Certican

Everolimus.

Excipients/Inactive Ingredients: Butylated hydroxytoluene (E321), magnesium stearate, lactose monohydrate, hypromellose, crospovidone, lactose anhydrous.

Pharmacotherapeutic group: selective immunosuppressive agents. ATC code: L04A A18.
Pharmacology: Mechanism of action (MOA): 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 antigen-activated T-cell proliferation, and thus clonal expansion, driven by T-cell-specific interleukins, e.g. interleukin-2 and interleukin-15. Everolimus inhibits an intracellular signalling pathway that normally leads to cell proliferation when triggered by the binding of these T-cell growth factors to their receptors. The blockage of this signal by everolimus causes cells to be arrested 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 thus 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. Everolimus generally inhibits growth-factor-stimulated proliferation of hematopoietic cells and non-hematopoietic cells such as vascular smooth muscle cells. Growth-factor-stimulated proliferation of vascular smooth muscle cells, 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. In the B201 study, the incidence of biopsy-proven acute rejection at 6 months in the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups was 21.6%, 18.2%, and 23.5%, respectively. In the B251 study, the incidence for the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups was 17.1%, 20.1%, and 23.5%, 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 could be improved with reduced exposure to ciclosporin while conserving efficacy for as long as blood trough everolimus concentration was maintained above 3 ng/mL. This concept was subsequently confirmed in two further Phase III studies (A2306 and A2307, including 237 and 256 patients respectively) which evaluated the efficacy and safety of Certican 1.5 and 3 mg Certican per day (initial dosing; subsequent dosing based on target trough concentration (C0) ≥3 ng/mL) in combination with reduced exposure to ciclosporin. In both studies, renal function was improved without compromising efficacy. In these studies however there was no non-Certican comparative arm.
A phase III, multicentre, randomized, open-label, controlled trial A2309, has been completed in which 833 de-novo renal transplant recipients were randomized 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 could be 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 to 8 ng/mL and 6 to 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 (C0 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 Tables 1 and 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 4.
Proteinuria was assessed at scheduled visits by spot analysis of urinary protein/creatinine and categorized by levels of clinical relevance as represented in Table 5. Few patients in any of the treatment groups reached the nephrotic threshold but a greater proportion of Certican patients was consistently in the sub-nephrotic category than was the case in the MPA group. A concentration effect was shown relating proteinuria levels to everolimus trough levels particularly at values of C_min above 8 ng/mL.
Adverse drug reactions reported with Certican regimen have been included (Table 16). 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 Tables 4 and 5.)

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Cardiac transplantation: In the phase III cardiac study (B253), Certican 1.5 mg/day and 3 mg/day, in combination with standard doses of ciclosporin for microemulsion and corticosteroids, were both compared with azathioprine (AZA) 1-3 mg/kg/day. The primary endpoint was a composite of the incidence of the following acute rejection ≥ISHLT grade 3A, acute rejection associated with hemodynamic compromise, graft loss, patient death or loss to follow-up 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. However, further analysis suggested that renal function could be improved with ciclosporin dose-reduction without loss of efficacy as long as everolimus blood values are maintained above a given threshold. Studies A2411 and A2310 have subsequently been carried out to investigate this.
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. The study included a total of 174 patients. Certican (N=92) 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 (N=84) was initiated at a dosage of 1,500 mg bid. Ciclosporin microemulsion doses were adjusted to target the following trough levels (ng/mL): (See Table 6).

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Renal function was improved with the reduced ciclosporin dosage regimen with mean creatinine clearance (Cockcroft-Gault formula) at 6 months: Certican: 65.4 v. MMF: 72.2 mL/mn, and at 12 months: Certican: 68.7 v. MMF: 71.8 mL/mn. Efficacy, expressed as the rate of biopsy-proven acute rejection episodes (ISHLT grade ≥3A), was maintained as comparable in the two groups at 12 months (Certican: 22.8% v. MMF: 29.8%).
Study A2310 is a phase III, multicenter, randomized, open-label study comparing the efficacy and safety of 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, the options being no-induction or induction with either basiliximab or thymoglobulin. All patients received corticosteroids.
Starting doses in the two Certican groups were 1.5 mg/day and 3 mg/day, subsequently modified from Day 4 onwards to maintain target blood trough everolimus levels of 3 to 8 ng/ml and 6 to 12 ng/ml respectively. The MMF dose was 3 g/day. Ciclosporin dosages were adapted to maintain the same target blood trough level windows as in study A2411. Blood concentrations of everolimus and ciclosporin are shown in Table 7.
Recruitment to the experimental, upper-dosage Certican treatment arm was prematurely discontinued because of an increased rate of fatalities within this treatment group, due to infection and cardiovascular disorders, occurring within the first 90 days post-randomization. The nature and pattern of the fatalities in this dosage arm did not suggest the difference to be linked to the presence or type of induction therapy.
Statistical comparisons are limited to comparisons between the completed treatment arms. The drug blood concentration levels actually achieved are described in Table 7. (See Table 7.)

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The primary efficacy endpoint was a composite failure variable, implying occurrence of any of the following: Biopsy Proven Acute Rejection (BPAR) episode of ISHLT grade >=3A, acute rejection (AR) episode associated with hemodynamic compromise (HDC), graft loss/re-transplant, death, or loss to follow-up. Efficacy outcome at 12 months is shown in Table 8. (See Table 8.)

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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 in the study sub-group of patients receiving thymoglobulin induction therapy. A notably higher 3-month incidence in severe infections in Certican than MMF patients in the thymoglobulin subgroup appears to reflect greater immunosuppressive potency. The imbalance in fatalities within the thymoglobulin subgroup being particularly evident among patients hospitalized prior to transplantation and with L-ventricular assistance devices, suggests greater vulnerability in such patients to the consequences of infectious complications.
Intravascular ultrasound (IVUS) studies were performed on a subset of patients to investigate changes post-transplantation (Month 12 value relative to a baseline value effected during the first three months post-transplant) in intimal thickness within a segment of the left anterior descending (LAD) coronary artery. The results of the measured change in maximum intimal thickness along with frequency of patients with cardiac allograft vasculopathy (defined as an increase in the maximal intimal thickness of 0.5mm or more) are described in Table 9. (See Table 9.)

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The reduced increase in intimal coronary thickness in Certican relative to MMF patients was apparent regardless of age, gender, presence or absence of diabetes and maximum level of serum cholesterol observed by Month 12.
Renal function over the course of study A2310, assessed by calculated glomerular filtration rate (GFR) using the MDRD formula, indicates a statistically significant difference of 5.5 mL/min/1.73m² (97.5% CI -10.9, -0.2) lower for the everolimus 1.5 mg group at Month 12.
Data suggest that the difference observed was mainly associated with the exposure to ciclosporin. This difference was reduced to 3.6 mL/min/1.73m² and not statistically significant (97.5% CI -8.9, 1.8) in centers where the mean ciclosporin levels were lower in patients receiving Certican than in patients randomized to the control arm, as recommended.
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:urinary creatinine levels measured in spot urine samples tended to be more elevated 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.
The adverse reactions for everolimus 1.5 mg group in Study A2310 are consistent with adverse drug reactions presented in Table 16. 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 b.i.d. was administered to HCV+ and HCV- patients with the initial Certican dose starting approximately 4 weeks after transplantation and was investigated vs. standard exposure tacrolimus up to 24 months (core study) and for an additional 12 month extension period up to 36 months post-transplant. Certican was dose adjusted to maintain target blood everolimus trough levels between 3 to 8 ng/mL for the Certican + Reduced tacrolimus arm. Mean everolimus trough levels were within the target ranges at all time points ranging from 3.4 to 6.3 ng/mL in the Certican + Reduced tacrolimus arm. Tacrolimus doses were subsequently adjusted to achieve target trough levels between 3 to 5 ng/mL through 12 months in the Certican + Reduced tacrolimus arm.
The primary endpoint of the study was to compare the efficacy failure rate, defined as the composite endpoint of treated biopsy proven acute rejection, graft loss or death with early tacrolimus minimization, facilitated by introduction of Certican starting approximately 4 weeks after liver transplantation, to standard exposure tacrolimus, at 12 months.
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%) (Table 10). The difference in estimates between Certican + Reduced tacrolimus and tacrolimus control was - 3.0% with 97.5% CI: (-8.7% to 2.6%). Regarding the rates of graft loss and fatal cases the Certican + Reduced tacrolimus arm was non-inferior compare to the tacrolimus control arm indicating no increased mortality risk in this population. A statistically significantly lower rate of acute rejection was seen in the Certican + Reduced tacrolimus arm (3.7%) compared to tacrolimus control arm (10.7%) (Table 11). Results are similar between HCV+ and HCV- patients. (See Tables 10 and 11.)

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Extension - primary efficacy results at 36 months: Of the total 231 patients who entered the extension for Certican + Reduced tacrolimus (n=106) and tacrolimus control (n=125), 84% and 86% of patients completed study medication, 91% and 94% of patients completed study phase with 16% and 14% of patients discontinuing study medication, respectively.
The incidence of patients with composite efficacy failure events (tBPAR, graft loss or death) at Month 36 since extension baseline (Month 24) was low and similar across the treatment arms at 1.9% (n=2), and 2.4% (n=3) in the Certican + Reduced tacrolimus and tacrolimus control arms respectively.
For the ITT population (all patients randomized in the core study), the Kaplan-Meier estimates of the primary composite efficacy endpoint (tBPAR, graft loss or death) to 36 months was lower in the Certican + Reduced tacrolimus arm (11.5%) than in the tacrolimus control arm (14.6%). The difference between Certican + Reduced tacrolimus and tacrolimus control was -3.2% (97.5% CI: -10.5%, 4.2%; p-value 0.3337).
Renal function: Comparison between treatment groups for change in eGFR (MDRD4) [mL/min/1.73 m²] from time of randomization (day 30) to Months 12, 24 and 36 for the ITT population is presented in Table 12. The eGFR at 12 months was higher for Certican + Reduced tacrolimus (80.6 mL/min/1.73 m²) in comparison to the tacrolimus control (70.3 mL/min/1.73m²) and a higher eGFR was also observed throughout the entire study. (See Table 12.)

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Statistically significant between-treatment group difference (Certican + Reduced tacrolimus vs. tacrolimus control arm) was observed in favor of Certican + Reduced tacrolimus arm for the mean eGFR from Week 6 up to Month 36 (including at study endpoint and treatment endpoint). At randomization, mean eGFR was 85.0 and 78.0 mL/min/1.73m² for the Certican + Reduced tacrolimus and tacrolimus control arms respectively. At the Month 36 time point, the difference in mean eGFR between Certican + Reduced tacrolimus and tacrolimus control was 15.2 mL/min/1.73m². The mean eGFR at Month 36 was 78.7 and 63.5 mL/min/1.73m² for the Certican + Reduced tacrolimus and tacrolimus control arms respectively.
Pharmacokinetics (PK): Absorption: Peak everolimus concentrations are reached 1 to 2 hours after administration of an oral dose. Everolimus blood concentrations in transplant patients are dose-proportional-over the dose range of 0.25 to 15 mg. The relative bioavailability of the dispersible tablet compared with the conventional tablet is 0.90 (90% CI 0.76 to 1.07) based on the AUC-ratio.
Food effect: the C_max and AUC of everolimus are reduced by 60% and 16%, respectively, when the tablet formulation is given with a high-fat meal. To minimize variability, Certican should either be consistently taken with food, or consistently taken without it.
Distribution: The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. 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.
Biotransformation/Metabolism: Everolimus is a substrate of CYP3A4 and P-glycoprotein. Following oral administration, it is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself. Hence, the parent substance is considered to contribute the majority of the overall pharmacological activity of everolimus.
Pediatric patients (below 18 years): Everolimus CL/F increased in a linear manner with patient age (1 to 16 years), body surface area (0.49 to 1.92 m²), and weight (11 to 77 kg). Steady-state CL/F was 10.2 ± 3.0 L/h/m² and elimination half-life was 30 ± 11 h. Nineteen pediatric 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 (C0) were 4.4 ± 1.7 ng/mL.
Geriatric patients (65 years or above): A limited reduction in everolimus oral CL of 0.33% per year was estimated in adults (age range studied was 16 to 70 years). No dose adjustment is considered necessary.
Race/Ethnicity: Based on analysis of population pharmacokinetics, oral clearance (CL/F) is, on average, 20% higher in Black transplant patients (see DOSAGE & ADMINISTRATION).
Excretion: After a single dose of radiolabelled everolimus in transplant patients receiving ciclosporin, most of the radioactivity (80%) was recovered from the faeces, and only a minor amount (5%) was excreted in urine. Parent drug was not detected in the urine or faeces.
Steady-state pharmacokinetics: The pharmacokinetics were comparable in kidney and heart transplant patients receiving everolimus twice daily with ciclosporin for microemulsion. Steady state is reached by day 4, with a 2 to 3-fold accumulation in blood levels as compared with exposure after the first dose. T_max occurs at 1 to 2 h postdose. At 0.75 and 1.5 mg b.i.d., C_max averages 11.1 ± 4.6 and 20.3 ± 8.0 ng/mL, respectively, and AUC averages 75 ± 31 and 131 ± 59 ng·h/mL, respectively. At 0.75 and 1.5 mg b.i.d., predose trough blood levels (C_min) average 4.1 ± 2.1 and 7.1 ± 4.6 ng/mL, respectively. Everolimus exposure remains stable over time in the first post-transplant year. C_min is significantly correlated with AUC, yielding a correlation coefficient between 0.86 and 0.94. Based on analysis of population pharmacokinetics 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.
Renal impairment: Post-transplant renal impairment (Cl_crea range, 11 to 107 mL/min) did not affect the pharmacokinetics of everolimus.
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; 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 (see DOSAGE & ADMINISTRATION).
Exposure-response relationships: The average everolimus trough concentration (C0) over the first 6 months post-transplant was related to the incidence of biopsy-confirmed acute rejection and of thrombocytopenia in renal and cardiac transplant patients (see Table 13). In hepatic transplant patients the relationship of everolimus trough concentrations and clinical events is less well defined, however, higher exposures do not correlate with increase in adverse events. (See Table 13.)

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Toxicology: Non-Clinical Safety Data: The non-clinical 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.
Everolimus appeared to exacerbate spontaneously background diseases (chronic myocarditis in rats, coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of GI tract in minipigs, skin lesions in mice and monkeys). 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.
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 adult 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.
Dosage regimen: General target population: Adults: Kidney and heart transplantation: An initial dose regimen of 0.75 mg b.i.d. which is recommended for the general kidney and heart transplant population, should be administered as soon as possible after transplantation.
Liver transplantation: The dose of 1.0 mg b.i.d is recommended for the hepatic transplant population with the initial dose approximately 4 weeks after transplantation.
Special populations: Black patients: The incidence of biopsy-proven acute rejection episodes was significantly higher in black renal transplant patients than in non-black patients. Limited information indicates that black patients, may require a higher Certican dose to achieve efficacy similar to that achieved in non-black patients at the recommended adult dose (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.
Pediatric patients (below 18 years): There are no adequate data of the use of Certican in children and adolescents to support its use in patients in these age groups.
Limited information is, however, available in renal transplant pediatric patients (see PHARMACOLOGY: PHARMACOKINETICS under Actions).
Geriatric patients (65 years or above): Clinical experience is limited in patients ≥65 years of age.
Nevertheless, there are no apparent differences in the pharmacokinetics of everolimus in patients ≥65 to 70 years of age as compared with younger adults (see PHARMACOLOGY: PHARMACOKINETICS under Actions).
Renal impairment: No dosage adjustment is required (see PHARMACOLOGY: PHARMACOKINETICS under Actions).
Hepatic impairment: Whole blood trough levels (C0) of everolimus should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced to approximately two-thirds of the normal dose. For patients with moderate hepatic impairment (Child-Pugh B) the dose should be reduced to approximately one half of the normal dose. For patients with severe hepatic impairment (Child-Pugh C) the dose should be reduced to at least one half of the normal dose. Further dose titration should be based on therapeutic drug monitoring (see PHARMACOLOGY: PHARMACOKINETICS under Actions).
Method of administration: Certican is for oral use only.
The daily dose of Certican should always be given orally in two divided doses (b.i.d.). Certican should be consistently given 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).
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 to 5 days intervals (see THERAPEUTIC DRUG MONITORING as follows).
Certican tablets should be swallowed whole with a glass of water and not crushed before use.
Therapeutic drug monitoring: Certican has a narrow therapeutic index which may require adjustments in dosing to maintain therapeutic response. Routine whole blood therapeutic drug level monitoring of everolimus is recommended. Based on exposure-efficacy and exposure-safety analysis, patients achieving everolimus whole blood trough levels (C0) ≥3.0 ng/mL have been found to have a lower incidence of biopsy-proven acute rejection in renal, cardiac and hepatic transplantation than patients whose trough levels (C0) are below 3.0 ng/mL. The recommended upper limit of the therapeutic range is 8 ng/mL. Exposure above 12 ng/mL has not been studied. These recommended ranges for everolimus are based on chromatographic methods.
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.
Ideally, dose adjustments of Certican should be based on trough levels (C0) obtained >4 to 5 days after the previous dose change. Since ciclosporin interacts with everolimus, everolimus levels may decrease if ciclosporin exposure is markedly reduced (i.e. trough concentration (C0) <50 ng/mL).
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 14.

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(Measured levels are shown in Pharmacology: PHARMACODYNAMICS under Actions).
Prior to dose reduction of ciclosporin it should be ascertained that steady state everolimus whole blood trough concentrations (C0) are equal to or above 3 ng/mL.
There are limited data regarding dosing Certican with ciclosporin trough concentrations (C0) 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, beginning one month after transplantation 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. For cardiac transplant patients, the ciclosporin dose should be guided by the experience in study 2411 and confirmed in study 2310 in which Certican was administered with ciclosporin with recommended reduced target trough concentrations (C0) as follows: See Table 15.

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(Measured levels are shown in Pharmacology: PHARMACODYNAMICS under Actions).
Prior to dose reduction of ciclosporin it should be ascertained that steady state everolimus whole blood trough concentrations (C0) are equal to or above 3 ng/mL.
In cardiac transplantation, there are limited data regarding dosing Certican with reduced ciclosporin trough concentrations (C0) of 50 to 100 ng/mL after 12 months. If the patient cannot tolerate reduction of ciclosporin exposure, the continued use of Certican should be reconsidered.
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 to 5 ng/mL. 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 were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).
Reported experience with overdose in humans is very limited. There was a single case of accidental ingestion of 1.5 mg everolimus by a 2-year old child, but no adverse events were observed. Single doses of 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 any of the excipients.

Management of immunosuppression: There are limited data regarding the use of Certican without calcineurin inhibitor (CNI) (ciclosporin or tacrolimus). An increased risk of acute rejection was observed in patients who discontinued the administration of CNI compared with those who continued the administration of CNI.
In clinical trials, Certican has been administered concurrently with ciclosporin for microemulsion, or with tacrolimus, basiliximab 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: 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 was observed within the first three months after transplantation in the subgroup of patients who had received induction with rabbit anti-thymocyte globulin combined with Certican, steroid and ciclosporin at the blood concentration recommended for heart transplantation (higher than in kidney transplantation). This was associated with greater mortality among patients who were both hospitalized and required ventricular assistance device prior to transplantation suggesting that they may have been particularly vulnerable to increased immunosuppression.
Serious and opportunistic infections: Patients on a regimen of immunosuppressive medicinal products, including Certican, are at increased risk of developing infections especially infections with opportunistic pathogens (bacterial, fungal, viral, protozoal). Fatal infections and sepsis have been reported in patients treated with Certican (see ADVERSE REACTIONS). Among opportunistic conditions to which immunosuppressed patients may be vulnerable are polyomavirus infections which include BK virus-associated nephropathy which can lead to kidney graft loss and the potentially fatal JC virus-associated progressive multiple leukoencephalopathy (PML). These infections, often related to total immunosuppressive burden, should be considered in the differential diagnosis of immunosuppressed patients with deteriorating kidney graft function or neurological symptoms.
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).
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.
Monitoring of whole blood trough levels (C0) of everolimus is recommended whenever inducers or inhibitors of CYP3A4 are co-administered or discontinued (see INTERACTIONS).
Lymphomas and other malignancies: Patients on 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 minimize exposure to UV light sunlight, and to use an appropriate sunscreen.
Hyperlipidemia: In transplant patients, concomitant use of Certican and ciclosporin for microemulsion or tacrolimus has been associated with an increase in 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 hyperlipidemia before initiating an immunosuppressive regimen including Certican. Similarly the risk/benefit of continued Certican therapy should be re-evaluated in patients with severe refractory hyperlipidemia.
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 respective Prescribing Information of these medicinal products (see INTERACTIONS).
Angioedema: Certican has been associated with the development of angioedema. In the majority 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 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 microangiopathic disorders: The concomitant administration of Certican with a calcineurin inhibitor (CNI) may increase the risk of CNI-induced hemolytic uremic syndrome, thrombotic thrombocytopenic purpura and thrombotic microangiopathy.
Interstitial lung disease/non-infectious pneumonitis: Cases of interstitial lung disease, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some fatal, have occurred in patients receiving rapamycins and their derivatives, including Certican. 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. Mostly, the condition resolves after discontinuation of Certican and/or addition of glucocorticoids. However, fatal cases have also occurred.
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: Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pregnancy: Risk Summary: There are no adequate data from the use of Certican in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and fetotoxicity. The potential risk to humans is unknown. Certican should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus.
Animal Data: In rats, everolimus crossed the placenta and was toxic to the conceptus. Everolimus caused embryo/fetotoxicity that was manifested as mortality, reduced fetal weight, and an increased incidence of skeletal variations and malformations at systemic exposures below the target therapeutic exposure in humans. In rabbits, embryotoxicity was evident by an increase in late resorptions at systemic exposures similar to those in humans.
Lactation: It is not known whether everolimus is excreted in breast milk, but in animal studies, everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking Certican should therefore not breast-feed.
Females and males of reproductive potential: Contraception: Females of reproductive potential should be advised to use highly effective contraception methods while they are receiving Certican and for up to 8 weeks after ending treatment.
Infertility: There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors (see PRECAUTIONS and Pharmacology: Toxicology: NON-CLINICAL SAFETY DATA under Actions).
In rat studies, female fertility was not affected.

Summary of the safety profile: Certican combined with ciclosporin, was studied in five trials in renal transplant recipients totaling 2,497 patients (including two studies without a non-Certican control group), and three trials in heart transplant recipients totaling 1,531 patients (intent to treat (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). The overall safety profile was not distinct from previous experiences with Certican and expectations in a liver transplant population up to 36 months.
The occurrence of the adverse events may depend on the degree and duration of the immunosuppressive regimen. In the studies combining Certican with full dose ciclosporin for microemulsion elevated serum creatinine was observed more frequently than in control patients. The elevation of serum creatinine was less frequent and mean and median serum creatinine values were lower in the trials in which Certican was administered with reduced-dose ciclosporin.
With the exception of elevation of serum creatinine, the safety profile of Certican in the trials in which it was administered with reduced-dose ciclosporin was similar to that described in the three pivotal studies in which full dose of ciclosporin was administered, although the overall incidence of adverse events was lower with reduced dose ciclosporin (see Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions). In controlled clinical trials in which a total of 3,256 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 0.6% developing lymphoma or lymphoproliferative disorder.
Tabulated summary of adverse drug reactions from clinical trials: 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 of the trials included non-Certican, CNI-based standard-therapy arms.
Table 16 contains adverse drug reactions possibly or probably related to Certican seen in phase III clinical trials. Unless noted as 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, or the same incidence in case the event is known as an ADR of the comparator (MPA in renal and heart transplant studies) (see PHARMACOLOGY: PHARMACODYNAMICS under Actions). Except where noted otherwise, the adverse reaction profile is relatively consistent across all transplant indications.
Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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 16.)

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Click on icon to see table/diagram/image

Adverse drug reactions from post-marketing spontaneous reports: The following adverse drug reactions (Table 17) have been derived from post-marketing experience with Certican via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. (See Table 17.)

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Everolimus is mainly metabolized in the liver and, to some extent, in the intestinal wall by CYP3A4. It is also a substrate for the multidrug efflux pump, P-glycoprotein (PgP). Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or PgP.
Observed interactions resulting in concomitant use not being recommended: Rifampicin (CYP3A4 inducer): Pre-treatment of healthy subjects with multiple-doses of rifampicin followed by a single dose of Certican increased everolimus clearance nearly 3-fold, decreasing C_max by 58% and AUC by 63%. Combination with rifampicin is not recommended (see PRECAUTIONS).
Ketoconazole (CYP3A4 inhibitor): Pre-treatment of healthy subjects with multiple-dose ketoconazole followed by a single dose of Certican increased everolimus C_max by 3.9-fold and AUC by 15.0-fold (see PRECAUTIONS).
Anticipated interactions resulting in concomitant use not being recommended: Strong inhibitors, inducers of CYP3A4: Concurrent treatment with strong CYP3A4-inhibitors and/or inducers is not recommended (e.g. itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, and/or rifampicin, rifabutin) (see PRECAUTIONS).
Observed interactions to be considered: Interactions affecting use of Certican: 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 increased the AUC of everolimus by 168% (range 46% to 365%), and C_max by 82% (range 25% to 158%), as compared with everolimus alone. Dose adjustment of everolimus may be needed if the ciclosporin dose is altered (see DOSAGE & ADMINISTRATION).
Erythromycin (CYP3A4 inhibitor): Pre-treatment of healthy subjects with multiple-dose erythromycin followed by a single dose of Certican increased everolimus C_max by 2.0-fold and AUC by 4.4-fold.
Verapamil (CYP3A4 inhibitor): Pre-treatment of healthy subjects with multiple-dose verapamil followed by a single dose of Certican increased everolimus C_max by 2.3-fold and AUC by 3.5-fold.
Interactions resulting in effects on other drugs: Ciclosporin (CYP3A4/PgP inhibitor): Certican had only a minor clinical influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.
Octreotide: Coadministration of everolimus with depot octreotide increased octreotide C_min with a geometric mean ratio (everolimus/placebo) of 1.47-fold.
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 Prescribing Information of HMG-CoA reductase inhibitors.
Midazolam (CYP3A4A substrate): In a two-period, fixed-sequence, crossover drug interaction study, 25 healthy subjects received a single oral 4 mg dose of midazolam in period 1. In period 2, they received everolimus 10 mg once-daily for 5 days and a single 4 mg dose of midazolam with the last dose of everolimus. The C_max of midazolam increased 1.25-fold (90% CI, 1.14 to 1.37) and the AUC_inf increased 1.30-fold (1.22 to 1.39). The half-life of midazolam was unaltered. This study indicated that everolimus is a weak inhibitor of CYP3A4.
Anticipated interactions to be considered: Interactions affecting the use of Certican: Moderate inducers of CYP3A4: Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood levels (e.g. St. John's wort (Hypericum perforatum), anticonvulsants (e.g. carbamazepine, phenobarbital, phenytoin), anti HIV drugs (e.g. efavirenz, nevirapine)).
Moderate inhibitors of CYP3A4: Moderate inhibitors of CYP3A4 and PgP may increase everolimus blood levels (e.g. antifungal substances: fluconazole, calcium channel blockers: nicardipine, diltiazem; protease inhibitors: nelfinavir, indinavir, amprenavir.
Inhibitors of PgP: Inhibitors of PgP may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentration.
CYP3A4 and CYP2D6 substrates: 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 exercized when co-administering everolimus with CYP3A4- and CYP2D6 substrates having a narrow therapeutic index. All in vivo interaction studies were conducted without concomitant use of ciclosporin.
Vaccination: Immunosuppressants may affect the response to vaccination and vaccination during treatment with Certican may therefore be less effective. The use of live vaccines should be avoided.
Drug-food/drink interactions: Grapefruit: Grapefruit and grapefruit juice affect cytochrome P450 and PgP activity and should therefore be avoided.

Incompatibilities: Not applicable.
Instructions for Use and Handling: No special requirements.

Do not store above 30°C. Store in the original package in order to protect from light and moisture.

Immunosuppressants

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

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