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).

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

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.

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.

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, the clinical condition of the patient should be monitored closely. Dose adjustments of Afinitor can be taken into consideration based on predicted AUC (see section 4.5).

Concomitant treatment with potent CYP3A4/PgP 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).

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.

Radiation therapy complications

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

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

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

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

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

CYP3A4 and PgP inhibitors increasing everolimus concentrations

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

CYP3A4 and PgP inducers decreasing everolimus concentrations

Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells.

Table 2 Effects of other active substances on everolimus

Active substance by interaction

Interaction – Change in Everolimus AUC/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 (see sections 4.2 and 4.4). 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)

Cannabidiol (PgP inhibitor)

AUC ↑2.5-fold

Cmax ↑2.5-fold

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.

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.

Radiation treatment

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

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 has 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.

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); not known (cannot be estimated from the available data). 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, lymphoedemag

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

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

Injury, poisoning and procedural complications

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/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

f Adverse reaction identified in the post-marketing setting

g Adverse reaction was determined based on post-marketing reports. Frequency was determined based on oncology studies safety pool.

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 studies 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.