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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(sir OH li mus)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM235958.pdf, must be dispensed with this medication.
REMS Components
Rapamune®: Released from REMS requirement 6/6/2011
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Prophylaxis of organ rejection in patients receiving renal transplants
Use: Unlabeled
Prophylaxis of organ rejection in heart transplant recipients; prevention acute graft-versus-host disease (GVHD) in allogeneic stem cell transplantation; treatment of refractory acute or chronic GVHD; treatment of soft tissue sarcoma (chordoma, angiomyolipoma, or lymphangioleiomyomatosis)
Pregnancy Risk Factor
C
Pregnancy Considerations
Animal studies have demonstrated embryotoxicity and fetotoxicity, as evidenced by increased mortality, reduced fetal weights and delayed ossification. There are no adequate and well-controlled studies in pregnant women. Effective contraception must be initiated before therapy with sirolimus and continued for 12 weeks after discontinuation.The National Transplantation Pregnancy Registry (NTPR, Temple University) is a registry for pregnant women taking immunosuppressants following any solid organ transplant. The NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant recipients at 877-955-6877.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for adverse reactions in the breast-fed infant, including possible immunosuppression, breast-feeding is not recommended.
Contraindications
Hypersensitivity to sirolimus or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Experienced physician: See “Other warnings/precautions” below.
• Infections: See “Concerns related to adverse effects” below.
• Liver transplants: See “Special populations” below.
• Lung transplants: See “Special populations” below.
• Malignancy: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Anaphylactic/hypersensitivity reactions: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been reported.
• Angioedema: Has been reported; concurrent use with other drugs known to cause angioedema (eg, ACE inhibitors) may increase risk.
• Infections: [U.S. Boxed Warning]: Immunosuppressive agents, including sirolimus, increase the risk of infection. Immune suppression may also increase the risk of opportunistic infections (including activation of latent viral infections including BK virus-associated nephropathy), fatal infections, and sepsis. Prophylactic treatment for Pneumocystis jirovecii pneumonia (PCP) should be administered for 1 year post-transplant; prophylaxis for cytomegalovirus (CMV) should be taken for 3 months post-transplant in patients at risk for CMV. Progressive multifocal leukoencephalopathy (PML), an opportunistic CNS infection caused by reactivation of the JC virus, has been reported in patients receiving immunosuppressive therapy, including sirolimus. Clinical findings of PML include apathy, ataxia, cognitive deficiency, confusion, and hemiparesis; promptly evaluate any patient presenting with neurological changes; consider decreasing the degree of immunosuppression with consideration to the risk of organ rejection in transplant patients.
• Interstitial lung disease: Cases of interstitial lung disease (eg, pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], pulmonary fibrosis) have been observed (some fatal); risk may be increased with higher trough levels.
• Hyperlipidemia: May increase serum lipids (cholesterol and triglycerides). Use with caution in patients with hyperlipidemia.
• Lymphocele/fluid accumulation: Use has been associated with an increased risk of fluid accumulation and lymphocele. Peripheral edema, lymphedema, ascites, and pleural and pericardial effusions (including significant effusions and tamponade) were reported; use with caution in patients in whom fluid accumulation may be poorly tolerated, such as in cardiovascular disease (heart failure or hypertension) and pulmonary disease.
• Malignancy: [U.S. Boxed Warning]: Immunosuppressive agents, including sirolimus, may be associated with the development of lymphoma and other malignancies, including an increased risk of skin cancer; limit sun and ultraviolet light exposure; use appropriate sun protection.
• Proteinuria: Increased urinary protein excretion has been observed when converting renal transplant patients from calcineurin inhibitors to sirolimus during maintenance therapy. A higher level of proteinuria prior to sirolimus conversion correlates with a higher degree of proteinuria after conversion. In some patients, proteinuria may reach nephrotic levels; nephrotic syndrome (new onset) has been reported.
• Renal effects: May increase serum creatinine and decrease GFR with long-term combination use of sirolimus and cyclosporine. Immunosuppressed patients are at an increased risk of BK viral-associated nephropathy which may impair renal function and cause graft loss; consider decreasing immunosuppressive burden if evidence of deteriorating renal function.
• Wound dehiscence/healing: May be associated with wound dehiscence and impaired healing; use caution in the perioperative period. Patients with a body mass index (BMI) >30 kg/m2 are at increased risk for abnormal wound healing.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; a reduction in the maintenance dose is recommended.
Concurrent drug therapy issues:
• Calcineurin inhibitors: Concurrent use with a calcineurin inhibitor (cyclosporine, tacrolimus) may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA).
• Cyclosporine: Safety and efficacy of combination therapy with cyclosporine in high immunologic risk patients have not been studied beyond 12 months of treatment. Monitor renal function closely when combined with cyclosporine; consider dosage adjustment or discontinue in patients with increasing serum creatinine.
• High potential for interactions: Avoid concurrent use of strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitors (eg, clarithromycin, erythromycin, telithromycin, itraconazole, ketoconazole, voriconazole) and strong CYP3A4 and/or P-gp inducers (eg, rifampin, rifabutin).
• Nephrotoxic drugs: Use with caution in patients concurrently taking medications which may alter renal function.
Special populations:
• Liver transplants: [U.S. Boxed Warning]: Sirolimus is not recommended for use in liver transplantation; studies indicate an association with an increase risk of hepatic artery thrombosis (HAT), graft failure, and increased mortality (with evidence of infection) in these patients when sirolimus is used in combination with cyclosporine and/or tacrolimus. Most cases of HAT occurred within 30 days of transplant.
• Lung transplants: [U.S. Boxed Warning]: Sirolimus is not recommended for use in lung transplantation. Bronchial anastomotic dehiscence cases have been reported in lung transplant patients when sirolimus was used as part of an immunosuppressive regimen; most of these reactions were fatal.
• Renal transplant: In renal transplant patients, de novo use without cyclosporine has been associated with higher rates of acute rejection. Sirolimus may delay recovery of renal function in patients with delayed allograft function.
Dosage form specific issues:
• Product interchangeability: 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. Monitor sirolimus levels if changes in dosage forms are made.
Other warnings/precautions:
• Appropriate use: Sirolimus should be used in combination with cyclosporine (and corticosteroids) initially. Cyclosporine may be withdrawn in low-to-moderate immunologic risk patients after 2-4 months, in conjunction with an increase in sirolimus dosage. In high immunologic risk patients, use in combination with cyclosporine and corticosteroids is recommended for the first year. Adjustment of immunosuppressive therapy beyond 12 months should be considered based on clinical judgement.
• Experienced physician: [U.S. Boxed Warning]: Should only be used by physicians experienced in immunosuppressive therapy and management of transplant patients. Adequate laboratory and supportive medical resources must be readily available.
• Laboratory monitoring: Sirolimus concentrations are dependent on the assay method (eg, chromatographic and immunoassay) used; assay methods are not interchangeable. Variations in methods to determine sirolimus whole blood concentrations, as well as interlaboratory variations, may result in improper dosage adjustments, which may lead to subtherapeutic or toxic levels. Determine the assay method used to assure consistency (or accommodations if changes occur), and for monitoring purposes, be aware of alterations to assay method or reference range. The manufacturer recommends high performance liquid chromatography (HPLC) as the reference standard to determine sirolimus trough concentrations.
Adverse Reactions
Incidence of many adverse effects is dose related.
>20%:
Cardiovascular: Peripheral edema (54% to 58%), hypertension (45% to 49%), edema (18% to 20%)
Central nervous system: Headache (34%), pain (29% to 33%), insomnia (13% to 22%)
Dermatologic: Acne (22%)
Endocrine & metabolic: Hypertriglyceridemia (45% to 57%), hypercholesterolemia (43% to 46%)
Gastrointestinal: Constipation (36% to 38%), abdominal pain (29% to 36%), diarrhea (25% to 36%), nausea (25% to 31%)
Genitourinary: Urinary tract infection (26% to 33%)
Hematologic: Anemia (23% to 33%), thrombocytopenia (14% to 30%)
Neuromuscular & skeletal: Arthralgia (25% to 31%)
Renal: Serum creatinine increased (39% to 40%)
3% to 20%:
Cardiovascular: Atrial fibrillation, CHF, DVT, facial edema, hypervolemia, hypotension, palpitation, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombosis, vasodilation
Central nervous system: Anxiety, chills, confusion, depression, dizziness, emotional lability, hypoesthesia, malaise, neuropathy, somnolence
Dermatologic: Rash (10% to 20%), skin carcinoma (up to 3%; includes basal cell carcinoma, squamous cell carcinoma, melanoma), cellulitis, dermal ulcer, dermatitis (fungal), ecchymosis, hirsutism, pruritus, skin hypertrophy, wound healing abnormal
Endocrine & metabolic: Acidosis, Cushing's syndrome, dehydration, diabetes mellitus, glycosuria, hypercalcemia, hyperglycemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia
Gastrointestinal: Abdomen enlarged, anorexia, dysphagia, eructation, esophagitis, flatulence, gastritis, gastroenteritis, gingival hyperplasia, gingivitis, ileus, mouth ulceration, oral moniliasis, stomatitis, weight loss
Genitourinary: Impotence, pelvic pain, scrotal edema, testis disorder
Hematologic: Hemolytic-uremic syndrome, hemorrhage, leukopenia, leukocytosis, polycythemia, TTP
Hepatic: Abnormal liver function tests, alkaline phosphatase increased, LDH increased
Local: Thrombophlebitis
Neuromuscular & skeletal: Arthrosis, bone necrosis, CPK increased, hyper-/hypotonia, leg cramps, myalgia, osteoporosis, paresthesia, tetany
Ocular: Abnormal vision, cataract, conjunctivitis
Otic: Ear pain, otitis media, tinnitus
Renal: Albuminuria, bladder pain, BUN increased, dysuria, hematuria, hydronephrosis, kidney pain, nephropathy (toxic), nocturia, oliguria, pyelonephritis, pyuria, tubular necrosis, urinary frequency, urinary incontinence, urinary retention
Respiratory: Asthma, atelectasis, bronchitis, cough, epistaxis, hypoxia, lung edema, pleural effusion, pneumonia, pulmonary embolism, rhinitis, sinusitis
Miscellaneous: Lymphoproliferative disease/lymphoma (1% to 3%), abscess, diaphoresis, flu-like syndrome, hernia, herpesvirus infection, infection (including opportunistic), lymphadenopathy, lymphocele, peritonitis, sepsis
<3%, postmarketing, and/or case reports: ALT increased, alveolar proteinosis, anaphylactoid reaction, anaphylaxis, anastomotic disruption, angioedema, ascites, AST increased, azoospermia, Clostridium difficile colitis, cytomegalovirus, Epstein-Barr virus, exfoliative dermatitis, fascial dehiscence, focal segmental glomerulosclerosis, hepatic necrosis, hepatotoxicity, hypersensitivity reaction, hypersensitivity vasculitis, hypophosphatemia, incisional hernia; interstitial lung disease (dose-related; includes pneumonitis, pulmonary fibrosis, and bronchiolitis obliterans organizing pneumonia [BOOP] with no identified infectious etiology); joint disorders, lymphedema, myocardial infarction, mycobacterial infection, nephropathy (BK virus-associated), nephrotic syndrome, neutropenia, pancreatitis, pancytopenia, pericardial effusion, Pneumocystis pneumonia, progressive multifocal leukoencephalopathy (PML), proteinuria, pulmonary hemorrhage, reversible posterior leukoencephalopathy syndrome (RPLS), tamponade, tuberculosis, wound dehiscence
Note: Hepatic artery thrombosis (HAT) and graft failure have been reported in liver transplant patients (not an approved use); bronchial anastomotic dehiscence has been reported in lung transplant patients (not an approved use)
Metabolism/Transport Effects
Substrate of CYP3A4 (major), P-glycoprotein; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (weak)
Drug Interactions
ACE Inhibitors: Sirolimus may enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a weak CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
Crizotinib: May increase the serum concentration of Sirolimus. Risk X: Avoid combination
CycloSPORINE: Sirolimus may enhance the adverse/toxic effect of CycloSPORINE. An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. CycloSPORINE may increase the serum concentration of Sirolimus. This is of specific concern with cyclosporine [MODIFIED]. Management: Administer oral doses of sirolimus 4 hours after doses of cyclosporine. Monitor for toxic effects of sirolimus if used with cyclosporine. Risk D: Consider therapy modification
CycloSPORINE (Systemic): Sirolimus may enhance the adverse/toxic effect of CycloSPORINE (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. CycloSPORINE (Systemic) may increase the serum concentration of Sirolimus. This is of specific concern with cyclosporine [MODIFIED]. Management: Administer oral doses of sirolimus 4 hours after doses of cyclosporine. Monitor for toxic effects of sirolimus if used with cyclosporine. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Efavirenz: May decrease the serum concentration of Sirolimus. Management: Closely monitor sirolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of sirolimus may be required. Risk D: Consider therapy modification
Fluconazole: May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Risk D: Consider therapy modification
Fosphenytoin: May decrease the serum concentration of Sirolimus. Management: Monitor for decreased sirolimus serum concentrations if phenytoin is intiated/dose increased. Monitor for increased sirolimus concentrations with phenytoin discontinuation/dose decrease. Sirolimus dose adjustments may be necessary. Risk D: Consider therapy modification
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
Itraconazole: May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Risk D: Consider therapy modification
Ketoconazole: May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Risk D: Consider therapy modification
Ketoconazole (Systemic): May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Macrolide Antibiotics: May decrease the metabolism of Sirolimus. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin; Spiramycin. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of Sirolimus. Management: Monitor for decreased sirolimus serum concentrations if phenytoin is intiated/dose increased. Monitor for increased sirolimus concentrations with phenytoin discontinuation/dose decrease. Sirolimus dose adjustments may be necessary. Risk D: Consider therapy modification
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Posaconazole: May increase the serum concentration of Sirolimus. Risk X: Avoid combination
Protease Inhibitors: May increase the serum concentration of Sirolimus. Risk C: Monitor therapy
Rifampin: May increase the metabolism of Sirolimus. Risk D: Consider therapy modification
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus: Sirolimus may enhance the adverse/toxic effect of Tacrolimus. Tacrolimus may enhance the adverse/toxic effect of Sirolimus. Sirolimus may decrease the serum concentration of Tacrolimus. Management: Tacrolimus and sirolimus should only be used concomitantly as part of a protocol with a known risk:benefit profile and an established safety record. Several regimens combining these agents have been associated with excess morbidity and/or mortality. Risk D: Consider therapy modification
Tacrolimus (Systemic): May enhance the adverse/toxic effect of Sirolimus. Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Systemic). Sirolimus may decrease the serum concentration of Tacrolimus (Systemic). Risk X: Avoid combination
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Tacrolimus (Topical): May enhance the adverse/toxic effect of Sirolimus. Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Topical). Risk D: Consider therapy modification
Telaprevir: May increase the serum concentration of Sirolimus. Management: Significant sirolimus dose reductions are likely to be required if used with telaprevir. Concurrent use should be performed with great caution and close monitoring of both sirolimus concentrations and clinical response. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Voriconazole: May increase the serum concentration of Sirolimus. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Food: Grapefruit juice may decrease clearance of sirolimus. Ingestion with high-fat meals decreases peak concentrations but increases AUC by 23% to 35%. Management: Avoid grapefruit juice. Take consistently (either with or without food) to minimize variability.
Herb/Nutraceutical: St John's wort may decrease sirolimus levels. Some herbal medications have immunostimulant properties (eg, echinacea). Herbs with hypoglycemic properties may increase the risk of sirolimus-induced hypoglycemia (eg, alfalfa). Management: Avoid St John's wort, cat's claw, and echinacea. Avoid alfalfa, aloe, bilberry, bitter melon, burdock, celery, damiana, fenugreek, garcinia, garlic, ginger, ginseng (American), gymnema, marshmallow, and stinging nettle.
Storage
Oral solution: Store under refrigeration, 2°C to 8°C (36°F to 46°F). Protect from light. 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 ≤15 days after opening. Product may be stored in amber syringe for a maximum of 24 hours (at room temperature or refrigerated). Discard syringe after single 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 and inhibits antibody production. Its mechanism differs from other immunosuppressants. Sirolimus binds to FKBP-12, an intracellular protein, to form an immunosuppressive complex which inhibits the regulatory kinase, mTOR (mammalian target of rapamycin). This inhibition suppresses cytokine mediated T-cell proliferation, halting progression from the G1 to the S phase of the cell cycle. It inhibits acute rejection of allografts and prolongs graft survival.
Pharmacodynamics/Kinetics
Absorption: Rapid
Distribution: 12 L/kg (range: 4-20 L/kg)
Protein binding: ~92%, primarily to albumin
Metabolism: Extensive; in intestinal wall via P-glycoprotein and hepatic via CYP3A4; to 7 major metabolites
Bioavailability: Oral solution: 14%; Oral tablet: 18%
Half-life elimination: Mean: 62 hours (range: 46-78 hours); extended in hepatic impairment (Child-Pugh class A or B) to 113 hours
Time to peak: Oral solution: 1-3 hours; Tablet: 1-6 hours
Excretion: Feces (91% due to P-glycoprotein-mediated efflux into gut lumen); urine (2%)
Dosage
Oral:
Low-to-moderate immunologic risk renal transplant patients: Children ≥13 years and Adults: Dosing by body weight:
<40 kg: Loading dose: 3 mg/m2 on day 1, followed by maintenance dosing of 1 mg/m2 once daily
≥40 kg: Loading dose: 6 mg on day 1; maintenance: 2 mg once daily
High immunologic risk renal transplant patients: Adults: Loading dose: Up to 15 mg on day 1; maintenance: 5 mg/day; obtain trough concentration between days 5-7 and adjust accordingly. Continue concurrent cyclosporine/sirolimus therapy for 1 year following transplantation. Further adjustment of the regimen must be based on clinical status.
Dosage adjustment:
Sirolimus dosages should be adjusted to maintain trough concentrations within desired range based on risk and concomitant therapy. Maximum daily dose: 40 mg. Dosage should be adjusted at intervals of 7-14 days to account for the long half-life of sirolimus. In general, dose proportionality may be assumed. New sirolimus dose equals current dose multiplied by (target concentration divided by current concentration). Note: If large dose increase is required, consider loading dose calculated as:
Loading dose equals (new maintenance dose minus current maintenance dose) multiplied by 3
Maximum dose in 1 day: 40 mg; if required dose is >40 mg (due to loading dose), divide loading dose over 2 days. Whole blood concentrations should not be used as the sole basis for dosage adjustment (monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters).
Maintenance therapy after withdrawal of cyclosporine:
Cyclosporine withdrawal is not recommended in high immunological risk patients. Following 2-4 months of combined therapy, withdrawal of cyclosporine may be considered in low-to-moderate immunologic 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. Dose-adjusted trough target concentrations are typically 16-24 ng/mL for the first year post-transplant and 12-20 ng/mL thereafter (measured by chromatographic methodology).
GVHD prophylaxis (unlabeled use): 12 mg loading dose on day -3, followed by 4 mg daily (target trough level: 3-12 ng/mL); taper off after 6-9 months (Armand, 2008; Cutler, 2007)
Treatment of refractory acute GVHD (unlabeled use): 4-5 mg/m2 for 14 days (no loading dose) (Benito, 2001)
Treatment of chronic GVHD (unlabeled use): 6 mg loading dose, followed by 2 mg daily (target trough level: 7-12 ng/mL) for 6-9 months (Couriel, 2005)
Dosage adjustment in renal impairment: No dosage adjustment (in loading or maintenance dose) is necessary in renal impairment. However, adjustment of regimen (including discontinuation of therapy) should be considered when used concurrently with cyclosporine and elevated or increasing serum creatinine is noted.
Dosage adjustment in hepatic impairment:
Loading dose: No adjustment required
Maintenance dose:
Mild-to-moderate hepatic impairment: reduce maintenance dose by ~33%
Severe hepatic impairment: reduce maintenance dose by ~50%
Administration: Oral
Initial dose should be administered as soon as possible after transplant. Sirolimus should be taken 4 hours after oral cyclosporine (Neoral® or Gengraf®). Should be administered consistently (with or without food).
Solution: Mix (by stirring vigorously) 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.
Tablet: Do not crush, split, or chew.
Monitoring Parameters
Monitor LFTs and CBC during treatment. Monitor sirolimus levels in all patients (especially in pediatric patients, patients ≥13 years of age weighing <40 kg, patients with hepatic impairment, or on concurrent potent inhibitors or inducers of CYP3A4 or P-gp, and/or if cyclosporine dosing is markedly reduced or discontinued), and when changing dosage forms of sirolimus. Also monitor serum cholesterol and triglycerides, blood pressure, serum creatinine, and urinary protein. Serum drug concentrations should be determined 3-4 days after loading doses and 7-14 days after dosage adjustments; however, these 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). Note: Concentrations and ranges are dependent on and will vary with assay methodology (chromatographic or immunoassay); assay methods are not interchangeable.
Reference Range
Note: Sirolimus concentrations are dependent on the assay method (eg, chromatographic and immunoassay) used; assay methods are not interchangeable. Determine the assay method used to assure consistency (or accommodations if changes occur) and for monitoring purposes, be aware of alterations to assay method or reference range.
Serum trough concentration goals for renal transplantation (based on HPLC methods):
Concomitant cyclosporine: 4-12 ng/mL
Low-to-moderate immunologic risk (after cyclosporine withdrawal): 16-24 ng/mL for the first year after transplant; after 1 year: 12-20 ng/mL
High immunologic risk (with cyclosporine): 10-15 ng/mL
Note: Trough concentrations vary based on clinical context and use of additional immunosuppressants. The following represents typical ranges.
When combined with tacrolimus and mycophenolate mofetil (MMF) without steroids: 6-8 ng/mL
As a substitute for tacrolimus (starting 4-8 weeks post-transplant), in combination with MMF and steroids: 8-12 ng/mL
Following conversion from tacrolimus to sirolimus >6 months post-transplant due to chronic allograft nephropathy: 4-6 ng/mL
Serum trough concentrations for GVHD prophylaxis in allogeneic stem cell transplant: 3-12 ng/mL (Cutler, 2007; Armand, 2008)
Dietary Considerations
Take consistently (with or without food) to minimize variability of absorption.
Patient Education
Do not mix sirolimus solution with anything other than water or orange juice. Do not crush, split, or chew tablets. 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). Maintain adequate hydration, unless instructed to restrict fluid intake. You will be susceptible 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, constipation, diarrhea, rash, acne, tremor, weight gain, or muscle or back pain. Inform prescriber of unresolved GI problems; respiratory difficulty, cough, or infection; persistent fever; skin rash or irritation; headache, insomnia, anxiety, confusion, or emotional lability; unusual bleeding; changes in voiding pattern or burning, itching, or pain on urination; persistent bone, joint, or muscle cramping, pain or weakness; numbness or tingling of extremities; chest pain, palpitations, or swelling of extremities; weight gain; or hearing or vision changes.
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. Monitor sirolimus levels if changes in dosage forms are made.
Sirolimus solution may cause irritation if administered undiluted.
High-risk renal transplant patients are defined (per the manufacturer's labeling) as African-American transplant recipients and/or repeat renal transplant recipients who lost a previous allograft based on an immunologic process and/or patients with high PRA (panel-reactive antibodies; peak PRA level >80%). Individual transplant centers may have differences in their definitions. For example, some centers would consider a PRA >50% to be at higher risk of rejection.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Mouth ulceration, oral moniliasis, stomatitis, gingival hyperplasia, gingivitis, and dysphagia.
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
Nursing: Physical Assessment/Monitoring
Assess lipid profiles; evaluate the need for medication intervention. Monitor blood pressure, weight, and renal function. Assess for signs of fluid retention and infection.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, oral:
Rapamune®: 1 mg/mL (60 mL) [contains ethanol 1.5%-2.5%, propylene glycol, soy]
Tablet, oral:
Rapamune®: 0.5 mg, 1 mg, 2 mg
Pricing: U.S. (www.drugstore.com)
Solution (Rapamune)
1 mg/mL (60): $662.01
Tablets (Rapamune)
0.5 mg (30): $189.98
1 mg (30): $346.99
2 mg (100): $2317.87
References
Antin J, Kim H, Cutler C, et al, "Sirolimus, Tacrolimus, and Low-Dose Methotrexate for Graft-Versus-Host Disease Prophylaxis in Mismatched Related Donor or Unrelated Donor Transplantation," Blood, 2003, 102(5):1601-5.
Armand P, Gannamaneni S, Kim HT, et al, “Improved Survival in Lymphoma Patients Receiving Sirolimus for Graft-Versus-Host Disease Prophylaxis After Allogeneic Hematopoietic Stem-Cell Transplantation With Reduced-Intensity Conditioning,” J Clin Oncol, 2008, 26(35):5767-74.
Benito AI, Furlong T, Martin PJ, et al, “Sirolimus (Rapamycin) for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease,” Transplantation, 2001, 72(12):1924-9.
Bissler JJ, McCormack FX, Young LR, et al, “Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis,” N Engl J Med, 2008, 358(2):140-51.
Couriel DR, Saliba R, Escalon MP, et al, “Sirolimus in Combination With Tacrolimus and Corticosteroids for the Treatment of Resistant Chronic Graft-Versus-Host Disease,” Br J Haematol, 2005, 130(3):409-17.
Cutler C, Kim H, Hochberg E, et al, "Sirolimus and Tacrolimus Without Methotrexate as Graft-Versus-Host Disease Prophylaxis After Matched Related Donor Peripheral Blood Stem Cell Transplantation,” Biol Blood Marrow Transplant, 2004, 10(5):328-36.
Cutler C, Li S, Ho VT, et al, “Extended Follow-Up of Methotrexate-Free Immunosuppression Using Sirolimus and Tacrolimus in Related and Unrelated Donor Peripheral Blood Stem Cell Transplantation,” Blood, 2007, 109(7):3108-14.
Ettinger RB and Grimm EM, “Safety and Efficacy of TOR Inhibitors in Pediatric Renal Transplant Recipients,” Am J Kidney Dis, 2001, 38(4 Suppl 2):22-8.
Kahan BD, “Efficacy of Sirolimus Compared With Azathioprine for Reduction of Acute Renal Allograft Rejection: A Randomised Multicentre Study. The Rapamune US Study Group,” Lancet, 2000, 356(9225):194-202.
McDonald AS, “A Worldwide, Phase III, Randomized, Controlled, Safety and Efficacy Study of a Sirolimus/Cyclosporine Regimen for Prevention of Acute Rejection in Recipients of Primary Mismatched Renal Allografts. RAPAMUNE Global Study Group,” Transplantation, 2001, 71(2):271-80.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Soft Tissue Sarcoma,” Version 2.2010. Available at http://www.nccn.org/professionals/physician_gls/PDF/sarcoma.pdf
Raichlin E, Bae JH, Khalpey Z, et al, “Conversion to Sirolimus as Primary Immunosuppression Attenuates the Progression of Allograft Vasculopathy After Cardiac Transplantation,” Circulation, 2007, 116(23):2726-33.
Sifontis NM, Coscia LA, Constantinescu S, et al, “Pregnancy Outcomes in Solid Organ Transplant Recipients With Exposure to Mycophenolate Mofetil or Sirolimus,” Transplantation, 2006, 82(12):1698-1702.
Stacchiotti S, Marrari A, Tamborini E, et al, “Response to Imatinib Plus Sirolimus in Advanced Chordoma,” Ann Oncol, 2009, 20(11):1886-94.
Stenton SB, Partovi N, and Ensom MH, “Sirolimus: The Evidence for Clinical Pharmacokinetic Monitoring,” Clin Pharmacokinet, 2005, 44(8):769-86.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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