Crizotinib

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Crizotinib is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Crizotinib is used to treat non-small cell lung cancer that has spread to other parts of the body.

Crizotinib may also be used for purposes not listed in this medication guide.

Crizotinib can cause serious heart or liver problems. Call your doctor at once if you have: headache with chest pain and severe dizziness, fast or pounding heartbeats, upper stomach pain, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

You should not use crizotinib if you are allergic to it.

To make sure crizotinib is safe for you, tell your doctor if you have:

• liver or kidney disease;
• a heart rhythm disorder;
• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);
• a personal or family history of Long QT syndrome; or
• if you take any heart or blood pressure medicines.

Crizotinib can harm an unborn baby.

• If you are a woman, do not take crizotinib if you are pregnant.
• If you are a man, use effective birth control if your sexual partner is able to get pregnant. An unborn baby can be harmed if a man fathers the child while he is taking crizotinib.
• Use birth control to prevent pregnancy while you are receiving crizotinib, whether you are a man or a woman. Keep using birth control for at least 3 months after treatment ends.
• Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking crizotinib.

It is not known whether crizotinib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using crizotinib.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• severe vision problems, including loss of vision;
• headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats;
• very slow heart rate;
• a light-headed feeling, like you might pass out;
• sudden chest pain or discomfort, wheezing, dry cough or cough with mucus, feeling short of breath;
• fever, swollen gums, painful mouth sores, pain when swallowing, cold or flu symptoms;
• easy bruising or bleeding (nosebleeds, bleeding gums); or
• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

• nausea, vomiting;
• diarrhea, constipation;
• swelling in your hands or feet;
• tired feeling; or
• vision problems such as blurred vision, increased sensitivity of your eyes to light, or seeing flashes of light or "floaters."

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Grapefruit and grapefruit juice may interact with crizotinib and lead to unwanted side effects. Avoid the use of grapefruit products while taking crizotinib.

This medicine may cause blurred vision and may impair your reactions. Be careful if you drive or do anything that requires you to be able to see clearly.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Other drugs may interact with crizotinib, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

XALKORI (crizotinib) is an oral receptor tyrosine kinase inhibitor. The molecular formula for crizotinib is C21H22Cl2FN5O. The molecular weight is 450.34 daltons. Crizotinib is described chemically as (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.  The chemical structure of crizotinib is shown below:

Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation). The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65.

XALKORI capsules are supplied as printed hard-shell capsules containing 250 mg or 200 mg of crizotinib together with colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, and hard gelatin capsule shells as inactive ingredients.

The pink opaque capsule shell components contain gelatin, titanium dioxide, and red iron oxide. The white opaque capsule shell components contain gelatin and titanium dioxide. The printing ink contains shellac, propylene glycol, strong ammonia solution, potassium hydroxide, and black iron oxide.

Dosage Forms And Strengths

• 250 mg capsules: hard gelatin capsule, size 0, pink opaque cap and body, with “Pfizer” on the cap and “CRZ 250” on the body.
• 200 mg capsules: hard gelatin capsule, size 1, white opaque body and pink opaque cap, with “Pfizer” on the cap and “CRZ 200” on the body.

Storage And Handling

Hard gelatin capsule with pink opaque cap and body, printed with black ink “Pfizer” on the cap, “CRZ 250” on the body; available in: Bottles of 60 capsules: NDC 0069-8140-20

Hard gelatin capsule with pink opaque cap and white opaque body, printed with black ink “Pfizer” on the cap, “CRZ 200” on the body; available in: Bottles of 60 capsules: NDC 0069-8141-20

Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Distributed by: Pfizer Labs, Division of Pfizer Inc., NY, NY 10017. Revised: Apr 2017

Mechanism Of Action

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.

Pharmacodynamics

In an ECG substudy conducted in 52 patients with ALK-positive NSCLC who received crizotinib 250 mg twice daily, the maximum mean QTcF (corrected QT by the Fridericia method) change from baseline was 12.3 ms (2-sided 90% upper CI: 19.5 ms). An exposure-QT analysis suggested a crizotinib plasma concentration-dependent increase in QTcF [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Following a single oral dose, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady-state systemic exposure [observed minimum concentration (Cmin) and AUC] appeared to increase in a greater than dose-proportional manner over the dose range of 200-300 mg twice daily.

The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following a single 250 mg oral dose.

A high-fat meal reduced crizotinib AUC from time zero to infinity (AUCinf) and maximum observed plasma concentration (Cmax) by approximately 14%. XALKORI can be administered with or without food [see DOSAGE AND ADMINISTRATION].

The geometric mean volume of distribution (Vss) of crizotinib was 1772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma.

Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1.

Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in patients.

Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.

The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/h) after 250 mg twice daily than after a single 250 mg oral dose (100 L/h), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.

Crizotinib is predominantly metabolized by CYP3A4/5. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites.

Specific populations

Hepatic impairment: As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, XALKORI has not been studied in patients with hepatic impairment. Clinical studies excluded patients with ALT or AST greater than 2.5 times ULN or greater than 5 times ULN if due to liver metastases. Patients with total bilirubin greater than 1.5 times ULN were also excluded [see Use in Specific Populations]. The population pharmacokinetic analysis using the data from approximately 1200 patients with cancer who received XALKORI suggested that baseline total bilirubin (0.1 to 2.1 mg/dL) or AST levels (7 to 124 U/L) did not have a clinically relevant effect on the exposure of crizotinib.

Renal impairment: The pharmacokinetics of crizotinib were evaluated using the population pharmacokinetic analysis in patients with mild (CLcr 60-89 mL/min, n=433) and moderate (CLcr 30-59 mL/min, n=137) renal impairment. Mild or moderate renal impairment has no clinically relevant effect on the exposure of crizotinib.

A study was conducted in 7 patients with severe renal impairment (CLcr < 30 mL/min) who did not require dialysis and 8 patients with normal renal function (CLcr ≥ 90 mL/min). All patients received a single 250 mg oral dose of XALKORI. The mean AUCinf for crizotinib increased by 79% and the mean Cmax increased by 34% in patients with severe renal impairment compared to those with normal renal function. Similar changes in AUCinf and Cmax were observed for the active metabolite of crizotinib [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Ethnicity: No clinically relevant difference in the exposure of crizotinib between Asian patients (n=523) and non-Asian patients (n=691).

Age: Age has no effect on the exposure of crizotinib based on the population pharmacokinetic analysis.

Body weight and gender: No clinically relevant effect of body weight or gender on the exposure of crizotinib based on the population pharmacokinetic analysis.

Drug Interactions

Strong CYP3A inhibitors: Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, increased crizotinib AUCinf and Cmax values by approximately 3.2-fold and 1.4-fold, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated [see DRUG INTERACTIONS].

Strong CYP3A inducers: Coadministration of crizotinib (250 mg twice daily) with rifampin (600 mg once daily), a strong CYP3A inducer, decreased crizotinib steady-state AUCtau and Cmax by 84% and 79%, respectively, compared to crizotinib alone [see DRUG INTERACTIONS].

Gastric pH elevating medications: In healthy subjects, coadministration of a single 250 mg oral dose of crizotinib following administration of esomeprazole 40 mg daily for 5 days did not result in a clinically relevant change in crizotinib exposure (AUCinf decreased by 10% and no change in Cmax).

CYP3A substrates: Coadministration of crizotinib (250 mg twice daily for 28 days) in patients increased the AUCinf of oral midazolam 3.7-fold compared to midazolam alone, suggesting that crizotinib is a moderate inhibitor of CYP3A [see DRUG INTERACTIONS].

Other CYP substrates: In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 are unlikely to occur.

Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may increase plasma concentrations of coadministered drugs that are predominantly metabolized by CYP2B6.

An in vitro study suggests that clinical drug-drug interactions as a result of crizotinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A are unlikely to occur.

UGT substrates: In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for uridine diphosphate glucuronosyltransferase (UGT)1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7 are unlikely to occur.

Substrates of transporters: Crizotinib inhibited P-gp in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of P-gp.

Crizotinib inhibited the hepatic uptake transporter, organic cation transporter (OCT) 1, and renal uptake transporter, OCT2, in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2.

Crizotinib did not inhibit the human hepatic uptake transport proteins, organic anion transporting polypeptides (OATP) B1 or OATP1B3, or the renal uptake transport proteins organic anion transporter (OAT) 1 or OAT3 in vitro at clinically relevant concentrations.

Other transporters: Crizotinib did not inhibit the hepatic efflux bile salt export pump transporter (BSEP) in vitro at clinically relevant concentrations.

Clinical Studies

ALK-Positive Metastatic NSCLC

The efficacy and safety of XALKORI for the treatment of patients with ALK-positive metastatic NSCLC, who had not received previous systemic treatment for advanced disease, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 1). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit, prior to randomization. The major efficacy outcome measure was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by independent radiology review (IRR) committee. Additional efficacy outcome measures included objective response rate (ORR) as assessed by IRR, duration of response (DOR), and overall survival (OS). Patient-reported lung cancer symptoms were assessed at baseline and periodically during treatment.

Patients were randomized to receive XALKORI (n=172) or chemotherapy (n=171). Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0-1, 2), race (Asian, non-Asian), and brain metastases (present, absent). Patients in the XALKORI arm received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Chemotherapy consisted of pemetrexed 500 mg/m² with cisplatin 75 mg/m² or carboplatin AUC of 5 or 6 mg·min/mL by intravenous infusion every 3 weeks for up to 6 cycles. Patients in the chemotherapy arm were not permitted to receive maintenance chemotherapy. At the time of documented disease progression, as per independent radiology review, patients randomized to chemotherapy were offered XALKORI.

The demographic characteristics of the overall study population were 62% female, median age of 53 years, baseline ECOG performance status 0 or 1 (95%), 51% White and 46% Asian, 4% current smokers, 32% past smokers, and 64% never smokers. The disease characteristics of the overall study population were metastatic disease in 98% of patients, 92% of patients' tumors were classified as adenocarcinoma histology, 27% of patients had brain metastases, and 7% received systemic chemotherapy as adjuvant or neoadjuvant therapy. Of those randomized to chemotherapy, 70% received XALKORI after IRR documented progression.

Study 1 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. The OS analysis conducted at the time of the PFS analysis did not suggest a difference in survival between arms. Table 7 and Figure 1 summarize the efficacy results. Exploratory patient-reported symptom measures of baseline and post-treatment dyspnea, cough, and chest pain suggested a delay in time to development of or worsening of dyspnea, but not cough or chest pain, in patients treated with XALKORI as compared to chemotherapy. The patient-reported delay in onset or worsening of dyspnea may be an overestimation, because patients were not blinded to treatment assignment.

Table 7: Previously Untreated ALK-Positive Metastatic NSCLC - Efficacy Results

Figure 1: Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 1

The efficacy and safety of XALKORI as monotherapy for the treatment of 347 patients with ALK-positive metastatic NSCLC, previously treated with 1 platinum-based chemotherapy regimen, were demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 2). The major efficacy outcome was PFS according to RECIST version 1.1 as assessed by IRR. Additional efficacy outcomes included ORR as assessed by IRR, DOR, and OS.

Patients were randomized to receive XALKORI 250 mg orally twice daily (n=173) or chemotherapy (n=174). Chemotherapy consisted of pemetrexed 500 mg/m² (if pemetrexed-naïve; n=99) or docetaxel 75 mg/m² (n=72) intravenously (IV) every 21 days. Patients in both treatment arms continued treatment until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Randomization was stratified by ECOG performance status (0-1, 2), brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor treatment (yes, no). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit, prior to randomization. At the time of the final analysis of overall survival, 154 (89%) patients randomized to the chemotherapy arm subsequently received XALKORI.

The demographic characteristics of the overall study population were 56% female, median age of 50 years, baseline ECOG performance status 0 or 1 (90%), 52% White and 45% Asian, 4% current smokers, 33% past smokers, and 63% never smokers. The disease characteristics of the overall study population were metastatic disease in at least 95% of patients and at least 93% of patients' tumors were classified as adenocarcinoma histology.

Study 2 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. Table 8 and Figure 2 summarize the efficacy results.

Table 8: Previously Treated ALK-Positive Metastatic NSCLC - Efficacy Results

Figure 2: Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 2

ROS1-Positive Metastatic NSCLC

The efficacy and safety of XALKORI was investigated in a multicenter, single-arm study (Study 3), in which patients with ROS1-positive metastatic NSCLC received XALKORI 250 mg orally twice daily. Patients were required to have histologically-confirmed advanced NSCLC with a ROS1 rearrangement, age 18 years or older, ECOG performance status of 0, 1, or 2, adequate organ function, and measurable disease. The efficacy outcome measures were ORR and DOR according to RECIST version 1.0 as assessed by IRR and investigator, with imaging performed every 8 weeks for the first 60 weeks.

Baseline demographic and disease characteristics were female (56%), median age of 53 years, baseline ECOG performance status of 0 or 1 (98%), White (54%), Asian (42%), past smokers (22%), never smokers (78%), metastatic disease (92%), adenocarcinoma (96%), no prior systemic therapy for metastatic disease (14%), and prior platinum-based chemotherapy for metastatic disease (80%). The ROS1 status of NSCLC tissue samples was determined by laboratory-developed break-apart FISH (96%) or RT-PCR (4%) clinical trial assays. For assessment by FISH, ROS1 positivity required that ≥ 15% of a minimum of 50 evaluated nuclei contained a ROS1 gene rearrangement.

Efficacy results are summarized in Table 9.

Table 9: ROS1-Positive Metastatic NSCLC - Efficacy Results*

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

Absorption

Bioavailability: 43% (mean absolute bioavailability)

Peak Plasma Time: 4-6 hr

Distribution

Protein Bound: 91% to human plasma proteins, independent of drug concentration

Vd: 1772 L, following 50 mg IV dose, indicating extensive distribution into tissues from plasma

P-glycoprotein (P-gp) substrate and inhibitor

Metabolism

Predominantly metabolized by CYP3A4/5

Time-dependent inhibitor of CYP3A

Primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites

Elimination

Half-life: 42 hr

Total body clearance: 60 L/hr (250 mg PO q12hr); 100 L/hr (250 mg PO qDay)

Excretion: Feces 63%; urine 22%

Pharmacogenomics

Patient selection for treatment is based on presence of ALK fusion gene

Verify presence of ALK fusion gene by using the diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit

Crizotinib is part of the drug class:

• Protein kinase inhibitors

This medication may cause serious side effects including:

• liver problems. Tell your doctor right away if you have:
  • yellowing of skin/eyes
  • fatigue
  • pain in upper-right area of the stomach
  • nausea
  • vomiting
  • dark urine
• lung inflammation (pneumonitis) that can be life-threatening. Call your doctor right away if you have new or worsened breathing difficulties.
• changes in your vision, dizziness, and tiredness. If you have these symptoms, use caution when driving a car, using machinery, or doing anything that needs you to be alert.
• changes in your heartbeat (called QT interval prolongation), very fast or abnormal heartbeats. Your doctor may check your heart during treatment with crizotinib. Tell your doctor right away if you have abnormal heartbeats, feel dizzy, or faint. These may be symptoms related to QT interval prolongation.This is a potentially life-threatening heart rhythm problem.
• harm to your unborn baby. Females who are able to become pregnant should use effective birth control during treatment with crizotinib and for at least 45 days after the final dose of crizotinib.

Do not drink grapefruit juice or eat grapefruit during your treatment with crizotinib. It may make the amount of crizotinib in your blood increase to a harmful level.

Do not take this medicine if you are allergic to any of its ingredients.

If you take too much crizotinib call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If crizotinib is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Usual Adult Dose for Non-Small Cell Lung Cancer:

250 mg orally twice a day

Use: Metastatic non-small cell lung cancer whose tumors are anaplastic lymphoma kinase-positive

In the U.S.

• Xalkori

Available Dosage Forms:

• Capsule

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Tyrosine Kinase Inhibitor

It is very important that your doctor check your progress at regular visits to make sure crizotinib is working properly. Blood tests may be needed to check for unwanted effects.

Using crizotinib while you are pregnant can harm your unborn baby. The medicine may also cause birth defects if the father is using it when his sexual partner becomes pregnant. Use an effective form of birth control during therapy and for at least 45 to 90 days after the last dose. If a pregnancy occurs while you are using crizotinib, tell your doctor right away.

crizotinib may cause swelling of the lungs (pneumonitis). Pneumonitis is a life-threatening condition and requires immediate medical attention. Check with your doctor right away if you have a cough with or without mucous, shortness of breath, troubled breathing, or a fever.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a slow, fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

Cancer medicines can cause constipation, diarrhea, nausea, or vomiting in most people, sometimes even after receiving medicines to prevent it. Ask your doctor or nurse about other ways to control these side effects.

crizotinib may cause dizziness, tiredness, blurred vision, or other vision problems (eg, flashes of lights, floaters, sensitivity of the eyes to light). If any of these occur, do not drive, use machines, or do anything else that could be dangerous if you are not able to see well. Check with your doctor if visual changes occur. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Talk with your doctor before using crizotinib if you plan to have children. Some men and women who use crizotinib have become infertile (unable to have children).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

• It is used to treat lung cancer.

• If you have an allergy to crizotinib or any other part of crizotinib.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have a long QT on ECG.
• If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this medicine, like certain drugs that are used for HIV, infections, or seizures. There are many drugs that must not be taken with crizotinib.
• If you are breast-feeding. Do not breast-feed while you take this medicine or within 45 days after your last dose.

This is not a list of all drugs or health problems that interact with crizotinib.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use crizotinib as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• To gain the most benefit, do not miss doses.
• Take with or without food.
• Swallow whole. Do not chew, open, or crush.
• If you throw up after taking a dose, do not repeat the dose. Take your next dose at your normal time.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is less than 6 hours until the next dose, skip the missed dose and go back to the normal time.
• Do not take 2 doses at the same time or extra doses.

• C-Met/Hepatocyte Growth Factor Receptor Tyrosine Kinase Inhibitor PF-02341066
• C-Met/HGFR Tyrosine Kinase Inhibitor PF-02341066
• MET Tyrosine Kinase Inhibitor PF-02341066
• PF-02341066

• Antineoplastic Agent, Anaplastic Lymphoma Kinase Inhibitor
• Antineoplastic Agent, Tyrosine Kinase Inhibitor

Tyrosine kinase receptor inhibitor, which inhibits anaplastic lymphoma kinase (ALK), Hepatocyte Growth Factor Receptor (HGFR, c-MET), ROS1 (c-ros), and Recepteur d’Origine Nantais (RON). ALK gene abnormalities due to mutations or translocations may result in expression of oncogenic fusion proteins (eg, ALK fusion protein) which alter signaling and expression and result in increased cellular proliferation and survival in tumors which express these fusion proteins. Approximately 2% to 7% of patients with NSCLC have the abnormal echinoderm microtubule-associated protein-like 4, or EML4-ALK gene (which has a higher prevalence in never smokers or light smokers and in patients with adenocarcinoma). Inhibition of ALK, ROS1, and c-Met phosphorylation is concentration-dependent. Crizotinib selectively inhibits ALK tyrosine kinase, which reduces proliferation of cells expressing the genetic alteration.

Distribution

Vss: 1772 L

Metabolism

Hepatic, via CYP3A4/5 (oxidation and dealkylation)

Excretion

Feces (63%; 53% as unchanged drug); urine (22%; 2% as unchanged drug)

Time to Peak

4 to 6 hours

Half-Life Elimination

Terminal: 42 hours

Protein Binding

91%

Non-small cell lung cancer, metastatic: Treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive or are ROS1-positive (as detected by an approved test)

Hepatotoxicity prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); crizotinib undergoes extensive hepatic metabolism and systemic exposure may be increased with impairment; use with caution.

Hepatotoxicity during treatment:

Grade 3 or 4 ALT or AST elevation (ALT or AST >5 x ULN) with ≤ grade 1 total bilirubin elevation (total bilirubin ≤1.5 x ULN): Withhold treatment until recovery to baseline or ≤ grade 1 (<3 x ULN), then resume at a reduced dose (200 mg twice daily).

Recurrent grade 3 or 4 ALT or AST elevation with ≤ grade 1 total bilirubin elevation: Withhold treatment until recovery to baseline or ≤ grade 1, then resume at the next lower reduced dose (250 mg once daily).

Recurrent grade 3 or 4 ALT or AST elevation on 250 mg once daily: Permanently discontinue.

Grade 2, 3, or 4 ALT or AST elevation (ALT or AST >3 x ULN) with concurrent grade 2, 3, or 4 total bilirubin elevation (>1.5 x ULN) in the absence of cholestasis or hemolysis: Permanently discontinue.

Applies to crizotinib: oral capsule

Cardiovascular

Common (1% to 10%): Electrocardiogram QT prolonged, bradycardia[Ref]

Hepatic

Very common (10% or more): ALT elevation (up to 76%), AST elevation (up to 61%)
Common (1% to 10%): Increased alkaline phosphatase, hepatic failure[Ref]

Hematologic

Very common (10% or more): Lymphopenia (up to 51%), neutropenia (up to 49%), anemia (up to 17%)
Common (1% to 10%): Leukopenia[Ref]

Respiratory

Very common (10% or more): Upper respiratory infection (up to 26%)
Common (1% to 10%): Pulmonary embolism, interstitial lung disease[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 60%), nausea (up to 55%), vomiting (up to 47%), constipation (up to 42%)
Common (1% to 10%): Dyspepsia, gastrointestinal perforation[Ref]

Ocular

Very common (10% or more): Vision disorders (up to 60%)[Ref]

Vision disorders included diplopia, photophobia, photopsia, blurred vision, reduced vision acuity, visual impairment, and vitreous floaters.[Ref]

Dermatologic

Common (1% to 10%): Rash[Ref]

General

The most common adverse reactions (25% or more) are vision disorder, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.[Ref]

Metabolic

Very common (10% or more): Hypophosphatemia (up to 28%), decreased appetite (up to 27%), hypokalemia (up to 18%), decreased weight (up to 10%)[Ref]

Nervous system

Neuropathy included dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, polyneuropathy, and skin burning sensation.[Ref]

Very common (10% or more): Dysgeusia (up to 26%), dizziness (up to 22%), neuropathy (up to 19%)
Common (1% to 10%): Syncope[Ref]

Other

Edema included face edema, generalized edema, local swelling, localized edema, peripheral edema, and periorbital edema.[Ref]

Very common (10% or more): Edema (up to 39%), fatigue (up to 27%)[Ref]

Renal

Common (1% to 10%): Renal cyst[Ref]

Some side effects of crizotinib may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Use with caution as hepatic impairment is likely to increase plasma concentrations of the drug.

Severe renal impairment (CrCl less than 30 mL/min) not requiring dialysis: 250 mg orally once a day

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.