Fyarro Drug Information

® 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).

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 . 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 4 (12%) patients each, decreased phosphate in 3 (9%) patients, and decreased hemoglobin and increased lipase in 2 (6%) patients each. Table 4 summarizes the adverse reactions in AMPECT. Table 4. Adverse Reactions ≥10% in Patients with PEComa Who Received FYARRO in AMPECT Grading according to NCI CTCAE Version 4.03 a Includes stomatitis, aphthous ulcer, mouth ulceration, esophageal ulcer b Includes diarrhea and enteritis c Includes abdominal pain, abdominal pain upper, and epigastric discomfort d Includes face edema, generalized edema, edema, edema peripheral, and periorbital edema e Includes dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and skin exfoliation f Includes all reported infections, including but not limited to, upper respiratory tract infection, urinary tract infection, sinusitis, skin infection, folliculitis, nasopharyngitis, pharyngitis, pharyngitis streptococcal, pneumonia, vaginal infection g Includes dysesthesia, hypoesthesia, neuropathy peripheral, paresthesia, and peripheral sensory neuropathy h Includes dizziness, dizziness postural, and vertigo i Includes arthralgia, back pain, musculoskeletal chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity j Includes cough, productive cough, and upper-airway cough syndrome k Includes dyspnea and dyspnea exertional l Includes epistaxis, hemorrhoidal hemorrhage, mouth hemorrhage, post procedural hemorrhage, and upper gastrointestinal hemorrhage.

Includes one fatal adverse reaction of upper GI hemorrhage *No Grade 4 reactions were reported FYARRO (N=34) Adverse Reaction All Grades (%) Grade 3 to 4* (%) Gastrointestinal Stomatitis a 79 18 Nausea 50 0 Diarrhea b 47

Vomiting 32 2.9 Abdominal Pain c 29 6 Constipation 24 2.9 Dry

Mouth 15 0 Hemorrhoids 12 0 General disorders Fatigue 68

Edema d 50 2.9 Pyrexia 24 0 Skin and subcutaneous tissue disorders

Rash e 68 0 Alopecia 24 0 Pruritus 18 0 Dry Skin 12 0 Nail disorder 12 0 Infections Infections f 59 12 Metabolism and nutrition Decreased appetite 44 0 Dehydration 15 6 Nervous system Dysgeusia 32 0 Headache 29 0 Peripheral neuropathy g 15 0 Dizziness h 12 0 Investigations Weight decreased 47 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain i 47

Respiratory, thoracic, and mediastinal disorders Cough j 35 0 Pneumonitis 18 0

Dyspnea k 12 0 Vascular disorders Hypertension 29

Hemorrhage l 24 2.9 Psychiatric disorders Insomnia 21 2.9 Eye disorders Vision

blurred 12 0 Table 5 summarizes the laboratory abnormalities in AMPECT. Table 5. Laboratory Abnormalities ≥10% That Worsened from Baseline in Patients with PEComa who Received FYARRO in AMPECT 1 Grading according to NCI CTCAE Version 4.03 2 The denominator used to calculate the rate varied from 33 to 34 based on the number of patients with a baseline value and at least one post-treatment value. FYARRO 2 (N=34) Laboratory Abnormality 1 All Grades (%) Grades 3 to 4 (%) Hematology Decreased lymphocytes 82 21 Decreased hemoglobin 68 6 Decreased leukocytes 41 0 Decreased neutrophils 35 0 Decreased platelets 35 0 Chemistry Increased creatinine 82 0 Increased triglycerides 52 0 Increased cholesterol 48 3 Increased alanine aminotransferase (ALT) 47

Decreased potassium 44 12 Decreased magnesium 42 0 Decreased albumin 35 2.9

Increased aspartate transaminase (AST) 32

Increased alkaline phosphatase 29 0 Decreased sodium 24 2.9 Decreased calcium 15

0 Decreased glucose 15 0 Decreased phosphate 15 9 Increased lipase 12 6 Increased glucose 12 12 Increased sodium 12 0 Clinically relevant adverse reactions occurring in <10% of patients included enteritis, edema, pancytopenia, acute kidney injury, and acute coronary syndrome.

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 . 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 . Moderate or Weak CYP3A4 Inducers: Use of FYARRO may result in decreased effectiveness.

Pregnancy Risk Summary Based on animal studies and the mechanism of action, FYARRO can cause fetal harm when administered to a pregnant woman . 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 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.

Pediatric Use The safety and efficacy of FYARRO in pediatric patients have not been established.

is contraindicated in patients with a history of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin . History of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin.