Sirolimus

Pronunciation: sir-OH-li-mus
Class: Immunosuppressive

Trade Names

Rapamune
- Solution, oral 1 mg/mL
- Tablets, oral 0.5 mg
- Tablets, oral 1 mg
- Tablets, oral 2 mg

Pharmacology

Inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine stimulation; inhibits antibody production.

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Pharmacokinetics

Absorption

T max is approximately 2 h in renal transplant patients; absorption is rapid. Bioavailability is 14% (oral solution) and 41% (tablet). To minimize variability, instruct patients to take oral solution and tablets consistently with or without food.

Distribution

Sirolimus is 92% protein bound (primarily to albumin) and Vd is 12 L/kg.

Metabolism

Sirolimus is a substrate for CYP3A4 and P-glycoprotein (P-gp). Sirolimus is extensively metabolized in the intestinal wall and liver, and undergoes countertransport from enterocytes of the small intestine into the gut lumen.

Elimination

91% is recovered from the feces; 2.2% is excreted in the urine. Half-life is approximately 62 h.

Special Populations

Renal Function Impairment

Minimal (2.2%) renal excretion of the drug and its metabolites.

Hepatic Function Impairment

Patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean C max . As the severity of hepatic impairment increased, there were steady increases in mean sirolimus half-life and decreases in the mean sirolimus clearance normalized for body weight.

Elderly

Sirolimus trough concentration data in renal transplant patients older than 65 y were similar to those in the adult population 18 to 65 y of age.

Gender

Cl is 12% lower and the half-life is prolonged in men compared with women.

Race

In a phase 3 trial, there were no differences between black and nonblack patients in sirolimus trough concentrations over time.

Indications and Usage

Prophylaxis of organ rejection in patients receiving renal transplants.

Unlabeled Uses

Treatment of psoriasis.

Contraindications

Hypersensitivity to sirolimus.

Dosage and Administration

Renal transplantation
Adults High immunologic risk

PO Loading dose up to 15 mg (3 mg/m 2 for patients weighing less than 40 kg) with a daily maintenance dose of 5 mg (1 mg/m 2 for patients weighing less than 40 kg). Obtain a sirolimus trough level between days 5 and 7; adjust the sirolimus dose as needed (max, 40 mg/day). Use with cyclosporine and corticosteroids for the first 12 months following transplantation.

Adults and Children 13 y and older who weigh 40 kg or more Low immunologic risk

PO Loading dose 6 mg with a daily maintenance dose of 2 mg (max, 40 mg/day). Use with cyclosporine and corticosteroids; at 2 to 4 months, progressively discontinue cyclosporine over 4 to 8 wk.

Children 13 y and older who weigh less than 40 kg Low immunologic risk

PO Loading dose 3 mg/m 2 with a daily maintenance dose of 1 mg/m 2 (max, 40 mg/day). Use with cyclosporine and corticosteroids; at 2 to 4 months, progressively discontinue cyclosporine over 4 to 8 wk.

Hepatic Function Impairment

PO Reduce maintenance dose by approximately 33% in patients with mild or moderate hepatic impairment and by 50% in patients with severe hepatic impairment; do not modify loading dose.

General Advice

  • May be given without regard to meals, but should be given consistently with or without food.
  • The tablet should be swallowed whole and not crushed, chewed, or split.
  • Patients who are unable to swallow the tablet should be prescribed the solution.
  • Prior to administration, solution must be diluted in at least 60 mL of water or orange juice only.
  • Sirolimus 2 mg tablets and solution are interchangeable on a mg-to-mg basis.
  • It is recommended that sirolimus be taken as soon as possible after transplantation, and 4 h after taking oral cyclosporine.
  • Once the maintenance dose is adjusted, the new maintenance dose should be continued for at least 7 to 14 days before further dosage adjustment.
  • Dosage adjustments can be based on a simple proportion: new sirolimus dose = current dose × (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dosage when it is necessary to increase sirolimus trough concentrations: sirolimus loading dose = 3 × (new maintenance dose - current maintenance dose). The maximum sirolimus dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg because of the addition of a loading dose, the loading dose should be administered over 2 days.
  • Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).
  • Sirolimus is an immunosuppressant agent. Follow safe handling procedures when preparing, administering, or dispensing sirolimus.
  • Administration of antimicrobial prophylaxis for Pneumocystis carinii pneumonia for 1 y following transplantation and cytomegalovirus prophylaxis for 3 mo after transplantation is recommended.

Storage/Stability

Store solution between 36° and 46°F. Protect from light. Once opened, use contents within 1 mo. If necessary, the bottle can be stored at room temperature for up to 15 days. An amber cap and syringe are provided for dosing. Product may be kept in syringe for maximum of 24 h at up to 77°F or refrigerated between 36° and 46°F. Discard syringe after 1 use. Use preparation immediately after dilution. Store tablets between 68° and 77°F. Protect from light.

Drug Interactions

ACE inhibitors (eg, captopril)

Risk of angioedema may be increased. Monitor the response of the patient. If an interaction is suspected, provide treatment as indicated.

Amiodarone

Sirolimus blood concentrations may be elevated, increasing the risk of toxicity. Consider prospectively lowering the sirolimus dose and frequently monitoring blood concentrations in order to minimize prolonged periods of increased concentrations and related toxicities.

Calcineurin inhibitor (cyclosporine, pimecrolimus, tacrolimus)

Risk of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and thrombotic microangiopathy may be increased. Closely monitor the response of the patient. If an interaction is suspected, provide treatment as indicated.

Cyclosporine

Sirolimus plasma concentrations may be increased; administer sirolimus 4 h after cyclosporine. Monitor sirolimus levels and adjust dosage as needed.

CYP3A4 and/or P-gp strong inducers (eg, rifampin, rifabutin)

Concomitant use may increase metabolism of sirolimus, decreasing sirolimus concentrations and efficacy. Avoid coadministration.

CYP3A4 and/or P-gp strong inhibitors (eg, clarithromycin, itraconazole, ketoconazole, telithromycin, voriconazole)

Concomitant use may decrease the metabolism of sirolimus, increasing sirolimus concentrations and the risk of toxicity. Avoid coadministration.

CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's wort)

Sirolimus concentrations may be reduced, decreasing the efficacy. Use with caution. Monitor sirolimus concentrations and adjust the dose as needed.

CYP3A4 inhibitors (eg, bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, grapefruit juice, indinavir, metoclopramide, nicardipine, ritonavir, verapamil)

Sirolimus concentrations may be elevated, increasing the risk of adverse reactions. Use with caution. Monitor sirolimus concentrations and adjust the dose as needed.

Disulfiram, furazolidone, metronidazole

Because sirolimus oral solution contains alcohol, coadministration of sirolimus oral solution and disulfiram, furazolidone, or metronidazole may produce acute and severe alcohol intolerance. Avoid coadministration.

Erythromycin

Erythromycin and sirolimus concentrations may be elevated, increasing the pharmacologic effects and the risk of adverse reactions. Coadministration is not recommended.

Fibric acids (eg, gemfibrozil)

Monitor for development of rhabdomyolysis and other adverse reactions during coadministration of sirolimus and fibric acid.

HMG-CoA reductase inhibitors (eg, simvastatin)

Sirolimus and HMG-CoA reductase inhibitor plasma concentrations may be elevated. Close monitoring for signs of adverse reactions (eg, rhabdomyolysis) due to either agent is warranted. Fluvastatin and pravastatin are less likely to interact and may be safer alternatives.

Mycophenolate mofetil

Mycophenolic acid trough concentrations may be elevated, increasing the risk of adverse reactions. Monitor mycophenolic acid concentrations and adjust the dose as needed.

Streptogramins (eg, dalfopristin/quinupristin)

Sirolimus concentrations may be elevated, increasing the pharmacologic effects and the risk of adverse reactions. Monitor sirolimus concentrations and observe the patient for adverse reactions. Adjust the sirolimus dose as needed.

Tacrolimus

Tacrolimus blood concentrations may be reduced by sirolimus, increasing the risk of organ transplant rejection. In addition, coadministration of tacrolimus and sirolimus in combination with corticosteroids has been associated with fatal cases of bronchial anastomotic dehiscence in lung transplant patients. Use with caution.

Vaccination

Response to vaccination may be less effective. Avoid live vaccines.

Verapamil

Verapamil and sirolimus concentrations may be elevated, increasing the pharmacologic effects and the risk of adverse reactions. Monitor sirolimus concentrations and adjust the dose as needed.

Adverse Reactions

Cardiovascular

Hypertension (49%); tachycardia, venous thromboembolism (including deep vein thrombosis and pulmonary embolism) (3% to less than 20%); pericardial effusion (postmarketing).

CNS

Headache (34%).

Dermatologic

Acne (22%); rash (20%); basal cell carcinoma, melanoma, squamous cell carcinoma (3% to less than 20%); exfoliative dermatitis (postmarketing).

GI

Constipation (38%); abdominal pain (36%); diarrhea (35%); nausea (31%); stomatitis (3% to less than 20%); pancreatitis (less than 3%); Clostridium difficile enterocolitis (postmarketing).

Genitourinary

Increased creatinine (40%); UTI (33%); decline in renal function (creatinine increased) in long-term combination of cyclosporine with sirolimus, pyelonephritis (3% to less than 20%); azoospermia, focal segmental glomerulosclerosis, nephrotic syndrome, proteinuria (postmarketing).

Hematologic-Lymphatic

Anemia (33%); thrombocytopenia (30%); leukopenia, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (3% to less than 20%); lymphoma/posttransplant lymphoproliferative disorder (less than 3%); lymphedema, neutropenia, pancytopenia (postmarketing).

Hepatic

Abnormal liver function tests, hepatotoxicity, including fatal hepatic necrosis, increased ALT and AST (postmarketing).

Hypersensitivity

Anaphylactic/anaphylactoid reactions, angioedema, hypersensitivity vasculitis (postmarketing).

Metabolic-Nutritional

Hypertriglyceridemia (57%); hypercholesterolemia (46%); hypokalemia, increased LDH (3% to less than 20%); hyperglycemia, hypophosphatemia (postmarketing).

Musculoskeletal

Arthralgia (31%); bone necrosis (3% to less than 20%).

Respiratory

Epistaxis, pneumonia (3% to less than 20%); alveolar proteinosis, interstitial lung disease including bronchiolitis obliterans organizing pneumonia, pneumonitis, and pulmonary fibrosis, pleural effusion, pulmonary hemorrhage (postmarketing).

Miscellaneous

Peripheral edema (58%); fever (34%); pain (33%); edema (20%); abnormal healing, herpes simplex, herpes zoster, lymphocele, sepsis (3% to less than 20%); malignancy (8%); cytomegalovirus, Epstein-Barr virus, mycobacterial infection including Mycobacterium tuberculosis (less than 3%); BK virus–associated nephropathy, tuberculosis (postmarketing).

Precautions

Warnings

Only health care providers experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus.

Immunosuppression

Increased susceptibility to infection and possible development of lymphoma may result from immunosuppression.

Liver transplantation – excess mortality, graft loss, and hepatic artery thrombosis

Coadministration of sirolimus and tacrolimus was associated with excess mortality and graft loss in de novo liver transplant patients.

The use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in hepatic artery thrombosis; most cases of hepatic artery thrombosis occurred within 30 days posttransplantation and most led to graft loss or death. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients and, therefore, such use is not recommended.

Lung transplantation – bronchial anastomotic dehiscence

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients and, therefore, such use is not recommended.


Monitor

Monitor whole blood sirolimus concentrations in patients receiving concentration-controlled sirolimus, patients 13 y and older who weigh less than 40 kg, patients likely to have altered drug metabolism (eg, hepatic impairment, coadministration of CYP3A4 inducers or inhibitors), and when a change in the sirolimus doseform is made. Periodic quantitative monitoring of urinary protein excretion is recommended. Closely monitor renal function during administration with cyclosporine. Monitor all patients for hyperlipidemia and infections. During sirolimus therapy with cyclosporine, monitor patients administered an HMG-CoA reductase inhibitor and/or fibrate for the possible development of rhabdomyolysis and other adverse reactions.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 13 y or in pediatric renal transplant patients younger than 18 y who are considered at high immunologic risk.

Elderly

Use with caution, usually starting at the low end of the dose range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Hypersensitivity

Hypersensitivity, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, has been reported.

Hepatic Function

Reduce the maintenance dosage in patients with hepatic impairment.

Antimicrobial prophylaxis

Pneumocystis carinii pneumonia has occurred in patients not receiving antimicrobial prophylaxis.

Cyclosporine

The safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients.

Fluid accumulation

There have been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults).

Infections

Immunosuppressed patients are at an increased risk for opportunistic infections, including activation of latent viral infections. This includes BK virus–associated nephropathy and cases of progressive multifocal leukoencephalopathy.

Interstitial lung disease

Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia, and pulmonary fibrosis), some fatal, have occurred in patients receiving immunosuppressive regimens, including sirolimus. In some cases, interstitial lung disease resolved upon discontinuation of sirolimus. The risk may be increased as the sirolimus trough level increases.

Lipids

Increased serum cholesterol and triglycerides requiring treatment may occur.

Lymphocele

Lymphocele, a surgical complication of renal transplantation, has occurred more often in a dose-related fashion in sirolimus-treated patients.

Proteinuria

Increased urinary protein excretion has been reported from 6 to 24 mo after conversion to sirolimus from calcineurin inhibitors.

Renal effects

Long-term coadministration of sirolimus with cyclosporine can be associated with deterioration of renal function. In patients with delayed graft function, sirolimus may delay recovery of renal function.

Skin cancer

Patients on immunosuppressive therapy are at increased risk for skin cancer and should limit exposure to sunlight and UV light.

Wound healing

Impaired or delayed wound healing has been reported.

Overdosage

Symptoms

Experience is limited. However, events occurring would be consistent with those listed in Adverse Reactions.

Patient Information

  • Advise patient receiving oral solution to review the Medication Guide before using and with each refill.
  • Instruct patient to take each dose consistently with or without food to minimize variability in blood levels and efficacy.
  • Advise patient taking cyclosporine solution (modified) or capsules (modified) to take sirolimus 4 h after taking the cyclosporine.
  • Caution patient to avoid ingesting grapefruit and grapefruit juice while taking this medication.
  • Instruct patient to continue taking other immunosuppressive and prophylactic medications prescribed by health care provider. Caution patient not to change the dose or stop taking any medications unless advised by health care provider.
  • Instruct women of childbearing potential to use effective contraception before starting therapy, during therapy, and for 12 wk following discontinuation of sirolimus.
  • Warn patient to avoid exposure to sun and sunlamps while using this medication because of increased risk of skin cancer. Advise patient to use sunscreens with high protective factor and wear protective clothing when exposure cannot be avoided.
  • Advise patient to immediately report any of the following to health care provider: signs or symptoms of transplant rejection (fever, pain at transplant site, rapid weight gain), fever or other signs of infection, sore throat, bothersome adverse reactions.
  • Warn patients that vaccination may be less effective during treatment with immunosuppressants, and to avoid the use of live vaccines.

Copyright © 2009 Wolters Kluwer Health.

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