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CERTICAN is a brand name for Everolimus. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 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…
Verbatim from this product's MHRA label. Tap a section to expand.
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 concentration monitoring. 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.
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 (see Therapeutic drug monitoring). Special population Black patients The incidence of biopsy-proven acute rejection episodes was significantly higher in black renal transplant patients compared with non-black patients.
2). Currently, the efficacy and safety data are too limited to allow specific recommendations for use of everolimus in black patients. Paediatric population In paediatric renal and hepatic transplant patients, Certican should not be used.
1). Elderly patients (≥65 years) Clinical experience in patients >65 years of age is limited. 2). 2). 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).
2). d. d. d. d. d. d. d. d. 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. 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.
a) Summary of the safety profile The frequencies of adverse reactions listed below are derived from analysis of the 12-month incidences of events reported in multicentre, randomised, controlled trials investigating Certican in combination with calcineurin inhibitors (CNI) and corticosteroids in adult transplant recipients.
All but two of the trials (in renal transplantation) included non-Certican, CNI-based standard-therapy arms. 1). 1). The most common events are: infections, anaemia, hyperlipidaemia, new onset of diabetes mellitus, insomnia, headache, hypertension, cough, constipation, nausea, peripheral oedema, impaired healing (including pleural and pericardial effusion).
e. degree and duration). In the studies combining Certican with ciclosporin, elevated serum creatinine was observed more frequently in patients administered Certican in combination with full-dose ciclosporin for microemulsion than in control patients.
1). The safety profile of Certican administered with reduced-dose ciclosporin was similar to that described in the 3 pivotal studies in which full-dose ciclosporin was administered, except that elevation of serum creatinine was less frequent, and mean and median serum creatinine values were lower, than in the Phase III studies.
b) Tabulated summary of adverse reactions Table 4 contains adverse drug reactions possibly or probably related to Certican seen in Phase III clinical trials. 1). Except where noted otherwise, the adverse reaction profile is relatively consistent across all transplant indications.
It is compiled according to MedDRA standard organ classes. Adverse reactions are listed according to their frequencies, which are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
Management of immunosuppression In clinical trials, Certican has been administered concurrently with ciclosporin for microemulsion, basiliximab, or with tacrolimus, and corticosteroids. Certican in combination with immunosuppressive agents other than these has not been adequately investigated.
Certican has not been adequately studied in patients at high immunological risk. Combination with thymoglobulin induction Strict caution is advised with the use of thymoglobulin (rabbit anti-thymocyte globulin) induction and the Certican/ciclosporin/steroid regimen.
1), an increased incidence of serious infections including fatal infections was observed within the first three months after transplantation in the subgroup of patients who had received induction with rabbit anti-thymocyte globulin.
Serious and opportunistic infections Patients treated with immunosuppressants, including Certican, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus-associated nephropathy and JC virus-associated progressive multiple leukoencephalopathy (PML).
These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
8). 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.
2). 2), everolimus therapeutic monitoring after starting treatment or after a dose adjustment should be performed until stable concentrations are reached. Interaction with oral CYP3A4 substrates Caution should be exercised when Certican is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions.
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5). Everolimus concentrations might be slightly lower following dispersible tablet administration. Ideally, dose adjustments of Certican should be based on trough concentrations obtained >4- 5 days after the previous dosing change. 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. 2). Dose adjustments should be based on stable everolimus trough concentrations.
Ciclosporin dose recommendation in renal transplantation Certican should not be used long-term together with full doses of ciclosporin. Reduced exposure to ciclosporin in Certican-treated renal transplant patients improves renal function.
1). Prior to dose reduction of ciclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations are equal to or above 3 ng/ml. […]
Table 4 Adverse drug reactions possibly or probably related to Certican Body system Incidence Adverse reaction Infections and infestations Very common Infections (viral, bacterial, fungal), upper respiratory tract infection, lower respiratory tract and lung infections (including pneumonia)1, urinary tract infections2 Common Sepsis, wound infection Neoplasms benign, malignant and unspecified Common Malignant or unspecified tumours, malignant and unspecified skin neoplasms Uncommon Lymphomas/post-transplant lymphoproliferative disorders (PTLD) Blood and lymphatic system disorders Very common Leukopaenia, anaemia/erythropenia, thrombocytopenia1 Common Pancytopenia, thrombotic microangiopathies (including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome) Endocrine disorders Uncommon Hypogonadism male (testosterone decreased, FSH and LH increased) 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 effusion3 Common Tachycardia Vascular disorders Very common Hypertension, venous thromboembolic events Common Lymphocoele4, epistaxis, renal graft thrombosis Respiratory, thoracic and mediastinal disorders Very common Pleural effusion1, cough1, dyspnoea1 Uncommon Interstitial lung disease5 Gastrointestinal disorders Very common Abdominal pain, diarrhoea, nausea, vomiting Common Pancreatitis, stomatitis/mouth ulceration, oropharyngeal pain Hepatobiliary disorders Uncommon Non infectious hepatitis, jaundice Skin and subcutaneous tissue disorders Common Angiooedema6, acne, rash Musculoskeletal and connective tissue disorders Common Myalgia, arthralgia Renal and urinary disorders Common Proteinuria2, renal tubular necrosis7 Reproductive system and breast disorders Common Erectile dysfunction, menstrual disorder (including amenorrhoea and menorrhagia) Uncommon Ovarian cyst General disorders and administration site conditions Very common Peripheral oedema, pain, healing impaired, pyrexia Common Incisional hernia Investigations Common Hepatic enzyme abnormal8 1common in renal and liver transplantation 2common in cardiac and liver transplantation 3in cardiac transplantation 4in renal and cardiac transplantation5the SMQ-based search for ILD showed the frequency of ILD in the clinical trials.
g. by infections. The frequency category given here is derived from the medical review of the known cases. 6predominantly in patients receiving concomitant ACE inhibitors 7in renal transplantation 8γ-GT, AST, ALT elevated c) Description of selected adverse reactions As preclinical toxicology studies have shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican therapy.
There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors. In controlled clinical trials in which a total of 3,256 patients receiving Certican in combination with other immunosuppressants were monitored for […]
g. 5). g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) may increase everolimus blood levels and is not recommended unless the benefit outweighs the risk. g. rifampicin, rifabutin, carbamazepine, phenytoin) is not recommended unless the benefit outweighs the risk.
If coadministration of inducers or inhibitors of CYP3A4 and/or PgP cannot be avoided, it is recommended that everolimus whole blood trough concentrations and the clinical condition of the patient be monitored while they are concurrently administered with everolimus and after their discontinuation.
5). 8). 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 and sunlight, and to use appropriate sunscreen.
Hyperlipidaemia The use of Certican with ciclosporin for microemulsion or tacrolimus in transplant patients has been associated with increased serum cholesterol and triglycerides that may require treatment. 5). 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. 5). 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 transplantation, 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 […]