Drug Safety-related Labeling Changes (SrLC)

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ZYKADIA (NDA-205755)

(CERITINIB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/07/2021 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Previously Untreated ALK-Positive Metastatic NSCLC

…

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg under fasted conditions included: vision disorder (4% comprised 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%). In addition, the adverse reaction of photosensitivity was reported in 1.1% of patients.

…

Previously Treated ALK-Positive Metastatic NSCLC

…

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg under fasted conditions included neuropathy (17% comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy), vision disorder (9% comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity), prolonged QT interval (4%), and bradycardia (3%). In addition, the adverse reaction of photosensitivity was reported in 1.2% of patients.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions underlined

…

Photosensitivity

Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure and to use sunscreen or protective clothing during treatment with ZYKADIA [see Adverse Reactions (6.1)].

…

PATIENT INFORMATION

Additions underlined

…

What should I avoid while taking ZYKADIA?

• You should not drink grapefruit juice or eat grapefruit during treatment with ZYKADIA. It may make the amount of ZYKADIA in your blood increase to a harmful level.

• Avoid spending time in sunlight during treatment with ZYKADIA. Your skin may become more sensitive to the sun and you may burn more easily. Use sunscreen and wear protective clothing that covers your skin to help protect against sunburn.

…

What are the ingredients in ZYKADIA? Active ingredient: ceritinib

Inactive ingredients capsules: colloidal silicon dioxide, hard gelatin capsule shells, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. Capsule shell contains FD&C Blue # 2, gelatin, and titanium dioxide.

…

08/19/2021 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Gastrointestinal Adverse Reactions

(Additions and/or revisions underlined)

Severe gastrointestinal adverse reactions occurred in patients treated with ZYKADIA 750 mg under fasted conditions [see Adverse Reactions (6.1)]. Diarrhea, nausea, vomiting, or abdominal pain occurred in 95% of 925 patients, including severe cases (Grade 3 or 4) in 14% of patients treated with ZYKADIA across clinical studies. Diarrhea, nausea, vomiting, or abdominal pain leading to dose interruptions or reductions occurred in 36% of patients and leading to treatment discontinuation occurred in 1.6% of patients.

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 79% of 108 patients treated with ZYKADIA at the recommended dose of 450 mg with food. Of these, 53% were Grade 1 events and 24% were Grade 2 events. One patient (0.9%) experienced Grade 3 diarrhea, and one patient (0.9%) experienced Grade 3 vomiting. One patient (0.9%) required dose adjustment due to vomiting. Eleven (10%) patients had diarrhea, nausea, vomiting, or abdominal pain that required at least one dose interruption.

Monitor and manage patients using standard of care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold ZYKADIA if gastrointestinal adverse reaction is severe or intolerable and is not responsive to antiemetics or antidiarrheals. Upon improvement, resume ZYKADIA at a reduced dose [see Dosage and Administration (2.3)].

5.2 Hepatotoxicity

(Additions and/or revisions underlined)

Drug-induced hepatotoxicity occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Elevations in alanine aminotransferase (ALT) > or equal to  5 times the upper limit of normal (ULN) occurred in 28% and elevations in aspartate aminotransferase (AST) > or equal to 5 times ULN occurred in 16% of 925 patients across clinical studies. Concurrent elevations in ALT> or equal to 3 times the ULN and total bilirubin > or equal to 2 times the ULN, with alkaline phosphatase < or equal to 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 [see Dosage and Administration (2.3)].

5.3 Interstitial Lung Disease/Pneumonitis

(Additions and/or revisions underlined)

Severe, life-threatening, or fatal interstitial lung diseases (ILD)/pneumonitis occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Across clinical studies, ILD/pneumonitis was reported in 2.4% of 925 patients treated with ZYKADIA. 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.

5.4 QT Interval Prolongation

(Additions and/or revisions underlined)

QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmia (e.g., torsades de pointes) or sudden death, occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Across clinical studies, 6% of 919 patients with at least one post-baseline electrocardiogram (ECG) assessment had an increase from baseline of QTc > 60 msec. Approximately 1.3% of patients taking ZYKADIA 750 mg under fasted conditions were found to have a QTc > or equal to 500 msec. ZYKADIA causes concentration-dependent increases in the QTc interval [see Clinical Pharmacology (12.2)]. Across clinical studies, 0.2% of patients discontinued ZYKADIA due to QTc 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 [see Dosage and Administration (2.3)].

5.5 Hyperglycemia

(Additions and/or revisions underlined)

Hyperglycemia occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. 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 anti-hyperglycemic medications as indicated. Based on the severity of the adverse reaction, withhold ZYKADIA with resumption at a reduced dose, or permanently discontinue ZYKADIA [see Dosage and Administration (2.3)].

5.6 Bradycardia

(Additions and/or revisions underlined)

Bradycardia occurred in patients treated with ZYKADIA [see Adverse Reactions (6.1)]. Across clinical studies, sinus bradycardia, defined as a heart rate < 50 beats per minute, was noted as a new finding in 1.1% of 925 patients.

Bradycardia was reported as an adverse 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 products known to cause bradycardia (e.g., beta-blockers, non- dihydropyridine 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 [see Dosage and Administration (2.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Dose Optimization Study: Dosing Regimen of 450 mg Daily With Food

In ASCEND-8, a dose optimization study, ZYKADIA 450 mg daily with food (N = 108) was compared to 750 mg daily under fasted conditions (N = 110) in both previously treated and untreated patients with ALK-positive NSCLC. 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 [see Clinical Pharmacology (12.3)]. The most common adverse reactions (? 25% incidence) in the 450 mg with food arm were diarrhea, nausea, abdominal pain, vomiting, and fatigue. The incidence and severity of gastrointestinal adverse reactions (diarrhea 59%, nausea 43%, and vomiting 38%) were reduced for patients treated with ZYKADIA 450 mg with food; Grade ? 3 adverse reactions were reported in two patients (1.9%): Grade 3 diarrhea and Grade 3 vomiting in one patient each [see Warnings and Precautions (5.1)].

In patients treated with ZYKADIA 450 mg with food, 24% of patients had an adverse reaction that required at least one dose reduction and 56% 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 8 weeks.

Previously Untreated ALK-Positive Metastatic NSCLC

The safety of ZYKADIA was evaluated in ASCEND-4, an open-label, randomized, active-controlled multicenter study of 376 previously untreated ALK-positive NSCLC patients [see Clinical Studies (14.1)]. Patients received ZYKADIA 750 mg daily (N = 189) under fasted conditions or chemotherapy and maintenance chemotherapy (N = 187). Chemotherapy regimens were pemetrexed (500 mg/m2) and investigator’s choice of cisplatin (75 mg/m2) or carboplatin [area under the curve (AUC) of 5 - 6 mg*min/mL] administered every 21 days. Patients who completed 4 cycles of chemotherapy without progressive disease received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days. The median duration of exposure to ZYKADIA was 18 months.

Previously Treated ALK-Positive Metastatic NSCLC

The safety of ZYKADIA was evaluated in ASCEND-1, a multicenter, single-arm, open-label clinical study of 255 ALK- positive patients (246 patients with NSCLC and 9 patients with other cancers who received ZYKADIA at a dose of 750 mg daily under fasted conditions) [see Clinical Studies (14.2)]. The median duration of exposure to ZYKADIA was 6 months.

The study population characteristics were: median age 53 years, age less than 65 (84%), female (53%), white (63%), Asian (34%), NSCLC adenocarcinoma histology (90%), never or former smoker (97%), Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 (89%), brain metastases (49%), and number of prior therapies 2 or more (67%).

Serious adverse reactions reported in 2% or more of patients in ASCEND-1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea.

7 Drug Interactions

7.1 Effect of Other Drugs on ZYKADIA

(Additions and/or revisions underlined)

Strong CYP3A Inhibitors

A strong CYP3A4/P-gp inhibitor (ketoconazole) increased the systemic exposure of ceritinib [see Clinical Pharmacology (12.3)], 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 [see Dosage and Administration (2.4)].

Do not consume grapefruit and grapefruit juice as they may inhibit CYP3A. Strong CYP3A Inducers

A strong CYP3A4/P-gp inducer (rifampin) decreased the systemic exposure of ceritinib [see Clinical Pharmacology (12.3)], which may decrease the efficacy of ZYKADIA. Avoid concurrent use of strong CYP3A inducers during treatment with ZYKADIA.

7.3 Drugs That Prolong QT Interval

(Newly added section)

ZYKADIA causes concentration-dependent increases in the QTc interval. When possible, avoid coadministration of ZYKADIA with other products with a known potential to prolong the QTc interval [see Warnings and Precautions (5.4), Clinical Pharmacology (12.2)].

7.4 Drugs That Cause Bradycardia

(Newly added section)

ZYKADIA can cause bradycardia. When possible, avoid coadministration of ZYKADIA with other products known to cause bradycardia [see Warnings and Precautions (5.6), Clinical Pharmacology (12.2)].

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Newly added information)

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating ZYKADIA [see Use in Specific Populations (8.1)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(Newly added information)

Read this Patient Information leaflet that comes with ZYKADIA before you start taking it and each time you get a refill.

There may be new information. This information does not take the place of talking to your healthcare provider about

your medical condition or treatment.

03/05/2019 (SUPPL-16)

Approved Drug Label (PDF)

7 Drug Interactions

7.2 Effect of Ceritinib on Other Drugs

(subsection revised)

CYP3A Substrates

Ceritinib increased the systemic exposure of a sensitive CYP3A substrate (midazolam).  Avoid coadministration of ZYKADIA with sensitive CYP3A substratesIf concomitant useis unavoidable, consider dose reduction of the sensitive CYP3A substrate(s). If ZYKADIA is coadministered with CYP3A substrates, refer to the CYP3A substrate labeling for dosage recommendation with strong CYP3A inhibitors.

CYP2C9 Substrates

Ceritinib increased the systemic exposure of a CYP2C9 substrate (warfarin). Increase the frequency of INR monitoring if coadministration with warfarin is unavoidable as the anti-coagulant effect of warfarin may be enhanced.

Avoid coadministration of ZYKADIA with CYP2C9 substrates for which minimal concentration changes may lead to serious toxicities. If concomitant use of such CYP2C9 substrates is unavoidable, consider dose reduction for the coadministered CYP2C9 substrates.

12/21/2017 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added information:

Data in the Warnings and Precautions section reflect the safety of ZYKADIA 750 mg daily under fasted conditions in 925 patients with ALK-positive NSCLC across a pool of seven clinical studies at systemic exposures similar to the recommended dose of 450 mg with food. In a dose optimization study (ASCEND-8), there were no clinically meaningful differences observed in the incidence of toxicities described in Warnings and Precautions between patients receiving 750 mg daily under fasted conditions and 450 mg with food, except for a reduction in gastrointestinal adverse reactions as described.

Additions and/or revisions underlined:

5.1 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 (Grade 3 or 4) in 14% of patients treated with ZYKADIA across clinical studies. Diarrhea, nausea, vomiting, or abdominal pain leading to dose interruptions or reductions occurred in 36% of patients and leading to treatment discontinuation occurred in 1.6% of patients.

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 one dose interruption.

Monitor and manage patients using standards of care …

5.4 QT Interval Prolongation

Additions and/or revisions underlined:

… Approximately 1.3% of patients taking ZYKADIA 750 mg fasted were found to have a QTc greater than 500 msec …

6 Adverse Reactions

Additions and/or revisions underlined:

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Gastrointestinal Adverse Reactions

6.1 Clinical Trials Experience

… The data in the Warnings and Precautions section reflect exposure to ZYKADIA 750 mg once daily under fasted conditions in 925 patients with ALK-positive NSCLC across seven clinical studies … 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.

 In ASCEND-8, a dose optimization study, ZYKADIA 450 mg daily with food (N=89) was compared to 750 mg daily under fasted conditions (N=90) in both previously treated and untreated patients with ALK-positive NSCLC. 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 greater than or equal to 3 adverse reaction was Grade 3 diarrhea in one patient (1.1%). In patients treated with ZYKADIA 450 mg with food, 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. The median time to first dose reduction due to any reason was 8 weeks.

Previously Untreated ALK-Positive Metastatic NSCLC  

The safety evaluation of ZYKADIA is based on ASCEND-4, an open-label, randomized, active-controlled multicenter study of 376 previously untreated ALK-positive NSCLC patients. Patients received ZYKADIA 750 mg daily (N=189) under fasted conditions or chemotherapy …

Following Table 3 Adverse Reactions (greater than 10% for All NCI CTCAE* Grades or greater than or equal to 2% for Grades 3-4) of Patients in ASCEND-4, addition underlined:

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg fasted included …

Previously Treated ALK-Positive Metastatic NSCLC

The safety evaluation of ZYKADIA is based on 255 ALK-positive patients in ASCEND-1 (246 patients with NSCLC and 9 patients with other cancers who received ZYKADIA at a dose of 750 mg daily (under fasted conditions). The median duration …

Following Table 5 Adverse Reactions (greater than 10% for All NCI CTCAE* Grades or greater than or equal to 2% for Grades 3-4) in ALK-Positive Patients Treated with ZYKADIA in ASCEND-1, addition underlined:

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA 750 mg fasted included …

8 Use in Specific Populations

8.2 Lactation

Risk Summary

Additions and/or revisions underlined:

… Because of the potential for serious adverse reactions including gastrointestinal adverse reactions, hepatotoxicity …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

• Gastrointestinal adverse reactions: Inform patients that diarrhea, nausea, vomiting, and abdominal pain are the most commonly reported gastrointestinal adverse reactions in patients treated with ZYKADIA. Inform patients of supportive care options such as antiemetic and antidiarrheal medications. Advise patients to contact their healthcare provider for severe or intolerable gastrointestinal symptoms …

• Dosing instructions: Advise patients to take ZYKADIA food.

PATIENT INFORMATION

Additions and/or revisions underlined:
ZYKADIA may cause serious side effects, including:

Stomach and intestinal (gastrointestinal) problems. ZYKADIA may cause stomach and intestinal problems, including diarrhea, nausea, vomiting, and stomach-area pain. Follow your healthcare provider’s instructions about taking medicines to help with these symptoms. Call your healthcare provider for advice if your symptoms are severe or cannot be tolerated.

How should I take ZYKADIA?

• Take ZYKADIA with food.

11/20/2017 (SUPPL-11)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.6 Hepatic Impairment

(Additions and/or revisions are underlined)

For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of ZYKADIA by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength. No dose adjustment is recommended in patients with mild (Child-Pugh A) or moderate (Child- Pugh B) hepatic impairment.

05/26/2017 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe or Persistent Gastrointestinal Toxicity

(Additions and/or revisions are underlined)

Severe gastrointestinal toxicity occurred in patients treated with ZYKADIA. Diarrhea, nausea, vomiting, or abdominal pain occurred in 95% of 925 patients, including severe cases (Grade 3 or 4) in 14% of patients treated with ZYKADIA across clinical studies. Dose interruptions or reductions due to diarrhea, nausea, vomiting, or abdominal pain occurred in 36% of patients and led to treatment discontinuation in 1.6% of patients.

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 as described in Table 2.

5.2 Hepatotoxicity

(Additions and/or revisions are underlined)

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 ULN occurred in 16% of 925 patients across clinical studies. Concurrent elevations in ALT greater than 3 times the ULN and total bilirubin greater than 2 times the ULN, with alkaline phosphatase less 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.

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 as described in Table 2.

5.3 Interstitial Lung Disease (ILD)/Pneumonitis

(Additions and/or revisions are underlined)

Severe, life-threatening, or fatal ILD/pneumonitis occurred in patients treated with ZYKADIA. Across clinical studies, ILD/pneumonitis was reported in 2.4% of 925 patients treated with ZYKADIA across clinical trials. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 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.

5.4 QT Interval Prolongation

(Additions and/or revisions are underlined)

QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmia (e.g., torsade de pointes) or sudden death, occurred in patients treated with ZYKADIA. Across clinical studies, 6% of 919 patients with at least one post-baseline ECG assessment experienced a QTc interval increase over baseline of greater than 60 msec. Approximately 1.3% of patients taking ZYKADIA 750 mg were found to have a QTc greater than 500 msec. A pharmacokinetic/pharmacodynamic analysis suggested that ZYKADIA causes concentration-dependent increases in the QTc interval. Across clinical studies, 0.2% of patients discontinued ceritinib due to QTc prolongation.

… Withhold ZYKADIA in patients who develop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec, then resume ZYKADIA at a reduced dose as described in Table 2…

5.5 Hyperglycemia

(Additions and/or revisions are underlined)

Hyperglycemia occurred in patients receiving ZYKADIA. Across clinical studies, CTCAE Grade 3 or 4 hyperglycemia, based on laboratory values, occurred in 13% of 925 patients.

…Based on the severity of the adverse drug reaction, withhold ZYKADIA until hyperglycemia is adequately controlled, then resume ZYKADIA at a reduced dose as described in Table 2…

5.6 Bradycardia

(Additions and/or revisions are underlined)

Bradycardia occurred in patients receiving ZYKADIA. Across clinical studies, sinus bradycardia, defined as a heart rate of less than 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.

…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 above, and if the concomitant medication can be adjusted or discontinued, resume ZYKADIA at a reduced dose as described in Table 2 upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring.

5.7 Pancreatitis

(Additions and/or revisions are underlined)

Pancreatitis occurred in patients receiving ZYKADIA. Pancreatitis, including one fatality, occurred in less than 1% of patients receiving ZYKADIA in clinical studies. CTCAE Grade 3 or 4 elevations of amylase occurred in 7% of patients receiving ZYKADIA  across clinical studies, while CTCAE 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 as described in Table 2.

5.8 Embryofetal Toxicity

(Additions and/or revisions are underlined)

Based on its mechanism of action and findings in animal studies, ZYKADIA can cause fetal harm when administered to a pregnant woman…Advise pregnant women of the potential risk to a fetus. Advise females 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 males with female partners of reproductive potential to use condoms during treatment with ZYKADIA and for 3 months following completion of therapy.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

The data in the Warnings and Precautions section reflect exposure to ZYKADIA 750 mg once daily in 925 patients with ALK-positive NSCLC across seven clinical studies, including ASCEND-4 and ASCEND-1, described below, a randomized active-controlled study, two single arm studies, and two dose-escalation studies. The majority of patients enrolled in these studies had received prior treatment with chemotherapy and/or crizotinib for NSCLC. Among these 925 patients the most common adverse reactions (greater than or equal to 25% incidence) were diarrhea, nausea, fatigue, vomiting, abdominal pain, decreased appetite, and weight loss. Approximately 62% of patients initiating treatment at the recommended dose required at least one dose reduction and the median time to first dose reduction was 7 weeks.

Previously Untreated ALK-Positive Metastatic NSCLC

The safety evaluation of ZYKADIA is based on ASCEND-4, an open-label, randomized, active-controlled multicenter study of 376 previously untreated ALK-positive NSCLC patients. Patients received ZYKADIA 750 mg daily (N=189) or chemotherapy plus maintenance chemotherapy (N=187). Chemotherapy regimens were pemetrexed (500 mg/m2) plus investigator’s choice of cisplatin (75 mg/m2) or carboplatin (AUC of 5 - 6 mg*min/mL) administered every 21 days.

Patients who completed 4 cycles of chemotherapy without progressive disease received pemetrexed (500 mg/m2) as single-agent maintenance therapy every 21 days.

The demographic characteristics of the study population were 57% female, median age 54 years (range: 22 to 81 years); 22% of patients were 65 years older, 54% White, 42% Asian, 2% Black, and 2% other races. Patients were enrolled in Europe (53%), Asia Pacific (42%), and South America (5%) regions. The majority of patients had adenocarcinoma (97%), never smoked (61%) and 32% had brain metastasis at screening. The median duration of exposure to ZYKADIA was 18 months.

Serious adverse reactions were reported in 72 patients (38%) treated with ZYKADIA. The most frequent serious adverse reactions were pneumonia (4%), pleural effusion (4%), vomiting (4%), nausea (3%), dyspnea (3%), hyperglycemia (3%), AST increased (2%), lung infection (2%), and pericardial effusion (2%). Among patients treated with ZYKADIA, 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 patients. The most frequent adverse reactions, reported in at least 10% of patients treated with ZYKADIA, that led to dose interruptions or reductions were: ALT increased (48%), AST increased (34%), vomiting (15%), blood creatinine increased (14%), GGT increased (13%), diarrhea (13%), and nausea (13%). The most frequent adverse reactions that led to discontinuation of ZYKADIA in 1% or more of patients in ASCEND-4 were blood creatinine increased (2.1%), amylase increased (1.1%), and lipase increased (1.1%). The following fatal adverse reactions occurred in 4 patients treated with ZYKADIA: myocardial infarction, respiratory tract infection, pneumonitis, and unknown cause.

Tables 3 and 4 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-4.

Table 3: Adverse Reactions (>10% for All NCI CTCAE* Grades or Greater than or Equal to 2% for Grades 3-4) of Patients in ASCEND-4 (Table has been added; please refer to label)

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA included: vision disorder (4%; comprised 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%).

Table 4: Laboratory Abnormalities Occurring in >10% (All NCI CTCAE Grades) of Patients in ASCEND-4 (Table has been added; please refer to label)

 

Previously Treated ALK-Positive Metastatic NSCLC

The safety evaluation of ZYKADIA is based on 255 ALK-positive patients in ASCEND-1 (246 patients with NSCLC and 9 patients with other cancers who received ZYKADIA at a dose of 750 mg daily)…

…Serious adverse drug reactions reported in 2% or more of patients in ASCEND-1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea… The most frequent adverse drug reactions that led to discontinuation in 1% or more of patients in ASCEND-1 were pneumonia, ILD/pneumonitis, and decreased appetite.

Tables 5 and 6 summarize the common adverse reactions and laboratory abnormalities observed in ZYKADIA-treated patients.

Table 5: Adverse Reactions (>10% for All NCI CTCAE* Grades or Greater than or Equal to 2% for Grades 3-4) in ALK-Positive Patients Treated with ZYKADIA in ASCEND-1

Table 6: Key Laboratory Abnormalities Occurring in >10% (All NCI CTCAE Grades) of ALK-Positive Patients Treated with ZYKADIA in ASCEND-1 (Table has been revised; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

Based on animal studies and its mechanism of action, ZYKADIA can cause fetal harm when administered to a pregnant woman. The limited available data on the use of ZYKADIA in pregnant women are insufficient to inform a risk. Administration of ceritinib to rats and rabbits during the period of organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits. Advise a pregnant woman of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

There are no data 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 a woman not to breastfeed during treatment with ZYKADIA and for 2 weeks following completion of therapy.

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Contraception

Females

ZYKADIA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ZYKADIA and for 6 months following completion of therapy.

Males

Based on the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with ZYKADIA and for 3 months following completion of therapy.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the 925 patients in clinical studies of ZYKADIA, 18% were 65 years or older, while 5% were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Gastrointestinal toxicity: Inform patients that diarrhea, nausea, vomiting, and abdominal pain are the most commonly reported adverse reactions in patients treated with ZYKADIA…

Hepatotoxicity: Inform patients of the signs and symptoms of hepatotoxicity…

Interstitial lung disease (ILD)/pneumonitis: Inform patients of the risks of severe or fatal ILD/pneumonitis…

Arrhythmias: Inform patients of the risks of QTc interval prolongation and bradycardia…

Hyperglycemia: Inform patients of the signs and symptoms of hyperglycemia…

Pancreatitis: 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.

Embryofetal toxicity: Advise pregnant women and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ZYKADIA and for 6 months following completion of therapy. Advise males with female partners of reproductive potential to use condoms during treatment with ZYKADIA and for 3 months following completion of therapy.

Lactation: Advise females not to breastfeed during treatment with ZYKADIA and for 2 weeks following completion of therapy.

Drug Interactions: Inform patients not to consume grapefruit and grapefruit juice during treatment with ZYKADIA.

Dosing Instructions: Take ZYKADIA at least 1 hour before or at least 2 hours after a meal…

PATIENT INFORMATION

(Additions and/or revisions are underlined)

Before you take ZYKADIA, tell your healthcare provider about all of your medical conditions, including if you:

• are pregnant or plan to become pregnant. ZYKADIA can harm your unborn baby. Females who are able to become pregnant should use an effective method of birth control during treatment with ZYKADIA and for 6 months after stopping ZYKADIA. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant.

  • Males with female partners who are able to become pregnant should use condoms during treatment with ZYKADIA and for 3 months after stopping ZYKADIA.

• are breastfeeding or plan to breastfeed. It is not known if ZYKADIA passes into your breast milk. Do not breastfeed during treatment with ZYKADIA and for 2 weeks after stopping ZYKADIA.

How should I take ZYKADIA?

• Take ZYKADIA at least 1 hour before or at least 2 hours after meals.

General information about the safe and effective use of ZYKADIA

…You can ask your healthcare provider or pharmacist for more information about ZYKADIA that is written for health professionals.