Fyarro Drug Information

FYARRO ® is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

Patients with Hepatic Impairment

The recommended dosage modification of FYARRO in patients with mild or moderate hepatic impairment is described in Table 3. Closely monitor patients with hepatic impairment for increased toxicity. Avoid use in patients with severe hepatic impairment.

Table 3.

Preparation and Administration FYARRO is a hazardous drug

Follow applicable special handling and disposal procedures. 1 FYARRO is supplied as a sterile lyophilized powder for reconstitution before use. READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION. Preparation: Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.

Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized powder, which has a cake-like appearance, as this will result in foaming. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized powder.

Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any powder occurs. Avoid shaking the vial to prevent the generation of foam. If foaming or clumping occurs, let suspension stand for at least 15 minutes until foam subsides.

If foaming or clumping is present after one hour, do not use the reconstituted suspension. Each mL of the reconstituted formulation will contain 5 mg sirolimus. The reconstituted suspension should be milky and homogenous without visible particulates.

If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion.

Transfer the volume of FYARRO required for the calculated dose into an empty sterile PVC or polyolefin infusion bag for administration without further dilution. The use of medical devices containing silicone oil as a lubricant (e.g., syringes and intravenous bags) to reconstitute and administer FYARRO may result in the formation of proteinaceous strands. Visually inspect reconstituted FYARRO suspension in the infusion bag prior to administration.

Discard reconstituted suspension if particulate matter, proteinaceous strands, or discoloration are observed. Administration: Administer the reconstituted FYARRO suspension intravenously over 30 minutes. Figure

Stability

Unopened vials of FYARRO are stable until the date indicated on the package when stored between 2ºC to 8ºC (36ºF to 46ºF) in the original package. Neither freezing nor thawing adversely affects the stability of the product. Stability of Reconstituted Suspension in the Vial Reconstituted FYARRO in the vial should be used immediately but may be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) for a maximum of 6 hours stored in the original carton to protect it from light.

Discard any unused portion. Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion when prepared as recommended in an infusion bag should be used immediately but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from light for a maximum of 9 hours. The total maximum combined refrigerated storage time of reconstituted FYARRO in the vial and in the infusion bag is 15 hours.

This may be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of 4 hours. Discard any unused portion.

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). 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. 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. 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. Table 4 summarizes the adverse reactions in AMPECT. Table 4.

Adverse Reactions ≥10% in Patients with PEComa Who Received FYARRO in AMPECT 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 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.

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