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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 (Study A2310, see Pharmacology: Pharmacodynamics under Actions), an increased incidence of serious infections was observed within the first 3 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 (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).
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 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 (see Interactions). The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen including Certican. Similarly the risk/benefit of continued Certican therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.
Patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the respective prescribing information of Certican (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 calcineurin inhibitor (CNI), there have been reports of worsening proteinuria when the CNI is replaced by Certican. Reversibility has been observed with interruption of Certican and reintroduction of the CNI. The safety and efficacy of conversion from CNI to Certican in such patients have not been established.
Patients receiving Certican should be monitored for proteinuria.
Renal Graft Thrombosis: An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, mostly within the first 30 days post-transplantation.
Wound-Healing Complications: Certican, like other mTOR inhibitors, can impair healing increasing the occurrence of post-transplant complications eg, wound dehiscence, fluid collections and wound infection which may require further surgical attention. Lymphocele is the most frequently reported such event in renal transplant recipients and tends to be more frequent in patients with higher body mass index. The frequency of pericardial and pleural effusion is increased in cardiac transplant recipients and the frequency of incisional hernias is increased in liver transplant recipients.
Thrombotic Microangiopathy/Thrombotic Thrombocytopenic Purpura/Haemolytic Uraemic Syndrome: The concomitant administration of Certican with a CNI may increase the risk of CNI-induced haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.
Interstitial Lung Disease/Non-Infectious Pneumonitis: A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been discounted through appropriate investigations. Cases of ILD have been reported with Certican which generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred (see Adverse Reactions).
New Onset Diabetes Mellitus: Certican has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients treated with Certican.
Male Infertility: There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors. Preclinical toxicology studies having shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican therapy.
Risk of Intolerance to Excipients: Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take Certican.
Effects on the Ability to Drive or 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 embryo/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 breastmilk, but in animal studies, everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking Certican should therefore, not breastfeed.
