Fyarro

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.

Dosage Modifications for Adverse Reactions

Table 1 lists the recommended dose reductions of FYARRO for adverse reactions.

Table 2 lists the recommended dosage modifications of FYARRO for adverse reactions.

Dosage Modifications for Concomitant Use with CYP3A4 and/or P-gp Inhibitors and Inducers

Reduce the dosage of FYARRO to 56 mg/m2 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 , Clinical Pharmacology ].

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 , Clinical Pharmacology ]. Closely monitor patients with hepatic impairment for increased toxicity. Avoid use in patients with severe hepatic impairment [see Use in Specific Populations ].

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.

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.

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 ]. 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.

Lactation

Risk Summary

There are no data on the presence of FYARRO in human milk or its effects on the breastfed child or on milk production.

It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action [see Clinical Pharmacology ]. Because of the potential for serious adverse reactions in breastfed infants from FYARRO, advise women not to breastfeed during treatment with FYARRO and for 2 weeks after the last dose.

Females and Males of Reproductive Potential

FYARRO can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions , Use in Specific Populations ].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating FYARRO.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with FYARRO and for 12 weeks after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with FYARRO and for 12 weeks after the last dose.

Infertility

Although there are no data on the impact of FYARRO on fertility, based on available clinical findings with oral formulation of sirolimus and findings in animals, male and female fertility may be compromised by the treatment with FYARRO [see Warnings and Precautions , Nonclinical Toxicology ]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of oral formulation of sirolimus. Azoospermia has been reported in males with the use of oral formulation sirolimus and has been reversible upon discontinuation in most cases.

Pediatric Use

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

Geriatric Use

Of the 34 patients treated with FYARRO, 44% were 65 years of age and older, and 6% were 75 years of age and older. Clinical studies of FYARRO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Hepatic Impairment

FYARRO is not recommended for use in patients with severe hepatic impairment. Reduce FYARRO dosage in patients with mild or moderate hepatic impairment [see Dosage and Administration , Clinical Pharmacology ].

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 , Adverse Reactions ]

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 , Adverse Reactions ].

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 , Adverse Reactions ].

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 , Adverse Reactions ].

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 reduced dose, or permanently discontinue FYARRO [see Dosage and Administration , Adverse Reactions ].

Interstitial Lung Disease / Non-Infectious Pneumonitis

FYARRO can cause interstitial lung disease (ILD) / non-infectious pneumonitis. ILD / non-infectious pneumonitis occurred in 18% of patients treated with FYARRO, of which all were Grades 1 or 2. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration ].

Hemorrhage

FYARRO can cause serious and sometimes fatal hemorrhage. Hemorrhage occurred in 24% of patients treated with FYARRO, including Grade 3 and Grade 5 events in 2.9% of patients each [see Adverse Reactions ]. Monitor patients for signs and symptoms of hemorrhage. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO [see Dosage and Administration ].

Hypersensitivity Reactions

FYARRO can cause hypersensitivity reactions [see Contraindications ].

• Hypersensitivity reactions, including anaphylactic, angioedema, exfoliative dermatitis and hypersensitivity vasculitis have been observed with administration of the oral formulation of sirolimus.
• Hypersensitivity reactions including anaphylaxis have been observed with human albumin administration.

Monitor patients closely for signs and symptoms of infusion reactions during and following each FYARRO infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion.

Reduce the rate, interrupt infusion, or permanently discontinue FYARRO based on severity and institute appropriate medical management as needed.

Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action [see Clinical Pharmacology ], FYARRO can cause fetal harm when administered to a pregnant woman. In animal studies, mechanistic target of rapamycin kinase (mTOR) inhibitors caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use effective contraception while using FYARRO and for 12 weeks after the last dose [see Use in Specific Populations ].

Male Infertility

Azoospermia or oligospermia may be observed in patients treated with FYARRO [see Use in Specific Populations , Nonclinical Toxicology ]. FYARRO is an anti-proliferative drug and affects rapidly dividing cells such as germ cells.

Immunizations and Risks Associated with Live Vaccines

No studies in conjunction with immunization have been conducted with FYARRO. Immunization during FYARRO treatment may be ineffective. Update immunizations according to immunization guidelines prior to initiating FYARRO, if possible. Immunization with live vaccines is not recommended during treatment and avoid close contact with those who have received live vaccines while on FYARRO. The interval between live vaccinations and initiation of FYARRO should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.

Risk of Transmission of Infectious Agents with Human Albumin

FYARRO contains human albumin, a derivative of human blood. Human albumin carries only a remote risk of transmission of viral diseases because of effective donor screening and product manufacturing processes. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been associated with albumin.