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ceritinib
Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor. It inhibits autophosphorylation of ALK and ALK-mediated phosphorylation of downstream cell signaling and proliferation of ALK-dependent cancer cells. It also inhibits insulin-like growth factor 1 receptor (IGF-IR), insulin receptor (INSR), and ROS1.
| Bioavailability |
Not determined. AUC and Cmax increased dose proportionally over 50 to 750 mg (fasted). |
| Peak plasma levels |
Cmax: 4 to 6 hours (fasted). |
| Effects with food |
750 mg dosing: Exposure increased with a high-fat meal (AUC 58%). No clinically significant difference observed in steady state exposure between 450 mg dosing with food vs 750 mg fasted dosing. |
Slight preferential distribution to RBCs relative to plasma.
| PPB |
97% |
| Cross blood brain barrier? |
Yes (animals) |
| Inactive metabolites |
Yes |
| Feces |
91%; 68% as unchanged drug |
| Urine |
1.3% |
| Half-life |
Terminal: 41 hours |
- Non-small cell lung cancer (NSCLC).
(Includes conditional approvals)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following related adverse effects were reported in ≥ 1% of patients receiving ceritinib in the open-label Phase III study in previously untreated ALK-positive locally advanced or metastatic NSCLC (750 mg daily, fasting). Severe adverse effects from other studies or post-marketing are also included. The overall safety profile of ceritinib at the recommended dose of 450 mg with food was consistent with ceritinib 750 mg fasted, except for a reduction in gastrointestinal adverse drug reactions.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Atrial fibrillation (maybe severe) | E | |||
| Bradycardia (3%) | E | ||||
| Pericarditis (4%) | E | ||||
| QT interval prolonged (11%) (maybe severe) | E | ||||
| Venous thromboembolism (1%) | E | ||||
| Dermatological | Rash (20%) | E | |||
| Gastrointestinal | Abdominal pain (40%) (4% severe) | E | |||
| Anorexia, weight loss (34%) | E | ||||
| Constipation (19%) | E | ||||
| Diarrhea (85%) (5% severe) | E | ||||
| Nausea, vomiting (69%) (5% severe) | E | ||||
| General | Fatigue (44%) (7% severe) | E | |||
| Hematological | Anemia (15%) | E | |||
| Hepatobiliary | ↑ Amylase / lipase (10%) (pancreatitis rare) | E | |||
| ↑ LFTs (69%) (50% severe) | E | ||||
| Metabolic / Endocrine | Hyperglycemia (11%) (6% severe) | E | |||
| ↓ PO4 (4%) | E | ||||
| Musculoskeletal | Musculoskeletal pain (19%) | E | |||
| Ophthalmic | Visual disorders (4%) | E | |||
| Renal | Creatinine increased (22%) (2% severe) | E | |||
| Respiratory | Pneumonitis (2%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for ceritinib include diarrhea, ↑ LFTs, nausea, vomiting, fatigue, abdominal pain, anorexia, weight loss, creatinine increased, rash, constipation and musculoskeletal pain.
Ceritinib produces concentration-dependent increases in QTc that may cause serious ventricular arrhythmias, including Torsades de Pointes. Symptomatic bradycardia has been reported; heart rate of < 50 beats/minute has occurred.
As compared to the 750 mg daily (fasted) dosing, the incidence and severity of GI toxicity appeared to be lower in a clinical study that used ceritinib 450 mg daily with food (e.g. diarrhea 76% vs 56%; nausea 50% vs 45%, vomiting 56% vs 35%; severe 12% vs 1%).
Although rare, pancreatitis (with fatality) has been reported.
Hyperglycemia has been reported and may be severe. Risk is higher in patients with diabetes and/or concurrent steroid use.
Severe interstitial lung disease (ILD)/pneumonitis including grade 3 or 4 events and fatalities has been reported.
Refer to protocol by which 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.
450 mg Orally Daily with food
| 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:
|
|
|
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 |
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). |
|
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. |
No overall differences in efficacy were observed between patients ≥ 65 years and younger patients.
Safety and efficacy has not been established in pediatric patients.
-
Administer ceritinib at the same time each day with food. Food can range from a snack to a full meal.
-
Capsules should be swallowed whole with water and not be chewed or crushed.
-
Avoid grapefruit or grapefruit juice 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
-
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
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).
Other Drug Properties:
-
Carcinogenicity:
Unknown
Carcinogenicity studies have not been performed.
-
Clastogenicity:
No
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
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.
-
Genotoxicity:
Yes
-
Mutagenicity:
No
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended.
-
Fertility effects:
Unknown
Ceritinib is primarily metabolized by CYP3A, may inhibit CYP3A, CYP2C9, CYP2A6 and CYP2E1.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of prolonged QT and Torsades de Pointes | additive | Avoid concomitant use with QT prolonging agents if possible; closely monitor QT |
| Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids) | ↑ risk of prolonged QT | additive | Caution; closely monitor electrolytes |
| Drugs that lower heart rate (i.e. beta blockers, calcium channel blockers, digoxin) | ↑ risk of bradycardia | additive | Avoid co-administration with agents that lower heart rate if possible; closely monitor HR |
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ ceritinib concentration and/or toxicity (co-admin with ketoconazole ↑ ceritinib AUC 2.9 fold) | ↓ metabolism of ceritinib | Avoid strong CYP3A4 inhibitors. If unavoidable, consider ceritinib dose reduction. Caution with concomitant use of moderate CYP3A4 inhibitors. Monitor for adverse reactions. |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ ceritinib concentration and/or efficacy (co-admin with rifampin ↓ ceritinib AUC by 70%) | ↑ metabolism of ceritinib | Avoid strong CYP3A4 inducers |
| P-glycoprotein inhibitors (i.e. quinidine, verapamil, cyclosporine) | ↑ ceritinib concentration and/or toxicity | inhibits drug efflux (in vitro data) | Caution and monitor with strong P-gp inhibitors |
| P-glycoprotein inducers (i.e. dexamethasone, rifampin) | ↓ ceritinib concentration and/or efficacy | promotes drug efflux (in vitro data) | Caution and monitor with strong P-gp inducers |
| CYP3A4 substrates (e.g. midazolam, cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↑ substrate concentration and/or toxicity. (midazolam AUC ↑ 5.4x with co-admin) | ceritinib may inhibit CYP3A (in vitro data) | Avoid co-administration with substrates that have narrow therapeutic indices. If unavoidable, consider substrate dose reduction. |
| CYP 2C9 substrates (e.g. warfarin, meloxicam, fluvastatin) | ↑ substrate concentration and/or toxicity | ceritinib may inhibit CYP2C9 (in vitro data) | Avoid co-administration with substrates that have narrow therapeutic indices. If unavoidable, consider substrate dose reduction. Increase INR monitoring with warfarin if concurrent use cannot be avoided. |
| CYP2A6 substrates (e.g. valproic acid, letrozole, disulfiram) | ↑ substrate concentration and/or toxicity | ceritinib may inhibit CYP2A6 (in vitro data) | Caution with concomitant use of CYP2A6 substrates; monitor for adverse reactions. |
| CYP2E1 substrates (e.g. ethanol, acetaminophen) | ↑ substrate concentration and/or toxicity | ceritinib may inhibit CYP2E1 (in vitro data) | Caution with concomitant use of CYP2E1 substrates; monitor for adverse reactions. |
| Drugs that reduce gastric acid (antacids, H2-receptor blockers, proton pump inhibitors) | ↓ ceritinib concentration, AUC, but no clinically significant changes in steady state exposure | ceritinib has pH dependent solubility (in vitro data) | If concurrent use necessary, give H2-blocker 10 hours before or 2 hours after ceritinib dose. Give antacids 2 hours before or 2 hours after ceritinib dose. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and monthly thereafter; more frequently in patients that develop liver enzyme elevations during treatment |
Lipase, amylase |
Baseline and as clinically indicated; more frequently if abnormal or symptoms of pancreatitis |
ECG |
Baseline and as clinically indicated; more frequent in patients at risk for QT prolongation |
Blood glucose |
Baseline and as clinically indicated; more frequent if diabetic |
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
Exceptional Access Program (EAP Website)
- 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
Ceritinib product monograph, Novartis Pharmaceuticals Canada Inc. January 2020.
Ceritinib prescribing information. Novartis Pharmaceuticals Corp. (USA). August 2021.
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 Sep;12(9):1357-67.
Shaw AT, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Jun 26;370(26):2537-9.
November 2021 Modified Indications, Administration guidelines and Interactions sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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