Ceritinib: Drug information
Copyright 1978-2018 Lexicomp, Inc. All rights reserved.
(For additional information see "Ceritinib: Patient drug information")

For abbreviations and symbols that may be used in Lexicomp (show table)
Brand Names: US
  • Zykadia
Brand Names: Canada
  • Zykadia
Pharmacologic Category
  • Antineoplastic Agent, Anaplastic Lymphoma Kinase Inhibitor;
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
Dosing: Adult

Note: Ceritinib is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics may be needed to prevent nausea and vomiting.

Non-small cell lung cancer (ALK-positive), metastatic: Oral: 450 mg once daily (with food); continue until disease progression or unacceptable toxicity.

Note: The recommended ceritinib dose is now 450 mg once daily with food (dose adjustment levels are also altered); the previous ceritinib dose was 750 mg once daily and administered on an empty stomach. Ceritinib 750 mg once daily in a fasted state may still be the approved dose in some regions outside of the US.

Missed doses: If a dose is missed, take the missed dose unless the next dose is due within 12 hours. If vomiting occurs, do not administer an additional dose, patients should continue with the next scheduled dose.

Dosage adjustment for concomitant therapy:

Strong CYP3A inhibitors: Avoid concomitant use of strong CYP3A inhibitors; if concurrent administration cannot be avoided, reduce ceritinib dose by approximately one-third (rounded to the nearest multiple of the 150 mg strength). After discontinuation of the strong CYP3A inhibitor, resume ceritinib therapy at the dose used prior to initiation of the CYP3A inhibitor.

Strong CYP3A inducers: Avoid concurrent use of strong CYP3A inducers during treatment with ceritinib.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 to 90 mL/minute: No dosage adjustment is necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Preexisting impairment:

Mild to moderate impairment (Child-Pugh classes A and B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): Reduce the dose by approximately one-third (rounded to the nearest multiple of the 150 mg strength).

Hepatotoxicity during treatment:

ALT or AST >5 times ULN with total bilirubin ≤2 times ULN: Interrupt therapy until recovery to baseline or ALT/AST ≤3 times ULN, then resume with a 150 mg dose reduction.

ALT or AST >3 times ULN with total bilirubin >2 times ULN in the absence of cholestasis or hemolysis: Permanently discontinue therapy.

Dosing: Adjustment for Toxicity

Recommended ceritinib dosage adjustment levels (when administered with food):

Initial starting dose: 450 mg once daily

First dose reduction: 300 mg once daily

Second dose reduction: 150 mg once daily

Discontinue if patients are unable to tolerate 150 mg daily.

Note: If dosage adjustments are required due to toxicity in regions outside of the US where the approved ceritinib dose remains 750 mg once daily (fasted), reduce the dose in decrements of 150 mg and discontinue if patients are unable to tolerate 300 mg daily (Soria 2017).

Cardiac:

Bradycardia:

Symptomatic bradycardia (not life-threatening): Interrupt therapy and evaluate concomitant medications known to cause bradycardia.

Upon recovery to asymptomatic bradycardia or to a heart rate ≥60 beats per minute, adjust the dose.

Alternatively, the following recommendations have been made: Upon recovery to asymptomatic bradycardia or to a heart rate ≥60 beats per minute. If concomitant medication is identified and discontinued or its dose adjusted, reinitiate ceritinib at its previous dose. If no concomitant medication is identified or if it is identified but not discontinued or not dose-adjusted, reinitiate ceritinib with the dose reduced by 150 mg (Zykadia Canadian product labeling).

Symptomatic bradycardia (life-threatening or requiring intervention) in patients taking concomitant medications known to cause bradycardia/hypotension: Interrupt therapy until recovery to asymptomatic bradycardia or to a heart rate ≥60 beats per minute.

If the concomitant medication can be adjusted or discontinued, resume ceritinib therapy with the dose reduced by 150 mg.

Alternatively, the following recommendations have been made: If concomitant medication can be discontinued or its dose adjusted, resume ceritinib with the dose reduced by 300 mg; monitor frequently; permanently discontinue ceritinib for recurrence (Zykadia Canadian product labeling).

Symptomatic bradycardia (life-threatening) in patients not taking concomitant medications known to cause bradycardia/hypotension: Permanently discontinue therapy.

QTc prolongation:

QTc interval >500 msec on at least 2 separate ECGs: Interrupt therapy until QTc interval is <481 msec or recovers to baseline if baseline QTc is ≥481 msec, then resume therapy with a 150 mg dose reduction.

QTc prolongation in combination with torsades de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia: Permanently discontinue therapy.

Gastrointestinal:

Severe or intolerable nausea, vomiting, or diarrhea (despite appropriate management): Interrupt therapy until improved, then resume treatment with a 150 mg dose reduction.

Lipase or amylase elevation >2 times ULN: Interrupt therapy and monitor serum lipase and amylase; upon recovery to <1.5 times ULN, resume treatment with a 150 mg dose reduction.

Metabolic: Persistent hyperglycemia >250 mg/dL (despite optimal antihyperglycemic therapy): Interrupt therapy until hyperglycemia is adequately controlled, then resume therapy with a 150 mg dose reduction. If hyperglycemia cannot be controlled (with optimal medical management), discontinue ceritinib.

Pulmonary: Treatment-related interstitial lung disease/pneumonitis (any grade): Permanently discontinue therapy.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Zykadia: 150 mg [contains fd&c blue #2 (indigotine)]

Generic Equivalent Available (US)

No

Administration

Ceritinib is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics may be needed to prevent nausea and vomiting.

Oral: Administer with food. Note: Ceritinib was previously recommended to be administered at a higher dose on an empty stomach, but should now be administered as 450 mg once daily with food.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Ceritinib may cause teratogenicity, reproductive toxicity, genotoxicity, and has a structural/toxicity profile similar to existing hazardous agents. Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016).

Use

Non-small cell lung cancer, metastatic: Treatment of anaplastic lymphoma kinase (ALK)-positive (as detected by an approved test) metastatic non-small cell lung cancer (NSCLC).

Medication Safety Issues
Sound-alike/look-alike issues:

Ceritinib may be confused with alectinib, brigatinib, cabozantinib, cobimetinib, crizotinib, neratinib

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

>10%:

Cardiovascular: Prolonged Q-T interval on ECG (4% to 12%)

Central nervous system: Fatigue (45% to 52%), noncardiac chest pain (21%), headache (19%), neuropathy (17%), dizziness (12%)

Dermatologic: Skin rash (16% to 21%), pruritus (11%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (84%), hyperglycemia (49% to 53%), decreased serum phosphate (36% to 38%), weight loss (24%)

Gastrointestinal: Diarrhea (56% to 86%), nausea (45% to 80%), vomiting (35% to 67%), abdominal pain (40% to 54%), increased serum amylase (37%), decreased appetite (34%), constipation (20% to 29%), increased serum lipase (13% to 28%), dyspepsia (≤16%), dysphagia (≤16%), gastroesophageal reflux disease (≤16%)

Hematologic & oncologic: Anemia (67% to 84%; grades 3/4: 4% to 5%), neutropenia (27%; grades 3/4: 2%), thrombocytopenia (16%; grades 3/4: 1%)

Hepatic: Increased serum ALT (80% to 91%; >5x ULN: 28%), increased serum AST (75% to 86%; >5x ULN: 16%), increased serum alkaline phosphatase (81%), increased serum bilirubin (15%)

Neuromuscular & skeletal; Back pain (19%), limb pain (13%), musculoskeletal pain (11%)

Renal: Increased serum creatinine (58% to 77%)

Respiratory: Cough (25%)

Miscellaneous: Fever (19%)

1% to 10%:

Cardiovascular: Pericarditis (4%), bradycardia (1% to 4%) pericardial effusion (≥2%), sinus bradycardia (1%)

Central nervous system: Seizure (≥2%)

Endocrine & metabolic: Dehydration (≥2%)

Hepatic: Hepatotoxicity (2%)

Ophthalmic: Visual disturbance (4% to 9%)

Renal: Renal failure (2%)

Respiratory: Pleural effusion (4%), pneumonia (4%), interstitial pulmonary disease (2% to 4%), pulmonary infection (≥2%), severe dyspnea (≥2%)

<1%, postmarketing and/or case reports: Pancreatitis

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Known hypersensitivity to ceritinib or any component of the formulation; congenital long QT syndrome or persistent Fridericia-corrected electrocardiogram interval (QTcF) of >500 msec.

Warnings/Precautions

Concerns related to adverse effects:

• Bradycardia: Symptomatic bradycardia has been reported; heart rate <50 beats/minute has occurred. If possible, avoid concurrent use with other agents known to cause bradycardia (eg, beta blockers, nondihydropyridine calcium channel blockers, clonidine, digoxin). Monitor heart rate and blood pressure regularly. If symptomatic bradycardia (not life-threatening) occurs, withhold treatment until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute, evaluate concurrent medications, and adjust ceritinib dose. Permanently discontinue for life-threatening bradycardia due to ceritinib; if life-threatening bradycardia occurs and concurrent medications associated with bradycardia can be discontinued or dose adjusted, restart ceritinib at a reduced dose (with frequent monitoring).

• Gastrointestinal toxicity: Severe and/or persistent gastrointestinal toxicity has occurred with ceritinib (at a dose of 750 mg in a fasted state). Diarrhea, nausea, vomiting, or abdominal pain occurred in the majority of patients in clinical trials using ceritinib 750 mg daily fasted (including some grade 3 and 4 events); over one-third of patients required treatment interruptions or dose reductions due to severe or persistent gastrointestinal toxicity. The incidence and severity of gastrointestinal toxicity were reduced in a clinical study utilizing ceritinib 450 mg daily with food (Cho 2017); most events were grade 1. Manage symptoms medically with appropriate therapy (eg, antidiarrheals, antiemetics, fluid replacement) as indicated. May require therapy interruption and/or dosage reduction. Ceritinib is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics may be needed to prevent nausea and vomiting. If vomiting occurs, do not administer an additional dose; continue with the next scheduled dose.

• Hepatotoxicity: Hepatotoxicity has been observed in patients treated with ceritinib in clinical trials, including ALT levels >5 times ULN in over one-quarter of patients and AST elevations in nearly one-fifth of patients. Concurrent ALT elevations >3 times ULN with total bilirubin >2 times ULN (with normal alkaline phosphatase) occurred rarely. Monitor liver function tests (eg, ALT, AST, total bilirubin) monthly and as clinically necessary, more frequently in patients who develop transaminase abnormalities. May require therapy interruption, dosage reduction, and/or permanent discontinuation.

• Hyperglycemia: Hyperglycemia, including grade 3 and 4 toxicity, has been observed in ceritinib-treated patients. Monitor fasting blood glucose levels at baseline and as clinically necessary. May require initiation or optimization of antihyperglycemic therapy. Temporarily interrupt therapy for hyperglycemia until adequately controlled; reduce dose upon recovery. If adequate glycemic control is not possible with medical management, permanently discontinue ceritinib.

• Pancreatitis: Although rare, pancreatitis (with fatality) has been reported. Grade 3 to 4 lipase and amylase elevations occurred in clinical trials. Monitor lipase and amylase prior to treatment and periodically during treatment as clinically necessary. May require treatment interruption and dose reduction.

• Pulmonary toxicity: Severe and life-threatening interstitial lung disease (ILD)/pneumonitis have been reported, including grade 3 or 4 events and fatalities. Monitor for signs/symptoms of pulmonary toxicity; permanently discontinue in patients diagnosed with treatment-related ILD/pneumonitis.

• QTc prolongation: QTc interval prolongation has occurred in clinical studies, and may be concentration-dependent. Based on post-baseline ECG assessment, a QTc interval increase of >60 msec over baseline was observed in a small percentage of patients; some patients experienced a QTc >500 msec (when taking ceritinib 750 mg daily fasted). QT prolongation may lead to an increased risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death. Avoid use in patients with congenital long QTc syndrome. Correct electrolyte abnormalities prior to initiating therapy. Periodically monitor ECG and electrolytes in patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QTc interval. QT prolongation may require treatment interruption, dosage reduction, or discontinuation. Permanently discontinue in patients who develop QTc interval prolongation in combination with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia.

Disease-related concerns:

• Hepatic impairment: Systemic exposure is increased and reduced initial doses are recommended in patients with severe impairment (Child-Pugh class C).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Drugs affecting gastric pH: In vitro studies indicate that ceritinib solubility and bioavailability may be decreased at higher pH; concurrent use with proton pump inhibitors, H2-receptor antagonists, or antacids has not been evaluated.

Other warnings/precautions:

• Administration: A pharmacokinetic study determined that ceritinib 450 mg once daily administered with food had similar exposure and with lower GI toxicities when compared to 750 mg administered in a fasted state (Cho 2017). Based on this, the recommended ceritinib dose is now 450 mg once daily with food.

• Anaplastic lymphoma kinase testing: Approved for use only in patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene. Information on approved tests for detection of ALK gene rearrangements may be found at http://www.fda.gov/CompanionDiagnostics.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C9 (moderate)

Drug Interactions

(For additional information: Launch drug interactions program)

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Risk C: Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk X: Avoid combination

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Risk C: Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Corticosteroids: May enhance the hyperglycemic effect of Ceritinib. Exceptions: Hydrocortisone (Ophthalmic). Risk C: Monitor therapy

CYP2C9 Substrates (High risk with Inhibitors): Ceritinib may increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (eg, warfarin, phenytoin) should be avoided when possible. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ceritinib. Risk X: Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Risk X: Avoid combination

CYP3A4 Substrates (High risk with Inhibitors): Ceritinib may increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Risk C: Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Risk C: Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Grapefruit Juice: May increase the serum concentration of Ceritinib. Risk X: Avoid combination

Hydroxychloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk X: Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Lornoxicam: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Lornoxicam. Risk C: Monitor therapy

Macimorelin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk X: Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk X: Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Risk D: Consider therapy modification

Probucol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk X: Avoid combination

Promazine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk X: Avoid combination

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Risk X: Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk C: Monitor therapy

QTc-Prolonging Agents (Moderate Risk): May enhance the QTc-prolonging effect of other QTc-Prolonging Agents (Moderate Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Risk D: Consider therapy modification

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Risk C: Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

St John's Wort: May decrease the serum concentration of Ceritinib. Risk X: Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Risk D: Consider therapy modification

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk X: Avoid combination

Xipamide: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk C: Monitor therapy

Food Interactions

Grapefruit and grapefruit juice may inhibit the metabolism of ceritinib and increase its systemic exposure. Management: Avoid grapefruit juice during therapy.

Pregnancy Implications

Based on findings in animal reproduction studies and its mechanism of action, ceritinib may cause fetal harm if administered to a pregnant woman. Women of reproductive potential should use effective contraception during treatment and for 6 months following therapy discontinuation. Based on the potential for genotoxicity, males with female partners of reproductive potential should use condoms during treatment and for 3 months following completion of therapy.

Breast-Feeding Considerations

It is not known if ceritinib is present in breast milk. Due to the potential for serious adverse reactions (gastrointestinal adverse reactions, pneumonitis, bradycardia, and pancreatitis) in the breastfed infant, breastfeeding is not recommended during treatment and for 2 weeks following completion of therapy.

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Monitoring Parameters

ALK positivity; renal function, liver function (ALT, AST, total bilirubin at baseline, monthly and as clinically necessary, more frequently in patients who develop transaminase abnormalities), fasting blood glucose (baseline and as clinically necessary), lipase and amylase (baseline and periodically as clinically necessary); electrolytes (baseline and periodically thereafter); cardiac monitoring (heart rate and QTc interval; ECG in patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or on concomitant medications known to prolong the QTc interval); blood pressure; signs/symptoms of gastrointestinal, pulmonary toxicity, and/or pancreatitis. Monitor adherence.

Mechanism of Action

Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), a tyrosine kinase involved in the pathogenesis of non-small cell lung cancer. ALK gene abnormalities due to mutations or translocations may result in expression of oncogenic fusion proteins (eg, ALK fusion protein) which alter signaling and expression and result in increased cellular proliferation and survival in tumors which express these fusion proteins. ALK inhibition reduces proliferation of cells expressing the genetic alteration. Ceritinib also inhibits insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Ceritinib has demonstrated activity in crizotinib-resistant tumors in NSCLC xenograft models.

Pharmacodynamics/Kinetics

Absorption: AUC and Cmax increased 73% and 41%, respectively, when a single ceritinib 500 mg dose was administered with a high-fat meal, and 58% and 43%, respectively when taken with a low-fat meal (when compared to fasting). A dose optimization study (comparing ceritinib 450 mg or 600 mg daily with food to ceritinib 750 mg [fasted]) found no clinically meaningful difference in the systemic steady-state exposure of ceritinib 450 mg (with food) compared to the 750 mg fasted arm (Cho 2017).

Distribution: 4,230 L (following a single 750 mg fasted dose), with a small preferential distribution to red blood cells versus plasma

Protein binding: 97% to human plasma proteins

Metabolism: Primarily hepatic via CYP3A

Half-life elimination: 41 hours (following a single 750 mg fasted dose)

Time to peak: ~4 to 6 hours

Excretion: Feces (~92% with 68% as unchanged drug); urine (~1%)

Pricing: US

Capsules (Zykadia Oral)

150 mg (70): $9,292.43

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Zykadia (AR, AT, AU, BB, CZ, DE, DK, EE, FI, FR, HK, HR, HU, IE, IL, JP, KR, LT, NO, PT, SE, SG, SI, SK);
  • Zykadiia (GB)
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REFERENCES

  1. <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 40-NF 35). Rockville, MD: United States Pharmacopeia Convention; 2017:83-102.
  2. Cho BC, Kim DW, Bearz A, et al. ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC). J Thorac Oncol. 2017;12(9):1357-1367. doi: 10.1016/j.jtho.2017.07.005. [PubMed 28729021]
  3. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017;35(28):3240-3261. doi: 10.1200/JCO.2017.74.4789. [PubMed 28759346]
  4. Masters GA, Temin S, Azzoli CG. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update [published correction appears in J Clin Oncol. 2016;34(11):1287]. J Clin Oncol. 2015;33(30):3488-3515 [PubMed 26324367]
  5. Roila F, Molassiotis A, Herrstedt J, et al ; participants of the MASCC/ESMO Consensus Conference Copenhagen 2015. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27(suppl 5):v119-v133. [PubMed 27664248]
  6. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189-1197. [PubMed 24670165]
  7. Soria JC, Tan DS, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-929. [PubMed 28126333]
  8. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016.
  9. Zykadia (ceritinib) [prescribing information]. East Hanover, NJ: Novartis; December 2017.
  10. Zykadia (ceritinib) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; February 2018.
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