Important Safety Information

Treatment with ZYKADIA may cause GI Adverse Reactions, Hepatic and Embryo-fetal Toxicities, Interstitial Lung Disease/Pneumonitis, QTc Interval Prolongation, Hyperglycemia, Bradycardia, Pancreatiti...

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Indication ZYKADIA® (ceritinib) capsules is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Efficacy

Previously Untreated Patients (ASCEND-4)

LET THE ALK INHIBITOR ZYKADIA BE YOUR FIRST-LINE CHOICE

EFFICACY AND SAFETY OF ZYKADIA® (ceritinib) IN PATIENTS WITH PREVIOUSLY UNTREATED ALK+ METASTATIC NSCLC ESTABLISHED IN AN OPEN-LABEL, RANDOMIZED, ACTIVE-CONTROLLED, MULTICENTER STUDY (ASCEND-4)1,2

 

In a dose optimization study (ASCEND-8), ZYKADIA 450 mg once daily with food was compared with 750 mg once daily under fasted conditions in both previously treated and untreated patients with ALK+ metastatic NSCLC. There was no clinically meaningful difference in the systemic steady-state exposure of ZYKADIA for the 450-mg once-daily with food arm compared with the 750-mg once-daily fasted arm.1

The recommended dose of 450 mg once daily with food was established as the safe and efficacious recommended dose of ZYKADIA.1

For more information on ASCEND-8, please click here.

AUC, area under the curve; BIRC, blinded independent review committee; DOIR, duration of intracranial response; DOR, duration of response; OIRR, overall intracranial response rate; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PROs, patient-reported outcomes; WHO, World Health Organization.
aExcept neoadjuvant or adjuvant systemic therapy (if relapse had occurred >12 months from the end of therapy).
bPemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or pemetrexed 500 mg/m2 + carboplatin AUC 5-6 mg•min/mL; 1 cycle=21 days.
cOnly patients without progressive disease continued to maintenance treatment.
*As determined by BIRC.
As determined by BIRC neuroradiologist.
Safety analyses were done in patients who received at least 1 dose of study drug (safety set).

APPROVED FOR FIRST-LINE USE IN PATIENTS WITH ALK+ METASTATIC NSCLC

PATIENT CHARACTERISTICS IN THE PREVIOUSLY UNTREATED CLINICAL STUDY1

START WITH POWERFUL FIRST-LINE EFFICACY

PFS IN OVERALL PATIENT POPULATION, WITH AND WITHOUT BRAIN METASTASES1

 

BIRC, blinded independent review committee; HR, hazard ratio; PFS, progression-free survival.

 

*As determined by BIRC.

 

ADDITIONAL SECONDARY OUTCOME MEASURES, INCLUDING OVERALL SURVIVAL, TUMOR RESPONSE, AND PATIENT-REPORTED OUTCOMES

DOR, duration of response; NE, not estimable; ORR, overall response rate; OS, overall survival.
The key secondary end point was OS. Other secondary end points included ORR, DOR determined by BIRC, and patient-reported outcomes.1,2

Previously Untreated Patients With Brain Metastases (Subgroup Analysis)

ZYKADIA SHOWED ANTITUMOR ACTIVITY IN THE BRAIN IN A SUBGROUP ANALYSIS OF PATIENTS WITH BRAIN METASTASES

  • 32% of patients had brain metastases at baseline (59 of 189 patients treated with ZYKADIA, 62 of 187 patients treated with chemotherapy)1,2
  • Antitumor activity of ZYKADIA was assessed in 55 patients with measurable disease as determined by the BIRC neuroradiologist at baseline according to RECIST 1.11

 

MORE THAN DOUBLE THE OIRR WITH ZYKADIA IN PATIENTS WITH MEASURABLE BRAIN METASTASES1

 

BIRC, blinded independent review committee; CR, complete response; OIRR, overall intracranial response rate; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors.

 

CNS RESPONSE IN PREVIOUSLY UNTREATED PATIENTS WITH BRAIN METASTASES (SUBGROUP ANALYSIS)

DOIR IN PATIENTS WITH BRAIN METASTASES (BIRC ASSESSED)1

CNS, central nervous system; DOIR, duration of intracranial response; NE, not estimable.

 

IMPORTANT SAFETY INFORMATION

  • The most frequent serious adverse reactions with ZYKADIA 750 mg fasted were pneumonia, pleural effusion, vomiting, nausea, dyspnea, hyperglycemia, AST increased, lung infection, pericardial effusion, convulsion, ILD/pneumonitis, and dehydration
  • The most common adverse reactions (incidence of at least 25%) in patients treated with ZYKADIA 750 mg fasted are diarrhea, nausea, fatigue, vomiting, abdominal pain, decreased appetite, and weight loss
  • In a dose optimization study (ASCEND-8), the overall safety profile of ZYKADIA 450 mg with food was consistent with ZYKADIA 750 mg fasted, except for a reduction in GI adverse reactions, while achieving comparable steady-state exposure. The incidence and severity of GI adverse reactions (diarrhea, nausea, vomiting) were reduced for patients treated with ZYKADIA 450 mg with food

Previously Treated Patients (ASCEND-1)

EFFICACY AND SAFETY IN PREVIOUSLY TREATED PATIENTS WITH ALK+ METASTATIC NSCLC ESTABLISHED IN ASCEND-1 REGISTRATION STUDY1,3

The efficacy and safety of ZYKADIA in previously treated patients was established in a multicenter, single-arm, open-label phase 1 clinical trial:

ZYKADIA – The Ascend-1 Registration Study Design

In a dose optimization study (ASCEND-8), ZYKADIA 450 mg once daily with food was compared with 750 mg once daily under fasted conditions in both previously treated and untreated patients with ALK+ metastatic NSCLC. There was no clinically meaningful difference in the systemic steady-state exposure of ZYKADIA for the 450-mg once-daily with food arm compared with the 750-mg once-daily fasted arm.1

The recommended dose of 450 mg once daily with food was established as the safe and efficacious recommended dose of ZYKADIA.1

For more information on ASCEND-8, please click here.

BIRC, blinded independent review committee; DOR, duration of response; ORR, overall response rate; RECIST, Response Evaluation Criteria In Solid Tumors.

aMajor efficacy outcome measure was ORR according to RECIST v1.0 as evaluated by both investigators and a BIRC.

bAdditional outcome measure was DOR according to RECIST v1.0 as evaluated by both investigators and a BIRC.

 

ZYKADIA DELIVERED CLINICAL RESPONSE IN 55% OF PATIENTS AFTER PROGRESSION OR INTOLERANCE ON CRIZOTINIB BASED ON INVESTIGATOR ASSESSMENT1

CLINICAL RESPONSE WITH ZYKADIA1,a

 

  • Investigator assessment, CR was 1.2% and PR was 53.4% 
  • In the BIRC assessment, CR was 2.5% and PR was 41.1%

 

ZYKADIA DELIVERED A MEDIAN DURATION OF RESPONSE OF 7.4 MONTHS BASED ON INVESTIGATOR ASSESSMENT1

CLINICAL RESPONSE WITH ZYKADIA1,3,b

BIRC, blinded independent review committee; CR, complete response; DOR, duration of response; NE, not estimable; ORR, overall response rate; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors.

aClinical efficacy was evaluated in 163 patients after progression on crizotinib.

bORR and DOR were determined by RECIST v1.0.

cDOR, which applies only to patients who achieved CR or PR, is the time from first documented response (CR or PR) to the date of first documented progression or death due to any cause.

References: 1. Zykadia [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017. 2. Soria J-C, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-929. 3. Data on file. Novartis Pharmaceuticals Corp; 2011.

INDICATION

ZYKADIA® (ceritinib) capsules is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION for ZYKADIA® (ceritinib) capsules

Gastrointestinal Adverse Reactions

  • Severe gastrointestinal toxicity occurred in patients treated with ZYKADIA 750 mg under fasted conditions. Diarrhea, nausea, vomiting, or abdominal pain occurred in 95% of 925 patients, including severe cases in 14% of patients treated with ZYKADIA across clinical studies
  • In a dose optimization study, the incidence and severity of gastrointestinal adverse reactions were reduced for patients treated with ZYKADIA 450 mg with food. Diarrhea, nausea, vomiting, or abdominal pain occurred in 76% of 89 patients treated with ZYKADIA at the recommended dose of 450 mg with food. Of these, the majority experienced grade 1 events (51%). One patient experienced grade 3 diarrhea. No patients had diarrhea, nausea, vomiting, or abdominal pain that required dose reduction; 8% of patients had diarrhea or nausea that required at least 1 dose interruption
  • Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Based on the severity of the adverse drug reaction, withhold ZYKADIA with resumption at a reduced dose

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 28% and elevations in aspartate aminotransferase (AST) greater than 5 times the ULN occurred in 16% of 925 patients treated with ZYKADIA 750 mg under fasted conditions across clinical studies. Concurrent elevations in ALT greater than 3 times the ULN and total bilirubin greater than 2 times the ULN occurred in 0.3% of patients across clinical studies. Approximately 1.0% of patients required permanent discontinuation due to hepatotoxicity. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of hepatotoxicity between the 750-mg under fasted conditions arm and the 450-mg with food arm.
  • Monitor with liver laboratory tests including ALT, 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

Interstitial Lung Disease/Pneumonitis

  • Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with ZYKADIA. Across clinical studies, ILD/pneumonitis was reported in 2.4% of 925 patients treated with ZYKADIA 750 mg under fasted conditions. Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 ILD/pneumonitis was reported in 1.3% of patients with fatal events reported in 0.2% of patients. Ten patients (1.1%) discontinued ZYKADIA across clinical studies due to ILD/pneumonitis. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of ILD/pneumonitis between the 750-mg under fasted conditions arm and the 450-mg with food arm
  • Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis

QTc Interval Prolongation

  • QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death, occurred in patients treated with ZYKADIA in clinical studies. Across clinical studies, 6% of 919 patients with at least 1 postbaseline electrocardiogram (ECG) assessment experienced a QTc interval increase over baseline of greater than 60 milliseconds (ms). Approximately 1.3% of patients taking ZYKADIA 750 mg fasted were found to have a QTc greater than 500 ms. A pharmacokinetic/pharmacodynamic analysis suggested that ZYKADIA causes concentration-dependent increases in the QTc interval. Across clinical studies, 0.2% of patients discontinued ZYKADIA due to QTc interval prolongation. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of QTc interval prolongation between the 750-mg under fasted conditions arm and the 450-mg with food arm
  • When possible, avoid use of ZYKADIA in patients with congenital long QT syndrome. Conduct periodic monitoring with 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 ms on at least 2 separate ECGs until the QTc interval is less than 481 ms or recovery to baseline if the QTc interval is greater than or equal to 481 ms, then resume ZYKADIA at a reduced dose. Permanently discontinue ZYKADIA in patients who develop QTc interval prolongation in combination with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia

Hyperglycemia

  • Hyperglycemia can occur in patients receiving ZYKADIA. Across clinical studies, CTCAE grade 3 or 4 hyperglycemia, based on laboratory values, occurred in 13% of 925 patients treated with ZYKADIA 750 mg under fasted conditions. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of hyperglycemia between the 750-mg under fasted conditions arm and the 450-mg with food arm
  • Monitor fasting serum glucose prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Initiate or optimize antihyperglycemic 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. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ZYKADIA

Bradycardia

  • Bradycardia occurred in patients receiving ZYKADIA. Across clinical studies, sinus bradycardia, defined as a heart rate of less than 50 beats per minute (bpm), was noted as a new finding in 1% of 925 patients treated with ZYKADIA 750 mg under fasted conditions. Bradycardia was reported as an adverse drug reaction in 1% of patients. No patient required discontinuation and 0.1% required interruption with subsequent dose reduction for bradycardia. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of bradycardia between the 750-mg under fasted conditions arm and the 450-mg with food arm
  • Avoid using ZYKADIA in combination with other agents known to cause bradycardia (eg, beta blockers, nondihydropyridine 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 higher, evaluate 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 higher, and if the concomitant medication can be adjusted or discontinued, resume ZYKADIA at a reduced dose

Pancreatitis

  • Pancreatitis occurred in patients receiving ZYKADIA. Pancreatitis, including 1 fatality, has been reported in less than 1% of patients receiving ZYKADIA 750 mg under fasted conditions in clinical studies. CTCAE grade 3 or 4 elevations of amylase occurred in 7% of patients receiving ZYKADIA 750 mg under fasted conditions across clinical studies, whereas CTCAE grade 3 or 4 elevations of lipase occurred in 14% of patients. In a dose optimization study, there were no clinically meaningful differences observed in the incidence of pancreatitis between the 750-mg under fasted conditions arm and the 450-mg with food Arm
  • 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

Embryo-fetal Toxicity

  • Based on its mechanism of action and findings in animal studies, ZYKADIA can 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 the recommended human dose caused increases in skeletal anomalies in rats and rabbits
  • Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during treatment with ZYKADIA and for 6 months following completion of therapy. Based on the potential for genotoxicity, advise men with female partners of reproductive potential to use condoms during treatment with ZYKADIA and for 3 months following completion of therapy

Lactation

  • No data exist regarding the presence of ceritinib or its metabolites in human milk, the effects of ceritinib on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions, including gastrointestinal toxicity, hepatotoxicity, pneumonitis, bradycardia, and pancreatitis, advise women not to breastfeed during treatment with ZYKADIA and for 2 weeks following completion of therapy

Adverse Reactions

  • The most common adverse reactions in ASCEND-4, which evaluated patients treated with 750 mg under fasted conditions, (incidence ≥25% all grades) were increased ALT/AST (91%/86%), diarrhea (85%), increased gamma-glutamyl transferase (GGT) (84%), increased alkaline phosphatase (81%), increased creatinine (77%), nausea (69%), vomiting (67%), anemia (67%), hyperglycemia (53%), fatigue (45%), abdominal pain (40%), decreased phosphate (38%), increased amylase (37%), decreased appetite (34%), and neutropenia (27%)
  • In ASCEND-4, which evaluated patients treated with 750 mg under fasted conditions, grade 3 or 4 adverse reactions (incidence ≥2%) were increased GGT (49%), ALT/AST (34%/21%), increased alkaline phosphatase (12%), hyperglycemia (10%), increased amylase (8%), fatigue (7%), increased lipase (6%), diarrhea (5%), vomiting (5%), weight loss (4%), abdominal pain (4%), anemia (4%), increased creatinine (4%), decreased phosphate (4%), nausea (3%), prolonged QT interval (3%), neutropenia (2%), and pericarditis (2%)
  • In ASCEND-4, which evaluated patients treated with 750 mg under fasted conditions, serious adverse drug reactions reported in at least 2% or more of patients treated with ZYKADIA were pneumonia, pleural effusion, vomiting, nausea, dyspnea, hyperglycemia, increased AST, lung infection, and pericardial effusion. Adverse reactions that led to death occurred in 4 patients treated with ZYKADIA, consisting of 1 each: myocardial infarction, respiratory tract infection, pneumonitis, and unknown cause
  • The most common adverse reactions in ASCEND-1, which evaluated patients treated with 750 mg under fasted conditions, (incidence ≥25% all grades) were diarrhea (86%), nausea (80%), increased ALT/AST (80%/75%), vomiting (60%), abdominal pain (54%), fatigue (52%), decreased appetite (34%), and constipation (29%)
  • In ASCEND-1, which evaluated patients treated with 750 mg under fasted conditions, grade 3/4 adverse reactions (incidence ≥2%) were increased ALT/AST (27%/13%), diarrhea (6%), fatigue (5%), nausea (4%), vomiting (4%), ILD/pneumonitis (3%), and abdominal pain (2%)
  • Serious adverse drug reactions reported in ASCEND-1, which evaluated patients treated with 750 mg under fasted conditions, (incidence >2%) were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Fatal adverse reactions occurred in 5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis (1 patient each)
  • In ASCEND-8, a dose optimization study of ZYKADIA 450 mg daily with food was compared with 750 mg daily under fasted conditions. 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. The incidence and severity of gastrointestinal adverse reactions (diarrhea 56%, nausea 45%, vomiting 35%) were reduced for patients treated with ZYKADIA 450 mg with food; the only grade ≥3 adverse reaction was grade 3 diarrhea in 1 patient (1.1%)

Drug Interactions

Effect of Other Drugs on Ceritinib

  • CYP3A inhibitors increase ceritinib plasma concentrations: Avoid concurrent use of ZYKADIA with strong CYP3A inhibitors. If concomitant use of strong CYP3A inhibitors 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
  • CYP3A inducers decrease ceritinib plasma concentrations: Avoid concurrent use of ZYKADIA with strong CYP3A inducers

Effect of Ceritinib on Other Drugs

  • Ceritinib may inhibit CYP3A and CYP2C9 at clinical concentrations. Avoid concurrent use of CYP3A and CYP2C9 substrates known to have narrow therapeutic indices or substrates primarily metabolized by CYP3A and CYP2C9 during treatment with ZYKADIA
  • If use of these medications is unavoidable, consider dose reduction of CYP3A substrates with narrow therapeutic indices and CYP2C9 substrates with narrow therapeutic indices

Drug-Food/Drink Interactions

  • Do not consume grapefruit and grapefruit juice as they may inhibit CYP3A in the gut wall and increase the bioavailability of ceritinib

Please see full Prescribing Information for ZYKADIA® (ceritinib) capsules.