Everolimus

The use of live vaccines should be avoided during treatment with everolimus. For paediatric patients with SEGA who do not require immediate treatment, completion of the recommended childhood series of live virus vaccinations is advised prior to the start of therapy according to local treatment guidelines.

Co-administration with 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 inducer cannot be avoided, the clinical condition of the patient should be monitored closely. Dose adjustments of everolimus can be taken into consideration based on predicted AUC.

Effects of other active substances on everolimus:

Co-administration with inhibitors 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 cannot be avoided, the clinical condition of the patient should be monitored closely. Dose adjustments of everolimus can be taken into consideration based on predicted AUC.

Concomitant treatment with potent CYP3A4/PgP inhibitors result in dramatically increased plasma concentrations of everolimus. There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of everolimus and potent inhibitors is not recommended.

Effects of other active substances on everolimus:

Caution should be exercised when everolimus is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If everolimus 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.

• 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.

Patients with SEGA associated with TSC

Patients <18 years of age:

Everolimus is not recommended for patients <18 years of age with SEGA and hepatic impairment.

Patients ≥18 years of age:

• Mild hepatic impairment (Child-Pugh A): 75% of the recommended starting dose calculated based on BSA (rounded to the nearest strength)
• Moderate hepatic impairment (Child-Pugh B): 50% of the recommended starting dose calculated based on BSA (rounded to the nearest strength)
• Severe hepatic impairment (Child-Pugh C): everolimus is only recommended if the desired benefit outweighs the risk. In this case, 25% of the dose calculated based on BSA (rounded to the nearest strength) must not be exceeded.

Everolimus whole blood trough concentrations should be assessed at least 1 week after any change in hepatic status (Child-Pugh).

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).

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

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.

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

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. The potential risk for humans is unknown.

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

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. Therefore, women taking everolimus should not breast-feed during treatment and for 2 weeks after the last dose.

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.

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.

Everolimus may have a minor or moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with everolimus.

Renal angiomyolipoma associated with tuberous sclerosis complex (TSC) / Subependymal giant cell astrocytoma (SEGA) associated with TSC / Refractory seizures associated with TSC

Summary of the safety profile

Three randomised, double-blind, placebo-controlled pivotal phase III studies, including double-blind and open label treatment periods, and a non-randomised, open-label, single-arm phase II study contribute to the safety profile of Votubia (n=612, including 409 patients <18 years of age; median duration of exposure 36.8 months [range 0.5 to 83.2]).

• EXIST-3 (CRAD001M2304): This was a randomised, double-blind, controlled, phase III trial comparing adjunctive treatment of low and high everolimus exposure (low trough [LT] range of 3-7 ng/ml [n=117] and high trough [HT] range of 9-15 ng/ml [n=130]) versus placebo (n=119), in patients with TSC and refractory partial-onset seizures receiving 1 to 3 antiepileptics. The median duration of the double-blind period was 18 weeks. The cumulative median duration exposure to Votubia (361 patients who took at least one dose of everolimus) was 30.4 months (range 0.5 to 48.8).
• EXIST-2 (CRAD001M2302): This was a randomised, double-blind, controlled, phase III trial of everolimus (n=79) versus placebo (n=39) in patients with either TSC plus renal angiomyolipoma (n=113) or sporadic lymphangioleiomyomatosis (LAM) plus renal angiomyolipoma (n=5). The median duration of blinded study treatment was 48.1 weeks (range 2 to 115) for patients receiving Votubia and 45.0 weeks (range 9 to 115) for those receiving placebo. The cumulative median duration of exposure to Votubia (112 patients who took at least one dose of everolimus) was 46.9 months (range 0.5 to 63.9).
• EXIST-1 (CRAD001M2301): This was a randomised, double-blind, controlled, phase III trial of everolimus (n=78) versus placebo (n=39) in patients with TSC who have SEGA, irrespective of age. The median duration of blinded study treatment was 52.2 weeks (range 24 to 89) for patients receiving Votubia and 46.6 weeks (range 14 to 88) for those receiving placebo. The cumulative median duration of exposure to Votubia (111 patients who took at least one dose of everolimus) was 47.1 months (range 1.9 to 58.3).
• CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimus in patients with SEGA (n=28). The median duration of exposure was 67.8 months (range 4.7 to 83.2).

The adverse events considered to be associated with the use of Votubia (adverse reactions), based upon the review and medical assessment of all adverse events reported in the above studies, are described below.

The most frequent adverse reactions (incidence ≥1/10) from the pooled safety data are (in decreasing order): stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting, cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, menstruation irregular, pharyngitis, decreased appetite, fatigue, hypercholesterolaemia, and hypertension.

The most frequent grade 3-4 adverse reactions (incidence ≥1%) were pneumonia, stomatitis, amenorrhoea, neutropenia, pyrexia, menstruation irregular, hypophosphataemia, diarrhoea, and cellulitis. The grades follow CTCAE Version 3.0 and 4.03.

Tabulated list of adverse reactions

Table 1 shows the incidence of adverse reactions based on pooled data of patients receiving everolimus in the three TSC studies (including both the double-blind and open-label extension phase, where applicable). Adverse reactions are listed according to MedDRA system organ class. 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 1. Adverse reactions reported in TSC studies:

^a Includes pneumocystis jirovecii (carinii) pneumonia (PJP, PCP).
^b Includes (very common) stomatitis, mouth ulceration, aphthous ulcer; (common) tongue ulceration, lip ulceration and (uncommon) gingival pain, glossitis.
^c Includes (very common) rash; (common) rash erythematous, erythema and (uncommon) rash generalised, rash maculo-papular, rash macular.
^d Frequency based upon number of women from 10 to 55 years of age while on treatment in the pooled data.
^e Adverse reaction identified in the post-marketing setting.

Description of selected adverse reactions

In clinical studies, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected reaction during periods of immunosuppression.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome), proteinuria and increased serum creatinine. Monitoring of renal function is recommended.

In clinical studies, everolimus has been associated with haemorrhage events. On rare occasions, fatal outcomes were observed in the oncology setting. No serious cases of renal haemorrhage were reported in the TSC setting.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome.

Additional adverse reactions of relevance observed in oncology clinical studies and post-marketing spontaneous reports, were cardiac failure, pulmonary embolism, deep vein thrombosis, impaired wound healing and hyperglycaemia.

In clinical studies and post-marketing spontaneous reports, angioedema has been reported with and without concomitant use of ACE inhibitors.

Paediatric population

In the pivotal phase II study, 22 of the 28 SEGA patients studied were below the age of 18 years and in the pivotal phase III study, 101 of the 117 SEGA patients studied were below the age of 18 years. In the pivotal phase III study in patients with TSC and refractory seizures, 299 of the 366 patients studied were below the age of 18 years. The overall type, frequency and severity of adverse reactions observed in children and adolescents have been generally consistent with those observed in adults, with the exception of infections which were reported at a higher frequency and severity in children below the age of 6 years. A total of 49 out of 137 patients (36%) aged <6 years had Grade ¾ infections, compared to 53 out of 272 patients (19%) aged 6 to <18 years and 27 out of 203 patients (13%) aged ≥18 years. Two fatal cases due to infection were reported in 409 patients aged <18 years receiving everolimus.

Elderly

In the oncology safety pooling, 37% of the patients treated with everolimus were ≥65 years of age. The number of oncology patients with an adverse reaction leading to discontinuation of everolimus was higher in patients ≥65 years of age (20% versus 13%). The most common adverse reactions leading to discontinuation were pneumonitis (including interstitial lung disease), fatigue, dyspnoea, and stomatitis.

Hormone receptor-positive advanced breast cancer / Neuroendocrine tumours of pancreatic origin / Neuroendocrine tumours of gastrointestinal or lung origin / Renal cell carcinoma

Summary of the safety profile

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

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

The most frequent Grade 3-4 adverse reactions (incidence ≥1/100 to <1/10) were stomatitis, anaemia, hyperglycaemia, infections, fatigue, diarrhoea, pneumonitis, asthenia, thrombocytopenia, neutropenia, dyspnoea, proteinuria, lymphopenia, haemorrhage, hypophosphataemia, rash, hypertension, pneumonia, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased and diabetes mellitus. The grades follow CTCAE Version 3.0 and 4.03.

Tabulated list of adverse reactions

Table 2 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 2. Adverse reactions reported in clinical studies:

^* 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] 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.

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.

In clinical studies and post-marketing spontaneous reports, angioedema has been reported with and without concomitant use of ACE inhibitors.

Elderly patients

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