Certican Tablets
Novartis Pharmaceuticals UK Ltd
contact details
Active ingredient
everolimus
Legal Category
POM: Prescription only medicine
Certican® 0.25 mg tablets
Certican® 0.75 mg tablets
Each tablet contains 0.25/0.75 mg everolimus.
Excipient(s) with known effect:
Each tablet contains 2/7 mg lactose monohydrate and 51/112 mg Anhydrous lactose.
For the full list of excipients, see section 6.1.
Tablet
Tablets are white to yellowish, marbled, round, flat with a bevelled edge.
0.25 mg (diameter of 6 mm): engraved with “C” on one side and “NVR” on the other.
0.75 mg (diameter of 8.5 mm): engraved with “CL” on one side and “NVR” on the other.
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 concentration monitoring.
Posology
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 (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. There is limited information indicating that black patients may require a higher Certican dose to achieve similar efficacy to non-black patients (see section 5.2). 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 (see section 5.1 and 5.2) and no recommendation on a posology can be made. In hepatic transplant paediatric patients, Certican should not be used (see section 5.1).
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 (see section 5.2).
Patients with renal impairment
No dosage adjustment is required (see section 5.2).
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). Further dose titration should be based on therapeutic drug monitoring (see section 5.2). Reduced doses rounded to the nearest tablet strength are tabulated below:
Table 1 Certican dose reduction in patients with hepatic impairment
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Normal hepatic function
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Mild hepatic impairment (Child-Pugh A)
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Moderate hepatic impairment (Child-Pugh B)
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Severe hepatic impairment (Child-Pugh C)
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Renal and cardiac transplantation
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0.75 mg b.i.d.
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0.5 mg b.i.d.
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0.5 mg b.i.d.
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0.25 mg b.i.d.
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Hepatic transplantation
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1 mg b.i.d.
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0.75 mg b.i.d.
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0.5 mg b.i.d.
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0.5 mg b.i.d.
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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 (see section 4.5). 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. 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 (see sections 4.4 and 5.2). 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. Based on experience gained from study A2309, ciclosporin exposure reduction should be started immediately after transplantation with the following recommended whole blood trough concentration windows:
Table 2 Renal transplantation: recommended target ciclosporin blood trough concentration windows
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Target ciclosporin C0 (ng/ml)
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Month 1
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Months 2-3
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Months 4-5
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Months 6-12
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Certican groups
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100-200
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75-150
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50-100
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25-50
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(Measured C0 and C2 concentrations are shown in section 5.1).
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.
There are limited data regarding dosing Certican with ciclosporin trough concentrations below 50 ng/ml, or C2 concentrations 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 their 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 concentrations. See section 5.1 for experience with reduced ciclosporin blood concentrations.
In cardiac transplantation, there are limited data regarding dosing Certican with ciclosporin trough concentrations of 50-100 ng/ml after 12 months.
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.
Tacrolimus dose recommendation in hepatic transplantation
Hepatic transplant patients should have their tacrolimus exposure reduced to minimise calcineurin-related renal toxicity. The tacrolimus dose should be reduced starting approximately 3 weeks after initiating co-administration with Certican, based on targeted tacrolimus blood trough concentrations (C0) of 3-5 ng/ml. In a controlled clinical trial, complete withdrawal of tacrolimus has been associated with an increased risk of acute rejections.
Certican has not been eva luated with full-dose tacrolimus in controlled clinical trials.
Method of administration
Certican is for oral use only.
The daily dose of Certican should always be given orally in two divided doses consistently either with or without food (see section 5.2) and at the same time as ciclosporin for microemulsion or tacrolimus (see Therapeutic drug monitoring).
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 Summary of Product Characteristics).
Certican is contraindicated in patients with a known hypersensitivity to everolimus, sirolimus, or to any of the excipients.
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. In a clinical study in heart transplant recipients (Study A2310, see section 5.1), 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. Fatal infections and sepsis have been reported in patients treated with Certican (see section 4.8).
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.
Liver function impairment
Close monitoring of everolimus whole blood trough concentrations (C0) and everolimus dose adjustment is recommended in patients with impaired hepatic function (see section 4.2).
Because of longer everolimus half-lives in patients with hepatic impairment (see section 5.2), 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. 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 (see section 4.5).
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, carbamazepine, phenytoin) is not recommended unless the benefit outweighs the risk. It is recommended that everolimus whole blood trough concentrations be monitored whenever inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5).
Lymphomas and other malignancies
Patients receiving a regimen of immunosuppressive medicinal products, including Certican, are at increased risk of developing lymphomas or other malignancies, particularly of the skin (see section 4.8). 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. Patients receiving Certican should be monitored for hyperlipidaemia and, if necessary, treated with lipid-lowering medicinal products and have appropriate dietary adjustments made (see section 4.5). 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-eva luated in patients with severe refractory hyperlipidaemia. Patients administered a HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the Summary of Product Characteristics for the medicinal product(s) concerned (see section 4.5).
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 comparison to standard exposure tacrolimus without Certican. 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 negative 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 concentrations. 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 switching from a CNI to Certican in such patients have not been establised. 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 accumulation 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 a 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 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
