZYKADIA 750 mg under fasted conditions had an adverse reaction that required at least one dose reduction and 66% of patients had an adverse reaction that required at least one dose interruption. The median time to first dose reduction due to any reason was 7 weeks. Dose Optimization Study: Dosing Regimen of 450 mg Daily With Food In ASCEND-8, a dose optimization study, ZYKADIA 450 mg daily with food (N = 108) was compared to 750 mg daily under fasted conditions (N = 110) in both previously treated and untreated patients with ALK-positive NSCLC. The overall safety profile of ZYKADIA 450 mg with food was consistent with ZYKADIA 750 mg fasted, except for a reduction in gastrointestinal adverse reactions, while achieving comparable steady-state exposure [see Clinical Pharmacology (12.3)] . The most common adverse reactions (≥ 25% incidence) in the 450 mg with food arm were diarrhea, nausea, abdominal pain, vomiting, and fatigue. The incidence and severity of gastrointestinal adverse reactions (diarrhea 59%, nausea 43%, and vomiting 38%) were reduced for patients treated with ZYKADIA 450 mg with food; Grade ≥ 3 adverse reactions were reported in two patients (1.9%): Grade 3 diarrhea and Grade 3 vomiting in one patient each [see Warnings and Precautions (5.1)] . In patients treated with ZYKADIA 450 mg with food, 24% of patients had an adverse reaction that required at least one dose reduction and 56% of patients had an adverse reaction that required at least one dose interruption. The median time to first dose reduction due to any reason was 8 weeks. Previously Untreated ALK-Positive Metastatic NSCLC The safety of ZYKADIA was evaluated in ASCEND-4, an open-label, randomized, active-controlled multicenter study of 376 previously untreated ALK-positive NSCLC patients [see Clinical Studies (14.1)] . Patients received ZYKADIA 750 mg daily (N = 189) under fasted conditions or chemotherapy and maintenance chemotherapy (N = 187). Chemotherapy regimens were pemetrexed (500 mg/m 2 ) and...
Drug Interactions
7 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, dose reduce ZYKADIA. ( 2.4 , 7.1 ) CYP3A Substrates : Avoid coadministration of ZYKADIA with sensitive CYP3A substrates. ( 7.2 ) CYP2C9 Substrates : Avoid coadministration of ZYKADIA with CYP2C9 substrates for which minimal concentration changes may lead to serious toxicities. ( 7.2 ) 7.1 Effect of Other Drugs on ZYKADIA Strong CYP3A Inhibitors A strong CYP3A4/P-gp inhibitor (ketoconazole) increased the systemic exposure of ceritinib [see Clinical Pharmacology (12.3)] , which may increase the incidence and severity of adverse reactions of ZYKADIA. Avoid concurrent use of strong CYP3A inhibitors during treatment with ZYKADIA. If concurrent use of strong CYP3A inhibitors is unavoidable, reduce the ZYKADIA dose [see Dosage and Administration (2.4)] . Do not consume grapefruit and grapefruit juice as they may inhibit CYP3A. Strong CYP3A Inducers A strong CYP3A4/P-gp inducer (rifampin) decreased the systemic exposure of ceritinib [see Clinical Pharmacology (12.3)] , which may decrease the efficacy of ZYKADIA. Avoid concurrent use of strong CYP3A inducers during treatment with ZYKADIA. 7.2 Effect of ZYKADIA on Other Drugs CYP3A Substrates Ceritinib increased the systemic exposure of a sensitive CYP3A substrate (midazolam) [see Clinical Pharmacology (12.3)] . Avoid coadministration of ZYKADIA with sensitive CYP3A substrates. If concomitant use is unavoidable, consider dose reduction of the sensitive CYP3A substrate(s). If ZYKADIA is coadministered with other CYP3A substrates, refer to the CYP3A substrate labeling for dosage recommendation with strong CYP3A inhibitors. CYP2C9 Substrates Ceritinib increased the systemic exposure of a CYP2C9 substrate (warfarin) [see Clinical Pharmacology (12.3)] . Increase the frequency of INR monitoring if coadministration with warfarin is unavoidable as the anti-coagulant effect of warfarin may be enhanced. Avoid coadministration of ZYKADIA with CYP2C9 substrates for which minimal concentration changes may lead to serious toxicities. If concomitant use of such CYP2C9 substrates is unavoidable, consider dose reduction for the coadministered CYP2C9 substrates. 7.3 Drugs That Prolong QT Interval ZYKADIA causes concentration-dependent increases in the QTc interval. When possible, avoid coadministration of ZYKADIA with other products with a known potential to prolong the QTc interval [see Warnings and Precautions (5.4), Clinical Pharmacology (12.2)] . 7.4 Drugs That Cause Bradycardia ZYKADIA can cause bradycardia. When possible, avoid coadministration of ZYKADIA with other products known to cause bradycardia [see Warnings and Precautions (5.6), Clinical Pharmacology (12.2)] .
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on animal studies and its mechanism of action [see Clinical Pharmacology (12.1)] , ZYKADIA can cause fetal harm when administered to a pregnant woman. The limited available data on the use of ZYKADIA in pregnant women are insufficient to inform a risk. Administration of ceritinib to rats and rabbits during the period of organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits ( see Data ). Advise a pregnant woman 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 are 2% to 4% and 15% to 20%, respectively. Data 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 > 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 > 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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING ZYKADIA 150 mg capsules Hard gelatin capsule with opaque blue cap and opaque white body; opaque blue cap marked in black ink with “LDK 150MG”, opaque white body marked in black ink with “NVR”. Available in: Bottles of 70 capsules…………………………………………………………………………………….NDC 0078-0640-70 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. ZYKADIA 150 mg tablets Film-coated tablet, light blue, round, biconvex with beveled edges, without score, debossed with “NVR” on one side and “ZY1” on the other side. Available in: Bottles of 84 tablets…………………………………………………………………………………NDC 0078-0694-84 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.