crizotinib

Action

Inhibits receptor tyrosine kinases, including ALK, hepatocyte growth factor receptor, and recepteur d'origine nantais. Translocations can affect the ALK gene, resulting in expression of oncogenic fusion proteins. Formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.

Availability

Capsules: 200 mg, 250 mg

Indications and dosages

➣ Anaplastic lymphoma kinase-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC)

Adults: 250 mg P.O. b.i.d. Dosing interruption or reduction to 200 mg P.O. b.i.d. may be required based on individual safety and tolerability; then 250 mg P.O. daily if further reduction is necessary.

Dosage adjustment

• Hepatotoxicity

• Hematologic toxicities

• Grade 3 QT interval prolongation

Contraindications

None

Precautions

Use cautiously in:

• hepatic impairment, severe renal impairment (creatinine clearance less than 30 ml/minute), end-stage renal disease

• congenital long QT syndrome (avoid use), congestive heart failure, bradyarrhythmias, electrolyte abnormalities, pulmonary disease

• concurrent use of drugs known to prolong QT interval (such as alfuzosin, amiodarone, ibutilide, or quetiapine)

• concurrent use of moderate CYP3A inhibitors

• concurrent use of strong CYP3A inducers or inhibitors (avoid use)

• concurrent use of CYP3A substrates with narrow therapeutic indices (avoid use)

• grapefruit, grapefruit juice, St. John's wort (avoid use)

• pregnant or breastfeeding patients

• children (safety and efficacy not established).

Administration

• Be aware that detection of ALK-positive NSCLC using an FDA-approved test is necessary before starting drug.

• Administer with or without food. Don't crush, dissolve, or open capsules.

Adverse reactions

CNS: headache, fatigue, dizziness, neuropathy, insomnia

CV: bradycardia, prolonged

QT interval

EENT: vision disorder

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, esophageal disorder, stomatitis

GU: complex renal cysts

Hematologic: neutropenia, thrombocytopenia, lymphopenia

Hepatic: hepatotoxicity

Musculoskeletal: arthralgia, back pain

Respiratory: upper respiratory tract infection, dyspnea, cough,

pneumonia, pulmonary embolism

Skin: rash

Other: edema, chest pain or discomfort, fever, decreased appetite, dysgeusia

Interactions

Drug-drug. CYP3A substrates with narrow therapeutic indices (such as alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus): inhibited metabolism of these drugs, leading to potential for serious adverse reactions

Moderate CYP3A inhibitors (such as diltiazem): possible increased crizotinib plasma concentration

Strong CYP3A inducers (including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin): decreased crizotinib plasma concentration

Strong CYP3A inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole): increased crizotinib plasma concentration

Drug-diagnostic tests. ALT, AST: increased levels

Lymphocytes, neutrophils, platelets: decreased levels

Drug-food. Grapefruit, grapefruit juice: increased crizotinib plasma concentration

High-fat meal: decreased crizotinib area under the curve and C_max.

Drug-herbs. St. John's wort: decreased crizotinib plasma concentration

Patient monitoring

See Monitor liver function tests (including ALT and total bilirubin) monthly and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Temporarily suspend drug, reduce dosage, or permanently discontinue drug as indicated.

• Monitor CBC with differential and renal function tests closely.

See Monitor patient for pulmonary signs and symptoms indicative of pneumonitis; permanently discontinue drug in patients diagnosed with treatment-related pneumonitis.

See Consider periodic ECGs and electrolyte monitoring in patients who have QT-interval prolongation or predisposition for QT-interval prolongation, or who are taking drugs known to prolong QT interval. Withhold drug in patients with Grade 3 QT-interval prolongation until recovery to Grade 1 or less; then resume at prescribed reduced dosage. Permanently discontinue drug if Grade 3 QT-interval prolongation recurs and in patients with Grade 4 QT-interval prolongation.

Patient teaching

• Tell patient to take drug with or without food, to avoid grapefruit and grapefruit juice, and not to crush, dissolve, or open capsules.

See Instruct patient to immediately report signs and symptoms of liver disorder (such as weakness, fatigue, nausea, vomiting, right upper abdominal pain, jaundice, yellowing of skin or eyes, or dark urine).

See Instruct patient to immediately report swelling of hands or feet, abnormal heartbeats, dizziness, or faintness.

• Inform patient that visual changes, such as perceived flashes of light, blurry vision, light sensitivity, and floaters, may occur and to report flashes or floaters to prescriber.

• Caution patient to use caution while driving and performing other hazardous activities, because of the risk of developing a vision disorder, dizziness, or fatigue while taking drug.

• Instruct patient to tell prescriber about all drugs he's taking, because some drugs have potential for serious drug interactions and shouldn't be taken with crizotinib.

• Advise patient not to use St. John's wort or other herbal supplements without consulting prescriber.

• Advise female patient of childbearing age to avoid becoming pregnant during treatment.

• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of drug for her treatment.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.