Crizotinib

Indications

Crizotinib is used for: Non-Small Cell Lung Cancer, Indicated for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase-positive Indicated for metastatic NSCLC tumors that are ROS1-positive

Adult Dose

Oral Adult Non-Small Cell Lung Cancer Indicated for 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. Also indicated for metastatic NSCLC tumors that are ROS1-positive. Select patients for treatment of metastatic NSCLC based on presence of ALK or ROS1 positivity in tumor specimens. Capsule 250 mg PO q12hr Continue treatment as long as patient is deriving clinical benefit from therapy Dose Modifications Dosing interruption and/or dose reduction to 200 mg PO q12hr may be required based on safety and tolerability; decrease to 250 mg PO qDay if further reduction is needed Hepatic impairment: Caution advised

Child Dose

Safety and efficacy not established

Renal Dose

Renal impairment Mild-to-moderate (CrCl 30-90 mL/min): No starting dose adjustment is needed; steady-state trough concentrations in these 2 groups were similar to those with normal renal function (ie, CrCl >90 mL/min) Severe (CrCl <30 mL/min) or end-stage renal disease: Caution advised

Administration

Take with or without food; a high-fat meal reduces AUCinf and Cmax by ~14% Capsules should be swallowed whole

Contra Indications

Hypersensitivity

Precautions

Severe, including fatal, treatment-related pneumonitis reported; monitor for pulmonary symptoms indicative of pneumonitis and permanently discontinue if diagnosed Hepatoxicity reported; elevations in ALT and total bilirubin reported; monitor q2wk for 2 months, then monthly and as clinically indicated with more frequent testing with Grade 2-4 elevations; temporarily suspend, reduce dose, or permanently discontinue dose as indicated (see Dose Modifications) Symptomatic bradycardia reported, including syncope; avoid coadministration with other drugs known to cause bradycardia; monitor heart rate and blood pressure regularly; temporarily suspend, reduce dose, or permanently discontinue (see Dosage Modifications) Caution when driving or operating machinery because of vision disorder, dizziness, or fatigue associated with treatment Can cause fetal harm when administered to pregnant women (see Pregnancy) Interstitial Lung Disease (ILD)/Pneumonitis reported; permanently discontinue in patients with ILD/pneumonitis Visual field defect with vision loss reported; optic atrophy and optic nerve disorder have been reported as potential causes of vision loss; discontinue with new onset of severe visual loss Lactation There is no information regarding the presence of crizotinib in human milk, the effects on the breastfed infant, or the effects on milk production Because of the potential for adverse reactions in breastfed infants, do not breastfeed during treatment and for 45 days after the final dose

Pregnancy-Lactation

Pregnancy Based on its mechanism of action, can cause fetal harm when administered to a pregnant woman Contraception Advise females of reproductive potential to use effective contraception during treatment and for at least 45 days following the final dose Advise males taking crizotinib with female partners of reproductive potential to use condoms during treatment and for at least 90 days after the final dose

Interactions

Adverse Effects

Side effects of Crizotinib : >10% ALT elevation (76%), AST elevation (61%), Vision disorder (60%), Diarrhea (60%), Nausea (55%), Lymphopenia (51%), Neutropenia (49%), Vomiting (47%), Constipation (42%), Edema (31%), Hypophosphatemia (28%), Decreased appetite (27%), Fatigue (27%), Dysgeusia (26%), Upper respiratory infection (26%), Dizziness (22%), Neuropathy (19%), Dysesthesia (19%), Gait disturbance (19%), Hypoesthesia (19%), Muscular weakness (19%), Neuralgia (19%), Peripheral neuropathy (19%), Paresthesia (19%), Peripheral sensory neuropathy (19%), Polyneuropathy (19%), Burning sensation in skin (19%), Hypokalemia (18%) 1-10% Weight decreased (10%), Rash (9%), Dyspepsia (8%), Pulmonary embolism (6%), QT prolongation (5%), Bradycardia (5%), Pneumonia (4.1%), Pneumonitits (4%), Renal cyst (4%), ARDS (4%), Pulmonary embolism (3.5%), Syncope (3%), Dyspnea (2.3%), Hepatic failure (1%), Esophagitis (2%) <1% Vision loss, grade 4 (0.2%), Hypogonadism; decreased blood testosterone (1%)

Mechanism of Action

Inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteur d’Origine Nantais (RON) The gene’s expression and signaling that contribute to increased cell proliferation and survival of the tumors become activated following the expression of ALK oncogenic fusion proteins Inhibits the signaling that promotes the expression of these oncogenic fusion proteins, thereby inhibiting tumor cell proliferation