Sirolimus

Trade Names:
Rapamune
- Solution, oral 1 mg/mL
- Tablets 1 mg
- Tablets 2 mg

Pharmacology

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

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, take both oral solution and tablets consistently with or without food.

Distribution

Sirolimus is 97% protein bound (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. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations.

Elimination

91% is recovered from feces; 2.2% is excreted in urine.

Special Populations

There is minimal (2.2%) renal excretion of the drug and its metabolites. No dosage adjustments are necessary in patients with renal function impairment.

Dosage adjustment is recommended for patients with mild to moderate hepatic function impairment.

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.

Cl is 12% lower and the half-life is prolonged in men compared with women; however, dosage adjustments based on gender are not needed.

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

Indications and Usage

Prophylaxis of organ rejection in patients receiving renal transplants.

Unlabeled Uses

Treatment of psoriasis.

Contraindications

Standard considerations.

Dosage and Administration

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

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.

PO Adjust dosage to 1 mg/m ² /day based on BSA. The loading dose should be 3 mg/m ² .

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.

PO Reduce maintenance dose by approximately 33%; do not modify loading dose.

General Advice

• May be given without regard to meals.
• The tablet should be swallowed whole and not crushed, chewed, or split.
• Patients unable to swallow the tablet should be prescribed the solution.
• Sirolimus 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.

Storage/Stability

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.

Drug Interactions

Risk of angioedema may be increased.

Risk of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and thrombotic microangiopathy may be increased.

Sirolimus plasma concentrations may be increased; administer sirolimus 4 h after cyclosporine.

Sirolimus concentrations may be reduced, decreasing the efficacy.

Sirolimus concentrations may be elevated, increasing the risk of adverse reactions.

Tacrolimus blood concentrations may be reduced by sirolimus.

Response to vaccination may be less effective.

Concentrations may be elevated by sirolimus, increasing the pharmacologic effects and risk of adverse reactions.

Laboratory Test Interactions

None well documented.

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%); diarrhea (35%); nausea (31%); stomatitis (3% to less than 20%); pancreatitis (less than 3%).

Genitourinary

UTI (33%); pyelonephritis (3% to less than 20%); azoospermia, 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).

Lab Tests

Increased creatinine (40%).

Metabolic-Nutritional

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).

Musculoskeletal

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

Respiratory

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

Miscellaneous

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).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 13 yr of age.

Elderly

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

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

Renal Function

Dosage adjustment is not necessary in patients with renal function impairment. However, decreased renal function may occur; monitor closely.

Hepatic Function

Reduce the dosage in patients with hepatic function impairment.

Antimicrobial prophylaxis

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.

Cyclosporine

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

Interstitial lung disease

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.

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.

Skin cancer

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.

Wound healing

Impaired or delayed wound healing has been reported in patients receiving sirolimus.

Overdosage

Symptoms

Experience is limited. However, events occurring would be consistent with those listed in the adverse reactions section.

Patient Information

• Advise patient receiving oral solution to review patient information for oral solution administration 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 over 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.

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