warnings and cautions
5 WARNINGS AND PRECAUTIONS Stomatitis: REVTORPYK can cause severe stomatitis, including mouth ulcers. Initiate steroid-containing alcohol-free mouthwash prior to starting treatment. Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity. ( 2.3 , 2.4 , 5.1 ) Dermatologic Adverse Reactions: REVTORPYK can cause severe rash. Monitor patients for rash and infectious sequelae. Instruct patients to limit sun exposure during REVTORPYK treatment. Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity. ( 2.4 , 5.2 ) Hyperglycemia: REVTORPYK can cause severe hyperglycemia. Evaluate blood glucose levels and hemoglobin A1c prior to starting and at regular intervals during treatment. Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity. ( 2.4 , 5.3 ) Embryo-Fetal Toxicity: REVTORPYK can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. Refer to the Prescribing Information of palbociclib and fulvestrant for pregnancy and contraception information. ( 5.4 , 8.1 , 8.3 ) 5.1 Stomatitis REVTORPYK can cause severe stomatitis, including ulcers and oral mucositis. In Study 1 of VIKTORIA-1, stomatitis occurred in 72% of patients treated with REVTORPYK with fulvestrant and palbociclib, including Grade 3 events in 22% of patients. Prophylactic steroid-containing alcohol-free mouthwash was required for a minimum of 8 weeks. The median time to onset was 7 days (range: 1 to 457 days). Stomatitis led to REVTORPYK dose reduction in 19% and permanent discontinuation in 3.8% of patients. Stomatitis occurred in 58% of patients treated with REVTORPYK with fulvestrant, including Grade 3 events in 12% of patients. The median time to onset was 4 days (range: 1 to 524 days). Stomatitis led to REVTORPYK dose reduction in 9% and permanent discontinuation in 1.5% of patients. Prophylactically initiate steroid-containing alcohol-free mouthwash to reduce the incidence and severity of stomatitis [see Dosage and Administration (2.3) ] . If stomatitis occurs, increase the frequency of mouthwash and administer other topical treatments as clinically indicated. Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity [see Dosage and Administration (2.4) ] . 5.2 Dermatologic Adverse Reactions REVTORPYK can cause severe rash. In Study 1 of VIKTORIA-1, rash occurred in 30% of patients treated with REVTORPYK in combination with fulvestrant and palbociclib, including Grade 3 events in 6% of patients. The median time to onset was 21 days (range: 3 to 260 days) after starting REVTORPYK. Rash led to REVTORPYK dose reduction in 5% and permanent discontinuation in 0.8% of patients. Rash occurred in 40% of patients treated with REVTORPYK in combination with fulvestrant, including Grade 3 events in 5% of patients. Rash led to REVTORPYK dose reduction in 6% and permanent discontinuation in 0.8% of patients. The median time to onset was 31.5 days (range: 2 to 407 days) after starting REVTORPYK. Monitor patients receiving REVTORPYK for rash and infectious sequelae. Instruct patients to limit sun exposure during REVTORPYK treatment. Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity [see Dosage and Administration (2.4) ] . 5.3 Hyperglycemia Severe hyperglycemia can occur in patients treated with REVTORPYK. Hyperglycemia is associated with drugs that inhibit the PI3K/AKT/mTOR pathway. In Study 1 of VIKTORIA-1, increased fasting glucose (FG) from baseline occurred in 46% of patients treated with REVTORPYK in combination with fulvestrant and palbociclib, including Grade 1 (FG >ULN to 160 mg/dL) in 36% of patients, Grade 2 (FG >160 to 250 mg/dL) in 8% of patients and Grade 3 (FG >250 to 500 mg/dL) in 0.9% of patients. Increased fasting glucose from baseline occurred in 57% of patients treated with REVTORPYK in combination with fulvestrant, including Grade 1 in 44% of patients, Grade 2 in 11% of patients and Grade 3 in 1.8% of patients. The safety of REVTORPYK in patients with Type 1 or uncontrolled Type 2 diabetes mellitus has not been established as these patients were excluded from Study 1 of VIKTORIA-1 [see Clinical Studies (14) ] . Before initiating treatment with REVTORPYK, test fasting glucose levels (FPG or FBG), HbA1c levels, and optimize fasting glucose. Achieve optimal glucose control before starting each REVTORPYK infusion [see Dosage and Administration (2.4) ] . Manage hyperglycemia with anti-hyperglycemic medications. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of FG levels. Consider consultation with a healthcare professional experienced in the treatment of hyperglycemia. Initiate at-home glucose monitoring for patients with HbA1c level >6.4%. Advise patients of the signs and symptoms of hyperglycemia and counsel patients on lifestyle changes. Withhold, reduce dose, or permanently discontinue REVTORPYK based on severity [see Dosage and Administration (2.4) ] . 5.4 Embryo-Fetal Toxicity Based on its mechanism of action, REVTORPYK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Inhibition of PI3K and mTOR pathways have been associated with adverse embryo-fetal growth and lethality in animals. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with REVTORPYK and for 2 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with REVTORPYK and for 2 weeks after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] . REVTORPYK is used in combination with fulvestrant, with or without palbociclib. Refer to the Prescribing Information of fulvestrant and palbociclib for pregnancy and contraception information. When REVTORPYK is used in combination, advise patients to use effective contraception during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.