Ceritinib (Monograph)

Brand name: Zykadia
Drug class: Antineoplastic Agents
- ALK Tyrosine Kinase Inhibitors
- Anaplastic Lymphoma Kinase Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
VA class: AN900
Chemical name: 5-Chloro-N2-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine
Molecular formula: C₂₈H₃₆ClN₅O₃S
CAS number: 1032900-25-6

Medically reviewed by Drugs.com on Oct 17, 2022. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of several receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK).

Uses for Ceritinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of metastatic NSCLC in patients whose cancer is ALK-positive as detected by an FDA-approved diagnostic test (designated an orphan drug by FDA for this use).

Guidelines for the treatment of stage IV NSCLC in patients with driver alterations in ALK generally support the use of ceritinib as an option in the first-line setting if alectinib and brigatinib are not available; ceritinib) also may be offered in the second-line setting if crizotinib was given in the first-line setting.

Ceritinib Dosage and Administration

General

Pretreatment Screening

• Confirmation of the presence of ALK rearrangement in tumor specimens of patients with metastatic non-small cell lung cancer (NSCLC) is necessary prior to initiating therapy with ceritinib.

• Perform pregnancy testing in females of reproductive potential.

Patient Monitoring

• Monitor lipase and amylase levels prior to initiating ceritinib treatment and periodically as clinically indicated.

• Monitor liver function tests (ALT and AST) and total bilirubin monthly and as clinically indicated. More frequent monitoring is warranted in patients who develop elevations of aminotransferase levels.

• Monitor fasting serum glucose prior to initiating ceritinib treatment and periodically as clinically indicated.

• Monitor BP and heart rate regularly. Monitor ECGs and electrolytes periodically in patients with congestive heart failure, electrolyte abnormalities, bradyarrhythmia, or patients taking QT_c-prolonging medications.

• Monitor for pulmonary symptoms suggestive of pneumonitis or interstitial lung disease.

• Monitor for severe GI adverse reactions. Manage patients with standard of care which may include antidiarrhea agents, fluid replacement, or antiemetics.

Administration

Oral Administration

Administer orally once daily with food.

If a dose of ceritinib is missed, do not take the missed dose within 12 hours of the next dose.

If a dose of ceritinib is vomited, do not take an extra dose. Take the next dose at the regularly scheduled time.

Dosage

Adults

NSCLC

Oral

450 mg once daily with food. Continue therapy until disease progression or unacceptable toxicity occurs.

Avoid concomitant use of potent CYP3A inhibitors. If concomitant use cannot be avoided, reduce ceritinib dosage by approximately 33% and round dosage to nearest 150-mg strength of ceritinib capsules or tablets (e.g., from 450 mg daily to 300 mg daily).

Dosage Modification for Toxicity

Oral

Treatment interruption, dosage reduction, and/or discontinuance of therapy may be necessary for adverse reactions.

If dosage reduction is required, reduce dosage as described in Table 1. Discontinue ceritinib if patients are unable to tolerate 150 mg once daily.

GI Toxicity

Oral

If severe or intolerable nausea, vomiting, or diarrhea occurs despite optimal antiemetics or antidiarrheal therapy, interrupt therapy until GI toxicity improves, and then resume at next lower dosage. (See Table 1.)

Hepatic Toxicity

Oral

If ALT or AST concentrations >5 times ULN with total bilirubin concentrations ≤2 times ULN occur, interrupt therapy. When liver function tests return to baseline or ≤3 times ULN, may resume at next lower dosage. (See Table 1.)

If ALT or AST concentrations >3 times ULN with total bilirubin concentrations >2 times ULN occur without cholestasis or hemolysis, permanently discontinue drug.

Interstitial Lung Disease/Pneumonitis

Oral

If treatment-related interstitial lung disease/pneumonitis of any grade occurs, permanently discontinue drug.

Prolongation of QT Interval

Oral

If QT_c interval >500 msec on ≥2 separate ECGs occurs, interrupt therapy. Once QT_c interval improves to <481 msec or returns to baseline (if baseline QT_c interval ≥481 msec), may resume at next lower dosage. If QT_c-interval prolongation recurs, reduce dosage by one dosage level. (See Table 1.)

If QT_c-interval prolongation occurs concurrently with torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia, permanently discontinue drug.

Bradycardia

Oral

If symptomatic, but non-life-threatening, bradycardia occurs, interrupt therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute. If no concomitant drugs known to cause bradycardia are identified, may resume ceritinib at next lower dosage. (See Table 1.)

If clinically important bradycardia requiring intervention or life-threatening bradycardia occurs in patients receiving concomitant drugs known to cause bradycardia or hypotension, interrupt therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute. If such concomitant drugs are discontinued or dosage adjusted, may resume ceritinib at next lower dosage with frequent monitoring. (See Table 1.)

If life-threatening bradycardia occurs in patients not receiving concomitant drugs known to cause bradycardia or hypotension, permanently discontinue drug.

Hyperglycemia

Oral

If persistent hyperglycemia with serum glucose concentrations >250 mg/dL occurs despite optimal antidiabetic agent therapy, interrupt therapy. Once adequate control of hyperglycemia is achieved, may resume ceritinib at next lower dosage. (See Table 1.) If hyperglycemia persists despite optimal medical management, discontinue ceritinib.

Pancreatitis

Oral

If serum lipase or amylase concentration >2 times ULN occurs, interrupt therapy. When serum concentrations improve to <1.5 times ULN, may resume ceritinib at next lower dosage. (See Table 1.)

Special Populations

Hepatic Impairment

Possible increased exposure to ceritinib.

Severe hepatic impairment (Child-Pugh class C): Reduce daily dosage by approximately 33%; round dosage to nearest 150-mg strength of ceritinib capsules or tablets (e.g., from 450 mg daily to 300 mg daily).

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustment not necessary.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Ceritinib

Contraindications

• None.

Warnings/Precautions

GI Toxicity

Severe GI toxicity has occurred.

Diarrhea, nausea, vomiting, or abdominal pain occurred in 95% of patients receiving ceritinib (750 mg once daily in a fasted state) in clinical trials; some cases were severe. Permanent discontinuance of therapy or dosage modification was necessary in some patients.

Incidence and severity of GI adverse effects were reduced in patients receiving ceritinib 450 mg once daily with food.

Monitor for GI toxicity and treat appropriately (e.g., antidiarrhea agents, antiemetics, fluid replacement) as necessary. Temporary interruption followed by dosage reduction or discontinuance of ceritinib may be necessary depending on severity of the GI toxicity.

Hepatic Toxicity

Drug-induced hepatotoxicity has occurred. ALT or AST elevations >5 times ULN reported in 28 or 16%, respectively, of patients receiving ceritinib 750 mg once daily in a fasting state. Elevations in ALT >3 times ULN and total bilirubin >2 times ULN with alkaline phosphatase <2 times ULN reported in 0.3% of ceritinib-treated patients. Permanent discontinuance of the drug was necessary in approximately 1% of patients.

Monitor liver function tests (i.e., ALT, AST, total bilirubin) monthly and as clinically indicated. More frequent repeat testing necessary in patients who develop transaminase elevations.

If hepatic toxicity occurs, temporary interruption followed by dosage reduction or discontinuance of therapy may be necessary depending on the severity.

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, or fatal ILD/pneumonitis may occur. In clinical trials evaluating ceritinib 750 mg once daily, ILD/pneumonitis occurred in 2.4% of patients receiving the drug in a fasting state; grade 3 or 4 ILD/pneumonitis occurred in 1.3% of patients and fatal ILD/pneumonitis occurred in 0.2% of patients. Permanent discontinuance of therapy was necessary in 10 patients (1.1%).

Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Exclude other potential causes of ILD or pneumonitis. In patients diagnosed with treatment-related ILD or pneumonitis, permanently discontinue ceritinib.

Prolongation of QT Interval

QT_c-interval prolongation reported; may increase risk for ventricular arrhythmias (e.g., torsades de pointes) or sudden death. The prolongation appears to occur in a plasma concentration-dependent manner.

Avoid use in patients with congenital long QT syndrome when possible.

Periodically monitor ECGs and serum electrolytes in patients with CHF, bradyarrhythmias, or electrolyte abnormalities or during concomitant use of drugs known to prolong the QT interval.

If QT_c-interval prolongation occurs, temporary interruption followed by dosage reduction or permanent discontinuance of ceritinib may be necessary.

Hyperglycemia

Hyperglycemia reported. Increased risk of hyperglycemia in patients with diabetes or glucose intolerance and in those receiving corticosteroids.

Monitor fasting serum glucose concentrations prior to initiation of therapy, during therapy and as clinically indicated. Initiate or optimize antidiabetic agents as clinically indicated. Temporary interruption followed by dosage reduction or discontinuance of therapy may be necessary depending on severity of hyperglycemia.

Bradycardia

Bradycardia reported.

Avoid use in patients receiving other drugs known to cause bradycardia when possible.

Monitor heart rate and BP regularly in all patients receiving ceritinib. If bradycardia occurs, temporary interruption followed by dosage reduction or discontinuance of therapy may be necessary.

Pancreatitis

Pancreatitis, sometimes fatal, reported.

Monitor serum lipase and amylase concentrations prior to initiation of therapy, periodically during therapy, and as clinically indicated. Temporary interruption followed by dosage reduction or discontinuance of therapy may be necessary depending on severity of toxicity.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity, embryotoxicity, fetotoxicity, and embryolethality demonstrated in animals.

Avoid pregnancy during therapy. (See Females and Males of Reproductive Potential under Cautions.)

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.) If used during pregnancy or if the patient becomes pregnant during therapy, apprise of potential fetal hazard.

Lactation

Not known whether ceritinib or its metabolites are distributed into human milk or if drug has any effect on milk production or the nursing infant. Breast-feeding not recommended during therapy and for 2 weeks after discontinuance of the drug.

Females and Males of Reproductive Potential

Prior to initiation of ceritinib therapy, verify pregnancy status of females of reproductive potential. Females of reproductive potential should be advised to use effective methods of contraception while receiving the drug and for 6 months after the drug is discontinued. Men who are partners of such women should use effective contraceptive methods during and for 3 months after discontinuance of the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

In clinical trials evaluating ceritinib 750 mg once daily in patients with ALK-positive NSCLC, 18% of patients were ≥65 years of age and 5% were ≥75 years of age. No overall differences in safety or efficacy in patients ≥65 years of age compared with younger adults.

Hepatic Impairment

Increased systemic exposure in individuals with severe hepatic impairment who received a single 750-mg dose of ceritinib; dosage reduction necessary.

Systemic exposure not altered by mild or moderate hepatic impairment; dosage adjustment not necessary in such patients.

Renal Impairment

Exposure not altered by mild or moderate renal impairment.

Not studied in patients with severe renal impairment (Cl_cr <30 mL/minute).

Common Adverse Effects

Most common (≥25%) adverse reactions were nausea, diarrhea, vomiting, abdominal pain, fatigue.

Drug Interactions

Metabolized principally by CYP3A. Substrate of P-glycoprotein (P-gp) in vitro.

May inhibit CYP isoenzymes 3A and 2C9 at clinically relevant concentrations; does not induce CYP isoenzymes 1A2, 2B6, or 2C9. Induces CYP3A4 in vitro.

In vitro, not a substrate of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, organic cation transporter (OCT) 1, organic anion transporter (OAT) 2, or organic anion transport protein (OATP) 1B1. Unlikely to inhibit P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 in vitro at clinically relevant concentrations.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased systemic exposure to, and increased toxicity of, ceritinib). Avoid concomitant use. If concomitant use cannot be avoided, reduce daily dosage of ceritinib by approximately 33% and round to the nearest 150-mg strength (e.g., from 450 mg daily to 300 mg daily). If the potent CYP3A inhibitor is discontinued, resume ceritinib therapy at the dosage used prior to initiation of the potent CYP3A inhibitor.

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased systemic exposure and decreased therapeutic efficacy of ceritinib). Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible pharmacokinetic interaction (increased plasma concentrations of CYP3A substrate). Avoid concomitant use of ceritinib and CYP3A substrates that have a narrow therapeutic index or substrates primarily metabolized by CYP3A. If concomitant use of CYP3A substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of the CYP3A substrate.

Substrates of CYP2C9: Possible pharmacokinetic interaction (increased plasma concentrations of CYP2C9 substrate). Avoid concomitant use of ceritinib and CYP2C9 substrates that have a narrow therapeutic index or substrates primarily metabolized by CYP2C9. If concomitant use of CYP2C9 substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of the CYP2C9 substrate.

Drugs Affecting Efflux Transport Systems

P-gp inhibitors: Potential pharmacokinetic interaction (increased plasma ceritinib concentrations).

Drugs Associated with QT Prolongation

Potential pharmacologic interaction (additive effect on QT-interval prolongation). Periodically monitor ECGs and electrolytes during concomitant use.

Drugs Associated with Bradycardia

Potential pharmacologic interaction (increased risk of bradycardia). Avoid concomitant use, if possible. (See Bradycardia under Cautions.)

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased solubility and reduced oral bioavailability of ceritinib) with drugs that increase gastric pH.

Specific Drugs and Foods

Ceritinib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained in about 4–6 hours.

Systemic exposure increases in greater than dose-proportional manner following repeated administration of ceritinib 50–750 mg once daily.

Steady-state concentrations are achieved in approximately 15 days.

Food

Administration of a single 500-mg dose of ceritinib with a high-fat meal (approximately 1000 calories and 58 g of fat) increased AUC and peak plasma concentrations by 73 and 41%, respectively.

Administration of a single 500-mg dose of ceritinib with a low-fat meal (approximately 330 calories and 9 g of fat) increased AUC and peak plasma concentrations by 58 and 43%, respectively.

Administration of a single 750-mg dose of ceritinib with a high-fat meal increased AUC and peak plasma concentrations by 64 and 58%, respectively.

Administration of a single 750-mg dose of ceritinib with a low-fat meal increased AUC and peak plasma concentrations by 39 and 42%, respectively.

Systemic exposure to ceritinib not substantially altered following administration of ceritinib 450 mg daily with food (approximately 100–500 calories and 1.5–15 g of fat) compared with ceritinib 750 mg daily in a fasted state.

Special Populations

In pharmacokinetic population analyses, age did not have a clinically important effect on the systemic exposure of ceritinib.

In patients with severe hepatic impairment (Child-Pugh class C) receiving a single 750-mg dose of ceritinib in a fasting state, mean systemic exposure to total and unbound ceritinib increased by 66 and 108%, respectively, compared with individuals with normal hepatic function.

Mild or moderate hepatic impairment (Child-Pugh class A or B) does not affect total or unbound systemic exposure to total or unbound ceritinib.

Mild (Cl_cr of 60–89 mL/minute) or moderate (Cl_cr of 30–59 mL/minute) renal impairment: Exposure similar to that in patients with normal renal function.

Severe renal impairment: Pharmacokinetics not studied.

Distribution

Extent

Not known whether ceritinib or its metabolites are distributed into human milk.

Plasma Protein Binding

97%.

Elimination

Metabolism

Principally metabolized by CYP3A4.

Elimination Route

Eliminated in feces (92%) and urine (1.3%).

Half-life

Mean terminal half-life: 41 hours.

Stability

Storage

Oral

Capsules

Store at 20–25°C (excursions permitted between 15–30°C).

Tablets

Store at 20–25°C (excursions permitted between 15–30°C).

Actions

• Inhibits several receptor tyrosine kinases, including ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor, and c-ros oncogene-1 (ROS-1); most active against ALK.

• Activating mutations or translocations of the ALK gene identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK). Formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.

• ALK rearrangements identified in approximately 3–7% of patients with NSCLC.

• Clinical resistance to crizotinib attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways. CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF.

• Inhibits ALK phosphorylation, ALK-mediated phosphorylation of the downstream signaling protein signal transducer and activator of transcription-3 (STAT-3), and proliferation of ALK-dependent cancer cells in vitro and in vivo.

• Inhibits proliferation of cell lines expressing EML4-ALK and nucleophosmin (NPM)-ALK fusion proteins in vitro.

• Demonstrates dose-dependent inhibition of EML4-ALK in mice and rats bearing NSCLC tumor xenografts that express EML4-ALK.

• Approximately 20-fold more potent than crizotinib against ALK in vitro.

• Exhibits dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts that express EML4-ALK with demonstrated resistance to crizotinib.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling.

• If a dose is missed, importance of advising patients to take it as soon as they remember unless it is less than 12 hours before the next dose, in which case they should not take the missed dose.

• If a dose is vomited, advise patients to not take an additional dose to replace the vomited dose. The next dose should be administered at the next scheduled time.

• Importance of informing patients that ceritinib should be taken with food. Importance of also advising patients to avoid grapefruit and grapefruit juice while taking ceritinib.

• Importance of informing patients that nausea, vomiting, diarrhea, and abdominal pain are the most common adverse effects associated with ceritinib therapy, as well as supportive treatment options (e.g., antiemetic and/or antidiarrhea agents). Importance of contacting clinician if severe or persistent adverse GI effects occur.

• Risk of hepatotoxicity; importance of liver function test monitoring. Importance of informing patients of the signs and symptoms of hepatotoxicity (e.g., fatigue, anorexia, nausea, vomiting, abdominal pain [especially right upper quadrant pain], jaundice, dark or “tea-colored” urine, generalized pruritus, unusual bleeding or bruising) and advising them to immediately report possible symptoms of hepatotoxicity to their clinician.

• Risk of severe or fatal interstitial lung disease/pneumonitis. Importance of advising patients that pneumonitis symptoms may be similar to those of lung cancer and to contact their clinician immediately if they experience any new or worsening pulmonary symptoms (e.g., dyspnea, shortness of breath, cough with or without mucus, chest pain, fever).

• Risk of QT_c-interval prolongation and bradycardia. Importance of informing clinicians immediately if new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, faintness, or changes in or new use of cardiovascular or antihypertensive therapy occurs.

• Risk of hyperglycemia, particularly in patients with diabetes or glucose intolerance and in those receiving corticosteroid medications. Importance of informing patients of the signs and symptoms of hyperglycemia (e.g., increased thirst, increased urination, increased appetite, fatigue, blurred vision, headache, difficulty thinking or concentrating, breath that smells like fruit) and advising patients to immediately contact their clinician if they experience such signs and symptoms.

• Risk of pancreatitis. Importance of informing clinicians immediately if signs or symptoms of pancreatitis (e.g., upper abdominal pain that may spread to the back) occur.

• Risk of fetal harm. Importance of patients informing their clinicians if they are pregnant or plan to become pregnant. If pregnancy occurs, advise patient of potential risk to the fetus.

• Advise women of reproductive potential that they should use effective methods of contraception while receiving ceritinib and for 6 months after discontinuance of therapy. Advise men who are partners with women of reproductive potential to use effective methods of contraception while receiving the drug and for 3 months after the drug is discontinued.

• Advise women to avoid breast-feeding while receiving ceritinib and for 2 weeks after discontinuance of therapy.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses (e.g., hepatic impairment, cardiovascular disease [including congenital long QT syndrome], diabetes mellitus or hyperglycemia).

• Advise patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ceritinib is available only from designated specialty distributors and pharmacies. The manufacturer should be contacted for additional information.

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