Axinix

1 INDICATIONS AND USAGE INLYTA is a kinase inhibitor indicated: • in combination with avelumab, for the first-line treatment of patients with advanced renal cell carcinoma (RCC). ( 1.1 ) • in combination with pembrolizumab, for the first-line treatment of patients with advanced RCC. ( 1.1 ) • as a single agent, for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. ( 1.2 ) 1.1 First-Line Advanced Renal Cell Carcinoma INLYTA in combination with avelumab is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). INLYTA in combination with pembrolizumab is indicated for the first-line treatment of patients with advanced RCC. 1.2 Second-Line Advanced Renal Cell Carcinoma INLYTA as a single agent is indicated for the treatment of advanced RCC after failure of one prior systemic therapy.

2 DOSAGE AND ADMINISTRATION • INLYTA 5 mg orally twice daily with avelumab 800 mg every 2 weeks. ( 2.1 ) • INLYTA 5 mg orally twice daily with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks. ( 2.1 ) • INLYTA as a single agent the starting dose is 5 mg orally twice daily. ( 2.1 ) • Dose adjustments can be made based on individual safety and tolerability. ( 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 ) • See Full Prescribing Information for dosage modifications for adverse reactions. ( 2.2 ) • 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 ) 2.1 Recommended Dosing First-Line Advanced RCC INLYTA in Combination with Avelumab The recommended starting dosage of INLYTA is 5 mg orally taken twice daily (12 hours apart) with or without food in combination with avelumab 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. When INLYTA is used in combination with avelumab, dose escalation of INLYTA above the initial 5 mg dose may be considered at intervals of two weeks or longer. Review the Full Prescribing Information for recommended avelumab dosing information. INLYTA in Combination with Pembrolizumab The recommended starting dosage of INLYTA is 5 mg orally twice daily (12 hours apart) with or without food in combination with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. When INLYTA is used in combination with pembrolizumab, dose escalation of INLYTA above the initial 5 mg dose may be considered at intervals of six weeks or longer. Review the Full Prescribing Information for recommended pembrolizumab dosing…

12.2 Pharmacodynamics The effect of a single oral dose of INLYTA (5 mg) in the absence and presence of 400 mg ketoconazole on the QTc interval was evaluated in a randomized, single-blinded, two-way crossover study in 35 healthy subjects. No large changes in mean QTc interval (i.e., >20 ms) from placebo were detected up to 3 hours post-dose. However, small increases in mean QTc interval (i.e., <10 ms) cannot be ruled out.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling [see Warnings and Precautions (5) ] : • Hypertension [see Warnings and Precautions (5.1) ] • Arterial thromboembolic events [see Warnings and Precautions (5.2) ] • Venous thromboembolic events [see Warnings and Precautions (5.3) ] • Hemorrhage [see Warnings and Precautions (5.4) ] • Cardiac failure [see Warnings and Precautions (5.5) ] • Gastrointestinal perforation and fistula formation [see Warnings and Precautions (5.6) ] • Thyroid dysfunction [see Warnings and Precautions (5.7) ] • Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.9) ] • Proteinuria [see Warnings and Precautions (5.10) ] • Hepatotoxicity [see Warnings and Precautions (5.11) ] • Hepatic impairment [see Warnings and Precautions (5.12) ] Most common adverse reactions (≥20%) are: INLYTA in combination with avelumab: diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache. ( 6.1 ) INLYTA in combination with pembrolizumab: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. ( 6.1 ) INLYTA as a single agent: 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 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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…

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS • Hypertension: Hypertension including hypertensive crisis has been observed. Blood pressure should be well-controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. Withhold and then dose reduce INLYTA or permanently discontinue based on severity of hypertension. ( 5.1 ) • Arterial and Venous Thromboembolic Events: 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. Permanently discontinue INLYTA if an arterial thromboembolic event occurs during treatment. Withhold INLYTA and then resume at same dose or permanently discontinue based on severity of VTE. ( 5.2 , 5.3 ) • Hemorrhage: 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. Withhold and then dose reduce INLYTA or discontinue based on severity and persistence of hemorrhage. ( 5.4 ) • Cardiac Failure: 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 dose reduction, dose interruption or permanent discontinuation of INLYTA. ( 5.5 ) • Gastrointestinal Perforation and Fistula Formation: Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. ( 5.6 ) • Hypothyroidism: Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. ( 5.7 ) • Impaired Wound Healing: Withhold INLYTA for at least 2 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. Resume INLYTA at a reduced dose or…

7 DRUG INTERACTIONS • Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the INLYTA dose. ( 2.2 , 7.1 ) • Avoid strong CYP3A4/5 inducers. ( 7.2 ) 7.1 CYP3A4/5 Inhibitors Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-administered, the INLYTA dose should be reduced [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] . 7.2 CYP3A4/5 Inducers Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, and St. John's wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ] . Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible.