Everolimus medac 5 mg Tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Produktens egenskaper Produktens egenskaper (SPC)

29-03-2019

Aktiva substanser:
everolimus
Tillgänglig från:
medac pharma s.r.l
ATC-kod:
L01EG02
INN (International namn):
everolimus
Dos:
5 mg
Läkemedelsform:
Tablett
Sammansättning:
butylhydroxitoluen Hjälpämne; everolimus 5 mg Aktiv substans; laktosmonohydrat Hjälpämne; laktos (vattenfri) Hjälpämne
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
57721
Tillstånd datum:
2019-03-29

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01-03-2019

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02-04-2019

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Everolimus medac 5 mg tablets

Everolimus medac 10 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Everolimus medac 5 mg tablets

Each tablet contains 5 mg everolimus.

Excipient with known effect:

Each tablet contains 149 mg lactose.

Everolimus medac 10 mg tablets

Each tablet contains 10 mg everolimus.

Excipient with known effect:

Each tablet contains 297 mg lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

Everolimus medac 5 mg tablets

White, oblong, flat, bevelled edge tablets, marked with “EV” on one side and “5” on the other.

Everolimus medac 10 mg tablets

White, oblong, flat, bevelled edge tablets, marked with “EV” on one side and “10” on the other.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Hormone receptor-positive advanced breast cancer

Everolimus medac is indicated for the treatment of hormone receptor-positive, HER2/neu negative

advanced

breast

cancer,

combination

with

exemestane,

postmenopausal

women

without

symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase

inhibitor.

Neuroendocrine tumours of pancreatic origin

Everolimus medac is indicated for the treatment of unresectable or metastatic, well- or moderately-

differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease.

Neuroendocrine tumours of gastrointestinal or lung origin

Everolimus medac is indicated for the treatment of unresectable or metastatic, well-differentiated

(Grade 1 or Grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin in adults

with progressive disease (see sections 4.4 and 5.1).

Renal cell carcinoma

Everolimus medac is indicated for the treatment of patients with advanced renal cell carcinoma, whose

disease has progressed on or after treatment with VEGF-targeted therapy.

4.2 Posology and method of administration

Treatment with Everolimus medac should be initiated and supervised by a physician experienced in the

use of anticancer therapies.

Posology

For the different dose regimens Everolimus medac is available as 5 mg and 10 mg tablets.

For doses 2,5 mg and 7,5 mg another everolimus containing product must be used to achieve these

doses.

The recommended dose is 10 mg everolimus once daily. Treatment should continue as long as clinical

benefit is observed or until unacceptable toxicity occurs.

If a dose is missed, the patient should not take an additional dose, but take the next prescribed dose as

usual.

Dose adjustment due to adverse reactions

Management of severe and/or intolerable suspected adverse reactions may require dose reduction

and/or temporary interruption of Everolimus medac therapy. For adverse reactions of Grade 1, dose

adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily

and must not be lower than 5 mg daily.

Table 1 summarises the dose adjustment recommendations for specific adverse reactions (see also

section 4.4).

Table 1 Everolimus medac dose adjustment recommendations

Adverse reaction

Severity

1

Everolimus medac dose adjustment

Grade 2

Consider interruption of therapy until symptoms improve

to Grade ≤1.

Re-initiate treatment at 5 mg daily.

Discontinue treatment if failure to recover within 4 weeks.

Grade 3

Interrupt treatment until symptoms resolve to Grade ≤1.

Consider re-initiating treatment at 5 mg daily. If toxicity

recurs at Grade 3, consider discontinuation.

Non-infectious

pneumonitis

Grade 4

Discontinue treatment.

Grade 2

Temporary dose interruption until recovery to Grade ≤1.

Re-initiate treatment at same dose.

If stomatitis recurs at Grade 2, interrupt dose until

recovery to Grade ≤1. Re-initiate treatment at 5 mg daily.

Grade 3

Temporary dose interruption until recovery to Grade ≤1.

Re-initiate treatment at 5 mg daily.

Stomatitis

Grade 4

Discontinue treatment.

Grade 2

If toxicity is tolerable, no dose adjustment required.

If toxicity becomes intolerable, temporary dose

interruption until recovery to Grade ≤1. Re-initiate

treatment at same dose.

If toxicity recurs at Grade 2, interrupt treatment until

recovery to Grade ≤1. Re-initiate treatment at 5 mg daily.

Grade 3

Temporary dose interruption until recovery to Grade ≤1.

Consider re-initiating treatment at 5 mg daily. If toxicity

recurs at Grade 3, consider discontinuation.

Other non-

haematological toxicities

(excluding metabolic

events)

Grade 4

Discontinue treatment.

Grade 2

No dose adjustment required.

Grade 3

Temporary dose interruption.

Re-initiate treatment at 5 mg daily.

Metabolic events

(e.g. hyperglycaemia,

dyslipidaemia)

Grade 4

Discontinue treatment.

Grade 2 (<75,

≥50x10

Temporary dose interruption until recovery to Grade ≤1

(≥75x10

/l). Re-initiate treatment at same dose.

Thrombocytopenia

Grade 3 & 4

(<50x10

Temporary dose interruption until recovery to Grade ≤1

(≥75x10

/l). Re-initiate treatment at 5 mg daily.

Grade 2

(≥1x10

No dose adjustment required.

Grade 3 (<1,

≥0.5x10

Temporary dose interruption until recovery to Grade ≤ 2

(≥1x10

/l). Re-initiate treatment at same dose.

Neutropenia

Grade 4

(<0.5x10

Temporary dose interruption until recovery to Grade ≤ 2

(≥1x10

/l). Re-initiate treatment at 5 mg daily.

Grade 3

Temporary dose interruption until recovery to Grade ≤2

(≥1.25x10

/l) and no fever.

Re-initiate treatment at 5 mg daily.

Febrile neutropenia

Grade 4

Discontinue treatment.

Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events

(CTCAE) v3.0

Special populations

Elderly patients (≥65 years)

No dose adjustment is required (see section 5.2).

Renal impairment

No dose adjustment is required (see section 5.2).

Hepatic impairment

Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily.

Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg daily.

Severe hepatic impairment (Child-Pugh C) – Everolimus medac is only recommended if the

desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded.

Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment

(see also sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Everolimus medac in children aged 0 to 18 years have not been established.

No data are available.

Method of administration

Everolimus medac should be administered orally once daily at the same time every day, consistently

either with or without food (see section 5.2). Everolimus medac tablets should be swallowed whole

with a glass of water. The tablets should not be chewed or crushed.

4.3 Contraindications

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients

listed in section 6.1.

4.4 Special warnings and precautions for use

Non-infectious pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-

infectious pneumonitis (including interstitial lung disease) has been frequently reported in patients

taking Everolimus medac (see section 4.8). Some cases were severe and on rare occasions, a fatal

outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients

presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough

or dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded

means

appropriate

investigations.

Opportunistic

infections

such

pneumocystis

jirovecii

(carinii) pneumonia (PJP, PCP) should be ruled out in the differential diagnosis of non-infectious

pneumonitis (see “Infections” below). Patients should be advised to report promptly any new or

worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or

no symptoms may continue Everolimus medac therapy without dose adjustments. If symptoms are

moderate (Grade 2) or severe (Grade 3) the use of corticosteroids may be indicated until clinical

symptoms resolve.

patients

require

corticosteroids

treatment

non-infectious

pneumonitis,

prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) may be considered.

Infections

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or

protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localised and

systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as

aspergillosis, candidiasis or pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) and viral infections

including reactivation of hepatitis B virus, have been described in patients taking Everolimus medac.

Some of these infections have been severe (e.g. leading to sepsis, respiratory or hepatic failure) and

occasionally fatal.

Physicians and patients should be aware of the increased risk of infection with Everolimus medac. Pre-

existing infections should be treated appropriately and should have resolved fully before starting

treatment with Everolimus medac. While taking Everolimus medac, be vigilant for symptoms and signs

of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider

interruption or discontinuation of Everolimus medac.

If a diagnosis of invasive systemic fungal infection is made, the Everolimus medac treatment should be

promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.

Cases of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome, have been

reported in patients who received everolimus. PJP/PCP may be associated with concomitant use of

corticosteroids or other immunosuppressive agents. Prophylaxis for PJP/PCP should be considered

when concomitant use of corticosteroids or other immunosuppressive agents are required.

Hypersensitivity reactions

Hypersensitivity

reactions

manifested

symptoms

including,

limited

anaphylaxis,

dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without

respiratory impairment) have been observed with everolimus (see section 4.3).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for

angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see

section 4.5).

Stomatitis

Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported

adverse reaction in patients treated with everolimus (see section 4.8). Stomatitis mostly occurs

within the first 8 weeks of treatment. A single-arm study in postmenopausal breast cancer

patients treated with everolimus plus exemestane suggested that an alcohol-free corticosteroid

oral solution, administered as a mouthwash during the initial 8 weeks of treatment, may

decrease the incidence and severity of stomatitis (see section 5.1). Management of stomatitis

may therefore include prophylactic and/or therapeutic use of topical treatments, such as an

alcohol-free

corticosteroid

oral

solution

mouthwash.

However

products

containing

alcohol, hydrogen peroxide, iodine and thyme derivatives should be avoided as they may

exacerbate the condition. Monitoring for and treatment of fungal infection is recommended,

especially in patients being treated with steroid-based medications. Antifungal agents should

not be used unless fungal infection has been diagnosed (see section 4.5).

Renal failure events

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in

patients

treated

with

Everolimus

medac

(see

section

4.8).

Renal

function

should

monitored

particularly where patients have additional risk factors that may further impair renal function.

Laboratory tests and monitoring

Renal function

Elevations of serum creatinine, usually mild, and proteinuria have been reported (see section 4.8).

Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein or

serum creatinine, is recommended prior to the start of Everolimus medac therapy and periodically

thereafter.

Blood glucose

Hyperglycaemia

been

reported

(see

section

4.8).

Monitoring

fasting

serum

glucose

recommended prior to the start of Everolimus medac therapy and periodically thereafter. More frequent

monitoring is recommended when Everolimus medac is co-administered with other medicinal products

that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before

starting a patient on Everolimus medac.

Blood lipids

Dyslipidaemia

(including

hypercholesterolaemia

hypertriglyceridaemia)

been

reported.

Monitoring of blood cholesterol and triglycerides prior to the start of Everolimus medac therapy and

periodically thereafter, as well as management with appropriate medical therapy, is recommended.

Haematological parameters

Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported (see section 4.8).

Monitoring of complete blood count is recommended prior to the start of Everolimus medac therapy

and periodically thereafter.

Functional carcinoid tumours

randomised,

double-blind,

multi-centre

trial

patients

with

functional

carcinoid

tumours,

Everolimus medac plus depot octreotide was compared to placebo plus depot octreotide. The study did

not meet the primary efficacy endpoint (progression-free-survival [PFS]) and the overall survival (OS)

interim analysis numerically favoured the placebo plus depot octreotide arm. Therefore, the safety and

efficacy of Everolimus medac in patients with functional carcinoid tumours have not been established.

Prognostic factors in neuroendocrine tumours of gastrointestinal or lung origin

In patients with non-functional gastrointestinal or lung neuroendocrine tumours and good prognostic

baseline factors, e.g. ileum as primary tumour origin and normal chromogranin A values or without

bone involvement, an individual benefit-risk assessment should be performed prior to the start of

Everolimus medac therapy. A limited evidence of PFS benefit was reported in the subgroup of patients

with ileum as primary tumour origin (see section 5.1).

Interactions

Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-

glycoprotein (PgP) should be avoided. If co-administration of a

moderate

CYP3A4 and/or PgP

inhibitor or inducer cannot be avoided, dose adjustments of Everolimus medac can be taken into

consideration based on predicted AUC (see section 4.5).

Concomitant

treatment

with

potent

CYP3A4

inhibitors

result

dramatically

increased

plasma

concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing

recommendations in this situation. Hence, concomitant treatment of Everolimus medac and

potent

inhibitors is not recommended.

Caution should be exercised when Everolimus medac is taken in combination with orally administered

CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If

Everolimus medac 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).

Hepatic impairment

Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B)

and severe (Child-Pugh C) hepatic impairment (see section 5.2).

Everolimus medac is only recommended for use in patients with severe hepatic impairment (Child-

Pugh C) if the potential benefit outweighs the risk (see sections 4.2 and 5.2).

No clinical safety or efficacy data are currently available to support dose adjustment recommendations

for the management of adverse reactions in patients with hepatic impairment.

Vaccinations

The use of live vaccines should be avoided during treatment with Everolimus medac (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or

glucose-galactose malabsorption should not take this medicine.

Wound healing complications

Impaired wound healing is a class effect of rapamycin derivatives, including everolimus. Caution

should therefore be exercised with the use of Everolimus medac in the peri-surgical period.

4.5 Interaction with other medicinal products and other forms of interaction

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore,

absorption and subsequent elimination of everolimus may be influenced by products that affect

CYP3A4 and/or PgP.

In vitro

, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor

of CYP2D6.

Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed

in Table 2 below.

CYP3A4 and PgP inhibitors increasing everolimus concentrations

Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by

decreasing metabolism or the efflux of everolimus from intestinal cells.

CYP3A4 and PgP inducers decreasing everolimus concentrations

Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by

increasing metabolism or the efflux of everolimus from intestinal cells.

Table 2 Effects of other active substances on everolimus

Active substance by

interaction

Interaction – Change in

Everolimus AUC/C

max

Geometric mean ratio

(observed range)

Recommendations concerning

co-administration

Potent CYP3A4/PgP inhibitors

Ketoconazole

AUC ↑15.3-fold

(range 11.2-22.5)

↑4.1-fold

Concomitant

treatment

Everolimus

potent

inhibitors is not recommended.

(range 2.6-7.0)

Itraconazole,

posaconazole,

voriconazole

Telithromycin, clarithromycin

Nefazodone

Ritonavir, atazanavir,

saquinavir, darunavir,

indinavir, nelfinavir

Not studied. Large increase in

everolimus

concentration

expected.

Moderate CYP3A4/PgP inhibitors

Erythromycin

AUC ↑4.4-fold

(range 2.0-12.6)

↑2.0-fold

(range 0.9-3.5)

Imatinib

AUC ↑ 3.7-fold

2.2-fold

Verapamil

AUC ↑3.5-fold

(range 2.2-6.3)

↑2.3-fold

(range1.3-3.8)

Ciclosporin oral

AUC ↑2.7-fold

(range 1.5-4.7)

↑1.8-fold

(range 1.3-2.6)

Fluconazole

Diltiazem

Not studied. Increased exposure

expected.

Dronedarone

Not studied. Increased exposure

expected.

Amprenavir,

fosamprenavir

Not studied. Increased exposure

expected.

caution

when

administration

moderate

CYP3A4

inhibitors

inhibitors cannot be avoided. If

patients

require

administration

moderate

CYP3A4 or PgP inhibitor, dose

reduction to 5 mg daily or 2.5

daily

considered.

However, there are no clinical

data with this dose adjustment.

between

subject

variability

recommended

dose

adjustments

optimal

individuals,

therefore

close

monitoring

side effects is recommended. If

moderate

inhibitor

discontinued,

consider

washout period of at least 2 to 3

days (average elimination time

most

commonly

used

moderate inhibitors) before the

Everolimus

medac

dose

returned to the dose used prior

initiation

administration.

Grapefruit juice or other food

affecting CYP3A4/PgP

Not studied. Increased exposure

expected (the effect varies

widely).

Combination should be avoided.

Potent and moderate CYP3A4 inducers

Rifampicin

AUC ↓63%

(range 0-80%)

↓58%

(range 10-70%)

Dexamethasone

Not studied. Decreased

exposure expected.

Carbamazepine,

phenobarbital, phenytoin

Not studied. Decreased

exposure expected.

Efavirenz, nevirapine

Not studied. Decreased

exposure expected.

Avoid the use of concomitant

potent

CYP3A4

inducers.

patients

require

administration

potent

CYP3A4

inducer,

Afinitor

dose increase from 10 mg daily

up to 20 mg daily should be

considered

using

increments

less

applied

Day 4 and 8 following start of

inducer.

This

dose

Afinitor

predicted

adjust

the AUC to the range observed

without

inducers.

However,

there are no clinical data with

this

dose

adjustment.

treatment

with

inducer

discontinued,

consider

washout period of at least 3 to 5

days

(reasonable

time

significant

enzyme

induction),

before

the Afinitor

dose is returned to the dose used

prior

initiation

administration.

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 concentration may be altered by everolimus

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 CYP3A substrate probe, with everolimus resulted in a 25%

increase in midazolam C

and a 30% increase in midazolam AUC

(0-inf)

. 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 (see section 4.4).

Co-administration of everolimus and depot octreotide increased octreotide C

with a geometric mean

ratio (everolimus/placebo) of 1.47. A clinically significant effect on the efficacy response to everolimus

in patients with advanced neuroendocrine tumours could not be established.

Co-administration of everolimus and exemestane increased exemestane C

and C

by 45% and 64%,

respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different

between the two treatment arms. No increase in adverse events related to exemestane was observed in

patients

with

hormone

receptor-positive

advanced

breast

cancer

receiving

combination.

increase in exemestane levels is unlikely to have an impact on efficacy or safety.

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for

angioedema (see section 4.4).

Vaccinations

The immune response to vaccination may be affected and, therefore, vaccination may be less effective

during treatment with Everolimus medac. The use of live vaccines should be avoided during treatment

with Everolimus medac (see section 4.4). Examples of live vaccines are: intranasal influenza, measles,

mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a

typhoid vaccines.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must use a highly effective method of contraception (e.g. oral,

injected, or implanted non-oestrogen-containing hormonal method of birth control, progesterone-based

contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device

[IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks after ending

treatment. Male patients should not be prohibited from attempting to father children.

Pregnancy

There are no adequate data from the use of everolimus in pregnant women. Studies in animals have

shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see section 5.3). The

potential risk for humans is unknown.

Everolimus is not recommended during pregnancy and in women of childbearing potential not using

contraception.

Breast-feeding

It is not known whether everolimus is excreted in

human

breast milk. However, in rats, everolimus

and/or its metabolites readily pass into the milk (see section 5.3). Therefore, women taking everolimus

should not breast-feed

during treatment and for 2 weeks after the last dose

Fertility

The potential for everolimus to cause infertility in male and female patients is unknown, however

amenorrhoea (secondary amenorrhoea and other menstrual irregularities) and associated luteinising

hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients.

Based on non-clinical findings, male and female fertility may be compromised by treatment with

everolimus (see section 5.3).

4.7 Effects on ability to drive and use machines

Everolimus medac may have a minor or moderate influence on the ability to drive and use machines.

Patients should be advised to be cautious when driving or using machines if they experience fatigue

during treatment with Everolimus medac.

4.8 Undesirable effects

Summary of the safety profile

The safety profile is based on pooled data from 2,879 patients treated with everolimus in eleven clinical

studies, consisting of five randomised, double-blind, placebo controlled phase III studies and six open-

label phase I and phase II studies, related to the approved indications.

The most common adverse reactions (incidence ≥1/10) from the pooled safety data were (in decreasing

order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia,

pneumonitis,

oedema

peripheral,

hyperglycaemia,

asthenia,

pruritus,

weight

decreased,

hypercholesterolaemia, epistaxis, cough and headache.

The most frequent Grade 3-4 adverse reactions (incidence ≥1/100 to <1/10) were stomatitis, anaemia,

hyperglycaemia, infections, fatigue, diarrhoea, pneumonitis, asthenia, thrombocytopenia, neutropenia,

dyspnoea,

proteinuria,

lymphopenia,

haemorrhage,

hypophosphataemia,

rash,

hypertension,

pneumonia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased and

diabetes mellitus. The grades follow CTCAE Version 3.0 and 4.03.

Tabulated list of adverse reactions

Table 3 presents the frequency category of adverse reactions reported in the pooled analysis considered

for the safety pooling. Adverse reactions are listed according to MedDRA system organ class and

frequency category. Frequency categories are defined using the following convention: 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). Within each frequency grouping, adverse reactions are presented in order of

decreasing seriousness.

Table 3 Adverse reactions reported in clinical studies

Infections and infestations

Very common

Infections

Blood and lymphatic system disorders

Very common

Anaemia

Common

Thrombocytopenia, neutropenia, leukopenia, lymphopenia

Uncommon

Pancytopenia

Rare

Pure red cell aplasia

Immune system disorders

Uncommon

Hypersensitivity

Metabolism and nutrition disorders

Very common

Decreased appetite, hyperglycaemia, hypercholesterolaemia

Common

Hypertriglyceridaemia, hypophosphataemia, diabetes

mellitus, hyperlipidaemia, hypokalaemia, dehydration,

hypocalcaemia

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Very common

Dysgeusia, headache

Uncommon

Ageusia

Eye disorders

Common

Eyelid oedema

Uncommon

Conjunctivitis

Cardiac disorders

Uncommon

Congestive cardiac failure

Vascular disorders

Common

Haemorrhage

, hypertension

Uncommon

Flushing, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

Very common

Pneumonitis

, epistaxis, cough

Common

Dyspnoea

Uncommon

Haemoptysis, pulmonary embolism

Rare

Acute respiratory distress syndrome

Gastrointestinal disorders

Very common

Stomatitis

, diarrhoea, nausea

Common

Vomiting,

mouth,

abdominal

pain,

mucosal

inflammation, oral pain, dyspepsia, dysphagia

Hepatobiliary disorders

Common

Aspartate

aminotransferase

increased,

alanine

aminotransferase increased

Skin and subcutaneous tissue disorders

Very common

Rash, pruritus

Common

skin,

nail

disorders,

mild

alopecia,

acne,

erythema,

onychoclasis, palmar-plantar erythrodysaesthesia syndrome,

skin exfoliation, skin lesion

Rare

Angioedema

Musculoskeletal and connective tissue disorders

Common

Arthralgia

Renal and urinary disorders

Common

Proteinuria*, blood creatinine increased, renal failure*

Uncommon

Increased daytime urination, acute renal failure*

Reproductive system and breast disorders

Common

Menstruation irregular

Uncommon

Amenorrhoea

General disorders and administration site conditions

Very common

Fatigue, asthenia, oedema peripheral

Common

Pyrexia

Uncommon

Non-cardiac chest pain, impaired wound healing

Investigations

Very common

Weight decreased

* See also subsection “Description of selected adverse reactions”

Includes all reactions within the ‘infections and infestations’ system organ class including (common)

pneumonia, urinary tract infection; (uncommon) bronchitis, herpes zoster, sepsis, abscess, and isolated

cases

opportunistic

infections

[e.g.

aspergillosis,

candidiasis,

pneumocystis

jirovecii

(carinii)

pneumonia (PJP, PCP) and hepatitis B (see also section 4.4)] and (rare) viral myocarditis

Includes different bleeding events from different sites not listed individually

Includes (common) pneumonitis, interstitial lung disease, lung infiltration and (rare) pulmonary

alveolar haemorrhage, pulmonary toxicity, and alveolitis

Includes (very common) stomatitis, (common) aphthous stomatitis, mouth and tongue ulceration and

(uncommon) glossodynia, glossitis

Frequency based upon number of women from 10 to 55 years of age in the pooled data

Description of selected adverse reactions

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with serious

cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected event

during periods of immunosuppression.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal

failure events (including fatal outcome) and proteinuria. Monitoring of renal function is recommended

(see section 4.4).

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases

of amenorrhoea (secondary amenorrhoea and other menstrual irregularities).

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases

of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome (see section 4.4).

In clinical trials and post-marketing spontaneous reports, angioedema has been reported with and

without concomitant use of ACE inhibitors (see section 4.4).

Elderly patients

In the safety pooling, 37% of the everolimus -treated patients were ≥65 years of age. The number of

patients with an adverse reaction leading to discontinuation of the medicinal product was higher in

patients

≥65

years

(20%

vs.

13%).

most

common

adverse

reactions

leading

discontinuation were pneumonitis (including interstitial lung disease), stomatitis, fatigue and dyspnoea.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows

continued

monitoring

benefit/risk

balance

medicinal

product.

Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9 Overdose

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been

given with acceptable acute tolerability. General supportive measures should be initiated in all cases of

overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic

group:

Antineoplastic

agents,

other

antineoplastic

agents,

protein

kinase

inhibitors, ATC code: L01XE10

Mechanism of action

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-

threonine kinase, the activity of which is known to be upregulated in a number of human cancers.

Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR

complex-1 (mTORC1) activity.

Inhibition of the mTORC1 signalling pathway interferes with the

translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and

eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell

cycle, angiogenesis and glycolysis. S6K1is thought to phosphorylate the activation function domain 1

of the oestrogen receptor, which is responsible for ligand-independent receptor activation. Everolimus

reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour angiogenic

processes. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial

cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce

glycolysis in solid tumours

in vitro

in vivo

Clinical efficacy and safety

Hormone receptor-positive advanced breast cancer

BOLERO-2 (study CRAD001Y2301), a randomised, double-blind, multicentre phase III study of

Everolimus medac + exemestane versus placebo + exemestane, was conducted in postmenopausal

women with oestrogen receptor-positive, HER2/neu negative advanced breast cancer with recurrence

or progression following prior therapy with letrozole or anastrozole. Randomisation was stratified by

documented sensitivity to prior hormonal therapy and by the presence of visceral metastasis. Sensitivity

to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response

[CR], partial response [PR], stable disease ≥24 weeks) from at least one prior hormonal therapy in the

advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence.

The primary endpoint for the study was progression-free survival (PFS) evaluated by RECIST

(Response

Evaluation

Criteria

Solid

Tumors),

based

investigator’s

assessment

(local

radiology). Supportive PFS analyses were based on an independent central radiology review.

Secondary endpoints included overall survival (OS), objective response rate, clinical benefit rate,

safety, change in quality of life (QoL) and time to ECOG PS (Eastern Cooperative Oncology Group

performance status) deterioration.

A total of 724 patients were randomised in a 2:1 ratio to the combination everolimus (10 mg daily) +

exemestane (25 mg daily) (n=485) or to the placebo + exemestane arm (25 mg daily) (n=239). At the

time of the final OS analysis, the median duration of everolimus treatment was 24.0 weeks (range 1.0-

199.1

weeks).

median

duration

exemestane

treatment

longer

everolimus

exemestane group at 29.5 weeks (1.0-199.1) compared to 14.1 weeks (1.0-156.0) in the placebo +

exemestane group.

The efficacy results for the primary endpoint were obtained from the final PFS analysis (see Table 4

and Figure 1). Patients in the placebo + exemestane arm did not cross over to everolimus at the time of

progression.

Table 4 BOLERO-2 efficacy results

Analysis

Everolimus

a

n=485

Placebo

a

n=239

Hazard ratio

p value

Median progression-free survival (months) (95% CI)

Investigator

radiological

review

(6.9 to 8.5)

(2.8 to 4.1)

0.45

(0.38 to 0.54)

<0.0001

Independent

radiological

review

11.0

(9.7 to 15.0)

(2.9 to 5.6)

0.38

(0.31 to 0.48)

<0.0001

Median overall survival (months) (95% CI)

Median overall

survival

31.0

(28.0 – 34.6)

26.6

(22.6 – 33.1)

0.89

(0.73 – 1.10)

0.1426

Best overall response (%) (95% CI)

Objective

12.6%

1.7%

n/ad

<0.0001

response rate

(9.8 to 15.9)

(0.5 to 4.2)

Clinical

benefit

rate

51.3%

(46.8 to 55.9)

26.4%

(20.9 to 32.4)

n/ad

<0.0001

Plus exemestane

Objective response rate = proportion of patients with complete or partial response

Clinical benefit rate = proportion of patients with complete or partial response or stable disease ≥24

weeks

Not applicable

p value is obtained from the exact Cochran-Mantel-Haenszel test using a stratified version of the

Cochran-Armitage permutation test

.

Figure 1 BOLERO-2 Kaplan-Meier progression-free survival curves (investigator radiological

review)

estimated

treatment

effect

supported

planned

subgroup

analysis

investigator assessment. For all analysed subgroups (age, sensitivity to prior hormonal therapy, number

of organs involved, status of bone-only lesions at baseline and presence of visceral metastasis, and

across major demographic and prognostic subgroups) a positive treatment effect was seen with

everolimus + exemestane with an estimated hazard ratio versus placebo + exemestane ranging from

0.25 to 0.60.

No differences in the time to ≥5% deterioration in the global and functional domain scores of QLQ-

C30 were observed in the two arms.

BOLERO-6

(Study

CRAD001Y2201),

three-arm,

randomised,

open-label,

phase

study

everolimus in combination with exemestane versus everolimus alone versus capecitabine in the

treatment of postmenopausal women with oestrogen receptor-positive, HER2/neu negative, locally

advanced, recurrent, or metastatic breast cancer after recurrence or progression on prior letrozole or

anastrozole.

The primary objective of the study was to estimate the HR of PFS for everolimus + exemestane versus

everolimus alone. The key secondary objective was to estimate the HR of PFS for everolimus +

exemestane versus capecitabine.

Other secondary objectives included the evaluation of OS, objective response rate, clinical benefit

rate, safety, time to ECOG performance deterioration, time to QoL deterioration, and treatment

satisfaction (TSQM). No formal statistical comparisons were planned.

A total of 309 patients were randomised in a 1:1:1 ratio to the combination of everolimus (10 mg daily)

+ exemestane (25 mg daily) (n=104), everolimus alone (10 mg daily) (n=103), or capecitabine (1250

mg/m2 dose twice daily for 2 weeks followed by one week rest, 3-week cycle) (n=102). At the time of

data cut-off, the median duration of treatment was 27.5 weeks (range 2.0-165.7) in the everolimus +

exemestane arm, 20 weeks (1.3-145.0) in the everolimus arm, and 26.7 weeks (1.4-177.1) in the

capecitabine arm. The result of the final PFS analysis with 154 PFS events observed based on local

investigator assessment showed an estimated HR of 0.74 (90% CI: 0.57, 0.97) in favour of the

everolimus + exemestane arm relative to everolimus arm. The median PFS was 8.4 months (90% CI:

6.6, 9.7) and 6.8 months (90% CI: 5.5, 7.2), respectively.

For the key secondary endpoint PFS the estimated HR was 1.26 (90% CI: 0.96, 1.66) in favour of

capecitabine over the everolimus + exemestane combination arm based on a total of 148 PFS events

observed.

Results of the secondary endpoint OS were not consistent with the primary endpoint PFS, with a trend

observed favouring the everolimus alone arm. The estimated HR was 1.27 (90% CI: 0.95, 1.70) for the

comparison of OS in the everolimus alone arm relative to the everolimus + exemestane arm. The

estimated HR for the comparison of OS in the everolimus + exemestane combination arm relative to

capecitabine arm was 1.33 (90% CI: 0.99, 1.79).

Advanced neuroendocrine tumours of pancreatic origin (pNET)

RADIANT-3 (study CRAD001C2324), a phase III, multicentre, randomised, double-blind study of

Everolimus medac plus best supportive care (BSC) versus placebo plus BSC in patients with advanced

pNET, demonstrated a statistically significant clinical benefit of Everolimus medac over placebo by a

2.4-fold prolongation of median progression-free-survival (PFS) (11.04 months versus 4.6 months),

(HR 0.35; 95% CI: 0.27, 0.45; p<0.0001) (see Table 5 and Figure 2).

RADIANT-3

involved

patients

with

well-

moderately-differentiated

advanced

pNET

whose

disease had progressed within the prior 12 months. Treatment with somatostatin analogues was allowed

as part of BSC.

The primary endpoint for the study was PFS evaluated by RECIST (Response Evaluation Criteria in

Solid Tumors). Following documented radiological progression, patients could be unblinded by the

investigator. Those randomised to placebo were then able to receive open-label Everolimus medac.

Secondary endpoints included safety, objective response rate, response duration and overall survival

(OS).

In total, 410 patients were randomised 1:1 to receive either Everolimus medac 10 mg/day (n=207) or

placebo

(n=203).

Demographics

were

well

balanced

(median

years,

male,

78.5%

Caucasian). Fifty-eight percent of the patients in both arms received prior systemic therapy. The

median duration of blinded study treatment was 37.8 weeks (range 1.1-129.9 weeks) for patients

receiving everolimus and 16.1 weeks (range 0.4-147.0 weeks) for those receiving placebo.

Following disease progression or after study unblinding, 172 of the 203 patients (84.7%) initially

randomised to placebo crossed over to open-label Everolimus medac. The median duration of open-

label treatment was 47.7 weeks among all patients; 67.1 weeks in the 53 patients randomised to

everolimus who switched to open-label everolimus and 44.1 weeks in the 172 patients randomised to

placebo who switched to open-label everolimus.

Table 5 RADIANT-3 – efficacy results

Population

Everolimus

n=207

Placebo

n=203

Hazard ratio

(95% CI)

p-value

Median progression-free survival (months) (95% CI)

Investigator

radiological

review

11.04

(8.41, 13.86)

4.60

(3.06, 5.39)

0.35

(0.27, 0.45)

<0.0001

Independent

radiological

review

13.67

(11.17, 18.79)

5.68

(5.39, 8.31)

0.38

(0.28, 0.51)

<0.0001

Median overall survival (months) (95% CI)

Median overall

survival

44.02

(35.61, 51.75)

37.68

(29.14, 45.77)

0.94

(0.73, 1.20)

0.300

Figure 3 RADIANT-3 – Kaplan-Meier progression-free survival curves (investigator radiological

review)

Advanced neuroendocrine tumours of gastrointestinal or lung origin

RADIANT-4 (study CRAD001T2302), a randomised, double-blind, multicentre, phase III study of

Everolimus medac plus best supportive care (BSC) versus placebo plus BSC was conducted in patients

with advanced, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours of

gastrointestinal or lung origin without a history of and no active symptoms related to carcinoid

syndrome.

The primary endpoint for the study was progression-free survival (PFS) evaluated by Response

Evaluation

Criteria

Solid

Tumors

(RECIST),

based

independent

radiology

assessment.

Supportive PFS analysis was based on local investigator review. Secondary endpoints included overall

survival (OS), overall response rate, disease control rate, safety, change in quality of life (FACT-G)

and time to World Health Organisation performance status (WHO PS) deterioration.

A total of 302 patients were randomised in a 2:1 ratio to receive either everolimus (10 mg daily)

(n=205) or placebo (n=97). Demographics and disease characteristics were generally balanced (median

age 63 years [range 22 to 86], 76% Caucasian, history of prior somatostatin analogue [SSA] use). The

median duration of blinded treatment was 40.4 weeks for patients receiving Everolimus medac and

19.6 weeks for those receiving placebo. Patients in the placebo arm did not cross-over to everolimus at

the time of progression.

The efficacy results for the primary endpoint were obtained from the final PFS analysis (see Table 6

and Figure 3).

Table 6 RADIANT-4 – Progression-free survival results

Population

Everolimus

n=205

Placebo

n=97

Hazard ratio

(95% CI)

p-value

a

Median progression-free survival (months) (95% CI)

Independent

radiological

review

11.01

(9.2, 13.3)

3.91

(3.6, 7.4)

0.48

(0.35, 0.67)

<0.0001

Investigator

radiological

review

13.96

(11.2, 17.7)

5.45

(3.7, 7.4)

0.39

(0.28, 0.54)

<0.0001

One-sided p-value from a stratified log-rank test

Figure 4 RADIANT-4 – Kaplan-Meier progression-free survival curves (independent radiological

review)

In supportive analyses, positive treatment effect has been observed in all subgroups with the exception

of the subgroup of patients with ileum as primary site of tumour origin (Ileum: HR=1.22 [95% CI: 0.56

to 2.65]; Non-ileum: HR=0.34 [95% CI: 0.22 to 0.54]; Lung: HR=0.43 [95% CI: 0.24 to 0.79]) (see

Figure 4).

Figure 5 RADIANT-4 – Progression free survival results by pre-specified patient subgroup

(independent radiological review)

The pre-planned OS interim analysis after 101 deaths (out of 191 required for final analysis) and 33

months follow-up favoured the everolimus arm; however, no statistically significant difference in OS

was noted (HR= 0.73 [95% CI: 0.48 to 1.11; p=0.071]).

No difference in the time to definitive deterioration of WHO PS (≥1 point) and time to definitive

deterioration in quality of life (FACT-G total score ≥7 points) was observed between the two arms.

Advanced renal cell carcinoma

RECORD-1 (study CRAD001C2240), a phase III, international, multicentre, randomised, double-blind

study comparing everolimus 10 mg/day and placebo, both in conjunction with best supportive care,

was conducted in patients with metastatic renal cell carcinoma whose disease had progressed on or

after treatment with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase inhibitor)

therapy (sunitinib, sorafenib, or both sunitinib and sorafenib). Prior therapy with bevacizumab and

interferon-α was also permitted. Patients were stratified according to Memorial Sloan-Kettering Cancer

Center (MSKCC) prognostic score (favourable- vs. intermediate- vs. poor-risk groups) and prior

anticancer therapy (1 vs. 2 prior VEGFR-TKIs).

Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid Tumours)

and assessed via a blinded, independent central review, was the primary endpoint. Secondary endpoints

included safety, objective tumour response rate, overall survival, disease-related symptoms, and quality

of life. After documented radiological progression, patients could be unblinded by the investigator:

those randomised to placebo were then able to receive open-label everolimus 10 mg/day. The

Independent Data Monitoring Committee recommended termination of this trial at the time of the

second interim analysis as the primary endpoint had been met.

In total, 416 patients were randomised 2:1 to receive Everolimus medac (n=277) or placebo (n=139).

Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88%

Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]). The median duration of blinded

study treatment was 141 days (range 19-451 days) for patients receiving everolimus and 60 days (range

21-295 days) for those receiving placebo.

Everolimus medac was superior to placebo for the primary endpoint of progression-free survival, with

a statistically significant 67% reduction in the risk of progression or death (see Table 7 and Figure 5).

Table 7 RECORD-1 – Progression-free survival results

Population

n

Everolimus

n=277

Placebo

n=139

Hazard ratio (95%

CI)

p-value

Median progression-free

survival (months) (95% CI)

Primary analysis

All (blinded

independent central

review)

(4.0-5.5)

(1.8-1.9)

0.33

(0.25-0.43)

<0.0001

Supportive/sensitivity analyses

All (local review by

investigator)

(4.6-5.8)

(1.8-2.2)

0.32

(0.25-0.41)

<0.0001

MSKCC prognostic score (blinded independent central review)

Favourable risk

(4.0-7.4)

(1.9-2.8)

0.31

(0.19-0.50)

<0.0001

Intermediate risk

(3.8-5.5)

(3.8-5.5)

(3.8-5.5)

(3.8-5.5)

Poor risk

(1.9-4.6)

(1.9-4.6)

(1.9-4.6)

(1.9-4.6)

Stratified log-rank test

Figure 6 RECORD-1 – Kaplan-Meier progression-free survival curves (independent central review)

Six-month PFS rates were 36% for Everolimus medac therapy compared with 9% for placebo

Confirmed objective tumour responses were observed in 5 patients (2%) receiving everolimus, while none

were observed in patients receiving placebo. Therefore, the progression-free survival advantage primarily

reflects the population with disease stabilisation (corresponding to 67% of the everolimus treatment group).

No statistically significant treatment-related difference in overall survival was noted (hazard ratio 0.87;

confidence interval: 0.65-1.17; p=0.177). Crossover to open-label everolimus following disease progression

for patients allocated to placebo confounded the detection of any treatment-related difference in overall

survival.

Other studies

Stomatitis is the most commonly reported adverse reaction in patients treated with everolimus (see

sections 4.4 and 4.8). In a post-marketing single-arm study in postmenopausal women with

advanced breast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 ml alcohol-free

oral solution was administered as a mouthwash (4 times daily for the initial 8 weeks of treatment) to

patients at the time of initiating treatment with everolimus (10 mg/day) plus exemestane (25

mg/day) to reduce the incidence and severity of stomatitis. The incidence of Grade ≥2 stomatitis at

8 weeks was 2.4% (n=2/85 evaluable patients) which was lower than historically reported. The

incidence of Grade 1 stomatitis was 18.8% (n=16/85) and no cases of Grade 3 or 4 stomatitis were

reported. The overall safety profile in this study was consistent with that established for everolimus

in the oncology and tuberous sclerosis complex (TSC) settings, with the exception of a slightly

increased frequency of oral candidiasis which was reported in 2.2% (n=2/92) of patients.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with

the reference medicinal product containing everolimus in all subsets of the paediatric population in

neuroendocrine tumours of pancreatic origin, thoracic neuroendocrine tumours and in renal cell carcinoma

(see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

In patients with advanced solid tumours, peak everolimus concentrations (C

) are reached at a median time

of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or with a light fat-

free snack. C

is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor

of PgP.

Food effect

In healthy subjects, high fat meals reduced systemic exposure to everolimus 10 mg (as measured by AUC)

by 22% and the peak plasma concentration C

by 54%. Light fat meals reduced AUC by 32% and C

42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile.

Distribution

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5,000

ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is confined to

plasma in cancer patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% both in

healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumours,

was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment.

Biotransformation

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main

circulating component in human blood. Six main metabolites of everolimus have been detected in human

blood,

including

three

monohydroxylated

metabolites,

hydrolytic

ring-opened

products,

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,

everolimus is considered to contribute the majority of the overall pharmacological activity.

Elimination

Mean oral clearance (CL/F) of everolimus after 10 mg daily dose in patients with advanced solid tumours

was 24.5 l/h. The mean elimination half-life of everolimus is approximately 30 hours.

No specific excretion studies have been undertaken in cancer patients; however, data are available from the

studies in transplant patients. Following the administration of a single dose of radiolabelled everolimus in

conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, while 5% was excreted

in the urine. The parent substance was not detected in urine or faeces.

Steady-state pharmacokinetics

After administration of everolimus in patients with advanced solid tumours, steady-state AUC

0-τ

was dose-

proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two weeks. C

dose-proportional between 5 and 10 mg. t

occurs at 1 to 2 hours post-dose. There was a significant

correlation between AUC

0-τ

and pre-dose trough concentration at steady-state.

Special populations

Hepatic impairment

The safety, tolerability and pharmacokinetics of everolimus were evaluated in two single oral dose studies of

everolimus tablets in 8 and 34 subjects with impaired hepatic function relative to subjects with normal

hepatic function.

In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-

Pugh B) was twice that found in 8 subjects with normal hepatic function.

In the second study of 34 subjects with different impaired hepatic function compared to normal subjects,

there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC

0-inf

) for subjects with mild (Child-

Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively.

Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects with hepatic

impairment based on their Child-Pugh status.

Based on the results of the two studies, dose adjustment is recommended for patients with hepatic

impairment (see sections 4.2 and 4.4).

Renal impairment

In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant

influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant renal

impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in

transplant patients.

Elderly patients

In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years)

on oral clearance of everolimus was detected.

Ethnicity

Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions.

Based on analysis of population pharmacokinetics, CL/F is on average 20% higher in black transplant

patients.

5.3 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

epididymides

uterine

atrophy)

several

species;

lungs

(increased

alveolar

macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells in monkeys and

minipigs, respectively, and degeneration of islet cells in monkeys), and eyes (lenticular anterior suture line

opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of age-related lipofuscin in

tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of background lesions). There was

no indication of kidney toxicity in monkeys or minipigs.

Everolimus

appeared

spontaneously

exacerbate

background

diseases

(chronic

myocarditis

rats,

coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal tract in

minipigs, skin lesions in mice and monkeys). These findings were generally observed at systemic exposure

levels within the range of therapeutic exposure or above, with the exception of the findings in rats, which

occurred below therapeutic exposure due to a high tissue distribution.

In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm

motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg which caused a

reduction in male fertility. There was evidence of reversibility.

In animal reproductive studies female fertility was not affected. However, oral doses of everolimus in female

rats at ≥0.1 mg/kg (approximately 4% of the AUC

0-24h

in patients receiving the 10 mg daily dose) resulted in

increases in pre-implantation loss.

Everolimus crossed the placenta and was toxic to the foetus. In rats, everolimus caused embryo/foetotoxicity

at systemic exposure below the therapeutic level. This was manifested as mortality and reduced foetal

weight. The incidence of skeletal variations and malformations (e.g. sternal cleft) was increased at 0.3 and

0.9 mg/kg. In rabbits, embryotoxicity was evident in an increase in late resorptions.

Genotoxicity

studies

covering

relevant

genotoxicity

endpoints

showed

evidence

clastogenic

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 3.9 and 0.2 times the estimated

clinical exposure.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Butylated hydroxytoluene (E321)

Hypromellose 3 cPs

Lactose monohydrate

Lactose anhydrous

Crospovidone type A

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

OPA/Alu/PVC-Alu blister

Everolimus medac 5 mg tablets

Packs containing 30 tablets.

Everolimus medac 10 mg tablets

Packs containing 30 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

unused

medicinal

product

waste

material

should

disposed

accordance

with

local

requirements.

7. MARKETING AUTHORISATION HOLDER

medac pharma s.r.l.

via Viggiano 90

00178 Rome

Italy

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

Date of latest renewal:

10. DATE OF REVISION OF THE TEXT

2019-03-01

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