Sirolimus

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Sirolimus

Definition

Sirolimus is indicated by the Food and Drug Administration (FDA) to be used after a kidney transplant to prevent the body from rejecting the new kidney. Sirolimus may also have a role in prevention of organ rejection in heart or lung transplantation, and prevention of graft-versus-host disease in patients undergoing bone marrow transplantation . Sirolimus (formerly known as rapamycin) became available at the end of 1999 and is marketed under the brand name Rapamune by Wyeth-Ayerst Laboratories.

Description

Sirolimus belongs to a class of macrolide antibiotics and is isolated from an organism named streptomyces hygriscopicus.

Sirolimus prevents the immune system from attacking the transplanted organ by decreasing the growth of certain chemicals in the body responsible for the immune function (B and T lymphocytes). Sirolimus works differently from other immunosuppressants used to prevent organ rejection after transplantation (azathioprine , mycophenolate mofetil , tacrolimus , cyclosporine , and steroids). It should be given in combination with cyclosporine and steroids to prevent acute rejection of a transplanted kidney. This drug is available as a tablet and a liquid and can be used in children and adults.

Recommended dosage

Adults

KIDNEY TRANSPLANTATION.

The first dose of 3 tablets (2 mg each) or 6 milliliters of oral solution should be given as soon as possible after a kidney is transplanted. Then, a maintenance dose of 2 mg should be given once a day.

Children over 13 years of age and Adults less than 40 kg (88 lbs)

KIDNEY TRANSPLANTATION.

3 mg of sirolimus per square meter of body surface area on day 1 after transplantation, followed by a maintenance dose of 1 mg per square meter per day.

Children less than 13 years of age

Check with a physician.

Administration

Sirolimus should be administered in combination with cyclosporine and steroids. To decrease the risk of side effects, sirolimus should be given four hours after cyclosporine. To avoid variations in blood levels, sirolimus should be taken consistently— either always with food or always without food. Sirolimus oral solution should only be mixed with water or orange juice and consumed immediately. Juices or liquids other than water or orange juice should not be used to mix sirolimus. Bottled sirolimus solution should be stored in the refrigerator, but not frozen. Refrigerated sirolimus solution may develop a slight haze. If haze is noticed, the drug should be left at room temperature and gently shaken until haze disappears. If a dose is missed, it should taken as soon as possible unless it is almost time for the next dose. Two doses at the same time should not be taken.

Precautions

Sirolimus may increase the risk of the following conditions:

infections caused by viruses and bacteria
lymphoma or skin cancer
elevated blood lipids (cholesterol and triglycerides)
decreased kidney function
lymphocele formation after a kidney transplantation.

Patients with the following conditions should use sirolimus with caution:

an allergic reaction to tacrolimus (has a similar structure to sirolimus)
liver disease (dose of sirolimus may need to be decreased)
treatment with medications that are broken down in the liver and that may interact with sirolimus
Pregnancy. These patients should use an effective method of birth control started before therapy with sirolimus and continued for 12 weeks after stopping this medication.

Patients should immediately alert their doctor if any of these symptoms develop:

fever, chills, sore throat
fast heartbeat
trouble breathing
unusual bleeding or bruising

Sirolimus should be taken consistently with regard to meals (either always taken with food or always taken on an empty stomach) and at least four hours after cyclosporine to decrease variability of blood sirolimus levels. Patients should avoid grapefruit or grapefruit juice because it may increase sirolimus levels in the blood. Those taking sirolimus will need to see a physician regularly to check blood and urine.

Side effects

The most common side effects include mild dose-related risk of bleeding, elevated blood cholesterol and triglyceride values, decreased kidney function, high blood pressure, diarrhea or constipation, rash, acne, joint pain, nausea, vomiting, stomachache, and decreased blood potassium and phosphate values. Sirolimus can decrease the number of red blood cells, which can cause a patient to look pale, feel tired, short of breath, and drowsy, and experience heart palpitations. People who are allergic to tacrolimus may develop an allergy when taking sirolimus.

Interactions

Sirolimus is broken down in the liver by the same enzyme system that also breaks down cyclosporine and tacrolimus. Because cyclosporine can increase sirolimus blood levels, sirolimus should be given four hours after the morning cyclosporine dose to decrease the risk of side effects. Diltiazem (Cardizem, Tiazac, Dilacor) and ketoconazole (Nizoral) can increase sirolimus blood levels. The use of ketoconazole should be avoided in patients taking sirolimus. Other drugs that are likely to increase sirolimus blood levels and increase its side effects include calcium channel blockers (used to treat high blood pressure), drugs that treat fungal infections (ketoconazole, itraconazole, fluconazole), macrolide antibiotics (erythromycin, clarithromycin), and anti-HIV drugs (ritonavir, nelfinavir, indinavir). Rifampin can greatly decrease sirolimus blood levels, potentially making it less effective. Other drugs that may decrease effectiveness of sirolimus include phenobarbital, carbamazepine , rifabutin, and phenytoin . Anyone who is taking these drugs should ask their physician if they could safely take sirolimus.

Olga Bessmertny, Pharm.D.

KEY TERMS

Immune system

—The body's mechanism to fight infections, toxic substances, and to recognize and neutralize or eliminate foreign material (for example, a body organ transplanted from another person).

Immunosuppressant

—An agent that decreases activity of immune system (for example, radiation or drugs).

Lymphocele

—A mass surrounded by an abnormal sac that contains lymph (fluid that is collected from tissues throughout the body) from diseased or injured lymphatic channels.

Lymphoma

—Any malignant (cancerous) disorder of lymphoid tissue.

Steroids

—Drugs such as prednisone or dexamethasone, which resemble body's natural hormones and are often used to decrease inflammation or to suppress activity of immune system.