Drug Interaction:
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.
Indication:
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ZYKADIA safely and effectively. See full prescribing information for ZYKADIA. ZYKADIA® (ceritinib) capsules, for oral use
Initial U.S. Approval: 2014
INDICATIONS AND USAGE
ZYKADIA is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
This indication is approved under accelerated approval based on tumor response rate and duration of response. 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.
DOSAGE AND ADMINISTRATION
? 750 mg orally once daily. Administer
ZYKADIA on an empty stomach (i.e., do not administer within 2 hours of a meal).
DOSAGE FORMS AND STRENGTHS
Capsules: 150 mg
-
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions (incidence of at least 25%) are diarrhea, nausea, elevated transaminases, vomiting, abdominal pain, fatigue, decreased appetite, and constipation.
Contra-Indications:
CONTRAINDICATIONS None
WARNINGS AND PRECAUTIONS
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.
Hepatotoxicity: ZYKADIA can cause hepatotoxicity. Monitor liver laboratory tests at least monthly. Withhold then dose reduce, or permanently discontinue ZYKADIA.
Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 4% of patients. Permanently discontinue ZYKADIA in patients diagnosed with treatmentrelated ILD/pneumonitis.
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.
Hyperglycemia:
ZYKADIA can cause hyperglycemia. Monitor fasting glucose prior to treatment and periodically thereafter as clinically indicated. Initiate or optimize anti-hyperglycemic medications as indicated.
Withhold then dose reduce, or permanently discontinue ZAYKADIA
Bradycardia:
ZYKADIA can cause bradycardia. Monitor heart rate and blood pressure regularly. Withhold then dose reduce, or permanently discontinue ZYKADIA.
Pancreatitis:
Elevations of lipase and/or amylase and pancreatitis can occur. Monitor lipase and amylase prior to treatment and periodically thereafter as clinically indicated.
Embryofetal Toxicity: ZYKADIA may cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
ZYKADIA is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
This indication is approved under accelerated approval based on tumor response rate and duration of response. 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.
DOSAGE AND ADMINISTRATION
? 750 mg orally once daily. Administer
ZYKADIA on an empty stomach (i.e., do not administer within 2 hours of a meal).
DOSAGE FORMS AND STRENGTHS Capsules: 150 mg
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients that diarrhea, nausea, vomiting, and abdominal pain are the most commonly reported adverse reactions in patients treated with ZYKADIA.
Inform patients of supportive care options such as anti-emetic and antidiarrheal medications.
Advise patients to contact their healthcare provider for severe or persistent gastrointestinal symptoms
Inform patients that if vomiting occurs during the course of treatment, they should not take an additional dose, but should continue with the next scheduled dose of ZYKADIA
Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity
Inform patients of the risks of severe or fatal ILD/pneumonitis.
Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms
Inform patients of the risks of QTc interval prolongation and bradycardia
Advise patients to contact their healthcare provider immediately to report new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, fainting, and changes in or new use of heart or blood pressure medications
Inform patients of the signs and symptoms of hyperglycemia.
Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperglycemia
Inform patients of the signs and symptoms of pancreatitis and the need to monitor lipase and amylase levels prior to the start of treatment and periodically thereafter as clinically indicated
Advise females to inform their healthcare provider if they are pregnant.
Inform females of reproductive potential of the risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with ZYKADIA and for at least 2 weeks following completion of therapy
Advise females not to breastfeed during treatment with ZYKADIA
Inform patients not to consume grapefruit and grapefruit juice during treatment with ZYKADIA
Take ZYKADIA on an empty stomach (i.e., do not take within 2 hours of a meal)
Advise patients to make up a missed dose of ZYKADIA unless the next dose is due within 12 hours
Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936
© Novartis
T2016-XX Month 2016
Reference
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Ceritinib is a kinase inhibitor. Targets of ceritinib inhibition identified in either biochemical or cellular assays at clinically relevant concentrations include ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1
Among these, ceritinib is most active against ALK. Ceritinib inhibited autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays.
2.Pharmacodynamics -
Cardiac Electrophysiology -Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of ceritinib on the QT interval in an open-label, dose-escalation, and expansion study.
A total of 304 patients were treated with ZYKADIA doses ranging from 50 to 750 mg with 255 patients treated with ZYKADIA 750 mg. One of 304 patients (less than 1%) was found to have a QTc greater than 500 msec and 10 patients (3%) had an increase from baseline QTc greater than 60 msec.
A central tendency analysis of the QTc data at average steady-state concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 16 msec at ZYKADIA 750 mg.
3.Pharmacokinetics
Absorption
After single oral administration of ZYKADIA in patients, peak plasma levels (Cmax) of ceritinib were achieved at approximately 4 to 6 hours, and area under the curve (AUC) and Cmax increased dose proportionally over 50 to 750 mg.
The absolute bioavailability of ZYKADIA has not been determined.
A food effect study conducted in healthy subjects with a single 500 mg ceritinib dose showed that a high-fat meal (containing approximately 1000 calories and 58 grams of fat) increased ceritinib AUC by 73% and Cmax by 41% and a low-fat meal (containing approximately 330 calories and 9 grams of fat) increased ceritinib AUC by 58% and Cmax by 43% as compared with the fasted state.
Distribution
Ceritinib is 97% bound to human plasma proteins, independent of drug concentration. The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg ZYKADIA dose in patients. Ceritinib also has a slight preferential distribution to red blood cells, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35.
Elimination
Following a single 750 mg ZYKADIA dose, the geometric mean apparent plasma terminal half-life (t1/2) of ceritinib was 41 hours in patients. Ceritinib demonstrates nonlinear PK over time. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h)
Metabolism:
In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma.
Excretion:
Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.
Specific Populations Age, Gender, Race, and Body Weight:
Age, gender, race, and body weight had no clinically important effect on the systemic exposure of ceritinib based on population pharmacokinetic analyses.
Hepatic Impairment: As ceritinib is eliminated primarily via the liver, patients with hepatic impairment may have increased exposure. A pharmacokinetic trial in patients with hepatic impairment has not been conducted.
Renal Impairment: A pharmacokinetic trial in patients with renal impairment has not been conducted as ceritinib elimination via the kidney is low (1.3% of a single oral administered dose).
Based on a population pharmacokinetic analysis of 97 patients with mild renal impairment (CLcr 60 to less than 90 mL/min), 22 patients with moderate renal impairment (CLcr 30 to less than 60 mL/min) and 183 patients with normal renal function (greater than or equal to 90 mL/min), ceritinib exposures were similar in patients with mild and moderate renal impairment and normal renal function, suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment.
Patients with severe renal impairment (CLcr less than 30 mL/min) were not included in the clinical trial.
Pediatrics: No trials have been conducted to evaluate the pharmacokinetics of ceritinib in pediatric patients.
Drug Interactions-
Effect of Strong CYP3A Inhibitors on Ceritinib: In vitro studies show that ceritinib is a substrate of CYP3A. Coadministration of a single 450 mg ZYKADIA dose with ketoconazole (a strong CYP3A inhibitor) 200 mg twice daily for 14 days increased ceritinib AUC (90% CI) by 2.9-fold (2.5, 3.3) and Cmax (90% CI) by 22% (7%, 39%) in 19 healthy subjects
Effect of Strong CYP3A Inducers on Ceritinib:
Coadministration of a single 750 mg ZYKADIA dose with rifampin (a strong CYP3A inducer) 600 mg daily for 14 days decreased ceritinib AUC (90% CI) by 70% (61%, 77%) and Cmax (90% CI) by 44% (24%, 59%) in 19 healthy subjects [see Drug Interactions (
Effect of Ceritinib on CYP Substrates:
Based on in vitro data, ceritinib may inhibit CYP3A and CYP2C9 at clinical concentrations. Time-dependent inhibition of CYP3A was also observed.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy-
Pregnancy Category D Risk Summary
Based on its mechanism of action, ZYKADIA may cause fetal harm when administered to a pregnant woman.
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.
2.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.
3.Pediatric Use -
The safety and effectiveness of ZYKADIA in pediatric patients have not been established.
4.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.
6. 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
A recommended dose has not been determined for patients with moderate to severe hepatic impairment.
7. 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
