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crizotinib
Crizotinib is a selective inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (including oncogenic variants). It also demonstrated activity as an inhibitor of the Hepatocyte Growth Factor Receptor.
| Bioavailability | 43% (range 32%-66%) |
| Effects with food | High-fat meal ↓ bioavailability by 14% (single dose) |
| Time to reach steady state | 15 days |
| Peak plasma levels |
4 hours (range: 2 - 9.33 hours) |
Extensively distributed into tissues
| PPB | 91% (independent of drug concentration) |
| Distribution Sites |
Extensively distributed to liver, uveal tract, adrenal gland, small intestine and pituitary gland.
|
| Active metabolites |
Yes |
| Inactive metabolites |
Yes |
Reduced clearance at steady state may be due to CYP3A autoinhibition by repeated crizotinib dosing.
| Half-life |
42 hours |
| Urine | 22% of dose (2.3% unchanged) |
| Feces | 63% of dose (53% unchanged) |
- Monotherapy for treatment of locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive.
- Monotherapy for treatment of patients with ROS1-positive locally advanced (not amenable to curative therapy) or metastatic NSCLC.
Notes:
- ALK or ROS1 positivity should be determined using a validated test.
- Approval for ROS1-positive NSCLC was based on objective response rate and duration of response in a small single-arm study.
- An overall survival benefit has not been demonstrated with crizotinib.
Emetogenic Potential:
The following adverse events are from a phase III study in previously untreated ALK-positive patients; life-threatening effects are included from other studies.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arterial thromboembolism (rare) | E | |||
| Bradycardia (14%) | I E | ||||
| Hypotension (5%) | E | ||||
| QT interval prolonged (6%) | E | ||||
| Venous thromboembolism (4%) | E | ||||
| Dermatological | Rash (11%) | E D | |||
| Gastrointestinal | Abdominal pain (26%) | E | |||
| Anorexia (30%) | E D | ||||
| Constipation (43%) (2% severe) | E | ||||
| Diarrhea (61%) (2% severe) | E | ||||
| Dyspepsia (14%) | E | ||||
| Dysphagia (10%) | E | ||||
| Mucositis (6%) | E | ||||
| Nausea, vomiting (56%) (2% severe) | E | ||||
| General | Edema (49%) (<1% severe) | E | |||
| Fatigue (29%) | E | ||||
| Fever (19%) | E | ||||
| Hematological | Disseminated intravascular coagulation (rare) | E | |||
| Hemorrhage (CNS; rare) | E | ||||
| Myelosuppression ± infection (21%) (11% severe) | E | ||||
| Hepatobiliary | ↑ LFTs (36%) (14% severe) | E | |||
| Infection | Infection (32%) (URTI) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (5%) (↓ K, ↓Na; severe) | E | |||
| Musculoskeletal | Musculoskeletal pain (16%) | E | |||
| Nervous System | Dizziness (18%) | E | |||
| Dysgeusia (26%) | E | ||||
| Neuropathy (21%) | E D | ||||
| Syncope (<1%) | E | ||||
| Ophthalmic | Visual disorders (71%) (1% severe ) | E D | |||
| Renal | Creatinine increased (5%) (may be severe) | E D | |||
| Other (5%) Renal cyst | E D | ||||
| Respiratory | Cough, dyspnea (18%) (may be severe) | E | |||
| Pneumonitis (1%) | D | ||||
* "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 crizotinib include visual disorders, diarrhea, nausea, vomiting, edema, constipation, ↑ LFTs, infection, anorexia, fatigue and abdominal pain.
Increased cardiovascular side effects such as bradycardia (which may occur several weeks after the start of therapy), QTc prolongation and hypotension were reported. Crizotinib should be used with caution in patients with increased QTc or at risk of bradycardia.
Visual disorders including diplopia, photopsia, blurred vision, vitreous floaters and general visual impairment have been reported and are usually mild in nature, but may result in severe visual loss with optic nerve atrophy. Ophthalmological evaluation is required if vision disorder persists or worsens. The onset of vision disorder was generally reported within the first week of drug administration. Discontinue crizotinib with new onset severe visual loss.
Gastrointestinal events including nausea, diarrhea, vomiting and constipation were most commonly reported but mild in nature and responded to supportive care (antiemetic and/or antidiarrheal and/or laxative medications), dose interruption or reduction. Median times to onset for diarrhea and constipation were 13 and 17 days, respectively.
CNS hemorrhage has been reported in pediatric patients with intracranial disease.
Fatalities due to crizotinib-induced hepatotoxicity have occurred rarely. Transaminase elevation onset was generally reported within 2 months of treatment initiation. Less than 1% of patients had concurrent elevations in ALT and/or AST ≥3 x ULN and total bilirubin ≥2 x ULN without significant elevations of alkaline phosphatase.
Severe or life-threatening pneumonitis was reported across clinical trials. Cases generally occurred within 3 months of starting therapy. Crizotinib should be discontinued if pneumonitis is confirmed.
Renal cysts have been reported, but are of uncertain clinical significance.
Use only in patients with known ALK-positive or ROS1-positive NSCLC confirmed using a validated assay.
Avoid using concomitantly with strong CYP3A4 inducers/inhibitors, or CYP3A4 substrates with narrow therapeutic indices and associated with severe arrhythmias.
Electrolyte abnormalities should be corrected prior to initiating treatment.
until disease progression or unacceptable toxicity
| Dose Level | Crizotinib Dose |
| 0 | 250mg twice daily |
| -1 | 200mg twice daily |
| -2 | 250 mg once daily |
| -3 | Discontinue |
|
Toxicity
|
Action
|
|
Grade 3 hematologic
|
Hold until recovery to ≤ grade 2; resume at same dose
|
|
Grade 4 hematologic
|
Hold until recovery to ≤ grade 2; resume at ↓ 1 dose level
|
|
Grade 3 or 4 AST/ALT WITH ≤ grade 1 bilirubin |
Hold until recovery to ≤ grade 1 or baseline; resume at ↓ 1 dose level |
| Bilirubin ≥ grade 2 and AST/ALT ≥ grade 2 (in the absence of cholestasis or hemolysis) | Discontinue |
|
QTc ≥ 500 msec without arrhythmia
|
Hold until ≤ 470 msec and correct electrolyte abnormalities; resume at ↓ 1 dose level |
| QTc ≥ 500 msec (or > 60 msec change from baseline) and Torsade de Pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmias | Discontinue |
|
Grade 2 or 3 bradycardia
(< 60 bpm; symptomatic, may be severe and medically significant, medical intervention indicated) |
Hold until recovery to ≤ grade 1* Evaluate contributing medications: If contributing concomitant medication is identified and is adjusted or discontinued, resume at same dose If there is no contributing concomitant medication or if concomitant medications are not adjusted/ discontinued, resume at ↓ 1 dose level |
|
Grade 4 bradycardia
(life-threatening consequences, urgent intervention indicated) |
Hold immediately Evaluate contributing medications: If contributing concomitant medication is identified and adjusted or discontinued, resume* at 250 mg once daily and monitor If no contributing concomitant medication identified, discontinue Discontinue with recurrence |
|
Signs or symptoms of pneumonitis / interstitial lung disease
|
Hold and investigate; discontinue permanently if confirmed |
| Severe visual loss (best corrected vision < 20/200 in one or both eyes) |
Discontinue and evaluate severe vision loss No data to support resuming; risk benefit must be assessed |
*Do not restart until heart rate ≥ 60 bpm and asymptomatic
| Hepatic Impairment | Crizotinib Starting dose |
| Mild | No dose adjustment necessary |
| Moderate (total bilirubin >1.5 to ≤3 x ULN and any AST) | 200 mg twice daily |
| Severe (total bilirubin >3 x ULN and any AST) | 250 mg once daily |
|
Renal Impairment
|
Crizotinib Starting Dose |
|
Mild or moderate
|
No dose adjustment necessary
|
|
Severe (CrCl < 30 mL/min) not requiring peritoneal dialysis or hemodialysis
|
250 mg once daily
|
|
Severe requiring peritoneal dialysis or hemodialysis
|
No data
|
There were no overall differences in safety or efficacy between patients aged 65 or older and younger patients and dosage adjustment is not required. However, edema, constipation, dysgeusia and nausea were reported more frequently in older patients.
Although exposure is higher in Asian patients, there is no increase in incidence of Grade 3 or 4 adverse events.
The safety and efficacy of crizotinib have not been established in the pediatric population. Effects on growth are likely. CNS hemorrhage was reported in pediatric trials.
-
Swallow capsules whole with a glass of water. Do not crush, dissolve, or open capsules.
-
Administer crizotinib with or without food.
-
Avoid grapefruit, starfruit, Seville oranges, their juices or products during crizotinib treatment
-
If a dose is missed, patient may take within 6 hours of missed dose. If more than 6 hours, the dose should be skipped and taken at the next planned time.
-
Store at room temperature and away from children or pets.
- Patients with congenital long QT syndrome or persistent QTcF ≥ 500 msec.
- Patients who have a hypersensitivity to this drug or any of its components.
-
Use with caution in patients who are at risk of QT prolongation or bradycardia (low potassium/magnesium, congenital QT prolongation, CHF, anti-arrhythmics, other QTc prolonging agents, prior anthracyclines, AV block, sick sinus, sinoatrial block or drugs leading to bradycardia etc.).
-
Use with caution in patients who have bradycardia at baseline (< 60 bpm), and in patients with cardiac disease, history of arrhythmias or who are on medications that may reduce heart rate.
-
Caution with driving or using machinery due to vision disorder including diplopia, photopsia, blurred vision, visual impairment and vitreous floaters.
-
Caution in patients with a history of thrombotic events. Crizotinib has not been studied in patients who have had arterial thromboembolism or CHF within the last 3 months.
-
Exercise caution in patients with hepatic impairment or severe renal impairment requiring dialysis.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
Documented in animals
-
Fetotoxicity:
Documented in animals
-
Teratogenicity:
No
-
Fertility effects:
Probable
Crizotinib 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:
Not recommended
Crizotinib is metabolized via CYP3A4/5 and is susceptible to drug interactions with CYP3A4 inhibitors and inducers, which may be clinically relevant. The drug is a moderate inhibitor of CYP3A4 and also inhibits P-gp, CYP2B6, UGT and OCT in vitro (theoretical interaction potential).
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP3A4 inhibitors (i.e. ketoconazole, voriconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges, starfruit or pomegranate ) | ↑ crizotinib concentration and/or toxicity (up to 3.2-fold ↑ in exposure) | ↓ metabolism of crizotinib | Avoid with strong CYP3A inhibitors; caution with moderate inhibitors |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ crizotinib concentration and/or efficacy (up to 82% ↓ in exposure) | ↑ metabolism of crizotinib | Avoid with strong CYP3A inducers; caution with moderate inducers |
| Drugs that raise gastric pH (e.g. antacid, proton pump inhibitor, H2-receptor antagonist) | ↓ bioavailability of crizotinib | ↓ solubility of crizotinib | Caution; dose adjustment not required |
| CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↑ CYP3A4 substrate concentration and/or toxicity | ↓ metabolism of CYP3A4 substrate | Avoid substrates with narrow therapeutic index and associated with severe arrhythmias (dihydroergotamine, ergotamine and pimozide); caution with other CYP3A4 substrates |
| P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) | Potentially ↑ P-gp substrate concentration and/or toxicity | ↓ metabolism of P-gp substrate (in vitro) | Caution |
| CYP 2B6 substrates (i.e. bupropion, cyclophosphamide, selegiline) | Potentially ↑ CYP2B6 substrate concentration and/or toxicity | ↓ metabolism of CYP2B6 substrates (in vitro) | Caution |
| Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids) | ↑ risk of life-threatening arrhythmias | Avoid where possible | |
| Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of life-threatening arrhythmias | Additive | Avoid where possible |
| Drugs that decrease heart rate (e.g. antiarrhythmics, beta blockers, non-dihydropyridine Ca channel blockers, cholinesterase inhibitors, sphingosine-1 phosphate receptor modulators) | ↑ risk of bradycardia | Additive | Avoid where possible |
| UGT substrates (e.g. raltegravir, irinotecan, morphine, naloxone) | Potentially ↑ substrate concentration and/or toxicity | ↓ metabolism of UGT substrates (in vitro) | Caution |
| OCT substrates (e.g. metformin) | Potentially ↑ substrate concentration and/or toxicity | ↓ metabolism of OCT substrates (in vitro) | Caution |
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 |
|---|---|
CBC |
baseline and at each visit; more frequent if severe myelosuppression, fever and/or infection |
| Liver function tests | baseline, every 2 weeks during the first 2 months, then monthly and as clinically indicated (more frequent with hepatotoxicity) |
Creatinine, electrolytes, including calcium, potassium and magnesium |
baseline and as clinically indicated |
ECG, heart rate and blood pressure |
baseline and as clinically indicated |
Renal imaging and urinalysis if renal cysts develop |
As clinically indicated |
Ophthalmoscopy and assessment of visual loss |
As clinically indicated |
Clinical toxicity assessment for signs of bleeding or infection and GI, ocular, hepatic, cardiac and nervous system effects, pneumonitis and venous thromboembolism |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
MUGA, especially for patients with cardiac risk factors |
baseline and as clinically indicated |
Exceptional Access Program (EAP Website)
- crizotinib - First or second-line treatment for ALK-positive advanced NSCLC, according to specific criteria
- crizotinib - First-line treatment for ROS1-positive locally advanced (not amenable to curative therapy) or metastatic NSCLC, according to specific criteria
Kwak E, Bang Y, Camidge DR, Shaw, Solomon B. Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer. NEJM 2010;363:1693-703.
Product Monograph: Xalkori® (crizotinib). Pfizer Canada Inc, January 21, 2019.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013 Jun 20;368(25):2385-94.
December 2020 Updated Supplementary Public Funding section
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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