Certican

Everolimus.

Certican tablets also contain the following excipients: Butylated hydroxytoluene (E321), magnesium stearate, lactose monohydrate, hypromellose, crospovidone, anhydrous lactose.

Pharmacotherapeutic Group: Selective immunosuppressive agents. ATC Code: L04AA18.
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 antigen-activated T-cell proliferation, and thus clonal expansion, driven by T-cell-specific interleukins eg, interleukin-2 and interleukin-15. Everolimus inhibits an intracellular signaling 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: Kidney Transplantation: Everolimus 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 2 phase III de novo renal transplant trials (B201 and B251). Mycofenolate mofetil (MMF) 1 g twice daily 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. This may be reversible with ciclosporin dose reduction.
Two phase III b studies (A2306 and A2307) evaluated the efficacy and safety of Certican 1.5 mg/day and 3 mg/day (initial dosing; subsequent dosing based on target trough concentration (C0) ≥3 ng/mL) in combination with reduced exposure to ciclosporin (monitored by C2) in de novo transplant recipients. In A2306, target C2 concentrations were 1000-1400 ng/mL in weeks 0-4, 700-900 ng/mL in weeks 5-8, 550-650 ng/mL in weeks 9-12, 350-450 ng/mL in weeks 13-52. In A2307 (combination with Simulect), target C2 concentrations were 500-700 ng/mL in weeks 0-8 and 350-450 ng/mL in weeks 9-52.
Actual trough concentrations (C0) and C2 for A2306 are provided in the table as follows: (See Table 1.)


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In A2306, 12-month results for the incidence of biopsy-proven rejection in the ITT population (N=237; 112 on Certican 1.5 mg/day and 125 on 3 mg/day) were 25.9% for the 1.5 mg/day group and 19.2% for the 3 mg/day group. Cross-study comparisons indicated that allograft function was better than that seen with Certican in studies involving full-dose ciclosporin. On-treatment median serum creatinine values at month 12 were 122 micromol/L in the 1.5 mg and 126 micromol/L in the 3-mg Certican group (mean: 126 and 134 micromol/L). On-treatment median creatinine clearance values according to Cockcroft-Gault were 69 and 62 mL/min in the 2 Certican groups (mean: 69 and 65 mL/min).
The A2307 study is similar in design to A2306, with the addition of two 20-mg doses of basiliximab at day 0 and day 4 and with lower target C2 levels for ciclosporin through the first 8 weeks following transplantation (weeks 0-8: 500-700 ng/mL, months 3-12: 350-450 ng/mL). Analyses of the 12-month results (ITT, N=256; 117 on Certican 1.5 mg/day and 139 on 3 mg/day) demonstrated incidences of biopsy-proven rejection of 13.7% for the 1.5 mg/day group and 15.8% for the 3 mg/day group. On-treatment median serum creatinine values at month 12 were 128 micromol/L in the 1.5mg and 126 micromol/L in the 3 mg Certican group (mean: 132 and 132 micromol/L). On-treatment median creatinine clearance values according to Cockcroft-Gault were 64 and 65 mL/min in the 2 Certican groups (mean: 68 and 65 mL/min).
Heart Transplantation: In the phase III heart 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 IV 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 1 matched slice of an automated pullback sequence), an important risk factor for long-term graft loss.
Ciclosporin doses were based on target trough levels (C0) as follows: Weeks 1-4: 250-400 ng/mL, months 1-6: 200-350 ng/mL, months 7-24: 100-300 ng/mL.
Actual trough concentrations (C0) are in the table as follows: (See Table 2.)


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Elevated serum creatinine was observed more frequently among subjects using Certican in combination with full dose of ciclosporin for microemulsion than in AZA patients. This effect suggests that Certican increases the ciclosporin-induced nephrotoxicity. This may be reversible with ciclosporin dose reduction, nevertheless, there are limited data regarding dosing Certican with ciclosporin trough concentrations (C0) <100 ng/mL after 6 months in cardiac transplantation.
Pharmacokinetics: Absorption: Peak everolimus concentrations are reached 1-2 hrs after administration of an oral dose. Everolimus blood concentrations in transplant patients are dose-proportional over the dose range of 0.25-15 mg. The relative bioavailability of the dispersible tablet compared with the conventional tablet is 0.9 (90% CI 0.76-1.07) 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 5-5000 ng/mL, is 17-73%. 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.
Metabolism: Everolimus is a substrate of CYP3A4 and P-glycoprotein. The main metabolic pathways identified in man were monohydroxylations and O-dealkylations. Two main metabolites were formed by hydrolysis of the cyclic lactone. Everolimus was the main circulating component in the blood. None of the main metabolites are likely to contribute significantly to the immunosuppressive activity of everolimus.
Excretion: After a single dose of radiolabelled everolimus in transplant patients receiving ciclosporin, most of the radioactivity (80%) was recovered from the feces and only a minor amount (5%) was excreted in urine. Parent drug was not detected in the urine or feces.
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 1-2 hrs post-dose. At 0.75 and 1.5 mg twice daily, C_max averages 11.1±4.6 and 20.3±8 ng/mL, respectively, and AUC averages 75±31 and 131±59 ng·hr/mL, respectively. At 0.75 and 1.5 mg twice daily, 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/hr (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 hrs.
Hepatic Impairment: The average AUC of everolimus in 8 patients with moderate hepatic impairment (Child-Pugh class B) was twice as high as that found in 8 healthy subjects. AUC was positively correlated with serum bilirubin concentration and with prolongation of prothrombin time and negatively correlated with serum albumin concentration. The AUC of everolimus tended to be greater than that in healthy subjects if bilirubin was >34 micromol/L and/or albumin concentration was <35 g/L. The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed but the effect on the AUC of everolimus is likely to be as large as, or larger than, the effect of moderate impairment (see Dosage & Administration).
Renal Impairment: Post-transplant renal impairment (Cl_cr range; 11-107 mL/min) did not affect the pharmacokinetics of everolimus.
Pediatrics: Everolimus CL/F increased in a linear manner with patient age (1-16 years), body surface area (0.49-1.92 m²) and weight (11-77 kg). Steady-state CL/F was 10.2±3 L/hr/m² and elimination half-life was 30±11 hrs. Nineteen pediatric de novo renal transplant patients (1-16 years) received Certican dispersible tablets at a dose of 0.8 mg/m² (max 1.5 mg) twice daily with ciclosporin for microemulsion. They achieved an everolimus AUC of 87±27 ng·hr/mL which is similar to adults receiving 0.75 mg twice daily. Steady-state trough levels (C0) were 4.4±1.7 ng/mL.
Elderly: A limited reduction in everolimus oral CL of 0.33%/year was estimated in adults (age range studied was 16-70 years). No dose adjustment is considered necessary.
Ethnicity: Based on analysis of population pharmacokinetics, oral clearance (CL/F) is, on average, 20% higher in Black transplant patients (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 kidney and heart transplant patients (see Table 3).


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Toxicology: Preclinical Safety Data: In a kidney transplantation model in cynomolgus monkeys, rejection occurred within 4-8 days in untreated animals. With administration of everolimus, rejection could be delayed until day 27 (median); the range was 8-91 days. At the higher dose of 1.5 mg/kg, the median rose to 59 days and the range was 28-85 days. With the comparator substance rapamycin, the median was 43 days (range 5-103 days) at the 0.75 mg/kg dose and 56 days (range 8-103 days) at the 1.5 mg/kg dose. It should be noted that prevention of rejection over the whole 103-day reporting period was only possible in 3 of 8 treated monkeys in the 1.5 mg/kg rapamycin group.
There was no statistically significant difference between the 2 treatment groups.
In animal studies, everolimus showed a low acute toxic potential. Following single oral doses of 2000 mg/kg (limit test), lethality or severe toxicity was not observed in mice or rats.
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.
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 arthritis in several organs. Histopathological findings in the kidney were also diagnosed.
In a male fertility study in rats, testicular morphology was affected at ≥0.5 mg/kg, 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/fetotoxicity, at systemic exposure below the therapeutic one, that was manifested as mortality and reduced fetal weight. The incidence of skeletal variations and malformations at 0.3 and 0.9 mg/kg (eg, 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.

Prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant. Certican should be used in combination with ciclosporin for microemulsion 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, which is recommended for the general kidney and heart transplant population, should be administered as soon as possible after transplantation. The daily dose of Certican should always be given orally in 2 divided doses (twice daily). Certican should be consistently given either with or without food (see Pharmacokinetics under Actions) and at the same time as ciclosporin for microemulsion (see Therapeutic Drug Monitoring in the succeeding text). 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 (see Certican dispersible tablets basic prescribing information).
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 days intervals (see Therapeutic Drug Monitoring in the succeeding text).
Black Patients: The incidence of biopsy-proven acute rejection episodes was significantly higher in Black 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 Pharmacokinetics under Actions). Currently, the efficacy and safety data are too limited to allow specific recommendations for use of Certican in Black patients.
Children and Adolescents: 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 Pharmacokinetics under Actions).
Elderly Patients (≥65 years): Clinical experience is limited in patients ≥65 years. Nevertheless, there are no apparent differences in the pharmacokinetics of Certican in patients ≥65-70 years as compared with younger adults (see section Pharmacokinetics under Actions).
Patients with Renal Impairment: No dosage adjustment is required (see Pharmacokinetics under Actions).
Patients with Hepatic Impairment: Whole blood trough levels (C0) of everolimus should be closely monitored in patients with impaired hepatic function. For patients with mild or moderate hepatic impairment (Child-Pugh class A or B), the dose should be reduced to approximately ½ of the normal dose if 2 of the following conditions apply: Bilirubin >34 micromol/L (>2 mg/dL), albumin <35 g/L (<3.5 g/dL), prothrombin time >1.3 INR (<4 sec prolongation). Further dose titration should be based on therapeutic drug monitoring (see Pharmacokinetics under Actions). Certican has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C, see Precautions).
Therapeutic Drug Monitoring: 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 ng/mL have been found to have a lower incidence of biopsy-proven acute rejection in both renal and heart transplantation than patients whose trough levels (C0) are <3 ng/mL. The recommended upper limit of the therapeutic range is 8 ng/mL. Exposure >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 >4-5 days after the previous dose change. Since ciclosporin interacts with everolimus, everolimus levels may decrease if ciclosporin exposure is markedly reduced (ie, 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, which, in the clinical study programme (B201 and B251), led to 12-hr trough blood levels ranging from 150-400 ng/mL for post-transplant weeks 1-4, and 100-300 ng/mL for post-transplant months 2-36. Reduced exposure to ciclosporin in Certican-treated renal transplant patients improves renal function. Ciclosporin exposure reduction should be started after 1 month post-transplantation. Based on the experience gained from Study A2306 (see Pharmacology under Actions), the following target ranges for ciclosporin exposure as defined per-protocol [ciclosporin blood concentrations measured 2 hrs after dose administration (C2)] are recommended: Weeks 0-4, 1000-1400 ng/mL, weeks 5-8, 700-900 ng/mL, weeks 9-12, 550-650 ng/mL, weeks 13-52, 350-450 ng/mL. In this study, measured ciclosporin trough blood concentrations (C0) (ng/mL) were: Month 1: 239±114; month 3: 131±85; month 6: 82±60; month 12: 61±28. It is important to ensure that both everolimus and ciclosporin levels do not fall below the therapeutic range early after transplantation to minimize the risk of efficacy failure.
Prior to dose reduction of ciclosporin, it should be ascertained that steady-state everolimus whole blood trough concentrations (C0) are ≥3 ng/mL.
There are limited data regarding dosing Certican with ciclosporin trough concentrations (C0) <50 ng/mL or C2 levels <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 (C0) (see Pharmacology: Table 2 under Actions).
In cardiac transplantation, there are limited data regarding dosing Certican with ciclosporin trough concentrations (C0) <175 ng/mL in the first 3 months, <135 ng/mL at 6 months and <100 ng/mL after 6 months.
Prior to dose reduction of ciclosporin, it should be ascertained that steady-state everolimus whole blood trough concentrations (C0) are ≥3 ng/mL.

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 Certican 1.5 mg 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.

Patients with a known hypersensitivity to everolimus, sirolimus or any of the excipients.
Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take Certican.
Use in pregnancy: 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 (see Toxicology under Actions). 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. Women of childbearing potential should be advised to use effective contraception methods while they are receiving Certican and for up to 8 weeks after ending treatment.
Use in 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 not therefore breastfeed.

In clinical trials, Certican has been administered concurrently with ciclosporin for microemulsion, 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. Kidney transplant recipients excluded from clinical studies were those with a cold ischemia time >40 hrs, those with positive T-cell crossmatches and those who were recipients of donor-specific transfusions. In heart transplantation studies, patients with panel-reactive antibody (PRA) >20% were excluded. In both indications, patients were excluded if they had received several solid organ transplants (including more than one kidney), if they had had a previous organ transplant or if they were recipients of ABO-incompatible organs. The immunological risk was considered slight to moderate in patients who were not excluded according to these criteria.
Certican has not been adequately studied in patients at high immunological risk.
Everolimus has not been studied in patients with severe hepatic impairment. Close monitoring of everolimus whole blood trough levels (C0) in patients with impaired hepatic function is therefore recommended.
Co-administration with strong CYP3A4-inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (eg, 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).
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.
Over-immunosuppression predisposes patients to infections especially infections with opportunistic pathogens. Fatal infections and sepsis have been reported (see Adverse Reactions).
In clinical trials with Certican, antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia was administered for the first 12 months following transplantation. Cytomegalovirus (CMV) prophylaxis was recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.
In transplant patients, concomitant use of Certican and ciclosporin for microemulsion has been associated with an increase in serum cholesterol and triglycerides that may require treatment. Patients receiving Certican should be monitored for hyperlipidaemia 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 adverse effects as described in the respective Prescribing Information of these medicinal products (see Interactions).
Regular monitoring of renal function is recommended in all patients. Appropriate adjustment of the immunosuppressive regimen, in particular, reduction of the ciclosporin dose should be considered in patients with elevated serum creatinine levels. Caution should be exercised when co-administering other medicinal products that are known to have a deleterious effect on renal function.
Concomitant administration of Certican and ACE inhibitors has frequently led to angioedema.
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 resolve on drug interruption with or without glucocorticoid therapy (see Adverse Reactions).
Effects on the Ability to Drive and Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.

Use in pregnancy: 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 (see Toxicology under Actions). 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. Women of childbearing potential should be advised to use effective contraception methods while they are receiving Certican and for up to 8 weeks after ending treatment.
Use in 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 not therefore breastfeed.

The frequencies of the adverse drug reactions listed as follows are derived from 3 clinical trials and represent pooled data from 1199 patients. The 3 trials were multicenter, randomized, double-blind, controlled trials 2 de novo kidney transplant trials and 1 de novo heart transplant trial, in which Certican at a dose of either 1.5 mg or 3 mg/day for at least 12 months, was co-administered with ciclosporin for microemulsion and with corticosteroids. In addition, the frequency of the adverse drug reactions of 2 open-label studies is included. Those studies evaluated efficacy and safety of Certican 1.5 and 3 mg/day in combination with reduced exposure to ciclosporin in de novo renal transplant recipients.
Adverse reactions are listed according to their frequency which are defined as: Very common >1/10, common >1/100 and <1/10, uncommon >1/1000 and <1/100, rare >1/10,000 and <1/1000, very rare <1/10,000.
The table as follows contains adverse drug reactions possibly or probably related to Certican seen in phase III clinical trials (renal and heart transplantation). It is compiled according to MedDRA standard organ classes: (See Table 4.)


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In controlled clinical trials in which patients were monitored for at least 1 year, lymphoma or lymphoproliferative disease developed in 1.4% of patients receiving Certican (1.5 or 3 mg/day) in combination with other immunosuppressants. Malignancies of the skin developed in 1.3% of patients and other types of malignancies developed in 1.2% of patients.
The occurrence of the adverse events may depend on the degree and duration of the immunosuppressive regimen. In the pivotal studies, elevated serum creatinine was observed more frequently in patients given Certican in combination with full dose ciclosporin for microemulsion than in control patients. The overall incidence of adverse events was lower with reduced dose of ciclosporin for microemulsion (see Pharmacology under Actions).
The safety profile of Certican in the 2 open-label trials was similar to that described in the 3 pivotal studies, except that elevation of serum creatinine was less frequent, and mean and median serum creatinine values were lower, than in the other 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 rapamycins and their derivatives, including Certican. Mostly, the condition resolves after discontinuation of Certican and/or addition of glucocorticoids.

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. Concurrent treatment with strong CYP3A4 inhibitors and/or inducers is not recommended. Inhibitors of PgP may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentration. 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 Certican with CYP3A4- and CYP2D6-substrates having a narrow therapeutic index. All in vivo interaction studies were conducted without concomitant use of 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 the AUC of Certican by 168% (range, 46-365%) and C_max by 82% (range, 25-158%), as compared with Certican alone. Dose adjustment of Certican may be needed if the ciclosporin dose is altered (see Dosage & Administration). Certican had only a minor clinical influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.
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).
Atorvastatin (CYP3A4-Substrate) and Pravastatin (PgP-Substrate): Single-dose administration of everolimus 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.
ACE Inhibitors: Concomitant administration of Certican and ACE inhibitors may increase the risk of angioedema.
Other Possible Interactions: Moderate inhibitors of CYP3A4 and PgP may increase everolimus blood levels (eg, antifungal substances: Fluconazole; macrolide antibiotics; erythromycin, calcium channel blockers: Verapamil, nicardipine, diltiazem; protease inhibitors: Nelfinavir, indinavir, amprenavir). Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood levels [eg, St. John's wort (Hypericum perforatum); anticonvulsants: Carbamazepine, phenobarbital, phenytoin, anti-HIV drugs: Efavirenz, nevirapine].
Grapefruit and grapefruit juice affect cytochrome P-450 and PgP activity and should therefore be avoided.
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.
Incompatibilities: Not applicable.

Store in the original package to protect from light and moisture.

Immunosuppressants

L01XE10 - everolimus ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.

G

Tab 0.25 mg (white to yellowish, marbled, round, flat with a bevelled edge, engraved with "C" on one side and "NVR" on the other) 6 x 10's. 0.5 mg (white to yellowish, marbled, round, flat with a bevelled edge, engraved with "CH" on one side and "NVR" on the other) 6 x 10's. 0.75 mg (white to yellowish, marbled, round, flat with a bevelled edge, engraved with "CL" on one side and "NVR" on the other) 6 x 10's.