Ceritinib

Class: Antineoplastic Agents
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
Brands: Zykadia

Medically reviewed on Jun 18, 2018

Introduction

Antineoplastic agent; an inhibitor of several receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK).^{1 2 3}

Uses for Ceritinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC in patients following failure (secondary to resistance or intolerance) of prior crizotinib therapy^{1 2 3} (designated an orphan drug by FDA for this use).⁴

Accelerated approval based on tumor response rate and duration of response; improvement in survival or disease-related symptoms not demonstrated.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.¹

About 3–7% of patients with NSCLC have ALK-positive disease; such patients typically are nonsmokers or light smokers, female, and younger in age, and often have adenocarcinoma.^{8 9 13 19 20 21 36 38 39 41}

Long-term therapeutic potential of crizotinib (another ALK inhibitor) is limited by eventual development of secondary resistance and development and/or progression of brain metastases (because of poor distribution of crizotinib into CSF).^{2 22 23 36 38 39 41} (See Actions.)

Ceritinib Dosage and Administration

General

• Monitor liver function tests monthly and as clinically indicated.¹ More frequent repeat testing recommended in patients who develop elevated serum transaminase concentrations during therapy.¹ (See Hepatic Toxicity under Dosage and Administration.)

• Monitor serum glucose concentrations as clinically indicated.¹ (See Hyperglycemia under Dosage and Administration.)

Restricted Distribution Program

• Obtain ceritinib through a limited network of specialty pharmacies.⁵

  Contact manufacturer at 888-669-6682 or consult the Zykadia website ([Web]) for specific availability information.^{1 5}

Administration

Oral Administration

Administer orally once daily on an empty stomach (i.e., ≥2 hours before or after a meal).¹ Systemic exposure when administered with a meal may exceed that of a typical dose taken in a fasted state, resulting in increased adverse effects.¹ (See Food under Pharmacokinetics.)

If a dose of ceritinib is missed, do not take the missed dose within 12 hours of the next dose.¹ (See Advice to Patients.)

Dosage

Adults

NSCLC

Oral

750 mg (five 150-mg capsules) once daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Dosage Modification for Toxicity

Oral

In the principal efficacy study, ≥1 dosage reduction was required in approximately 60% of patients (most commonly for GI toxicity); median time to first dosage reduction was 7 weeks.^{1 3}

When dosage reduction is necessary, reduce daily dosage in decrements of 150 mg.¹

If a dosage of 300 mg daily requires further reduction, discontinue the drug.¹

Hepatic Toxicity

Oral

If ALT or AST concentrations >5 times ULN with total bilirubin concentrations ≤2 times ULN occur, interrupt therapy.¹ When liver function tests return to baseline or ≤3 times ULN, may resume ceritinib with a 150-mg dosage reduction.¹

If ALT or AST concentrations >3 times ULN with total bilirubin concentrations >2 times ULN occur without cholestasis or hemolysis, permanently discontinue drug.¹

Interstitial Lung Disease/Pneumonitis

Oral

If treatment-related interstitial lung disease/pneumonitis of any grade occurs, permanently discontinue drug.¹ (See Interstitial Lung Disease (ILD)/Pneumonitis under Cautions.)

Cardiovascular Toxicity

Oral

If QT_c-interval prolongation >500 msec on ≥2 separate ECGs occurs, interrupt ceritinib therapy.¹ Once QT_c-interval prolongation improves to <481 msec or returns to baseline (if baseline QT_c interval ≥481 msec), may resume ceritinib with a 150-mg dosage reduction.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.¹ (See Prolongation of QT Interval under Cautions.)

If symptomatic, but non-life-threatening, bradycardia occurs, interrupt ceritinib therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats per minute occurs.¹ Evaluate concomitant medications known to cause bradycardia, and adjust dosage of ceritinib.¹ (See Interactions.)

If clinically significant bradycardia requiring intervention or life-threatening bradycardia occurs in patients receiving concomitant medications known to cause bradycardia or hypotension, interrupt ceritinib therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats per minute occurs.¹ If therapy with the concomitant medication can be adjusted or discontinued, may resume ceritinib with a 150-mg dosage reduction and frequent monitoring.¹

If life-threatening bradycardia occurs in patients not receiving concomitant medications known to cause bradycardia or hypotension, permanently discontinue drug.¹ (See Bradycardia under Cautions.)

GI Toxicity

Oral

If severe or intolerable nausea, vomiting, or diarrhea occurs despite appropriate medical therapy (e.g., antiemetics, antidiarrhea agents), interrupt therapy.¹ Once GI toxicity improves, may resume ceritinib with a 150-mg dosage reduction.¹ (See Severe or Persistent GI Toxicity under Cautions.)

Hyperglycemia

Oral

If persistent hyperglycemia with serum glucose concentrations >250 mg/dL occurs despite optimal antidiabetic agent therapy, interrupt therapy.¹ Once adequate control of hyperglycemia is achieved, may resume ceritinib with a 150-mg dosage reduction.¹ However, if hyperglycemia persists despite optimal medical management, discontinue ceritinib.¹ (See Hyperglycemia under Cautions.)

Special Populations

Hepatic Impairment

Possible increased exposure to ceritinib.¹

Moderate or severe hepatic impairment: Recommended dosage not determined.¹ (See Hepatic Impairment under Cautions.)

Mild hepatic impairment: Dosage adjustment not necessary.¹

Renal Impairment

No specific dosage recommendations.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.¹ (See Geriatric Use under Cautions.)

Cautions for Ceritinib

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Severe or Persistent GI Toxicity

Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of patients receiving the recommended dosage of ceritinib (750 mg once daily) in the principal efficacy study, with severe cases reported in 14% of the patients.¹ Over one-third (38%) of patients required dosage modification.¹

Monitor for GI toxicity and treat appropriately (e.g., antidiarrhea agents, antiemetics, fluid replacement) as necessary.¹ Temporary interruption, followed by dosage reduction or discontinuance of ceritinib may be necessary depending on severity of the GI toxicity.¹ (See GI Toxicity under Dosage and Administration.)

Hepatic Toxicity

Drug-induced hepatotoxicity has occurred.¹ ALT elevations >5 times ULN reported in 27% of patients in the primary efficacy study; permanent discontinuance of the drug was necessary in 1 of 255 patients (0.4%).¹

Monitor liver function tests, including ALT, AST, and total bilirubin, monthly and as clinically indicated.¹ More frequent repeat testing necessary in patients who develop transaminase elevations.¹

If hepatic toxicity occurs, temporary interruption, followed by dosage reduction or discontinuance of therapy may be necessary depending on the severity.¹ (See Hepatic Toxicity under Dosage and Administration.)

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, or fatal ILD/pneumonitis may occur.¹ In the primary efficacy study, pneumonitis occurred in 4% of patients, grade 3 or 4 ILD or pneumonitis occurred in 3% of patients, and fatal ILD/pneumonitis occurred in one patient (0.4%).¹

Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis (see Advice to Patients).¹ Exclude other potential causes of ILD or pneumonitis.¹ In patients diagnosed with treatment-related ILD or pneumonitis, permanently discontinue ceritinib.¹ (See Interstitial Lung Disease/Pneumonitis under Dosage and Administration.)

Prolongation of QT Interval

QT_c-interval prolongation reported.¹ The prolongation appears to occur in a plasma concentration-dependent manner.¹

Avoid use in patients with congenital long QT syndrome when possible.¹

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.¹ (See Specific Drugs and Foods under Interactions.)

If QT_c-interval prolongation occurs, temporary interruption, followed by dosage reduction or permanent discontinuance of ceritinib may be necessary.¹ (See Cardiovascular Toxicity under Dosage and Administration.)

Hyperglycemia

Hyperglycemia reported.¹ Increased risk of grade 3 or 4 hyperglycemia in patients with diabetes or glucose intolerance and in those receiving corticosteroids.¹

Monitor serum glucose concentrations and initiate or optimize antidiabetic agents as clinically indicated.¹ Temporary interruption, followed by dosage reduction or discontinuance of therapy may be necessary depending on severity of hyperglycemia.¹ (See Hyperglycemia under Dosage and Administration.)

Bradycardia

Bradycardia reported.¹

Avoid use in patients receiving other drugs known to cause bradycardia when possible.¹ (See Interactions.)

Monitor heart rate and BP regularly in all patients receiving ceritinib.¹ If bradycardia occurs, temporary interruption, followed by dosage reduction or discontinuance of therapy may be necessary.¹ (See Cardiovascular Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity, embryotoxicity, fetotoxicity, and embryolethality demonstrated in animals.¹

Avoid pregnancy during therapy.¹ Women of childbearing potential should use effective methods of contraception while receiving the drug and for ≥2 weeks after the drug is discontinued.¹ If used during pregnancy or if the patient becomes pregnant during therapy, apprise of potential fetal hazard.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether ceritinib or its metabolites are distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety, efficacy, and pharmacokinetics not established in pediatric patients.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.¹

Hepatic Impairment

Formal pharmacokinetic studies not conducted.¹ Because principally eliminated by the liver, increased ceritinib exposure likely in patients with hepatic impairment.¹

In a population pharmacokinetic analysis, systemic exposure not altered by mild hepatic impairment; dosage adjustment not necessary in such patients.¹ (See Special Populations under Pharmacokinetics.)

Not studied in patients with moderate or severe hepatic impairment; recommended dosage not determined in such patients.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Exposure not altered by mild or moderate renal impairment.¹ (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment (Cl_cr <30 mL/minute).¹

Common Adverse Effects

Adverse effects: Diarrhea,¹ nausea,¹ vomiting,¹ abdominal pain,¹ constipation,¹ esophageal disorder (e.g., dyspepsia, gastroesophageal reflux disease, dysphagia),¹ fatigue,¹ decreased appetite,¹ neuropathy (including paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, and polyneuropathy),¹ rash.¹

Laboratory abnormalities: Anemia,¹ increased ALT and/or AST concentrations,¹ increased S_cr concentrations,¹ hyperglycemia,¹ hypophosphatemia,¹ increased lipase concentrations,¹ hyperbilirubinemia.^{1 2}

Interactions for Ceritinib

Metabolized principally by CYP3A4.¹ Substrate of CYP3A and P-glycoprotein (P-gp) in vitro.¹

May inhibit CYP isoenzymes 3A and 2C9 at clinically relevant concentrations; does not induce CYP isoenzymes 1A2, 2B6, or 2C9.^{1 6} Induces CYP3A4 in vitro.⁶

In vitro, not a substrate or inhibitor 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) 1B1.¹ Does not inhibit apical efflux transporters, P-gp, OATP1B3, renal organic anion transporters (OAT) 1 and OAT3, or OCT2 in vitro at clinically relevant concentrations.¹

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased systemic exposure of ceritinib).¹ Avoid concomitant use.¹ 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 750 mg daily to 450 mg daily).¹ If the potent CYP3A inhibitor is discontinued, resume ceritinib therapy at the dosage used prior to initiation of the potent CYP3A inhibitor.¹

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased systemic exposure of ceritinib).¹ Avoid concomitant use.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible pharmacokinetic interaction (increased plasma concentrations of CYP3A substrate).¹ Avoid concomitant use of ceritinib and CYP3A substrates that have a narrow therapeutic index or substrates primarily metabolized by CYP3A.¹ If concomitant use of CYP3A substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of the CYP3A substrate.¹

Substrates of CYP2C9: Possible pharmacokinetic interaction (increased plasma concentrations of CYP2C9 substrate).¹ Avoid concomitant use of ceritinib and CYP2C9 substrates that have a narrow therapeutic index or substrates primarily metabolized by CYP2C9.¹ If concomitant use of CYP2C9 substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of the CYP2C9 substrate.¹

Inhibitors of P-gp

P-gp inhibitors: Potential pharmacokinetic interaction (increased plasma ceritinib concentrations).¹

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation).¹ Periodically monitor ECGs and electrolytes during concomitant use.¹ (See Prolongation of QT Interval under Cautions.)

Drugs Associated with Bradycardia

Potential pharmacologic interaction (increased risk of bradycardia).¹ Avoid concomitant use, if possible.¹ (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.^{1 6}

Specific Drugs and Foods

Ceritinib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained in about 4–6 hours.¹

Systemic exposure increases in greater than dose-proportional manner following repeated administration of ceritinib 50–750 mg once daily.¹

Steady-state concentrations are achieved in approximately 15 days.¹

Absolute bioavailability not established.¹

Food

Administration with a high-fat meal (approximately 1000 calories and 58 g of fat) increased AUC and peak plasma concentrations by 73 and 41%, respectively.¹

Administration with a low-fat meal (approximately 330 calories and 9 g of fat) increased AUC and peak plasma concentrations by 58 and 43%, respectively.¹

Administration of a ≥600 mg dose of ceritinib with a meal expected to increase systemic exposure beyond that of a 750-mg dose taken in a fasted state.¹

Special Populations

In pharmacokinetic population analyses, age did not have a clinically important effect on the systemic exposure of ceritinib.¹

In a population pharmacokinetic analysis, systemic exposure was similar in patients with mild hepatic impairment and those with normal hepatic function.¹

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.¹

Severe renal impairment: Pharmacokinetics not studied.¹

Distribution

Extent

Not known whether ceritinib or its metabolites are distributed into human milk.¹

Plasma Protein Binding

97%.¹

Elimination

Metabolism

Principally metabolized by CYP3A4.¹

Elimination Route

Eliminated in feces (92.3%) and urine (1.3%).¹

Half-life

Mean terminal half-life: 41 hours.¹

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).¹

Actions

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

• Activating mutations or translocations of the ALK gene identified in several malignancies^{7 17} and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).^{3 8 9 10 11 15} 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.^{2 6 7 9 11}

• ALK rearrangements identified in approximately 3–7% of patients with NSCLC.^{36 38 39}

• 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.^{36 38 39 41} CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF.^{36 38 39 41}

• Inhibits ALK phosphorylation,^{1 3 16} 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.¹

• Inhibits proliferation of cell lines expressing EML4-ALK and nucleophosmin (NPM)-ALK fusion proteins in vitro.¹

• Demonstrates dose-dependent inhibition of EML4-ALK in mice and rats bearing NSCLC tumor xenografts that express EML4-ALK.¹

• Approximately 20-fold more potent than crizotinib against ALK in vitro.¹⁶

• Exhibits dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts that express EML4-ALK with demonstrated resistance to crizotinib.¹

Advice to Patients

• Importance of instructing patients to read the manufacturer's patient information.¹

• 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.¹

• Importance of informing patients that ceritinib should be taken on an empty stomach since taking the drug with food may increase blood concentrations and the risk of adverse effects; importance of instructing patients not to eat for ≥2 hours before and after taking the drug.¹ Importance of also advising patients to avoid grapefruit and grapefruit juice while taking ceritinib.¹

• 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).¹ Importance of contacting clinician if severe or persistent adverse GI effects occur.¹

• Risk of hepatotoxicity; importance of liver function test monitoring.¹ Importance of informing patients of 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.¹

• Risk of severe or fatal ILD/pneumonitis.¹ 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).¹

• Risk of QT_c-interval prolongation and bradycardia.¹ 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.¹

• Risk of hyperglycemia, particularly in patients with diabetes or glucose intolerance and in those receiving corticosteroid medications.¹ 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.¹

• Risk of fetal harm.¹ Necessity of advising women of childbearing potential that they should use effective methods of contraception while receiving ceritinib and for ≥2 weeks after the drug is discontinued.¹ Importance of patients informing their clinicians if they are pregnant or plan to become pregnant.¹ If pregnancy occurs, advise of potential risk to fetus.¹

• Importance of advising women to avoid breast-feeding while receiving ceritinib therapy.¹

• Importance of informing clinicians 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).¹

• Importance of informing patients of other important precautionary information.¹ (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.

Distribution of ceritinib is restricted. ⁵ (See Restricted Distribution under Dosage and Administration: General.)

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