Afinitor

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



2 

1. NAME OF THE MEDICINAL PRODUCT 

 

Afinitor 2.5 mg tablets 

Afinitor 5 mg tablets 

Afinitor 10 mg tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Afinitor 2.5 mg tablets 

Each tablet contains 2.5 mg everolimus. 

 

Excipient with known effect 

Each tablet contains 74 mg lactose. 

 

Afinitor 5 mg tablets 

Each tablet contains 5 mg everolimus. 

 

Excipient with known effect 

Each tablet contains 149 mg lactose. 

 

Afinitor 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. 

 

Afinitor 2.5 mg tablets 

White to slightly yellow, elongated tablets of approximately 10.1 mm in length and 4.1 mm in width, 

with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other. 

 

Afinitor 5 mg tablets 

White to slightly yellow, elongated tablets of approximately 12.1 mm in length and 4.9 mm in width, 

with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other. 

 

Afinitor 10 mg tablets 

White to slightly yellow, elongated tablets of approximately 15.1 mm in length and 6.0 mm in width, 

with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other. 

 

 

  



3 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Hormone receptor-positive advanced breast cancer 

Afinitor is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced 

breast cancer, in combination with exemestane, in postmenopausal women without symptomatic 

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

 

Neuroendocrine tumours of pancreatic origin 

Afinitor 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 

Afinitor 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 

Afinitor 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 Afinitor should be initiated and supervised by a physician experienced in the use of 

anticancer therapies. 

 

Posology 

For the different dose regimens Afinitor is available as 2.5 mg, 5 mg and 10 mg tablets. 

 

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 Afinitor 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). 

 

  



4 

Table 1 Afinitor dose adjustment recommendations 

 

Adverse reaction Severity1 Afinitor dose adjustment 

Non-infectious 

pneumonitis 

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. 

 Grade 4 Discontinue treatment. 

Stomatitis 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. 

 Grade 4 Discontinue treatment. 

Other 

non-haematological 

toxicities 

(excluding 

metabolic events) 

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. 

 Grade 4 Discontinue treatment. 

Metabolic events 

(e.g. 

hyperglycaemia, 

dyslipidaemia) 

Grade 2 No dose adjustment required. 

 Grade 3 Temporary dose interruption. 

Re-initiate treatment at 5 mg daily. 

 Grade 4 Discontinue treatment. 

Thrombocytopenia Grade 2 

(<75, ≥50x109/l) 
Temporary dose interruption until recovery to Grade 1 

(≥75x109/l). Re-initiate treatment at same dose. 

 Grade 3 & 4 

(<50x109/l) 
Temporary dose interruption until recovery to Grade 1 

(≥75x109/l). Re-initiate treatment at 5 mg daily. 

Neutropenia Grade 2 

(≥1x109/l) 

No dose adjustment required. 

 Grade 3 

(<1, ≥0.5x109/l) 
Temporary dose interruption until recovery to Grade 2 

(≥1x109/l). Re-initiate treatment at same dose. 

 Grade 4 

(<0.5x109/l) 
Temporary dose interruption until recovery to Grade 2 

(≥1x109/l). Re-initiate treatment at 5 mg daily. 

Febrile neutropenia Grade 3 Temporary dose interruption until recovery to Grade 2 

(≥1.25x109/l) and no fever. 

Re-initiate treatment at 5 mg daily. 

 Grade 4 Discontinue treatment. 
1 Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse 

Events (CTCAE) v3.0 

 

  



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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) – Afinitor 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 Afinitor in children aged 0 to 18 years have not been established. No data 

are available. 

 

Method of administration 

Afinitor should be administered orally once daily at the same time every day, consistently either with 

or without food (see section 5.2). Afinitor 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 Afinitor (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 

by means of appropriate investigations. Opportunistic infections such as 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 Afinitor 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. 

 

For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, 

prophylaxis for PJP/PCP may be considered. 

 



6 

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 PJP/PCP and viral infections including reactivation of hepatitis B 

virus, have been described in patients taking Afinitor. 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 Afinitor. Pre-existing 

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

with Afinitor. While taking Afinitor, 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 Afinitor. 

 

If a diagnosis of invasive systemic fungal infection is made, the Afinitor treatment should be promptly 

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

 

Cases of 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 by symptoms including, but not limited to, 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 Afinitor (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 

Afinitor 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 as a 

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 medicinal products. 

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 Afinitor (see section 4.8). Renal function should be monitored particularly where 

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

 

  



7 

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 Afinitor therapy and periodically thereafter. 

 

Blood glucose 

Hyperglycaemia has been reported (see section 4.8). Monitoring of fasting serum glucose is 

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

monitoring is recommended when Afinitor is co-administered with other medicinal products that may 

induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a 

patient on Afinitor. 

 

Blood lipids 

Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported. 

Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor 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 Afinitor therapy and 

periodically thereafter. 

 

Functional carcinoid tumours 

In a randomised, double-blind, multi-centre trial in patients with functional carcinoid tumours, 

Afinitor 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 Afinitor 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 

Afinitor therapy. 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 Afinitor can be taken into consideration 

based on predicted AUC (see section 4.5). 

 

Concomitant treatment with potent CYP3A4 inhibitors result in 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 Afinitor and potent inhibitors is 

not recommended. 

 

Caution should be exercised when Afinitor is taken in combination with orally administered CYP3A4 

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

 



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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). 

 

Afinitor 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 Afinitor (see section 4.5). 

 

Lactose 

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

glucose-galactose malabsorption should not take this medicinal product. 

 

Wound healing complications 

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

should therefore be exercised with the use of Afinitor 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. 

 

  



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Table 2 Effects of other active substances on everolimus 

 

Active substance by 

interaction 

 

Interaction – Change in 

Everolimus AUC/Cmax 

Geometric mean ratio 

(observed range) 

Recommendations concerning 

co-administration 

 
Potent CYP3A4/PgP inhibitors 

Ketoconazole AUC ↑15.3-fold 

(range 11.2-22.5) 

Cmax ↑4.1-fold 

(range 2.6-7.0) 

Concomitant treatment of Afinitor 

and potent inhibitors is not 

recommended. 

Itraconazole, 

posaconazole, 

voriconazole 

Not studied. Large increase in 

everolimus concentration is 

expected. 

Telithromycin, 

clarithromycin 

Nefazodone 

Ritonavir, atazanavir, 

saquinavir, darunavir, 

indinavir, nelfinavir 

 
Moderate CYP3A4/PgP inhibitors 

Erythromycin AUC ↑4.4-fold 

(range 2.0-12.6) 

Cmax ↑2.0-fold 

(range 0.9-3.5) 

Use caution when 

co-administration of moderate 

CYP3A4 inhibitors or PgP 

inhibitors cannot be avoided. If 

patients require co-administration 

of a moderate CYP3A4 or PgP 

inhibitor, dose reduction to 5 mg 

daily or 2.5 mg daily may be 

considered. However, there are no 

clinical data with this dose 

adjustment. Due to between 

subject variability the 

recommended dose adjustments 

may not be optimal in all 

individuals, therefore close 

monitoring of side effects is 

recommended. If the moderate 

inhibitor is discontinued, consider 

a washout period of at least 2 to 

3 days (average elimination time 

for most commonly used moderate 

inhibitors) before the Afinitor dose 

is returned to the dose used prior to 

initiation of the co-administration. 

Imatinib AUC ↑ 3.7-fold 
Cmax ↑ 2.2-fold 

Verapamil AUC ↑3.5-fold 

(range 2.2-6.3) 

Cmax ↑2.3-fold 

(range1.3-3.8) 

Ciclosporin oral AUC ↑2.7-fold 

(range 1.5-4.7) 

Cmax ↑1.8-fold 

(range 1.3-2.6) 

Fluconazole Not studied. Increased exposure 

expected. Diltiazem 

Dronedarone Not studied. Increased exposure 

expected. 

Amprenavir, 

fosamprenavir 

Not studied. Increased exposure 

expected. 

Grapefruit juice or 

other food affecting 

CYP3A4/PgP 

Not studied. Increased exposure 

expected (the effect varies 

widely). 

Combination should be avoided. 

 



10 

Potent and moderate CYP3A4 inducers 

Rifampicin AUC ↓63% 

(range 0-80%) 

Cmax ↓58% 

(range 10-70%) 

Avoid the use of concomitant 

potent CYP3A4 inducers. If 

patients require co-administration 

of a potent CYP3A4 inducer, an 

Afinitor dose increase from 10 mg 

daily up to 20 mg daily should be 

considered using 5 mg increments 

or less applied on Day 4 and 8 

following start of the inducer. This 

dose of Afinitor is predicted to 

adjust the AUC to the range 

observed without inducers. 

However, there are no clinical data 

with this dose adjustment. If 

treatment with the inducer is 

discontinued, consider a washout 

period of at least 3 to 5 days 

(reasonable time for significant 

enzyme de-induction), before the 

Afinitor dose is returned to the 

dose used prior to initiation of the 

co-administration. 

Dexamethasone Not studied. Decreased exposure 

expected. 

Carbamazepine, 

phenobarbital, 

phenytoin 

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. 

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 Cmax 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 Cmin 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 Cmin and C2h 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 reactions related to exemestane was observed 

in patients with hormone receptor-positive advanced breast cancer receiving the combination. The 

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

Afinitor (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. 



11 

 

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 
 

Afinitor 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 Afinitor. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

The safety profile is based on pooled data from 2,879 patients treated with Afinitor 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. 

 



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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 a, * 

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 b, hypertension 

Uncommon Flushing, deep vein thrombosis 

Respiratory, thoracic and mediastinal disorders 

Very common Pneumonitis c, epistaxis, cough 

Common Dyspnoea 

Uncommon Haemoptysis, pulmonary embolism 

Rare Acute respiratory distress syndrome 

Gastrointestinal disorders 

Very common Stomatitis d, diarrhoea, nausea 

Common Vomiting, dry 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 Dry 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 



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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 e 

Uncommon Amenorrhoea e* 

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” 
a 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 of opportunistic infections [e.g. aspergillosis, candidiasis, PJP/PCP 

and hepatitis B (see also section 4.4)] and (rare) viral myocarditis 
b Includes different bleeding events from different sites not listed individually 
c Includes (very common) pneumonitis, (common) interstitial lung disease, lung infiltration and 

(rare) pulmonary alveolar haemorrhage, pulmonary toxicity, and alveolitis 
d Includes (very common) stomatitis, (common) aphthous stomatitis, mouth and tongue ulceration 

and (uncommon) glossodynia, glossitis 
e 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 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 Afinitor-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 of age (20% vs. 13%). The most common adverse reactions leading to 

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 of the benefit/risk balance of the medicinal product. Healthcare 

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

listed in Appendix V. 

 



14 

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 and 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 

Afinitor + 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 in Solid Tumors), based on the 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. 

 

  



15 

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). The median duration of exemestane treatment was longer in the 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 Afinitora 

n=485 

Placeboa 

n=239 

Hazard ratio p value 

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

Investigator radiological review 7.8 

(6.9 to 8.5) 

3.2 

(2.8 to 4.1) 

0.45 

(0.38 to 0.54) 

<0.0001 

Independent radiological review 11.0 

(9.7 to 15.0) 

4.1 

(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 response rateb 

 

12.6% 

(9.8 to 15.9) 

1.7% 

(0.5 to 4.2) 
n/ad <0.0001e 

     

Clinical benefit ratec 51.3% 

(46.8 to 55.9) 

26.4% 

(20.9 to 32.4) 
n/ad <0.0001e 

a Plus exemestane 
b Objective response rate = proportion of patients with complete or partial response 
c Clinical benefit rate = proportion of patients with complete or partial response or stable disease 

≥24 weeks 
d Not applicable 
e p value is obtained from the exact Cochran-Mantel-Haenszel test using a stratified version of the 

Cochran-Armitage permutation test. 

 



16 

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

radiological review) 

 
The estimated PFS treatment effect was supported by planned subgroup analysis of PFS per 

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 (HR) 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), a three-arm, randomised, open-label, phase II study of 

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. 

0 

20 

40 

60 

80 

100 

Time (weeks) 

 

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 

Everolimus 

Placebo 

Number of Patients still at Risk 
Time(weeks) 

Hazard Ratio = 0.45 

95% CI [0.38, 0.54] 

Everolimus 10 mg + exemestane: 7.82 months 

Placebo + exemestane: 3.19 months 

Kaplan-Meier medians 

Everolimus 10 mg + exemestane (n/N = 310/485) 

Placebo + exemestane (n/N = 200/239) 

Censoring Times 

Log-rank p value: <0.0001 

  0   6  12  18  24  30  36  42  48  54  60  66  72  78  84  90  96 102 108 114 120 

485 436 366 304 257 221 185 158 124  91  66  50  35  24  22  13  10     8     2     1     0 

239 190 132  96  67  50  39  30  21  15  10    8    5    3    1    1    1     0     0     0     0 



17 

 

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. 

 

Figure 2 BOLERO-6 Kaplan-Meier progression-free survival curves (investigator 

radiological review) 

 

 
 

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). 

 

  

Hazard Ratio = 0.74 
90% CI [0.57;0.97] 

 
Kaplan-Meier medians 

Everolimus/Exemestane: 36.57 [28.71;42.29] weeks 
Everolimus: 29.43 [24.00;31.29] weeks 

Time (Weeks) 

P
ro

b
a
b
ili

ty
 (

%
) 

o
f 
e
v
e
n
t 

No of patients still at risk 

Time (weeks) 
Everolimus/Exemestane 

Everolimus 
 

Censoring Times 

Everolimus/Exemestane (n/N=80/104) 
Everolimus (n/N=74/103) 



18 

Advanced neuroendocrine tumours of pancreatic origin (pNET) 

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

Afinitor plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pNET, 

demonstrated a statistically significant clinical benefit of Afinitor 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 3). 

 

RADIANT-3 involved patients with well- and 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 Afinitor. 

 

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

(OS). 

 

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

(n=203). Demographics were well balanced (median age 58 years, 55% 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 Afinitor. 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 Afinitor 

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 

 



19 

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 

Afinitor 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 in Solid Tumors (RECIST), based on 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 Afinitor and 

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

the time of progression. 

 

  

0 

10 

20 

30 

40 

50 

60 

70 

80 

90 

100 

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 

Hazard Ratio = 0.35 
95% CI [0.27, 0.45] 

Log-rank p value = <0.001 

Kaplan-Meier medians 
Afinitor : 11.04 months 

Placebo :  4.60 months 

Censoring times 
Afinitor (n=207) 

Placebo (n=203) 

P
ro

b
a
b
ili

ty
 (

%
) 

 

No. of patients still at risk 

Afinitor 

Placebo 

Time (months) 

 

207 189 153 126 114 80 49 36 28 21 10 6 2 0 0 0 

203 117  98  59  52 24 16  7  4  3  2 1 1 1 1 0 



20 

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

and Figure 4). 

 

Table 6 RADIANT-4 – Progression-free survival results 

 

Population Afinitor 

n=205 

Placebo 

n=97 

Hazard ratio 

(95% CI) 

p-valuea 

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 

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

 

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

radiological review) 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

0 2 4 6 8 10 12 15 18 21 24 27 30 

0             2            4             6             8            10           12                  15                   18                  21                  24                   27                  30 

205      168          145         124        101           81           65                  52                   26                  10                  3                     0                    0 

97         65           39            30          24            21          17                  15                    11                  6                    5                     1                    0 

Time (months) 

 

Hazard Ratio = 0.48 

95% CI [0.35, 0.67] 

Log-rank p value = <0.001 

Kaplan-Meier medians 
Everolimus + BSC: 11.01 [9.23;13.31] months 

Placebo + BSC: 3.91 [3.58;7.43] months 

Censoring times 
Everolimus + BSC (n/N = 113/205) 
Placebo + BSC (n/N = 65/97) 

Number of Patients still at Risk 
Time(months) 

Everolimus 

Placebo 

P
ro

b
a
b
ili

ty
 (

%
) 

o
f 
e
v
e
n
t 



21 

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 5). 

 

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. 

 

  

All (N=302) 

<65 years (N=159) 

≥65 years (N=143) 

0 (N=216) 

1 (N=86) 

Yes (N=157) 

No (N=145) 

Yes (N=77) 

No (N=225) 

Lung (N=90) 

Ileum (N=71) 

Non-ileum* (N=141) 

Grade 1 (N=194) 

Grade 2 (N=107) 

≤10% (N=228) 

>10% (N=72) 

>2xULN (N=139) 

≤2xULN (N=138) 

>ULN (N=87) 

≤ULN (N=188) 

Everolimus + BSC Placebo + BSC 
In favour of 

Age 

WHO PS 

Prior SSA 

Prior 

chemotherapy 

Primary tumour 

origin 

Tumour grading 

Liver tumour 

burden 

Baseline CgA 

Baseline NSE 

*Non-ileum: stomach, colon, rectum, appendix, caecum, duodenum, jejunum, carcinoma of unknown primary 

origin and other gastrointestinal origin 

ULN: Upper limit of normal 

CgA: Chromogranin A 

NSE: Neuron specific enolase 

Hazard ratio (95% CI) from stratified Cox model 

 



22 

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 Afinitor (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. 

 

Afinitor 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 6). 

 

Table 7 RECORD-1 – Progression-free survival results 

 

Population n Afinitor 

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) 

416 4.9 

(4.0-5.5) 

1.9 

(1.8-1.9) 

0.33 

(0.25-0.43) 

<0.0001a 

Supportive/sensitivity analyses 

All (local review by 

investigator) 

416 5.5 

(4.6-5.8) 

1.9 

(1.8-2.2) 

0.32 

(0.25-0.41) 

<0.0001a 

MSKCC prognostic score (blinded independent central review) 

Favourable risk 120 5.8 

(4.0-7.4) 

1.9 

(1.9-2.8) 

0.31 

(0.19-0.50) 

<0.0001 

Intermediate risk 235 4.5 

(3.8-5.5) 

1.8 

(1.8-1.9) 

0.32 

(0.22-0.44) 

<0.0001 

Poor risk 61 3.6 

(1.9-4.6) 

1.8 

(1.8-3.6) 

0.44 

(0.22-0.85) 

0.007 

a Stratified log-rank test 

 



23 

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

review) 

 

 
 

Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo. 

 

Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, 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 Afinitor 

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 Afinitor 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 Afinitor (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 Afinitor (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 

Afinitor 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). 

Hazard Ratio = 0.33 

95% CI [0.25, 0.43] 

 

Kaplan-Meier medians 

Everolimus: 4.90 months 

Placebo: 1.87 months 

 

Log-rank p value = <0.0001 

Censoring Times 

Everolimus (n/N = 155/277) 

Placebo (n/N = 111/139) 

Time (months) 

P
ro

b
a
b
ili

ty
 (

%
) 

No. of patients still at risk 

Time (months) 

Afinitor 

Placebo 



24 

 

5.2 Pharmacokinetic properties 
 

Absorption 

In patients with advanced solid tumours, peak everolimus concentrations (Cmax) 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. Cmax 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 Cmax by 54%. Light fat meals reduced AUC by 32% 

and Cmax by 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, Vd 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, 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, 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 AUC0-τ was 

dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within 2 weeks. 

Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was a 

significant correlation between AUC0-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 Afinitor 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. 

 



25 

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. AUC0-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 in epididymides and uterine atrophy) in 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 to spontaneously exacerbate background diseases (chronic myocarditis in 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 AUC0-24h 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. 

 



26 

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 3.9 and 0.2 times the 

estimated clinical exposure. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Butylhydroxytoluene 

Magnesium stearate 

Lactose monohydrate 

Hypromellose 

Crospovidone type A 

Lactose anhydrous 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

3 years. 

 

6.4 Special precautions for storage 
 

Do not store above 25°C. 

 

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 containing 10 tablets. 

 

Afinitor 2.5 mg tablets 

Packs containing 30 or 90 tablets. 

 

Afinitor 5 mg tablets 

Packs containing 10, 30 or 90 tablets. 

 

Afinitor 10 mg tablets 

Packs containing 10, 30 or 90 tablets. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 
 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 



27 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Afinitor 2.5 mg tablets 

EU/1/09/538/009 

EU/1/09/538/010 

 

Afinitor 5 mg tablets 

EU/1/09/538/001 

EU/1/09/538/003 

EU/1/09/538/007 

 

Afinitor 10 mg tablets 

EU/1/09/538/004 

EU/1/09/538/006 

EU/1/09/538/008 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 03 August 2009 

Date of latest renewal: 02 April 2019 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu 

  



28 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



29 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Novartis Farmacéutica SA 

Ronda de Santa Maria 158 

08210 Barberà del Vallès, Barcelona 

Spain 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 
The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic Safety Update Reports 

 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 

 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 
 

  



30 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



31 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
  



32 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Afinitor 2.5 mg tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 2.5 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

30 tablets 

90 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. 

Store in the original package in order to protect from light and moisture. 

 

 



33 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/09/538/009 30 tablets 

EU/1/09/538/010 90 tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Afinitor 2.5 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 
NN: 

  



34 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Afinitor 2.5 mg tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



35 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Afinitor 5 mg tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 5 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

10 tablets 

30 tablets 

90 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. 

Store in the original package in order to protect from light and moisture. 

 

 



36 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/09/538/007 10 tablets 

EU/1/09/538/001 30 tablets 

EU/1/09/538/003 90 tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Afinitor 5 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 
NN: 

  



37 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Afinitor 5 mg tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



38 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Afinitor 10 mg tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 10 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

10 tablets 

30 tablets 

90 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. 

Store in the original package in order to protect from light and moisture. 

 

 



39 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/09/538/008 10 tablets 

EU/1/09/538/004 30 tablets 

EU/1/09/538/006 90 tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Afinitor 10 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



40 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Afinitor 10 mg tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



41 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 
 



42 

Package leaflet: Information for the patient 

 

Afinitor 2.5 mg tablets 

Afinitor 5 mg tablets 

Afinitor 10 mg tablets 

everolimus 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 
 

1. What Afinitor is and what it is used for 

2. What you need to know before you take Afinitor 

3. How to take Afinitor 

4. Possible side effects 

5. How to store Afinitor 

6. Contents of the pack and other information 

 

 

1. What Afinitor is and what it is used for 

 

Afinitor is an anticancer medicine containing the active substance everolimus. Everolimus reduces the 

blood supply to the tumour and slows down the growth and spread of cancer cells. 

 

Afinitor is used to treat adult patients with: 

 hormone receptor-positive advanced breast cancer in postmenopausal women, in whom other 
treatments (so called “non-steroidal aromatase inhibitors”) no longer keep the disease under 

control. It is given together with a medicine called exemestane, a steroidal aromatase inhibitor, 

which is used for hormonal anticancer therapy. 

 advanced tumours called neuroendocrine tumours that originate from the stomach, bowels, lung 
or pancreas. It is given if the tumours are inoperable and do not overproduce specific hormones 

or other related natural substances. 

 advanced kidney cancer (advanced renal cell carcinoma), where other treatments (so-called 
“VEGF-targeted therapy”) have not helped stop your disease. 

 

 

2. What you need to know before you take Afinitor 

 

Afinitor will only be prescribed for you by a doctor with experience in cancer treatment. Follow all the 

doctor’s instructions carefully. They may differ from the general information contained in this leaflet. 

If you have any questions about Afinitor or why it has been prescribed for you, ask your doctor. 

 

Do not take Afinitor 

 if you are allergic to everolimus, to related substances such as sirolimus or temsirolimus, or to 
any of the other ingredients of this medicine (listed in section 6). 

If you think you may be allergic, ask your doctor for advice. 

 



43 

Warnings and precautions 

Talk to your doctor before taking Afinitor: 

 if you have any problems with your liver or if you have ever had any disease which may have 
affected your liver. If this is the case, your doctor may need to prescribe a different dose of 

Afinitor. 

 if you have diabetes (high level of sugar in your blood). Afinitor may increase blood sugar 
levels and worsen diabetes mellitus. This may result in the need for insulin and/or oral 

antidiabetic agent therapy. Tell your doctor if you experience any excessive thirst or increased 

frequency of urination. 

 if you need to receive a vaccine while taking Afinitor. 

 if you have high cholesterol. Afinitor may elevate cholesterol and/or other blood fats. 

 if you have had recent major surgery, or if you still have an unhealed wound following surgery. 
Afinitor may increase the risk of problems with wound healing. 

 if you have an infection. It may be necessary to treat your infection before starting Afinitor. 

 if you have previously had hepatitis B, because this may be reactivated during treatment with 
Afinitor (see section 4 ‘Possible side effects’). 

 

Afinitor may also: 

 weaken your immune system. Therefore, you may be at risk of getting an infection while you 
are taking Afinitor. If you have fever or other signs of an infection, consult with your doctor. 

Some infections may be severe and may have fatal consequences. 

 impact your kidney function. Therefore, your doctor will monitor your kidney function while 
you are taking Afinitor. 

 cause shortness of breath, cough and fever. 

 cause mouth ulcers and sores to develop. Your doctor might need to interrupt or discontinue 
your treatment with Afinitor. You might need treatment with a mouthwash, gel or other 

products. Some mouthwashes and gels can make ulcers worse, so do not try anything without 

checking with your doctor first. Your doctor might restart treatment with Afinitor at the same 

dose or at a lower dose. 

Tell your doctor if you experience these symptoms. 

 

You will have regular blood tests during treatment. These will check the amount of blood cells (white 

blood cells, red blood cells and platelets) in your body to see if Afinitor is having an unwanted effect 

on these cells. Blood tests will also be carried out to check your kidney function (level of creatinine) 

and liver function (level of transaminases) and your blood sugar and cholesterol levels. This is because 

these can also be affected by Afinitor. 

 

Children and adolescents 

Afinitor is not to be used in children or adolescents (age below 18 years). 

 

Other medicines and Afinitor 
Afinitor may affect the way some other medicines work. If you are taking other medicines at the same 

time as Afinitor, your doctor may need to change the dose of Afinitor or the other medicines. 

 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 



44 

The following may increase the risk of side effects with Afinitor: 

 ketoconazole, itraconazole, voriconazole, or fluconazole and other antifungals used to treat 
fungal infections. 

 clarithromycin, telithromycin or erythromycin, antibiotics used to treat bacterial infections. 

 ritonavir and other medicines used to treat HIV infection/AIDS. 

 verapamil or diltiazem, used to treat heart conditions or high blood pressure. 

 dronedarone, a medicine used to help regulate your heart beat. 

 ciclosporin, a medicine used to stop the body from rejecting organ transplants. 

 imatinib, used to inhibit the growth of abnormal cells. 

 angiotensin-converting enzyme (ACE) inhibitors (such as ramipril) used to treat high blood 
pressure or other cardiovascular problems. 

 nefazodone, used to treat depression. 
 

The following may reduce the effectiveness of Afinitor: 

 rifampicin, used to treat tuberculosis (TB). 

 efavirenz or nevirapine, used to treat HIV infection/AIDS. 

 St. John’s wort (Hypericum perforatum), a herbal product used to treat depression and other 
conditions. 

 dexamethasone, a corticosteroid used to treat a wide variety of conditions including 
inflammatory or immune problems. 

 phenytoin, carbamazepine or phenobarbital and other anti-epileptics used to stop seizures or fits. 
 

These medicines should be avoided during your treatment with Afinitor. If you are taking any of them, 

your doctor may switch you to a different medicine, or may change your dose of Afinitor. 

 

Afinitor with food and drink 

Avoid grapefruit and grapefruit juice while you are on Afinitor. 

 

Pregnancy, breast-feeding and fertility 

 

Pregnancy 

Afinitor could harm your unborn baby and is not recommended during pregnancy. Tell your doctor if 

you are pregnant or think that you may be pregnant. Your doctor will discuss with you whether you 

should take this medicine during your pregnancy. 

 

Women who could potentially become pregnant should use highly effective contraception during 

treatment and for up to 8 weeks after ending treatment. If, despite these measures, you think you may 

have become pregnant, ask your doctor for advice before taking any more Afinitor. 

 

Breast-feeding 

Afinitor could harm your breast-fed baby. You should not breast-feed during treatment and for 

2 weeks after the last dose of Afinitor. Tell your doctor if you are breast-feeding. 

 

Female fertility 

Absence of menstrual periods (amenorrhoea) has been observed in some female patients receiving 

Afinitor. 

 

Afinitor may have an impact on female fertility. Talk to your doctor if you wish to have children. 

 

Male fertility 

Afinitor may affect male fertility. Talk to your doctor if you wish to father a child. 

 

Driving and using machines 

If you feel unusually tired (fatigue is a very common side effect), take special care when driving or 

using machines. 

 



45 

Afinitor contains lactose 

Afinitor contains lactose (milk sugar). If you have been told by your doctor that you have an 

intolerance to some sugars, contact your doctor before taking this medicine. 

 

 

3. How to take Afinitor 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

The recommended dose is 10 mg, taken once a day. Your doctor will tell you how many tablets of 

Afinitor to take. 

 

If you have liver problems, your doctor may start you on a lower dose of Afinitor (2.5, 5 or 7.5 mg per 

day). 

 

If you experience certain side effects while you are taking Afinitor (see section 4), your doctor may 

lower your dose or stop treatment, either for a short time or permanently. 

 

Take Afinitor once a day, at about the same time every day, consistently either with or without food. 

 

Swallow the tablet(s) whole with a glass of water. Do not chew or crush the tablets. 

 

If you take more Afinitor than you should 

 If you have taken too much Afinitor, or if someone else accidentally takes your tablets, see a 
doctor or go to a hospital immediately. Urgent treatment may be necessary. 

 Take the carton and this leaflet, so that the doctor knows what has been taken. 
 

If you forget to take Afinitor 

If you miss a dose, take your next dose as scheduled. Do not take a double dose to make up for the 

forgotten tablets. 

 

If you stop taking Afinitor 

Do not stop taking Afinitor unless your doctor tells you to. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

STOP taking Afinitor and seek medical help immediately if you experience any of the following signs 

of an allergic reaction: 

 difficulty breathing or swallowing 

 swelling of the face, lips, tongue or throat 

 severe itching of the skin, with a red rash or raised bumps 
 

Serious side effects of Afinitor include: 

 

Very common (may affect more than 1 in 10 people) 

 Increased temperature, chills (signs of infection) 

 Fever, coughing, difficulty breathing, wheezing (signs of inflammation of the lung, also known 
as pneumonitis) 

 



46 

Common (may affect up to 1 in 10 people) 

 Excessive thirst, high urine output, increased appetite with weight loss, tiredness (signs of 
diabetes) 

 Bleeding (haemorrhage), for example in the gut wall 

 Severely decreased urine output (sign of kidney failure) 
 

Uncommon (may affect up to 1 in 100 people) 

 Fever, skin rash, joint pain and inflammation, as well as tiredness, loss of appetite, nausea, 
jaundice (yellowing of the skin), pain in the upper right abdomen, pale stools, dark urine (may 

be signs of hepatitis B reactivation) 

 Breathlessness, difficulty breathing when lying down, swelling of the feet or legs (signs of heart 
failure) 

 Swelling and/or pain in one of the legs, usually in the calf, redness or warm skin in the affected 
area (signs of blockade of a blood vessel (vein) in the legs caused by blood clotting) 

 Sudden onset of shortness of breath, chest pain or coughing up blood (potential signs of 
pulmonary embolism, a condition that occurs when one or more arteries in your lungs become 

blocked) 

 Severely decreased urine output, swelling in the legs, feeling confused, pain in the back (signs 
of sudden kidney failure) 

 Rash, itching, hives, difficulty breathing or swallowing, dizziness (signs of serious allergic 
reaction, also known as hypersensitivity) 

 

Rare (may affect up to 1 in 1,000 people) 

 Shortness of breath or rapid breath (signs of acute respiratory distress syndrome) 

 

If you experience any of these side effects, tell your doctor immediately as this might have 

life-threatening consequences. 

 

Other possible side effects of Afinitor include: 

 

Very common (may affect more than 1 in 10 people) 

 High level of sugar in the blood (hyperglycaemia) 

 Loss of appetite 

 Disturbed taste (dysgeusia) 

 Headache 

 Nose bleeds (epistaxis) 

 Cough 

 Mouth ulcers 

 Upset stomach including feeling sick (nausea) or diarrhoea 

 Skin rash 

 Itching (pruritus) 

 Feeling weak or tired 

 Tiredness, breathlessness, dizziness, pale skin, signs of low level of red blood cells (anaemia) 

 Swelling of arms, hands, feet, ankles or other part of the body (signs of oedema) 

 Weight loss 

 High level of lipids (fats) in the blood (hypercholesterolaemia) 
 

  



47 

Common (may affect up to 1 in 10 people) 

 Spontaneous bleeding or bruising (signs of low level of platelets, also known as 
thrombocytopenia) 

 Breathlessness (dyspnoea) 

 Thirst, low urine output, dark urine, dry flushed skin, irritability (signs of dehydration) 

 Trouble sleeping (insomnia) 

 Headache, dizziness (sign of high blood pressure, also known as hypertension) 

 Fever, sore throat, mouth ulcers due to infections (signs of low level of white blood cells, 
leukopenia, lymphopenia and/or neutropenia) 

 Fever 

 Inflammation of the inner lining of the mouth, stomach, gut 

 Dry mouth 

 Heartburn (dyspepsia) 

 Being sick (vomiting) 

 Difficulty in swallowing (dysphagia) 

 Abdominal pain 

 Acne 

 Rash and pain on the palms of your hands or soles of your feet (hand-foot syndrome) 

 Reddening of the skin (erythema) 

 Joint pain 

 Pain in the mouth 

 Menstruation disorders such as irregular periods 

 High level of lipids (fats) in the blood (hyperlipidaemia, raised triglycerides) 

 Low level of potassium in the blood (hypokalaemia) 

 Low level of phosphate in the blood (hypophosphataemia) 

 Low level of calcium in the blood (hypocalcaemia) 

 Dry skin, skin exfoliation, skin lesions 

 Nail disorders, breaking of your nails 

 Mild loss of hair 

 Abnormal results of liver blood tests (increased alanine and aspartate aminotransferase) 

 Abnormal results of renal blood tests (increased creatinine) 

 Swelling of the eyelid 

 Protein in the urine 
 

Uncommon (may affect up to 1 in 100 people) 

 Weakness, spontaneous bleeding or bruising and frequent infections with signs such as fever, 
chills, sore throat or mouth ulcers (signs of low level of blood cells, also known as 

pancytopenia) 

 Loss of sense of taste (ageusia) 

 Coughing up blood (haemoptysis) 

 Menstruation disorders such as absence of periods (amenorrhoea) 

 Passing urine more often during daytime 

 Chest pain 

 Abnormal wound healing 

 Hot flushes 

 Discharge from the eye with itching and redness, pink eye or red eye (conjunctivitis) 
 

Rare (may affect up to 1 in 1,000 people) 

 Tiredness, breathlessness, dizziness, pale skin (signs of low level of red blood cells, possibly 
due to a type of anaemia called pure red cell aplasia) 

 Swelling of the face, around the eyes, mouth, and inside the mouth and/or throat, as well as the 
tongue and difficulty breathing or swallowing (also known as angioedema), may be signs of an 

allergic reaction 

 



48 

If these side effects get severe please tell your doctor and/or pharmacist. Most of the side effects 

are mild to moderate and will generally disappear if your treatment is interrupted for a few 

days. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

5. How to store Afinitor 
 

 Keep this medicine out of the sight and reach of children. 

 Do not use this medicine after the expiry date which is stated on the carton and blister foil. The 
expiry date refers to the last day of that month. 

 Do not store above 25°C. 

 Store in the original package in order to protect from light and moisture. 

 Open the blister just before taking the tablets. 

 Do not use this medicine if any pack is damaged or shows signs of tampering. 
 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Afinitor contains 

 The active substance is everolimus. 

 Each tablet of Afinitor 2.5 mg contains 2.5 mg everolimus. 

 Each tablet of Afinitor 5 mg contains 5 mg everolimus. 

 Each tablet of Afinitor 10 mg contains 10 mg everolimus. 

 The other ingredients are butylhydroxytoluene, magnesium stearate, lactose monohydrate, 
hypromellose, crospovidone type A and lactose anhydrous. 

 

What Afinitor looks like and contents of the pack 

Afinitor 2.5 mg tablets are white to slightly yellowish, elongated tablets. They are engraved with 

“LCL” on one side and “NVR” on the other. 

Afinitor 5 mg tablets are white to slightly yellowish, elongated tablets. They are engraved with “5” on 

one side and “NVR” on the other. 

Afinitor 10 mg tablets are white to slightly yellowish, elongated tablets. They are engraved with 

“UHE” on one side and “NVR” on the other. 

 

Afinitor 2.5 mg is available in blister packs containing 30 or 90 tablets. 

Afinitor 5 mg and Afinitor 10 mg are available in blister packs containing 10, 30 or 90 tablets. 

Not all pack sizes or strengths may be marketed in your country. 

 

  



49 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Farmacéutica SA 

Ronda de Santa Maria 158 

08210 Barberà del Vallès, Barcelona 

Spain 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 
Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 
SIA Novartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 
Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 
Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 
Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 
Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 
Novartis Pharma B.V. 

Tel: +31 88 04 52 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 
Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 
Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 
Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 
Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 



50 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 
Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 
Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 
Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 
Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET