Immunosuppressant Agent

Prophylaxis of organ rejection in patients receiving renal transplants, in combination with cyclosporine and corticosteroids

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Embryotoxicity and fetotoxicity may occur, as evidenced by increased mortality, reduced fetal weights and delayed ossification. Effective contraception must be initiated before therapy with sirolimus and continued for 12 weeks after discontinuation. Excretion in breast milk unknown. Breast-feeding is not recommended.

Hypersensitivity to sirolimus or any component of the formulation

Immunosuppressive agents, including sirolimus, increase the risk of infection and may be associated with the development of lymphoma. Only physicians experienced in the management of organ transplant patients should prescribe sirolimus. May increase serum lipids (cholesterol and triglycerides). Use with caution in patients with hyperlipidemia. May decrease GFR and increase serum creatinine. Use caution in patients with renal impairment, or when used concurrently with medications which may alter renal function. Has been associated with an increased risk of lymphocele. Avoid concurrent use of ketoconazole.

Incidence of many adverse effects are dose related

Cardiovascular: Hypertension (39% to 49%), peripheral edema (54% to 64%), edema (16% to 24%), chest pain (16% to 24%)

Central nervous system: Fever (23% to 34%), headache (23% to 34%), pain (24% to 33%), insomnia (13% to 22%)

Dermatologic: Acne (20% to 31%), rash (10% to 20%)

Endocrine & metabolic: Hypercholesterolemia (38% to 46%), hyperkalemia (12% to 17%), hypokalemia (11% to 21%), hypophosphatemia (15% to 23%), hyperlipidemia (38% to 57%)

Gastrointestinal: Abdominal pain (28% to 36%), nausea (25% to 36%), vomiting (19% to 25%), diarrhea (25% to 42%), constipation (28% to 38%), dyspepsia (17% to 25%), weight gain (8% to 21%)

Genitourinary: Urinary tract infection (20% to 33%)

Hematologic: Anemia (23% to 37%), leukopenia (9% to 15%), thrombocytopenia (13% to 40%)

Neuromuscular & skeletal: Arthralgia (25% to 31%), weakness (22% to 40%), back pain (16% to 26%), tremor (21% to 31%)

Renal: Increased serum creatinine (35% to 40%)

Respiratory: Dyspnea (22% to 30%), upper respiratory infection (20% to 26%), pharyngitis (16% to 21%)

3% to 20%:

Cardiovascular: Atrial fibrillation, congestive heart failure, hypervolemia, hypotension, palpitation, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombosis, vasodilation

Central nervous system: Chills, malaise, anxiety, confusion, depression, dizziness, emotional lability, hypesthesia, hypotonia, insomnia, neuropathy, somnolence

Dermatologic: Dermatitis (fungal), hirsutism, pruritus, skin hypertrophy, dermal ulcer, ecchymosis, cellulitis

Endocrine & metabolic: Cushing's syndrome, diabetes mellitus, glycosuria, acidosis, dehydration, hypercalcemia, hyperglycemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia

Gastrointestinal: Enlarged abdomen, anorexia, dysphagia, eructation, esophagitis, flatulence, gastritis, gastroenteritis, gingivitis, gingival hyperplasia, ileus, mouth ulceration, oral moniliasis, stomatitis, weight loss

Genitourinary: Pelvic pain, scrotal edema, testis disorder, impotence

Hematologic: Leukocytosis, polycythemia, TTP, hemolytic-uremic syndrome, hemorrhage

Hepatic: Abnormal liver function tests, increased alkaline phosphatase, increased LDH, increased transaminases, ascites

Local: Thrombophlebitis

Neuromuscular & skeletal: Increased CPK, arthrosis, bone necrosis, leg cramps, myalgia, osteoporosis, tetany, hypertonia, paresthesia

Ocular: Abnormal vision, cataract, conjunctivitis

Otic: Ear pain, deafness, otitis media, tinnitus

Renal: Increased BUN, increased serum creatinine, albuminuria, bladder pain, dysuria, hematuria, hydronephrosis, kidney pain, tubular necrosis, nocturia, oliguria, pyuria, nephropathy (toxic), urinary frequency, urinary incontinence, urinary retention

Respiratory: Asthma, atelectasis, bronchitis, cough, epistaxis, hypoxia, lung edema, pleural effusion, pneumonia, rhinitis, sinusitis

Miscellaneous: Abscess, facial edema, flu-like syndrome, hernia, infection, lymphadenopathy, lymphocele, peritonitis, sepsis, diaphoresis

Experience with overdosage has been limited. Dose-limiting toxicities include immune suppression. Reported symptoms of overdose include atrial fibrillation. Treatment is supportive, dialysis is not likely to facilitate removal.

CYP3A4 substrate and P-glycoprotein substrate

Cyclosporine increases C_max and AUC of sirolimus during concurrent therapy, and cyclosporine clearance may be reduced during concurrent therapy. Sirolimus should be taken 4 hours after cyclosporine oral solution and/or capsules.

Diltiazem and ketoconazole increase serum concentrations or sirolimus; clearance of sirolimus is increased by rifampin

Grapefruit juice may reduce the metabolism of sirolimus, and should not be used to dilute this product

Other inhibitors of CYP3A4 (eg, calcium channel blockers, antifungal agents, macrolide antibiotics, gastrointestinal prokinetic agents, HIV-protease inhibitors) are likely to increase sirolimus concentrations

Decreased effect: Inducers of CYP3A4 (eg, rifampin, phenobarbital, carbamazepine, rifabutin, phenytoin) are likely to decrease serum concentrations of sirolimus

Protect from light and store under refrigeration (2°C to 8°C/36°F to 46°F). (Stable for 24 months under these conditions). A slight haze may develop in refrigerated solutions, but the quality of the product is not affected. After opening, solution should be used in 1 month. If necessary, may be stored at temperatures up to 25°C (77°F) for several days after opening (not longer than 30 days). Product may be stored in amber syringe for a maximum of 24 hours (at room temperature or refrigerated). Discard syringe after use. Solution should be used immediately following dilution.

Sirolimus inhibits T-lymphocyte activation and proliferation in response to antigenic and cytokine stimulation. Its mechanism differs from other immunosuppressants. It inhibits acute rejection of allografts and prolongs graft survival.

Absorption: Rapid

Distribution: 12 L/kg (±7.52 L/kg)

Protein binding: 92%, primarily to albumin

Metabolism: Hepatic metabolism is extensive; substrate for CYP3A4 and P-glycoprotein

Bioavailability: 14%

Half-life: Mean, 62 hours

Time to peak: 1-3 hours

Elimination: In feces (91%), and urine (2.2%)

Oral:

Children greater than or equal to 13 years or Adults <40 kg: Loading dose: 3 mg/m² (day 1); followed by a maintenance of 1 mg/m²/day.

Dosage adjustment in renal impairment: No dosage adjustment is necessary in renal impairment

Dosage adjustment in hepatic impairment: Reduce maintenance dose by approximately 33% in hepatic impairment. Loading dose is unchanged.

Amber oral dose syringe should be used to withdraw solution from the bottle. Syringe should then be emptied, or, if a pouch is used, the entire contents should be squeezed out into a glass or plastic cup. The solution in the cup should be mixed with at least 2 ounces of water or orange juice. No other liquids should be used for dilution. Patient should drink diluted solution immediately. The cup should then be refilled with an additional 4 ounces of water or orange juice, stirred vigorously, and the patient should drink the contents at once.

Monitor sirolimus levels in pediatric patients, patients with hepatic impairment, or on concurrent inhibitors or inducers of CYP3A4, and/or if cyclosporine dosing is markedly reduced or discontinued. Also monitor serum cholesterol and triglycerides, blood pressure, and serum creatinine. Routine therapeutic drug level monitoring is not required in most patients.

Mean serum trough concentrations: 9 ng/mL for the 2 mg/day treatment groups and 17 ng/mL in the 5 mg/day group

No information available to require special precautions

No effects or complications reported

Do not get pregnant while taking this medication. Use reliable contraception while on this medication and for 3 months after discontinuation. May be taken with or without food but take medication consistently with respect to meals (always take with food or always take on an empty stomach).

Solution, oral: 1 mg/mL (1 mL, 2 mL, 5mL, 60 mL, 150 mL)