ZYKADIA® (ceritinib)

ZYKADIA® (ceritinib)

ZYKADIA® (ceritinib)

Ceritinib is a kinase inhibitor for oral administration. The molecular formula for ceritinib is C28H36N5O3ClS. The molecular weight is 558.14 g/mol. Ceritinib is described chemically as 5-Chloro-N4-[2-[(1-methylethyl)sulfonyl]phenyl]- N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine.

Indications and usage

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

Mechanism of Action

Ceritinib is a kinase inhibitor. Targets of ceritinib inhibition identified in either biochemical or cellular assays at clinically relevant concentrations include ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Among these, ceritinib is most active against ALK. Ceritinib inhibited autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays.

Ceritinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. Ceritinib exhibited dose-dependent anti-tumor activity in mice bearing EML4-ALK-positive NSCLC xenografts with demonstrated resistance to crizotinib, at concentrations within a clinically relevant range.

Dosage and administration

Patient Selection: Select patients for treatment of metastatic NSCLC with ZYKADIA based on the presence of ALK positivity in tumor specimens

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.

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Contraindications

None.

Warnings and precautions

Gastrointestinal Adverse Reactions: Severe gastrointestinal adverse reactions 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.

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

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: Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis and permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis

QT Interval Prolongation: 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. 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: 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

Bradycardia: Avoid using ZYKADIA in combination with other products known to cause bradycardia (e.g., 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: 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 from 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 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

Drug interactions

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. Avoid concurrent use of strong CYP3A inducers during treatment with ZYKADIA.

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.

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

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Use in specific populations

Pregnancy: 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.

Lactation: There are no data regarding the presence of ceritinib or its metabolites in human milk, the effects of ceritinib on the breastfed child or its effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with ZYKADIA and for 2 weeks following completion of therapy.

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

Geriatric Use: 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.

Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of ZYKADIA. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (ChildPugh B) hepatic impairment.

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