AFINITOR 5mg tablets medication leaflet

Afinitor 2.5 mg tablets

Afinitor 5 mg tablets

Afinitor 10 mg tablets

Afinitor 2.5 mg tablets

Each tablet contains 2.5 mg everolimus.

Each tablet contains 74 mg lactose.

Afinitor 5 mg tablets

Each tablet contains 5 mg everolimus.

Each tablet contains 149 mg lactose.

Afinitor 10 mg tablets

Each tablet contains 10 mg everolimus.

Each tablet contains 297 mg lactose.

For the full list of excipients, see section 6.1.

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.

Hormone receptor-positive advanced breast cancer

Afinitor is indicated for the treatment of hormone receptor-positive, HER2/neu negative advancedbreast cancer, in combination with exemestane, in postmenopausal women without symptomaticvisceral 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-differentiatedneuroendocrine 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 withprogressive disease (see sections 4.4 and 5.1).

Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma, whose diseasehas progressed on or after treatment with VEGF-targeted therapy.

Treatment with Afinitor should be initiated and supervised by a physician experienced in the use ofanticancer therapies.

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 clinicalbenefit 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 asusual.

Dose adjustment due to adverse reactions

Management of severe and/or intolerable suspected adverse reactions may require dose reductionand/or temporary interruption of Afinitor therapy. For adverse reactions of Grade 1, dose adjustment isusually not required. If dose reduction is required, the recommended dose is 5 mg daily and must notbe lower than 5 mg daily.

Table 1 summarises the dose adjustment recommendations for specific adverse reactions (see alsosection 4.4).

Table 1 Afinitor dose adjustment recommendations

Adverse reaction Severity1 Afinitor dose adjustment

Non-infectious Grade 2 Consider interruption of therapy until symptoms improvepneumonitis 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 toxicityrecurs 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 untilrecovery 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 Grade 2 If toxicity is tolerable, no dose adjustment required.

non-haematological If toxicity becomes intolerable, temporary dosetoxicities interruption until recovery to Grade 1. Re-initiate(excluding treatment at same dose.metabolic events) If toxicity recurs at Grade 2, interrupt treatment untilrecovery 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 toxicityrecurs at Grade 3, consider discontinuation.

Grade 4 Discontinue treatment.

Metabolic events Grade 2 No dose adjustment required.

(e.g.

hyperglycaemia,dyslipidaemia)

Grade 3 Temporary dose interruption.

Re-initiate treatment at 5 mg daily.

Grade 4 Discontinue treatment.

Thrombocytopenia Grade 2 Temporary dose interruption until recovery to Grade 1(<75, ≥50x109/l) (≥75x109/l). Re-initiate treatment at same dose.

Grade 3 & 4 Temporary dose interruption until recovery to Grade 1(<50x109/l) (≥75x109/l). Re-initiate treatment at 5 mg daily.

Neutropenia Grade 2 No dose adjustment required.

(≥1x109/l)

Grade 3 Temporary dose interruption until recovery to Grade 2(<1, ≥0.5x109/l) (≥1x109/l). Re-initiate treatment at same dose.

Grade 4 Temporary dose interruption until recovery to Grade 2(<0.5x109/l) (≥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

No dose adjustment is required (see section 5.2).

No dose adjustment is required (see section 5.2).

* 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 desiredbenefit 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).

The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No dataare available.

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

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipientslisted in section 6.1.

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 inpatients taking Afinitor (see section 4.8). Some cases were severe and on rare occasions, a fataloutcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patientspresenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, coughor dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been excludedby means of appropriate investigations. Opportunistic infections such as pneumocystis jirovecii(carinii) pneumonia (PJP/PCP) should be ruled out in the differential diagnosis of non-infectiouspneumonitis (see “Infections” below). Patients should be advised to report promptly any new orworsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few orno 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 symptomsresolve.

For patients who require use of corticosteroids for treatment of non-infectious pneumonitis,prophylaxis for PJP/PCP may be considered.

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viralor protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localisedand systemic infections, including pneumonia, other bacterial infections, invasive fungal infectionssuch as aspergillosis, candidiasis or PJP/PCP and viral infections including reactivation of hepatitis Bvirus, 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-existinginfections should be treated appropriately and should have resolved fully before starting treatmentwith Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis ofinfection is made, institute appropriate treatment promptly and consider interruption or discontinuationof Afinitor.

If a diagnosis of invasive systemic fungal infection is made, the Afinitor treatment should be promptlyand 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 immunosuppressiveagents. Prophylaxis for PJP/PCP should be considered when concomitant use of corticosteroids orother immunosuppressive agents are required.

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 withoutrespiratory 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 forangioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (seesection 4.5).

Stomatitis

Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adversereaction in patients treated with Afinitor (see section 4.8). Stomatitis mostly occurs within the first8 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 amouthwash during the initial 8 weeks of treatment, may decrease the incidence and severity ofstomatitis (see section 5.1). Management of stomatitis may therefore include prophylactic and/ortherapeutic use of topical treatments, such as an alcohol-free corticosteroid oral solution as amouthwash. However products containing alcohol, hydrogen peroxide, iodine and thyme derivativesshould be avoided as they may exacerbate the condition. Monitoring for and treatment of fungalinfection 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 inpatients treated with Afinitor (see section 4.8). Renal function should be monitored particularly wherepatients have additional risk factors that may further impair renal function.

Laboratory tests and monitoring

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 orserum 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 isrecommended prior to the start of Afinitor therapy and periodically thereafter. More frequentmonitoring is recommended when Afinitor is co-administered with other medicinal products that mayinduce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting apatient 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 periodicallythereafter, 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 andperiodically 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 meetthe primary efficacy endpoint (progression-free-survival [PFS]) and the overall survival (OS) interimanalysis numerically favoured the placebo plus depot octreotide arm. Therefore, the safety andefficacy 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 prognosticbaseline factors, e.g. ileum as primary tumour origin and normal chromogranin A values or withoutbone 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 ileumas primary tumour origin (see section 5.1).

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 PgPinhibitor or inducer cannot be avoided, the clinical condition of the patient should be monitoredclosely. Dose adjustments of Afinitor can be taken into consideration based on predicted AUC (seesection 4.5).

Concomitant treatment with potent CYP3A4/PgP inhibitors result in dramatically increased plasmaconcentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosingrecommendations in this situation. Hence, concomitant treatment of Afinitor and potent inhibitors isnot recommended.

Caution should be exercised when Afinitor is taken in combination with orally administered CYP3A4substrates with a narrow therapeutic index due to the potential for drug interactions. If Afinitor istaken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide,terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should bemonitored for undesirable effects described in the product information of the orally administered

CYP3A4 substrate (see section 4.5).

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 thepotential benefit outweighs the risk (see sections 4.2 and 5.2).

No clinical safety or efficacy data are currently available to support dose adjustment recommendationsfor the management of adverse reactions in patients with hepatic impairment.

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

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

Impaired wound healing is a class effect of rapamycin derivatives, including everolimus. Cautionshould therefore be exercised with the use of Afinitor in the peri-surgical period.

Radiation therapy complications

Serious and severe radiation reactions (such as radiation oesophagitis, radiation pneumonitis andradiation skin injury), including fatal cases, have been reported when everolimus was taken during, orshortly after, radiation therapy. Caution should therefore be exercised for the potentiation ofradiotherapy toxicity in patients taking everolimus in close temporal relationship with radiationtherapy.

Additionally, radiation recall syndrome (RRS) has been reported in patients taking everolimus whohad received radiation therapy in the past. In the event of RRS, interrupting or stopping everolimustreatment should be considered.

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 inhibitorof CYP2D6.

Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP arelisted in Table 2 below.

CYP3A4 and PgP inhibitors increasing everolimus concentrations

Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations bydecreasing 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 byincreasing metabolism or the efflux of everolimus from intestinal cells.

Table 2 Effects of other active substances on everolimus

Active substance by Interaction - Change in Recommendations concerninginteraction Everolimus AUC/Cmax co-administration

Geometric mean ratio(observed range)

Potent CYP3A4/PgP inhibitors

Ketoconazole AUC ↑15.3-fold Concomitant treatment of Afinitor(range 11.2-22.5) and potent inhibitors is not

Cmax ↑4.1-fold recommended.

(range 2.6-7.0)

Itraconazole, posaconazole, Not studied. Large increase invoriconazole everolimus concentration is

Telithromycin, expected.

clarithromycin

Nefazodone

Ritonavir, atazanavir,saquinavir, darunavir,indinavir, nelfinavir

Moderate CYP3A4/PgP inhibitors

Erythromycin AUC ↑4.4-fold Use caution when(range 2.0-12.6) co-administration of moderate

Cmax ↑2.0-fold CYP3A4 inhibitors or PgP(range 0.9-3.5) inhibitors cannot be avoided. If

Imatinib AUC ↑ 3.7-fold patients require co-administration

Cmax ↑ 2.2-fold of a moderate CYP3A4 or PgP

Verapamil AUC ↑3.5-fold inhibitor, dose reduction to 5 mg(range 2.2-6.3) daily or 2.5 mg daily may be

Cmax ↑2.3-fold considered. However, there are no(range1.3-3.8) clinical data with this dose

Ciclosporin oral AUC ↑2.7-fold adjustment. Due to between(range 1.5-4.7) subject variability the

Cmax ↑1.8-fold recommended dose adjustments(range 1.3-2.6) may not be optimal in all

Cannabidiol (PgP inhibitor) AUC ↑2.5-fold individuals, therefore close

C ↑2.5-fold monitoring of side effects ismax

Fluconazole Not studied. Increased exposure recommended (see sections 4.2 and

Diltiazem expected. 4.4). If the moderate inhibitor is

Dronedarone Not studied. Increased exposure discontinued, consider a washoutexpected. period of at least 2 to 3 days

Amprenavir, fosamprenavir Not studied. Increased exposure (average elimination time for mostexpected. commonly used moderateinhibitors) before the Afinitor doseis returned to the dose used prior toinitiation of the co-administration.

Grapefruit juice or other Not studied. Increased exposure Combination should be avoided.

food affecting CYP3A4/PgP expected (the effect varieswidely).

Potent and moderate CYP3A4 inducers

Rifampicin AUC ↓63% Avoid the use of concomitant(range 0-80%) potent CYP3A4 inducers. If

Cmax ↓58% patients require co-administration(range 10-70%) of a potent CYP3A4 inducer, an

Dexamethasone Not studied. Decreased exposure Afinitor dose increase from 10 mgexpected. daily up to 20 mg daily should be

Carbamazepine, Not studied. Decreased exposure considered using 5 mg incrementsphenobarbital, phenytoin expected. or less applied on Day 4 and 8

Efavirenz, nevirapine Not studied. Decreased exposure following start of the inducer. Thisexpected. dose of Afinitor is predicted toadjust the AUC to the rangeobserved without inducers.

However, there are no clinical datawith this dose adjustment. Iftreatment with the inducer isdiscontinued, consider a washoutperiod of at least 3 to 5 days(reasonable time for significantenzyme de-induction), before the

Afinitor dose is returned to thedose used prior to initiation of theco-administration.

St John’s Wort (Hypericum Not studied. Large decrease in Preparations containing St John’sperforatum) exposure expected. Wort should not be used duringtreatment 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 makeinhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in thegut cannot be excluded. An interaction study in healthy subjects demonstrated that co-administrationof 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 dueto inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability oforally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure ofsystemically administered CYP3A4 substrates is not expected (see section 4.4).

Co-administration of everolimus and depot octreotide increased octreotide Cmin with a geometric meanratio (everolimus/placebo) of 1.47. A clinically significant effect on the efficacy response toeverolimus 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 differentbetween the two treatment arms. No increase in adverse reactions related to exemestane was observedin patients with hormone receptor-positive advanced breast cancer receiving the combination. Theincrease 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 forangioedema (see section 4.4).

The immune response to vaccination may be affected and, therefore, vaccination may be less effectiveduring 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 typhoidvaccines.

Radiation treatment

Potentiation of radiation treatment toxicity has been reported in patients receiving everolimus (seesections 4.4 and 4.8).

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-basedcontraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device[IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks afterending treatment. Male patients should not be prohibited from attempting to father children.

There are no adequate data from the use of everolimus in pregnant women. Studies in animals haveshown reproductive toxicity effects including embryotoxicity and foetotoxicity (see section 5.3). Thepotential risk for humans is unknown.

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

It is not known whether everolimus is excreted in human breast milk. However, in rats, everolimusand/or its metabolites readily pass into the milk (see section 5.3). Therefore, women taking everolimusshould not breast-feed during treatment and for 2 weeks after the last dose.

The potential for everolimus to cause infertility in male and female patients is unknown, howeveramenorrhoea (secondary amenorrhoea and other menstrual irregularities) and associated luteinisinghormone (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 witheverolimus (see section 5.3).

Afinitor has minor or moderate influence on the ability to drive and use machines. Patients should beadvised to be cautious when driving or using machines if they experience fatigue during treatmentwith Afinitor.

The safety profile is based on pooled data from 2,879 patients treated with Afinitor in eleven clinicalstudies, 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 (indecreasing 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) increasedand diabetes mellitus. The grades follow CTCAE Version 3.0 and 4.03.

Table 3 presents the frequency category of adverse reactions reported in the pooled analysisconsidered for the safety pooling. Adverse reactions are listed according to MedDRA system organclass and frequency category. Frequency categories are defined using the following convention: verycommon (≥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); not known (cannot be estimated from the available data). Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3 Adverse reactions reported in clinical studies

Very common Infections a, *

Very common Anaemia

Common Thrombocytopenia, neutropenia, leukopenia, lymphopenia

Uncommon Pancytopenia

Rare Pure red cell aplasia

Uncommon Hypersensitivity

Very common Decreased appetite, hyperglycaemia, hypercholesterolaemia

Common Hypertriglyceridaemia, hypophosphataemia, diabetes mellitus, hyperlipidaemia,hypokalaemia, dehydration, hypocalcaemia

Common Insomnia

Very common Dysgeusia, headache

Uncommon Ageusia

Common Eyelid oedema

Uncommon Conjunctivitis

Uncommon Congestive cardiac failure

Common Haemorrhage b, hypertension, lymphoedemag

Uncommon Flushing, deep vein thrombosis

Very common Pneumonitis c, epistaxis, cough

Common Dyspnoea

Uncommon Haemoptysis, pulmonary embolism

Rare Acute respiratory distress syndrome

Very common Stomatitis d, diarrhoea, nausea

Common Vomiting, dry mouth, abdominal pain, mucosal inflammation, oral pain, dyspepsia,dysphagia

Common Aspartate aminotransferase increased, alanine aminotransferase increased

Very common Rash, pruritus

Common Dry skin, nail disorders, mild alopecia, acne, erythema, onychoclasis, palmar-plantarerythrodysaesthesia syndrome, skin exfoliation, skin lesion

Rare Angioedema*

Common Arthralgia

Common Proteinuria*, blood creatinine increased, renal failure*

Uncommon Increased daytime urination, acute renal failure*

Common Menstruation irregular e

Uncommon Amenorrhoea e*

Very common Fatigue, asthenia, oedema peripheral

Common Pyrexia

Uncommon Non-cardiac chest pain, impaired wound healing

Very common Weight decreased

Not knownf Radiation recall syndrome, potentiation of radiation reaction

* 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/PCPand hepatitis B (see also section 4.4)] and (rare) viral myocarditisb Includes different bleeding events from different sites not listed individuallyc Includes (very common) pneumonitis, (common) interstitial lung disease, lung infiltration and(rare) pulmonary alveolar haemorrhage, pulmonary toxicity, and alveolitisd Includes (very common) stomatitis, (common) aphthous stomatitis, mouth and tongue ulcerationand (uncommon) glossodynia, glossitise Frequency based upon number of women from 10 to 55 years of age in the pooled dataf Adverse reaction identified in the post-marketing settingg Adverse reaction was determined based on post-marketing reports. Frequency was determinedbased on oncology studies safety pool.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated withserious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is anexpected event during periods of immunosuppression.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renalfailure 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 casesof amenorrhoea (secondary amenorrhoea and other menstrual irregularities).

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with casesof PJP/PCP, some with fatal outcome (see section 4.4).

In clinical studies and post-marketing spontaneous reports, angioedema has been reported with andwithout concomitant use of ACE inhibitors (see section 4.4).

In the safety pooling, 37% of the Afinitor-treated patients were ≥65 years of age. The number ofpatients with an adverse reaction leading to discontinuation of the medicinal product was higher inpatients ≥65 years of age (20% vs. 13%). The most common adverse reactions leading todiscontinuation were pneumonitis (including interstitial lung disease), stomatitis, fatigue anddyspnoea.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have beengiven with acceptable acute tolerability. General supportive measures should be initiated in all cases ofoverdose.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EG02

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a keyserine-threonine kinase, the activity of which is known to be upregulated in a number of humancancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibitsmTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes withthe 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 involvedin the cell cycle, angiogenesis and glycolysis. S6K1is thought to phosphorylate the activation functiondomain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation.

Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumourangiogenic 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 toreduce glycolysis in solid tumours in vitro and in vivo.

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 withoestrogen receptor-positive, HER2/neu negative advanced breast cancer with recurrence orprogression following prior therapy with letrozole or anastrozole. Randomisation was stratified bydocumented 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 (completeresponse [CR], partial response [PR], stable disease ≥24 weeks) from at least one prior hormonaltherapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior torecurrence.

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 (localradiology). 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 Groupperformance status) deterioration.

A total of 724 patients were randomised in a 2:1 ratio to the combination everolimus (10 mg daily) +exemestane (25 mg daily) (n=485) or to the placebo + exemestane arm (25 mg daily) (n=239). At thetime of the final OS analysis, the median duration of everolimus treatment was 24.0 weeks (range1.0-199.1 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 4and Figure 1). Patients in the placebo + exemestane arm did not cross over to everolimus at the time ofprogression.

Table 4 BOLERO-2 efficacy results

Analysis Afinitora Placeboa Hazard ratio p valuen=485 n=239

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

Investigator radiological review 7.8 3.2 0.45 <0.0001(6.9 to 8.5) (2.8 to 4.1) (0.38 to 0.54)

Independent radiological review 11.0 4.1 0.38 <0.0001(9.7 to 15.0) (2.9 to 5.6) (0.31 to 0.48)

Median overall survival (months) (95% CI)

Median overall survival 31.0 26.6 0.89 0.1426(28.0 - 34.6) (22.6 - 33.1) (0.73 - 1.10)

Best overall response (%) (95% CI)

Objective response rateb 12.6% 1.7%n/ad <0.0001e(9.8 to 15.9) (0.5 to 4.2)

Clinical benefit ratec 51.3% 26.4%n/ad <0.0001e(46.8 to 55.9) (20.9 to 32.4)a Plus exemestaneb Objective response rate = proportion of patients with complete or partial responsec Clinical benefit rate = proportion of patients with complete or partial response or stable disease≥24 weeksd Not applicablee p value is obtained from the exact Cochran-Mantel-Haenszel test using a stratified version of the

Cochran-Armitage permutation test.

Figure 1 BOLERO-2 Kaplan-Meier progression-free survival curves (investigatorradiological review)

Hazard Ratio = 0.4595% CI [0.38, 0.54]

Log-rank p value: <0.000180 Kaplan-Meier medians

Everolimus 10 mg + exemestane: 7.82 months

Placebo + exemestane: 3.19 months

Censoring Times60 Everolimus 10 mg + exemestane (n/N = 310/485)

Placebo + exemestane (n/N = 200/239)0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120

Time (weeks)

Number of Patients still at Risk

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

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

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

The estimated PFS treatment effect was supported by planned subgroup analysis of PFS perinvestigator 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 witheverolimus + exemestane with an estimated hazard ratio (HR) versus placebo + exemestane rangingfrom 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 ofeverolimus in combination with exemestane versus everolimus alone versus capecitabine in thetreatment of postmenopausal women with oestrogen receptor-positive, HER2/neu negative, locallyadvanced, recurrent, or metastatic breast cancer after recurrence or progression on prior letrozole oranastrozole.

The primary objective of the study was to estimate the HR of PFS for everolimus + exemestane versuseverolimus alone. The key secondary objective was to estimate the HR of PFS for everolimus +exemestane versus capecitabine.

Other secondary objectives included the evaluation of OS, objective response rate, clinical benefit rate,safety, time to ECOG performance deterioration, time to QoL deterioration, and treatment satisfaction(TSQM). No formal statistical comparisons were planned.

A total of 309 patients were randomised in a 1:1:1 ratio to the combination of everolimus (10 mgdaily) + 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 thetime of data cut-off, the median duration of treatment was 27.5 weeks (range 2.0-165.7) in theeverolimus + 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 investigatorassessment 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) and6.8 months (90% CI: 5.5, 7.2), respectively.

Figure 2 BOLERO-6 Kaplan-Meier progression-free survival curves (investigatorradiological review)

Hazard Ratio = 0.7490% 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

Censoring Times

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

Everolimus (n/N=74/103)

No of patients still at risk Time (Weeks)

Time (weeks)

Everolimus/Exemestane

For the key secondary endpoint PFS the estimated HR was 1.26 (90% CI: 0.96, 1.66) in favour ofcapecitabine over the everolimus + exemestane combination arm based on a total of 148 PFS eventsobserved.

Results of the secondary endpoint OS were not consistent with the primary endpoint PFS, with a trendobserved favouring the everolimus alone arm. The estimated HR was 1.27 (90% CI: 0.95, 1.70) for thecomparison of OS in the everolimus alone arm relative to the everolimus + exemestane arm. Theestimated HR for the comparison of OS in the everolimus + exemestane combination arm relative tocapecitabine arm was 1.33 (90% CI: 0.99, 1.79).

Probability (%) of event

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-foldprolongation 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 whosedisease had progressed within the prior 12 months. Treatment with somatostatin analogues wasallowed 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 theinvestigator. 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 durationof blinded study treatment was 37.8 weeks (range 1.1-129.9 weeks) for patients receiving everolimusand 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%) initiallyrandomised to placebo crossed over to open-label Afinitor. The median duration of open-labeltreatment was 47.7 weeks among all patients; 67.1 weeks in the 53 patients randomised to everolimuswho switched to open-label everolimus and 44.1 weeks in the 172 patients randomised to placebo whoswitched to open-label everolimus.

Table 5 RADIANT-3 - efficacy results

Population Afinitor Placebo Hazard ratio p-valuen=207 n=203 (95% CI)

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

Investigator radiological 11.044.60 0.35 <0.0001review (8.41, 13.86) (3.06, 5.39) (0.27, 0.45)

Independent radiological 13.67 5.68 0.38 <0.0001review (11.17, 18.79) (5.39, 8.31) (0.28, 0.51)

Median overall survival (months) (95% CI)

Median overall survival 44.02 37.68 0.94 0.300(35.61, 51.75) (29.14, 45.77) (0.73, 1.20)

Figure 3 RADIANT-3 - Kaplan-Meier progression-free survival curves (investigatorradiological review)

Hazard Ratio = 0.3595% CI [0.27, 0.45]90 Log-rank p value = <0.001

Kaplan-Meier medians80 Afinitor : 11.04 months

Placebo : 4.60 months

Censoring times

Afinitor (n=207)

Placebo (n=203)0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Time (months)

No. of pat ients still at risk

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

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

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 withadvanced, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours ofgastrointestinal or lung origin without a history of and no active symptoms related to carcinoidsyndrome.

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 overallsurvival (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.

Probability (%)

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 and19.6 weeks for those receiving placebo. After primary PFS analysis, 6 patients from the placebo armcrossed over to open-label everolimus.

The efficacy results for the primary endpoint PFS (independent radiological review) were obtainedfrom the final PFS analysis (see Table 6 and Figure 4). The efficacy results for PFS (investigatorradiological review) were obtained from the final OS analysis (see Table 6).

Table 6 RADIANT-4 - Progression-free survival results

Population Afinitor Placebo Hazard ratio p-valuean=205 n=97 (95% CI)

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

Independent radiological 11.013.91 0.48 <0.001review (9.2, 13.3) (3.6, 7.4) (0.35, 0.67)

Investigator radiological 14.39 5.45 0.40 <0.001review (11.24, 17.97) (3.71, 7.39) (0.29, 0.55)a One-sided p-value from a stratified log-rank test

Figure 4 RADIANT-4 - Kaplan-Meier progression-free survival curves (independentradiological review)

Hazard Ratio = 0.4890 95% CI [0.35, 0.67]80 Kaplan-Meier medians

Everolimus + BSC: 11.01 [9.23;13.31] months

Placebo + BSC: 3.91 [3.58;7.43] months

Log-rank p value = <0.001

Censoring times

Everolimus + BSC (n/N = 113/205)

Placebo + BSC (n/N = 65/97)0 2 4 6 8 10 12 15 18 21 24 27 30

Time (months)

N umber of Patients still at Risk

T ime(months) 0 2 4 6 8 10 12 15 18 21 24 27 30

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

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

Probability (%) of event

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

All (N=302)<65 years (N=159)

Age≥65 years (N=143)0 (N=216)

WHO PS1 (N=86)

Yes (N=157)

Prior SSA

No (N=145)

Prior Yes (N=77)chemotherapy No (N=225)

Lung (N=90)

Primary tumour

Ileum (N=71)origin

Non-ileum* (N=141)

Grade 1 (N=194)

Tumour grading

Grade 2 (N=107)

Liver tumour ≤10% (N=228)burden >10% (N=72)

Baseline CgA >2xULN (N=139)≤2xULN (N=138)>ULN (N=87)

Baseline NSE≤ULN (N=188)

Everolimus + BSC Placebo + BSC

In favour of

* Non-ileum: stomach, colon, rectum, appendix, caecum, duodenum, jejunum, carcinoma of unknown primaryo rigin and other gastrointestinal origin

U LN: Upper limit of normal

C gA: Chromogranin A

N SE: Neuron specific enolase

H azard ratio (95% CI) from stratified Cox model

The final overall survival (OS) analysis did not show a statistically significant difference betweenthose patients who received Afinitor or placebo during the blinded treatment period of the study(HR=0.90 [95% CI: 0.66 to 1.22]).

No difference in the time to definitive deterioration of WHO PS (HR=1.02; [95% CI: 0.65, 1.61]) andtime to definitive deterioration in quality of life (FACT-G total score HR=0.74; [95% CI: 0.50, 1.10])was observed between the two arms.

Advanced renal cell carcinoma

RECORD-1 (study CRAD001C2240), a phase III, international, multicentre, randomised,double-blind study comparing everolimus 10 mg/day and placebo, both in conjunction with bestsupportive care, was conducted in patients with metastatic renal cell carcinoma whose disease hadprogressed on or after treatment with VEGFR-TKI (vascular endothelial growth factor receptortyrosine kinase inhibitor) therapy (sunitinib, sorafenib, or both sunitinib and sorafenib). Prior therapywith 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-riskgroups) 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-relatedsymptoms, and quality of life. After documented radiological progression, patients could be unblindedby the investigator: those randomised to placebo were then able to receive open-label everolimus10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at thetime 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 blindedstudy 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 astatistically 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 Placebo Hazard ratio p-valuen=277 n=139 (95%CI)

Median progression-freesurvival (months) (95% CI)

All (blinded independent 416 4.9 1.9 0.33 <0.0001acentral review) (4.0-5.5) (1.8-1.9) (0.25-0.43)

Supportive/sensitivity analyses

All (local review by 416 5.5 1.9 0.32 <0.0001ainvestigator) (4.6-5.8) (1.8-2.2) (0.25-0.41)

MSKCC prognostic score (blinded independent central review)

Favourable risk 120 5.8 1.9 0.31 <0.0001(4.0-7.4) (1.9-2.8) (0.19-0.50)

Intermediate risk 235 4.5 1.8 0.32 <0.0001(3.8-5.5) (1.8-1.9) (0.22-0.44)

Poor risk 61 3.6 1.8 0.44 0.007(1.9-4.6) (1.8-3.6) (0.22-0.85)a Stratified log-rank test

Figure 6 RECORD-1 - Kaplan-Meier progression-free survival curves (independent centralreview)

Censoring Times

Everolimus (n/N = 155/277)

Placebo (n/N = 111/139)

Hazard Ratio = 0.3395% CI [0.25, 0.43]

Kaplan-Meier medians

Everolimus: 4.90 months

Placebo: 1.87 months

Log-rank p value = <0.0001

Time (months)

No. of patients still at risk

Time (months)

Afinitor

Placebo

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, whilenone were observed in patients receiving placebo. Therefore, the progression-free survival advantageprimarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitortreatment group).

No statistically significant treatment-related difference in overall survival was noted (hazardratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor followingdisease progression for patients allocated to placebo confounded the detection of any treatment-relateddifference in overall survival.

Other studies

Stomatitis is the most commonly reported adverse reaction in patients treated with Afinitor (seesections 4.4 and 4.8). In a post-marketing single-arm study in postmenopausal women with advancedbreast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 ml alcohol-free oral solutionwas administered as a mouthwash (4 times daily for the initial 8 weeks of treatment) to patients at thetime of initiating treatment with Afinitor (10 mg/day) plus exemestane (25 mg/day) to reduce theincidence 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 1stomatitis was 18.8% (n=16/85) and no cases of Grade 3 or 4 stomatitis were reported. The overallsafety profile in this study was consistent with that established for everolimus in the oncology andtuberous sclerosis complex (TSC) settings, with the exception of a slightly increased frequency of oralcandidiasis which was reported in 2.2% (n=2/92) of patients.

Probability (%)

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 onpaediatric use).

In patients with advanced solid tumours, peak everolimus concentrations (Cmax) are reached at amedian time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditionsor with a light fat-free snack. Cmax is dose-proportional between 5 and 10 mg. Everolimus is a substrateand moderate inhibitor of PgP.

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 phaseconcentration-time profile.

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood isconfined to plasma in cancer patients given everolimus 10 mg/day. Plasma protein binding isapproximately 74% both in healthy subjects and in patients with moderate hepatic impairment. Inpatients with advanced solid tumours, Vd was 191 l for the apparent central compartment and 517 l forthe apparent peripheral compartment.

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the maincirculating component in human blood. Six main metabolites of everolimus have been detected inhuman blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products,and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animalspecies used in toxicity studies, and showed approximately 100 times less activity than everolimusitself. Hence, everolimus is considered to contribute the majority of the overall pharmacologicalactivity.

Mean oral clearance (CL/F) of everolimus after 10 mg daily dose in patients with advanced solidtumours 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 availablefrom the studies in transplant patients. Following the administration of a single dose of radiolabelledeverolimus 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 wasdose-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 asignificant correlation between AUC0-τ and pre-dose trough concentration at steady-state.

The safety, tolerability and pharmacokinetics of everolimus were evaluated in two single oral dosestudies of Afinitor tablets in 8 and 34 subjects with impaired hepatic function relative to subjects withnormal hepatic function.

In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment(Child-Pugh B) was twice that found in 8 subjects with normal hepatic function.

In the second study of 34 subjects with different impaired hepatic function compared to normalsubjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC0-inf) for subjectswith 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 withhepatic impairment based on their Child-Pugh status.

Based on the results of the two studies, dose adjustment is recommended for patients with hepaticimpairment (see sections 4.2 and 4.4).

In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significantinfluence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplantrenal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics ofeverolimus in transplant patients.

In a population pharmacokinetic evaluation in cancer patients, no significant influence of age(27-85 years) on oral clearance of everolimus was detected.

Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liverfunctions. Based on analysis of population pharmacokinetics, CL/F is on average 20% higher in blacktransplant patients.

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 (increasedalveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells inmonkeys and minipigs, respectively, and degeneration of islet cells in monkeys), and eyes (lenticularanterior suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation ofage-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation ofbackground 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 gastrointestinaltract in minipigs, skin lesions in mice and monkeys). These findings were generally observed atsystemic exposure levels within the range of therapeutic exposure or above, with the exception of thefindings 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 spermmotility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg which caused areduction in male fertility. There was evidence of reversibility.

In animal reproductive studies female fertility was not affected. However, oral doses of everolimus infemale rats at ≥0.1 mg/kg (approximately 4% of the AUC0-24h in patients receiving the 10 mg dailydose) resulted in increases in pre-implantation loss.

Everolimus crossed the placenta and was toxic to the foetus. In rats, everolimus causedembryo/foetotoxicity at systemic exposure below the therapeutic level. This was manifested asmortality 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 increasein late resorptions.

Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic ormutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenicpotential in mice and rats up to the highest doses, corresponding respectively to 3.9 and 0.2 times theestimated clinical exposure.

Butylhydroxytoluene

Magnesium stearate

Lactose monohydrate

Hypromellose

Crospovidone type A

Lactose anhydrous

Not applicable.

3 years.

Do not store above 25°C.

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

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.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

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

Date of first authorisation: 03 August 2009

Date of latest renewal: 02 April 2019

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

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