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 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.

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Safety Profile

Adverse Reactions, Across 7 Clinical Studies (including ASCEND-4 and ASCEND-1)

The overall safety profile reflects exposure to ZYKADIA 750 mg once daily under fasted conditions in 925 patients with ALK-positive NSCLC across 7 clinical studies, including ASCEND-4 and ASCEND-1. 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.

Adverse Reactions, Previously Untreated Patients (ASCEND-4)

ADVERSE REACTIONS (>10% FOR ALL NCI CTCAEa GRADES OR ≥2% FOR GRADE 3/4) IN PATIENTS WITH PREVIOUSLY UNTREATED ALK+ METASTATIC NSCLC WITH 750-mg FASTED DOSE1

GI, gastrointestinal; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
aNCI CTCAE (version 4.03).
bTwelve patients randomized to chemotherapy did not receive study drug.
cAbdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort).
dEsophageal disorder (dyspepsia, gastroesophageal reflux disease, dysphagia).
eFatigue (fatigue and asthenia).
fRash (rash, dermatitis acneiform, rash maculo-papular).
gPericarditis (pericardial effusion and pericarditis).

 

LABORATORY ABNORMALITIES OCCURRING IN >10% (ALL NCI CTCAE GRADES) OF PATIENTS WITH PREVIOUSLY UNTREATED ALK+ METASTATIC NSCLC WITH 750-mg FASTED DOSE1

 

  • Among patients treated with ZYKADIA 750 mg once daily fasted, dose interruptions due to adverse reactions occurred in 77%, dose reductions were required in 66%, and adverse reactions that led to discontinuation of therapy occurred in 12% of patients1
    • The most common adverse reactions (incidence >10%) that led to dose interruptions or reductions were: increased ALT (48%), increased AST (34%), vomiting (15%), increased blood creatinine (14%), increased GGT (13%), diarrhea (13%), and nausea (13%)1
    • The most frequent adverse reactions that led to discontinuation of ZYKADIA in 1% or more of patients were blood creatinine increased (2.1%), amylase increased (1.1%), and lipase increased (1.1%)1
    • The most frequent serious adverse reactions among patients treated with ZYKADIA were pneumonia (4%), pleural effusion (4%), vomiting (4%), nausea (3%), dyspnea (3%), hyperglycemia (3%), increased AST (2%), lung infection (2%), and pericardial effusion (2%)1

ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma-glutamyl transpeptidase; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
aTwelve patients randomized to chemotherapy did not receive study drug.
bIn the ZYKADIA arm, no patients had baseline lipase laboratory assessments, 112 had postbaseline assessments. In the chemotherapy arm, 1 patient had baseline lipase laboratory assessments but no postbaseline assessment; 49 patients had postbaseline assessments.

Adverse Reactions, Dose Optimization Study (ASCEND-8)

FDA-APPROVED RECOMMENDED DOSE: 450 mg ONCE DAILY WITH FOOD*

ZYKADIA STARTING DOSE BASED ON ASCEND-8 DOSE OPTIMIZATION STUDY

In ASCEND-8, a dose optimization study, ZYKADIA 450 mg once daily with food (n=89) was compared with 750 mg once daily under fasted conditions (n=90) in both previously treated and untreated patients with ALK+ metastatic NSCLC. The primary pharmacokinetic analysis investigated the steady-state pharmacokinetics and safety of ZYKADIA. The overall safety and exposure profile of ZYKADIA 450 mg once daily with food was consistent with ZYKADIA 750 mg once daily fasted, except for a reduction in the incidence and severity of GI adverse reactions, while achieving comparable steady-state exposure.1

 

CONSISTENT SAFETY AND EXPOSURE PROFILE WITH IMPROVED GI TOLERABILITY AT RECOMMENDED 450-mg ONCE-DAILY DOSE WITH FOOD

In ASCEND-8:

  • The overall safety profile of ZYKADIA 450 mg with food was consistent with ZYKADIA 750 mg fasted, with the exception of GI adverse reactions, which had an improved tolerability profile1
  • The most common adverse reactions (≥25% incidence) in the 450-mg group with food were diarrhea, nausea, abdominal pain, vomiting, and fatigue
  • The incidence and severity of GI 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 1 case of grade 3 diarrhea1
  • 10% of patients had an adverse reaction that required at least one dose reduction and 42% of patients had an adverse reaction that required at least one dose interruption

FDA, US Food and Drug Administration; GI, gastrointestinal.
*Food=approximately 100 to 500 calories and 1.5 to 15 grams of fat.

Adverse Reactions, Previously Treated Patients (ASCEND-1)

ADVERSE REACTION PROFILE IN ASCEND-1

Data included below reflect the safety of ZYKADIA 750 mg once daily under fasted conditions at systemic exposures similar to the recommended dose of 450 mg once daily with food. In a dose optimization study (ASCEND-8), there were no clinically meaningful differences observed in the incidence of toxicities between patients receiving 750 mg once daily under fasted conditions and 450 mg once daily with food, except for a reduction in the incidence and severity of GI adverse reactions.1

 

ADVERSE REACTIONS (>10% FOR ALL NCI CTCAEa GRADES OR ≥2% FOR GRADE 3/4) IN PATIENTS WITH PREVIOUSLY TREATED ALK+ METASTATIC NSCLC WITH 750-mg FASTED DOSE1

 

GI, gastrointestinal; ILD, interstitial lung disease; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
a
NCI CTCAE (version 4.03).

bAbdominal pain (abdominal pain, upper abdominal pain, abdominal discomfort, epigastric discomfort).

cEsophageal disorder (dyspepsia, gastroesophageal reflux disease, dysphagia).

dFatigue (fatigue, asthenia).

eRash (rash, maculopapular rash, acneiform dermatitis).

 

KEY LABORATORY ABNORMALITIES (>10% FOR ALL NCI CTCAE GRADES OR ≥1% FOR GRADE 3/4) IN PREVIOUSLY TREATED PATIENTS WITH ALK+ METASTATIC NSCLC WITH 750-mg FASTED DOSE1

ALT, alanine transaminase; AST, aspartate transaminase; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

  • Serious adverse reactions (incidence ≥2%) in ASCEND-1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea2
  • The most common adverse reactions (incidence >10%) that led to dose reductions or interruptions in previously treated patients with ZYKADIA 750 mg fasted were: increased ALT, nausea, increased AST, diarrhea, and vomiting. Dose reductions due to adverse reactions occurred in 59% of patients2

References: 1. Zykadia [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 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.

INDICATION

ZYKADIA 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

Gastrointestinal Adverse Reactions

  • ZYKADIA can cause 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
  • The incidence and severity of gastrointestinal adverse reactions were reduced for patients treated with ZYKADIA 450 mg with food in a dose optimization study (ASCEND-8). 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 reaction, withhold ZYKADIA with resumption at a reduced dose

Hepatotoxicity

  • Drug-induced hepatotoxicity occurred in patients treated with ZYKADIA. Elevations in alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) occurred in 28% and elevations in aspartate aminotransferase (AST) >5 times the ULN occurred in 16% of 925 patients treated across clinical studies. Concurrent elevations in ALT >3 times the ULN and total bilirubin >2 times the ULN occurred in 0.3% of patients across clinical studies. Approximately 1% of patients required permanent discontinuation due to hepatotoxicity
  • 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 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. Common Terminology Criteria for Adverse Events 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
  • 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 post-baseline electrocardiogram (ECG) assessment experienced a QTc interval increase over baseline of >60 milliseconds (ms). Approximately 1.3% of patients taking ZYKADIA 750 mg fasted were found to have a QTc >500 ms. ZYKADIA causes concentration-dependent increases in the QTc interval. Across clinical studies, 0.2% of patients discontinued ZYKADIA due to QTc interval prolongation
  • 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. Based on the severity of the adverse reaction, withhold ZYKADIA with resumption at a reduced dose or permanently discontinue ZYKADIA

Hyperglycemia

  • Hyperglycemia can occur in patients receiving ZYKADIA. Across clinical studies, grade 3 or 4 hyperglycemia, based on laboratory values, occurred in 13% of 925 patients
  • 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 reaction, withhold ZYKADIA with resumption at a reduced dose or permanently discontinue ZYKADIA

Bradycardia

  • Bradycardia occurred in patients receiving ZYKADIA. Across clinical studies, sinus bradycardia, defined as a heart rate <50 beats per minute, was noted as a new finding in 1% of 925 patients. 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
  • 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. Based on the severity of the adverse reaction, withhold ZYKADIA with resumption at a reduced dose upon resolution of bradycardia or permanently discontinue ZYKADIA

Pancreatitis

  • Pancreatitis occurred in patients receiving ZYKADIA. Pancreatitis, including 1 fatality, has been reported in <1% of patients receiving ZYKADIA across clinical studies. Grade 3 or 4 elevations of amylase occurred in 7% of patients receiving ZYKADIA across clinical studies, whereas grade 3 or 4 elevations of lipase occurred in 14% of patients
  • 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 below 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

Adverse Reactions

  • The most common adverse reactions (incidence of ≥25%) in patients treated with ZYKADIA 450 mg with food were diarrhea (56%), nausea (45%), vomiting (35%), and fatigue (32%)
  • The most common adverse reactions (incidence of ≥25%) in patients treated with ZYKADIA mg 750 mg under fasted conditions across clinical trials were diarrhea (86%), nausea (80%), vomiting (67%), abdominal pain (54%), fatigue (52%), and decreased appetite (34%). The most common grade 3 or 4 adverse reactions (incidence ≥2%) were fatigue (7%), diarrhea (6%), vomiting (5%), weight loss (4%), abdominal pain (4%), nausea (4%), ILD/pneumonitis (3%), prolonged QT interval (3%), and pericarditis (2%)
  • The most common laboratory abnormalities in patients treated with ZYKADIA across clinical trials (incidence ≥25%) were increased ALT/AST (91%/86%), increased gamma-glutamyl transpeptidase (GGT) (84%), anemia (84%), increased alkaline phosphatase (81%), increased creatinine (77%), hyperglycemia (53%), decreased phosphate (38%), increased amylase (37%), increased lipase (28%), and neutropenia (27%). The most common laboratory abnormalities grade 3 or 4 adverse reactions (incidence ≥2%) were increased GGT (49%), increased ALT/AST (34%/21%), hyperglycemia (13%), increased alkaline phosphatase (12%), increased lipase (10%), increased amylase (8%), decreased phosphate (7%), anemia (5%), increased creatinine (4%), and neutropenia (2%)
  • Across clinical studies, other clinically important adverse reactions observed in >2% of patients treated with ZYKADIA included: neuropathy (17%; composed of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy); vision disorder (9%; composed of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, reduced visual acuity, or vitreous floaters); bradycardia (4%); ILD/pneumonitis (2%); hepatotoxicity (2%); and renal failure (2%)

Drug Interactions

  • A strong CYP3A4/P-gp inhibitor (ketoconazole) increased the systemic exposure of ceritinib, 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
  • A strong CYP3A4/P-gp inducer (rifampin) decreased the systemic exposure of ceritinib, which may decrease the efficacy of ZYKADIA. Avoid concurrent use of strong CYP3A inducers during treatment with ZYKADIA

Drug-Food/Drink Interactions

  • Do not consume grapefruit and grapefruit juice as they may inhibit CYP3A

Please see full Prescribing Information.