4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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

In paediatric renal and hepatic transplant patients, Certican should not be used. The safety and efficacy of Certican in paediatric cardiac transplant patients has not been established (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

Normal hepatic function

Mild hepatic impairment (Child-Pugh A)

Moderate hepatic impairment (Child-Pugh B)

Severe hepatic impairment (Child-Pugh C)

Renal and cardiac transplantation

0.75 mg b.i.d.

0.5 mg b.i.d.

0.5 mg b.i.d.

0.25 mg b.i.d.

Hepatic transplantation

1 mg b.i.d.

0.75 mg b.i.d.

0.5 mg b.i.d.

0.5 mg b.i.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. 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

Target ciclosporin C0 (ng/ml)

Month 1

Months 2-3

Months 4-5

Months 6-12

Certican groups

100-200

75-150

50-100

25-50

(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 evaluated 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).

4.3. Contraindications

Certican is contraindicated in patients with a known hypersensitivity to everolimus, sirolimus, or to any of the excipients listed in section 6.1.

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 P-glycoprotein (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 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 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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

Table 3 Effects of other active substances on everolimus

Active substance by interaction

Interaction – Change in Everolimus AUC/Cmax Geometric mean ratio (observed range)

Recommendations concerning co- administration

Strong CYP3A4/PgP inhibitors

Ketoconazole

AUC ↑15.3-fold

(range 11.2-22.5)

Cmax ↑4.1-fold

(range 2.6-7.0)

Co-administration with strong CYP3A4/PgP-inhibitors is not recommended unless the benefit outweighs the risk.

Itraconazole, posaconazole, voriconazole

Not studied. Large increase in everolimus concentration is expected.

Telithromycin, clarithromycin

Nefazodone

Ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir

Moderate CYP3A4/PgP inhibitors

Erythromycin

AUC ↑4.4-fold

(range 2.0-12.6)

Cmax ↑2.0-fold

(range 0.9-3.5)

Everolimus whole blood trough concentrations should be monitored whenever inhibitors of CYP3A4/PgP are concurrently administered and after their discontinuation.

Use caution when co-administration of moderate CYP3A4 inhibitors or PgP inhibitors cannot be avoided.

Closely monitor for side effects and adjust the everolimus dose as needed (see sections 4.2 and 4.4).

Imatinib

AUC ↑3.7-fold

Cmax ↑2.2-fold

Verapamil

AUC ↑3.5-fold

(range 2.2-6.3)

Cmax ↑2.3-fold

(range1.3-3.8)

Ciclosporin oral

AUC ↑2.7-fold

(range 1.5-4.7)

Cmax ↑1.8-fold

(range 1.3-2.6)

Cannabidiol (P-gp inhibitor)

AUC ↑ 2.5-fold

Cmax ↑ 2.5-fold

Fluconazole

Not studied. Increased exposure expected.

Diltiazem, nicardipine

Dronedarone

Not studied. Increased exposure expected.

Amprenavir, fosamprenavir

Not studied. Increased exposure expected.

Grapefruit juice or other food affecting CYP3A4/PgP

Not studied. Increased exposure expected (the effect varies widely).

Combination should be avoided.

Strong and moderate CYP3A4 inducers

Rifampicin

AUC ↓63%

(range 0-80%)

Cmax ↓58%

(range 10-70%)

Co-administration with strong CYP3A4-inducers is not recommended unless the benefit outweighs the risk.

Rifabutin

Not studied. Decreased exposure expected.

Carbamazepine

Not studied. Decreased exposure expected.

Phenytoin

Not studied. Decreased exposure expected.

Phenobarbital

Not studied. Decreased exposure expected.

Everolimus whole blood trough concentrations should be monitored whenever inducers of CYP3A4 are concurrently administered and after their discontinuation.

Efavirenz, nevirapine

Not studied. Decreased exposure expected.

St John's Wort

(Hypericum perforatum)

Not studied. Large decrease in exposure expected.

Preparations containing St John's Wort should not be used during treatment with everolimus

Agents whose plasma concentrations may be altered by everolimus:

Octreotide

Co-administration of everolimus (10 mg daily) with depot octreotide increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47-fold.

Ciclosporin

Certican had a minor clinical influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.

Atorvastatin (CYP3A4 substrate) and pravastatin (PgP substrate)

Single-dose administration of Certican with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However, these results cannot be extrapolated to other HMG-CoA reductase inhibitors. Patients should be monitored for the development of rhabdomyolysis and other adverse events as described in the Summary of Product Characteristics of HMG-CoA reductase inhibitors.

Oral CYP3A4A substrates

Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A4 substrate probe, with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC. The effect is likely to be due to inhibition of intestinal CYP3A4 by everolimus. Hence, everolimus may affect the bioavailability of orally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is not expected. If everolimus 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.

Vaccinations

Immunosuppressants may affect the response to vaccination and vaccination during treatment with Certican may be less effective. The use of live vaccines should be avoided.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, 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 embryo/foetotoxicity (see section 5.3). The potential risk for humans is unknown. Certican should not be given to pregnant women unless the potential benefit outweighs the potential risk for the foetus. Women of childbearing potential should be advised to use effective contraception methods while they are receiving Certican and up to 8 weeks after treatment has been stopped.

Breast-feeding

It is not known whether everolimus is excreted in human milk. In animal studies, everolimus and/or its metabolites were readily transferred into the milk of lactating rats. Therefore, women who are taking Certican should not breast feed.

Fertility

There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors (see section 4.4, 4.8, and 5.3). The potential for everolimus to cause infertility in male and female patients is unknown, however, male infertility and secondary amenorrhoea have been observed.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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. Certican combined with ciclosporin was studied in five trials in renal transplant recipients totalling 2,497 patients (including two studies without a non-Certican control group), and three trials in heart transplant recipients totalling 1,531 patients (ITT populations, see section 5.1).

Certican combined with tacrolimus was studied in one trial, which included 719 liver transplant recipients (ITT population, see section 5.1).

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).

The occurrence of the adverse events may depend on the immunosuppressive regimen (i.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. The overall incidence of adverse events was lower with reduced-dose ciclosporin for microemulsion (see section 5.1).

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. Unless noted otherwise, these disorders have been identified by an increased incidence in the Phase III studies comparing Certican-treated patients with patients on a non-Certican, standard-therapy regimen, or the same incidence in case the event is a known ADR of the comparator MPA in renal and heart transplant studies (see section 5.1). 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).

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. This broad search also included cases caused by related events, e.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 at least 1 year, a total of 3.1% developed malignancies, with 1.0% developing skin malignancies and 0.60% developing lymphomas or lymphoproliferative disorders.

Cases of interstitial lung disease, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious aetiology, some fatal, have occurred in patients receiving rapamycin and derivatives, including Certican. Mostly, the condition resolves after discontinuation of Certican and/or addition of glucocorticoids. However, fatal cases have also occurred.

d) Adverse drug reactions from post-marketing spontaneous reports

The following adverse drug reactions have been derived from post-marketing experience with Certican via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Table 5 Adverse drug reactions from spontaneous reports and literature (frequency not known)

Body system

Incidence

Adverse reaction

Metabolism and nutrition disorders

Not known

Iron deficiency

Vascular disorders

Not known

Leukocytoclastic vasculitis, lymphoedema

Respiratory, thoracic and mediastinal disorders

Not known

Pulmonary alveolar proteinosis

Skin and subcutaneous tissue disorders

Not known

Erythroderma

Paediatric population

The safety information in children and adolescents is based on the data of 36-months in renal and 24-months in hepatic paediatric transplant patients (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In animal studies, everolimus showed low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2000 mg/kg (limit test) in either mice or rats.

Reported experience with overdose in humans is very limited; there is a single case of accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse events were observed. Single doses 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.