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CERTICAN 0.1 MG DISPERSIBLE TABLETS

Active substance(s): EVEROLIMUS

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Certican 0.1 mg dispersible tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each dispersible tablet contains 0.1 mg everolimus.
Excipient(s) with known effect:
Each dispersible tablet contains 1 mg lactose monohydrate and 72 mg anhydrous
lactose.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Dispersible tablet
Dispersible tablets are white to yellowish, marbled, round, flat with a bevelled edge.
0.1 mg (diameter of 7 mm): engraved with “I” on one side and “NVR” on the other.

4

CLINICAL PARTICULARS

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
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

Renal and
cardiac
transplantation
Hepatic
transplantation

Normal
hepatic
function

Mild hepatic
impairment
(Child-Pugh A)

Moderate
hepatic
impairment
(Child-Pugh B)

Severe hepatic
impairment
(Child-Pugh C)

0.75 mg b.i.d.

0.5 mg b.i.d.

0.5 mg b.i.d.

0.25 mg b.i.d.

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 troughconcentration windows
Target ciclosporin C0 (ng/ml)
Certican groups

Month 1
100-200

Months 2-3
75-150

Months 4-5
50-100

Months 6-12
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).
For further instructions see section 6.6.

4.3

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

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
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-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 posttransplant 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 dispersible tablets contain lactose. Patients with rare hereditary problems of
galactose intolerance, severe 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 Pglycoprotein 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)

Strong CYP3A4/PgP inhibitors
AUC ↑15.3-fold
Ketoconazole
(range 11.2-22.5)
Cmax ↑4.1-fold
(range 2.6-7.0)
Not studied. Large increase in
Itraconazole,
everolimus concentration is
posaconazole,
expected.
voriconazole
Telithromycin,
clarithromycin
Nefazodone
Ritonavir, atazanavir,
saquinavir, darunavir,
indinavir, nelfinavir
Moderate CYP3A4/PgP inhibitors
AUC ↑4.4-fold
Erythromycin
(range 2.0-12.6)
Cmax ↑2.0-fold
(range 0.9-3.5)
AUC ↑3.7-fold
Imatinib
Cmax ↑2.2-fold

Verapamil

Ciclosporin oral

Fluconazole
Diltiazem
nicardipine
Dronedarone
Amprenavir,
fosamprenavir

AUC ↑3.5-fold
(range 2.2-6.3)
Cmax ↑2.3-fold
(range1.3-3.8)
AUC ↑2.7-fold
(range 1.5-4.7)
Cmax ↑1.8-fold
(range 1.3-2.6)
Not studied. Increased exposure
expected.
Not studied. Increased exposure
expected.
Not studied. Increased exposure
expected.

Recommendations concerning coadministration

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

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

Use caution when coadministration of moderate
CYP3A4 inhibitors or PgP inhibitors
cannot be avoided.

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

Rifabutin

AUC ↓63%
(range 0-80%)
Cmax ↓58%
(range 10-70%)
Not studied. Decreased exposure
expected.

Carbamazepine

Not studied. Decreased exposure
expected.

Phenytoin

Not studied. Decreased exposure
expected.

Phenobarbital

Not studied. Decreased exposure
expected.

Efavirenz, nevirapine

Not studied. Decreased exposure
expected.

St John’s Wort
(Hypericum perforatum)

Not studied. Large decrease in
exposure expected.

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

Everolimus whole blood trough
concentrations should be
monitored whenever inducers of
CYP3A4 are concurrently
administered and after their
discontinuation.
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
No studies of the effects on the ability to drive and use machines have been
performed.

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 nonCertican, 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

Common

Malignant or unspecified tumours, malignant and
unspecified skin neoplasms

Uncommon

Lymphomas/post-transplant lymphoproliferative
disorders (PTDL)

Neoplasms benign,
malignant and
unspecified

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

Very common

Hypertension, venous thromboembolic events

Common

Lymphocoele4, epistaxis, renal graft thrombosis

Very common

Pleural effusion1, cough1, dyspnoea1

Uncommon

Interstitial lung disease5

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)

Vascular disorders

Respiratory, thoracic
and mediastinal
disorders

Gastrointestinal
disorders

General disorders and
administration site
conditions

Investigations

Uncommon

Ovarian cyst

Very common

Peripheral oedema, pain, healing impaired, pyrexia

Common

Incisional hernia

Common

Hepatic enzyme abnormal8

1

common in renal and liver transplantation
common in cardiac and liver transplantation
3
in cardiac transplantation
4
in 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.
6
predominantly in patients receiving concomitant ACE inhibitors
7
in renal transplantation
8
γ-GT, AST, ALT elevated
2

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

Vascular disorders

Not known

Leukocytoclastic vasculitis

Respiratory, thoracic and
mediastinal disorders

Not known

Pulmonary alveolar proteinosis

Skin and subcutaneous tissue
disorders

Not known

Erythroderma

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.

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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: selective immunosuppressive agents. ATC code: LO4AA18.
Mechanism of action
Everolimus, a proliferation signal inhibitor, prevents allograft rejection in rodent and nonhuman primate models of allotransplantation. It exerts its immunosuppressive effect by
inhibiting the proliferation, and thus clonal expansion, of antigen-activated T cells, which is
driven by T cell-specific interleukins, e.g. interleukin-2 and interleukin-15. Everolimus
inhibits an intracellular signalling pathway, which is triggered upon binding of these T cell
growth factors to their respective receptors, and which normally leads to cell proliferation.
The blockage of this signal by everolimus leads to an arrest of the cells at the G1 stage of the
cell cycle.
At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12.
In the presence of everolimus, the growth factor-stimulated phosphorylation of the p70 S6
kinase is inhibited. Since p70 S6 kinase phosphorylation is under the control of FRAP (also
called mTOR), this finding suggests that the everolimus-FKBP-12 complex binds to and thus

interferes with the function of FRAP. FRAP is a key regulatory protein that governs cell
metabolism, growth and proliferation; disabling FRAP function thus explains the cell cycle
arrest caused by everolimus.
Everolimus thus has a different mode of action to ciclosporin. In preclinical models of
allotransplantation, the combination of everolimus and ciclosporin was more effective than
either compound alone.
The effect of everolimus is not restricted to T cells. It inhibits growth factor-stimulated
proliferation of hematopoietic as well as non-hematopoietic cells in general, such as vascular
smooth muscle cells. Growth factor-stimulated vascular smooth muscle cell proliferation,
triggered by injury to endothelial cells and leading to neointima formation, plays a key role in
the pathogenesis of chronic rejection. Preclinical studies with everolimus have shown
inhibition of neointima formation in a rat aorta allotransplantation model.
Clinical efficacy and safety
Renal transplantation
Certican in fixed doses of 1.5 mg/day and 3 mg/day, in combination with standard doses of
ciclosporin for microemulsion and corticosteroids, was investigated in two Phase III de novo
adult renal transplant trials (B201 and B251). Mycophenolate mofetil (MMF) 1 g b.i.d was
used as comparator. The co-primary composite endpoints were efficacy failure (biopsyproven acute rejection, graft loss, death or loss to follow-up) at 6 months, and graft loss, death
or loss to follow-up at 12 months. Certican was, overall, non-inferior to MMF in these trials.
The incidence of biopsy-proven acute rejection at 6 months in the B201 study was 21.6%,
18.2%, and 23.5% for the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups,
respectively. In study B251, the incidences were 17.1%, 20.1%, and 23.5% for the Certican
1.5 mg/day, Certican 3 mg/day and MMF groups, respectively.
Reduced allograft function with elevated serum creatinine was observed more frequently
among subjects using Certican in combination with full-dose ciclosporin for microemulsion
than in MMF patients. This effect suggests that Certican increases ciclosporin nephrotoxicity.
Drug concentration-pharmacodynamic analysis showed that renal function was not impaired
with reduced exposure to ciclosporin, while conserving efficacy for as long as the blood
trough everolimus concentration was maintained above 3ng/ml. This concept was
subsequently confirmed in two further Phase III studies (A2306 and A2307, including 237
and 256 patients, respectively), which evaluated the efficacy and safety of Certican 1.5 mg
and 3 mg per day (initial dosing; subsequent dosing based on target trough concentration ≥3
ng/ml) in combination with reduced exposure to ciclosporin. In both studies, renal function
was preserved without compromising efficacy. In these studies, however, there was no nonCertican comparative arm. A Phase III, multicentre, randomised, open-label, controlled trial
(A2309) has been completed in which 833 de novo renal transplant recipients were
randomised to one of two Certican regimens, differing by dosage, and combined with
reduced-dose ciclosporin or a standard regimen of sodium mycophenolate (MPA) +
ciclosporin, and treated for 12 months. All patients received induction therapy with
basiliximab pre-transplant, and on Day 4 post-transplant. Steroids were given as required
post-transplant.
Starting dosages in the two Certican groups were 1.5 mg/d and 3 mg, given b.i.d.,
subsequently modified from Day 5 onwards to maintain target blood trough everolimus
concentrationsof 3-8 ng/ml and 6-12 ng/ml, respectively. Sodium mycophenolate dosage was
1.44 g/d. Ciclosporin dosages were adapted to maintain target blood trough concentration
windows as shown in Table 6. The actual measured values for blood concentrations of
everolimus and ciclosporin (C0 and C2) are shown in Table 7.

Although the higher-dosage Certican regimen was as effective as the lower-dosage regimen,
the overall safety was poorer, and so the higher-dosage regimen is not recommended.
The lower-dosage regimen for Certican is recommended (see section 4.2).
Table 6

Study A2309: Target ciclosporin blood trough-concentration windows

Target ciclosporin C0
(ng/ml)
Certican groups
MPA group
Table 7

Mo 1

Mo 2-3

Mo 4-5

Mo 6-12

100-200
200-300

75-150
100-250

50-100
100-250

25-50
100-250

Study A2309: Measured trough blood concentrations of ciclosporin and
everolimus

Trough
concentrations
(ng/ml)

Certican groups
(low-dose ciclosporin)

MPA
(standard
ciclosporin)
Myfortic 1.44 g
Co
C2
239 ±
934 ±
130
438
250 ±
992 ±
119
482
182 ± 65
821 ±
273
163 ±
751 ±
103
269
149 ± 69
648 ±
265
137 ± 55 587± 241

Certican 1.5 mg
Certican 3.0 mg
C2
Co
C2
Co
Ciclosporin
195 ±
847 ±
192 ±
718 ±
Day 7
106
412
104
319
173 ± 84
770 ±
177 ± 99
762 ±
Month 1
364
378
122 ± 53
580 ±
123 ± 75
548 ±
Month 3
322
272
88 ± 55
408 ±
80 ± 40
426 ±
Month 6
226
225
55± 24
319 ±
51 ± 30
296 ±
Month 9
172
183
55 ± 38
291 ±
49 ± 27
281 ±
Month 12
155
198
(Target Co 6-12)
(Target Co 3-8)
Everolimus
Day 7
4.5 ± 2.3
8.3 ± 4.8
Month 1
5.3 ± 2.2
8.6 ± 3.9
Month 3
6.0 ± 2.7
8.8 ± 3.6
Month 6
5.3 ± 1.9
8.0 ± 3.1
Month 9
5.3 ± 1.9
7.7 ± 2.6
Month 12
5.3 ± 2.3
7.9 ± 3.5
Numbers are mean ± SD of measured values with C0 = trough concentration, C2 = value 2
hours post-dose.
The primary efficacy endpoint was a composite failure variable (biopsy-proven acute
rejection, graft loss, death or loss to follow-up). The outcome is shown in Table 8.
Table 8

Study A2309: Composite and individual efficacy endpoints at 6 and
12 months (incidence in ITT population)

Composite endpoint (10
criterion)
Difference % (Certican - MPA)
95% CI

Certican 1.5 mg
Certican 3.0 mg
MPA 1.44 g
N=277
N=279
N=277
% (n)
% (n)
% (n)
6 mo
12 mo
6 mo
12 mo
6 mo
12 mo
19.1 (53) 25.3 (70) 16.8 (47) 21.5 (60) 18.8 (52) 24.2 (67)
0.4%
(-6.2,
6.9)

1.1%
(-6.1,
8.3)

-1.9%
(-8.3,
4.4)

-2.7%
(-9.7, 4.3)

-

-

Individual endpoints (20 criteria)
Treated BPAR
10.8 (30) 16.2 (45) 10.0 (28) 13.3 (37) 13.7 (38) 17.0 (47)
Graft loss
4.0 (11) 4.3 (12) 3.9 (11) 4.7 (13)
2.9 (8)
3.2 (9)
Death
2.2 (6)
2.5 (7)
1.8 (5)
3.2 (9)
1.1 (3)
2.2 (6)
Loss to follow-up
3.6 (10) 4.3 (12)
2.5 (7)
2.5 (7)
1.8 (5)
3.2 (9)
Combined endpoints (20 criteria)
Graft loss / Death
5.8 (16) 6.5 (18) 5.7 (16) 7.5 (21) 4.0 (11) 5.4 (15)
Graft loss / Death / Loss to FU 9.4 (26) 10.8 (30) 8.2 (23) 10.0 (28) 5.8 (16) 8.7 (24)
mo = months, 10 = primary, 20 = secondary, CI = confidence interval, non-inferiority margin was 10%
Composite endpoint: treated biopsy-proven acute rejection (BPAR), graft loss, death, or loss to
follow-up (FU)
Changes in renal function, as shown by calculated glomerular filtration rate (GFR) using the
MDRD formula, are shown in Table 9.
Proteinuria was assessed at scheduled visits by spot analysis of urinary protein/creatinine (see
Table 10). A concentration effect was shown relating proteinuria levels to everolimus trough
concentrations, particularly at Cmin values above 8 ng/ml.
Adverse events reported more frequently in the recommended (lower-dosage) Certican
regimen than in the MPA control group have been included in Table 4. A lower frequency of
viral infections was reported for Certican-treated patients, resulting principally from lower
reporting rates for CMV infection (0.7% vs. 5.95%) and BK virus infection (1.5% vs. 4.8%).
Table 9

Study A2309: Renal function (MDRD-calculated GFR) at 12 months (ITT
population)
Certican 1.5 mg
N=277
54.6
2.37
(-1.7, 6.4)

Certican 3.0 mg
N=279
51.3
-0.89
(-5.0, 3.2)

MPA 1.44 g
N=277
52.2
-

12-month mean GFR (ml/min/1.73 m2)
Difference in mean (everolimus MPA)
95% CI
12-month GFR missing value imputation: graft loss = 0; death or loss to follow-up for renal
function = LOCF1 (last-observation-carried-forward approach 1: End of Treatment (up to Month
12)).
MDRD: modification of diet in renal disease
Table 10

Study A2309: Urinary protein to creatinine ratio

Category of proteinuria (mg/mmol)
subnephrotic%(n)
normal%(n) mild%(n)
(<3.39)
(3.39-<33.9) (33.9-<339)
0.4 (1)
64.2 (174)
32.5 (88)
0.7 (2)
59.2 (164)
33.9 (94)
1.8 (5)
73.1 (198)
20.7 (56)

Treatment
Certican 1.5 mg
Month 12
(TED)
Certican 3 mg
MPA 1.44 g
1 mg/mmol = 8.84 mg/g
TED: Treatment endpoint (Mo 12 value or last observation carried forward)

nephrotic%(n)
(>339)
3.0 (8)
5.8 (16)
4.1 (11)

Cardiac transplantation
In the Phase III cardiac study (B253), both Certican 1.5 mg/day and 3 mg/day, in combination
with standard doses of ciclosporin for microemulsion and corticosteroids, was investigated vs.
azathioprine (AZA) 1-3 mg/kg/day. The primary endpoint was a composite of the incidence
of acute rejection ≥ISHLT grade 3A, acute rejection associated with haemodynamic
compromise, graft loss, patient death or loss to follow-up at 6, 12 and 24 months. Both doses
of Certican were superior to AZA at 6, 12 and 24 months. The incidence of biopsy-proven
acute rejection ≥ISHLT grade 3A at month 6 was 27.8% for the 1.5 mg/day group, 19% for
the 3 mg/day group and 41.6% for the AZA group, respectively (p = 0.003 for 1.5 mg vs.
control, <0.001 for 3 mg vs. control).
Based on coronary artery intravascular ultrasound data obtained from a subset of the study
population, both Certican doses were statistically significantly more effective than AZA in
preventing allograft vasculopathy (defined as an increase in maximum intimal thickness from
baseline ≥ 0.5mm in at least one matched slice of an automated pullback sequence), an
important risk factor for long-term graft loss.
Elevated serum creatinine was observed more frequently among subjects using Certican in
combination with full-dose ciclosporin for microemulsion than in AZA patients. These results
indicated that Certican increases ciclosporin-induced nephrotoxicity.
Study A2411 was a randomised, 12-month, open-label study comparing Certican in
combination with reduced doses of ciclosporin microemulsion and corticosteroids to
mycophenolic mofetil (MMF) and standard doses of ciclosporin microemulsion and
corticosteroids in de novo cardiac transplant patients. Certican was initiated at 1.5 mg/day and
the dose was adjusted to maintain target blood everolimus trough concentrations of 3-8 ng/ml.
MMF dosage was initiated at 1500 mg b.i.d. Ciclosporin microemulsion doses were adjusted
to the following target trough concentrations (ng/ml):
Table 11

Target ciclosporin trough concentrations by month

Target ciclosporin
C0
Certican group
MMF group

Mo 1

Mo 2

200-350
200-350

150-250
200-350

Mo 3-4
100-200
200-300

Mo 5-6
75-150
150-250

Mo 7-12
50-100
100-250

Actual blood concentrations measured are shown in Table 12.
Table 12

Visit

Study A2411: Summary statistics for CsA blood concentrations* (mean ±
SD)
Certican group
(N=91)
C0

MMF group
(N=83)
C0

154 ± 71
n=79
245 ± 99
Mo 1
n=76
199 ± 96
Mo 3
n=70
157
± 61
Mo 6
n=73
133 ± 67
Mo 9
n=72
110 ± 50
Mo 12
n=68
*:whole blood trough concentrations (C0)

155 ± 96
n=74
308 ± 96
n=71
256 ± 73
n=70
219 ± 83
n=67
187 ± 58
n=64
180 ± 55
n=64

Day 4

Changes in renal function are shown in Table 13. Efficacy outcome is shown in Table 14.
Table 13
Study A2411: Changes in creatinine clearance during study (patients
with paired values)
Estimated creatinine clearance (Cockcroft-Gault)*
ml/mn
Value at
Difference
Baseline
timepoint
between groups
Mean (± SD)
Mean (± SD)
Mean (95% CI)
-7.3
Certican (n=87)
73.8 (± 27.8)
68.5 (± 31.5)
Month 1
(-18.1, 3.4)
MMF (n=78)
77.4 (± 32.6)
79.4 (± 36.0)
-5.0
Certican (n=83)
74.4 (± 28.2)
65.4 (± 24.7)
Month 6
(-13.6, 2.9)
MMF (n=72)
76.0 (± 31.8)
72.4 (± 26.4)
Certican (n=71)
74.8 (± 28.3)
68.7 (± 27.7)
-1.8
Month 12
(-11.2, 7.5)
MMF (n=71)
76.2 (± 32.1)
71.9 (± 30.0)
* includes patients with value at both baseline and visit
Table 14

Study A2411: Efficacy event rates (incidence in ITT population)

Efficacy endpoint

Certican
n=92

MMF
n=84

Difference in event rates
Mean (95% CI)

At 6 months
Biopsy-proven acute
rejection ≥ ISHLT
18 (19.6%)
23 (27.4%)
-7.8 (-20.3, 4.7)
grade 3A
Composite efficacy
26 (28.3%)
31 (36.9%)
-8.6 (-22.5, 5.2)
failure *
At 12 months
Biopsy-proven acute
rejection ≥ ISHLT
21 (22.8%)
25 (29.8%)
-6.9 (-19.9, 6.1)
grade 3A
Composite efficacy
30 (32.6%)
35 (41.7%)
-9.1 (-23.3, 5.2)
failure*
Death or graft
10 (10.9%)
10 (11.9%)
loss/re-transplant
* Composite efficacy failure: any of the following – acute rejection ≥ grade 3A, acute
rejection with haemodynamic compromise, graft loss, death or loss to follow-up.

Study A2310 is a Phase III, multicentre, randomised, open-label study comparing two
Certican/reduced-dose ciclosporin regimens against a standard mycophenolate mofetil
(MMF)/ciclosporin regimen over 24 months. The use of induction therapy was centre-specific
(no-induction or basiliximab or thymoglobulin). All patients received corticosteroids.
Starting doses in the Certican groups were 1.5 mg/d and 3 mg/d, and were adjusted to target
blood trough everolimus concentrations of 3-8 ng/ml and 6-12 ng/ml, respectively. The MMF
dose was 3 g/d. Ciclosporin dosages targeted the same blood trough concentrations as in study
A2411. Blood concentrations of everolimus and ciclosporin are shown in Table 15.
Recruitment to the experimental, higher-dosage Certican treatment arm was prematurely
discontinued because of an increased rate of fatalities, due to infection and cardiovascular
disorders, occurring within the first 90 days post-randomisation.
Table 15

Study A2310: Measured trough blood concentrations of ciclosporin (CsA)
and everolimus

Certican 1.5mg/reduced-dose CsA
MMF 3g/std-dose CsA
N=279
N=268
everolimus
(C0 ciclosporin (C0 ng/ml)
ng/ml)
Day 4
5.7 (4.6)
153 (103)
151 (101)
Month 1
5.2 (2.4)
247 (91)
269 (99)
Month 3
5.4 (2.6)
209 (86)
245 (90)
Month 6
5.7 (2.3)
151 (76)
202 (72)
Month 9
5.5 (2.2)
117 (77)
176 (64)
Month 12
5.4 (2.0)
102 (48)
167 (66)
Numbers are the mean (standard deviation) of measured values of C0=trough concentration
Visit window

Efficacy outcome at 12 months is shown in Table 16.
Table 16

Study A2310: Incidence rates of efficacy endpoints by treatment group (ITT
population – 12-month analysis)

Certican 1.5mg
MMF
N=279
N=271
Efficacy endpoints
n (%)
n (%)
Primary: Composite efficacy failure
99 (35.1)
91 (33.6)
- AR associated with HDC
11 (3.9)
7 (2.6)
63
(22.3)
67
(24.7)
- BPAR of ISHLT grade ≥ 3A
- Death
22 (7.8)
13 (4.8)
- Graft loss/re-transplant
4 (1.4)
5 (1.8)
- Loss to follow-up
9 (3.2)
10 (3.7)
Composite efficacy failure: biopsy-proven acute rejection (BPAR) episodes of ISHLT grade ≥
3A, acute rejection (AR) associated with haemodynamic compromise (HDC), graft loss/retransplant, death, or loss to follow-up.
The higher fatality rate in the Certican arm relative to the MMF arm was mainly the result of
an increased rate of fatalities from infection in the first three months among Certican patients
receiving thymoglobulin induction therapy. The imbalance in fatalities within the
thymoglobulin subgroup was particularly evident among patients hospitalised prior to
transplantation and with L-ventricular assistance devices (see section 4.4).

Renal function over the course of study A2310, assessed by calculated glomerular filtration
rate (GFR) using the MDRD formula, was 5.5 ml/min/1.73m2 (97.5% CI -10.9, -0.2) lower
for the everolimus 1.5 mg group at Month 12.
This difference was mainly observed in centres where the mean ciclosporin concentrations
were similar throughout the study period in patients receiving Certican and in patients
randomised to the control arm. This finding underlines the importance of reducing the
ciclosporinconcentrationswhen combined with everolimus as indicated in Table 17 (see also
section 4.2):
Table 17

Target ciclosporin trough concentrations per month

Target ciclosporin C0
Certican group
MMF group

Mo 1
200-350
200-350

Mo 2
150-250
200-350

Mo 3-4
100-200
200-300

Mo 5-6
75-150
150-250

Mo 7-12
50-100
100-250

Additionally, the difference was mainly driven by a difference developed during the first
month post-transplantation when patients are still in an unstable haemodynamic situation,
possibly confounding the analysis of renal function. Thereafter, the decrease in mean GFR
from Month 1 to Month 12 was significantly smaller in the everolimus group than in the
control group (-6.4 vs. -13.7 ml/min, p=0.002).
Proteinuria, expressed as urinary protein: creatinine levels measured in spot urine samples,
tended to be higher in the Certican-treated patients. Sub-nephrotic values were observed in
22% of the patients receiving Certican compared to MMF patients (8.6%). Nephrotic levels
were also reported (0.8%), representing 2 patients in each treatment group (see section 4.4).
The adverse reactions for the everolimus 1.5 mg group in Study A2310 are consistent with the
adverse drug reactions presented in Table 4. A lower rate of viral infections was reported for
Certican-treated patients, resulting principally from a lower reporting rate for CMV infection
compared to MMF (7.2% vs. 19.4%).
Hepatic transplantation
In the Phase III adult hepatic transplant study (H2304), reduced exposure tacrolimus and
Certican 1.0 mg twice daily was administered to patients, with the initial Certican dose
4 weeks after transplantation, and was investigated versus standard exposure tacrolimus.
Certican was dose adjusted to maintain target blood everolimus trough concentrations
between 3-8 ng/ml for the Certican + reduced tacrolimus arm. Tacrolimus doses were
subsequently adjusted to achieve target trough concentrations between 3-5 ng/ml during
12 months in the Certican + reduced tacrolimus arm.
Only 2.6% of study participants in H2304 were black so this study provides only limited
efficacy and safety data on this population (see section 4.2)
Overall, in the 12-month analysis, the incidence of the composite endpoint (tBPAR, graft loss
or death) was lower in the Certican + reduced tacrolimus arm (6.7%) compared to the
tacrolimus control arm (9.7%) and consistent results were observed at 24 months (see
Table 18).
The results of individual components of the composite endpoint are shown in Table 19.

Table 18

Study H2304: Comparison between treatment groups for Kaplan-Meier
incidence rates of primary efficacy endpoints (ITT population - 12 and 24month analysis)

Statistic

EVR+Reduced TAC
N=245
12-month
24-month

Number of composite efficacy failures
(tBPAR, graft loss or death) from
randomisation till Month 24/12
KM estimate of incidence rate of
composite efficacy failure (tBPAR*, graft
loss or death) at Month 24/12
Difference in KM estimates (vs. control)
97.5% CI for difference
P-value Z-test (EVR+Reduced TAC Control = 0)
(No difference test)
P-value* Z-test (EVR+Reduced TAC Control ≥0.12)
(Non-inferiority test)

16

24

6.7%

10.3%

-3.0%
(-8.7%,
2.6%)
0.230

2.2%
(-8.8%,
4.4%)
0.452

<0.001

<0.001

TAC control
N=243
1224-month
month
23
29

9.7%

12.5%

*tBPAR = treated biopsy-proven acute rejection
Table 19

Efficacy
endpoints

Graft loss
12-month
24-month
Death
12-month
24-month
BPAR1
12-month
24-month
tBPAR2
12-month
24-month

Study H2304: Comparison between treatment groups for incidence rates of
secondary efficacy endpoints (ITT population – 12 and 24-month analysis)
EVR/Reduced
TAC
N=245
n (%)

TAC
control
N=243
n (%)

Risk diff. (95%
CI)

P-value*

6 (2.4)
9 (3.9)

3 (1.2)
7 (3.2)

1.2 (-7.8, 10.2)
0.8% (-3.2, 4.7)

0.5038
0.661

9 (3.7)
12 (5.2)

6 (2.5)
10 (4.4)

1.2 (-7.8, 10.1)
0.8% (-3.7, 5.2)

0.6015
0.701

10 (4.1)
14 (6.1)

26 (10.7)
30 (13.3)

-6.6 (-11.2, -2.0)
-7.2% (-13.5, -0.9)

0.0052
0.010

7 (2.9)
11 (4.8)

17 (7.0)
18 (7.7)

-4.1 (-8.0, -0.3)
-2.9% (-7.9, 2.2)

0.0345
0.203

1. BPAR = biopsy-proven acute rejection; 2. tBPAR = treated biopsy-proven acute rejection
*All p-values are for two-sided test and were compared to 0.05 significance level.
Comparison between treatment groups for change in eGFR (MDRD4) [ml/min/1.73 m2] from
time of randomisation (day 30) to Month 12 and 24 demonstrated superior renal function for
the Certican + reduced tacrolimus arm (see Table 20).
Table 20

Study H2304: Comparison between treatment groups for eGFR (MDRD 4)

at Month 12 (ITT population – 12 and 24-month analysis)
Difference vs. control
Treatment
EVR+Reduced
TAC
12-month

N

LS mean
(SE)

LSM mean
(SE)

244

-2.23 (1.54)

8.50 (2.12)

97.5% CI

(3.74,
13.27)
(1.9, 11.42)

Pvalue(1)

P-value(2)

<0.001

<0.001

24-month
245
-7.94 (1.53) 6.66 (2.12)
<0.0001
0.0018
TAC control
12-month
243
-10.73 (1.54)
24-month
243
-14.60 (1.54)
Least squares means, 97.5% confidence intervals and p-values are from an ANCOVA model
containing treatment and HCV status as factors, and baseline eGFR as a covariate.
P-value (1): Non-inferiority test with NI margin = -6 ml/min/1.73m2, at one-sided 0.0125
level.
P-value (2): Superiority test at two-sided 0.025 levels.
Paediatric population
There is insufficient data in children and adolescents to recommend the use of Certican in
renal transplantation (see section 4.2). In hepatic transplant paediatric patients, Certican
should not be used (see section 4.2).
Renal transplantation
In paediatric renal allograft recipients (1-18 years of age; n=30), Certican was assessed in a
12-month, multi-center, randomized, open-label trial with two parallel groups (1:1) evaluating
the use of Certican in combination with reduced tacrolimus and corticosteroid withdrawal at 6
months post transplantation in comparison to mycophenolate mofetil with standard
tacrolimus. The efficacy for Certican with reduced tacrolimus and steroid withdrawal was
comparable to mycophenolate mofetil with standard tacrolimus 13.3% (2/15) vs 6.7% (1/15)
for the primary efficacy composite failure endpoint of biopsy proven acute rejection, graft
loss and death. There were no deaths or graft losses. Extrapolation from Certican adult kidney
transplant data to Certican paediatric study data and literature showed that the primary
efficacy composite endpoint was lower than that observed in adults. Renal function calculated
by estimated glomerular filtration rate (eGFR) was numerically better with Certican compared
to mycophenolate mofetil with standard tacrolimus. The mean difference in eGFR from
randomization to 12-months between groups was 7.2 mL/min/1.73m2.
Altogether 6/15 patients in the Certican group vs. 1/15 in the control group were withdrawn
from study therapy. Reasons for study drug discontinuation were in the Certican group: 1
aphthous stomatitis, 1 PTLD, 1 increased blood triglycerides, 1 rejection, 1 withdrawal of
consent, 1 administrative reason; in the control group:1 increased creatinine/tacrolimus
toxicity. This affects the possibility to evaluate efficacy in terms of long-term renal function.
Two patients in the Certican group vs. one in the control had a biopsy proven rejection.
Hepatic transplantation
In paediatric hepatic transplant recipients (month 1-18 years of age; n=25) receiving either a
full-size liver allograft or a technically modified liver allograft from a deceased or living
donor, Certican with reduced tacrolimus or ciclosporin was evaluated in a 12-month, multicenter, single arm study. Based on this study with extrapolation to adult study data, the
efficacy of Certican with reduced tacrolimus or ciclosporin is comparable to that observed in
adults for the primary efficacy composite endpoint of treated biopsy-proven acute rejection,

graft loss and death (0% vs. 6.7%). The gain in estimated glomerular filtration rate (eGFR)
from randomization to 12-months was higher in Certican paediatric patients (9.1
mL/min/1.73m2) to that observed in adults treated with Certican (8.50 mL/min/1.73m2 vs.
control (see Table 20)).
In paediatric hepatic transplant recipients, there was no negative impact in growth or sexual
maturation observed, however, compared to adults and published literature, there were higher
rates of serious infections, and GI disorders (particularly gastroenteritis, vomiting, diarrhoea,
and stomatitis). Incidence rates for post-transplant lymphoproliferative disorder in the group
of children under 7 years of age, and notably in EBV negative children under 2 years of age,
were higher compared to adults and published literature. Based on the safety data the
benefit/risk profile does not support recommendations for use.

5.2

Pharmacokinetic properties

Absorption
After oral administration, peak everolimus concentrations occur 1 to 2 hours post-dose.
Everolimus blood concentrations are dose proportional over the dose range of 0.25 to 15 mg
in transplant patients. The relative bioavailability of the dispersible tablet compared with the
tablet is 0.90 (90% CI 0.76-1.07) based on the AUC ratio.
Food effect
Everolimus Cmax and AUC are reduced by 60% and 16% when the tablet formulation is given
with a high-fat meal. To minimise variability, Certican should be taken consistently with or
without food.
Distribution
The blood-to-plasma ratio of everolimus is concentration-dependent, ranging from 17% to
73% over the range of 5 to 5,000 ng/ml. Plasma protein binding is approximately 74% in
healthy subjects and patients with moderate hepatic impairment. The distribution volume
associated with the terminal phase (Vz/F) in maintenance renal transplant patients is
342 ± 107 litres.
Biotransformation
Everolimus is a substrate of CYP3A4 and P-glycoprotein. Following oral administration, it is
the main circulating component in human blood. Six main metabolites of everolimus have
been detected in human blood, including three monohydroxylated metabolites, two hydrolytic
ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites
were also identified in animal species used in toxicity studies, and showed approximately 100
times less activity than everolimus itself. Hence, the parent substance is considered to
contribute the majority of the overall pharmacological activity of everolimus.
Elimination
After a single dose of radiolabelled everolimus to transplant patients receiving ciclosporin, the
majority (80%) of radioactivity was recovered from the faeces, and only a minor amount (5%)
was excreted in urine. Parent drug was not detected in urine and faeces.
Steady-state pharmacokinetics
Pharmacokinetics were comparable for kidney and heart transplant patients receiving
everolimus twice daily simultaneously with ciclosporin for microemulsion. Steady-state is
reached by day 4 with an accumulation in blood concentrations of 2 to 3-fold compared with
exposure after the first dose. Tmax occurs at 1 to 2 hours post-dose. Cmax averages 11.1 ± 4.6
and 20.3 ± 8.0 ng/ml and AUC averages 75 ± 31 and 131 ± 59 ng.h/ml at 0.75 and 1.5 mg
b.i.d., respectively. Pre-dose trough blood concentrations (Cmin) average 4.1 ± 2.1 and

7.1 ± 4.6 ng/ml at 0.75 and 1.5 mg b.i.d., respectively. Everolimus exposure remains stable
over time in the first post-transplant year. Cmin is significantly correlated with AUC, yielding a
correlation coefficient between 0.86 and 0.94. Based on a population pharmacokinetic
analysis, oral clearance (CL/F) is 8.8 litres/hour (27% interpatient variation) and the central
distribution volume (Vc/F) is 110 litres (36% interpatient variation). Residual variability in
blood concentrations is 31%. The elimination half-life is 28 ± 7 hours.
Special populations
Hepatic impairment
Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC
in 6 patients with mild hepatic impairment (Child-Pugh Class A) was 1.6-fold higher; in two
independently studied groups of 8 and 9 patients with moderate hepatic impairment (ChildPugh Class B), the average AUC was 2.1-fold and 3.3-fold higher, respectively; and in 6
patients with severe hepatic impairment (Child-Pugh Class C), the average AUC was 3.6-fold
higher. Mean half-lives were 52, 59 and 78 hours in mild, moderate and severe hepatic
impairment. The prolonged half-lives delay the time to reach steady-state everolimus blood
concentrations.
Renal impairment
Post-transplant renal impairment (CCr range 11-107 ml/min) did not affect the
pharmacokinetics of everolimus.
Paediatric population
Fourteen paediatric de novo renal transplant patients (2 to 16 years) received Certican
dispersible tablets at a starting dose of 0.8 mg/m2 (maximum 1.5 mg) twice daily with
ciclosporin for microemulsion. Their doses were subsequently individualised based on
therapeutic drug monitoring to maintain everolimus pre-dose trough concentrations ≥3 ng/ml.
At steady state, the everolimus trough level was 6.2 ± 2.4 ng/ml, Cmax was 18.2 ± 5.5 ng/ml,
and AUC was 118 ± 28 ng.h/ml, which are comparable to adults receiving Certican targeted
to similar pre-dose trough concentrations. The steady-state CL/F was 7.1 ± 1.7 l/h/m2 and the
elimination half-life was 30 ± 11 h in paediatric patients.
Elderly patients
A limited reduction in everolimus oral clearance by 0.33% per year was estimated in adults
(age range studied was 16-70 years). No dose adjustment is considered necessary.
Ethnicity
Based on a population pharmacokinetic analysis, oral clearance (CL/F) is, on average, 20%
higher in black transplant patients. See section 4.2.
Exposure-response relationships
The average everolimus trough concentration over the first 6 months post-transplant was
related to the incidence of biopsy-confirmed acute rejection and of thrombocytopenia in renal
and cardiac transplant patients (see Table 21). In hepatic transplant patients, the relationship
between average everolimus trough concentrations and the incidence of biopsy-proven acute
rejection is less well defined. No correlation between higher everolimus exposure and adverse
events such as thrombocytopenia has been observed (see Table 21).
Table 21

Exposure-response relationships for everolimus in transplant patients

Trough concentration (ng/ml)
Freedom from rejection
Thrombocytopenia

Renal transplantation:
≤ 3.4 3.5 - 4.5
4.6 - 5.7
68%
81%
86%
10%
9%
7%

5.8 – 7.7
81%
14%

7.8 - 15.0
91%
17%

(<100 x 109/l)
Trough concentration (ng/ml)
Freedom from rejection
Thrombocytopenia
(<75 x 109/l)
Trough concentration (ng/ml)
Freedom from treated BPAR
Thrombocytopenia
(≤75×109/l)

5.3

Cardiac transplantation:
≤ 3.5 3.6 - 5.3
5.4 - 7.3
65%
69%
80%
5%
5%
6%
Hepatic transplantation:
≤3
3-8
88%
98%
35%
13%

7.4 – 10.2
85%
8%

10.3 - 21.8
85%
9%

≥8
92%
18%

Preclinical safety data

The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and
rabbits. The major target organs were male and female reproductive systems (testicular
tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several
species, and, in rats only, lungs (increased alveolar macrophages) and eyes (lenticular anterior
suture line opacities). Minor kidney changes were seen in the rat (exacerbation of age-related
lipofuscin in tubular epithelium) and the mouse (exacerbation of background lesions). There
was no indication of kidney toxicity in monkeys or minipigs.
Spontaneously occurring background diseases (chronic myocarditis in the rat, Coxsackie virus
infection in plasma and heart in monkeys, coccidial infestation of GI tract in minipigs, skin
lesions in mice and monkeys) appeared to be exacerbated by treatment with everolimus.
These findings were generally observed at systemic exposure concentrations within the range
of therapeutic exposure or above, with the exception of findings in rats, which occurred below
therapeutic exposure due to high tissue distribution.
Ciclosporin in combination with everolimus caused higher systemic exposure to everolimus and
increased toxicity. There were no new target organs in the rat. Monkeys showed haemorrhage
and arteritis in several organs.
In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above,
and sperm motility, sperm count and plasma testosterone levels were diminished at 5 mg/kg,
which is within the range of therapeutic exposure and caused a decrease in male fertility.
There was evidence of reversibility. Female fertility was not affected, but everolimus crossed
the placenta and was toxic to the conceptus. In rats, everolimus caused embryo/foetotoxicity
at systemic exposure below the therapeutic exposure, which was manifested as mortality and
reduced foetal weight. The incidence of skeletal variations and malformations at 0.3 and
0.9 mg/kg (e.g. sternal cleft) was increased. In rabbits, embryotoxicity was evident by an
increase in late resorptions.
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of
clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not
indicate any oncogenic potential in mice and rats up to the highest doses, corresponding
respectively to 8.6 and 0.3 times the estimated clinical exposure.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Butylated hydroxytoluene (E321)
Magnesium stearate (E470 B)
Lactose monohydrate
Hypromellose Type 2910
Crospovidone Type A
Lactose anhydrous
Colloidal anhydrous silica

6.2

Incompatibilities
When ciclosporin for microemulsion is administered via a nasogastric tube, it
should be administered before Certican. The two medicinal products should
not be mixed.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Store in the original package in order to protect from light and moisture.

6.5

Nature and contents of container
Aluminium/polyamide/aluminium/PVC blister.
Packs containing 50/60/100/250 dispersible tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Dispersible tablet
Administration with a 10 ml oral syringe. Place the Certican dispersible tablets into a
syringe. The maximum amount of Certican that can be dispersed in a 10 ml syringe is
1.25 mg. Add water to the 5 ml mark. Wait 90 seconds, while shaking gently. After
dispersion, administer directly into the mouth. Rinse the syringe with 5 ml water and
administer into the mouth. Drink an additional 10 to 100 ml of water, or diluted
syrup.

Administration with a plastic cup. Place the Certican dispersible tablets in
approximately 25 ml of water in a plastic cup. The maximum amount of Certican that
can be dispersed in 25 ml of water is 1.5 mg. The cup is left for approx. 2 minutes to
allow the tablets to disintegrate, and is swirled gently before drinking. Immediately
rinse the cup with an additional 25 ml of water and drink completely.
Administration via nasogastric tube. Place the Certican dispersible tablets in a small
plastic medicine beaker that contains 10 ml water. Wait 90 seconds, while swirling
gently. Put the dispersion into a syringe and inject slowly (within 40 seconds) into the
nasogastric tube. Rinse the beaker (and the syringe) 3 times with 5 ml water and
inject into the tube. Finally, flush the tube with 10 ml water. The nasogastric tube
should be clamped for a minimum of 30 minutes after Certican administration.

7

MARKETING AUTHORISATION HOLDER
Novartis Pharmaceuticals UK Limited
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR

8

MARKETING AUTHORISATION NUMBER(S)
PL 00101/0965

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION

Date of first authorisation: 25 November 2014
Date of latest renewal: 02 September 2016

10

DATE OF REVISION OF THE TEXT
25/07/2016

+ Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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