Crizotinib – Uses, Dosage, Side Effects, Interaction

Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist
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Crizotinib is an orally available aminopyridine-based inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and the c-Met/hepatocyte growth factor receptor (HGFR) with antineoplastic activity. Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK dysregulation and gene rearrangements are associated with a series of tumors.

Crizotinib is a selective tyrosine kinase receptor inhibitor used in the therapy of selected cases of advanced non-small cell lung cancer. Crizotinib is associated with transient elevations in serum aminotransferase levels during treatment and rare instances of clinically apparent acute liver injury that can be severe and even fatal.

Crizotinib is a 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidine-4-yl)pyrazol-4-yl]pyridin-2-amine that has R configuration at the chiral centre. The active enantiomer acts as a kinase inhibitor and is used for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) It has a role as an antineoplastic agent, a biomarker and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It is an enantiomer of an ent-crizotinib.

Mechanism of Action

Crizotinib is a tyrosine kinase receptor inhibitor. More specifically, it inhibits anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), and Recepteur d’Origine Nantais (RON). Abnormalities in the ALK gene caused by mutations or translocations may lead to the expression of oncogenic fusion proteins. In patients with NSCLC, they have the EML4-ALK gene. Crizotinib inhibits ALK tyrosine kinase which ultimately results in decreased proliferation of cells that carry the genetic mutation and tumor survivability.

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. About 4% of patients with non-small cell lung carcinoma have a chromosomal rearrangement that generates a fusion gene between EML4 (‘echinoderm microtubule-associated protein-like 4’) and ALK (‘anaplastic lymphoma kinase’), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype.[rx] The kinase activity of the fusion protein is inhibited by crizotinib.[rx] Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-Ras gene. The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[rx][rx]ALK mutations are thought to be important in driving the malignant phenotype in about 15% of cases of neuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.[rx]

Crizotinib inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.[rx] Crizotinib is thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[rx][rx] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.[rx]

Indications

  • Crizotinib is used for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic-lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
  • Crizotinib is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test.[rx] Crizotinib is also indicated for the treatment of relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive in pediatric patients 1 year of age and older and young adults. The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.[rx] Additionally, crizotinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive.[rx]
  • Xalkori is indicated for the first-line treatment of adults with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC).
  • Xalkori is indicated for the treatment of adults with previously treated anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC).
  • Treatment of lung malignant neoplasms
  • Treatment of anaplastic large cell lymphoma, Treatment of inflammatory myofibroblastic tumors
  • Metastatic Non-Small Cell Lung Cancer
  • Refractory Anaplastic Large Cell Lymphoma
  • Recurrent Inflammatory Myofibroblastic Tumors
  • Refractory Inflammatory Myofibroblastic Tumors
  • Relapsed Anaplastic Large Cell Lymphoma
  • Unresectable Inflammatory Myofibroblastic Tumors

Use in Cancer

Crizotinib is approved to treat:

Crizotinib is also being studied in the treatment of other types of cancer.

Contraindications

  • low amount of magnesium in the blood
  • low amount of potassium in the blood
  • anemia
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • a decreased number of lymphocytes in the blood
  • a painful condition that affects the nerves in the legs and arms called peripheral neuropathy
  • torsades de pointes, a type of abnormal heart rhythm
  • slow heartbeat
  • prolonged QT interval on EKG
  • chronic heart failure
  • abnormal EKG with QT changes from birth
  • a type of inflammation of the lung called interstitial pneumonitis
  • high amount of bilirubin in the blood
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • chronic kidney disease stage 4 (severe)
  • chronic kidney disease stage 5 (failure)
  • Child-Pugh class B liver impairment
  • Child-Pugh class C liver impairment

Dosage

Strengths: 250 mg; 200 mg

Non-Small Cell Lung Cancer

  • 250 mg orally twice a day
  • For the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test
  • Select patients for the treatment of metastatic NSCLC based on the presence of ALK or ROS1 positivity in tumor specimens.
  • Continue treatment until the disease progresses or has unacceptable toxicity.

Pediatric Dose for Lymphoma

  • 280 mg/m2 orally twice a day
  • For the treatment of pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive
  • The safety and efficacy of this drug have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.
  • The safety and effectiveness of this drug in combination with chemotherapy have not been established in patients with newly diagnosed ALCL.
  • Continue treatment until the disease progresses or has unacceptable toxicity.
  • The recommended dosage of this drug is based on body surface area.
  • It may be necessary to combine different strengths of the capsules to obtain the desired dose.
  • Antiemetics are recommended prior to and during treatment.
  • Provide antiemetic and antidiarrheal agents for gastrointestinal toxicities as appropriate.
  • Consider IV or oral hydration therapy for patients at risk of dehydration and administer electrolytes as clinically indicated.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (capsules):
    • For non-small cell lung cancer:
      • Adults—250 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed and tolerated.
      • Children—Use and dose must be determined by your doctor.
    • For systemic anaplastic large cell lymphoma:
      • Adults and children 1 year of age and older—Dose is based on body surface area (BSA) and must be determined by your doctor. The dose is usually 280 milligrams per square meter (mg/m[2]) of BSA, taken 2 times a day. Your doctor may adjust your dose as needed and tolerated.
        • BSA 1.70 meter squared (m2) or more—500 mg 2 times a day.
        • BSA 1.52 to 1.69 m2—450 mg 2 times a day.
        • BSA 1.17 to 1.51 m2—400 mg 2 times a day.
        • BSA 0.81 to 1.16 m2—250 mg 2 times a day.
        • BSA 0.60 to 0.80 m2—200 mg 2 times a day.
      • Children younger than 1 year of age—Use and dose must be determined by your doctor.
    • For inflammatory myofibroblastic tumor:
      • Adults—250 milligrams (mg) 2 times a day. Your doctor may adjust your dose as needed and tolerated.
      • Children 1 year of age and older—Dose is based on body surface area (BSA) and must be determined by your doctor. The dose is usually 280 milligrams per square meter (mg/m[2]) of BSA, taken 2 times a day. Your doctor may adjust your dose as needed and tolerated.
        • BSA 1.70 meter squared (m2) or more—500 mg 2 times a day.
        • BSA 1.52 to 1.69 m2—450 mg 2 times a day.
        • BSA 1.17 to 1.51 m2—400 mg 2 times a day.
        • BSA 0.81 to 1.16 m2—250 mg 2 times a day.
        • BSA 0.60 to 0.80 m2—200 mg 2 times a day.
      • Children younger than 1 year of age—Use and dose must be determined by your doctor.

Renal Dose Adjustments

Anaplastic Lymphoma Kinase (ALK) or ROS1-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC):

  • Mild or moderate renal dysfunction (CrCl 30 to 89 mL/min): No adjustment is recommended.
  • Severe renal dysfunction (CrCl less than 30 mL/min) not requiring dialysis: 250 mg orally once a day

Systemic Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma (ALCL):

  • Mild or moderate renal dysfunction (CrCl 30 to 89 mL/min): No adjustment is recommended.
  • Severe renal dysfunction (CrCl less than 30 mL/min) not requiring dialysis: Second dose reduction based on body surface area (BSA).

Liver Dose Adjustments

Anaplastic Lymphoma Kinase (ALK) or ROS1-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC):

  • Mild liver dysfunction (AST greater than upper limit of normal [ULN] and total bilirubin less than or equal to 1 times ULN or any AST and total bilirubin greater than 1 x ULN but less than or equal to 1.5 x ULN): No adjustment recommended.
  • Moderate liver dysfunction (any AST and total bilirubin greater than 1.5 x ULN and less than or equal to 3 x ULN): 200 mg orally twice a day
  • Severe liver dysfunction (any AST and total bilirubin greater than 3 x ULN): 250 mg orally once a day

Systemic Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma (ALCL):

  • Mild liver dysfunction (AST greater than upper limit of normal [ULN] and total bilirubin less than or equal to 1 times ULN or any AST and total bilirubin greater than 1 x ULN but less than or equal to 1.5 x ULN): No adjustment recommended.
  • Moderate liver dysfunction (any AST and total bilirubin greater than 1.5 x ULN and less than or equal to 3 x ULN): First dose reduction based on body surface area (BSA).
  • Severe liver dysfunction (any AST and total bilirubin greater than 3 x ULN): Second dose reduction based on BSA.

Dose Adjustments

Anaplastic Lymphoma Kinase (ALK) or ROS1-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC):

Dose modifications for adverse reactions:

  • First dose reduction: 200 mg orally twice a day
  • Second dose reduction: 250 mg orally once a day
  • Permanently discontinue therapy if unable to tolerate 250 mg orally once a day

DOSAGE MODIFICATION FOR HEMATOLOGIC TOXICITIES:

  • Grade 3: Withhold until recovery to Grade 2 or less, then resume at the same dose schedule.
  • Grade 4: Withhold until recovery to Grade 2 or less, then resume at the next lower dose.

DOSAGE MODIFICATION FOR NON-HEMATOLOGIC TOXICITIES:
HEPATOTOXICITY:

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN: Withhold therapy until recovery to baseline or less than or equal to 3 x ULN, then resume at next lower dosage.
  • ALT or AST elevation greater than 3 x ULN with concurrent total bilirubin elevation greater than 1.5 x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue therapy.

INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS:

  • Any grade drug-related ILD/pneumonitis: Permanently discontinue therapy.

QT PROLONGATION:

  • QTc greater than 500 ms on at least 2 separate ECGs: Withhold therapy until recovery to baseline or to a QTc less than 481 ms, then resume at the next lower dosage.
  • QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de Pointes, or polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia: Permanently discontinue therapy.

BRADYCARDIA:

  • Symptomatic may be severe and medically significant, medical intervention indicated: Withhold therapy until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above; if concomitant medication contributing to bradycardia is identified and it’s discontinued or dose adjusted, resume therapy at previous dose; if no contributing medication is identified or that medication is not discontinued or dose adjusted, resume therapy at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above.
  • Life-threatening, urgent intervention indicated: Permanently discontinue therapy if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued or its dose is adjusted, resume therapy at 250 mg once a day upon recovery to asymptomatic or to a heart rate of 60 bpm or grater with frequent monitoring. In case of recurrence, permanently discontinue therapy.

SEVERE VISION LOSS (GRADE 4 OCULAR DISORDER): Discontinue therapy during evaluation of severe vision loss.

Dosage Modification for Concomitant Use of Strong CYP450 3A Inhibitors:

  • Avoid concomitant use of strong CYP450 3A inhibitors; if concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg orally once daily.
  • After discontinuation of a strong CYP450 3A inhibitor, resume the crizotinib dose used prior to initiating the strong CYP450 3A inhibitor.

Systemic Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma (ALCL):
Recommended Dosage Based on Body Surface Area (BSA) and Dose Modification for ALCL Adverse Dose Reactions:

  • Less than 0.60 m2: Not established
    0.60 to 0.80 m2: 200 mg orally twice a day
  • First dose reduction: 250 mg once a day
  • Second dose reduction: Permanently discontinue

0.81 to 1.16 m2: 250 mg orally twice a day

  • First dose reductions: 200 mg twice a day
  • Second dose reduction: 250 mg once a day; permanently discontinue if unable to tolerate

1.17 to 1.51 m2: 400 mg orally twice a day

  • First dose reduction: 250 mg twice a day
  • Second dose reduction: 200 mg twice a day; permanently discontinue if unable to tolerate

1.52 to 1.69 m2: 450 mg orally twice a day

  • First dose reduction: 250 mg twice a day
  • Second dose reduction: 200 mg twice a day; permanently discontinue if unable to tolerate

1.70 m2 or greater: 500 mg orally twice a day

  • First dose reduction: 400 mg twice a day
  • Second dose reduction of 250 mg twice a day; permanently discontinue if unable to tolerate

DOSAGE MODIFICATION FOR HEMATOLOGIC ADVERSE REACTIONS:
ABSOLUTE NEUTROPHIL COUNT (ANC):
If less than 0.5 x 10(9)/L:

  • First occurrence: Withhold until recovery to ANC greater than 1 x 10(9)/L and resume at the next lower dosage.
  • Second occurrence: Permanently discontinue for recurrence complicated by febrile neutropenia or infection and if uncomplicated Grade 4 neutropenia, either permanently discontinue, or withhold until recovery to ANC greater than 1 x 10(9)/L and resume at the next lower dosage or may permanently discontinue if unable to tolerate.

PLATELET COUNT:

  • If 25 to 50 x 10(9)/L with bleeding: Withhold until recovery to platelet count greater than 50 x 10(9)/L and bleeding resolves; resume at the same dosage.
  • If less than 25 x 10(9)/L: Withhold until recovery to platelet count greater than 50 x 10(9)/L and resume at the next lower dosage; permanently discontinue for recurrence.

ANEMIA:

  • If hemoglobin is less than 8 g/dL: Withhold until recovery to 8 g/dL or more, then resume at the same dosage.
  • If life-threatening anemia; urgent intervention is indicated: Withhold until recovery to 8 g/dL, then resume at the next lower dosage; permanently discontinue for recurrence.

DOSAGE MODIFICATION FOR NON-HEMATOLOGIC TOXICITIES:
HEPATOTOXICITY:

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN: Withhold therapy until recovery to baseline or less than or equal to 3 x ULN, then resume at next lower dosage.
  • ALT or AST elevation greater than 3 x ULN with concurrent total bilirubin elevation greater than 1.5 x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue therapy.

INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS:

  • Any grade drug-related ILD/pneumonitis: Permanently discontinue therapy.

QT PROLONGATION:

  • QTc greater than 500 ms on at least 2 separate ECGs: Withhold therapy until recovery to baseline or to a QTc less than 481 ms, then resume at next lower dosage.
  • QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes, or polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia: Permanently discontinue therapy.

BRADYCARDIA:
Symptomatic, may be severe and medically significant, medical intervention indicated:

  • Withhold therapy until recovery to a resting heart rate according to the patient’s age (based on the 2.5th percentile per age-specific norms)
  • 1 to less than 2 years: 91 bpm or above
  • 2 to 3 years: 82 bpm or above
  • 4 to 5 years: 72 bpm or above
  • 6 to 8 years: 64 bpm or above
  • Greater than 8 year: 60 bpm or above
  • Life-threatening, urgent intervention indicated: Permanently discontinue therapy if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued or its dose is adjusted, resume therapy at the second dose reduction level upon recovery to asymptomatic or to the above-mentioned heart rate criteria with frequent monitoring.

OCULAR TOXICITY, INCLUDING VISUAL LOSS:

  • Visual symptoms Grade 1 (mild symptoms) or Grade 2 (moderate symptoms affecting ability to perform age-appropriate activities of daily living): Monitor symptoms and report any symptoms to an eye specialist. Consider dose reduction for Grade 2 visual disturbances.
  • Visual loss (Grade 3 or 4 ocular disorder, marked decrease in vision): Withhold pending evaluation of severe visual loss. Permanently discontinue for Grade 3 or 4 if no other cause found on evaluation

GASTROINTESTINAL TOXICITY:
Nausea:

  • For Grade 3 (inadequate oral intake for more than 3 days, medical intervention required) despite maximum medical treatment: Withhold until resolved, and then resume at the next lower dose level.

Vomiting:

  • For Grade 3 (more than 6 episodes in 24 hours for more than 3 days, medical intervention required, e.g., tube feeding or hospitalization) or Grade 4 (life-threatening consequences, urgent intervention indicated) despite maximum medical treatment: Withhold until resolved, and then resume at the next lower dose level.

Diarrhea:

  • For Grade 3 (an increase of 7 or more stools per day over baseline; incontinence; hospitalization indicated) or Grade 4 (life-threatening consequences, urgent intervention indicated): Withhold until resolved; then resume at the next lower dose level or may permanently discontinue if unable to tolerate. Permanently discontinue for recurrence.

Dosage Modification for Concomitant Use of Strong CYP450 3A Inhibitors:

  • Avoid concomitant use of strong CYP450 3A inhibitors; if concomitant use is unavoidable, reduce the dose of crizotinib to the second dose reduction based on BSA.
  • After discontinuation of a strong CYP450 3A inhibitor, resume the crizotinib dose used prior to initiating the strong CYP450 3A inhibitor.

Administration advice:

  • Take it with or without food.
  • Swallow the capsules whole.
  • Make up a missed dose unless the next dose is due within 6 hours.
  • If vomiting occurs after taking a dose, take the next dose at the regular time.
  • Evaluate pediatric patients for their ability to swallow intact capsules.
  • Administer this drug to pediatric patients under adult supervision.
  • Consider the administration of antiemetics prior to and during treatment if appropriate.
  • Provide antiemetic and antidiarrheal agents for gastrointestinal toxicities as needed.
  • Consider IV or oral hydration therapy for patients at risk of dehydration and administer electrolytes as clinically indicated.
  • Preparation, handling, and disposal of this drug should be performed in a manner consistent with safe procedures for cytotoxic agents.

Side Effects

The Most Common

  • constipation
  • stomach pain
  • sores in the mouth
  • change in ability to taste food
  • decreased appetite
  • heartburn
  • headache
  • numbness, burning, or tingling in the hands or feet
  • rash
  • muscle, bone, or back pain
  • pain in the arms, legs, hands, or feet
  • trouble breathing or shortness of breath
  • cough
  • fever
  • swelling of the arms, hands, feet, ankles, or lower legs
  • chest pain
  • slow or irregular heartbeat, dizziness, or fainting
  • weakness
  • excessive tiredness, decreased appetite, nausea, vomiting, pain in the right upper part of the stomach, dark urine, or itching
  • diarrhea
  • nausea
  • vomiting
  • difficulty swallowing
  • unusual bleeding or bruising

More common

  • Black, tarry stools
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • blurred or loss of vision
  • body aches or pain
  • chest pain, discomfort, or tightness
  • chills
  • colicky or burning stomach pain
  • constipation
  • cough
  • diarrhea
  • difficult or labored breathing
  • difficulty in swallowing
  • disturbed color perception
  • double vision
  • ear congestion
  • fever
  • halos around lights
  • headache
  • hoarseness
  • increased sensitivity to pain or touch
  • irregular heartbeat
  • lightheadedness, dizziness, or fainting
  • loss of appetite
  • loss of voice
  • lower back or side pain
  • nerve pain
  • night blindness
  • the overbright appearance of lights
  • pain in the back of the throat or chest when swallowing
  • pain or burning in the throat
  • painful or difficult urination
  • pale skin
  • rapid weight gain
  • recurrent fainting
  • runny or stuffy nose
  • seeing flashes or sparks of light
  • slow or irregular heartbeat
  • sneezing
  • sore throat
  • sores, ulcers, or white spots on the lips or tongue or inside the mouth
  • swelling
  • trouble breathing
  • tunnel vision
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • vomiting
  • vomiting blood or material that looks like coffee grounds
  • weakness in the arms, hands, legs, or feet

Rare

  • Anxiety
  • blue lips, fingernails, or skin
  • clay-colored stools
  • confusion
  • dark urine
  • dry mouth
  • fast heartbeat
  • flushed, dry skin
  • fruit-like breath odor
  • increased hunger
  • increased thirst
  • increased urination
  • irregular, fast or slow, or shallow breathing
  • itching, skin rash
  • loss of consciousness
  • nausea
  • stomach pain or tenderness
  • sweating
  • swelling of the feet or lower legs
  • yellow eyes or skin

Drug Interaction

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

Based on findings from animal studies and its mechanism of action, this drug can cause fetal harm when administered to a pregnant woman. This drug can harm a developing fetus. Verify the pregnancy status of females of reproductive potential prior to initiating treatment. Females of reproductive potential should use effective contraception during therapy and for at least 45 days after the last dose. Because of the potential for genotoxicity, males with female partners of reproductive potential should use condoms during therapy and for at least 90 days after the last dose.

Lactation

No information is available on the clinical use of crizotinib during breastfeeding. Because crizotinib is 91% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 42 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during crizotinib therapy and for 45 days after the last dose.

How should this medicine be used?

Crizotinib comes as a capsule to take by mouth. It is usually taken with or without food twice a day. Take crizotinib at around the same times every day. Follow the directions on your prescription label carefully and ask your doctor or pharmacist to explain any part you do not understand. Take crizotinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole; do not split, chew, or crush them. Do not touch capsules that are broken or crushed.

Your doctor may temporarily or permanently stop your treatment, decrease the dose, or tell you to take your medication less often if you experience serious side effects of crizotinib. Crizotinib may cause nausea, vomiting, and diarrhea. Your doctor may give you another medication to help prevent and treat nausea and vomiting. Your doctor may also give you medicine to treat diarrhea. Tell your doctor how you are feeling during your treatment.

If you vomit after taking crizotinib, do not take another dose. Continue your regular dosing schedule.

Continue to take crizotinib even if you feel well. Do not stop taking crizotinib without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking crizotinib,

  • tell your doctor and pharmacist if you are allergic to crizotinib, any other medications, or any of the ingredients in crizotinib capsules. Ask your pharmacist or check the manufacturer’s patient information for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had long QT syndrome (a rare heart problem that may cause irregular heartbeat, fainting, or sudden death), a slow heartbeat, heart failure, vision problems, lung problems other than lung cancer, or liver or kidney disease.
  • tell your doctor if you are pregnant or plan to become pregnant. You will need to have a pregnancy test before you start treatment with crizotinib. If you are female, you should use birth control during your treatment and for 45 days after your final dose. If you are male, you and your female partner should use birth control during your treatment and for 90 days after your final dose. Talk to your doctor about which method of birth control you should use. If you become pregnant while taking crizotinib, call your doctor immediately. Crizotinib may harm the fetus.
  • tell your doctor if you are breastfeeding. Do not breastfeed during your treatment and for 45 days after your final dose.
  • you should know that this medication may decrease fertility in men and women. Talk to your doctor about the risks of taking crizotinib.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking crizotinib.
  • you should know that crizotinib may cause vision problems, dizziness, and excessive tiredness. Do not drive a car or operate machinery until you know how this medication affects you.
  • plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Crizotinib may make your skin sensitive to sunlight.
  • you should know that crizotinib may cause vision problems, including vision loss. Your doctor may tell you to have an eye exam before starting your treatment and during your treatment with crizotinib. Call your doctor right away if you have any of the following symptoms: changes in vision, double or blurred vision, sensitivity to light, seeing sudden flashes of light, seeing new or increased floaters (spots in your vision), or any other problems with your vision.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202570s030lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202570s021lbl.pdf
  3. https://go.drugbank.com/drugs/DB08865
  4. https://medlineplus.gov/druginfo/meds/a612018.html
  5. https://en.wikipedia.org/wiki/Crizotinib
  6. https://www.drugs.com/crizotinib.html
  7. https://pubchem.ncbi.nlm.nih.gov/compound/Crizotinib
  8. https://www.webmd.com/drugs/2/drug-156966/crizotinib-oral/details/list-contraindications
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    http://www.ebi.ac.uk/Information/termsofuse.html
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    ChEMBL Protein Target Tree
    https://www.ebi.ac.uk/chembl/g/#browse/targets
  10. Comparative Toxicogenomics Database (CTD)
    http://ctdbase.org/about/legal.jsp
    https://ctdbase.org/detail.go?type=chem&acc=D000077547
  11. Drug Gene Interaction database (DGIdb)
    http://www.dgidb.org/downloads
    https://www.dgidb.org/drugs/CRIZOTINIB
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    Crizotinib
    https://www.drugbank.ca/drugs/DB08865
  13. IUPHAR/BPS Guide to PHARMACOLOGY
    https://www.guidetopharmacology.org/about.jsp#license
    https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4903
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  14. Therapeutic Target Database (TTD)
    Crizotinib
    http://idrblab.net/ttd/data/drug/details/D03ZBT
  15. CAS Common Chemistry
    https://creativecommons.org/licenses/by-nc/4.0/
    Crizotinib
    https://commonchemistry.cas.org/detail?cas_rn=877399-52-5
  16. ChemIDplus
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    Crizotinib [USAN:INN]
    https://chem.nlm.nih.gov/chemidplus/sid/0877399525
    ChemIDplus Chemical Information Classification
    https://chem.nlm.nih.gov/chemidplus/
  17. EPA DSSTox
    LICENSE
    https://www.epa.gov/privacy/privacy-act-laws-policies-and-resources
    Crizotinib
    https://comptox.epa.gov/dashboard/DTXSID701009329
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  18. European Chemicals Agency (ECHA)
    https://echa.europa.eu/web/guest/legal-notice
    3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine
    https://echa.europa.eu/information-on-chemicals
    3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/171274
  19. FDA Global Substance Registration System (GSRS)
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    CRIZOTINIB
    https://gsrs.ncats.nih.gov/ginas/app/beta/substances/53AH36668S
  20. ChEBI
    Crizotinib
    http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:64310
    ChEBI Ontology
    http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
  21. FDA Pharm Classes
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    CRIZOTINIB
    https://dailymed.nlm.nih.gov/dailymed/browse-drug-classes.cfm
    FDA Pharmacological Classification
    https://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162549.htm
  22. LiverTox
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    Crizotinib
    https://www.ncbi.nlm.nih.gov/books/n/livertox/Crizotinib/
  23. NCI Thesaurus (NCIt)
    https://www.cancer.gov/policies/copyright-reuse
    https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C74061
    NCI Thesaurus Tree
    https://ncit.nci.nih.gov
  24. ClinicalTrials.gov
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
    https://clinicaltrials.gov/
  25. DailyMed
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    CRIZOTINIB
    https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=CRIZOTINIB
  26. European Medicines Agency (EMA)
    https://www.ema.europa.eu/en/about-us/legal-notice
    Xalkori (EMEA/H/C/002489)
    https://www.ema.europa.eu/en/medicines/human/EPAR/xalkori
    crizotinib (P/0361/2018)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001493-pip02-18
    crizotinib (P/0036/2021)
    https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001493-pip03-18-m01
  27. Drugs and Lactation Database (LactMed)
    LICENSE
    https://www.nlm.nih.gov/copyright.html
    Crizotinib
    https://www.ncbi.nlm.nih.gov/books/NBK500840/
  28. DTP/NCI
    https://www.cancer.gov/policies/copyright-reuse
    NSC749005
    https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=749005
  29. EU Clinical Trials Register
    https://www.clinicaltrialsregister.eu/
  30. FDA Orange Book
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book
  31. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  32. WHO Anatomical Therapeutic Chemical (ATC) Classification
    https://www.whocc.no/copyright_disclaimer/
    https://www.whocc.no/atc/
    ATC Code
    https://www.whocc.no/atc_ddd_index/
  33. FDA Medication Guides
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    Xalkori
    https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=medguide.page
  34. National Drug Code (NDC) Directory
    https://www.fda.gov/about-fda/about-website/website-policies#linking
    CRIZOTINIB
    https://www.fda.gov/drugs/drug-approvals-and-databases/national-drug-code-directory
  35. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
    Crizotinib (PF-02341066)
    https://mona.fiehnlab.ucdavis.edu/spectra/browse?query=compound.metaData%3Dq%3D%27name%3D%3D%22InChIKey%22%20and%20value%3D%3D%22KTEIFNKAUNYNJU-GFCCVEGCSA-N%22%27
  36. NCI Cancer Drugs
    LICENSE
    https://www.cancer.gov/policies/copyright-reuse
    Crizotinib
    https://www.cancer.gov/about-cancer/treatment/drugs/crizotinib
  37. NIPH Clinical Trials Search of Japan
    https://rctportal.niph.go.jp/en/
  38. NLM RxNorm Terminology
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
    crizotinib
    https://rxnav.nlm.nih.gov/id/rxnorm/1148495
  39. Protein Data Bank in Europe (PDBe)
    http://www.ebi.ac.uk/pdbe-srv/pdbechem/chemicalCompound/show/VGH
  40. PubChem
    https://pubchem.ncbi.nlm.nih.gov
    PFAS and Fluorinated Compounds in PubChem
    https://gitlab.lcsb.uni.lu/eci/pubchem-docs/-/raw/main/pfas-tree/PFAS_Tree.pdf?inline=false
  41. RCSB Protein Data Bank (RCSB PDB)
    https://www.rcsb.org/pages/policies
    https://www.rcsb.org/
  42. SpectraBase
    Crizotinib
    https://spectrabase.com/spectrum/bPDE7OdaMZ
    Crizotinib
    https://spectrabase.com/spectrum/6jm1cMAnKtI
    Crizotinib
    https://spectrabase.com/spectrum/DkWMjlkDTYG
  43. Springer Nature
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=15745&sourceid=30052205-195891318
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=15745&sourceid=30052205-195887068
  44. Thieme Chemistry
    https://creativecommons.org/licenses/by-nc-nd/4.0/
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=22163&sourceid=30052205-195887285
  45. Wikidata
    LICENSE
    CCZero
    https://creativecommons.org/publicdomain/zero/1.0/
    Crizotinib
    https://www.wikidata.org/wiki/Q5186964
  46. Wiley
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=wiley&sourceid=126102
  47. Medical Subject Headings (MeSH)
    https://www.nlm.nih.gov/copyright.html
    Crizotinib
    https://www.ncbi.nlm.nih.gov/mesh/2028061
    MeSH Tree
    http://www.nlm.nih.gov/mesh/meshhome.html
    Antineoplastic Agents
    https://www.ncbi.nlm.nih.gov/mesh/68000970
    Protein Kinase Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68047428
  48. KEGG
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    USP drug classification
    http://www.genome.jp/kegg-bin/get_htext?br08302.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
    Drug Groups
    http://www.genome.jp/kegg-bin/get_htext?br08330.keg
    Drug Classes
    http://www.genome.jp/kegg-bin/get_htext?br08332.keg
  49. UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
    GHS Classification Tree
    http://www.unece.org/trans/danger/publi/ghs/ghs_welcome_e.html
  50. PATENTSCOPE (WIPO)
    SID 390694348
    https://pubchem.ncbi.nlm.nih.gov/substance/390694348
  51. NCBI
    https://www.ncbi.nlm.nih.gov/projects/linkout

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