Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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 and/or P-glycoprotein (PgP) Co-administration with strong inhibitors of CYP3A4 and/or the multidrug efflux pump P­glycoprotein (PgP) (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) may increase everolimus blood levels and is not recommended unless the benefit outweighs the risk.
Coadministration with strong inducers of CYP3A4 and/or PgP (e.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. Dose adjustments of everolimus may be required (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-evaluated 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 Prescribing Information 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 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 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 consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled out 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 section 4.8).

New onset diabetes mellitus
Certican has been shown to increase the risk of new onset diabetes mellitus after transplantation.
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. As preclinical toxicology studies have shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican therapy.


Risk of intolerance of excipients
Certican tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effects on Driving

4.7   Effects on ability to drive and use machines
Certican has no or negligible influence on the ability to drive and use machines.