sirolimus (systemic)

Contraindicated in:

Hypersensitivity;
Alcohol intolerance/sensitivity (solution contains ethanol);
Severe hepatic impairment;
OB: Pregnancy.

Use Cautiously in:

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

Adv. Reactions/Side Effects ⬆ ⬇

Reflects combined therapy with corticosteroids and cyclosporine

CV: edema, hypotension, pericardial effusion

Derm: acne, rash, ↓wound healing, thrombocytopenic purpura

Endo: hyperglycemia

F and E: hypokalemia

GI: ascites, hepatotoxicity

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

Hemat: leukopenia, thrombocytopenia, anemia

Metab: hypercholesterolemia, hypertriglyceridemia

MS: arthralgia

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

Resp: interstitial lung disease, pulmonary hypertension

Misc: ANGIOEDEMA, INFECTION (INCLUDING ACTIVATION OF LATENT VIRAL INFECTIONS SUCH AS BK VIRUS-ASSOCIATED NEPHROPATHY AND CLOSTRIDIOIDES DIFFICILE-ASSOCIATED DIARRHEA), Clostridioides difficile-associated diarrhea), lymphocele, LYMPHOMA

Interactions ⬆ ⬇

Drug-drug:

Cyclosporine (modified) significantly ↑ levels and the risk of toxicity; administer sirolimus 4 hr after cyclosporine.
Strong CYP3A4 inhibitors, including ketoconazole, voriconazole, itraconazole, clarithromycin, and erythromycin, may ↑ levels and the risk of toxicity; avoid concurrent use.
Diltiazem, verapamil, nicardipine, clotrimazole, fluconazole, metoclopramide, cimetidine, danazol, letermovir, and protease inhibitors may ↑ levels and the risk of toxicity; monitor sirolimus levels and adjust dose as necessary.
Strong CYP3A4 inducers, includingrifampin and rifabutin, may ↓ levels and effectiveness; avoid concurrent use.
Carbamazepine, phenobarbital, phenytoin, and rifapentine may ↓ levels and effectiveness.
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; fatalities have been reported (not approved for this use).
Concurrent use with tacrolimus and corticosteroids in liver transplantation may ↑ risk of hepatic artery thrombosis; fatalities 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 and the risk of toxicity.
Cannabidiol may ↑ levels and the risk of toxicity; monitor sirolimus levels and adjust dose as necessary.

Drug-Natural Products:

Concomitant use with echinacea and melatonin may interfere with immunosuppression.
St. John's wort may ↓ levels and effectiveness.

Drug-Food:

Grapefruit juice may ↑ levels and the risk of toxicity; avoid concurrent ingestion.

Availability ⬆ ⬇

(Generic available)

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

Route/Dosage ⬆ ⬇

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.

Hepatic Impairment

PO (Adults and Children ): Mild or moderate hepatic impairment:↓ maintenance dose by 33%; loading dose is unchanged; Severe hepatic impairment:↓ maintenance dose by 50%; loading dose is unchanged.

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.

Hepatic Impairment

(Adults ): Mild or moderate hepatic impairment:↓ dose by 33%; Severe hepatic impairment:↓ dose by 50%.

US Brand Names ⬆ ⬇

Action ⬆ ⬇

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

Therapeutic effects:

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

Classifications ⬆ ⬇

Therapeutic Classification: Immunosuppressant agents

Pharmacokinetics ⬆ ⬇

Absorption: 14% absorbed following oral administration.

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 in the liver via the CYP3A4 isoenzyme; 91% excreted in feces.

Half-Life: 62 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	rapid	1–2 hr	24 hr

Patient/Family Teaching ⬆ ⬇

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.
- May cause fetal harm. Advise females of reproductive potential 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 and female infertility.
- Emphasize the importance of repeated lab tests during sirolimus therapy.

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Indications ⬇

Contraind./Precautions ⬆ ⬇