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.
Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for, 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.
Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment.
INLYTA has the potential to adversely affect wound healing. Withhold INLYTA for at least 2 days prior to elective surgery. Do not administer INLYTA for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming INLYTA after resolution of wound healing complications has not been established.
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 with INLYTA.
Liver enzyme elevation has occurred during treatment with INLYTA as a single agent. INLYTA in combination with pembrolizumab can cause hepatotoxicity with higher than expected frequencies of Grades 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Monitor ALT, AST, and bilirubin before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used for monotherapy. Consider withholding INLYTA and/or pembrolizumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life-threatening hepatotoxicity.
For patients with moderate hepatic impairment, the starting dose of INLYTA should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.
INLYTA can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception. When INLYTA is used in combination with pembrolizumab, refer to the full Prescribing Information of pembrolizumab for pregnancy and contraception information.
Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose of INLYTA. 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.
Fatal adverse reactions (ARs) occurred in 3.3% of patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism, and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.
The most common (≥20%) ARs (all grades, vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC were diarrhea (56% vs 45%), fatigue/asthenia (52% vs 51%), hypertension (48% vs 48%), hepatotoxicity (39% vs 25%), nausea (28% vs 32%), constipation (21% vs 15%), hypothyroidism (35% vs 32%), decreased appetite (30% vs 29%), palmar-plantar erythrodysesthesia (28% vs 40%), stomatitis/mucosal inflammation (27% vs 41%), rash (25% vs 21%), dysphonia (25% vs 3.3%), and cough (21% vs 14%).
The most common (≥20%) Grade 3/4 ARs (vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC were hypertension (24% vs 20%) and hepatotoxicity (20% vs 4.9%).
The most common (≥20%) lab abnormalities (all grades, vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC included hyperglycemia (62% vs 54%), increased ALT (60% vs 44%), increased AST (57% vs 56%), increased creatinine (43% vs 40%), hyponatremia (35% vs 29%), hyperkalemia (34% vs 22%), hypoalbuminemia (32% vs 34%), hypercalcemia (27% vs 15%), hypophosphatemia (26% vs 49%), increased alkaline phosphatase (26% vs 30%), hypocalcemia (22% vs 29%), increased blood bilirubin (22% vs 21%), prolonged activated partial thromboplastin time (22% vs 14%), lymphopenia (33% vs 46%), anemia (29% vs 65%), and thrombocytopenia (27% vs 78%).
The most common (≥20%) ARs (all grades, vs sorafenib) in patients receiving INLYTA as second-line treatment for advanced RCC 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%), palmar-plantar erythrodysesthesia 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 ARs (vs sorafenib) occurring in patients receiving INLYTA as second-line treatment for advanced RCC were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%).
The most common (≥20%) lab abnormalities (all grades, vs sorafenib) occurring in patients receiving INLYTA as second-line treatment for advanced RCC 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%).