FYARRO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FYARRO (FYARRO).
FYARRO (sirolimus protein-bound particles for injectable suspension) is an mTOR inhibitor. Sirolimus binds to FKBP-12 and inhibits mTOR complex 1 (mTORC1), reducing phosphorylation of downstream effectors such as S6K1 and 4E-BP1, thereby inhibiting cell growth, proliferation, and angiogenesis.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. Sirolimus is a substrate of P-glycoprotein (P-gp). |
| Excretion | Primarily via biliary/fecal excretion (approximately 77% of the dose recovered in feces as metabolites); renal excretion accounts for approximately 18%. |
| Half-life | Approximately 53 hours (terminal elimination half-life), supporting once-weekly IV administration. |
| Protein binding | Highly protein bound (>99%) primarily to albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Approximately 3.3 L/kg, indicating extensive tissue distribution beyond plasma volume. |
| Bioavailability | Not applicable; FYARRO is administered as an intravenous infusion (bioavailability is 100% by IV route). |
| Onset of Action | Clinical effect observed within 2-4 weeks after initiation of IV infusion based on tumor response assessments. |
| Duration of Action | Duration of therapeutic action is continuous with weekly dosing; clinical effects are maintained throughout the dosing interval. |
Recommended dose is 100 mg/m² (up to 200 mg maximum) administered as an intravenous infusion over 30 minutes once weekly on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.
| Dosage form | POWDER |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. Reduce dose to 50 mg/m² (maximum 100 mg) for GFR 15-29 mL/min. Not recommended for GFR <15 mL/min or on dialysis. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose to 50 mg/m² (maximum 100 mg). Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy have not been established in pediatric patients. No recommended dose. |
| Geriatric use | No specific dose adjustment required based on age alone. Monitor renal function and adjust dose per renal guidelines. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for FYARRO (FYARRO).
| Breastfeeding | It is not known whether sirolimus or its metabolites are present in human milk. However, based on the drug's lipophilicity and high protein binding, excretion into breast milk is expected. The M/P ratio is not available. Because of the potential for serious adverse reactions in breastfed infants, including immunosuppression and growth retardation, breastfeeding is contraindicated during FYARRO treatment and for at least 2 weeks after the last dose. |
| Teratogenic Risk | FYARRO (sirolimus protein-bound particles for injectable suspension) is an mTOR inhibitor. Based on its mechanism of action and animal studies, it can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have shown embryotoxicity, fetotoxicity, and teratogenicity at sub-therapeutic doses. There are no adequate and well-controlled studies in pregnant women. In the first trimester, exposure is associated with a high risk of structural anomalies. In the second and third trimesters, it may affect fetal growth and development. It is recommended to avoid pregnancy during treatment and for 12 weeks after the last dose. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
["Hypersensitivity to sirolimus or any component of the formulation"]
| Precautions | ["Increased risk of serious infections (bacterial, viral, fungal, protozoal)","Increased risk of renal dysfunction and acute renal failure","Avoid concomitant use with strong CYP3A4 or P-gp inducers or inhibitors","Monitor for pulmonary toxicity (interstitial lung disease, pneumonitis)","Hepatic impairment: Reduce dose in moderate impairment; avoid in severe impairment","May increase risk of myelosuppression, including anemia, leukopenia, and thrombocytopenia","Monitor serum lipids; may require antihyperlipidemic therapy","Rare cases of posterior reversible encephalopathy syndrome (PRES) reported"] |
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| Fetal Monitoring | Monitor pregnancy status in women of reproductive potential prior to starting FYARRO. During pregnancy, if exposure occurs, monitor fetal growth and development with serial ultrasounds. After delivery, assess the infant for potential adverse effects such as immunosuppression, growth delay, and myelosuppression. Females of reproductive potential should use effective contraception during therapy and for 12 weeks after the final dose. |
| Fertility Effects | FYARRO may impair male and female fertility. In animal studies, sirolimus caused reduced spermatogenesis, testicular atrophy, and ovarian cycle disruption. In human males, oligospermia has been reported. These effects may be reversible upon discontinuation. The impact on female fertility is not well characterized, but amenorrhea has been observed in clinical trials. Therefore, FYARRO may reduce fertility in both sexes. |