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Zykadia

Generic Name: 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

Introduction

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

Uses for Zykadia

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 therapy1 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 1–7% of patients with NSCLC have ALK-positive disease;2 6 7 10 12 13 14 19 such patients typically are nonsmokers or light smokers and often have adenocarcinoma.8 13 19 20 21

ALK-positive NSCLC usually is initially sensitive to crizotinib (another ALK inhibitor) but eventually becomes resistant, which limits the drug's long-term therapeutic potential.2 22 23 (See Actions.)

Zykadia 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 () 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 QTc-interval prolongation >500 msec on ≥2 separate ECGs occurs, interrupt ceritinib therapy.1 Once QTc-interval prolongation improves to <481 msec or returns to baseline (if baseline QTc interval ≥481 msec), may resume ceritinib with a 150-mg dosage reduction.1

If QTc-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 Zykadia

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

QTc-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 QTc-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 (Clcr <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 Scr concentrations,1 hyperglycemia,1 hypophosphatemia,1 increased lipase concentrations,1 hyperbilirubinemia.1 2

Interactions for Zykadia

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

Drug

Interaction

Comments

Antacids

Possible decreased ceritinib bioavailability secondary to decreased solubility at higher pH1 6

Antiarrhythmic agents, class IA (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol)

Possible additive effect on QT-interval prolongation1 25 26

Quinidine: Possible increased concentrations of quinidine1

Possible additive effect on QT-interval prolongation1

Periodically monitor ECG and electrolytes1

Quinidine: Avoid concomitant use1

If concomitant use cannot be avoided, consider reducing dosage of quinidine and periodically monitor ECG and electrolytes1

Antifungals, azoles (e.g., ketoconazole)

Potent CYP3A inhibitors: Possible increased ceritinib exposure1

Ketoconazole (200 mg twice daily) increased ceritinib (single 450-mg dose) AUC and peak concentrations by 2.9-fold and 22%, respectively1

Potent CYP3A inhibitors: 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 to 450 mg daily)1

If the potent CYP3A inhibitor is discontinued, resume ceritinib at the dosage used prior to initiation of the potent CYP3A inhibitor1

Antimycobacterials, rifamycins (e.g., rifampin)

Possible decreased ceritinib exposure1

Rifampin (600 mg daily) decreased AUC and peak concentrations of ceritinib (single 750-mg dose) by 70 and 44%, respectively1

Avoid concomitant use1

Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, haloperidol, pimozide, thioridazine)

Possible additive effect on QT-interval prolongation1 25 26

Pimozide: Possible increased concentrations of pimozide1

Periodically monitor ECG and electrolytes1

Pimozide: avoid concomitant use; if concomitant use cannot be avoided, consider reducing dosage of pimozide1

β-adrenergic blocking agents

Possible additive bradycardic effects1

Avoid concomitant use, if possible1

Calcium-channel blocking agents, nondihydropyridine (e.g., diltiazem, verapamil)

Possible additive bradycardic effects1

Avoid concomitant use, if possible1

Carbamazepine

Possible decreased ceritinib exposure1

Avoid concomitant use1

Citalopram

Possible additive effect on QT-interval prolongation1 25 26

Periodically monitor ECG and electrolytes1

Clarithromycin

Possible additive effect on QT-interval prolongation1 25 26

Periodically monitor ECG and electrolytes1

Clonidine

Possible additive bradycardic effects1

Avoid concomitant use, if possible1

Digoxin

Possible additive bradycardic effects1

Avoid concomitant use, if possible1

Ergot derivatives (e.g., dihydroergotamine, ergotamine)

Possible increased concentrations of ergot derivative1

Avoid concomitant use1

If concomitant use cannot be avoided, consider reducing dosage of ergot derivative1

Grapefruit or grapefruit juice

Possible increased ceritinib concentrations1

Avoid concomitant use1

Histamine H2-receptor antagonists

Possible decreased ceritinib bioavailability secondary to decreased solubility at higher pH1 6

HIV protease inhibitors that are potent CYP3A inhibitors (e.g., ritonavir)

Possible increased ceritinib exposure1

Avoid concomitant use1

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 to 450 mg daily)1

If the protease inhibitor is discontinued, resume ceritinib at the dosage used prior to initiation of the potent CYP3A inhibitor1

Immunosuppressive agents (e.g., cyclosporine, sirolimus, tacrolimus)

Possible increased concentrations of the immunosuppressive agent1

Avoid concomitant use1

If concomitant use cannot be avoided, consider reducing dosage of the immunosuppressive agent1

Macrolides (e.g., clarithromycin, telithromycin)

Potent CYP3A inhibitors: Possible increased ceritinib exposure1

Macrolides that prolong QT interval: Possible additive effect on QT-interval prolongation1 25 26

Potent CYP3A inhibitors: 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 750 to 450 mg daily).1 If the macrolide is discontinued, resume ceritinib at the dosage used prior to initiation of the potent CYP3A inhibitor1

Macrolides that prolong QT interval: Periodically monitor ECG and electrolytes1

Nefazodone

Possible increased ceritinib exposure1

Avoid concomitant use1

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 to 450 mg daily)1

If nefazodone is discontinued, resume ceritinib at the dosage used prior to initiation of nefazodone1

Opiate agonists (alfentanil, fentanyl)

Possible increased concentrations of opiate agonist1

Avoid concomitant use1

If concomitant use cannot be avoided, consider reducing dosage of the opiate agonist1

Phenytoin

Possible decreased ceritinib exposure1

Possible increased concentrations of phenytoin1

Avoid concomitant use1

If concomitant use cannot be avoided, consider reducing dosage of phenytoin1

Proton-pump inhibitors

Possible decreased ceritinib bioavailability secondary to decreased solubility at higher pH1 6

St. John’s wort (Hypericum perforatum)

Possible reduced ceritinib exposure1

Avoid concomitant use1

Warfarin

Possible increased concentrations of warfarin1

Avoid concomitant use1

If concomitant use cannot be avoided, consider reducing dosage of warfarin1

Zykadia 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 (Clcr of 60–89 mL/minute) or moderate (Clcr 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 malignancies7 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

  • The EML4-ALK oncogene is identified in approximately 1–7% of patients with NSCLC.2 7 9 10 11 12 13 14 15 16 17

  • 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

  • Clinical resistance to crizotinib attributed to several possible mechanisms, including secondary mutations of ALK, activation of alternate signaling pathways, expression of another oncogenic fusion protein, or gene amplification.15 16

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 QTc-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.)

Ceritinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

150 mg

Zykadia

Novartis

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Novartis Pharmaceuticals Corporation. Zykadia (ceritinib) capsules prescribing information. East Hanover, NJ: 2014 Apr.

2. Shaw AT, Kim DW, Mehra R et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014; 370:1189-97. [PubMed 24670165]

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205755Orig1s000: Summary review. From FDA website.

4. US Food and Drug Administration. FDA Application: Search Orphan Drug Designations and approvals. Rockville, MD. From FDA web site.

5. Novartis Oncology. Zykadia (ceritinib) pharmacy network. 2014 Apr. From Novartis for Healthcare Professionals website.

6. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205755Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

7. Kwak EL, Bang YJ, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010; 363:1693-703. [PubMed 20979469]

8. Pearson R, Kolesar JM. Targeted therapy for NSCLC: ALK inhibition. J Oncol Pharm Pract. 2011; 18:271-4. [PubMed 21844131]

9. Sasaki T, Jänne PA. New strategies for treatment of ALK-rearranged non-small cell lung cancers. Clin Cancer Res. 2011; 17:7213-8. [PubMed 22010214]

10. Food and Drug Administration. FDA news release: FDA approves Xalkori with companion diagnostic test for a type of late-stage lung cancer. Rockville, MD; 2011 Aug 26. From FDA web site.

11. Husain H, Rudin CM. ALK-targeted therapy for lung cancer: ready for prime time. J Oncology. 2011; 25:1-6.

12. Tiseo M, Gelsomino F, Bartolotti M et al. Anaplastic lymphoma kinase as a new target for the treatment of non-small-cell lung cancer. Expert Rev Anticancer Ther. 2011; 11:1677-87. [PubMed 22050016]

13. Gaughan EM, Costa DB. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol. 2011; 3:113-25. [PubMed 21904575]

14. Garber K. ALK, lung cancer, and personalized therapy: portent of the future?. J Natl Cancer Inst. 2010; 102:672-5. [PubMed 20460631]

15. Iwama E, Okamoto I, Harada T et al. Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer. Onco Targets Ther. 2014; 7:375-385. [PubMed 24623980]

16. Friboulet L, Li N, Katayama R et al. The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non-Small Cell Lung Cancer. Cancer Discov. 2014; 4:662-73. [PubMed 24675041]

17. Marsilje TH, Pei W, Chen B et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5 - chloro - N2 - (2 - isopropoxy - 5 - methyl - 4 - (piperidin - 4 - yl)phenyl) - N4 - (2 - (isopropylsulfonyl)phenyl)pyrimidine - 2,4 - diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013; 56:5675-90. [PubMed 23742252]

18. LDK378 versus chemotherapy in ALK rearranged (ALK positive) patients previously treated with chemotherapy (platinum doublet) and crizotinib. From ClinicalTrials.gov registry. Accessed 2014 Jun 5.

19. Pfizer Inc. New York, NY: Personal communication (crizotinib).

20. Crinò L, Kim D, Riely GJ, et al. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol. 2011; 29 (American Society of Clinical Oncology Annual Meeting Abstracts):Abstr. No. 7514.

21. Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol. 2011; 29 (Suppl.): Abstr. No. 2501.

22. Doebele RC, Pilling AB, Aisner DL et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012; 18:1472-82.

23. Katayama R, Shaw AT, Khan TM et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Trans Med. 2012; 4:120ra17. [PubMed 22277784]

24. Anon. Ceritinib (Zykadia) for non-small cell lung cancer. Med Lett Drugs Ther. 2014; 56:62-3.

25. Forest Pharmaceuticals, Inc. Celexa (citalopram hydrobromide) tablets and oral solution prescribing information. St. Louis, MO; 2012 Mar.

26. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010; 70:16-23.

27. LDK378 versus chemotherapy in previously untreated patients with ALK rearranged non-small cell lung cancer. From ClinicalTrials.gov registry. Accessed 2014 Aug 12.

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