Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: L04AA10
Sirolimus inhibits T-cell activation induced by most stimuli, by blocking calcium-dependent and calcium-independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition of mTOR results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression.
In animals, sirolimus has a direct effect on T- and B-cell activation, suppressing immune-mediated reactions, such as allograft rejection.
LAM involves lung tissue infiltration with smooth muscle-like cells that harbour inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.
Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin elimination-Rapamune maintenance study, which included patients receiving a renal allograft from a cadaveric or living donor. In addition, re-transplant recipients whose previous grafts survived for at least 6 months after transplantation were included. Ciclosporin was not withdrawn in patients experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum creatinine higher than 400 mol/L, or who had inadequate renal function to support ciclosporin withdrawal. Patients at high immunological risk of graft loss were not studied in sufficient number in the ciclosporin elimination-Rapamune maintenance studies and are not recommended for this treatment regimen.
At 12, 24 and 36 months, graft and patient survival were similar for both groups. At 48 months, there was a statistically significant difference in graft survival in favour of the Rapamune following ciclosporin elimination group compared to the Rapamune with ciclosporin therapy group (including and excluding loss to follow-up). There was a significantly higher rate of first biopsy-proven rejection in the ciclosporin elimination group compared to the ciclosporin maintenance group during the period post-randomisation to 12 months (9.8% vs. 4.2%, respectively). Thereafter, the difference between the two groups was not significant.
The mean calculated glomerular filtration rate (GFR) at 12, 24, 36, 48 and 60 months was significantly higher for patients receiving Rapamune following ciclosporin elimination than for those in the Rapamune with ciclosporin therapy group. Based upon the analysis of data from 36 months and beyond, which showed a growing difference in graft survival and renal function, as well as significantly lower blood pressure in the ciclosporin elimination group, it was decided to discontinue subjects from the Rapamune with ciclosporin group. By 60 months, the incidence of non-skin malignancies was significantly higher in the cohort who continued ciclosporin as compared with the cohort who had ciclosporin withdrawn (8.4% vs. 3.8%, respectively). For skin carcinoma, the median time to first occurrence was significantly delayed.
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients (6-120 months after transplantation) was assessed in a randomised, multicentre, controlled trial, stratified by calculated GFR at baseline (20-40 mL/min vs. above 40 mL/min). Concomitant immunosuppressive agents included mycophenolate mofetil, azathioprine, and corticosteroids. Enrollment in the patient stratum with baseline calculated GFR below 40 mL/min was discontinued due to an imbalance in safety events (see section 4.8).
In the patient stratum with baseline calculated GFR above 40 mL/min, renal function was not improved overall. The rates of acute rejection, graft loss, and death were similar at 1 and 2 years. Treatment emergent adverse events occurred more frequently during the first 6 months after Rapamune conversion. In the stratum with baseline calculated GFR above 40 mL/min, the mean and median urinary protein to creatinine ratios were significantly higher in the Rapamune conversion group as compared to those of the calcineurin inhibitors continuation group at 24 months (see section 4.4). New onset nephrosis (nephrotic syndrome) was also reported (see section 4.8).
At 2 years, the rate of non-melanoma skin malignancies was significantly lower in the Rapamune conversion group as compared to the calcineurin inhibitors continuation group (1.8% and 6.9%). In a subset of the study patients with a baseline GFR above 40 mL/min and normal urinary protein excretion, calculated GFR was higher at 1 and 2 years in patients converted to Rapamune than for the corresponding subset of calcineurin inhibitor continuation patients. The rates of acute rejection, graft loss, and death were similar, but urinary protein excretion was increased in the Rapamune treatment arm of this subset.
In an open-label, randomised, comparative, multi-centre study where renal transplant patients were either converted from tacrolimus to sirolimus 3 to 5 months post-transplant or remained on tacrolimus, there was no significant difference in renal function at 2 years. There were more adverse events (99.2% vs. 91.1%, p=0.002*) and more discontinuations from the treatment due to adverse events (26.7% vs. 4.1%, p<0.001*) in the group converted to sirolimus compared to the tacrolimus group. The incidence of biopsy confirmed acute rejection was higher (p=0.020*) for patients in the sirolimus group (11, 8.4%) compared to the tacrolimus group (2, 1.6%) through 2 years; most rejections were mild in severity (8 of 9 [89%] T-cell BCAR, 2 of 4 [50%] antibody mediated BCAR) in the sirolimus group. Patients who had both antibody-mediated rejection and T-cell-mediated rejection on the same biopsy were counted once for each category. More patients converted to sirolimus developed new onset diabetes mellitus defined as 30 days or longer of continuous or at least 25 days non-stop (without gap) use of any diabetic treatment after randomisation, a fasting glucose ≥126 mg/dL or a non-fasting glucose ≥200 mg/dL after randomisation (18.3% vs. 5.6%, p=0.025*). A lower incidence of squamous cell carcinoma of the skin was observed in the sirolimus group (0% vs. 4.9%). *Note: p-values not controlled for multiple testing.
In two multi-centre clinical studies, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil (MMF), corticosteroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with a calcineurin inhibitor, MMF, corticosteroids, and an IL-2 receptor antagonist (see section 4.4). Renal function was not better in the treatment arms with de novo sirolimus without a calcineurin inhibitor. An abbreviated dosing schedule of daclizumab was used in one of the studies.
In a randomised, comparative evaluation of ramipril versus placebo for the prevention of proteinuria in kidney transplant patients converted from calcineurin inhibitors to sirolimus, a difference in the number of patients with BCAR through 52 weeks was observed [13 (9.5%) vs. 5 (3.2%), respectively; p=0.073]. Patients initiated on ramipril 10 mg had a higher rate of BCAR (15%) compared to patients initiated on ramipril 5 mg (5%). Most rejections occurred within the first six months following conversion and were mild in severity; no graft losses were reported during the study (see section 4.4).
The safety and efficacy of Rapamune for treatment of S-LAM were assessed in a randomised, double-blind, multicentre, controlled trial. This study compared Rapamune (dose adjusted to 5-15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation period in patients with TSC-LAM or S-LAM. Eighty-nine (89) patients were enrolled at 13 study sites in the United States, Canada, and Japan of which 81 patients had S-LAM; of these patients with S-LAM, 39 were randomised to receive placebo and 42 to receive Rapamune. The key inclusion criteria was post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% of predicted during the baseline visit. In patients with S-LAM, enrolled patients had moderately advanced lung disease, with baseline FEV1 of 49.2±13.6% (mean ±SD) of the predicted value. The primary endpoint was the difference between the groups in the rate of change (slope) in FEV1. During the treatment period in patients with S-LAM, the mean ±SE FEV1 slope was -12±2 mL per month in the placebo group and 0.3±2 mL per month in the Rapamune group (p<0.001). The absolute between-group difference in the mean change in FEV1 during the treatment period was 152 mL, or approximately 11% of the mean FEV1 at enrollment.
As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity (-12±3 vs. 7±3 mL per month, respectively, p<0.001), serum vascular endothelial growth factor D (VEGF-D; -8.6±15.2 vs. -85.3±14.2 pg/mL per month, respectively, p<0.001), and quality of life (Visual Analogue Scale – Quality of Life [VAS-QOL] score: -0.3±0.2 vs. 0.4±0.2 per month, respectively, p=0.022) and functional performance (-0.009±0.005 vs. 0.004±0.004 per month, respectively, p=0.044) in patients with S-LAM. There was no significant between-group difference in this interval in the change in functional residual capacity, 6-minute walk distance, diffusing capacity of the lung for carbon monoxide, or general well-being score in patients with S-LAM.
Rapamune was assessed in a 36-month controlled clinical study enrolling renal transplant patients below 18 years of age considered at high-immunologic risk, defined as having a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. Subjects were to receive Rapamune (sirolimus target concentrations of 5 to 15 ng/mL) in combination with a calcineurin inhibitor and corticosteroids or to receive calcineurin-inhibitor-based immunosuppression without Rapamune. The Rapamune group failed to demonstrate superiority to the control group in terms of the first occurrence of biopsy confirmed acute rejection, graft loss, or death. One death occurred in each group. The use of Rapamune 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 total cholesterol), and urinary tract infections (see section 4.8).
An unacceptably high frequency of PTLD was seen in a paediatric clinical transplant study when full-dose Rapamune was administered to children and adolescents in addition to full-dose calcineurin inhibitors with basiliximab and corticosteroids (see section 4.8).
In a retrospective review of hepatic veno-occlusive disease (VOD) in patients who underwent myeloablative stem cell transplantation using cyclosphophamide and total body irradiation, an increased incidence of hepatic VOD was observed in patients treated with Rapamune, especially with concomitant use of methotrexate.
Much of the general pharmacokinetic information was obtained using the Rapamune oral solution, which is summarised first. Information directly related to the tablet formulation is summarised specifically in the Oral tablet section.
Following administration of the Rapamune oral solution, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination with simultaneously administered ciclosporin (Sandimune) is approximately 14%. Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold. The terminal half-life in stable renal transplant patients after multiple oral doses was 62 ± 16 hours. The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days. The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements.
Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity. After a single dose of [14C] sirolimus in healthy volunteers, the majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine.
Clinical studies of Rapamune did not include a sufficient number of patients above 65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients above 65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age.
In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger paediatric patients (580 mL/h/kg) than for older paediatric patients (450 mL/h/kg) as compared with adults (287 mL/h/kg). There was a large variability for individuals within the age groups.
Sirolimus concentrations were measured in concentration-controlled studies of paediatric renal-transplant patients who were also receiving ciclosporin and corticosteroids. The target for trough concentrations was 10-20 ng/mL. At steady-state, 8 children aged 6-11 years received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m²) while 14 adolescents aged 12-18 years received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86 ± 0.61 mg/m²). The younger children had a higher weight-normalised CL/F (214 mL/h/kg) compared with the adolescents (136 mL/h/kg). These data indicate that younger children might require higher bodyweight-adjusted doses than adolescents and adults to achieve similar target concentrations. However, the development of such special dosing recommendations for children requires more data to be definitely confirmed.
In mild and moderate hepatically impaired patients (Child-Pugh classification A or B), mean values for sirolimus AUC and t1/2 were increased 61% and 43%, respectively, and CL/F was decreased 33% compared to normal healthy subjects. In severe hepatically impaired patients (Child-Pugh classification C), mean values for sirolimus AUC and t1/2 were increased 210% and 170%, respectively, and CL/F was decreased by 67% compared to normal healthy subjects. The longer half-lives observed in hepatically impaired patients delay reaching steady-state.
The pharmacokinetics of sirolimus were similar in various populations, with renal function ranging from normal to absent (dialysis patients).
The 0.5 mg tablet is not fully bioequivalent to the 1 mg, 2 mg and 5 mg tablets when comparing Cmax. Multiples of the 0.5 mg tablets should therefore not be used as a substitute for other tablet strengths.
In healthy subjects, the mean extent of bioavailability of sirolimus after single-dose administration of the tablet formulation is about 27% higher relative to the oral solution. The mean Cmax was decreased by 35%, and mean tmax increased by 82%. The difference in bioavailability was less marked upon steady-state administration to renal transplant recipients, and therapeutic equivalence has been demonstrated in a randomised study of 477 patients. When switching patients between oral solution and tablet formulations, it is recommended to give the same dose and to verify the sirolimus trough concentration 1 to 2 weeks later to assure that it remains within recommended target ranges. Also, when switching between different tablet strengths, verification of trough concentrations is recommended.
In 24 healthy volunteers receiving Rapamune tablets with a high-fat meal, Cmax, tmax and AUC showed increases of 65%, 32%, and 23%, respectively. To minimise variability, Rapamune tablets should be taken consistently with or without food. Grapefruit juice affects CYP3A4-mediated metabolism and must, therefore, be avoided.
Sirolimus concentrations, following the administration of Rapamune tablets (5 mg) to healthy subjects as single doses are dose proportional between 5 and 40 mg.
Clinical studies of Rapamune did not include a sufficient number of patients above 65 years of age to determine whether they will respond differently than younger patients. Rapamune tablets administered to 12 renal transplant patients above 65 years of age gave similar results to adult patients (n=167) 18 to 65 years of age.
In most patients receiving Rapamune tablets with a loading dose of 6 mg followed by an initial maintenance dose of 2 mg, whole blood sirolimus trough concentrations rapidly achieved steady-state concentrations within the recommended target range (4 to 12 ng/mL, chromatographic assay). Sirolimus pharmacokinetic parameters following daily doses of 2 mg Rapamune tablets administered in combination with ciclosporin microemulsion (4 hours prior to Rapamune tablets) and corticosteroids in 13 renal transplant patients, based on data collected at months 1 and 3 after transplantation, were: Cmin,ss 7.39 ± 2.18 ng/mL; Cmax,ss 15.0 ± 4.9 ng/mL; tmax,ss 3.46 ± 2.40 hours; AUCτ,ss 230 ± 67 ng.h/mL; CL/F/WT, 139 ± 63 mL/h/kg (parameters calculated from LC-MS/MS assay results). The corresponding results for the oral solution in the same clinical study were Cmin,ss 5.40 ± 2.50 ng/mL, Cmax,ss 14.4 ± 5.3 ng/mL, tmax,ss 2.12 ± 0.84 hours, AUCτ,ss 194 ± 78 ng.h/mL, CL/F/W 173 ± 50 mL/h/kg. Whole blood trough sirolimus concentrations, as measured by LC/MS/MS, were significantly correlated (r2=0.85) with AUCτ,ss.
Based on monitoring in all patients during the period of concomitant therapy with ciclosporin, mean (10th, 90th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 8.6 ± 3.0 ng/mL (5.0 to 13 ng/mL) and 2.1 ± 0.70 mg (1.5 to 2.7 mg), respectively (see section 4.2).
From month 3 to month 12, following discontinuation of ciclosporin, mean (10th, 90th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 19 ± 4.1 ng/mL (14 to 24 ng/mL) and 8.2 ± 4.2 mg (3.6 to 13.6 mg), respectively (see section 4.2). Therefore, the sirolimus dose was approximately 4-fold higher to account for both the absence of the pharmacokinetic interaction with ciclosporin (2-fold increase) and the augmented immunosuppressive requirement in the absence of ciclosporin (2-fold increase).
In a clinical trial of patients with LAM, the median whole blood sirolimus trough concentration after 3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 9.0 ng/mL; n=37). With concentration-control (target concentrations 5 to 15 ng/mL), the median sirolimus concentration at the end of 12 months of treatment was 6.8 ng/mL (interquartile range 5.9 to 8.9 ng/mL; n=37).
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use, were as follows: pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis.
Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese Hamster Ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.
Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse). It is known that malignancies (lymphoma) secondary to the chronic use of immunosuppressive agents can occur and have been reported in patients in rare instances. In mouse, chronic ulcerative skin lesions were increased. The changes may be related to chronic immunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of a species-dependent response to lutenising hormone levels and are usually considered of limited clinical relevance.
In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversible reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights and/or histological lesions (e.g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification) (see section 4.6).
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