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60 X 0.25 mg
60 X 0.5 mg
60 X 0.75 mg
Adults: An initial dose regimen of 0.75 mg twice daily in co-administration with ciclosporin 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 in co-administration with tacrolimus is recommended for the hepatic transplant population with the initial dose approximately 4 weeks after transplantation. Patients receiving Certican may require dose adjustments based on blood concentrations achieved, tolerability, individual response, change in co-medications and the clinical situation. Dose adjustments can be made at 4-5 day intervals.
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. 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 data in children and adolescents to recommend the use of Certican in renal transplantation and no recommendation on a posology can be made. In hepatic transplant paediatric patients, Certican should not be used.
Elderly patients (≥ 65 years): 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.
Patients with renal impairment: No dosage adjustment is required.
Patients with impaired hepatic function: Everolimus whole blood trough concentrations 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), to approximately one half of the normal dose for patients with moderate hepatic impairment (Child Pugh Class B), and to 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.
Therapeutic Drug Monitoring: The use of drug assays with adequate performance characteristics when targeting low concentrations of ciclosporin or tacrolimus is recommended. Certican has a narrow therapeutic index which may require adjustments in dosing to maintain therapeutic response. Routine everolimus whole blood therapeutic drug concentration monitoring is recommended. Based on exposure-efficacy and exposure-safety analysis, patients achieving everolimus whole blood trough concentrations ≥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 patients whose trough concentrations 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. Ideally, dose adjustments of Certican should be based on trough concentrations obtained >4-5 days after the previous dosing change. There is an interaction between ciclosporin and everolimus, and everolimus concentrations may therefore decrease if ciclosporin exposure is markedly reduced (i.e. trough concentration <50 ng/ml). Patients with hepatic impairment should preferably have trough concentrations in the upper part of the 3-8 ng/ml exposure range. After starting treatment or after a dose adjustment, monitoring should be performed every 4 to 5 days until 2 consecutive trough concentrations show stable everolimus concentrations, as the prolonged half-lives in hepatically impaired patients delay the time to reach steady state. Dose adjustments should be based on stable everolimus trough concentrations.
For full details see prescribing information.
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.
Certican is contraindicated in patients with a known hypersensitivity to everolimus, sirolimus or any of the excipients.
Management of immunosuppression: 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, 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. 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.
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.
Interaction with strong inhibitors or 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.
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. 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 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 hyperlipidaemia and, if necessary, treated with lipid-lowering medicinal products and appropriate dietary adjustments made. 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 respective Prescribing Information of these medicinal products.
Angioedema: Certican has been associated with the development of angioedema. In the majority of cases reported patients were receiving ACE inhibitors as co-mediacation.
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 coadministering 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. Reversability 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 complication: Certican, like other mTOR inhibitors, can impair healing increasing the occurrence of posttransplant complications such as wound dehiscence, fluid collections and wound infection which may require further surgical attention. Lymphcele 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 purpora/ 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.
Vaccinations: Immunosuppressants may affect the 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.
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.
For full details see prescribing information.
Infections and infestations: Very common: Infections (viral, bacterial, fungal), upper respiratory tract infection, lower respiratory tract and lung infections (including pneumonia), urinary tract infections. Common: Sepsis, wound infection.
Neoplasms benign, malignant and unspecified: Common: Malignant or unspecified tumours, malignant and unspecified skin neoplasms.
Blood and lymphatic system disorders: Very common: Leukopaenia, anaemia/erythropenia, thrombocytopenia. Common: Pancytopenia, thrombotic microangiopathies (including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome).
Metabolism and nutrition disorders: Very common: Hyperlipidaemia (cholesterol and triglycerides), new onset diabetes mellitus, hypokalaemia.
Psychiatric disorders: Very common: Insomnia, anxiety
Nervous system disorders: Very common: Headache
Cardiac disorders: Very common: Pericardial effusion. Common: Tachycardia
Vascular disorders: Very common: Hypertension, venous thromboembolic events. Common: Lymphocele, epistaxis, renal graft thrombosis.
Respiratory, thoracic and mediastinal disorders: Very common: Pleural effusion, cough, dyspnoea.
Gastrointestinal disorders: Very common: Abdominal pain, diarrhoea ,nausea, vomiting. Common: Pancreatitis, stomatitis/mouth ulceration, oropharyngeal pain.
Skin and subcutaneous tissue disorders: Common: Angiooedema, acne, rash.
Musculoskeletal and connective tissue disorders: Common: Myalgia, arthralgia.
Renal and urinary disorders: Common: Proteinuria, renal tubular necrosis.
Reproductive system and breast disorders: Common: Erectile dysfunction, menstrual disorder (including amenorrhoea and menorrhagia).
General disorders and administration site conditions: Very common: Peripheral oedema, pain, healing impaired, pyrexia. Common: Incisional hernia.
Investigations: Common: Hepatic enzyme abnormal.
For full details see prescribing information.
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 (PgP). 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 a mixed inhibitor of CYP2D6. All in vivo interaction studies were conducted without concomitant ciclosporin.
For full details see prescribing information.
Pregnancy and Lactation
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. 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.
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.
For full details see prescribing information.
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 2,000 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.
Storage: Do not Store above 30°C. Protect from light and moisture.