FYARRO

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/m2 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. 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 Permanently discontinue FYARRO in patients who are unable to tolerate FYARRO after three dose reductions. 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 Adverse Reaction Severity Severity based on Common Terminology Criteria for Adverse Events Version 4.03. 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 Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]. 2.4 Patients with Hepatic Impairment The recommended dosage modification of FYARRO in patients with mild or moderate hepatic impairment is described in Table 3 [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . Closely monitor patients with hepatic impairment for increased toxicity. Avoid use in patients with severe hepatic impairment [see Use in Specific Populations ( 8.6 )] . Table 3. Recommended FYARRO Dosage in Patients with Mild or Moderate Hepatic Impairment Hepatic Impairment (based on NCI criteria) Dosage Mild (total bilirubin ≤ULN, AST >ULN or total bilirubin >1 to 1.5×ULN, any AST) 75 mg/m 2 Moderate (total bilirubin >1.5 to 3.0×ULN, any AST) 56 mg/m 2 2.5 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: 1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. 2. 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. 3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly on to the lyophilized powder, which has a cake-like appearance, as this will result in foaming. 4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized powder. 5. 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. 6 . 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. 7. 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. image of proper solution flow onto the INSIDE WALL OF THE VIAL 2.6 Stability Unopened vials of FYARRO are stable until the date indicated on the package when stored between 2°C to 8°C (36°F to 46°F) 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 2°C to 8°C (36°F to 46°F) 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.

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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).