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Shaw AT et al. N Engl J Med. 2014;370(13):1189–1197

Cho BC et al. J Thorac Oncol. 2017;12(9):1357–1367

FDA and EMA prescribing information and miscellaneous sources

 

Ceritinib 450 mg/dose; administer orally once daily, continually, with food (total dose/week = 3150 mg)

 

Notes:

  • On December 21, 2017, the U.S. FDA revised the approved dosage regimen to 450 mg administered orally once daily with food based on similar systemic exposure and improved gastrointestinal tolerability compared to the 750-mg dose administered without food found in the ASCEND-8 study. The study found similar systemic exposure between the 450 mg (fed state) and 750 mg (fasting state) regimens, but improved gastrointestinal tolerability with the former

  • Patients who delay taking ceritinib at a regularly scheduled time may take a missed dose if the interval remaining before the next regularly scheduled dose is ≥12 hours. If vomiting occurs after a dose of ceritinib, take the next dose at the next regularly scheduled time

  • In patients with a history of diabetes mellitus, optimize antihyperglycemic medications prior to initiating ceritinib. If ceritinib therapy is interrupted, patients receiving antihyperglycemic medications should be monitored for hypoglycemia

  • Ceritinib is metabolized by cytochrome P450 (CYP) CYP3A subfamily enzymes. Avoid using ceritinib with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin) when possible. If concurrent use with a strong CYP3A4 inhibitor is required, reduce the ceritinib dose by approximately 33%. Avoid using ceritinib with strong CYP3A4 inducers (eg, carbamazepine, rifampin, phenytoin, phenobarbital, St John’s wort).

  • Advise patients to not consume grapefruit and grapefruit juice as they may inhibit CYP3A in the gut wall and increase the bioavailability of ceritinib

  • Ceritinib may inhibit CYP3A4 and CYP2C9; use caution and consider dose reduction, when appropriate, of concurrently used CYP3A4 and CYP2C9 substrates, especially if the substrate has a narrow therapeutic index (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, warfarin, phenytoin)

 

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

 

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

 

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be CONSIDERED:

  • Antibacterial—not indicated

  • Antifungal—not indicated

  • Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Diarrhea management

Latent or delayed onset diarrhea:

  • Loperamide 4 mg orally initially after the first loose or liquid stool, then

  • Loperamide 2 mg orally every 2 hours during waking hours, plus

  • Loperamide 4 mg orally every 4 hours during hours of sleep

    • Continue for at least 12 hours after diarrhea resolves

    • Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

    • Rehydrate orally with fluids and electrolytes during a diarrheal episode

    • If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists <48 hours despite loperamide, stop loperamide and hospitalize the patient for IV hydration

      Alternatively, a trial of diphenoxylate hydrochloride 2.5 mg with atropine sulfate 0.025 mg (eg, Lomotil)

    • Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily

    • Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed onset diarrhea:

  A fluoroquinolone (eg, ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm3 with or without accompanying fever in association with diarrhea

  • Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

 

Patient Population Studied

A phase 1 study involved 130 patients with locally advanced or metastatic, ALK-rearranged, cancer. The majority of patients (122; 94%) had advanced NSCLC. Eligible patients were aged ≥18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status score ≤2. A total of 59 patients underwent a dose-escalation phase. An additional 71 patients were then treated at the maximum tolerated dose (750 mg daily) determined in the dose-escalation phase

 

Efficacy (N = 122)

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Overall response rate 58%
Overall response rate for patients who received 750 mg daily 59%

Overall response rate is the percentage of patients who experienced a confirmed partial or complete response to the study drug

Note: Results are shown for the patients with advanced NSCLC. Of the 8 patients who had other types of advanced cancer, 2 had a response to the study drug

 

Therapy Monitoring

  1. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, or fluid replacement, as indicated

  2. Monitor with liver laboratory tests including ALT, AST, and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations

  3. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis

  4. Obtain an ECG and evaluate electrolytes at baseline. Conduct periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval.

  5. Monitor fasting serum glucose prior to the start of ceritinib treatment and periodically thereafter as clinically indicated

  6. Monitor lipase and amylase prior to the start of ceritinib treatment and periodically thereafter as clinically indicated

 

Treatment Modifications

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Starting dose = 450 mg once daily with food

Dose levels 450 mg / 300 mg / 150 mg

Adverse Event Treatment Modification
≥G3 ALT or AST elevation (>5× ULN) + total bilirubin ≤2× ULN Withhold ceritinib until recovery to baseline or ALT and AST ≤3× ULN, then resume ceritinib but reduce the dose by 150 mg
≥G2 ALT or AST elevation [>3× ULN] + total bilirubin >2× ULN Permanently discontinue ceritinib
Any grade treatment-related ILD/pneumonitis Permanently discontinue ceritinib
Severe or intolerable nausea, vomiting or diarrhea despite optimal antiemetic or antidiarrheal therapy Withhold until improved, then resume ceritinib but reduce the dose by 150 mg
Persistent hyperglycemia >250 mg/dL despite optimal antihyperglycemic therapy Withhold ceritinib until hyperglycemia is adequately controlled, then resume ceritinib but reduce the dose by 150 mg. If adequate hyperglycemic control cannot be achieved with optimal medical management, discontinue ceritinib
G3 lipase or amylase elevation [>2× ULN] Withhold ceritinib and monitor serum lipase and amylase. After recovery to <1.5× ULN resume ceritinib but reduce the dose by 150 mg
Concomitant use of a strong CYP3A inhibitor is unavoidable Reduce the ceritinib dose by ∼1/3, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ceritinib dose taken prior to initiating the strong CYP3A4 inhibitor
Dose adjustments for cardiac adverse events
QTc interval >500 msec on ≥2 separate ECGs Withhold ceritinib until QTc interval <481 msec or recovery to baseline if baseline QTc ≥481 msec, then resume ceritinib but reduce the dose by 150 mg
QTc interval prolongation in combination with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Permanently discontinue ceritinib
Symptomatic bradycardia that is not life-threatening Withhold ceritinib until recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm. Evaluate concomitant medications known to cause bradycardia. Resume ceritinib but reduce the dose by 150 mg
Clinically significant bradycardia requiring intervention or life-threatening bradycardia in patients taking a concomitant medication also known to cause bradycardia or a medication known to cause hypotension Withhold ceritinib until recovery to asymptomatic bradycardia or to a heart rate ≥60 bpm. If the concomitant medication can be adjusted or discontinued then resume ceritinib but reduce the dose by 150 mg
Life-threatening bradycardia in patients who are not taking a concomitant medication also known to cause bradycardia or known to cause hypotension Permanently discontinue ceritinib

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; ILD, interstitial lung disease; ULN, upper limit of normal

 

Notes:

  • Advise the use of effective contraception during treatment with ceritinib and for at least 2 weeks following completion of therapy

  • Ceritinib is eliminated primarily via the liver and drug exposure may be increased in patients with hepatic impairment. Patients with mild hepatic impairment do not require dose adjustments. A recommended dose for patients with moderate to severe hepatic impairment has not been determined

  • No dose adjustment is recommended for patients with mild or moderate renal impairment. The safety of alectinib in patients with creatinine clearance <30 mL/min has not been studied

 

Adverse Events (N = 130)

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Grade 3/4 (%)
Any event 49
Elevated ALT level 21
Elevated AST level 11
Elevated lipase level 7
Diarrhea 7
Nausea 5
Vomiting 5
Fatigue 5
Hypophosphatemia 3
Elevated amylase level 2
Elevated blood alkaline phosphatase level 2
Hyperglycemia 2

According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0

Notes: Only events reported in ≥2% and suspected to be related to the study drug are included in this table. All events were reversible on discontinuation of ceritinib treatment. Four cases of interstitial lung disease and 1 case of asymptomatic grade 3 prolongation of the QT interval were thought to possibly be related to ceritinib treatment. Dose reduction was required in 51% of patients, and permanent discontinuation of the study drug owing to an adverse event occurred in 6% of patients. Of the patients receiving the maximum tolerated dose of 750 mg daily, 62% required dose reduction. No treatment-related deaths occurred.

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