Crizotinib – Uses, Dosage, Side Effects, Interaction

Use in Cancer

Crizotinib is approved to treat:

• Anaplastic large cell lymphoma that is ALK-positive and systemic. It is used in children aged 1 year and older and young adults whose cancer has relapsed (come back) or is refractory (does not respond to treatment).
• An inflammatory myofibroblastic tumor that is ALK-positive. It is used in adults and children aged 1 year and older whose cancer is relapsed, refractory, or cannot be removed by surgery.
• Non-small cell lung cancer is ALK-positive or ROS1-positive and has spread to other parts of the body.

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 pain?, numbness?, tingling, or weakness?. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।" data-rx-term="neuropathy" data-rx-definition="Neuropathy means nerve damage or irritation causing pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।">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 infection?, or irritation, often causing pain?, swelling?, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।" data-rx-term="inflammation" data-rx-definition="Inflammation is the body’s response to injury, infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।">inflammation? of the lung called interstitial pneumonitis
• high amount of jaundice?. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।" data-rx-term="bilirubin" data-rx-definition="Bilirubin is a yellow pigment that can build up in jaundice. সহজ বাংলা: জন্ডিসে বাড়তে পারে এমন হলুদ রঞ্জক।">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.

References