EVEROLIMUS

Treatment with Everolimus Tablets should be initiated and supervised by a physician experienced in the use of anticancer therapies. 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 Everolimus Tablets 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. 4). Table 1 Everolimus Tablets dose adjustment recommendations Adverse reaction Severity1 Everolimus Tablets dose adjustment Grade 2 Consider interruption of therapy until symptoms improve to Grade ≤1.

Re-initiate treatment at 5 mg daily. Discontinue treatment if failure to recover within 4 weeks. Grade 3 Interrupt treatment until symptoms resolve to Grade ≤1. Consider re-initiating treatment at 5 mg daily. If toxicity recurs at Grade 3, consider discontinuation.

Non-infectious pneumonitis Grade 4 Discontinue treatment. Grade 2 Temporary dose interruption until recovery to Grade ≤1. Re-initiate treatment at same dose. If stomatitis recurs at Grade 2, interrupt dose until recovery to Grade ≤1. Re-initiate treatment at 5 mg daily.

Grade 3 Temporary dose interruption until recovery to Grade <1. Re-initiate treatment at 5 mg daily. Stomatitis Grade 4 Discontinue treatment. 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.

2). 2). 5 mg daily. - Moderate hepatic impairment (Child-Pugh B) - the recommended dose is 5 mg daily. Severe hepatic impairment (Child-Pugh C) - Everolimus Tablets are only recommended if the desired benefit outweighs the risk. 5 mg daily must not be exceeded.

Summary of the safety profile The safety profile is based on pooled data from 2,879 patients treated with everolimus in eleven clinical studies, consisting of five randomised, double-blind, placebo controlled phase III studies and six open-label phase I and phase II studies, related to the approved indications.

The most common adverse reactions (incidence ≥1/10) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia, pneumonitis, oedema peripheral, hyperglycaemia, asthenia, pruritus, weight decreased, hypercholesterolaemia, epistaxis, cough and headache.

The most frequent Grade 3-4 adverse reactions (incidence ≥1/100 to <1/10) were stomatitis, anaemia, hyperglycaemia, infections, fatigue, diarrhoea, pneumonitis, asthenia, thrombocytopenia, neutropenia, dyspnoea, proteinuria, lymphopenia, haemorrhage, hypophosphataemia, rash, hypertension, pneumonia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased and diabetes mellitus.

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. g. 4)] and (rare) viral myocarditis b Includes different bleeding events from different sites not listed individually c Includes (common) pneumonitis, 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 stage g Adverse reaction was determined based on post-marketing reports.

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

g. leading to sepsis, respiratory or hepatic failure) and occasionally fatal. Physicians and patients should be aware of the increased risk of infection with Everolimus Tablets. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Everolimus Tablets.

While taking Everolimus Tablets, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Everolimus Tablets. If a diagnosis of invasive systemic fungal infection is made, the Everolimus Tablets treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.

1.