INLYTA (axitinib) Patient Management

Transcription

1 A nurse s handbook about INLYTA (axitinib) tablets INLYTA (axitinib) Patient Management INLYTA (axitinib) for the treatment of advanced RCC after failure of one prior systemic therapy Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis

2 AXIS was designed to evaluate INLYTA in an EXCLUSIVELY 2nd-line mrcc patient population TRIAL OVERVIEW Multicenter, open-label, phase 3 trial of 723 patients with mrcc after failure of 1st-line therapy Patients were randomized 1:1 to either INLYTA 5 mg twice daily (n=361) or sorafenib 400 mg twice daily (n=362) and were stratified by ECOG performance status (0 or 1) and prior therapy 1 The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), overall survival (OS), and safety and tolerability 1,2 CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; HR=hazard ratio; mrcc=metastatic renal cell carcinoma; RECIST=Response Evaluation Criteria in Solid Tumors. Patients in the phase 3 trial had been treated with one prior systemic therapy containing sunitinib (54%), cytokine(s) (35%), bevacizumab (8%), or temsirolimus (3%) ECOG performance status (both INLYTA and sorafenib): 0 (55%) and 1 (45%) INLYTA (axitinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis The most common ( 20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%) 2

3 In the phase 3 AXIS trial, after failure of one prior systemic therapy INLYTA proven superior progression-free survival vs sorafenib in 2nd-line mrcc In the phase 3 head-to-head AXIS trial PRIMARY ENDPOINT SECONDARY ENDPOINTS Superior PFS with INLYTA (n=361) vs sorafenib (n=362) HR=0.67 (95% CI: 0.54, 0.81); P<.0001 Median PFS with INLYTA was 6.7 months vs 4.7 months with sorafenib 95% CI: 6.3, 8.6 and 4.6, 5.6, respectively INLYTA more than doubled ORR vs sorafenib ORR was 19.4% with INLYTA (n=361) (95% Cl: 15.4, 23.9) and 9.4% with sorafenib (n=362) (95% Cl: 6.6, 12.9) Risk ratio=2.06 (95% Cl: 1.4, 3.0) The P value for the risk ratio is not included because it was not adjusted for multiple testing All responses were partial responses per RECIST criteria 1 OS HR=0.97 (95% Cl: 0.80, 1.17); P=NS The difference between the treatment arms was not statistically significant Median OS was 20.1 months with INLYTA (n=361) (95% Cl: 16.7, 23.4) and 19.2 months with sorafenib (n=362) (95% Cl: 17.5, 22.3) AXIS is the ONLY positive phase 3 trial designed to evaluate an exclusively 2nd-line patient population. 1 * *Based on MEDLINE literature review for phase 3 trials in mrcc as of August Important Safety Information The most common ( 10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%) The most common ( 20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%) 3

4 Oral dosing for your patients STARTING DOSE: 5 mg TWICE DAILY DOSE ADJUSTMENTS CAN BE MADE BASED ON INDIVIDUAL AND TOLERABILITY Administer doses approximately 12 hours apart Swallow whole with a glass of water May be taken with or without food The half-life of INLYTA ranges from 2.5 to 6.1 hours, which supports twice-daily dosing For patients with moderate hepatic impairment (Child-Pugh class B) or those concomitantly receiving strong CYP3A4/5 inhibitor, reduce the starting dose by approximately half. 5 mg 1 mg Tablets shown are not actual size. Do not break apart INLYTA tablets Film-coated tablets in 2 different strengths allow for titration. INLYTA (axitinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment 4

5 Dose titration Management of some AEs may require temporary interruption or permanent discontinuation and/or dose reduction. Starting dose: 5 mg TWICE DAILY 2 mg TWICE TWICE TWICE TWICE DAILY DAILY DAILY DAILY 3 mg 7 mg 10 mg If a dose reduction from the starting dose is required: Reduce dose to 3 mg twice daily Reduce dose to 2 mg twice daily if additional dose reduction is required Dose increase criteria: Patients tolerate INLYTA for at least 2 consecutive weeks with no AEs >grade 2 and are normotensive without antihypertension medication Dose may be increased to 7 mg twice daily if patients meet dose increase criteria at the starting dose Dose may be further increased to 10 mg twice daily if patients meet the dose increase criteria at the 7-mg dose TIP Keeping track of patients side effects while they re taking INLYTA is very important. Please see strategies to help manage certain side effects on pages Important Safety Information Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers 5

6 Strong inhibitors or inducers of CYP3A4/5 may affect INLYTA plasma concentrations INLYTA is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1 INHIBITORS Avoid coadministration of INLYTA with strong CYP3A4/5 inhibitors Selection of an alternate concomitant medication is recommended If INLYTA must be administered with a strong CYP3A4/5 inhibitor, the dose of INLYTA should be reduced INDUCERS Avoid coadministration of INLYTA with strong CYP3A4/5 inducers Moderate CYP3A4/5 inducers may also reduce INLYTA plasma exposure and should be avoided if possible INLYTA (axitinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment 6

7 Examples of CYP3A4/5 inhibitors and inducers INHIBITORS Strong inhibitors ketoconazole itraconazole clarithromycin atazanavir indinavir nefazodone nelfinavir ritonavir saquinavir telithromycin voriconazole Strong inducers rifampin dexamethasone phenytoin carbamazepine rifabutin rifapentin phenobarbital Hypericum perforatum (St John s wort) INDUCERS Moderate inducers bosentan efavirenz etravirine modafinil nafcillin Grapefruit or grapefruit juice may also increase INLYTA concentrations. Important Safety Information Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA 7

8 Summary of Warnings and Precautions Hypertension including hypertensive crisis has been observed. Arterial and venous thrombotic events have been observed and can be fatal. Hemorrhagic events, including fatal events, have been reported. Cardiac failure has been observed and can be fatal. Gastrointestinal perforation and fi s t ula, including death, have occurred. Hypothyroidism requiring thyroid hormone replacement has been reported. Blood pressure should be well controlled prior to initiating INLYTA Monitor for hypertension and treat as needed For persistent hypertension, despite use of antihypertensive medications, reduce the dose of INLYTA Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis Use with caution in patients who are at increased risk or who have a history of these events INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA Management of cardiac failure may require permanent discontinuation of INLYTA Use with caution in patients at risk for gastrointestinal perforation or fistula Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment Monitor thyroid function before initiation of, and periodically throughout, treatment 8

9 Summary of Warnings and Precautions (cont d) Wound healing complications Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. Proteinuria Liver enzyme elevation has been observed during treatment. Hepatic impairment Pregnancy No formal studies of the effect of INLYTA on wound healing have been conducted Stop INLYTA at least 24 hours prior to scheduled surgery If signs or symptoms occur, permanently discontinue treatment Monitor for proteinuria before initiation of, and periodically throughout, treatment For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment For patients with moderate hepatic impairment, the starting dose should be decreased INLYTA has not been studied in patients with severe hepatic impairment Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA 9

10 Safety profile demonstrated in the phase 3, head-to-head AXIS trial vs sorafenib All-causality AEs occurring in 10% of patients who received INLYTA or sorafenib ADVERSE EVENT * National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. INLYTA (n=359) ALL GRADES* GRADE 3/4* sorafenib (n=355) ALL GRADES* GRADE 3/4* Diarrhea 55% 11% 53% 7% Hypertension 40% 16% 29% 11% Fatigue 39% 11% 32% 5% Decreased appetite 34% 5% 29% 4% Nausea 32% 3% 22% 1% Dysphonia 31% 0% 14% 0% Palmar-plantar erythrodysesthesia syndrome 27% 5% 51% 16% Weight decreased 25% 2% 21% 1% Vomiting 24% 3% 17% 1% Asthenia 21% 5% 14% 3% Constipation 20% 1% 20% 1% Hypothyroidism 19% <1% 8% 0% Cough 15% 1% 17% 1% Mucosal inflammation 15% 1% 12% 1% Arthralgia 15% 2% 11% 1% Stomatitis 15% 1% 12% 1% Dyspnea 15% 3% 12% 3% Abdominal pain 14% 2% 11% 1% Headache 14% 1% 11% 0% Pain in extremity 13% 1% 14% 1% Rash 13% <1% 32% 4% Proteinuria 11% 3% 7% 2% Dysgeusia 11% 0% 8% 0% Dry skin 10% 0% 11% 0% Dyspepsia 10% 0% 2% 0% Pruritus 7% 0% 12% 0% Alopecia 4% 0% 32% 0% Erythema 2% 0% 10% <1% INLYTA (axitinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. 10

11 Fewer patients discontinued INLYTA due to AEs vs sorafenib in the phase 3 AXIS trial Discontinuation rates due to all-causality AEs Patients (%) % 13 % Overall, 61% of patients receiving INLYTA discontinued treatment vs 71% of patients receiving sorafenib In both study groups, the most common reasons for discontinuation included disease progression or relapse and AEs 1 Fewer patients receiving INLYTA had dose modifications or temporary delay of treatment due to AEs compared with patients receiving sorafenib (55% vs 62%, respectively) 0 INLYTA (n=359) sorafenib (n=355) TIP Make sure patients know the side effects they may experience and what to do if they develop certain side effects. Review treatment plans with your patients and provide them with all necessary contact information. Please see strategies to help manage certain side effects on pages Important Safety Information Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers 11

12 Safety profile demonstrated in the phase 3, head-to-head AXIS trial vs sorafenib Laboratory abnormalities occurring in 10% of patients who received INLYTA or sorafenib LABORATORY ABNORMALITY n INLYTA ALL GRADES* GRADE 3/4* n sorafenib ALL GRADES* HEMATOLOGY Hemoglobin decreased % <1% % 4% Lymphocytes (absolute) decreased % 3% % 4% Platelets decreased % <1% % 0% White blood cells decreased % 0% % <1% CHEMISTRY Creatinine increased % 0% % <1% Bicarbonate decreased % <1% % 0% Hypocalcemia % 1% % 2% ALP increased % 1% % 1% Hyperglycemia % 2% % 2% Lipase increased % 5% % 15% Amylase increased % 2% % 2% ALT increased % <1% % 2% AST increased % <1% % 1% Hypernatremia % 1% % 1% Hypoalbuminemia % <1% % 3% Hyperkalemia % 3% % <1% Hypoglycemia % <1% 319 8% 1% Hyponatremia % 4% % 2% Hypophosphatemia % 2% % 16% GRADE 3/4* * National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. INLYTA (axitinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. 12

13 Concomitant medications Ask your patients about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tell them that INLYTA and certain other medicines can affect each other, causing serious side effects ASK YOUR PATIENTS IF THEY ARE TAKING Dexamethasone Bosentan Modafinil St John s wort (Hypericum perforatum) Tell your patients: To talk to their doctor or pharmacist if they are not sure if their medicine is one listed above If they are taking any medicines for the conditions listed above, their doctor may need to prescribe a different medicine or change their dose of INLYTA To talk with their doctor before they start taking any new medicine TIP Important Safety Information Medicine for: Asthma Tuberculosis Seizures Bacterial infections Fungal infections Depression HIV/AIDS Advise your patients to know the medicines they take and to keep a list of them to show their doctor and pharmacist when they get a new medicine. The most common ( 20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%) The most common ( 10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%) 13

14 Tips to help manage certain side effects The tips in this section are based on published general guidelines for managing side effects common among people with advanced RCC or other cancers. Not all side effects are manageable. Dose interruptions and/or reductions may be needed during treatment. Patients should be sure to talk to their healthcare professional about any side effects they experience. High blood pressure Patients should be advised: Take antihypertensive medications as prescribed 3 Recognize signs of potentially dangerous high blood pressure (eg, severe headache, shortness of breath, nosebleeds) 4 Follow healthy lifestyle choices: regular exercise, weight control, moderate alcohol consumption, sodium restriction 3 Diarrhea Fatigue Over-the-counter or prescription medications may help manage this condition. 9,10 Patients should be advised: Take short naps and breaks instead of long ones 9,10 Eat well and drink plenty of fluids 9,10 Take short walks and/or do light exercise 9,10 Do relaxing activities as a distraction (eg, listening to music or reading) 9,10 Stay as active as possible 3 Try to maintain normal work and social schedules 3 Over-the counter medication may help treat this AE. 3,5-9 Patients should be advised: Eat yogurt containing probiotics Eat foods containing soluble fiber Eat small but frequent meals Drink fluids, such as water, diluted cranberry juice, broth, decaffeinated tea or coffee Decreased weight or appetite A registered dietitian (RD) may have additional ideas to offer. 11 Patients should be advised: Eat several small meals a day 5 or 6 isn t out of the question 9 Eat when hungry 9 Enjoy snacks and strive to make them nutritious. Find calories and protein in dried fruits, nuts, cheeses, and even milkshakes 9 Add gravy, butter, or cheese to favorite foods for added protein and calories 9 Drink fluids between meals rather than filling up with them during meals 11 Please see Important Safety Information throughout this brochure and full Prescribing Information attached. 14

15 Decreased weight or appetite (cont d) Ask a friend or family member to cook if they are feeling too tired. It can be surprising how many people are willing to help 11 If mouth pain makes eating difficult, consider avoiding spicy foods; eat foods that are soft, or use a straw for liquids 12 If taste changes affect eating, try cold or frozen foods to minimize taste; flavor foods with herbs, sugar, or sauces to maximize taste; and keep a clean and healthy mouth by brushing and fl o s s in go f te n 13 If an upset stomach makes it difficult to eat, avoid heavy meals, coffee, and alcohol; try sleeping in an upright position; and reduce stress with meditation, yoga, or music 9,14 Hand-foot syndrome Specific treatments that may include lotions, moisturizers, or pain medicines can help manage this condition. 17 Patients should be advised 17 : Wear loose cotton clothes Use sunscreen Clean hands and feet with lukewarm water instead of hot and gently pat dry Apply creams containing lanolin or urea to the hands and feet liberally and often Avoid tight-fitting shoes and jewelry or rubbing pressure on the hands and feet Do not shave off blisters Nausea/vomiting Prescription medications may be available to alleviate these symptoms. 9 Patients should be advised 9 : Avoid fatty, fried, spicy, or highly sweet foods Eat bland foods and drink clear liquids Eat smaller, more frequent meals Reduce food aromas and other stimuli with strong odors, and eat food at room temperature to lessen the odor Listen to soft music, watch a favorite television program, or enjoy the company of others Dysphonia Patients should be advised: Drink plenty of water and avoid irritants (eg, dust, smoke, alcohol, industrial chemicals) 15,16 Give their voice a break write things down 16 Avoid voice strain by not shouting or whispering 16 Constipation Patients should be advised 11 : Drink more fluids Take a stool softener Add fiber to their diet Increase physical activity Get an enema Please see Important Safety Information throughout this brochure and full Prescribing Information attached. 15

16 INitiate Now voucher program Pfizer is committed to helping eligible patients receive INLYTA therapy quickly. 15-Day Trial Voucher BIN: GROUP: MEMBER: XXXXXXXXXXX By enrolling in the 15-day trial voucher offer for INLYTA, you acknowledge that you currently meet the eligibility criteria and will comply with the Terms and Conditions described below: Voucher is valid for 15 days of dosing of INLYTA, not to exceed 10 mg once daily for 15 days, for new patients. No claim for reimbursement for product dispensed pursuant to this voucher may be submitted to any third-party payer, whether a private or government payer. This free trial voucher cannot be combined with any other rebate/coupon, free trial, or similar offer for the specified prescription. This free trial is not health insurance. Offer good only in the United States and Puerto Rico. Only patients new to INLYTA may use this voucher. By redeeming this voucher, you certify that you are not currently using INLYTA. Only 1 voucher per person may be redeemed under this program. This voucher is not transferable. Pfizer reserves the right to rescind, revoke, or amend this free trial voucher without notice. The free trial voucher expires 7/1/2016. Typical savings with this voucher for insured patients is estimated to be $147, or the full out-of-pocket cost (copay) for the insured patient for a 15-day prescription. To Pharmacist: Redeem only when affixed to a valid signed prescription for INLYTA (axitinib). Submit claim for maximum 15 days of INLYTA tablets to PDM using BIN Your customer will receive 15 days of therapy at no charge. For pharmacy processing questions, please call the help desk at EXPIRATION DATE: DD/MM/YYYY 7/1/2016. New patients can start therapy as soon as possible with a free 15-day trial of INLYTA regardless of coverage status* *Limits, terms, and conditions apply. Pfizer Co-Pay One savings program The Pfizer Co-Pay One program offers eligible, commercially insured patients: Pfizer Co-pay One Savings Card BIN: GROUP: ID#: XXXXXXXXXXX EXPIRATION DATE: 12/31/2015 DD/MM/YYYY Limits, terms, and conditions apply. This card is not health insurance. CO-PAY SAVINGS No more than $ 10 monthly out-of-pocket cost for the product below for eligible, commercially insured patients Please visit inlyta.com to see full Prescribing Information and Patient Information, including a complete discussion of the risks. There is no membership fee. I agree to the terms and conditions received with this card. Reduced out-of-pocket cost with no more than $10 spent per month Simple enrollment with no financial conditions, enrollment forms, or faxing Co-pay savings upon activation Limits, terms, and conditions apply. The offer will be accepted only at participating pharmacies. This offer is not health insurance. No membership fees apply. Please see savings card for complete terms and conditions. For any questions, please call or visit Pfizer Inc, 235 East 42nd Street, New York, NY INLYTA (axitinib) is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis The most common ( 20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%) 16

17 INLYTA is available through specific specialty pharmacies Contact the specialty pharmacy directly to fill a patient s prescription if one of the following applies: Your office knows the patient s specialty pharmacy that supplies the patient s medicine Your patient knows that the specialty pharmacy is covered in his/her plan and that the pharmacy is in the INLYTA network Your office uses a specialty pharmacy that is in the patient s network The provider s office Submits INLYTA prescriptions to the specialty pharmacy via: SPECIALTY PHARMACY ORDERING PROCESS The specialty pharmacy Verifies the patient s coverage for INLYTA Helps with prior authorization if required PHONE FAX INTERNET Submits any supporting documentation to the payer Can help patients seek co-pay assistance Schedules shipment of product to the patient s home Bills the payer for the cost of the product Bills the patient for remaining co-pay/coinsurance For questions or to determine the patient s specialty pharmacy, call Pfizer RxPathways at Important Safety Information The most common ( 20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%) The most common ( 10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%) 17

18 Pfizer RxPathways helps eligible patients get access to their Pfizer medicines by offering a range of support services.* Pfizer RxPathways offers 2 online resources to help you and your patients get started with the program: Pfizer RxPathways Provider Portal Enables you and your staff to: Begin the enrollment process for new patients Check patients enrollment history Verify patients benefits Reorder medicine for enrolled patients Track medicine shipments Receive alerts that highlight important tasks and events Pfizer RxPathways website Access more information about Pfizer RxPathways, download an application, or order program materials for your patients and/or to display in your waiting room. Pfizer RxPathways offers services for the: Insured Underinsured Uninsured For program information and questions, please call *Services vary by product. Pfizer RxPathways is a joint program of Pfizer Inc and the Pfizer Patient Assistance Foundation. 18

19 In the phase 3 AXIS trial, after failure of one prior systemic therapy INLYTA (axitinib) proven superior progression-free survival vs sorafenib in 2nd-line mrcc Superior PFS with INLYTA (n=361) vs sorafenib (n=362) HR=0.67 (95% CI: 0.54, 0.81); P<.0001 Median PFS with INLYTA was 6.7 months vs 4.7 months with sorafenib 95% CI: 6.3, 8.6 and 4.6, 5.6, respectively Checklist to help guide patients treatment expectations Explain to your patients that they are likely to have side effects while taking INLYTA Remind patients to communicate any side effects they have as soon as possible Emphasize the importance of tracking their side effects by explaining that their HCP may adjust their dose of INLYTA depending on the side effects they experience Ask patients about all the medicines they take, including prescription and nonprescription medicines, vitamins, and herbal supplements Review treatment plans with your patients and provide them with all necessary contact information Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis The most common ( 20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%) References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807): Data on file. Pfizer Inc, New York, NY. 3. Wood LS. Managing the side effects of sorafenib and sunitinib. Community Oncol. 2006;3(9): American Heart Association. Hypertensive crisis. HighBloodPressure/AboutHighBloodPressure/Hypertensive-Crisis_UCM_301782_Article.jsp. Accessed August 19, Muehlbauer PM, Thorpe D, Davis A, Drabot R, Rawlings BL, Kiker E. Putting evidence into practice: evidence-based interventions to prevent, manage, and treat chemotherapy- and radiotherapy-induced diarrhea. Clin J Oncol Nurs. 2009;13(3): Roigas J. Clinical management of patients receiving tyrosine kinase inhibitors for advanced renal cell carcinoma. Eur Urol Suppl. 2008;7(9): Wood LS. Management of vascular endothelial growth factor and multikinase inhibitor side effects. Clin J Oncol Nurs. 2009;13(suppl 6): Oncology Nursing Society. Putting evidence into practice (PEP): preventing and treating diarrhea related to chemotherapy and/or radiation therapy American Cancer Society. Caring for the patient with cancer at home: a guide for patients and families. Accessed August 19, National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Cancer-related fatigue. V Accessed August 20, American Cancer Society. Navigating cancer care: side effects. Accessed September 10, The Ohio State University Comprehensive Cancer Center: Arthur G. James Cancer Hospital & Richard J. Solove Research Institute. Cancer therapy: managing side effects mouth sores. Accessed September 10, Rehwaldt M, Wickham R, Purl S, Tariman J, et al. Self-care strategies to cope with taste changes after chemotherapy. Oncol Nurs Forum. 2009; 36(2):E47-E Cleveland Clinic. Diseases & conditions: indigestion. Accessed September 10, Schwartz SR, Cohen SM, Dailey SH, et al. Clinical practice guideline: hoarseness (dysphonia). Otolaryngol Head Neck Surg. 2009;141(3 suppl 2):S1-S Rosen CA, Anderson D, Murry T. Evaluating hoarseness: keeping your patient s voice healthy. Am Fam Physician. 1998;57(11): Kollmannsberger C, Bjarnason G, Burnett P, et al. Sunitinib in metastatic renal cell carcinoma: recommendations for management of noncardiovascular toxicities. Oncologist. 2011;16(5): AXU Pfizer Inc. All rights reserved. November 2015

20 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INLYTA safely and effectively. See full prescribing information for INLYTA. INLYTA (axitinib) tablets for oral administration Initial U.S. Approval: RECENT MAJOR CHANGES Warnings and Precautions, Cardiac Failure (5.5) 08/ INDICATIONS AND USAGE INLYTA is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. (1) DOSAGE AND ADMINISTRATION The starting dose is 5 mg orally twice daily. Dose adjustments can be made based on individual safety and tolerability. (2.1, 2.2) Administer INLYTA dose approximately 12 hours apart with or without food. (2.1) INLYTA should be swallowed whole with a glass of water. (2.1) If a strong CYP3A4/5 inhibitor is required, decrease the INLYTA dose by approximately half. (2.2) For patients with moderate hepatic impairment, decrease the starting dose by approximately half. (2.2) DOSAGE FORMS AND STRENGTHS mg and 5 mg tablets (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Hypertension including hypertensive crisis has been observed. Blood pressure should be well-controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. (5.1) Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for these events. (5.2, 5.3) Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. (5.4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing 2.2 Dose Modification Guidelines 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypertension and Hypertensive Crisis 5.2 Arterial Thromboembolic Events 5.3 Venous Thromboembolic Events 5.4 Hemorrhage 5.5 Cardiac Failure 5.6 Gastrointestinal Perforation and Fistula Formation 5.7 Thyroid Dysfunction 5.8 Wound Healing Complications 5.9 Reversible Posterior Leukoencephalopathy Syndrome 5.10 Proteinuria 5.11 Elevation of Liver Enzymes 5.12 Hepatic Impairment 5.13 Pregnancy 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 CYP3A4/5 Inhibitors 7.2 CYP3A4/5 Inducers 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food [see Clinical Pharmacology (12.3)]. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. 2.2 Dose Modification Guidelines Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions (5)]. If dose reduction from 5 mg twice Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. (5.5) Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. (5.6) Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. (5.7) Stop INLYTA at least 24 hours prior to scheduled surgery. (5.8) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. Permanently discontinue INLYTA if signs or symptoms of RPLS occur. (5.9) Monitor for proteinuria before initiation of, and periodically throughout, treatment with INLYTA. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment with INLYTA. (5.10) Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST and bilirubin before initiation of, and periodically throughout, treatment with INLYTA. (5.11) The starting dose of INLYTA should be decreased if used in patients with moderate hepatic impairment. INLYTA has not been studied in patients with severe hepatic impairment. (2.2, 5.12) INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. (5.13, 8.1) ADVERSE REACTIONS The most common ( 20%) adverse reactions are diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc at or FDA at FDA-1088 or DRUG INTERACTIONS Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the INLYTA dose. (2.2, 7.1) Avoid strong CYP3A4/5 inducers. (7.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling Revised: 8/ Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Hypertension 17.2 Arterial/Venous Thromboembolic Events 17.3 Hemorrhage 17.4 Cardiac Failure 17.5 Gastrointestinal Disorders 17.6 Abnormal Thyroid Function 17.7 Wound Healing Complications 17.8 Reversible Posterior Leukoencephalopathy Syndrome 17.9 Pregnancy Concomitant Medications *Sections or subsections omitted from the Full Prescribing Information are not listed. daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3 5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmaco kinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions (5.12), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

21 3 DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with Pfizer on one side and 1 XNB on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with Pfizer on one side and 5 XNB on the other side. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hypertension and Hypertensive Crisis In a controlled clinical study with INLYTA for the treatment of patients with RCC, hyper - tension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmhg or diastolic blood pressure >100 mmhg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)]. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension [see Dosage and Administration (2.2)]. 5.2 Arterial Thromboembolic Events In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)]. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. 5.3 Venous Thromboembolic Events In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. 5.4 Hemorrhage In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. 5.5 Cardiac Failure In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA. 5.6 Gastrointestinal Perforation and Fistula Formation In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastro intestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastro intestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. 5.7 Thyroid Dysfunction In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypo thyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 µu/ml before treatment, elevations of TSH to 10 µu/ml occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib [see Adverse Reactions (6.1)]. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. 5.8 Wound Healing Complications No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. 5.9 Reversible Posterior Leukoencephalopathy Syndrome In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions (6.1)]. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known Proteinuria In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib [see Adverse Reactions (6.1)]. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment Elevation of Liver Enzymes In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA Hepatic Impairment The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)] Pregnancy INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described [see Adverse Reactions (6.1)] reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib [see Clinical Studies (14)]. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label [see Warnings and Precautions ( )]: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, cardiac failure, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, hepatic impairment and fetal development. 6.1 Clinical Trials Experience The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common ( 20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. Table 1 presents adverse reactions reported in 10% patients who received INLYTA or sorafenib.