Chemical formula: C₅₁H₇₉NO₁₃ Molecular mass: 914.187 g/mol PubChem compound: 5284616
Sirolimus interacts in the following cases:
Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g. St. John’s Wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin).
Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels. Such inhibitors include certain antifungals (e.g. clotrimazole, fluconazole, itraconazole, voriconazole), certain antibiotics (e.g. troleandomycin, telithromycin, clarithromycin), certain protease inhibitors (e.g. ritonavir, indinavir, boceprevir, and telaprevir), nicardipine, bromocriptine, cimetidine, and danazol.
Grapefruit juice affects CYP3A4-mediated metabolism, and should therefore be avoided.
Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins.
Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver.
Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels. Co-administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended.
The concomitant administration of sirolimus and angiotensin-converting enzyme (ACE) inhibitors has resulted in angioneurotic oedema-type reactions. Elevated sirolimus levels, for example due to interaction with strong CYP3A4 inhibitors, (with/without concomitant ACE inhibitors) may also potentiate angioedema. In some cases, the angioedema has resolved upon discontinuation or dose reduction of sirolimus.
Increased rates of biopsy confirmed acute rejection (BCAR) in renal transplant patients have been observed with concomitant use of sirolimus with ACE inhibitors. Patients receiving sirolimus should be monitored closely if taking ACE inhibitors concomitantly.
In clinical studies, the concomitant administration of sirolimus and HMG-CoA reductase inhibitors and/or fibrates was well-tolerated. During sirolimus therapy with or without CsA, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse reactions.
Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, including sirolimus, vaccination may be less effective. The use of live vaccines should be avoided during treatment with sirolimus.
Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to sirolimus. New onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study. Based on information from an open-label randomised study, conversion from the calcineurin inhibitor tacrolimus to sirolimus in maintenance renal transplant patients was associated with an unfavourable safety profile without efficacy benefit and can therefore not be recommended.
The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopaenic purpura/thrombotic microangiopathy (HUS/TTP/TMA).
The clearance of sirolimus may be reduced in patients with impaired hepatic function. In patients with severe hepatic impairment, it is recommended that the maintenance dose of sirolimus be reduced by approximately one-half.
It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function. It is not necessary to modify the sirolimus loading dose.
In patients with severe hepatic impairment, monitoring should be performed every 5 to 7 days until 3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment or after loading dose due to the delay in reaching steady-state because of the prolonged half-life.
Impairments of sperm parameters have been observed among some patients treated with sirolimus. These effects have been reversible upon discontinuation of sirolimus in most cases.
The rate and extent of sirolimus absorption was significantly increased by ciclosporin A (CsA). Sirolimus administered concomitantly (5 mg), and at 2 hours (5 mg) and 4 hours (10 mg) after CsA (300 mg), resulted in increased sirolimus AUC by approximately 183%, 141% and 80%, respectively. The effect of CsA was also reflected by increases in sirolimus Cmax and tmax. When given 2 hours before CsA administration, sirolimus Cmax and AUC were not affected. Single-dose sirolimus did not affect the pharmacokinetics of ciclosporin (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. It is recommended that sirolimus be administered 4 hours after ciclosporin (microemulsion).
Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as cisapride and metoclopramide.
The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-fold, 1.3-fold, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is administered, sirolimus blood levels should be monitored and a dose adjustment may be necessary.
Multiple-dose administration of erythromycin and sirolimus oral solution significantly increased the rate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The Cmax, tmax, and AUC of plasma erythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively. Sirolimus levels should be monitored and appropriate dose reductions of both medicinal products should be considered.
Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from sirolimus oral solution as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. Co-administration of sirolimus and ketoconazole is not recommended.
Administration of multiple doses of rifampicin decreased sirolimus whole blood concentrations following a single 10 mg dose of sirolimus oral solution. Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased AUC and Cmax by approximately 82% and 71%, respectively. Co-administration of sirolimus and rifampicin is not recommended.
Multiple-dose administration of verapamil and sirolimus oral solution significantly affected the rate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC were increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil Cmax and AUC were both increased 1.5-fold, and tmax was decreased 24%. Sirolimus levels should be monitored, and appropriate dose reductions of both medicinal products should be considered.
Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7-fold and 11-fold, respectively. Co-administration of sirolimus and voriconazole is not recommended.
There have been reports of impaired or delayed wound healing in patients receiving sirolimus, including lymphocele in renal transplant patients and wound dehiscence. Patients with a body mass index (BMI) greater than 30 kg/m² may be at increased risk of abnormal wound healing based on data from the medical literature.
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults), in patients receiving sirolimus.
Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis.
Among these conditions in renal transplant patients are BK virus-associated nephropathy and JC virus-associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
Cases of Pneumocystis carinii pneumonia have been reported in renal transplant patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation.
Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after renal transplantation, particularly for patients at increased risk for CMV disease.
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus.
The use of sirolimus was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered sirolimus should be monitored for hyperlipidaemia using laboratory tests and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen, including sirolimus. Similarly the risk/benefit of continued sirolimus therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.
There are no or limited amount of data from the use of sirolimus in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Sirolimus should not be used during pregnancy unless clearly necessary. Effective contraception must be used during sirolimus therapy and for 12 weeks after sirolimus has been stopped.
Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is unknown whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during treatment with sirolimus.
Effective contraception must be used during sirolimus therapy and for 12 weeks after sirolimus has been stopped.
Impairments of sperm parameters have been observed among some patients treated with sirolimus. These effects have been reversible upon discontinuation of sirolimus in most cases.
Sirolimus has no known influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed.
The most commonly reported adverse reactions (occurring in 10% of patients) are thrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH).
The incidence of any adverse reaction(s) may increase as the trough sirolimus level increases.
The following list of adverse reactions is based on experience from clinical studies and on postmarketing experience.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Most patients were on immunosuppressive regimens, which included sirolimus in combination with other immunosuppressive agents.
Very common: Pneumonia; Fungal infection; Viral infection; Bacterial infection; Herpes simplex infection; Urinary tract infection
Common: Sepsis; Pyelonephritis; Cytomegalovirus infection; Herpes zoster caused by the varicella zoster virus
Uncommon: Clostridium difficile colitis; Mycobacterial infection (including tuberculosis); Epstein-Barr virus infection
Common: Non-melanoma skin cancer*
Uncommon: Lymphoma*; Malignant melanoma*; Post transplant lymphoproliferative disorder
Not known: Neuroendoc rine carcinoma of the skin*
Very common: Thrombocytopaenia; Anaemia; Leucopenia
Common: Haemolytic uraemic syndrome; Neutropaenia
Uncommon: Pancytopaenia; Thrombotic thrombocytopaenic purpura
Common: Hypersensitivity (including angioedema, anaphylactic reaction, and anaphylactoid reaction)
Very common: Hypokalaemia; Hypophosphataemia; Hyperlipidaemia (including hypercholesterolaemia); Hyperglycaemia; Hypertriglyceridaemia; Diabetes mellitus
Very common: Headache
Not known: Posterior reversible encephalopathy syndrome
Very common: Tachycardia
Common: Pericardial effusion
Very common: Hypertension; Lymphocele
Common: Venous thrombosis (including deep vein thrombosis)
Uncommon: Lymphoedema
Common: Pulmonary embolism; Pneumonitis*; Pleural effusion; Epistaxis
Uncommon: Pulmonary haemorrhage
Rare: Alveolar proteinosis
Very common: Abdominal pain; Constipation; Diarrhoea; Nausea
Common: Pancreatitis; Stomatitis; Ascites
Liver function test abnormal (including alanine aminotransferase increased and aspartate aminotransferase increased)
Uncommon: Hepatic failure*
Very common: Rash; Acne
Uncommon: Dermatitis exfoliative
Rare: Hypersensitivity vasculitis
Very common: Arthralgia
Common: Osteonecrosis
Very common: Proteinuria
Uncommon: Nephrotic syndrome; Focal segmental glomerulosclerosis*
Very common: Menstrual disorder (including amenorrhoea and menorrhagia)
Common: Ovarian cyst
Very common: Oedema; Oedema peripheral; Pyrexia; Pain; Impaired healing*
Very common: Blood lactate dehydrogenase increased; Blood creatinine increased
* See section below.
Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin.
Cases of BK virus-associated nephropathy, as well as cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including sirolimus.
Hepatoxicity has been reported. The risk may increase as the trough sirolimus level increases. Rare reports of fatal hepatic necrosis have been reported with elevated trough sirolimus levels.
Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliterans organising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectious aetiology have occurred in patients receiving immunosuppressive regimens including sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the trough sirolimus level increases.
Impaired healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia, and anastomotic disruption (e.g. wound, vascular, airway, ureteral, biliary).
Impairments of sperm parameters have been observed among some patients treated with sirolimus. These effects have been reversible upon discontinuation of sirolimus in most cases.
In patients with delayed graft function, sirolimus may delay recovery of renal function. The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA.
Focal segmental glomerulosclerosis has been reported.
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults) in patients receiving sirolimus.
In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (target levels of 12-20 ng/mL in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this sirolimus treatment arm (n=60, median time post-transplant 36 months).
Ovarian cysts and menstrual disorders (including amenorrhoea and menorrhagia) have been reported. Patients with symptomatic ovarian cysts should be referred for further evaluation. The incidence of ovarian cysts may be higher in premenopausal females compared to postmenopausal females. In some cases, ovarian cysts and these menstrual disorders have resolved upon discontinuation of sirolimus.
Controlled clinical studies with posology comparable to that currently indicated for the use of sirolimus in adults have not been conducted in children or adolescents below 18 years of age).
Safety was assessed in a controlled clinical study enrolling renal transplant patients below 18 years of age considered of high immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatment regimen studied (continuous use of sirolimus in combination with calcineurin inhibitor) is not indicated for adult or paediatric patients.
In another study enrolling renal transplant patients 20 years of age and below that was intended to assess the safety of progressive corticosteroid withdrawal (beginning at six months post-transplantation) from an immunosuppressive regimen initiated at transplantation that included full-dose immunosuppression with both sirolimus and a calcineurin inhibitor in combination with basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed post-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be Epstein-Barr virus (EBV) seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD. All patients who developed PTLD were aged below 18 years.
There is insufficient experience to recommend the use of sirolimus in children and adolescents.
Safety was assessed in a controlled study involving 89 patients with LAM, of which 81 patients had S-LAM and 42 of whom were treated with sirolimus. The adverse drug reactions observed in patients with S-LAM were consistent with the known safety profile of the product for the indication prophylaxis of organ rejection in renal transplantation with the addition of weight decreased, which was reported in the study at a greater incidence with sirolimus when compared to that observed with placebo (common, 9.5% vs. common, 2.6%).
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