sirolimus (systemic)

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

Contraind./Precautions ⬆ ⬇

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.

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%.

Availability ⬆ ⬇

(Generic available)

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

Assessment ⬆ ⬇

Monitor BP closely during therapy. Hypertension is a common complication of sirolimus therapy and should be treated.
Assess for any new signs or symptoms that may be suggestive of PML, an opportunistic infection of the brain that leads to death or severe disability; withhold dose and notify health care professional promptly. Symptoms of PML may include hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia. Consider decreasing the amount of immunosuppression in these patients.
Lymphangioleiomyomatosis: Monitor for signs and symptoms of lymphangioleiomyomatosis (wheezing; cough, which may be bloody; shortness of breath; chest pain; pneumothorax) periodically during therapy.

Lab Test Considerations:

Monitor sirolimus blood levels when dose forms are changed and in patients likely to have altered drug metabolism, patients ≥13 yr who weigh <40 kg, patients with hepatic impairment, and during concurrent administration of drugs that may interact with sirolimus. Trough concentrations of ≥15 ng/mL are associated with an ↑ in adverse effects.
- Monitor patients for hyperlipidemia. May require additional interventions to treat hyperlipidemia.
- May cause anemia, leukopenia, thrombocytopenia, and hypokalemia.
- May cause ↑ AST, ↑ ALT, hypophosphatemia, and hyperglycemia.

Implementation ⬆ ⬇

Therapy with sirolimus should be started as soon as possible post-transplant. Concurrent therapy with cyclosporine and corticosteroids is recommended. Sirolimus should be taken 4 hr after cyclosporine (Modified, Neoral).
- Sirolimus should be ordered only by health care professionals skilled in immunosuppressive therapy, with the staff and facilities to manage renal transplant patients.
PO: Administer consistently with or without food. DNC: Swallow tablet whole; do not crush, break, or chew. Do not administer with or mix with grapefruit juice.
- To dilute from bottle, use amber oral dose syringe to withdraw prescribed amount. Empty sirolimus from syringe into a glass or plastic container holding at least 2 oz (60 mL) of water or orange juice; do not use other liquids. Stir vigorously and drink at once. Refill container with at least 4 oz of additional liquid, stir vigorously, and drink at once.
- Store bottles in refrigerator. Protect from light. Solution may develop a slight haze when refrigerated; allow to stand at room temperature and shake gently until haze disappears. Sirolimus may remain in syringe at room temperature or refrigerated for up to 24 hr. Discard syringe after 1 use. Oral solution must be used within 1 mo of opening bottle.

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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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇