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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Efficacy

Previously Untreated Patients (ASCEND-4)

LET THE ALK INHIBITOR ZYKADIA BE YOUR FIRST-LINE CHOICE

EFFICACY AND SAFETY OF ZYKADIA 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; 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. 3. Data on file. Novartis Pharmaceuticals Corp; 2011.

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.