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Nanoparticle albumin bound sirolimus (nab-sirolimus): Drug information

Nanoparticle albumin bound sirolimus (nab-sirolimus): Drug information
(For additional information see "Nanoparticle albumin bound sirolimus (nab-sirolimus): Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Fyarro
Pharmacologic Category
  • Antineoplastic Agent, mTOR Kinase Inhibitor;
  • Immunosuppressant Agent;
  • mTOR Kinase Inhibitor
Dosing: Adult

Note: Administer sirolimus (protein bound) in a setting where cardiopulmonary resuscitation medication and equipment are available. Sirolimus (protein bound) may be associated with a moderate emetic potential; antiemetics may be required to prevent nausea and vomiting. Refer to the Sirolimus (Conventional) monograph for dosing and information related to the oral sirolimus formulation.

Perivascular epithelioid cell tumor, malignant, locally advanced or metastatic: IV: 100 mg/m2 on days 1 and 8 every 21 days until disease progression or unacceptable toxicity (Wagner 2021).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, mild or moderate renal impairment had no clinically significant effect on sirolimus pharmacokinetics.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST): Reduce dose to 75 mg/m2; closely monitor for increased toxicity.

Moderate impairment (total bilirubin >1.5 to 3 times ULN and any AST): Reduce dose to 56 mg/m2; closely monitor for increased toxicity.

Severe impairment: Avoid sirolimus (protein bound) use.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Obesity: Adult

American Society of Clinical Oncology guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full weight-based dosing with subsequent cycles if cause of toxicity (eg, hepatic or renal impairment) is clearly established and fully resolved (ASCO [Griggs 2021]).

Dosing: Adjustment for Toxicity: Adult
Sirolimus (Protein Bound) Dose Reduction Levels

Usual initial dose

100 mg/m2

First dose reduction

75 mg/m2

Second dose reduction

56 mg/m2

Third dose reduction

45 mg/m2

Permanently discontinue sirolimus (protein bound) if unable to tolerate 45 mg/m2.

Sirolimus (Protein Bound) Dosage Modifications for Adverse Reactions

Adverse Reaction

Severity

Sirolimus (Protein Bound) Dosage Modification

Hematologic toxicities

Anemia

Grade 2

Withhold sirolimus (protein bound) until hemoglobin is ≥8 g/dL, then restart at the same dose level.

≥ Grade 3

Withhold sirolimus (protein bound) until hemoglobin is ≥8 g/dL, then restart at the same dose level.

If ≥ grade 3 anemia recurs, resume sirolimus (protein bound) at a reduced dose level.

Neutropenia

Grade 2 or 3

Withhold sirolimus (protein bound) until ANC is ≥1,500/mm3, then restart at the same dose level.

Grade 4

Withhold sirolimus (protein bound) until ANC is ≥1,500/mm3, then restart at a reduced dose level.

Thrombocytopenia

Grade 2

Withhold sirolimus (protein bound) until platelets are >100,000/mm3, then restart at the same dose level.

≥ Grade 3

Withhold sirolimus (protein bound) until platelets are >100,000/mm3, then restart at a reduced dose level.

Nonhematologic toxicities

GI toxicity: Stomatitis

Grade 2 or 3

Withhold sirolimus (protein bound) until ≤ grade 1, then restart at the same dose (for first occurrence). If grade 2 or 3 stomatitis recurs, restart at a reduced dose level.

Grade 4

Permanently discontinue sirolimus (protein bound).

Hemorrhage

Grade 2 or 3

Withhold sirolimus (protein bound) until ≤ grade 1, then restart at a reduced dose.

If grade 2 or 3 hemorrhage recurs, permanently discontinue sirolimus (protein bound).

Grade 4

Permanently discontinue sirolimus (protein bound).

Hyperglycemia

≥ Grade 3

Withhold sirolimus (protein bound) until ≤ grade 2, then restart at a reduced dose level.

Hypokalemia

Any

Implement potassium supplementation as clinically indicated.

Grade 2

Withhold sirolimus (protein bound) until ≤ grade 1, then restart at the same dose level.

If grade 2 hypokalemia recurs, restart at a reduced dose level.

≥ Grade 3

Withhold sirolimus (protein bound) until ≤ grade 1, then restart at a reduced dose level.

If ≥ grade 3 hypokalemia recurs, permanently discontinue sirolimus (protein bound).

Infections

Grade 3

Withhold sirolimus (protein bound) until resolved, then restart at a reduced dose level.

If grade 3 infection recurs, permanently discontinue sirolimus (protein bound).

Grade 4

Withhold sirolimus (protein bound) until resolved, then restart at a reduced dose level or permanently discontinue sirolimus (protein bound).

Infusion reaction

Based on severity

Reduce the infusion rate, interrupt infusion, or permanently discontinue sirolimus (protein bound) based on severity.

Institute appropriate medical management as clinically indicated.

Pulmonary toxicity: Interstitial lung disease (ILD)/noninfectious pneumonitis

Grade 2

Withhold sirolimus (protein bound) for up to 3 weeks until ≤ grade 1, then restart at a reduced dose level.

If not resolved to ≤ grade 1 within 3 weeks, permanently discontinue sirolimus (protein bound).

If grade 2 ILD/noninfectious pneumonitis recurs, permanently discontinue sirolimus (protein bound).

≥ Grade 3

Permanently discontinue sirolimus (protein bound).

Other adverse reactions

Grade 3

Withhold sirolimus (protein bound) until ≤ grade 1, then restart at the same dose level.

If grade 3 adverse reaction recurs, restart at a reduced dose level.

Grade 4

Permanently discontinue sirolimus (protein bound).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension Reconstituted, Intravenous [preservative free]:

Fyarro: 100 mg (1 ea) [contains albumin human]

Generic Equivalent Available: US

No

Prescribing and Access Restrictions

Fyarro is available through specialty pharmacies and distributors. Information regarding access is available from the manufacturer's assistance program at https://aadiassist.com/Content/fyarro-fact-sheet.pdf or at 1-855-223-4482.

Administration: Adult

IV: Infuse over 30 minutes. Administer sirolimus (protein bound) in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor closely for hypersensitivity/infusion reactions during and after infusion (monitor for at least 2 hours after the first infusion and as clinically necessary for subsequent infusions).

Sirolimus (protein bound) may be associated with a moderate emetic potential; antiemetics may be required to prevent nausea and vomiting.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it meets the criteria for a hazardous drug. Sirolimus (protein bound) is a hazardous drug (per product labeling).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use: Labeled Indications

Perivascular epithelioid cell tumor, malignant, locally advanced or metastatic: Treatment of locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa) in adults.

Medication Safety Issues
Sound-alike/look-alike issues:

Sirolimus (protein bound) may be confused with everolimus, sirolimus (conventional), sirolimus (topical), tacrolimus, temsirolimus.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.

>10%:

Cardiovascular: Edema (50%), hypertension (29%)

Dermatologic: Alopecia (24%), nail disease (12%), pruritus (18%), skin rash (68%), xeroderma (12%)

Endocrine & metabolic: Decreased serum albumin (35%), decreased serum calcium (15%), decreased serum glucose (15%), decreased serum magnesium (42%), decreased serum phosphate (15%), decreased serum sodium (24%), dehydration (15%; severe dehydration: 6%), hyperglycemia (12%), hypokalemia (44%), increased serum cholesterol (48%), increased serum potassium (44%), increased serum sodium (12%), increased serum triglycerides (52%), weight loss (47%)

Gastrointestinal: Abdominal pain (29%; severe abdominal pain: 6%), constipation (24%), decreased appetite (44%), diarrhea (47%; grade 3: 3%), dysgeusia (32%), hemorrhoids (12%), increased serum lipase (12%), nausea (50%), stomatitis (79%; grade 3: 18%), vomiting (32%; grade 3: 3%), xerostomia (15%)

Hematologic & oncologic: Anemia (68%; grades 3: 6%), decreased white blood cell count (41%), hemorrhage (24%; grades ≥3: 3%), lymphocytopenia (82%; grades 3/4: 21%), neutropenia (35%), thrombocytopenia (35%)

Hepatic: Increased serum alanine aminotransferase (47%), increased serum alkaline phosphatase (29%), increased serum aspartate aminotransferase (32%)

Infection: Infection (59%; including urinary tract infection, upper respiratory infection, and sinusitis), serious infection (12%; including abdominal infection, pneumonia, and skin infection)

Nervous system: Dizziness (12%), fatigue (68%), headache (29%), insomnia (21%), peripheral neuropathy (15%)

Neuromuscular & skeletal: Musculoskeletal pain (47%)

Otic: Blurred vision (12%)

Renal: Increased serum creatinine (82%)

Respiratory: Cough (35%), dyspnea (12%), interstitial pulmonary disease (≤18%), pneumonitis (≤18%)

Miscellaneous: Fever (24%)

1% to 10%:

Cardiovascular: Acute coronary syndrome (<10%), edema (<10%)

Gastrointestinal: Enteritis (<10%)

Hematologic & oncologic: Pancytopenia (<10%), upper gastrointestinal hemorrhage (6%)

Renal: Acute kidney injury (<10%)

Frequency not defined:

Dermatologic: Acneiform eruption (dermatitis)

Genitourinary: Cystitis (noninfective)

Contraindications

History of severe hypersensitivity to sirolimus, other rapamycin derivatives, albumin, or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Sirolimus (protein bound) may cause hematologic toxicity, including anemia, thrombocytopenia, and neutropenia. Grade 3 anemia was observed.

• GI toxicity: Stomatitis, including mouth ulcers and oral mucositis, occurred in a majority of patients treated with sirolimus (protein bound), including grade 3 stomatitis. Stomatitis was mostly first reported within 8 weeks of treatment.

• Hemorrhage: Sirolimus (protein bound) can cause serious and sometimes fatal hemorrhage; hemorrhage was reported in almost one-fourth of patients.

• Hyperglycemia: Sirolimus (protein bound) is associated with hyperglycemia, most commonly reported as grade 3 hyperglycemia.

• Hypersensitivity: Sirolimus (protein bound) may cause hypersensitivity reactions. Conventional sirolimus (the oral formulation) is associated with hypersensitivity reactions including anaphylactic, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis. Sirolimus (protein bound) contains albumin, which is associated with hypersensitivity reactions including anaphylaxis. Administer sirolimus (protein bound) in a setting where cardiopulmonary resuscitation medication and equipment are available.

• Hypokalemia: Sirolimus (protein bound) can cause hypokalemia; grade 3 hypokalemia has been observed.

• Infection: Sirolimus (protein bound) can cause infections. Infections commonly reported included urinary tract infections (UTIs), upper respiratory tract infections, and sinusitis. Grade 3 infections were observed, including cases of grade 3 UTI, pneumonia, skin, and abdominal infections.

• Pulmonary toxicity: Sirolimus (protein bound) may cause interstitial lung disease (ILD)/noninfectious pneumonitis. All cases of ILD/noninfectious pneumonitis were grades 1 or 2.

Concurrent drug therapy issues:

• Vaccination: Sirolimus (protein bound) has not been studied in conjunction with immunization. Immunization during sirolimus (protein bound) treatment may be ineffective. Prior to initiating sirolimus (protein bound), if possible, update immunizations according to immunization guidelines. Immunization with live vaccines is not recommended during sirolimus (protein bound) treatment. Patients receiving sirolimus (protein bound) should avoid close contact with individuals who have received live vaccines. The interval between live vaccinations and sirolimus (protein bound) initiation should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.

Dosage form specific issues:

• Albumin: Sirolimus (protein bound) contains albumin, which confers a remote risk of viral disease transmission and a remote theoretical risk of transmission of Creutzfeldt-Jakob disease.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Sirolimus Products may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased. Risk C: Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA vaccine at least 28 days after the primary vaccine dose. Patients should also receive 2 booster doses of mRNA vaccine - one 2 months after the 2nd (additional) dose and another 4 months after the first booster dose. Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series, and a booster dose 3 months after the 3rd dose in the primary series, to patients taking immunosuppressive medications. Patients 12 years of age and older should also receive a 2nd booster 4 months after the first booster. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

CYP3A4 Inducers (Weak): May decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a moderate CYP3A4 inhibitor. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

CYP3A4 Inhibitors (Weak): May increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification

Maribavir: May increase the serum concentration of Sirolimus Products. Risk C: Monitor therapy

Micafungin: May increase the serum concentration of Sirolimus Products. Risk C: Monitor therapy

Milk Thistle: May increase the serum concentration of Sirolimus Products. Risk C: Monitor therapy

Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Pacritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Pacritinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy

Spironolactone: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Tacrolimus (Systemic): May enhance the adverse/toxic effect of Sirolimus Products. Sirolimus Products may enhance the adverse/toxic effect of Tacrolimus (Systemic). Sirolimus Products may decrease the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination

Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Treosulfan: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination

Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Food Interactions

Grapefruit or grapefruit juice may increase serum sirolimus concentrations. Management: Avoid grapefruit and grapefruit juice.

Reproductive Considerations

Verify pregnancy status prior to treatment. Patients who could become pregnant should use effective contraception during therapy and for 12 weeks after the last sirolimus (protein bound) dose. Patients with partners who could become pregnant should also use effective contraception during therapy and for 12 weeks after the last dose of sirolimus (protein bound).

Sirolimus may impair fertility. Ovarian cysts, amenorrhea, menorrhagia, azoospermia, or oligospermia have been observed following use of conventional sirolimus (oral formulation).

Also refer to sirolimus (conventional) for additional information.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to sirolimus (protein bound) may cause fetal harm. Adverse events were observed in animal reproduction studies following use of conventional sirolimus (oral formulation) at doses equivalent to or less than the recommended equivalent human starting dose.

Also refer to sirolimus (conventional) for additional information.

Breastfeeding Considerations

It is not known if sirolimus is present in breast milk.

Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 2 weeks after the last sirolimus (protein bound) dose.

Dietary Considerations

Avoid grapefruit and grapefruit juice.

Monitoring Parameters

CBC with differential at baseline and every 2 months for the first year, then every 3 months thereafter; more frequently if clinically indicated. Potassium levels at baseline and periodically. Monitor fasting serum glucose at baseline; during treatment, monitor serum glucose every 3 months (or as clinically indicated) in patients without diabetes; monitor more frequently in patients with diabetes. Verify pregnancy status prior to treatment (in patients who can become pregnant). Monitor for signs/symptoms of hemorrhage, hyperglycemia, infections (including opportunistic infections), pulmonary toxicity, and/or stomatitis. Monitor closely during and after infusion for hypersensitivity/infusion reactions (monitor for at least 2 hours after the first infusion and as clinically necessary for subsequent infusions).

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Sirolimus (protein bound) is an albumin-bound nanoparticle sirolimus formulation that inhibits mammalian (mechanistic) target of rapamycin (mTOR) (Wagner 2021). mTOR controls key cellular processes such as cell survival, growth, and proliferation, and is commonly dysregulated in several human cancers. In cells, sirolimus forms an immunosuppressive complex, sirolimus-FKBP-12 complex, which binds to and inhibits activation of the mTOR complex 1 (mTORC1). Inhibition of mTOR by sirolimus reduces cell proliferation, angiogenesis, and glucose uptake. In preclinical models, IV administration of nanoparticle protein bound sirolimus has demonstrated higher intratumor accumulation, greater mTOR inhibition, and higher tumor growth inhibition compared to oral mTOR inhibitors (Wagner 2021).

Pharmacokinetics

Protein binding: >99%, primarily to serum albumin.

Metabolism: Hepatic, via CYP3A4.

Half-life elimination: ~59 hours.

Excretion: Oral: Feces (91%), Urine (2%).

Pricing: US

Suspension (reconstituted) (Fyarro Intravenous)

100 mg (per each): $8,142.00

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  1. <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). United States Pharmacopeia Convention; 2020:74-92.
  2. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
  3. Fyarro (sirolimus [protein bound]) [prescribing information]. Pacific Palisades, CA: Aadi Bioscience Inc; November 2021.
  4. Griggs JJ, Bohlke K, Balaban EP, et al. Appropriate systemic therapy dosing for obese adult patients with cancer: ASCO guideline update. J Clin Oncol. 2021;39(18):2037-2048. doi:10.1200/JCO.21.00471 [PubMed 33939491]
  5. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed November 29, 2021.
  6. Wagner AJ, Ravi V, Riedel RF, et al. nab-Sirolimus for patients with malignant perivascular epithelioid cell tumors. J Clin Oncol. 2021;39(33):3660-3670. doi:10.1200/JCO.21.01728 [PubMed 34637337]
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