Sirolimus, a mechanistic target of rapamycin kinase (mTOR) inhibitor, is an antineoplastic agent.1 Albumin-bound sirolimus is a preparation of sirolimus formulated as albumin-bound nanoparticles.1
Perivascular Epithelioid Cell Tumor (PEComa)
Albumin-bound sirolimus is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).1, 4 Albumin-bound sirolimus has been designated an orphan drug by FDA for this use.3
Safety and efficacy of albumin-bound sirolimus for the treatment of locally advanced unresectable or metastatic malignant PEComa were established in an open-label multicenter, single-arm clinical trial (AMPECT).1 A total of 31 patients were included in the efficacy analysis.1 The median age of these patients was 60 years (range 34-78 years); 81% were female, 74% were white, 10% were Black, and 84% had metastatic disease.1, 4 The majority of patients (94%) received prior treatment with surgery, radiation therapy, and/or systemic therapy.1 Patients received albumin-bound sirolimus 100 mg/m2 on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity.1, 3 The primary endpoint was objective response rate evaluated by independent radiology review 6 months after the last patient was enrolled.4 Secondary endpoints included duration of response, progression-free survival, and safety.4
The overall response rate was 39%, with one complete and 11 partial responses.1, 4 Although median duration of response was not reached, 58% of responders had a response lasting more than 24 months.1, 2
Dispensing and Administration Precautions
Albumin-bound sirolimus is administered by IV infusion after reconstitution of the lyophilized drug.1
Store unopened vials of albumin-bound sirolimus between 2°C to 8°C in the original package.1 Freezing and thawing do not affect the stability of the product.1
Reconstitution and Administration
Albumin-bound sirolimus is commercially available as a lyophilized powder that must be reconstituted to an injectable suspension prior to IV infusion.1 To reconstitute the powder, inject 20 mL of 0.9% sodium chloride injection slowly (over a minimum period of 1 minute) into the vial containing the lyophilized powder using aseptic technique.1 Direct the flow of solution towards the inside wall of the vial rather than directly onto the lyophilized cake to avoid foaming.1 Once injection of 0.9% sodium chloride into the vial is complete, allow the vial to sit for a minimum of 5 minutes to ensure thorough wetting of the lyophilized cake/powder.1 Swirl or gently invert the vial (do not shake) for at least 2 minutes until the cake/powder is completely dissolved; foaming should be avoided.1 If foaming or clumping occurs, allow the reconstituted albumin-bound sirolimus suspension to stand for at least 15 minutes until foaming subsides.1 Do not use the reconstituted suspension if foaming or clumping is present after 1 hour.1
The reconstituted suspension has a final sirolimus concentration of 5 mg/mL.1
The reconstituted suspension should be milky and homogenous without visible particulates.1 If particulates or settling are visible, gently invert the vial again to ensure complete resuspension prior to use.1 Discard the reconstituted suspension if precipitates are observed.1 If the reconstituted suspension is not used immediately, the vial may be stored in the refrigerator at 2°C to 8°C for a maximum of 6 hours in the original carton to protect the drug from light.1
Visually inspect the reconstituted suspension prior to administration.1 Discard the drug if particulate matter, proteinaceous strands, or discoloration is observed.1
To prepare the drug for administration, transfer the volume of reconstituted albumin-bound sirolimus required for the calculated dose into an empty sterile PVC or polyolefin infusion bag and administer without further dilution.1 Discard any unused portion.1
If not used immediately, the reconstituted suspension in the infusion bag may be refrigerated at 2°C to 8°C and protected from light for a maximum of 9 hours.1 The total maximum combined refrigerated storage time of reconstituted albumin-bound sirolimus in the vial and in the infusion bag is 15 hours.1 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.1 Discard any unused portion.1
Administer reconstituted albumin-bound sirolimus by IV infusion over 30 minutes.1
Dosage of albumin-bound sirolimus is expressed in terms of sirolimus.1
Perivascular Epithelioid Cell Tumor (PEComa)
The recommended dosage of albumin-bound sirolimus for the treatment of PEComa in adults is 100 mg/m2 as an IV infusion on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.1
Dosage Modifications for Adverse Reactions
Dosage interruption, reduction, or discontinuance of albumin-bound sirolimus therapy may be necessary based on severity of adverse reactions.1 See Table 1 for recommended dose reductions and table 2 for recommended dosage modifications/interventions for adverse reactions.1
Dose Reduction | Dose |
|---|---|
First dose reduction | 75 mg/m2 (25% reduction from 100 mg/m2 )1 |
Second dose reduction | 56 mg/m2 (25% reduction from 75 mg/m2 )1 |
Third dose reductiona | 45 mg/m2 (20% reduction from 56 mg/m2 )1 |
aPermanently discontinue albumin-bound sirolimus in patients who are unable to tolerate it after 3 dose reductions.1
Adverse Reaction | Dosage Modification |
|---|---|
Stomatitis | Grade 2 or 3: Withhold until grade ≤1.1 Restart at the same dose for first occurrence.1 If recurs, restart at reduced dose level.1 |
| Grade 4: Permanently discontinue.1 |
Anemia | Grade 2: Withhold until hemoglobin ≥8 g/dL.1 Restart at the same dose level.1 |
| Grade ≥3: Withhold until hemoglobin ≥8 g/dL.1 Restart at the same dose level.1 If recurs, resume at reduced dose level.1 |
Thrombocytopenia | Grade 2: Withhold until platelet count >100,000/mm3.1 Restart at the same dose level.1 |
| Grade ≥3: Withhold until platelet count >100,000/mm3.1 Restart at reduced dose level.1 |
Neutropenia | Grade 2 or 3: Withhold until absolute neutrophil count (ANC) ≥1500/mm3.1 Restart at the same dose level.1 |
| Grade 4: Withhold until ANC ≥1500/mm3.1 Restart at reduced dose level.1 |
Infections | Grade 3: Withhold until infection is resolved, then restart at reduced dose level.1 If recurs, permanently discontinue.1 |
| Grade 4: Withhold until infection is resolved.1 Restart at reduced dose level or permanently discontinue.1 |
Hypokalemia | Grade 2: Withhold until grade ≤1.1 Restart at the same dose level. If recurs, restart at reduced dose level.1 |
| Grade ≥3: Withhold until grade ≤1.1 Restart at reduced dose level.1 If recurs, permanently discontinue.1 |
Hyperglycemia | Grade ≥3: Withhold until grade ≤2.1 Restart at reduced dose level.1 |
Interstitial Lung Disease/Noninfectious Pneumonitis | Grade 2: Withhold for up to 3 weeks until grade ≤1, then restart at reduced dose level.1 If not resolved to Grade ≤1 within 3 weeks, permanently discontinue.1 If recurs, permanently discontinue.1 |
| Grade ≥3: Permanently discontinue.1 |
Hemorrhage | Grade 2 or 3: Withhold until grade ≤1, then resume at reduced dose.1 If recurs, permanently discontinue.1 |
| Grade 4: Permanently discontinue.1 |
Other Adverse Reactions | Grade 3: Withhold until grade ≤1, then restart at same dose level.1 If recurs, restart at reduced dose level.1 |
| Grade 4: Permanently discontinue.1 |
In patients with mild hepatic impairment (total bilirubin ≤ULN, AST >ULN or total bilirubin >1 to 1.5×ULN, any AST), reduce initial dose of albumin-bound sirolimus to 75 mg/m2.1
In patients with moderate hepatic impairment (total bilirubin >1.5 to 3×ULN and any AST), reduce initial dose to 56 mg/m2.1
Closely monitor patients with hepatic impairment for increased toxicity.1 Avoid use in patients with severe hepatic impairment.1
CYP3A4 and/or P-gp Inhibitors and Inducers
Reduce the initial dose of albumin-bound sirolimus to 56 mg/m2 when used concomitantly with a moderate or weak cytochrome P-450 3A4 (CYP3A4) inhibitor.1
Avoid concomitant use with drugs that are strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitors and inducers and with grapefruit and grapefruit juice.1
Stomatitis, including mouth ulcers and oral mucositis, occurred in 79% of patients treated with albumin-bound sirolimus, including 18% that were grade 3 in severity.1 Stomatitis was most often first reported within 8 weeks of treatment.1 Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue albumin-bound sirolimus.1
Albumin-bound sirolimus can cause myelosuppression including anemia, thrombocytopenia, and neutropenia.1 Anemia occurred in 68% of patients who received the drug in clinical studies; 6% were grade 3.1 Thrombocytopenia and neutropenia occurred in 35% of patients each.1
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.1 Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue albumin-bound sirolimus.1
Albumin-bound sirolimus can cause infections.1 Infections such as urinary tract infections (UTI), upper respiratory tract infections, and sinusitis occurred in 59% of patients in clinical studies.1 Grade 3 infections occurred in 12% of patients, including a single case each of a UTI, pneumonia, skin, and abdominal infection.1
Monitor patients for infections, including opportunistic infections.1 Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue albumin-bound sirolimus.1
Albumin-bound sirolimus can cause hypokalemia.1 Hypokalemia occurred in 44% of patients in clinical studies, including 12% that were grade 3 in severity.1
Monitor potassium levels prior to starting albumin-bound sirolimus and implement potassium supplementation as medically indicated.1 Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue albumin-bound sirolimus.1
Albumin-bound sirolimus can cause hyperglycemia.1 Hyperglycemia occurred in 12% of patients treated with albumin-bound sirolimus, all of which were grade 3 events.1
Monitor fasting serum glucose prior to starting albumin-bound sirolimus.1 During treatment, monitor serum glucose every 3 months in nondiabetic patients, or as clinically indicated.1 Monitor serum glucose more frequently in diabetic patients.1 Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue albumin-bound sirolimus.1
Interstitial Lung Disease/Noninfectious Pneumonitis
Albumin-bound sirolimus can cause interstitial lung disease (ILD)/non-infectious pneumonitis.1 ILD/non-infectious pneumonitis occurred in 18% of patients treated with albumin-bound sirolimus in clinical studies, of which all were grade 1 or 2 in severity.1 Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue albumin-bound sirolimus.1
Albumin-bound sirolimus can cause serious and sometimes fatal hemorrhage.1 Hemorrhage occurred in 24% of patients treated with albumin-bound sirolimus in clinical studies, including grade 3 and grade 5 events in 2.9% of patients each.1
Monitor patients for signs and symptoms of hemorrhage.1 Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue albumin-bound sirolimus.1
Albumin-bound sirolimus can cause hypersensitivity reactions.1
Hypersensitivity reactions, including anaphylaxis, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been observed with administration of the oral formulation of sirolimus.1 Hypersensitivity reactions including anaphylaxis also have been observed with human albumin administration.1
Monitor patients closely for signs and symptoms of infusion reactions during and following each albumin-bound sirolimus infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.1 Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion.1
Reduce the rate, interrupt infusion, or permanently discontinue albumin-bound sirolimus based on severity and institute appropriate medical management as needed.1
Fetal/Neonatal Morbidity and Mortality
Based on animal studies and the mechanism of action, albumin-bound sirolimus can cause fetal harm when administered to a pregnant woman.1 In animal studies, mechanistic target of rapamycin kinase (mTOR) inhibitors caused embryofetal 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.1
Advise pregnant women of the potential risk to a fetus.1 Advise females of reproductive potential to avoid becoming pregnant and to use effective contraception while using albumin-bound sirolimus and for 12 weeks after the last dose.1
Azoospermia or oligospermia may be observed in patients treated with albumin-bound sirolimus.1 Albumin-bound sirolimus is an antiproliferative drug and affects rapidly dividing cells such as germ cells.1
Immunizations and Risks Associated with Live Vaccines
No studies in conjunction with immunization have been conducted with albumin-bound sirolimus.1 Immunization during sirolimus treatment may be ineffective.1 Update immunizations according to immunization guidelines prior to initiating albumin-bound sirolimus, if possible.1 Immunization with live vaccines is not recommended during treatment and avoid close contact with those who have received live vaccines while on albumin-bound sirolimus.1 The interval between live vaccinations and initiation of albumin-bound sirolimus should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.1
Risk of Transmission of Infectious Agents with Human Albumin
Albumin-bound sirolimus contains human albumin, a derivative of human blood.1 Human albumin carries only a remote risk of transmission of viral diseases because of effective donor screening and product manufacturing processes.1 A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote.1 No cases of transmission of viral diseases or CJD have ever been associated with albumin.1
Albumin-bound sirolimus can cause fetal harm when administered to a pregnant woman, based on animal studies and the mechanism of action.1 Although there are no data on the use of albumin-bound sirolimus in pregnant women, there are limited data on the use of sirolimus during pregnancy.1 In animal studies, oral sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses.1 Advise pregnant women of the potential risk to a fetus.1
There are no data on the presence of albumin-bound sirolimus in human milk or its effects on the breastfed child or on milk production.1
It is not known whether sirolimus is present in human milk.1 There are no data on its effects on the breastfed infant or milk production.1 The pharmacokinetic and safety profiles of sirolimus in infants are not known.1 Sirolimus is present in the milk of lactating rats.1 There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action.1 Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with albumin-bound sirolimus and for 2 weeks after the last dose.1
Females and Males of Reproductive Potential
Albumin-bound sirolimus can cause fetal harm when administered to a pregnant woman.1
Verify pregnancy status of females of reproductive potential prior to initiating albumin-bound sirolimus.1 Advise females of reproductive potential to use effective contraception during treatment with albumin-bound sirolimus and for 12 weeks after the last dose.1 Advise males with female partners of reproductive potential to use effective contraception during treatment with albumin-bound sirolimus and for 12 weeks after the last dose.1
Although there are no data on the impact of albumin-bound sirolimus on fertility, based on available clinical findings with an oral formulation of sirolimus and findings in animals, male and female fertility may be compromised by the treatment with albumin-bound sirolimus.1 Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of oral sirolimus.1 Azoospermia has been reported in males with the use of oral sirolimus and has been reversible upon discontinuation in most cases.1
The safety and efficacy of albumin-bound sirolimus in pediatric patients have not been established.1
Clinical studies of albumin-bound sirolimus did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.1
Albumin-bound sirolimus is not recommended for use in patients with severe hepatic impairment.1 Reduce dosage of the drug in patients with mild or moderate hepatic impairment.1
The most common (≥30%) adverse reactions reported with albumin-bound sirolimus were stomatitis, fatigue, rash, infection, nausea, edema, diarrhea, musculoskeletal pain, decreased weight, decreased appetite, cough, vomiting, and dysgeusia.1
The most common (≥6%) grade 3 to 4 laboratory abnormalities observed with albumin-bound sirolimus were decreased lymphocytes, increased glucose, decreased potassium, decreased phosphate, decreased hemoglobin, and increased lipase.1
Sirolimus is metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP3A, and is a substrate of both CYP3A4 and P-gp.1
No studies evaluating the drug interaction potential of albumin-bound sirolimus have been conducted.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Strong CYP3A4 Inhibitors or Inducers
Avoid concomitant use of albumin-bound sirolimus with strong CYP3A4 inhibitors or inducers.1 Avoid concomitant use of albumin-bound sirolimus with grapefruit or grapefruit juice.1
Moderate or Weak CYP3A4 Inhibitors
Use of albumin-bound sirolimus with moderate or weak CYP3A4 inhibitors may result in increased levels of sirolimus.1 Reduce the dosage of albumin-bound sirolimus when used concomitantly with a moderate or weak CYP3A4 inhibitor.1
Moderate or Weak CYP3A4 Inducers
Use of albumin-bound sirolimus with moderate or weak CYP3A4 inducers may result in decreased effectiveness.1
Drugs Affecting or Affected by Transport Proteins
Avoid concomitant use of albumin-bound sirolimus with P-gp inhibitors or inducers.1
Albumin-bound sirolimus is a preparation of sirolimus formulated as albumin-bound nanoparticles.1 Sirolimus is an inhibitor of mechanistic target of rapamycin kinase (mTOR, previously known as mammalian target of rapamycin).1 mTOR, a serine threonine kinase, is downstream of the PI3K/AKT pathway, controls key cellular processes such as cell survival, growth, and proliferation, and is commonly dysregulated in several human cancers.1 Albumin has a long plasma half-life, broad binding affinity, and accumulates in tumors, areas of inflammation, and tissue remodeling.4 The pharmacologic and pharmacokinetic profiles of albumin-bound sirolimus are distinct from conventional sirolimus and other mTOR inhibitors.4
In cells, sirolimus binds to the immunophilin, FK binding protein-12 (FKBP-12) to generate an immunosuppressive complex.1, 2 The sirolimus-FKBP-12 complex binds to and inhibits activation of the mechanistic target of rapamycin complex 1 (mTORC1).1, 2 Inhibition of mTOR by sirolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in both in-vitro and in-vivo studies.1
In a nonclinical study in athymic mice bearing human tumor xenografts, IV administration of albumin-bound sirolimus resulted in higher tumor accumulation of sirolimus, inhibition of an mTOR target in the tumor, and tumor growth inhibition compared to administration of an oral formulation of sirolimus at the same weekly total dose.1, 2
Sirolimus is extensively metabolized in the liver by cytochrome P-450 (CYP) isoenzymes, principally CYP3A4.1 It is excreted primarily in the feces and a minor amount in urine (2%).1 The mean elimination half-life of sirolimus is approximately 59 hours.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injectable suspension, for IV infusion | 100 mg (of sirolimus as albumin-bound particles) | Fyarro® | Aadi Bioscience |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions April 25, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Aadi Bioscience. Fyarro® (sirolimus protein-bound particles for injectable suspension [albumin-bound]) injection prescribing information. Pacific Palisades, CA; 2022 June.
2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2023 Feb 7. [Web]
3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 213312Orig1s000: Integrated review. From FDA website. Accessed 2023 Feb 7. [Web]
4. Wagner, AJ, Ravi V, Riedel RF, et al. nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors. J Clin Oncol. 2021; 39:3660-3670.