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Ceritinib

10:00 • Antineoplastic Agents (AHFS primary)

■ Ceritinib, an inhibitor of several receptor tyrosine kinases including anaplasticlymphoma kinase (ALK), is an antineoplastic agent.

Uses■ Non-small Cell Lung Cancer

Ceritinib is used for the treatment of adults with anaplastic lymphoma kinase(ALK)-positive metastatic non-small cell lung cancer (NSCLC) following failure(secondary to resistance or intolerance) of prior crizotinib therapy. The drug has beendesignated an orphan drug by the FDA for use in this condition. The acceleratedapproval of ceritinib for this indication is based on tumor response rate and duration ofresponse; there currently are no clinical data demonstrating an improvement in survivalor disease-related symptoms with the drug. Continued approval for this indicationmay be contingent on verification and description of clinical benefit of ceritinib inconfirmatory studies.

The results of several studies indicate that a relatively small subset of patients withNSCLC (approximately 1–7%) have ALK-positive disease, which indicates potentialresponsiveness to ALK inhibitor therapy (e.g., ceritinib, crizotinib). Patients with thisform of lung cancer typically are nonsmokers or have a history of light smoking andoften have adenocarcinoma. Patients with ALK-positive NSCLC usually are initiallysensitive to crizotinib but eventually become resistant, limiting the drug's long-termtherapeutic potential. (See Description.)

The current indication for ceritinib is based principally on the results of amulticenter, single-arm, open-label study that enrolled 163 adult patients withmetastatic ALK-positive NSCLC whose cancer had progressed with or who wereintolerant of crizotinib. All patients in this study received an initial ceritinib dosageof 750 mg once daily. The primary efficacy end point was overall response rate (asevaluated by both investigators and a Blinded Independent Central Review Committee[BIRC]); an additional outcome measure was duration of response. The median age ofpatients enrolled in the study was 52 years; 91% of the patients had progressed duringcrizotinib therapy and 93% had adenocarcinoma histology. In the efficacy analysis, theBIRC-assessed overall response rate with ceritinib was 43.6%; partial responses wereachieved in 41.1% of patients and 2.5% had a complete response. The investigator-assessed overall response rate with ceritinib was comparable (54.6%), with partialresponses achieved in 53.4% of patients and complete responses achieved in 1.2% ofpatients. The median BIRC-assessed duration of response was 7.1 months, and themedian investigator-assessed duration of response was similar (7.4 months).

Phase 3 controlled trials comparing ceritinib as single-agent therapy with standard-of-care chemotherapy in patients with treatment-naive, or previously treated, ALK-positive NSCLC are underway. Ceritinib currently is not indicated for use in patientswith treatment-naive ALK-positive NSCLC†.

Dosage and Administration■ General

Because ceritinib may cause hepatotoxicity, the manufacturer states that liverfunction tests should be monitored monthly and as clinically indicated. Morefrequent repeat testing is recommended in patients who develop elevated serumtransaminase concentrations during therapy. (See Hepatic Toxicity under Dosage:Dosage Modification, in Dosage and Administration.)

Because ceritinib may cause hyperglycemia, the manufacturer states that serumglucose concentrations should be monitored during therapy as clinically indicated. (SeeHyperglycemia under Dosage: Dosage Modification, in Dosage and Administration.)Restricted Distribution Program

Ceritinib can only be obtained through a limited network of specialty pharmacies.Clinicians may contact the manufacturer (Novartis) by telephone at 888-669-6682or consult the Zykadia® website for specific availability information (http://www.zykadia.com/health-care-professional/pharmacy-network.jsp).■ Administration

Ceritinib is administered orally once daily on an empty stomach (i.e., the drugshould be taken at least 2 hours before or after a meal). Systemic exposure when thedrug is administered with a meal may exceed that of a typical dose taken in a fastedstate and result in increased adverse effects. (See Description.)■ DosageNon-small Cell Lung Cancer

The recommended adult dosage of ceritinib for the treatment of anaplasticlymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC)following failure (secondary to resistance or intolerance) of prior crizotinib therapy is

750 mg (five 150-mg capsules) once daily. Ceritinib therapy should be continued untildisease progression or unacceptable toxicity occurs.Dosage Modification for Toxicity

In the principal efficacy study, at least one dosage reduction from the recommendedinitial ceritinib dosage (750 mg once daily) was necessary in approximately 60% ofpatients (most commonly for GI toxicity); the median time to the first dosage reductionwas 7 weeks.

When dosage modification is necessary, the daily dosage of ceritinib should bereduced in decrements of 150 mg; however, if a dosage of 300 mg daily requiresfurther reduction, ceritinib should be discontinued.

Hepatic Toxicity.If an elevation in serum alanine aminotransferase (ALT) or aspartate

aminotransferase (AST) concentrations exceeding 5 times the upper limit of normal(ULN) occurs with an elevation in total bilirubin concentrations no more than 2 timesthe ULN, ceritinib therapy should be withheld until the liver function test results returnto baseline values or decrease to no more than 3 times the ULN. Ceritinib therapy maythen be resumed with a 150-mg dosage reduction.

If an elevation in ALT or AST concentrations exceeding 3 times the ULN occurswith an elevation in total bilirubin concentrations exceeding 2 times the ULN in theabsence of cholestasis or hemolysis, therapy with ceritinib should be permanentlydiscontinued. (See Hepatic Toxicity under Cautions: Warnings/Precautions.)

Interstitial Lung Disease/Pneumonitis.If treatment-related interstitial lung disease/pneumonitis of any grade occurs,

ceritinib therapy should be permanently discontinued. (See Interstitial Lung Disease/Pneumonitis under Cautions: Warnings/Precautions.)

Cardiovascular Toxicity.If corrected QT (QTc) interval exceeds 500 msec on at least 2 separate ECGs,

ceritinib therapy should be withheld until the QTc interval is less than 481 msec orreturns to baseline (if baseline QTc interval is 481 msec or more). Ceritinib therapymay then be resumed with a 150-mg dosage reduction.

If QTc-interval prolongation occurs concurrently with torsades de pointes,polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia,ceritinib therapy should be permanently discontinued. (See Prolongation of QT Intervalunder Cautions: Warnings/Precautions.)

If symptomatic, but non-life-threatening, bradycardia occurs, therapy with ceritinibshould be withheld until recovery to asymptomatic bradycardia or to a heart rateof 60 beats per minute or more occurs. Concomitant medications known to causebradycardia should be evaluated, and the dosage of ceritinib should be adjusted. (SeeDrug Interactions: Drugs Associated with Bradycardia.)

If clinically significant bradycardia requiring intervention or life-threateningbradycardia occurs in patients receiving concomitant medications known to causebradycardia or hypotension, therapy with ceritinib should be withheld until recoveryto asymptomatic bradycardia or to a heart rate of 60 or more beats per minuteoccurs. If therapy with the concomitant medication can be adjusted or discontinued,ceritinib therapy may then be resumed with a 150-mg dosage reduction and frequentmonitoring.

If life-threatening bradycardia occurs in patients not receiving concomitantmedications known to cause bradycardia or hypotension, ceritinib therapy should bepermanently discontinued. (See Bradycardia under Cautions: Warnings/Precautions.)

GI Toxicity.In patients experiencing severe or intolerable nausea, vomiting, or diarrhea despite

appropriate medical therapy (e.g., antiemetics, antidiarrhea agents), ceritinib therapyshould be withheld until the GI symptoms have improved. Ceritinib may then beresumed with a 150-mg dosage reduction. (See Severe or Persistent GI Toxicity underCautions: Warnings/Precautions.)

Hyperglycemia.If persistent hyperglycemia with serum glucose concentrations exceeding 250

mg/dL occurs despite optimal antidiabetic agent therapy, ceritinib therapy should bewithheld until adequate control of the hyperglycemia is achieved. Ceritinib therapymay then be resumed with a 150-mg dosage reduction. However, if hyperglycemiapersists despite optimal medical management, ceritinib therapy should be discontinued.(See Hyperglycemia under Cautions: Warnings/Precautions.)Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of ceritinib with drugs that are potent inhibitors of cytochromeP-450 (CYP) isoenzyme 3A should be avoided. If concomitant use of a potent CYP3Ainhibitor cannot be avoided, the manufacturer recommends reducing the daily dosageof ceritinib by approximately 33% and rounding dosage to the nearest 150-mg strengthof ceritinib capsules (e.g., from 750 mg daily to 450 mg daily). If concomitant use ofthe potent CYP3A inhibitor is discontinued, the ceritinib dosage should be returnedto the dosage used prior to initiation of the potent CYP3A inhibitor. (See Inhibitors ofCYP3A under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)■ Special Populations

Patients with hepatic impairment may have an increased exposure to ceritinib.No dosage adjustment is necessary in patients with mild hepatic impairment. Themanufacturer states that the recommended dosage of ceritinib in patients with moderate

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or severe hepatic impairment has not been determined. (See Hepatic Impairment underWarnings/Precautions: Specific Populations, in Cautions.)

There are currently no special dosage recommendations for geriatric patients orpatients with renal impairment. (See Geriatric Use and also see Renal Impairmentunder Warnings/Precautions: Specific Populations, in Cautions.)

Cautions■ Contraindications

The manufacturer states that there are no known contraindications to the use ofceritinib.■ Warnings/PrecautionsSevere or Persistent GI Toxicity

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

Patients receiving ceritinib should be monitored for development of GI toxicity andtreated as necessary with appropriate therapy (e.g., antidiarrhea agents, antiemetics,fluid replacement). Temporary interruption, followed by dosage reduction ordiscontinuance of ceritinib may be necessary depending on the severity of the GItoxicity. (See GI Toxicity under Dosage: Dosage Modification for Toxicity, in Dosageand Administration.)Hepatic Toxicity

Drug-induced hepatotoxicity has occurred in patients receiving ceritinib. Elevationsin alanine aminotransferase (ALT) exceeding 5 times the upper limit of normal (ULN)were reported in 27% of ceritinib-treated patients in the primary efficacy study;permanent discontinuance of the drug due to transaminase elevations and jaundice wasnecessary in 1 of 255 patients (0.4%) in this study.

The manufacturer states that liver function tests, including ALT, aspartateaminotransferase (AST), and total bilirubin, should be monitored once every monthand as clinically indicated during ceritinib therapy, with more frequent testing inpatients who develop transaminase elevations during therapy. Temporary interruption,followed by dosage reduction or permanent discontinuance of ceritinib may benecessary depending on the severity of the hepatic toxicity. (See Hepatic Toxicityunder Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)Interstitial Lung Disease/Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis mayoccur in patients receiving ceritinib. In the primary efficacy study, pneumonitisoccurred in 4% of ceritinib-treated patients, grade 3 or 4 ILD or pneumonitis occurredin 3% of patients, and fatal ILD/pneumonitis was reported in one patient (0.4%).Discontinuance of ceritinib due to ILD or pneumonitis occurred in 1% of ceritinib-treated patients.

Patients receiving ceritinib should be monitored for pulmonary symptomsindicative of ILD or pneumonitis (see Advice to Patients), and other potentialcauses of ILD or pneumonitis should be excluded. Ceritinib should be permanentlydiscontinued in patients who are diagnosed with treatment-related ILD or pneumonitis.(See Interstitial Lung Disease/Pneumonitis under Dosage: Dosage Modification forToxicity, in Dosage and Administration.)Prolongation of QT Interval

Prolongation of the corrected QT (QTc) interval has been reported in patientsreceiving ceritinib. The prolongation appears to occur in a plasma concentration-dependent manner. An increase in the QTc interval exceeding 60 msec from baselineoccurred in 3% of patients receiving ceritinib in the primary efficacy study. In theclinical development program, a QTc interval exceeding 500 msec occurred in one of304 ceritinib-treated patients (less than 1%) and 3% of ceritinib-treated patients had anincrease exceeding 60 msec from baseline; dosages in these studies ranged from 50–750 mg daily.

Ceritinib should be avoided in patients with congenital long QT syndrome, ifpossible. The manufacturer recommends periodic monitoring of ECGs and serumelectrolytes during ceritinib therapy in patients with congestive heart failure,bradyarrhythmias, or electrolyte abnormalities and in those who are receiving drugsknown to prolong the QT interval. (See Drug Interactions: Drugs that Prolong the QTInterval.)

Temporary interruption, followed by dosage reduction of ceritinib is necessarywhen the QTc interval exceeds 500 msec on at least 2 separate ECGs. When QTc-interval prolongation occurs concurrently with torsades de pointes, polymorphicventricular tachycardia, or signs and/or symptoms of serious arrhythmia, ceritinibtherapy should be permanently discontinued. (See Cardiovascular Toxicity underDosage: Dosage Modification for Toxicity, in Dosage and Administration.)Hyperglycemia

Hyperglycemia has been reported in patients receiving ceritinib. In the primaryefficacy study, grade 3 or 4 hyperglycemia occurred in 13% of ceritinib-treatedpatients. The risk of grade 3 or 4 hyperglycemia was increased by sixfold in patients

with diabetes or glucose intolerance and by twofold in those concurrently receivingcorticosteroids.

Serum glucose concentrations should be monitored in patients receiving ceritinib asclinically indicated. Antidiabetic agents should be initiated or optimized as necessary.Temporary interruption, followed by dosage reduction or discontinuance of ceritinibmay be necessary depending on the severity of the hyperglycemia. (See Hyperglycemiaunder Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)Bradycardia

Ceritinib may cause bradycardia. In the primary efficacy study, sinus bradycardia(defined as a heart rate of less than 50 beats per minute) was reported as a new findingin 1% of ceritinib-treated patients; bradycardia was reported as an adverse drugreaction in 3% of patients in this study.

Ceritinib should be avoided in patients who are receiving other drugs knownto cause bradycardia when possible. (See Drug Interactions: Drugs associated withBradycardia.)

Heart rate and blood pressure should be monitored regularly in all patientsreceiving ceritinib.

Temporary interruption, followed by dosage reduction is necessary if non-life-threatening, symptomatic bradycardia occurs. If life-threatening bradycardia occurs inpatients who are not concomitantly receiving medications known to cause bradycardiaor hypotension, ceritinib therapy should be permanently discontinued. However, ifassociated with a concomitant medication known to cause bradycardia or hypotension,ceritinib should be withheld until recovery to asymptomatic bradycardia or to a heartrate of 60 beats per minute or more occurs. If the concomitant medication can beadjusted or discontinued, ceritinib therapy can be resumed at a reduced dosage uponrecovery to asymptomatic bradycardia or to a heart rate of 60 beats per minute or moreoccurs; such patients should be monitored frequently. (See Cardiovascular Toxicityunder Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action, ceritinib may cause fetal harm if administeredto pregnant women. Ceritinib produced developmental toxicity, including dose-relatedskeletal abnormalities (e.g., delayed or incomplete ossification, skeletal variations)and a low incidence of visceral abnormalities, when administered to pregnant animalsin dosages associated with exposure levels lower than those associated with therecommended human dosage; maternal toxicity, abortion, and embryolethality alsowere observed. Pregnancy should be avoided during therapy. Women of childbearingpotential should use effective methods of contraception while receiving the drug andfor at least 2 weeks after the drug is discontinued. If ceritinib is used during pregnancyor if the patient becomes pregnant while receiving the drug, the patient should beapprised of the potential fetal hazard. (See Advice to Patients.)Specific Populations

Pregnancy.Category D. (See Users Guide and also see Fetal/Neonatal Morbidity and Mortality

under Cautions: Warnings/Precautions.)Lactation.It is not known whether ceritinib or its metabolites are distributed into human milk.

Because many drugs are distributed into human milk and because of the potential forserious adverse reactions to ceritinib in nursing infants, a decision should be madewhether to discontinue nursing or the drug, taking into account the importance of thedrug to the woman.

Pediatric Use.Safety, efficacy, and pharmacokinetics of ceritinib have not been established in

pediatric patients.Geriatric Use.Clinical studies of ceritinib did not include sufficient numbers of patients 65

years of age and older to determine whether geriatric patients respond differentlythan younger adults. In the primary efficacy trial evaluating ceritinib in patients withmetastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer(NSCLC), 16% of patients receiving ceritinib at the recommended dosage were 65years of age or older.

In pharmacokinetic population analyses, age did not have a clinically importanteffect on the systemic exposure of ceritinib in adults.

Hepatic Impairment.Formal pharmacokinetic studies of ceritinib have not been conducted in patients

with hepatic impairment. However, ceritinib is eliminated principally by the liver andincreased exposure to the drug may occur in patients with hepatic impairment.

In a population pharmacokinetic analysis, the systemic exposure to ceritinib wassimilar in patients with mild hepatic impairment (total bilirubin concentration nomore than the ULN with AST concentration exceeding the ULN or total bilirubinconcentration exceeding 1–1.5 times the ULN with any AST concentration) and thosewith normal hepatic function. Ceritinib dosage adjustment is not recommended inpatients with mild hepatic impairment.

Because the pharmacokinetics of ceritinib have not been studied in patients withmoderate to severe hepatic impairment, the recommended dosage of the drug has notyet been determined in such patients.

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Renal Impairment.Formal pharmacokinetic studies of ceritinib have not been conducted in patients

with renal impairment. In a population pharmacokinetic analysis, the pharmacokineticsof ceritinib were similar in patients with mild (creatinine clearance of 60–89 mL/minute) or moderate (creatinine clearance of 30–59 mL/minute) renal impairmentcompared with patients with normal renal function. Patients with severe renalimpairment (creatinine clearance less than 30 mL/minute) were not included in theclinical trials.■ Common Adverse Effects

Adverse effects reported in more than 10% of patients receiving ceritinib in themain efficacy trial include diarrhea, nausea, vomiting, abdominal pain, constipation,esophageal disorder (including dyspepsia, gastroesophageal reflux disease, anddysphagia), fatigue, decreased appetite, neuropathy (including paresthesia, muscularweakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensoryneuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, andpolyneuropathy), and rash.

Laboratory abnormalities reported in more than 10% of patients receiving ceritinibin the main efficacy trial include anemia, elevated concentrations of transaminases(i.e., ALT, AST), elevated concentrations of serum creatinine, hyperglycemia,hypophosphatemia, increased lipase concentrations, and hyperbilirubinemia.

Drug InteractionsCeritinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.

In vitro, ceritinib is a substrate of CYP3A and P-glycoprotein (P-gp). In vitro studiesalso indicate that ceritinib may inhibit CYP isoenzymes 3A and 2C9 at clinicallyrelevant concentrations. In vitro, ceritinib induces CYP3A4, but does not induce CYPisoenzymes 1A2, 2B6, or 2C9.

In vitro, ceritinib is 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. Ceritinib also does not inhibit apical efflux transporters, P-gp, OATP1B3, renalorganic anion transporters (OAT) 1 and OAT3, or OCT2 in vitro at clinically relevantconcentrations.■ Drugs Affecting Hepatic Microsomal EnzymesInhibitors of CYP3A

Concomitant use of ceritinib with potent inhibitors of CYP3A is likely to increasesystemic exposure of ceritinib. When the potent CYP3A inhibitor ketoconazole (200mg twice daily for 14 days) was administered concomitantly with ceritinib (as asingle 450-mg dose) in healthy individuals, AUC and peak plasma concentrationsof ceritinib increased by 2.9-fold and 22%, respectively. The steady-state AUC ofceritinib following concurrent administration of ketoconazole (200 mg twice daily for14 days) with reduced dosages of ceritinib is expected to be similar to the steady-stateAUC of ceritinib alone.

Concomitant use of potent CYP3A inhibitors, including certain antivirals (e.g.,ritonavir), macrolide antibiotics (e.g., telithromycin), antifungals (e.g., ketoconazole),and nefazodone, should be avoided during ceritinib therapy. If concomitant use of apotent CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing thedaily dosage of ceritinib by approximately 33% and rounding to the nearest 150-mgstrength of ceritinib capsules (e.g., from 750 mg daily to 450 mg daily). If concomitantuse of the potent CYP3A inhibitor is discontinued, the ceritinib dosage should bereturned to the dosage used prior to initiation of the potent CYP3A4 inhibitor.Inducers of CYP3A

Concomitant use of ceritinib with potent inducers of CYP3A (e.g., carbamazepine,phenytoin, rifampin) may result in decreased systemic exposure of ceritinib and shouldbe avoided. When the potent CYP3A4 inducer rifampin (600 mg daily for 14 days)was administered concomitantly with ceritinib (as a single 750-mg dose) in healthyindividuals, AUC and peak plasma concentrations of ceritinib decreased by 70 and44%, respectively.

Use of St. John's wort (Hypericum perforatum), a potent CYP3A inducer, alsoshould be avoided during ceritinib therapy.■ Drugs Metabolized by Hepatic Microsomal EnzymesSubstrates of CYP3A

Ceritinib may inhibit CYP3A at clinically relevant concentrations and potentiallycan increase plasma concentrations of other drugs metabolized by CYP3A.Concomitant use of ceritinib with CYP3A substrates with a narrow therapeutic index(e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide,quinidine, sirolimus, tacrolimus) or substrates primarily metabolized by CYP3A shouldbe avoided. If concomitant use of CYP3A substrates with a narrow therapeutic indexcannot be avoided, a dosage reduction of the CYP3A substrate should be considered.Substrates of CYP2C9

Ceritinib may inhibit CYP2C9 at clinically relevant concentrations and potentiallycan increase plasma concentrations of other drugs metabolized by CYP2C9.Concomitant use of ceritinib with CYP2C9 substrates that have a narrow therapeuticindex (e.g., phenytoin, warfarin) or substrates principally metabolized by CYP2C9

should be avoided. If concomitant use of CYP2C9 substrates with a narrow therapeuticindex cannot be avoided, a dosage reduction of the CYP2C9 substrate should beconsidered.■ Drugs Affecting the P-glycoprotein Transport System

Ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If ceritinib isadministered with drugs that inhibit P-gp (e.g., ketoconazole), increased concentrationsof ceritinib may occur.■ Drugs that Prolong the QT Interval

Because ceritinib has been associated with QT-interval prolongation, themanufacturer recommends periodic monitoring of ECGs and electrolytes in ceritinib-treated patients concurrently receiving other drugs known to prolong the QTinterval, including class IA antiarrhythmics (e.g., quinidine, procainamide), classIII antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g.,chlorpromazine, haloperidol, pimozide, thioridazine), citalopram, and clarithromycin.(See Prolongation of QT Interval under Cautions: Warnings/Precautions.)■ Drugs Associated with Bradycardia

Because ceritinib has been associated with bradycardia, the manufacturerrecommends that concurrent use with other drugs known to cause bradycardia (e.g., β-adrenergic blocking agents, nondihydropyridine calcium-channel blocking agents [e.g.,diltiazem, verapamil], clonidine, digoxin) be avoided, if possible. (See Bradycardiaunder Cautions: Warnings/Precautions.)■ Drugs Affecting Gastric Acidity

Although formal studies with ceritinib have not been conducted to date, thepossibility exists that drugs that increase gastric pH (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) may decrease the solubility of ceritiniband subsequently reduce its bioavailability.■ Grapefruit

Grapefruit products are CYP3A inhibitors and should be avoided because of thepotential for increased plasma ceritinib concentrations during concurrent use.

DescriptionCeritinib, an inhibitor of receptor tyrosine kinases, including anaplastic lymphoma

kinase (ALK), insulin-like growth factor receptor-1 (IGFR-1), insulin receptor, andc-ros oncogene-1 (ROS-1), is an antineoplastic agent. Among these tyrosine kinases,ceritinib is most active against ALK.

Activating mutations or translocations of the ALK gene have been identified inseveral malignancies and can result in the expression of oncogenic fusion proteins(e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK). Such ALKgene rearrangements have been identified in approximately 1–7% of patients withNSCLC. Formation of ALK fusion proteins such as EML4-ALK results in activationand dysregulation of the gene's expression and signaling, which can contribute toincreased cell proliferation and survival in tumors expressing these proteins. In vitroand in vivo, ceritinib has demonstrated inhibition of ALK phosphorylation, ALK-mediated phosphorylation of the downstream signaling protein signal transducer andactivator of transcription-3 (STAT-3), and proliferation of ALK-dependent cancer cells.In vitro, ceritinib inhibited proliferation of cell lines that expressed EML4-ALK andnucleophosmin (NPM)-ALK fusion proteins. The drug also has demonstrated dose-dependent inhibition of EML4-ALK in mice and rats bearing NSCLC tumor xenograftsthat expressed EML4-ALK. In vitro, ceritinib is approximately 20-fold more potentthan crizotinib in its activity against ALK.

At clinically relevant concentrations, ceritinib has demonstrated dose-dependentantitumor activity in mice bearing NSCLC tumor xenografts that expressed EML4-ALK with demonstrated resistance to crizotinib. Clinical resistance to crizotinib hasbeen attributed to several possible resistance mechanisms. Limited data to date suggestthat secondary mutations of ALK (e.g., L1196M, G1269A) are responsible for onlyabout 30% of cases of acquired crizotinib resistance. The remaining cases appear to bedue to several other resistance mechanisms, such as activation of alternate signalingpathways, expression of another oncogenic fusion protein, or gene amplification. Inpreclinical studies in cell-line models, ceritinib inhibited several crizotinib-resistantALK kinase domain mutant forms.

The absolute bioavailability of ceritinib has not been established. Peak plasmaconcentrations of ceritinib are achieved about 4–6 hours following single-dose,oral administration of the drug. Following repeated administration of ceritinib 50–750 mg once daily, systemic exposure increases in a greater than dose-proportionalmanner. Following multiple-dose administration of ceritinib 750 mg daily, steady-stateconcentrations of the drug were achieved in approximately 15 days. Systemic exposureto ceritinib is increased when the drug is administered with food. Oral administrationof a single 500-mg dose of ceritinib with a low-fat (approximately 330 calories and9 g of fat) or high-fat meal (approximately 1000 calories and 58 g of fat) resultedin increases in systemic exposure of 58 or 73%, respectively, and increases in peakplasma concentrations by 43 or 41%, respectively, compared with the fasted state.Administration of a 600 mg or higher dose of ceritinib with a meal is expected toresult in an increase in systemic exposure exceeding that of a 750-mg dose takenin a fasted state. Ceritinib is predominantly metabolized by the cytochrome P-450

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(CYP) isoenzyme 3A4. The drug is 97% bound to plasma proteins. Following oraladministration of a single 750-mg radiolabeled dose of ceritinib, 92.3% of the dosewas recovered in feces and 1.3% was recovered in urine; unchanged drug accountedfor 68% of the dose recovered in feces. The mean terminal half-life of ceritinib is 41hours.

Advice to PatientsImportance of instructing patients to read the manufacturer's patient information.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 theyshould not take the missed dose.

Importance of informing patients that ceritinib should be taken on an emptystomach since taking the drug with food may increase blood concentrations and therisk of adverse effects; importance of instructing patients not to eat for at least 2hours before and after taking the drug. Importance of also advising patients to avoidgrapefruit and grapefruit juice while taking ceritinib.

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

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

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

Risk of QTc-interval prolongation and bradycardia. Importance of informingclinicians immediately if new chest pain or discomfort, changes in heartbeat,palpitations, dizziness, lightheadedness, faintness, or changes in or new use ofcardiovascular or antihypertensive therapy occurs.

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

Risk of fetal harm. Necessity of advising women of childbearing potential thatthey should use effective methods of contraception while receiving ceritinib and for atleast 2 weeks after discontinuance of therapy. Importance of patients informing theirclinicians if they are pregnant or plan to become pregnant. If pregnancy occurs, advisepatient of potential risk to the fetus.

Importance of advising women to avoid breast-feeding while receiving ceritinibtherapy.

Importance of informing clinicians of existing or contemplated concomitanttherapy, 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 orhyperglycemia).

Importance of informing patients of other important precautionary information.(See Cautions.)

Overview® (see Users Guide). For additional information on this drug untila more detailed monograph is developed and published, the manufacturer’slabeling should be consulted. It is essential that the manufacturer’slabeling be consulted for more detailed information on usual cautions,precautions, contraindications, potential drug interactions, laboratory testinterferences, and acute toxicity. For further information on the pharmacologyof antineoplastic agents, resistance, and general principles in cancerchemotherapy, see the Antineoplastic Agents General Statement 10:00 at http://www.ahfsdruginformation.com. For further information on the handling ofantineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs athttp://www.ahfsdruginformation.com.

PreparationsExcipients in commercially available drug preparations may have clinically

important effects in some individuals; consult specific product labeling for details.Distribution of ceritinib is restricted. (See Restricted Distribution under Dosage and

Administration: General.)

CeritinibOral

CeritinibCapsules

150 mg

Zykadia®, Novartis

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

© Copyright, October 31, 2014, American Society of Health-System Pharmacists, Inc.