Sirolimus information from DrugsUpdate
P - Contraindicated in pregnancy
L - Contraindicated in lactation
FI - Food *
Sirolimus, also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It is marketed under the trade name Rapamune by Wyeth.
Pharmacodynamics
Pharmacokinetics
Sirolimus is a potent non-calcineurin inhibiting immunosuppressant used for renal transplantation. It inhibits T-lymphocyte activation and proliferation. It also inhibits antibody production. It has been shown to possess antifungal and antineoplastic properties.
Absorption
Rapidly absorbed in the GI tract after oral admin.
Distribution
Extensively bound to plasma proteins.
Metabolism
Metabolised by CYP3A4 via demethylation or hydroxylation.
Excretion
Mainly excreted via faeces; only about 2% excreted in the urine.
Sirolimus Indications / Sirolimus Uses
Information Not Available
Sirolimus Adverse Reactions / Sirolimus Side Effects
GI disturbances, tremor, acne, impaired renal function, hyperlipidaemia, peripheral oedema, headache, pain, asthenia and hypertension. Arthralgia, hypokalaemia, pyelonephritis, leucopenia, anaemia and angioedema.
Potentially Fatal: Fatal hepatic necrosis.
Precautions
Monitor
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.
Overdosage
General supportive measures should be used.
Special Precautions
Hepatic or renal impairment. Kidney function should be monitored. Avoid exposure to sun or ultraviolet light. May increase risk of infection and development of lymphoma. Use in lung or liver transplant patients is not recommended as the safety and efficacy of sirolimus in such patients have not been established.
Other Drug Interactions
Inhibitors of CYP3A4 such as ketoconazole and protease inhibitors may increase the plasma concentrations of sirolimus. Concurrent admin with ciclosporin may lead to changes in the rate and extent of sirolimus absorption thus the drugs should be taken at least 4 hr apart. Increased risk of calcineurin inhibitor-induced haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura or thrombotic microangiopathy when used with a calcineurin inhibitor. May lead to angioneurotic oedema-type reactions when used with ACE inhibitor. May decrease response to vaccines.
Other Interactions
Food Interaction
Concomitant use with grapefruit juice should be avoided. Concurrent use with St. John's wort may decrease serum concentrations of sirolimus.
Dosage
Oral
Prophylaxis of organ rejection in kidney allograft recipients
Adult: For low-moderate risk patients: Loading dose: 6 mg on day 1, followed by a maintenance dose of 2 mg once daily, given 4 hours after ciclosporin. Adjust dose to obtain whole blood through concentrations of 4-12 ng/ml, and reduce doses of ciclosporin and corticosteroids gradually. After 2-3 months, ciclosporin should be gradually discontinued over 4-8 weeks while dose of sirolimus is adjusted to obtain trough concentrations of 12-20 ng/ml. For patients at high immunological risk such as black Afro-Caribbean patients and/or repeat renal transplant patients, sirolimus may be continued with ciclosporin and corticosteroids for the 1st year after transplantation. Recommended loading dose: 15 mg, followed by an initial maintenance dose of 5 mg daily; further adjustments are made based on whole blood trough concentrations.
Child: Used with ciclosporin and corticosteroids: >13 years and weighing <40 kg: Loading dose of 3 mg/m2 BSA, followed by initial maintenance of 1 mg/m2/day. Adjust dose to obtain whole blood trough concentrations of 4-12 ng/ml, and reduce doses of ciclosporin and corticosteroids gradually. After 2-3 months, ciclosporin should be gradually discontinued over 4-8 weeks while dose of sirolimus adjusted to obtain trough concentrations of 12-20 ng/ml. If ciclosporin withdrawal is unsuccessful, usage of sirolimus should not exceed 3 months after transplantation. Max: 40 mg/day.
Hepatic impairment: Maintenance dose should be reduced by one-third.
Food(before/after)
May be taken with or without food. (Take consistently either always w/ or always without meals. Avoid grapefruit juice.)
List of Contraindications
Sirolimus and Pregnancy
Contraindicated in pregnancy
Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.
Sirolimus and Lactation
Contraindicated in lactation
Sirolimus and Children
Safety and efficacy not established in children younger than 13 years of age.
Sirolimus and Geriatic
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.
Sirolimus and Other Contraindications
Pregnancy and lactation.
Storage
Oral
Oral solution: Refrigerate at 2-8°C. Tablet: Store at 20-25°C. Protect from light.
Lab interference
Oral
Oral solution: Refrigerate at 2-8°C. Tablet: Store at 20-25°C. Protect from light.
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