Uses of Crizonil: - Non-small cell lung cancer 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 Hypersensitivity

Targeted Cancer Therapy

Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The 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. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.

How to use Crizotinib: Take this medicine in the dose and duration as advised by your doctor. Do not chew, crush or break it. Crizotinib may be taken with or without food, but it is better to take it at a fixed time. Administration: Take with or without food; a high-fat meal reduces AUCinf and Cmax by ~14% Capsules should be swallowed whole 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

CYP3A Inhibitors: Concurrent use of Crizotinib should be avoided with strong CYP3A inhibitors including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazoleCYP3A Inducers: Concurrent use of Crizotinib should be avoided with strong CYP3A inducers including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort CYP3A Substrates: Concurrent use of Crizotinib should be avoided with CYP3A substrates with narrow therapeutic indices including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus

Hypersensitivity

Common - Nausea - Vomiting - Diarrhea - Constipation - Abdominal pain - Visual impairment - Dizziness - Taste change - Fatigue - Decreased appetite - Rash - Decreased white blood cell count (neutrophils) >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%)

Based on its mechanism of action, Crizotinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Crizotinib during pregnancy. Females of reproductive potential should be advised of the potential risk to a fetus and use of effective contraception.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 patients should not breastfeed during treatment with Crizotinib and for 45 days after the final dose.

Precaution: 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

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Targeted Cancer Therapy

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

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