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CERI

Cancer Type: Lung, Non-Small Cell  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    ceritinib - Second-line monotherapy of ALK-positive locally advanced (not amenable to curative therapy) or metastatic NSCLC, in patients who have experienced disease progression or intolerance to crizotinib, according to specific criteria
A - Regimen Name

CERI Regimen
ceritinib


Disease Site
Lung - Non-Small Cell

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

Monotherapy for the treatment of patients with ALK-positive locally advanced (not amenable to curative therapy) or metastatic NSCLC who have progressed on, or were intolerant to crizotinib.


Supplementary Public Funding

ceritinib
Exceptional Access Program (ceritinib - Second-line monotherapy of ALK-positive locally advanced (not amenable to curative therapy) or metastatic NSCLC, in patients who have experienced disease progression or intolerance to crizotinib, according to specific criteria)

 
B - Drug Regimen

ceritinib
450 mg PO Daily

(outpatient prescription as 150 mg capsules)

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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate – Consider prophylaxis daily

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

A supply of loperamide should be provided for diarrhea.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated.

Electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia) should be corrected prior to starting treatment.

Patients must have documented ALK-positive status based on a validated ALK assay.

Dosage with toxicity

Dose level Ceritinib dose (mg/day)
0 450
-1 300
-2 150
-3 Discontinue

 

Toxicity

Severity

Ceritinib Dose

Nausea, vomiting or diarrhea

Grade 3 or intolerable, despite optimal antiemetic and antidiarrheal therapy.

Hold until improved, restart at ↓ 1 dose level.

Hyperglycemia (> 250 mg/dL or 14 mmol/L)

Persistent hyperglycemia despite optimal anti-hyperglycemic therapy.

Hold until controlled, restart at ↓ 1 dose level.

Discontinue if adequate control cannot be achieved with optimal medical management.

Bradycardia (HR < 60 bpm)

Symptomatic, non-life-threatening

Hold until asymptomatic or heart rate ≥ 60 bpm.

If medication(s) contributing to bradycardia/hypotension is discontinued or dose adjusted, restart ceritinib at same dose.

If no contributing medication(s) is identified or cannot be discontinued/dose adjusted, restart ceritinib at ↓ 1 dose level.

Life-threatening

Hold until asymptomatic or heart rate ≥ 60 bpm.

If medication(s) contributing to bradycardia/hypotension is discontinued or dose adjusted, restart ceritinib at ↓ 1 dose level.

Discontinue permanently:

  • If potentiating medications cannot be identified and discontinued
  • For recurrence

Prolonged QTcF

> 500 msec on at least 2 separate ECGs

Hold until baseline or < 481 msec, restart at ↓ 1 dose level.

Torsades de pointes or polymorphic ventricular tachycardia or signs and symptoms of other serious arrhythmia

Discontinue.

Elevated LFTs

AST or ALT > 5 x ULN AND total bilirubin ≤ 1.5 x ULN

Hold until baseline or ≤ 3 x ULN, restart at ↓ 1 dose level.

AST or ALT > 3 x ULN AND total bilirubin > 2 x ULN (without cholestasis or hemolysis)

Discontinue.

Elevated lipase or amylase

> 2 x ULN

Hold until ≤ 1.5 x ULN, restart at ↓ 1 dose level if pancreatitis is ruled out.

If pancreatitis is confirmed, discontinue and manage appropriately.

Suspected ILD/pneumonitis

Any grade

Hold and investigate; discontinue if confirmed.



Hepatic Impairment

Hepatic Impairment

Ceritinib Dose

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).


Renal Impairment

Creatinine Clearance

Ceritinib Dose

≥ 30 to 90 mL/minute

No dosage adjustment necessary.

< 30 mL/minute; patients on dialysis

Use with caution; No data available.


Dosage in the Elderly

No overall differences in efficacy were observed between patients ≥ 65 years and younger patients.


 
F - Adverse Effects

Refer to ceritinib drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Diarrhea (maybe severe)

  • Nausea, vomiting

  • ↑ LFTs (maybe severe)

  • Fatigue

  • Abdominal pain

  • Anorexia, weight loss

  • Creatinine increased (maybe severe)

  • Rash

  • Constipation

  • Musculoskeletal pain

  • Anemia

  • QT interval prolonged

  • Hyperglycemia (maybe severe)

  • ↑Amylase / lipase (maybe severe)

  • Pericarditis

  • Bradycardia

  • Venous thromboembolism

  • Atrial fibrillation

  • ↓ PO4

  • Visual disorders

  • Pneumonitis

 
G - Interactions

Refer to ceritinib drug monograph(s) for additional details


  • Avoid concomitant use with QT prolonging agents if possible; closely monitor QT.

  • Avoid co-administration with agents that lower heart rate if possible; closely monitor HR.

  • Avoid strong CYP3A4 inhibitors; consider ceritinib dose adjustment.

  • Avoid strong CYP3A4 inducers.

  • Avoid co-administration with CYP3A4, CYP2C9, CYP2A6 or CYP2E1 substrates that have narrow therapeutic indices.

  • Avoid concomitant use with drugs that reduce gastric acid (antacids, H2-receptor blockers, proton pump inhibitors) if possible. If concurrent use is necessary, give H2-blocker 10 hours before or 2 hours after ceritinib dose. Give antacids 2 hours before or 2 hours after ceritinib dose.

 
H - Drug Administration and Special Precautions

Refer to ceritinib drug monograph(s) for additional details


Administration

  • Administer ceritinib (450 mg and dose reductions) at the same time each day with food. Food can range from a snack to a full meal. (Ceritinib was previously recommended to be given at a higher dose on an empty stomach).

  • Capsules should be swallowed whole with water and not be chewed or crushed.

  • Avoid fruit or juice from grapefruit, Seville oranges or starfruit as they may inhibit CYP3A in the gut wall and may increase the bioavailability of ceritinib.

  • If a dose is missed it may be taken as soon as possible, unless the next dose is due within 12 hours.

  • If vomiting occurs after taking the dose, do not take a replacement dose. Continue with the next scheduled dose.

  • Store at room temperature, between 15oC to 30oC
     



Contraindications

  • Patients who have a hypersensitivity to this drug or any of its components

  • Patients with congenital long QT syndrome or with a persistent QTcF > 500 msec
     

 

Warnings/Precautions

Not recommended for use in:

  • ALK-negative patients

  • Patients who are taking medications known for QT prolongation
     

Use with caution in:

  • Patients who are at risk of prolonged QT (electrolyte imbalances, cardiovascular disease, diabetes, autonomic neuropathy, females, older patients).

  • Patients with baseline bradycardia (HR < 60 bpm), history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular block, ischemic heart disease or congestive heart failure, or taking agents known to cause bradycardia or hypotension.

  • Patients with severe renal impairment requiring peritoneal dialysis or hemodialysis (ceritinib has not been studied in these patients).
     

 

Pregnancy and Lactation

  • Ceritinib is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose.

  • Breastfeeding is not recommended.

  • Fertility effects: Unknown

 

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

 

Recommended Clinical Monitoring

  • ECG; Baseline and as clinically indicated; more frequent in patients at risk for QT prolongation

  • Fasting blood glucose; Baseline and as clinically indicated; more frequent if diabetic

  • Lipase, amylase; Baseline and as clinically indicated; more frequently if abnormal or symptoms of pancreatitis

  • Liver function tests; Baseline and monthly thereafter; more frequently in patients that develop liver enzyme elevations during treatment

  • Renal function tests and electrolytes; Baseline and as clinically indicated

  • Clinical toxicity assessment for gastrointestinal, skin, cardiac (blood pressure and heart rate), and respiratory toxicity; At each visit

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Ceritinib drug monograph, Cancer Care Ontario.

Shaw AT, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Jun 26;370(26):2537-9.


August 2019 Updated Adverse Effects and Dosing, Administration and Monitoring sections and emetic risk category.


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.