Trade Names:Rapamune- Solution, oral 1 mg/mL- Tablets 1 mg- Tablets 2 mg
Inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine stimulation; inhibits antibody production.
T max is approximately 2 h in renal transplant patients; absorption is rapid. Bioavailability is 14% (oral solution) and 41% (tablet). To minimize variability, take both oral solution and tablets consistently with or without food.
Sirolimus is 97% protein bound (albumin) and Vd is 12 L/kg.
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. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations.
91% is recovered from feces; 2.2% is excreted in urine.
There is minimal (2.2%) renal excretion of the drug and its metabolites. No dosage adjustments are necessary in patients with renal function impairment.Hepatic Function Impairment
Dosage adjustment is recommended for patients with mild to moderate hepatic function impairment.Elderly
Clinical studies did not include a sufficient number of patients older than 65 yr of age to determine whether they respond differently than younger patients.Gender
Cl is 12% lower and the half-life is prolonged in men compared with women; however, dosage adjustments based on gender are not needed.Race
In a phase 3 trial, there were no differences in sirolimus trough concentrations over time between black and nonblack patients.
Prophylaxis of organ rejection in patients receiving renal transplants.
Treatment of psoriasis.
Only health care providers experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus.Adults
PO Recommended loading dose of 6 mg with a daily maintenance dose of 2 mg (loading dose 3 times the maintenance dose) in a regimen with cyclosporine and corticosteroids.Adults and children 13 yr of age and older who weigh less than 40 kg
PO Adjust dosage to 1 mg/m 2 /day based on BSA. The loading dose should be 3 mg/m 2 .Coadministration with CyclosporineAdults and Children 13 yr of age and older
PO In patients receiving sirolimus with cyclosporine, start with a loading dosage up to sirolimus 15 mg on day 1 posttransplantation. Starting on day 2, a maintenance dosage of 5 mg/day should be given. Obtain a sirolimus trough level between days 5 and 7; adjust the sirolimus dose.Hepatic Function Impairment
PO Reduce maintenance dose by approximately 33%; do not modify loading dose.
Store oral solution bottle in refrigerator (36° to 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 max of 24 h at up to 77°F or refrigerated (36° to 46°F). Discard syringe after 1 use. Use preparation immediately after dilution. Store tablets at controlled room temperature (68° to 77°F). Protect from light.
Risk of angioedema may be increased.Calcineurin inhibitor
Risk of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and thrombotic microangiopathy may be increased.Cyclosporine
Sirolimus plasma concentrations may be increased; administer sirolimus 4 h after cyclosporine.CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort)
Sirolimus concentrations may be reduced, decreasing the efficacy.CYP3A4 inhibitors (eg, atorvastatin, bromocriptine, cimetidine, cisapride, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, grapefruit juice, indinavir, itraconazole, ketoconazole, metoclopramide, nicardipine, ritonavir, telithromycin, verapamil, voriconazole)
Sirolimus concentrations may be elevated, increasing the risk of adverse reactions.Tacrolimus
Tacrolimus blood concentrations may be reduced by sirolimus.Vaccination
Response to vaccination may be less effective.Verapamil
Concentrations may be elevated by sirolimus, increasing the pharmacologic effects and risk of adverse reactions.
None well documented.
Hypertension (49%); tachycardia, venous thromboembolism including deep vein thrombosis and pulmonary embolism (3% to less than 20%); pericardial effusion (postmarketing).
Acne (22%); rash (20%); basal cell carcinoma, melanoma, squamous cell carcinoma (3% to less than 20%); exfoliative dermatitis (postmarketing).
Constipation (38%); diarrhea (35%); nausea (31%); stomatitis (3% to less than 20%); pancreatitis (less than 3%).
UTI (33%); pyelonephritis (3% to less than 20%); azoospermia, nephrotic syndrome, proteinuria (postmarketing).
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).
Abnormal liver function tests, hepatotoxicity including fatal hepatic necrosis, increased ALT and AST (postmarketing).
Anaphylactic/anaphylactoid reactions, angioedema, hypersensitivity vasculitis (postmarketing).
Increased creatinine (40%).
Hypertriglyceridemia (57%); hypercholesterolemia (46%); abnormal healing, including fascial dehiscence, incisional hernia, and anastomosis disruption, hypokalemia, increased LDH (3% to less than 20%); hyperglycemia, hypophosphatemia (postmarketing).
Arthralgia (31%); bone necrosis (3% to less than 20%).
Epistaxis, pneumonia (3% to less than 20%); interstitial lung disease including bronchiolitis obliterans organizing pneumonia, pneumonitis and pulmonary fibrosis, pleural effusion, pulmonary hemorrhage (postmarketing).
Peripheral edema (58%); abdominal pain (36%); fever (34%); pain (33%); edema (20%); herpes simplex, herpes zoster, lymphocele, sepsis (3% to less than 20%); cytomegalovirus, Epstein-Barr virus, mycobacterial infection including Mycobacterium tuberculosis (less than 3%); tuberculosis (postmarketing).
Increased susceptibility to infection and possible development of lymphoma may result from immunosuppression.Liver transplantation – excess mortality, graft loss, and hepatic artery thrombosis (HAT)
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 HAT; most cases of HAT occurred within 30 days posttransplantation and most led to graft loss or death.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 liver or lung transplant patients, and, therefore, such use is not recommended.
Monitor whole blood sirolimus concentrations in patients receiving concentration-controlled sirolimus, patients 13 years of age and older who weigh less than 40 kg, and patients likely to have altered drug metabolism (eg, patients with hepatic function impairment, coadministration of CYP3A4 inducers or inhibitors). Periodic quantitative monitoring of urinary protein excretion is recommended.
Category C .
Safety and efficacy not established in children younger than 13 yr of age.
Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.
Hypersensitivity, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, has been reported.
Dosage adjustment is not necessary in patients with renal function impairment. However, decreased renal function may occur; monitor closely.
Reduce the dosage in patients with hepatic function impairment.
Pneumocystis carinii pneumonia has occurred in patients not receiving antimicrobial prophylaxis. Administration of antimicrobial prophylaxis for 1 yr following transplantation is recommended. Cytomegalovirus prophylaxis for 3 mo after transplantation is recommended.
The safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients.
Cases of interstitial lung disease (including pneumonitis and, infrequently, bronchiolitis fibrosa 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.
Increased serum cholesterol and triglycerides requiring treatment may occur.
Lymphocele, a surgical complication of renal transplantation, has occurred more often in a dose-related fashion in sirolimus-treated patients.
Increased urinary protein excretion has been reported from 6 to 24 mo after conversion to sirolimus from calcineurin inhibitors.
Patients on immunosuppressive therapy are at increased risk for skin cancer. Instruct patients to limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor.
Impaired or delayed wound healing has been reported in patients receiving sirolimus.
Experience is limited. However, events occurring would be consistent with those listed in the adverse reactions section.
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