• Prevention of organ rejection in allogenic kidney transplantation (with corticosteroids and cyclosporine).
• Treatment of lymphangioleiomyomatosis (LAM)

Contraindicated in:

• Hypersensitivity
• Alcohol intolerance/sensitivity (solution contains ethanol)
• Concurrent ketoconazole, voriconazole, itraconazole, erythromycin, clarithromycin, rifampin, rifabutin, or grapefruit juice
• Severe hepatic impairment
• OB: Pregnancy (may cause fetal harm).

Use Cautiously in:

• Mild to moderate hepatic impairment
• Lactation: Use while breast feeding only if potential maternal benefit justifies potential risk to infant
• Women of reproductive potential
• Pedi: Children <13 yr (safety and effectiveness not established).

Reflects combined therapy with corticosteroids and cyclosporine

CV: edema, hypotension, pericardial effusion.

Derm: acne, rash, thrombocytopenic purpura.

F and E: hypokalemia.

Endo: hyperglycemia.

GI: ascites, hepatotoxicity.

GU: amenorrhea, infertility (males), menorrhagia, ovarian cysts, renal impairment.

Hemat: leukopenia, thrombocytopenia, anemia.

Metab: hypercholesterolemia, hypertriglyceridemia.

MS: arthralgias.

Neuro: tremor , PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML), insomnia.

Resp: interstitial lung disease, pulmonary hypertension.
Misc: ANGIOEDEMA, (INCLUDING ACTIVATION OF LATENT VIRAL INFECTIONS SUCH AS BK VIRUS-ASSOCIATED NEPHROPATHY AND CLOSTRIDIOIDES DIFFICILEINFECTION -ASSOCIATED DIARRHEA [CDAD]), ↓ wound healing, lymphocele, lymphoma.

Drug-Drug:

• Cyclosporine (modified) greatly ↑ blood levels (administer sirolimus 4 hr after cyclosporine).
• Drugs that inhibit the CYP3A4 enzyme system may be expected to ↑ blood levels and the risk of adverse reactions.
• Ketoconazole, voriconazole, itraconazole, clarithromycin, and erythromycin significantly ↑ blood levels (concurrent use is contraindicated).
• Blood levels are also ↑ by diltiazem and verapamil (monitor sirolimus levels and adjust dose as necessary) and may be ↑ by nicardipine, verapamil, clotrimazole, fluconazole, metoclopramide, cimetidine, danazol, and protease inhibitors.
• Rifampin and rifabutin↑ metabolism by stimulating the CYP3A4 enzyme system and significantly ↓ blood levels.
• Blood levels may also be ↓ by carbamazepine, phenobarbital, phenytoin, and rifapentine.
• Risk of renal impairment may be ↑ by concurrent use of other nephrotoxic agents.
• Concurrent use with tacrolimus and corticosteroids in lung transplantation may ↑ risk of anastomotic dehiscence; fatalites have been reported (not approved for this use).
• Concurrent use with tacrolimus and corticosteroids in liver transplantation may ↑ risk of hepatic artery thrombosis; fatalites have been reported (not approved for this use).
• Concurrent use with ACE inhibitors may ↑ risk of angioedema.
• May ↓ antibody response to and ↑ risk of adverse reactions to live-virus vaccines; avoid vaccination.
• May ↑ verapamil levels.

Drug-Natural Products:

• Concomitant use with echinacea and melatonin may interfere with immunosuppression.
• St. John's wort may ↑ blood levels and the risk of toxicity.

Drug-Food:

• Grapefruit juice↓ CYP3A4 metabolism and ↑ levels; do not use as a diluent and avoid concurrent ingestion.

(Generic available)

• Oral solution (contains alcohol): 1 mg/mL;
• Tablet: 0.5 mg; 1 mg; 2 mg;

Kidney Transplantation

• PO (Adults and Children 13 yr): 6-mg loading dose, followed by 2 mg/day maintenance dose. Dosing following cyclosporine withdrawal — Patients at low to moderate risk for rejection after transplantation may be withdrawn from cyclosporine over 4–8 wk beginning 2–4 mo after transplant. Thereafter, sirolimus dose should be titrated upward to maintain a whole blood trough level of 12–14 ng/mL. Clinical assessment should also be used to gauge dose. Dose changes can be made at 7–14 day intervals. The following formula may also be used: sirolimus maintenance dose = current dose × (target concentration/current concentration). If a large ↑ is needed, a loading dose may be given and blood levels reassessed 3–4 days later. Loading dose may be calculated by the following formula: sirolimus loading dose = 3 × (new maintenance dose-current maintenance dose). Loading doses >40 mg should be spread over 2 days.
• PO (Adults and Children 13 yr and <40 kg): 3 mg/m² loading dose, followed by 1 mg/m²/day maintenance dose. See adjustments above for doses following cyclosporine withdrawal.

Lymphangioleiomyomatosis

• PO (Adults): 2 mg once daily. Monitor whole blood trough level in 10–20 days and titrate dose to maintain level of 5–15 ng/mL. The following formula may also be used to adjust dose: sirolimus maintenance dose = current dose × (target concentration/current concentration). Further dose changes can be made at 7–14 day intervals. Once stable dose achieved, should monitor whole blood trough levels at least every 3 mo.

Rapamune

• Inhibits T-lymphocyte activation/proliferation, which occurs as a response to antigenic and cytokine stimulation; antibody production is also inhibited.

• Decreased incidence and severity of organ rejection.
• Improvement in pulmonary function

Therapeutic Classification: Immunosuppressant agents

Absorption: Rapidly absorbed following oral administration (14% bioavailability).

Distribution: Concentrates in erythrocytes; distributes to heart, intestines, kidneys, liver, lungs, muscle, spleen, and testes in high concentrations.

Protein Binding: 92%.

Metabolism/Excretion: Extensively metabolized (some metabolism by P450 3A4 system); 91% excreted in feces.

Half-life: 62 hr.

(blood levels)

• Instruct patient to take sirolimus at the same time each day, as directed. Advise patient to avoid taking with or diluting with grapefruit juice. Do not skip or double up on missed doses. Do not discontinue medication without advice of health care professional.
  • Advise patient to avoid grapefruit and grapefruit juice during therapy.
  • Reinforce the need for lifelong therapy to prevent transplant rejection. Review symptoms of rejection for transplanted organ and stress need to notify health care professional immediately if they occur.
  • Advise patient to notify health care professional if swelling of your face, eyes, or mouth; trouble breathing or wheezing; throat tightness; chest pain or tightness; feeling dizzy or faint; rash or peeling of skin; swelling of hands or feet; or symptoms of PML occur.
  • Advise patient to wear sunscreen and protective clothing and limit time in sunlight and UV light due to increased risk of skin cancer.
  • Caution patient to notify health care professional if signs of infection occur.
  • Advise patient to avoid vaccinations with a live virus during therapy; sirolimus may decrease vaccine effectiveness.
  • Advise patient of the risk of taking sirolimus during pregnancy. Caution women of reproductive potential to use effective contraception prior to, during, and for 12 wk following therapy. May cause male infertility.
  • Emphasize the importance of repeated lab tests during sirolimus therapy.

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