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 

 

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. (2.2, 5.1) ? Hepatotoxicity: ZYKADIA can cause hepatotoxicity. Monitor liver laboratory tests at least monthly. Withhold then dose reduce, or permanently discontinue ZYKADIA. (2.2, 5.2) ? Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 4% of patients. Permanently discontinue ZYKADIA in patients diagnosed with treatmentrelated ILD/pneumonitis. (2.2, 5.3)

 

Proprietary Name-        ZYKADIA*

 

Established Name-      Ceritinib

 

Applicant-                   NOVARTIS PHARMACEUTICALS INC.

 

Indication-      For the treament of patients with anaplastic lymphoma

                         Kinase (ALK) positive , metastatic non-small cell

                         Cancer (NSCLC) with disease progression on or who 

                         are intolerant to crizotinib                                                                                  

                                       

Approval Date- 29/4/2014

 

Approved by  U.S.FDA    (Ref- FDA approved List- 2014)

 

 

LIST OF  APPROVED DRUG FROM 01-01-2015 To  31-12-2015 

ISSUED BY NEW DRUG DIVISION - DRUG CONTROLLER GENERAL- INDIA

 

Sr.No   Name of Drug                             Indication                        Date of Issue

 

9.          Ceritinib 150mg Hard gelatin                                             13-06-2015

              Capsules

 

              For the treatment of patients with Anaplastic 

              Lymphoma Kinase (ALK )- positive metablatic 

              non-small cell lung cancer (NSCLC) who have

              progressed on or are intolerant to Crizotininb              

                                                                                       

Approved by  DCG INDIA    (Ref- DCGI  approved List- 01-01-2015 To 31-12-3015)

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. 

 

Indication-      For the treament of patients with anaplastic lymphoma

                         Kinase (ALK) positive , metastatic non-small cell

                         Cancer (NSCLC) with disease progression on or who 

                         are intolerant to crizotinib                                                                                  

 

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.

 

2.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.

 

Systemic exposure of ceritinib was increased when administered with a meal. 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 

 

 

 

 

 

 

 

 

 

  

 

 

 

 

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. 

 

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. 

 

The pharmacokinetics of ceritinib has not been studied in patients with moderate to severe hepatic impairment 

 

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). 

 

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.

 

 

 

 

 

 

 

 

 

 

  

 

 

 

 

  

 

 

 

 

8 USE IN SPECIFIC POPULATIONS 8.1 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. 8.3 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. 8.4 Pediatric Use The safety and effectiveness of ZYKADIA in pediatric patients have not been established. 8.5 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. 8.6 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 [see Clinical Pharmacology (12.3)]. A recommended dose has not been determined for patients with moderate to severe hepatic impairment.  8.7 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, ZYKADIA may cause fetal harm when administered to a pregnant woman [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. 11

 

DESCRIPTION ZYKADIA (ceritinib) is a tyrosine kinase inhibitor for oral administration. The molecular formula for ceritinib is C28H36N5O3ClS. The molecular weight is 558.14 g/mole. Ceritinib is described chemically as 5-Chloro-N4-[2-[(1methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine. 

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