sirolimus


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sirolimus

 [sĭ-ro´lĭ-mәs]
a macrolide antibiotic obtained from Streptomyces hygroscopicus, having immunosuppressant properties; used to prevent rejection of kidney transplants. Administered orally.

sirolimus

Rapamune

Pharmacologic class: Macrocyclic lactone

Therapeutic class: Immunosuppressant

Pregnancy risk category C

FDA Box Warning

• Immunosuppression may increase patient's susceptibility to infection and lymphoma development. Give under supervision of physician experienced in immunosuppressive therapy and management of renal transplant patients, in facility with adequate diagnostic and treatment resources. Physician responsible for maintenance therapy should have complete information needed for patient follow-up.

• Safety and efficacy of sirolimus as an immunosuppressant haven't been established in liver or lung transplant patients; therefore, such use isn't recommended.

• Sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. Many of these patients had evidence of infection at or near time of death. In this and another study in de novo liver transplant patients, sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in hepatic artery thrombosis (HAT); most cases of HAT occurred within 30 days after transplantation and most led to graft loss or death.

• Cases of bronchial anastomotic dehiscence, most fatal, have occurred in de novo lung transplant patients when sirolimus was used as part of an immunosuppressive regimen.

Action

Inhibits early activation and proliferation of T lymphocytes and inhibits cell cycle progression at a later stage

Availability

Oral solution: 1 mg/ml

Tablets: 1 mg, 2 mg

Indications and dosages

Prevention of organ rejection in patients with kidney transplants

Adults and adolescents older than age 13 who weigh more than 40 kg (88 lb): Initially, 6 mg P.O. as a single dose as soon as possible after transplantation, then a maintenance dosage of 2 mg P.O. once daily. Usually given with cyclosporine and corticosteroids.

Dosage adjustment

• Mild to moderate hepatic failure

Contraindications

• Hypersensitivity to drug or its components

Precautions

Use cautiously in:
• renal or hepatic disease, cancer, diabetes mellitus, hyperlipidemia, infectious complications
• patients with liver or lung transplants (use not recommended)
• concurrent use of aminoglycosides, amphotericin B, and other nephrotoxic agents
• concurrent use of strong CYP3A4 inhibitors such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin or strong CYP3A4 inducers such as rifampin or rifabutin (use not recommended)
• pregnant or breastfeeding patients
• children younger than age 13.

Administration

• Administer consistently either with or without food.
• Use syringe provided to withdraw prescribed amount. Dilute oral solution in a glass or plastic (not Styrofoam) cup containing at least 2 oz of water or orange juice. Don't use other fluids, especially grapefruit juice.
• Swirl cup to mix drug thoroughly; discard syringe. Administer diluted drug right away. Then fill cup with 4 oz of water or orange juice, and have patient drink fluid right away.

If solution touches skin or mucous membranes, immediately wash affected area with soap and water.
• Wait 4 hours after the cyclosporine dose (if prescribed) before giving sirolimus.

Adverse reactions

CNS: headache, drowsiness, paresthesia, hypoesthesia, hypertonia, hypertonia, emotional lability, dizziness, confusion, syncope, malaise, asthenia, depression, anxiety, tremor, insomnia

CV: hypertension, hypotension, tachycardia, chest pain, edema, palpitations, vasodilation, peripheral edema, peripheral vascular disorders, thrombophlebitis, thrombosis, heart failure, atrial fibrillation, hemorrhage, pericardial effusion

EENT: abnormal vision, cataract, conjunctivitis, hearing loss, ear pain, otitis media, tinnitus, epistaxis, rhinitis, sinusitis, pharyngitis

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, hernia, enlarged abdomen, ascites, esophagitis, eructation, flatulence, gastritis, gastroenteritis, dysphagia, stomatitis, mouth ulcers, oral candidiasis, anorexia, peritonitis

GU: dysuria, nocturia, pyuria, urinary retention, hematuria, albuminuria, urinary frequency or incontinence, urinary tract infection, pelvic pain, kidney or bladder pain, hydronephrosis, erectile dysfunction, scrotal edema, testes disorders, oliguria, GU tract hemorrhage, renal tubular necrosis, toxic nephropathy

Hematologic: anemia, bruising, poly-cythemia, leukocytosis, thrombocytopenia, leukopenia, thrombotic thrombocytopenia

Metabolic: hyperlipidemia, glycosuria, hyperglycemia, diabetes mellitus, hypokalemia, hypophosphatemia, hypovolemia, hypercalcemia, dehydration, Cushing's syndrome, acidosis

Respiratory: dyspnea, cough, upper respiratory infection, bronchitis, hypoxia, pneumonia, atelectasis, pleural effusion, pulmonary edema, asthma, interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia, pulmonary fibrosis)

Skin: skin ulcers, skin hypertrophy, pruritus, fungal dermatitis, hirsutism, rash, acne, cellulites, non-melanoma skin cancer

Other: gingivitis, gum hyperplasia, weight changes, neck pain, fever, abscess, chills, facial edema, flulike symptoms, infection, lymphadenopathy, abnormal healing, lymphocele, fluid accumulation (including lymphedema, ascites), opportunistic infections (such as tuberculosis, fatal infections, sepsis), hypersensitivity reactions (including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, hypersensitivity vasculitis) lymphoma

Interactions

Drug-drug.Aminoglycosides, amphotericin, other nephrotoxic drugs: increased risk of nephrotoxicity

Bromocriptine, cimetidine, clarithromycin, danazol, erythromycin, fluconazole, indinavir, itraconazole, metoclopramide, nicardipine, ritonavir, verapamil, other CYP3A4 inhibitors: decreased sirolimus metabolism and increased blood level

Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, other CYP3A4 inducers: decreased sirolimus blood level

Cyclosporine, diltiazem: increased sirolimus blood level

Live-virus vaccines: reduced vaccine efficacy

Drug-diagnostic tests.Blood urea nitrogen, cholesterol, creatinine, hepatic enzymes, lipids, red blood cells: increased levels

Calcium, glucose, phosphate, white blood cells: increased or decreased levels

Hemoglobin, magnesium, platelets, sodium: decreased levels

Drug-food.Grapefruit juice: decreased sirolimus metabolism and increased blood level

Drug-herbs.Astragalus, echinacea, melatonin, St. John's wort: decreased sirolimus efficacy

Patient monitoring

• Watch closely for signs and symptoms of infection and hypersensitivity reactions.
• Monitor renal function tests, lipid panel, electrolyte levels, blood chemistry studies, and sirolimus blood level.
• Evaluate all body systems carefully, especially cardiovascular, respiratory, and renal.
• Assess neurologic status closely. Implement safety precautions as needed to prevent injury.
• Be aware that cases of Pneumocystis carinii pneumonia have occurred in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for P. carinii pneumonia should be administered for 1 year following transplantation. In addition, cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.
• Watch for abnormal wound healing, especially in patients with body mass index greater than 30 kg/m2.

Patient teaching

• Teach patient correct procedure for taking drug.
• Advise patient to take consistently either with or without food, but not with grapefruit juice.
• Instruct patient to wait 4 hours after cyclosporine dose (if prescribed) before taking sirolimus.

Tell patient to wash affected area with soap and water immediately if drug touches his skin or mucous membranes.
• Inform patient that drug affects almost every body system. Advise him to report significant adverse reactions.

Advise patient that drug lowers resistance to infection. Instruct him to immediately report fever, cough, breathing problems, sore throat, or other signs and symptoms of infection.
• Caution patient to avoid driving and other hazardous activities until he knows how drug affects concentration and alertness.

Instruct patient to immediately report unusual bleeding or bruising.

Advise female patient to use effective contraception before and during therapy and for 12 weeks after discontinuation.

Caution patient to limit exposure to sunlight and ultraviolet light. Advise him to wear protective clothing and to use sunscreen with a high protection factor to help prevent skin cancer.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.

sirolimus

/si·ro·li·mus/ (sĭ-ro´lĭ-mus) a macrolide antibiotic having immunosuppressant properties; used to prevent rejection of kidney transplants.

sirolimus

(sə-rō′lə-məs)
n.
An immunosuppressive drug produced by the actinomycete Streptomyces hygroscopicus, C15H79NO13, used in combination with cyclosporine and corticosteroids to prevent rejection of transplanted tissues or organs. Also called rapamycin.

sirolimus

an immunosuppressant.
indications It is used after organ transplantation to prevent rejection. Recommended use is in combination with cyclosporine and corticosteroids.
contraindications Known hypersensitivity to this drug or any of its components prohibits its use.
adverse effects Life-threatening effects are anemia, leukopenia, thrombocytopenia, purpura, albuminuria, hematuria, proteinuria, renal failure, pleural effusion, atelectasis, and lymphoma. Other adverse effects include nausea, vomiting, diarrhea, constipation, hypertension, insomnia, chills, fever, urinary tract infections, hyperglycemia, increased creatinine, edema, hypercholesterolemia, hyperlipidemia, hypophosphatemia, weight gain, hyperkalemia, hyperuricemia, hypokalemia, hypomagnesemia, blurred vision, and photophobia. Common side effects include atrial fibrillation, congestive heart failure, hypotension, palpitations, tachycardia, tremors, headache, paresthesia, dyspnea, rash, and acne.

sirolimus

A macrolide immunosuppressant that is structurally similar to tacrolimus. It suppresses B- and T-cell proliferation, lymphokine synthesis, and T-cell response to IL2 by acting on target of rapamycin (TOR).

sirolimus

Rapamycin, Rapamune® Immunology A macrolide immunosuppressant structurally similar to tacrolimus; it suppresses B- and T-cell proliferation, lymphokine synthesis, T-cell response to IL-2. See TOR. Cf Cyclosporine, Tacrolimus.

sirolimus

An immunosuppressant drug used to reduce the risk of transplant rejection especially in kidney transplantation. It has also been found helpful as an eluting drug in reducing the failure rate of coronary artery stents.
References in periodicals archive ?
for the new drug application (NDA) for intravitreal (IVT ) sirolimus (DE-109), the company said.
Item 3 - Sirolimus Release Stent or Cobalt Chromium Derivative
19,20 Interestingly sirolimus was a rescue therapy in one KTR who experienced tacrolimus-related hepatotoxicity.
There were no significant differences (all groups) in the total dosages and concentrations of tacrolimus and sirolimus among the three groups.
At this stage, the case was reviewed again in view of the clinical, analytical and radiological findings, and although the initial histological results were not compatible, a diagnosis of GSD was made and it was decided to start treatment with sirolimus after the patient signed her informed consent.
The mean sirolimus dose was 2 mg daily, with blood trough levels ranging between 3.
Drugs that reduce the growth and proliferation of tumor cells by inhibiting mTOR (mammalian target of rapamycin), including sirolimus, are believed to reduce this risk, said Pritesh S.
Of the 9 patients described in the literature, 8 were treated with sirolimus [2,5-7, 9] and only 1 was treated with everolimus [4].
Because kidney failure developed in the patient at postoperative month 3, tacrolimus therapy was discontinued and sirolimus therapy was initiated (2-3 mg/day depending on the blood level).
Their findings suggested transplant drugs such as sirolimus may unlock the key against HIV as it affects viral persistence in the body.
Importantly, they also discovered that patients who took the immunosuppressant sirolimus as part of their treatment regimen had fewer cells in their blood that were infected with HIV over time and may suggest that immune-modifying drugs such as sirolimus may affect the level of HIV persistence.
A more detailed analysis showed that the concentrations of drugs such as tacrolimus and sirolimus, which are used to prevent rejection following transplantation, vary throughout the year in a manner that closely reflects changes in the level of vitamin D in the body.