Zykadia Drug Information

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

Patient Selection

Select patients for treatment of metastatic NSCLC with ZYKADIA based on the presence of ALK positivity in tumor specimens. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. 2. 2 Recommended Dosage The recommended dosage of ZYKADIA is 450 mg orally once daily with food until disease progression or unacceptable toxicity. If a dose of ZYKADIA is missed, make up that dose unless the next dose is due within 12 hours.

If vomiting occurs during the course of treatment, do not administer an additional dose and continue with the next scheduled dose of ZYKADIA. 2. 3 Dosage Modifications for Discontinue ZYKADIA for patients unable to tolerate 150 mg taken orally once daily with food. Dosage modifications for selected adverse reactions of ZYKADIA are provided in Table 2. If dose reduction is required due to an adverse reaction not listed in Table 2, then reduce the daily dose of ZYKADIA by 150 mg.

Table 2: Recommended ZYKADIA Dosage Modifications for 2. 4 Dosage Modification for Strong CYP3A Inhibitors Avoid concurrent use of strong CYP3A inhibitors during treatment with ZYKADIA. If concurrent use of a strong CYP3A inhibitor 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 CYP3A inhibitor.

Dosage Modification for Patients With Severe Hepatic Impairment For patients with severe hepatic impairment (Child-Pugh C), reduce the ZYKADIA dose by approximately one-third, rounded to the nearest multiple of the 150 mg dosage strength.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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, 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 (≥ 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.

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. The most common adverse reactions (≥ 25% incidence) in the 450 mg with food arm were diarrhea, nausea, abdominal pain, vomiting, and fatigue.

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. 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. Patients received ZYKADIA 750 mg daily (N = 189) under fasted conditions or chemotherapy and maintenance chemotherapy (N = 187).

The median duration of exposure to ZYKADIA was 18 months. 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 metastases at screening.

The following fatal adverse reactions occurred in 4 patients treated with ZYKADIA: Myocardial infarction, respiratory tract infection, pneumonitis, and unknown cause. Serious adverse reactions were reported in 38% of patients treated with ZYKADIA. 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.

Tables 3 and 4 summarize adverse reactions and laboratory abnormalities, respectively, in ASCEND-4. Table 3: Adverse Reactions (> 10% for All Grades* or ≥ 2% for Grades 3-4) of Patients in ASCEND-4 *National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). *For frequency of gastrointestinal adverse reactions at the recommended dose of 450 mg with food. a Twelve patients randomized to chemotherapy did not receive study drug. b Abdominal pain (abdominal pain, abdominal pain upper, abdominal discomfort, and epigastric discomfort). c Esophageal disorder (dyspepsia, gastroesophageal reflux disease, and dysphagia). d Fatigue (fatigue and asthenia). e Rash (rash, dermatitis acneiform, rash maculo-papular). f Pericarditis (pericardial effusion and pericarditis). In addition, the adverse reaction of photosensitivity was reported in 1.1% of patients.

Table 4: Laboratory Abnormalities Occurring in > 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). Fatal adverse reactions in patients treated with ZYKADIA 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). Serious adverse 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 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 adverse reactions and laboratory abnormalities, respectively, in ASCEND-1. Table 5: Adverse Reactions (> 10% for All Grades* or ≥ 2% for Grades 3-4) in ALK-Positive Patients Treated With ZYKADIA in ASCEND-1 4 3 Abbreviation: ALK, anaplastic lymphoma kinase. *National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). *For frequency of gastrointestinal adverse reactions at the recommended dose of 450 mg with food. a Abdominal pain (abdominal pain, upper abdominal pain, abdominal discomfort, and epigastric discomfort). b Esophageal disorder (dyspepsia, gastroesophageal reflux disease, and dysphagia). c Fatigue (fatigue and asthenia). d Rash (rash, maculopapular rash, and acneiform dermatitis).

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%). Table 6: Key Laboratory Abnormalities Occurring in > 10% (All Grades*) of ALK-Positive Patients Treated With ZYKADIA in ASCEND-1

Effect of Other Drugs on ZYKADIA Strong CYP3A Inhibitors

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.

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, which may decrease the efficacy of ZYKADIA.

Effect of ZYKADIA on Other Drugs CYP3A Substrates

Ceritinib increased the systemic exposure of a sensitive CYP3A substrate (midazolam). Avoid coadministration of ZYKADIA with sensitive CYP3A substrates. If concomitant use is unavoidable, consider dose reduction of the sensitive CYP3A substrate(s).

If ZYKADIA is coadministered with other 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.

Drugs That Prolong QT Interval

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.

Drugs That Cause Bradycardia ZYKADIA can cause bradycardia

When possible, avoid coadministration of ZYKADIA with other products known to cause bradycardia.

Pregnancy 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 ( see Data ).

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 respectively. Data Animal Data In an embryo-fetal development study in which pregnant rats were administered daily doses of ceritinib during organogenesis, dose-related skeletal anomalies were observed at doses as low as 50 mg/kg (less than 0.5-fold the human exposure by AUC at the recommended dose).

Findings included delayed ossifications and skeletal variations. In pregnant rabbits administered ceritinib daily during organogenesis, dose-related skeletal anomalies, including incomplete ossification, were observed at doses equal to or > 2 mg/kg/day (approximately 0.015-fold the human exposure by AUC at the recommended dose). A low incidence of visceral anomalies, including absent or malpositioned gallbladder and retroesophageal subclavian cardiac artery, was observed at doses equal to or > 10 mg/kg/day (approximately 0.13-fold the human exposure by AUC at the recommended dose).

Maternal toxicity and abortion occurred in rabbits at doses of 35 mg/kg or greater. In addition, embryolethality was observed in rabbits at a dose of 50 mg/kg.

Pediatric Use The safety and effectiveness of ZYKADIA in pediatric patients have not been established.