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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.
Inhibits early activation and proliferation of T lymphocytes and inhibits cell cycle progression at a later stage
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.
• Mild to moderate hepatic failure
• Hypersensitivity to drug or its components
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.
• 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.
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
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
• 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.
• 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.