Certican

Everolimus.

Each tablet contains 0.25/0.5/0.75 mg everolimus.
Each tablet contains 2/4/7 mg lactose monohydrate and 51/74/112 mg anhydrous lactose.
Excipients/Inactive Ingredients: Butylated hydroxytoluene (E321), Magnesium stearate, Lactose monohydrate, Hypromellose, Crospovidone, Lactose anhydrous.

Pharmacotherapeutic Group: selective immunosuppressive agents. ATC Code: L04A A 18.
Pharmacology: Pharmacodynamics: Everolimus, a proliferation signal inhibitor, prevents allograft rejection in rodent and non-human primate models of allotransplantation. It exerts its immunosuppressive effect by inhibiting the proliferation, and thus clonal expansion, of antigen-activated T cells which is driven by T cell-specific interleukins, e.g. interleukin-2 and interleukin-15. Everolimus inhibits an intracellular signalling pathway which is triggered upon binding of these T cell growth factors to their respective receptors, and which normally leads to cell proliferation. The blockage of this signal by everolimus leads to an arrest of the cells at the G₁ stage of the cell cycle.
At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus the growth factor-stimulated phosphorylation of the p70 S6 kinase is inhibited. Since p70 S6 kinase phosphorylation is under the control of FRAP (also called m-TOR), this finding suggests that the everolimus-FKBP-12 complex binds to and this interferes with the function of FRAP. FRAP is a key regulatory protein which governs cell metabolism, growth and proliferation; disabling FRAP function thus explains the cell cycle arrest caused by everolimus.
Everolimus, thus, has a different mode of action than ciclosporin. In preclinical models of allotransplantation, the combination of everolimus and ciclosporin was more effective than either compound alone.
The effect of everolimus is not restricted to T cells. It rather inhibits in general growth factor-stimulated proliferation of hematopoietic as well as non-hematopoietic cells, like, for instance, that of vascular smooth muscle cells. Growth factor-stimulated vascular smooth muscle cell proliferation, triggered by injury to endothelial cells and leading to neointima formation, plays a key role in the pathogenesis of chronic rejection. Preclinical studies with everolimus have shown inhibition of neointima formation in a rat aorta allotransplantation model.
Clinical studies: Renal transplantation: Certican in fixed doses of 1.5 mg/day and 3 mg/day, in combination with standard doses of ciclosporin for microemulsion and corticosteroids was investigated in two phase III de novo renal transplant trials (B201 and B251). Mycofenolate mofetil (MMF) 1 g b.i.d was used as comparator. The co-primary composite endpoints were efficacy failure (biopsy-proven acute rejection, graft loss, death or loss to follow-up) at 6 months, and graft loss, death or loss to follow-up at 12 months. Certican was, overall, non-inferior to MMF in these trials. The incidence of biopsy-proven acute rejection at 6 months in the B201 study was 21.6 %, 18.2 %, and 23.5 % for the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups, respectively. In study B251, the incidences were 17.1 %, 20.1 %, and 23.5 % for the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups respectively.
Reduced allograft function with elevated serum creatinine was observed more frequently among subjects using Certican in combination with full dose ciclosporin for microemulsion than in MMF patients. This effect suggests that Certican increases ciclosporin nephrotoxicity. Drug concentration-pharmacodynamic analysis showed that renal function was not impaired with reduced exposure to ciclosporin while conserving efficacy for as long as blood trough everolimus concentration was maintained above 3ng/mL. This concept was subsequently confirmed in two further Phase III studies (A2306 and A2307, including 237 and 256 patients respectively) which evaluated efficacy and safety of Certican 1.5 and 3 mg per day (initial dosing, subsequent dosing based on target trough concentration ≥3 ng/ml) in combination with reduced exposure to ciclosporin. In both studies, renal function was preserved without compromising efficacy. In these studies however there was no non-Certican comparative arm.
A phase III, multicentre, randomised, open-label, controlled trial A2309, has been completed in which 833 de-novo renal transplant recipients were randomised to either one of two Certican regimens, differing by dosage, and combined with reduced-dose ciclosporin or a standard regimen of sodium mycophenolate (MPA) + ciclosporin and treated for 12 months. All patients received induction therapy with basiliximab pre-transplant and on Day 4 post-transplant. Steroids were given as required post-transplant.
Starting dosages in the two Certican groups were 1.5 mg/d and 3 mg, given b.i.d., subsequently modified from Day 5 onwards to maintain target blood trough everolimus levels of 3-8 ng/mL and 6-12 ng/mL respectively. Sodium mycophenolate dosage was 1.44 g/d. Ciclosporin dosages were adapted to maintain target blood trough-level windows as shown in table 1. The actual measured values for blood concentrations of everolimus and ciclosporin (Co and C2) are shown in table 2.
Although the higher dosage Certican regimen was as effective as the lower-dosage regimen, the overall safety was worse and so the upper-dosage regimen is not recommended.
The lower dosage regimen for Certican is that recommended (see Dosage & Administration). (See Table 1 and Table 2.)

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The primary efficacy endpoint was a composite failure variable (biopsy-proven acute rejection, graft loss, death or loss to follow-up). The outcome is shown in table 3. (See Table 3.)

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Changes in renal function, as shown by calculated glomerular filtration rate (GFR) using the MDRD formula are shown in table 3.
Proteinuria was assessed at scheduled visits by spot analysis of urinary protein/creatinine (see table 5). A concentration effect was shown relating proteinuria levels to everolimus trough levels particularly at values of Cmin above 8 ng/mL.
Adverse events reported more frequently in the recommended (lower-dosage) Certican regimen than in the MPA control group have been included previously (Table 19). A lower frequency for viral infection was reported for Certican-treated patients resulting principally from lower reporting rates for CMV infection (0.7% versus 5.95%) and BK virus infection (1.5% versus 4.8%). (See Table 4 and Table 5.)

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Cardiac transplantation: In the phase III cardiac study (B253), both Certican 1.5 mg/day and 3 mg/day in combination with standard doses of ciclosporin for microemulsion and corticosteroids, was investigated vs. azathioprine (AZA), 1-3 mg/kg/day. The primary endpoint was a composite of incidence of acute rejection ≥ISHLT grade 3A, acute rejection associated with haemodynamic compromise, graft loss, patient death or loss to follow-up at 6, 12 and 24 months. Both doses of Certican were superior to AZA at 6, 12 and 24 months. The incidence of biopsy proven acute rejection ≥ISHLT grade 3A at month 6 was 27.8 % for the 1.5 mg/day group, 19 % for the 3 mg/day group and 41.6% for the AZA group respectively (p = 0.003 for 1.5 mg vs control, < 0.001 for 3 mg vs control).
Based on coronary artery intravascular ultrasound data obtained from a subset of the study population, both Certican doses were statistically significantly more effective than AZA in preventing allograft vasculopathy (defined as an increase in maximum intimal thickness from baseline ≥0.5 mm in at least one matched slice of an automated pullback sequence), an important risk factor for long term graft loss.
Elevated serum creatinine was observed more frequently among subjects using Certican in combination with full dose of ciclosporin for microemulsion than in AZA patients. These results indicated that Certican increases the ciclosporin-induced nephrotoxicity.
Study A2411 was a randomized, 12 months, open-label study comparing Certican in combination with reduced doses of ciclosporin microemulsion and corticosteroids to mycophenolic mofetil (MMF) and standard doses of ciclosporin microemulsion and corticosteroids in de-novo cardiac transplant patients. Certican was initiated at 1.5 mg/day and the dose was adjusted to maintain target blood everolimus trough levels between 3-8 ng/mL. MMF dosage was initiated at 1,500 mg bid. Ciclosporin microemulsion doses were adjusted to target the following trough levels (ng/mL): (See Table 6.)

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Actual blood levels measured are shown in table 7. (See Table 7.)

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Changes in renal functions are shown in table 8. Efficacy outcome is shown in table 9. (See Table 8 and Table 9.)

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Study A2310 is a phase III, multicenter, randomized, open-label study comparing two Certican/reduced-dose ciclosporin regimens against a standard mycophenolate mofetil (MMF)/ciclosporin regimen over 24 months. The use of induction therapy was center-specific (no-induction or basiliximab or thymoglobulin). All patients received corticosteroids.
Starting doses in the Certican groups were 1.5 mg/d and 3 mg/d, and were adjusted to target blood trough everolimus levels of 3-8 ng/ml and 6-12 ng/ml respectively. MMF dose was 3 g/d. Ciclosporin dosages targeted the same blood trough levels as in study A2411. Blood concentrations of everolimus and ciclosporin are shown in table 10.
Recruitment to the experimental, upper-dosage Certican treatment arm was prematurely discontinued because of an increased rate of fatalities, due to infection and cardiovascular disorders, occurring within the first 90 days post-randomization. (See Table 10.)

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Efficacy outcome at 12 months is shown in Table 11. (See Table 11.)

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The higher fatality rate in the Certican arm relative to the MMF arm was mainly the result of an increased rate of fatalities from infection in the first three months among Certican patients receiving thymoglobulin induction therapy. The imbalance in fatalities within the thymoglobulin subgroup was particularly evident among patients hospitalized prior to transplantation and with L-ventricular assistance devices (see Precautions).
Renal function over the course of study A2310, assessed by calculated glomerular filtration rate (GFR) using the MDRD formula, was 5.5 mL/min/1.73m² (97.5% CI -10.9, -0.2) lower for the everolimus 1.5 mg group at Month 12.
This difference was mainly observed in centers where the mean ciclosporin levels were similar throughout the study period in patients receiving Certican and in patients randomized to the control arm. This finding underlines the importance of reducing the ciclosporin levels when combined with everolimus as indicated in the table as follows (see Dosage & Administration): (See Table 12.)

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Additionally, the difference was mainly driven by a difference developed during the first month post-transplantation when patients are still in an unstable hemodynamic situation possibly confounding the analysis of renal function. Thereafter, the decrease in mean GFR from Month 1 to Month 12 was significantly smaller in the everolimus group than in the control group (-6.4 vs -13.7 mL/min, p=0.002).
Proteinuria, expressed as urinary protein: creatinine levels measured in spot urine samples tended to be higher in the Certican-treated patients. Sub-nephrotic values were observed in 22% of the patients receiving Certican compared to MMF patients (8.6%). Nephrotic levels were also reported (0.8%), representing 2 patients in each treatment group (see Precautions).
The adverse reactions for everolimus 1.5 mg group in Study A2310 are consistent with adverse drug reactions presented in table 17. A lower rate of viral infections was reported for Certican-treated patients resulting principally from a lower reporting rate for CMV infection compared to MMF (7.2% vs 19.4%).
Hepatic transplantation: In the phase III adult hepatic transplant study (H2304), reduced exposure tacrolimus and Certican 1.0 mg twice daily was administered to patients with the initial Certican dose starting approximately 4 weeks after transplantation and was investigated versus standard exposure tacrolimus. Certican was dose adjusted to maintain target blood everolimus trough levels between 3-8 ng/ml for the Certican + reduced tacrolimus arm. Tacrolimus doses were subsequently adjusted to achieve target trough levels between 3-5 ng/ml through 12 months in the Certican + reduced tacrolimus arm.
Overall, in the 12 month analysis, the incidence of the composite endpoint (tBPAR, graft loss or death) was lower in Certican + reduced tacrolimus arm (6.7%) compared to the tacrolimus control arm (9.7%) and consistent results were observed at 24 months (see table 13).
The results of individual components of the composite endpoint are shown in table 14. (See Table 13 and Table 14.)

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Comparison between treatment groups for change in eGFR (MDRD4) [ml/min/1.73 m²] from time of randomization (day 30) to Month 12 and 24 demonstrated superior renal function for Certican + reduced tacrolimus arm (see Table 15).

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Pharmacokinetics: Absorption: After oral dosing, peak everolimus concentrations occur 1 to 2 h postdose. Everolimus blood concentrations are dose proportional over the dose range 0.25 to 15 mg in transplant patients. The relative bioavailability of the dispersible tablet compared with the tablet is 0.90 (90 % CI 0.76-1.07) based on the AUC-ratio. Food effect: Everolimus Cmax and AUC are reduced by 60 % and 16 % when the tablet formulation is given with a high fat meal. To minimize variability, Certican should be taken consistently with or without food.
Distribution: The blood-to-plasma ratio of everolimus is concentration-dependent ranging from 17 % to 73 % over the range of 5 to 5000 ng/ml. Plasma protein binding is approximately 74 % in healthy subjects and patients with moderate hepatic impairment. The distribution volume associated with the terminal phase (Vz/F) in maintenance renal transplant patients is 342 ± 107 l.
Metabolism: Everolimus is a substrate of CYP3A4 and P-glycoprotein. The main metabolic pathways identified in man were mono-hydroxylations and O-dealkylations. Two main metabolites were formed by hydrolysis of the cyclic lactone. Everolimus was the main circulating component in blood. None of the main metabolites are likely to contribute significantly to the immunosuppressive activity of everolimus.
Excretion: After a single dose of radiolabeled everolimus to transplant patients receiving ciclosporin the majority (80 %) of radioactivity was recovered from the faeces, and only a minor amount (5 %) was excreted in urine. Parent drug was not detected in urine and faeces.
Steady-state pharmacokinetics: Pharmacokinetics were comparable for kidney and heart transplant patients receiving everolimus twice daily simultaneously with ciclosporin for microemulsion. Steady-state is reached by day 4 with an accumulation in blood levels of 2 to 3-fold compared with the exposure after the first dose. Tmax occurs at 1 to 2 h postdose. Cmax averages 11.1 ± 4.6 and 20.3 ± 8.0 ng/ml and AUC averages 75 ± 31 and 131 ± 59 ng.h/ml at 0.75 and 1.5 mg bid, respectively. Predose trough blood levels (Cmin) average 4.1 ± 2.1 and 7.1 ± 4.6 ng/ml at 0.75 and 1.5 mg bid, respectively. Everolimus exposure remains stable over time in the first post-transplant year. Cmin is significantly correlated with AUC yielding a correlation coefficient between 0.86 and 0.94. Based on a population pharmacokinetic analysis oral clearance (CL/F) is 8.8 l/h (27 % interpatient variation) and the central distribution volume (Vc/F) is 110 l (36 % interpatient variation). Residual variability in blood concentrations is 31%. The elimination half-life is 28 ± 7 h.
Hepatic impairment: Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 6 patients with mild hepatic impairment (Child-Pugh Class A) was 1.6-fold higher; in two independently studied groups of 8 and 9 patients with moderate hepatic impairment (Child-Pugh Class B) the average AUC was 2.1 fold and 3.3 fold higher respectively; and in 6 patients with severe hepatic impairment (Child-Pugh Class C) the average AUC was 3.6 fold higher. Mean half-lives were 52, 59, and 78 hours in mild, moderate, and severe hepatic impairment. The prolonged half-lives delay the time to reach steady-state everolimus blood levels.
Renal impairment: Post-transplant renal impairment (Clcrea range, 11-107 ml/min) did not affect the pharmacokinetics of everolimus.
Paediatrics: Everolimus CL/F increased in a linear manner with patient age (1 to 16 years), body surface area (0.49-1.92 m²), and weight (11-77 kg). Steady-state CL/F was 10.2 ± 3.0 L/h/m² and elimination half-life was 30 ± 11 h. Nineteen paediatric de novo renal transplant patients (1 to 16 years) received Certican dispersible tablets at a dose of 0.8 mg/m² (maximum 1.5 mg) twice-daily with ciclosporin for microemulsion. They achieved an everolimus AUC of 87 ± 27 ng·h/ml which is similar to adults receiving 0.75 mg twice daily. Steady-state trough levels were 4.4 ± 1.7 ng/ml.
Elderly: A limited reduction in everolimus oral CL by 0.33 % per year was estimated in adults (age range studied was 16-70 years). No dose adjustment is considered necessary.
Ethnicity: Based on a population pharmacokinetic analysis, oral clearance (CL/F) is, on average, 20 % higher in Black transplant patients. See Dosage & Administration.
Exposure-response relationships: The average everolimus trough concentration over the first 6 months posttransplant was related to the incidence of biopsy-confirmed acute rejection and of thrombocytopenia in renal and cardiac transplant patients. (see table 16).
In hepatic transplant patients the relationship of the average everolimus trough concentrations and the incidence of biopsy-proven acute rejection is less well defined. No correlation between a higher everolimus exposure and adverse events like thrombocytopenia has been observed (see Table 16).

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Toxicology: Preclinical safety data: The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and rabbits. The major target organs were male and female reproductive systems (testicular tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several species, and, only in rats, lungs (increased alveolar macrophages) and eyes (lenticular anterior suture line opacities). Minor kidney changes were seen in the rat (exacerbation of age-related lipofuscin in tubular epithelium) and the mouse (exacerbation of background lesions). There was no indication of kidney toxicity in monkeys or minipigs.
Spontaneously occurring background diseases (chronic myocarditis in the rat, Coxsackie virus infection in plasma and heart in monkeys, coccidial infestation of GI tract in minipigs, skin lesions in mice and monkeys) appeared to be exacerbated by the treatment with everolimus. These findings were generally observed at systemic exposure levels within the range of therapeutic exposure or above, with the exception of findings in rats, which occurred below therapeutic exposure due to a high tissue distribution.
Ciclosporin in combination with everolimus caused higher systemic exposure to everolimus and increased toxicity. There were no new target organs in the rat. Monkeys showed hemorrhage and arteritis in several organs.
In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone levels were diminished at 5 mg/kg which is within the range of therapeutic exposure and caused a decrease in male fertility. There was evidence of reversibility. Female fertility was not affected, but everolimus crossed the placenta and was toxic to the conceptus. In rats, everolimus caused embryo/foetotoxicity, at systemic exposure below the therapeutic one, that was manifested as mortality and reduced foetal weight. The incidence of skeletal variations and malformations at 0.3 and 0.9 mg/kg (e.g. sternal cleft) was increased. In rabbits, embryotoxicity was evident by an increase in late resorptions.
Genotoxicity studies covering relevant genotoxicity end-points showed no evidence of clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic potential in mice and rats up to the highest doses corresponding respectively to 8.6 and 0.3 times the estimated clinical exposure.

Kidney and heart transplantation: Certican is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant. In kidney and heart transplantation, Certican should be used in combination with ciclosporin for microemulsion and corticosteroids.
Liver transplantation: Certican is indicated for the prophylaxis of organ rejection in patients receiving a hepatic transplant. In liver transplantation, Certican should be used in combination with tacrolimus and corticosteroids.

Treatment with Certican should only be initiated and maintained by physicians who are experienced in immunosuppressive therapy following organ transplantation and who have access to everolimus whole blood levels monitoring.
Adults: An initial dose regimen of 0.75 mg twice daily is recommended for the general kidney and heart transplant population, administered as soon as possible after transplantation.
The dose of 1.0 mg twice daily is recommended for the hepatic transplant population with the initial dose approximately 4 weeks after transplantation.
The daily dose of Certican should always be given orally in two divided doses consistently either with or without food (see Pharmacology: Pharmacokinetics under Actions) and at the same time as ciclosporin for microemulsion or tacrolimus (see Therapeutic drug monitoring as follows).
Certican is for oral use only.
Certican tablets should be swallowed whole with a glass of water and not crushed before use. For patients unable to swallow whole tablets, Certican dispersible tablets are also available.
Patients receiving Certican may require dose adjustments based on blood levels achieved, tolerability, individual response, change in co-medications and the clinical situation. Dose adjustments can be made at 4-5 day intervals (see Therapeutic drug monitoring as follows).
Black patients: The incidence of biopsy-proven acute rejection episodes was significantly higher in black renal transplant patients compared with non-black patients. There is limited information indicating that black patients may require a higher Certican dose to achieve similar efficacy to non-black patients (see Pharmacology: Pharmacokinetics under Actions). Currently, the efficacy and safety data are too limited to allow specific recommendations for use of everolimus in black patients.
Paediatric population: There is insufficient experience to recommend the use of Certican in children and adolescents. Limited information is available in renal transplant paediatric patients (see Pharmacology: Pharmacokinetics under Actions).
Elderly patients (≥ 65 years): The clinical experience in patients > 65 years of age is limited. Although data are limited, there are no apparent differences in the pharmacokinetics of everolimus in patients ≥ 65-70 years of age (see Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: No dosage adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Patients with impaired hepatic function: Everolimus whole blood trough levels should be closely monitored in patients with impaired hepatic function. The dose should be reduced to approximately two thirds of the normal dose for patients with mild hepatic impairment (Child-Pugh Class A ), approximately one half of the normal dose for patients with moderate hepatic impairment (Child-Pugh Class B), and approximately one third of the normal dose for patients with severe hepatic impairment (Child Pugh Class C). Further dose titration should be based on therapeutic drug monitoring (see Pharmacology: Pharmacokinetics under Actions). Reduced doses rounded to the nearest tablet strength are tabulated as follows: (See Table 17.)

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Therapeutic Drug Monitoring: Routine everolimus whole blood therapeutic drug level monitoring is recommended. Based on exposure-efficacy and exposure-safety analysis, patients achieving everolimus whole blood trough levels ≥3.0 ng/ml have been found to have a lower incidence of biopsy-proven acute rejection in renal, cardiac and hepatic transplantation compared with the patients whose trough levels are below 3.0 ng/ml. The upper limit to the therapeutic range is recommended at 8 ng/ml. Exposure above 12 ng/ml has not been studied. These recommended ranges for everolimus are based on chromatographic method.
It is especially important to monitor everolimus blood concentrations, in patients with hepatic impairment, during concomitant administration of strong CYP3A4 inducers and inhibitors, when switching formulation and/or if ciclosporin dosing is markedly reduced (see Interactions). Everolimus concentrations might be slightly lower following the dispersible tablet administration.
Optimally, dose adjustments of Certican should be based on trough levels obtained >4-5 days after the previous dosing change. There is an interaction of ciclosporin on everolimus, and consequently, everolimus levels may decrease if ciclosporin exposure is markedly reduced (i.e. trough concentration <50 ng/ml).
Patients with hepatic impairment should preferably have trough levels in the upper part of the 3-8 ng/ml exposure range.
Monitoring should be performed every 4 to 5 days until 2 consecutive trough levels have shown stable everolimus concentrations after starting treatment or after a dose adjustment because the prolonged half-lives in hepatic impaired patients delay the time to reach steady state (see Precautions and Pharmacology: Pharmacokinetics under Actions). Dose adjustments should be based on stable everolimus trough concentrations.
Ciclosporin dose recommendation in renal transplantation: Certican should not be used long-term together with full doses of ciclosporin. Reduced exposure to ciclosporin in Certican-treated renal transplant patients improves renal function. Based on experience gained from study A2309, ciclosporin exposure reduction should be started immediately after transplantation with the following recommended whole blood trough level windows: (See Table 18.)

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Prior to dose reduction of ciclosporin it should be ascertained that steady state everolimus whole blood trough concentrations are equal to or above 3 ng/mL.
There are limited data regarding dosing Certican with ciclosporin trough concentrations below 50 ng/ml, or C2 levels below 350 ng/ml, in the maintenance phase. If the patient cannot tolerate reduction of ciclosporin exposure, the continued use of Certican should be reconsidered.
Ciclosporin dose recommendation in cardiac transplantation: Cardiac transplant patients in the maintenance phase should have ciclosporin dose reduced as tolerated in order to improve kidney function. If impairment of renal function is progressive or if the calculated creatinine clearance is < 60 ml/min, the treatment regimen should be adjusted. In cardiac transplant patients, the ciclosporin dose may be based on ciclosporin blood trough levels. See Pharmacology: Pharmacodynamics under Actions for experience with reduced ciclosporin blood levels.
In cardiac transplantation, there are limited data regarding dosing Certican with ciclosporin trough concentrations of 50-100 ng/mL after 12 months.
Prior to dose reduction of ciclosporin it should be ascertained that steady state everolimus whole blood trough concentrations are equal to or above 3 ng/ml.
Tacrolimus dose recommendation in hepatic transplantation: Hepatic transplant patients should have the tacrolimus exposure reduced to minimize calcineurin related renal toxicity. The tacrolimus dose should be reduced starting approximately 3 weeks after initiation of dosing in combination with Certican based on tacrolimus blood trough levels (C0) targeting 3-5 ng/ml. In a controlled clinical trial, complete withdrawal of tacrolimus has been associated with an increased risk of acute rejections.
Certican has not been evaluated with full dose tacrolimus in controlled clinical trials.

In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2,000 mg/kg (limit test) in either mice or rats.
Reported experience with overdose in humans is very limited, there is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year old child where no adverse events were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability.
General supportive measures should be initiated in all cases of overdose.

Certican is contraindicated in patients with a known hypersensitivity to everolimus, sirolimus, or to any of the excipients.

Management of immunosuppression: Certican has been administered in clinical trials concurrently with ciclosporin for microemulsion, basiliximab, or with tacrolimus, and corticosteroids. Certican in combination with immunosuppressive agents other than these has not been adequately investigated.
Certican has not been adequately studied in patients at high immunological risk.
Combination with thymoglobulin induction: Strict caution is advised with the use of thymoglobulin (rabbit anti-thymocyte globulin) induction and the Certican/ciclosporin/steroid regimen. In a clinical study in heart transplant recipients (Study A2310, see Pharmacology: Pharmacodynamics under Actions), an increased incidence of serious infections including fatal infections was observed within the first three months after transplantation in the subgroup of patients who had received induction with rabbit anti-thymocyte globulin.
Serious and opportunistic infections: Patients treated with immunosuppressants, including Certican, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multiple 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. Fatal infections and sepsis have been reported in patients treated with Certican (see Adverse Reactions).
In clinical trials with Certican, antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia and Cytomegalovirus (CMV) was recommended following transplantation, particularly for patients at increased risk for opportunistic infections.
Liver function impairment: Close monitoring of everolimus whole blood trough levels (C0) and everolimus dose adjustment is recommended in patients with impaired hepatic function (see Dosage & Administration).
Because of longer everolimus half-lives in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions), everolimus therapeutic monitoring after starting treatment or after a dose adjustment should be performed until stable concentrations are reached.
Interaction with oral CYP3A4 substrates: Caution should be exercised when Certican is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Certican is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see Interactions).
Interaction with strong inhibitors, inducers of CYP3A4: Co-administration with strong CYP3A4-inhibitors (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (e.g. rifampicin, rifabutin) is not recommended unless the benefit outweighs the risk. It is recommended that everolimus whole blood trough levels be monitored whenever inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see Interactions).
Lymphomas and other malignancies: Patients receiving a regimen of immunosuppressive medicinal products, including Certican, are at increased risk of developing lymphomas or other malignancies, particularly of the skin (see Adverse Reactions). The absolute risk seems related to the duration and intensity of immunosuppression rather than to the use of a specific medicinal product. Patients should be monitored regularly for skin neoplasms and advised to minimise exposure to UV light, sunlight and use appropriate sunscreen.
Hyperlipidemia: The use of Certican with ciclosporin for microemulsion or tacrolimus in transplant patients has been associated with increased serum cholesterol and triglycerides that may require treatment. Patients receiving Certican should be monitored for hyperlipidemia and, if necessary, treated with lipid-lowering medicinal products and appropriate dietary adjustments made (see Interactions). The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen including Certican. Similarly the risk/benefit of continued Certican therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.
Patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the Summary of Product Characteristics for the medicinal products concerned (see Interactions).
Angioedema: Certican has been associated with the development of angioedema. In the marjority of cases reported patients were receiving ACE inhibitors as co-medication.
Everolimus and calcineurin inhibitor-induced renal dysfunction: In renal and cardiac transplant, Certican with full-dose ciclosporin increases the risk of renal dysfunction. Reduced doses of ciclosporin are required for use in combination with Certican in order to avoid renal dysfunction. Appropriate adjustment of the immunosuppressive regimen, in particular reduction of the ciclosporin dose should be considered in patients with elevated serum creatinine levels.
In a liver transplant study, Certican with reduced tacrolimus exposure has not been found to worsen renal function in comparison to standard exposure tacrolimus.
Regular monitoring of renal function is recommended in all patients. Caution should be exercised when co-administering other medicinal products that are known to have a deleterious effect on renal function.
Proteinuria: The use of Certican with calcineurin inhibitors in transplant recipients has been associated with increased proteinuria. The risk increases with higher everolimus blood levels.
In renal transplant patients with mild proteinuria while on maintenance immunosuppressive therapy including a calcineurin inhibitor (CNI) there have been reports of worsening proteinuria when the CNI is replaced by Certican. Reversibility has been observed with interruption of Certican and reintroduction of the CNI. The safety and efficacy of conversion from CNI to Certican in such patients have not been established.
Patients receiving Certican should be monitored for proteinuria.
Renal graft thrombosis: An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, mostly within the first 30 days post-transplantation.
Wound-healing complications: Certican, like other mTOR inhibitors, can impair healing increasing the occurrence of post-transplant complications such as wound dehiscence, fluid collections and wound infection which may require further surgical attention. Lymphocele is the most frequently reported such event in renal transplant recipients and tends to be more frequent in patients with higher body mass index. The frequency of pericardial and pleural effusion is increased in cardiac transplant recipients and the frequency of incisional hernias is increased in liver transplant recipients.
Thrombotic microangiopathy/Thrombotic thrombocytopenic purpura/Haemolytic uraemic syndrome: The concomitant administration of Certican with a calcineurin inhibitor (CNI) may increase the risk of CNI-induced haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.
Vaccination: Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, including everolimus, vaccination may be less effective. The use of live vaccines should be avoided.
Interstitial lung disease/non-infectious pneumonitis: A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been discounted through appropriate investigations. Cases of ILD have been reported with Certican which generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred (see Adverse Reactions).
New onset diabetes mellitus: Certican has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients treated with Certican.
Male infertility: There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors. Preclinical toxicology studies having shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican therapy.
Risk of intolerance to excipients: Certican tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.

There are no adequate data from the use of Certican in pregnant women. Studies in animals have shown reproductive toxicity effects including embryo/foetotoxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown. Certican should not be given to pregnant women unless the potential benefit outweighs the potential risk for the foetus. Women of childbearing potential should be advised to use effective contraception methods while they are receiving Certican and up to 8 weeks after treatment has been stopped.
It is not known whether everolimus is excreted in human milk. In animal studies, everolimus and/or its metabolites were readily transferred into milk of lactating rats. Therefore women who are taking Certican should not breast feed.

The frequencies of adverse reactions listed as follows are derived from analysis of the 12-month incidences of events reported in multicenter, randomized, controlled trials investigating Certican in combination with calcineurin inhibitors (CNI) and corticosteroids in transplant recipients. All but two of the trials (in renal transplant) included non-Certican, CNI-based standard-therapy arms. Certican combined with ciclosporin, was studied in five trials in renal transplant recipients totalising 2497 patients, and three trials in heart transplant recipients totalising 1531 patients (ITT populations, see Pharmacology: Pharmacodynamics under Actions).
Certican combined with tacrolimus, was studied in one trial, which included 719 liver transplant recipients (ITT population, see Pharmacology: Pharmacodynamics under Actions).
Table 17 contains adverse drug reactions possibly or probably related to Certican seen in phase III clinical trials. Unless noted otherwise, these disorders have been identified by an increased incidence in the phase III studies comparing Certican-treated patients with patients on a non-Certican, standard therapy regimens (see Pharmacology: Pharmacodynamics under Actions). Except where noted otherwise, the adverse reaction profile is relatively consistent across all transplant indications. It is compiled according to MedDRA standard organ classes: Adverse reactions are listed according to their frequencies which are defined as: 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); very rare (< 1/10,000). (See Table 19.)

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Preclinical toxicology studies having shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican therapy. There are literature reports of reversible azospermia and oligospermia in patients treated with mTOR inhibitors.
In controlled clinical trials in which a total of 3256 patients receiving Certican in combination with other immunosuppressants were monitored for at least 1 year, a total of 3.1% developed malignancies, with 1.0% developing skin malignancies and 0.60% developing lymphoma or lymphoproliferative disorder.
The occurrence of the adverse events may depend on the immunosuppressive regimen (i.e. degree and duration). In the studies combining Certican with ciclosporin elevated serum creatinine was observed more frequently in patients dosed with Certican in combination with full dose ciclosporin for microemulsion than in control patients. The overall incidence of adverse events was lower with reduced dose ciclosporin for microemulsion (see Pharmacology: Pharmacodynamics under Actions).
The safety profile of Certican administered with reduced-dose ciclosporin was similar to that described in the 3 pivotal studies in which full dose of ciclosporin was administered, except that elevation of serum creatinine was less frequent, and mean and median serum creatinine values were lower, than in the phase III studies.
Cases of interstitial lung disease, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some fatal, have occurred in patients receiving rapamycin and derivatives, including Certican. Mostly, the condition resolves after discontinuation of Certican and/or addition of glucocorticoids. However, fatal cases have also occurred.

Everolimus is mainly metabolised by CYP3A4 in the liver and to some extent in the intestinal wall and is a substrate for the multidrug efflux pump, P-glycoprotein. Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-glycoprotein. Concurrent treatment with strong 3A4-inhibitors and inducers is not recommended. Inhibitors of P-glycoprotein may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. In vitro, everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of medicinal products eliminated by these enzymes. Thus, caution should be exercised when co-administering everolimus with 3A4- and 2D6 substrates with a narrow therapeutic index. All in vivo interaction studies were conducted without concomitant ciclosporin.
Ciclosporin (CYP3A4/PgP inhibitor): The bioavailability of everolimus was significantly increased by co-administration of ciclosporin. In a single-dose study in healthy subjects, ciclosporin for microemulsion (Neoral) increased everolimus AUC by 168 % (range, 46 % to 365 %) and Cmax by 82 % (range, 25 % to 158 %) compared with administration of everolimus alone. Dose adjustment of everolimus might be needed if the ciclosporin dose is altered (see Dosage & Administration). Certican had a clinically minor influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.
Rifampicin (CYP3A4 inducer): Pre-treatment of healthy subjects with multiple-dose rifampicin followed by a single dose of Certican increased everolimus clearance nearly 3-fold, and decreased Cmax by 58 % and AUC by 63 %. Combination with rifampicin is not recommended (see Precautions).
Atorvastatin (CYP3A4-substrate) and pravastatin (PgP-substrate): Single-dose administration of Certican with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However, these results cannot be extrapolated to other HMG-CoA reductase inhibitors.
Patients should be monitored for the development of rhabdomyolysis and other adverse events as described in the Summary of Product Characteristics of HMG-CoA reductase inhibitors.
Oral CYP3A4A substrates: An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A4 substrate probe, with everolimus resulted in a 25 % increase in midazolam Cmax and a 30 % increase in midazolam AUC. The effect is likely due to inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability of orally co-administered CYP3A4 substrates. However a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is not expected. If everolimus is taken with orally administered CYP3A4 substrates with narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate.
Other possible interactions: Moderate inhibitors of CYP3A4 and PgP may increase everolimus blood levels (e.g. antifungal substances: fluconazole; macrolide antibiotics: erythromycin; calcium channel blockers: verapamil, nicardipin, diltiazem; protease inhibitors: nelfinavir, indinavir, amprenavir. Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood levels (e.g. St. John's wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin; anti HIV drugs: efavirenz, nevirapine).
Grapefruit and grapefruit juice affect cytochrome P450 and PgP activity and should therefore be avoided.
Vaccination: Immunosuppressants may affect response to vaccination and vaccination during treatment with Certican may be less effective. The use of live vaccines should be avoided.

Special precautions for disposal and other handling: No special requirements.
Incompatibilities: Not applicable.

Store in the original package in order to protect from light and moisture.
Shelf-Life: 3 years.

Immunosuppressants

L04AH02 - everolimus ; Belongs to the class of mammalian target of rapamycin (mTOR) kinase inhibitors. Used as immunosuppressants.

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