Axitinib

INLYTA is a kinase inhibitor indicated: • in combination with avelumab, for the first-line treatment of patients with advanced renal cell carcinoma (RCC). • in combination with pembrolizumab, for the first-line treatment of patients with advanced RCC. • as a single agent, for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.

Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.

• INLYTA 5 mg orally twice daily with avelumab 800 mg every 2 weeks. • INLYTA 5 mg orally twice daily with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks. • INLYTA as a single agent the starting dose is 5 mg orally twice daily. • Dose adjustments can be made based on individual safety and tolerability. • Administer INLYTA dose approximately 12 hours apart with or without food. • INLYTA should be swallowed whole with a glass of water. • See Full Prescribing Information for dosage modifications for adverse reactions. • If a strong CYP3A4/5 inhibitor is required, decrease the INLYTA dose by approximately half. • For patients with moderate hepatic impairment, decrease the starting dose by approximately half.

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• 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. • 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. • Hemorrhage: Hemorrhagic events, including fatal events, have been reported.

The following clinically significant adverse reactions are discussed elsewhere in the labeling: • Hypertension • Arterial thromboembolic events • Venous thromboembolic events • Hemorrhage • Cardiac failure • Gastrointestinal perforation and fistula formation • Thyroid dysfunction • Reversible posterior leukoencephalopathy syndrome • Proteinuria • Hepatotoxicity • Hepatic impairment 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.

• Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the INLYTA dose. • Avoid strong CYP3A4/5 inducers. 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. CYP3A4/5 Inducers Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).