sirolimus protein bound (Rx)

>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%)

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

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.

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%

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