sirolimus protein bound (Rx)

Brand and Other Names:Fyarro
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 100mg/vial

Perivascular Epithelioid Cell Tumor

Indicated for locally advanced or metastatic malignant perivascular epithelioid cell tumor (PEComa)

100 mg/m2 IV on Days 1 and 8 of each 21-day cycle

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction recommendations

  • First dose reduction: 75 mg/m2 (25% reduction from 100 mg/m2)
  • Second dose reduction: 56 mg/m2 (25% reduction from 75 mg/m2)
  • Third dose reduction: 45 mg/m2 (20% reduction from 56 mg/m2)

Stomatitis

  • Grade 2 or 3: Withhold until Grade ≤1; restart at same dose for first occurrence; if recurs, restart at reduced dose level
  • Grade 4: Permanently discontinue

Anemia

  • Grade 2: Withhold until Hgb ≥8 g/dL; restart at same dose level
  • Grade ≥3: Withhold until Hgb ≥8 g/dL; restart at same dose level; if recurs, restart at reduced dose level

Thrombocytopenia

  • Grade 2: Withhold until platelet count >100x 109/L; restart at same dose level
  • Grade ≥3: Withhold until platelet count >100x 109/L; restart at reduced dose level

Neutropenia

  • Grade 2-3: Withhold until ANC >1,5x 109/L; restart at same dose level
  • Grade 4: Withhold until ANC >1,5x 109/L; restart at reduced dose level

Infections

  • Grade 3: Withhold until resolved; restart at reduced dose level; if recurs, permanently discontinue
  • Grade 4: Withhold until resolved; restart at reduced dose level OR permanently discontinue

Hypokalemia

  • Grade 2: Withhold until Grade ≤1; restart at same dose level; if recurs, restart at reduced dose level
  • Grade ≥3: Withhold until Grade ≤1; restart at reduced dose level; if recurs, permanently discontinue

Hyperglycemia

  • Grade ≥3: Withhold until Grade ≤2; restart at reduced dose level

Interstitial lung disease/noninfectious pneumonitis

  • Grade 2
    • Withhold for up to 3 weeks until Grade ≤1; restart at reduced dose level
    • If not resolved to Grade ≤1 within 3 weeks, permanently discontinue
    • If recurs, permanently discontinue
  • Grade ≥3
    • Permanently discontinue

Hemorrhage

  • Grade 2 or 3: Withhold until Grade ≤1; restart at reduced dose level; if recurs, permanently discontinue
  • Grade 4: Permanently discontinue

Other reactions

  • Grade 3: Withhold until Grade ≤1; restart at same dose level; if recurs, restart at reduced dose level
  • Grade 4: Permanently discontinue

Coadministration with CYP3A4 and/or P-gp inhibitors

  • Strong CYP3A4 and/or P-gp inhibitors: Avoid concomitant use
  • Grapefruit or grapefruit juice: Avoid concomitant use
  • Moderate or weak CYP3A4 inhibitors: Reduce sirolimus protein bound dose to 56 mg/m2

Coadministration with CYP3A4 and/or P-gp inducers

  • Strong CYP3A4 and/or P-gp inducers: Avoid concomitant use

Renal impairment

  • Mild or moderate (CrCl 30-89 mL/min): No dosage adjustment required
  • Severe (CrCl <30 mL/min): Not studied

Hepatic impairment

  • Mild (TB ≤ULN, AST >ULN or TB >1 to 1.5x ULN and any AST): Decrease dose to 75 mg/m2
  • Moderate (TB >1.5 to 3 x ULN and any AST): Decrease dose to 56 mg/m2

Dosing Considerations

Females of reproductive potential: Verify pregnancy status before initiating

Monitoring

  • Obtain blood cell counts at baseline and every 2 months during first year of treatment and every 3 months thereafter, or more frequently if clinically indicated
  • Obtain potassium level before initiating and as medically indicated
  • Obtain fasting glucose before initiating and every 3 month or as clinically indicated in nondiabetic patients; monitor more frequently in diabetic patients
  • Monitor for signs and symptoms of hemorrhage

Safety and efficacy not established

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Interactions

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                  Minor (0)

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                    Adverse Effects

                    >10%

                    General, all grades

                    • Stomatitis (79%)
                    • Fatigue (68%)
                    • Infections (59%)
                    • Edema (50%)
                    • Nausea (50%)
                    • Diarrhea (47%)
                    • Weight decreased (47%)
                    • Musculoskeletal pain (47%)
                    • Decrease appetite (44%)
                    • Cough (35%)
                    • Vomiting (32%)
                    • Dysgeusia (32%)
                    • Abdominal pain (29%)
                    • Headache (29%)
                    • Hypertension (29%)
                    • Constipation (24%)
                    • Pyrexia (24%)
                    • Hemorrhage (24%)
                    • Insomnia (21%)
                    • Pneumonitis (18%)
                    • Dry mouth (15%)
                    • Dehydration (15%)
                    • Peripheral neuropathy (15%)
                    • Hemorrhoids (12%)
                    • Dry skin (12%)
                    • Nail disorder (12%)
                    • Dizziness (12%)
                    • Dyspnea (12%)
                    • Vision blurred (12%)

                    Laboratory abnormalities, all grades

                    • Decreased lymphocytes (82%)
                    • Increased creatinine (82%)
                    • Decreased hemoglobin (68%)
                    • Increased triglycerides (52%)
                    • Increased cholesterol (48%)
                    • Increased ALT (47%)
                    • Decreased potassium (44%)
                    • Decreased magnesium (42%)
                    • Decreased leukocytes (41%)
                    • Decreased neutrophils (35%)
                    • Decreased platelets (35%)
                    • Decreased albumin (35%)
                    • Increased AST (32%)
                    • Increased alkaline phosphatase (29%)
                    • Decreased sodium (24%)
                    • Decreased calcium (15%)
                    • Decreased glucose (15%)
                    • Decreased phosphate (15%)
                    • Increased lipase (12%)
                    • Increased glucose (12%)
                    • Increased sodium (12%)

                    General, Grades 3-4

                    • Stomatitis (18%)
                    • Infections (12%)

                    Laboratory abnormalities, Grades 3-4

                    • Decreased lymphocytes (21%)
                    • Decreased potassium (12%)
                    • Increased glucose (12%)

                    1-10%

                    Enteritis (<10%)

                    Pancytopenia (<10%)

                    Acute kidney injury (<10%)

                    Acute coronary syndrome (<10%)

                    General, Grades 3-4

                    • Abdominal pain (6%)
                    • Dehydration (6%)
                    • Diarrhea (2.9%)
                    • Vomiting (2.9%)
                    • Constipation (2.9%)
                    • Fatigue (2.9%)
                    • Edema (2.9%)
                    • Musculoskeletal pain (2.9%)
                    • Hypertension (2.9%)
                    • Hemorrhage (2.9%)
                    • Insomnia (2.9%)

                    Laboratory abnormalities, Grades 3-4

                    • Decreased phosphate (9%)
                    • Increased lipase (6%)
                    • Increased cholesterol (3%)
                    • Decreased albumin (2.9%)
                    • Increased AST/ALT (2.9%)
                    • Decreased sodium (2.9%)
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                    Warnings

                    Contraindications

                    History of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin

                    Cautions

                    See dosage modifications for recommendations to withhold treatment, reduce dose, or permanently discontinue

                    Stomatitis, including mouth ulcers and oral mucositis, reported most often within 8 weeks of treatment

                    May cause myelosuppression, including anemia, thrombocytopenia, and neutropenia

                    Can cause infections; common infections reported in clinical trials included urinary tract infections, upper respiratory tract infections, and sinusitis

                    Can cause hypokalemia; potassium supplementation may be indicated

                    Hyperglycemia may occur in nondiabetic or diabetic patients

                    Interstitial lung disease/noninfectious pneumonitis reported

                    Can cause serious and sometimes fatal hemorrhage

                    Hypersensitivity reactions (to sirolimus or albumin) reported (eg, anaphylaxis, angioedema, exfoliative dermatitis, hypersensitivity vasculitis)

                    Based on animal studies and mechanism of action, can cause fetal harm when administered to pregnant females

                    Sirolimus is an antiproliferative drug and affects rapidly dividing cells (eg, as germ cells); azoospermia or oligospermia may be observed in males

                    Drug interaction overview

                    • Substrate of both CYP3A4 and p-gp
                    • CYP3A4 and/or P-gp inhibitors
                      • Strong CYP3A4 and/or P-gp inhibitors: Avoid coadministration
                      • Moderate or weak CYP3A4 inhibitors: Reduce sirolimus dose
                    • CYP3A4 and/or P-gp inducers
                      • Strong CYP3A4 and/or P-gp inducers: Avoid coadministration
                      • Moderate or weak CYP3A4 inducers: Coadministration may decrease sirolimus efficacy
                    • Vaccines
                      • No studies in conjunction with immunization conducted
                      • Immunization during treatment may be ineffective
                      • Update immunizations according to immunization guidelines before initiating siroliumus, if possible
                      • Live vaccines: Immunization with live vaccines is not recommended during treatment and avoid close contact with those who have received live vaccines while taking sirolimus
                      • Interval between live vaccinations and initiating sirolimus should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies
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                    Pregnancy & Lactation

                    Pregnancy

                    Based on animal studies and the mechanism of action, can cause fetal harm when administered to pregnant females

                    Verify pregnancy status of females of reproductive potential before initiating

                    Animal studies

                    • Studies with oral sirolimus formulation have shown that it crosses the placenta and is toxic to the conceptus at subtherapeutic doses

                    Contraception

                    • Females or males with female partners of reproductive potential: Use effective contraception during treatment and for 12 weeks after last dose

                    Infertility

                    • Based on available clinical findings with oral sirolimus and findings in animals, male and female fertility may be compromised
                    • Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) reported in females with the use of oral sirolimus
                    • Azoospermia reported in males with the use of oral sirolimus and has been reversible upon discontinuation in most cases

                    Lactation

                    Data are not available on presence in human milk or its effects on breastfed children or milk production

                    Unknown if present in human milk

                    Advise females not to breastfeed during treatment and for 2 weeks after last dose

                    Pregnancy Categories

                    A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                    B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                    C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                    D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                    X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                    NA: Information not available.

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                    Pharmacology

                    Mechanism of Action

                    Inhibitor of mechanistic target of rapamycin kinase (mTOR, previously known as mammalian target of rapamycin), a serine-threonine kinase, is downstream of the PI3K/AKT pathway; mTOR controls key cellular processes such as cell survival, growth, and proliferation; mTOR is commonly dysregulated in several human cancers

                    Sirolimus binds to immunophilin, FK binding protein-12 (FKBP-12), to generate an immunosuppressive complex; this complex binds to and inhibits activation of mTOR complex 1 (mTORC1)

                    Sirolimus is bound to human albumin to achieve higher accumulation in solid tumors; albumin is accumulated in tumor tissues, either due to the leaky capillary system and defective lymphatic drainage of tumors or through an active gp60/caveolae-mediated transport process across tumor blood vessel endothelium

                    PEComa is a rare form of sarcoma driven by mTOR activation

                    Absorption

                    Peak plasma concentration: 2,590 ng/mL

                    AUC: 22,100 ng⋅hr/mL

                    Distribution

                    Protein bound: >99%, primarily to serum albumin

                    Metabolism

                    Predominantly metabolized by CYP3A4

                    Elimination

                    Half-life: 59 hr

                    Excretion: Feces 91%; urine 2%

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                    Administration

                    IV Compatibilities

                    0.9% NaCl

                    IV Preparation

                    Reconstitution

                    • Aseptically, reconstitute each vial by injecting 20 mL of 0.9% NaCl over 1 minute directing solution flow onto the inside wall of the vial; to prevent foaming, do not inject directly onto the lyophilized powder
                    • Allow vial to sit for at least 5 minutes to ensure proper wetting of the lyophilized powder
                    • Gently swirl and/or invert vial slowly for at least 2 minutes until complete dissolution of any powder occurs; avoid shaking vial to prevent the generation of foam
                    • If foaming or clumping occurs, let suspension stand for at least 15 minutes until foam subsides; if foaming or clumping is present after 1 hr, discard reconstituted suspension
                    • Resulting suspension contains 5 mg/mL
                    • Reconstituted suspension should be milky and homogenous without visible particulates; if particulates or settling visible, gently inverted vial again to ensure complete resuspension before use
                    • Discard if precipitates observed
                    • Discard any unused portion using hazardous drug protocol

                    Transfer to polyuvinylchloride (PVC) or polyolefin infusion bag

                    • Without further dilution, transfer volume required for calculated dose into empty sterile PVC or polyolefin infusion bag for administration
                    • Use of medical devices containing silicone oil as a lubricant (eg, syringes and IV bags) to reconstitute and administer sirolimus protein bound may result in formation of proteinaceous strands
                    • Visually inspect reconstituted suspension in infusion bag before administration; discard if particulate matter, proteinaceous strands, or discoloration observed
                    • Use immediately; if unable to administer immediately, see storage

                    IV Administration

                    Infuse IV over 30 minutes

                    Infusion reaction monitoring

                    • Monitor closely for signs and symptoms of infusion reactions during and following each infusion in a setting where cardiopulmonary resuscitation medication and equipment are available
                    • Monitor for at least 2 hr after first infusion and as clinically needed for each subsequent infusion
                    • If necessary, reduce rate, interrupt infusion, or permanently discontinue based on severity and institute appropriate medical management as needed

                    Storage

                    Unopened vials

                    • Refrigerate at 2-8ºC (36-46ºF)
                    • Store in original package to protect from light
                    • Neither freezing nor thawing adversely affects product stability
                    • Hazardous drug; follow applicable special handling and disposal procedures

                    Reconstituted suspension in vial

                    • Refrigerate at 2-8ºC (36-46ºF) for maximum of 6 hr
                    • Store in original carton to protect from light

                    Reconstituted suspension in infusion bag

                    • Refrigerate at 2-8ºC (36-46ºF) and protect from light for maximum of 9 hr

                    Total combined refrigeration time

                    • Total maximum combined refrigerated storage time of reconstituted product in vial and infusion bag is 15 hr
                    • This may be followed by storage in infusion bag at ambient temperature (~ 25ºC) and lighting conditions for a maximum of 4 hr
                    • Discard any unused portion using hazardous drug protocol
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                    Formulary

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                    The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    NC NOT COVERED – Drugs that are not covered by the plan.
                    Code Definition
                    PA Prior Authorization
                    Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                    QL Quantity Limits
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