Sirolimus

Pronunciation

(sir OH li mus)

U.S. Brand Names

Rapamune®

Generic Available

Canadian Brand Names

Rapamune®

Use

Prophylaxis of organ rejection in patients receiving renal transplants, in combination with corticosteroids and cyclosporine (cyclosporine may be withdrawn in low-to-moderate immunological risk patients after 2-4 months, in conjunction with an increase in sirolimus dosage)

Use - Unlabeled/Investigational

Investigational: Immunosuppression in other forms of solid organ transplantation

Pregnancy Risk Factor

Pregnancy Implications

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.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to sirolimus or any component of the formulation

Warnings/Precautions

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. Monitor renal function closely when combined with cyclosporine; consider dosage adjustment or discontinue in patients with increasing serum creatinine. Has been associated with an increased risk of lymphocele. Avoid concurrent use of potent CYP3A4 inhibitors or strong inducers of either CYP3A4 or P-glycoprotein.

Sirolimus is neither approved nor recommended for use in liver transplant patients; studies indicate an association with an increase risk of hepatic artery thrombosis and graft failure in these patients. Cases of bronchial anastomotic dehiscence have been reported in lung transplant patients when sirolimus was used as part of an immunosuppressive regimen; most of these reactions were fatal. Use in patients with lung transplants is not recommended. Safety and efficacy of cyclosporine withdrawal in high-risk patients is not currently recommended. Safety and efficacy in children <13 years of age have not been established.

Adverse Reactions

Incidence of many adverse effects is dose related

>20%:

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%)

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

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%), thrombocytopenia (13% to 40%)

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

Renal: Serum creatinine increased (35% to 40%)

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

3% to 20%:

Cardiovascular: Atrial fibrillation, CHF, hypervolemia, hypotension, palpitation, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombosis, vasodilation, venous thromboembolism

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, rash (10% to 20%)

Endocrine & metabolic: Cushing's syndrome, diabetes mellitus, glycosuria, acidosis, dehydration, hypercalcemia, hyperglycemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hyperkalemia (12% to 17%)

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, leukopenia (9% to 15%)

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

Local: Thrombophlebitis

Neuromuscular & skeletal: Arthrosis, bone necrosis, CPK increased, leg cramps, myalgia, osteoporosis, tetany, hypertonia, paresthesia

Ocular: Abnormal vision, cataract, conjunctivitis

Otic: Ear pain, deafness, otitis media, tinnitus

Renal: Albuminuria, bladder pain, BUN increased, 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, diaphoresis, facial edema, flu-like syndrome, hernia, infection, lymphadenopathy, lymphocele, peritonitis, sepsis

Postmarketing and/or case reports: Anaphylaxis; anaphylactoid reaction; interstitial lung disease (pneumonitis, pulmonary fibrosis, and bronchiolitis obliterans organizing pneumonia) with no identified infectious etiology; fascial dehiscence; hepatic necrosis; neutropenia; pancytopenia; anastomotic disruption. In liver transplant patients (not an approved use), an increase in hepatic artery thrombosis and graft failure were noted in clinical trials. In lung transplant patients (not an approved use), bronchial anastomotic dehiscence have been reported.

Overdosage/Toxicology

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.

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)

Cyclosporine capsules (modified) or cyclosporine oral solution (modified) increase Cmax 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 (modified) and/or cyclosporine capsules (modified).

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of sirolimus. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins. Concurrent use is not recommended.

CYP3A4 inhibitors: May increase the levels/effects of sirolimus. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil. Concurrent use is not recommended.

Diltiazem may increase serum concentrations of sirolimus; monitor. Verapamil and nicardipine may share this effect.

Erythromycin: May increase serum concentrations of sirolimus.

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

Ketoconazole: May increase serum concentrations of sirolimus; not recommended.

P-gp inducers: May decrease serum concentrations of sirolimus.

Rifampin: May decrease serum concentrations; not recommended.

Vaccines: Vaccination may be less effective and use of live vaccines should be avoided during sirolimus therapy.

Voriconazole: Sirolimus serum concentrations may be increased; concurrent use is contraindicated.

Ethanol/Nutrition/Herb Interactions

Food: Do not administer with grapefruit juice; may decrease clearance of sirolimus. Ingestion with high-fat meals decreases peak concentrations but increases AUC by 35%. Sirolimus should be taken consistently either with or without food to minimize variability.

Herb/Nutraceutical: St John's wort may decrease sirolimus levels; avoid concurrent use. Avoid cat's claw, echinacea (have immunostimulant properties).

Stability

Oral solution: Protect from light and store under refrigeration, 2°C to 8°C (36°F to 46°F). 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 (up to 24 hours for pouches and not >15 days for bottles). 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.

Tablet: Store at room temperature of 20°C to 25°C (68°F to 77°F); protect from light

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Absorption: Rapid

Distribution: 12 L/kg (± 7.52 L/kg)

Protein binding: 92%, primarily to albumin

Metabolism: Extensively hepatic via CYP3A4 and P-glycoprotein

Bioavailability: 14%

Half-life elimination: Mean: 62 hours

Time to peak: 1-3 hours

Excretion: Feces (91%); urine (2.2%)

Dosage

Oral:

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

Adults 40 kg: Loading dose: For de novo transplant recipients, a loading dose of 3 times the daily maintenance dose should be administered on day 1 of dosing. Maintenance dose: 2 mg/day. Doses should be taken 4 hours after cyclosporine, and should be taken consistently either with or without food.

Withdrawal of cyclosporine:

Following 2-4 months of combined therapy, withdrawal of cyclosporine may be considered in low-to-moderate risk patients. Cyclosporine withdrawal in not recommended in high immunological risk patients. Cyclosporine should be discontinued over 4-8 weeks, and a necessary increase in the dosage of sirolimus (up to fourfold) should be anticipated due to removal of metabolic inhibition by cyclosporine and to maintain adequate immunosuppressive effects.

Sirolimus dosages should be adjusted to maintain trough concentrations of 12-24 ng/mL. Dosage should be adjusted at intervals of 7-14 days to account for the long half-life of sirolimus. Considerable increases in dosage may require an additional loading dose, calculated as the difference between the target concentration and the current concentration, multiplied by a factor of 3. Loading doses >40 mg may be administered over two days. Serum concentrations should not be used as the sole basis for dosage adjustment (monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters).

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.

Administration

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. Sirolimus should be taken 4 hours after cyclosporine oral solution (modified) or cyclosporine capsules (modified)

Monitoring Parameters

Monitor sirolimus levels in pediatric patients, patients

13 years of age weighing <40 kg, patients with hepatic impairment, or on concurrent potent 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. Serum concentrations should not be used as the sole basis for dosage adjustment, especially during withdrawal of cyclosporine (monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters).

Reference Range

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

Dietary Considerations

Take consistently, with or without food, to minimize variability of absorption.

Patient Education

Take as directed; do not alter dose or discontinue without consulting prescriber. Do not ever mix sirolimus solution with anything other than water or orange juice (avoid taking with grapefruit juice). May be taken with or without food, but should be taken consistently with regard to food (always on an empty stomach or always with food). Consult prescriber about timing of any other prescribed or OTC medications. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You will be susceptible to infection (avoid crowds and exposure to infection). If you have diabetes, monitor glucose levels closely (drug may alter glucose levels). Limit exposure to sunlight by wearing protective clothing or sunscreen. You may experience nausea, vomiting, loss of appetite (small, frequent meals, good mouth care, chewing gum, or sucking hard candy may help); constipation (increase exercise, fluids, fruit, or fiber may help); or diarrhea (yogurt or buttermilk); or muscle or back pain (mild analgesic). Inform prescriber of any adverse effects including, but not limited to, unresolved GI problems; respiratory difficulty, cough, infection; skin rash or irritation; headache, insomnia, anxiety, confusion, emotional lability; changes in voiding pattern, burning, itching, or pain on urination; persistent bone, joint, or muscle cramping, pain or weakness; chest pain, palpitations, swelling of extremities; weight gain of 3-5 pounds per week; vision changes or hearing; or any other adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Additional Information

Sirolimus tablets and oral solution are not bioequivalent, due to differences in absorption. Clinical equivalence was seen using 2 mg tablet and 2 mg solution. It is not known if higher doses are also clinically equivalent.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Insomnia is common; may cause anxiety, confusion, depression, emotional lability, and somnolence

Mental Health: Effects on Psychiatric Treatment

Leukopenia is common; use caution with clozapine and carbamazepine; nefazodone may increase serum levels of sirolimus

Dosage Forms

Solution, oral [bottle]: 1 mg/mL (60 mL, 150 mL) [contains ethanol 1.5% to 2.5%; packaged with 1 mL, 2 mL, or 5 mL oral syringes]

Solution, oral [unit-dose pouch]: 1 mg/mL (1 mL, 2 mL, 5 mL) [contains ethanol 1.5% to 2.5%; packaged in cartons of 30]

Tablet: 1 mg, 2 mg, 5 mg

International Brand Names

Rapamune® (AT, BE, BR, CA, CH, CO, CZ, DE, DK, ES, FI, FR, GB, IE, IL, IT, NO, NZ, PL, RO, SE, SG, TH)

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