FYARRO

1 INDICATIONS AND USAGE FYARRO ® is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). FYARRO is an mTOR inhibitor indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of FYARRO is 100 mg/m 2 administered as an IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of FYARRO is 100 mg/m 2 administered as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. 2.2 Dosage Modifications for Adverse Reactions Table 1 lists the recommended dose reductions of FYARRO for adverse reactions. Table 1. Recommended dose reductions of FYARRO for adverse reactions. *Permanently discontinue FYARRO in patients who are unable to tolerate FYARRO after three dose reductions. Dose Reduction Dose First Dose Reduction 75 mg/m 2 (25% reduction from 100 mg/m 2 ) Second Dose Reduction 56 mg/m 2 (25% reduction from 75 mg/m 2 ) Third Dose Reduction* 45 mg/m 2 (20% reduction from 56 mg/m 2 ) Table 2 lists the recommended dosage modifications of FYARRO for adverse reactions. Table 2. Recommended FYARRO Dosage Modifications for Adverse Reactions *Severity based on Common Terminology Criteria for Adverse Events Version 4.03. Adverse Reaction Severity* Dosage Modifications Stomatitis [see Warnings and Precautions ( 5.1 )] Grade 2 or 3 Withhold FYARRO until Grade ≤1. Restart at the same dose for first occurrence. If recurs, restart at reduced dose level. Grade 4 Permanently discontinue FYARRO. Anemia [see Warnings and Precautions ( 5.2 )] Grade 2 Withhold FYARRO until Hb ≥8 g/dL. Restart at the same dose level. Grade ≥3 Withhold FYARRO until Hb ≥8 g/dL. Restart at the same dose level. If recurs, resume at reduced dose level. Thrombocytopenia [see Warnings and Precautions ( 5.2 )] Grade 2 Withhold FYARRO until platelet count >100×10 9 /L. Restart at the same dose level. Grade ≥3 Withhold FYARRO until platelet count >100×10 9 /L. Restart at reduced dose level. Neutropenia [see Warnings and Precautions ( 5.2 )] Grade 2 or 3 Withhold FYARRO until absolute neutrophil count ≥1.5×10 9 /L. Restart at the same dose level. Grade 4 Withhold FYARRO until absolute neutrophil count ≥1.5×10 9 /L. Restart at reduced dose level. Infections [see Warnings and Precautions ( 5.3 )] Grade 3 Withhold FYARRO until resolved. Restart at reduced dose level. If recurs, permanently discontinue FYARRO. Grade 4 Withhold FYARRO until resolved. Restart at reduced dose level or permanently discontinue FYARRO. Hypokalemia [see Warnings and Precautions ( 5.4 )] Grade 2 Withhold FYARRO until Grade ≤1. Restart at the same dose level. If recurs, restart at reduced dose level. Grade ≥3 Withhold FYARRO until Grade ≤1. Restart at reduced dose level. If recurs, permanently discontinue FYARRO. Hyperglycemia [see Warnings and Precautions ( 5.5 )] Grade ≥3 Withhold FYARRO until Grade ≤2. Restart at reduced dose level. Interstitial Lung Disease / Non- Infectious Pneumonitis [see Warnings and Precautions ( 5.6 )] Grade 2 Withhold FYARRO for up to 3 weeks until Grade ≤1. Restart at reduced dose level. If not resolved to Grade ≤1 within 3 weeks, permanently discontinue FYARRO. If recurs, permanently discontinue FYARRO. Grade ≥3 Permanently discontinue FYARRO. Hemorrhage [see Warnings and Precautions ( 5.7 )] Grade 2 or 3 Withhold FYARRO until Grade ≤1. Resume at reduced dose. If recurs, permanently discontinue FYARRO. Grade 4 Permanently discontinue FYARRO. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 Withhold FYARRO until Grade ≤1. Restart at the same dose level. If recurs, restart at reduced dose level. Grade 4 Permanently discontinue FYARRO. 2.3 Dosage Modifications for Concomitant Use with CYP3A4 and/or P-gp Inhibitors and Inducers Reduce the dosage of FYARRO to 56 mg/m 2 when used concomitantly with a moderate or weak cytochrome P-450 3A4 (CYP3A4) inhibitor. Avoid concomitant use with drugs that are strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitors and inducers and with grapefruit and grapefruit juice [see Dru…

5 WARNINGS AND PRECAUTIONS Stomatitis : Withhold, resume at reduced dose, or permanently discontinue based on severity. ( 5.1 ) Myelosuppression : Monitor blood counts prior to and during FYARRO treatment as clinically indicated. Withhold, resume at reduced dose, or permanently discontinue based on severity. ( 5.2 ) Infections : May result from immunosuppression. Monitor for signs and symptoms of infection. Withhold, resume at reduced dose, or permanently discontinue based on severity. ( 5.3 ) Hypokalemia and hyperglycemia : Monitor serum potassium and glucose prior to starting FYARRO and as clinically indicated. Withhold, resume at reduced dose, or permanently discontinue based on severity. ( 5.4 , 5.5 ) ILD/Non-Infectious Pneumonitis : Monitor for new or worsening respiratory symptoms or radiological changes. Withhold, resume at reduced dose, or permanently discontinue based on severity. ( 5.6 ) Hemorrhage: Monitor for signs and symptoms. Withhold, resume at reduced dose, or permanently discontinue based on severity. ( 5.7 ) Hypersensitivity Reactions : Monitor for hypersensitivity during and following each FYARRO infusion. Monitor for at least 2 hours following completion of the first infusion and as clinically indicated for each subsequent infusion. Reduce the rate, interrupt infusion, or permanently discontinue based on severity. ( 5.8 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential hazard to the fetus and to use effective contraception. ( 5.9 ) Male Infertility : Azoospermia or oligospermia may occur. ( 5.10 ) Immunizations : Avoid live vaccines ( 5.11 ) 5.1 Stomatitis Stomatitis , including mouth ulcers and oral mucositis , occurred in 79% of patients treated with FYARRO, including 18% Grade 3. Stomatitis was most often first reported within 8 weeks of treatment. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 )] . 5.2 Myelosuppression FYARRO can cause myelosuppression including anemia, thrombocytopenia and neutropenia. Anemia occurred in 68% of patients; 6% were Grade 3. Thrombocytopenia and neutropenia occurred in 35% of patients each. Obtain blood counts at baseline and every 2 months for the first year of treatment and every 3 months thereafter, or more frequently if clinically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 )]. 5.3 Infections FYARRO can cause infections. Infections such as urinary tract infections (UTI), upper respiratory tract infections and sinusitis occurred in 59% of patients. Grade 3 infections occurred in 12% of patients, including a single case each of a UTI, pneumonia, skin, and abdominal infections. Monitor patients for infections, including opportunistic infections. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 )] . 5.4 Hypokalemia FYARRO can cause hypokalemia. Hypokalemia occurred in 44% of patients, including 12% Grade 3 events. Monitor potassium levels prior to starting FYARRO and implement potassium supplementation as medically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 )] . 5.5 Hyperglycemia FYARRO can cause hyperglycemia. Hyperglycemia occurred in 12% of patients treated with FYARRO, all of which were Grade 3 events. Monitor fasting serum glucose prior to starting FYARRO. During treatment, monitor serum glucose every 3 months in non-diabetic patients, or as clinically indicated. Monitor serum glucose more frequently in diabetic patients. Based on the severity of the adverse reaction, withhold, resume at redu…

4 CONTRAINDICATIONS FYARRO is contraindicated in patients with a history of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin [see Warnings and Precautions ( 5.8 )] . History of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin. ( 4 )

7 DRUG INTERACTIONS Strong CYP3A4 and/or P-gp Inhibitors or Inducers : Avoid concomitant use. ( 2.3 , 7.1 ) Moderate or Weak CYP3A4 Inhibitors : Reduce FYARRO dose. ( 2.3 , 7.1 ) 7.1 Effects of Other Drugs on FYARRO CYP3A4 and/or P-gp Inhibitors or Inducers CYP3A4 and/or P-gp inhibitors may increase sirolimus concentrations, which may increase the risk of FYARRO adverse reactions. CYP3A4 and/or P-gp inducers may decrease sirolimus concentrations, which may reduce FYARRO effectiveness. Strong CYP3A4 and/or P-gp Inhibitors or Inducers: Avoid concomitant use of FYARRO with strong CYP3A4 and/or P-gp inhibitors or strong CYP3A4 and/or P-gp inducers [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )] . Grapefruit or Grapefruit Juice: Avoid concomitant use of FYARRO with grapefruit or grapefruit juice. Moderate or Weak CYP3A4 Inhibitors: Reduce the dosage of FYARRO when used concomitantly with a moderate or weak CYP3A4 inhibitor [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )] . Moderate or Weak CYP3A4 Inducers: Use of FYARRO may result in decreased effectiveness.

8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action, FYARRO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . Although there are no data on the use of FYARRO in pregnant women, there are limited data on the use of sirolimus during pregnancy. In animal studies, oral sirolimus was embryo/fetotoxic in rats [see Data ] at sub-therapeutic doses. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Reproductive studies in animals have not been performed with FYARRO. Studies with an oral formulation of sirolimus have shown that it crosses the placenta and is toxic to the conceptus. In rat embryo-fetal development studies, pregnant rats were administered an oral formulation of sirolimus during the period of organogenesis (Gestational Day 6-15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg and reduced fetal weight at 1 mg/kg. The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg. Maternal toxicity (weight loss) was observed at 2 mg/kg. The NOAEL for maternal toxicity was 1 mg/kg. In rabbit embryo-fetal development studies, pregnant rabbits were administered an oral formulation of sirolimus during the period of organogenesis (Gestational Day 6-18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg; however, at doses of 0.05 mg/kg and above, the ability to sustain a pregnancy was impaired (i.e., embryo-fetal abortion or early resorption). Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg. In a pre- and post-natal development study in rats, pregnant females were dosed with an oral formation of sirolimus during gestation and lactation (Gestational Day 6 through Lactation Day 20). An increased incidence of dead pups occurred at 0.5 mg/kg, resulting in reduced live litter size. At 0.1 mg/kg, there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (e.g., morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest oral dose tested.

6 ADVERSE REACTIONS The following adverse reactions have been associated with FYARRO in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions ( 5 )] . Stomatitis [see Warnings and Precautions ( 5.1 )] Myelosuppression [see Warnings and Precautions ( 5.2 )] Infections [see Warnings and Precautions ( 5.3 )] Hypokalemia [see Warnings and Precautions ( 5.4 )] Hyperglycemia [see Warnings and Precautions ( 5.5 )] Interstitial Lung Disease (ILD) / Non-Infectious Pneumonitis [see Warnings and Precautions ( 5.6 )] Hemorrhage [see Warnings and Precautions ( 5.7 )] Hypersensitivity [see Warnings and Precautions ( 5.8 )] The most common (≥30%) adverse reactions were stomatitis, fatigue, rash, infection, nausea, edema, diarrhea, musculoskeletal pain, decreased weight, decreased appetite, cough, vomiting, and dysgeusia. ( 6.1 ) The most common (≥6%) Grade 3 to 4 laboratory abnormalities were decreased lymphocytes, increased glucose, decreased potassium, decreased phosphate, decreased hemoglobin, and increased lipase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aadi Bioscience, Inc. at 1-888-BIO-AADI (888-246-2234) 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 clinical trials of another drug and may not reflect the rates observed in practice. The safety of FYARRO was assessed in a single-arm study (AMPECT). Thirty-four patients received FYARRO 100 mg/m 2 on Days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity [see Clinical Studies ( 14.1 )] . Among the 34 patients who received FYARRO, 16 (47%) were exposed for 6 months or longer and 7 (21%) were exposed for greater than 1 year. The median age of patients who received FYARRO was 59.5 years (range 27 to 78 years), 82% were female and Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 (76%) or 1 (24%). Race was 71% White, 9% Black, 9% Asian, 3% Hawaiian/Pacific Islander and 9% Other/Not Reported. Ethnicity was 82% not Hispanic or Latino, 15% Hispanic or Latino, and 3% Not Reported. Serious adverse reactions occurred in 14 (41%) patients who received FYARRO. Serious adverse reactions in >5% of patients, including 4 (12%) patients with infection and 2 (6%) patients each with abdominal pain, dehydration, and upper gastrointestinal hemorrhage. Fatal adverse reactions occurred in 1 (2.9%) patient who received FYARRO and experienced upper gastrointestinal hemorrhage. Permanent discontinuation of FYARRO due to an adverse reaction occurred in 3 (9%) patients. Adverse reactions which resulted in permanent discontinuation of FYARRO included pneumonitis, anemia, and noninfective cystitis. Dosage interruptions of FYARRO due to an adverse reaction occurred in 22 (65%) patients. Adverse reactions which required dosage interruption in >5% of patients included stomatitis in 6 (18%) patients, pneumonitis in 5 (15%) patients, anemia in 3 (9%) patients, and dehydration, dermatitis acneiform, and thrombocytopenia in 2 (6%) patients each. Dose reductions of FYARRO due to an adverse reaction occurred in 12 (35%) patients. Adverse reactions which required dose reductions in >5% of patients included stomatitis and pneumonitis in 3 (9%) patients each. The most common adverse reactions (≥30%) were stomatitis in 27 (79%) patients, fatigue and rash in 23 (68%) patients each, infection in 20 (59%) patients, nausea and edema in 17 (50%) patients each, diarrhea, musculoskeletal pain and decreased weight in 16 (47%) patients each, decreased appetite in 15 (44%) patients, cough in 12 (35%) patients, and vomiting and dysgeusia in 11 (32%) patients each. The most common Grade 3 to 4 laboratory abnormalities (≥6%) were decreased lymphocytes in 7 (21%) patients, increased glucose and decreased potassium in …