Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1.
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) was described very commonly in patients taking everolimus in the advanced renal cell carcinoma (RCC) setting (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 section “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 Votubia therapy without dose adjustments. If symptoms are moderate, consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Votubia may be reinitiated at a daily dose approximately 50% lower than the dose previously administered.
For cases where symptoms of non-infectious pneumonitis are severe, Votubia therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Votubia may be reinitiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances.
For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) may be considered.
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoal 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 pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) and viral infections including reactivation of hepatitis B virus, have been described in patients taking everolimus. Some of these infections have been severe (e.g. leading to sepsis [including septic shock], respiratory or hepatic failure) and occasionally fatal in adult and paediatric patients (see section 4.8).
Physicians and patients should be aware of the increased risk of infection with Votubia. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Votubia. While taking Votubia, 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 Votubia.
If a diagnosis of invasive systemic fungal infection is made, Votubia treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.
Cases of pneumocystis jirovecii (carinii) pneumonia (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 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).
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, including mouth ulcerations and oral mucositis, is the most commonly reported adverse reaction in patients treated with Votubia (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 (everolimus) 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 (in adults) 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).
Serious cases of haemorrhage, some with a fatal outcome, have been reported in patients treated with everolimus in the oncology setting. No serious cases of renal haemorrhage were reported in the TSC setting.
Caution is advised in patients taking Votubia, particularly during concomitant use with active substances known to affect platelet function or that can increase the risk of haemorrhage as well as in patients with a history of bleeding disorders. Healthcare professionals and patients should be vigilant for signs and symptoms of bleeding throughout the treatment period, especially if risk factors for haemorrhage are combined.
Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Votubia (see section 4.8). Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients treated with Votubia (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 Votubia therapy and periodically thereafter.
Hyperglycaemia has been reported in patients taking Votubia (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Votubia therapy and periodically thereafter. More frequent monitoring is recommended when Votubia is co-administered with other medicinal products that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a patient on Votubia.
Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported in patients taking Votubia. Monitoring of blood cholesterol and triglycerides prior to the start of Votubia therapy and periodically thereafter, as well as management with appropriate medical therapy, is also recommended.
Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported in patients treated with Votubia (see section 4.8). Monitoring of complete blood count is recommended prior to the start of Votubia therapy and periodically thereafter.
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. Monitoring of everolimus through concentrations and dose adjustments of Votubia may be required (see section 4.5).
Concomitant treatment with potent CYP3A4/PgP inhibitors result in dramatically increased blood concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Votubia and potent inhibitors is not recommended.
Caution should be exercised when Votubia is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Votubia is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine, ergot alkaloid derivatives or carbamazepine), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see section 4.5).
Votubia is not recommended for use in patients:
The use of live vaccines should be avoided during treatment with Votubia (see section 4.5). For paediatric patients 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.
Impaired wound healing is a class effect of rapamycin derivatives, including Votubia. Caution should therefore be exercised with the use of Votubia in the peri-surgical period.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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.
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 3 below.
Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing metabolism or the efflux of everolimus from intestinal cells.
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 3. 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 Votubia 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. For patients with renal angiomyolipoma associated with TSC: If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, dose reduction to 5 mg or 2.5 mg daily may be considered. However, there are no clinical data with this dose adjustment. Due to between subject variability the recommended dose adjustments may not be optimal in all individuals, therefore close monitoring of side effects is recommended. If the moderate inhibitor is discontinued, consider a washout period of at least 2 to 3 days (average elimination time for most commonly used moderate inhibitors) before the Votubia dose is returned to the dose used prior to initiation of the co-administration (see also Therapeutic drug monitoring in section 4.2). For patients with SEGA associated with TSC: If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, reduce the daily dose by approximately 50%. Further dose reduction may be required to manage adverse reactions (see sections 4.2 and 4.4). Everolimus trough concentrations should be assessed at least 1 week after the addition of a moderate CYP3A4 or PgP inhibitor. 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 Votubia dose is returned to the dose used prior to initiation of the co-administration. The everolimus trough concentration should be assessed at least 1 week later (see sections 4.2 and 4.4). |
| Imatinib | AUC ↑ 3.7-fold Cmax ↑ 2.2-fold | |
| Verapamil | AUC ↑3.5-fold (range 2.2-6.3) Cmax ↑2.3-fold (range 1.3-3.8) | |
| 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. For patients with renal angiomyolipoma associated with TSC: If patients require co-administration of a potent CYP3A4 inducer, a Votubia 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 Votubia 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 Votubia dose is returned to the dose used prior to initiation of the co-administration (see also Therapeutic drug monitoring in section 4.2). For patients with SEGA associated with TSC: Patients receiving concomitant potent CYP3A4 inducers may require an increased Votubia dose to achieve the same exposure as patients not taking potent inducers. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. If concentrations are below 5 ng/ml, the daily dose may be increased by 2.5 mg every 2 weeks, checking the trough level and assessing tolerability before increasing the dose. The addition of another concomitant strong CYP3A4 inducer may not require additional dose adjustment. Assess the everolimus trough level 2 weeks after initiating the additional inducer. Adjust the dose by increments of 2.5 mg as necessary to maintain the target trough concentration. Discontinuation of one of multiple strong CYP3A4 inducers may not require additional dose adjustment. Assess the everolimus trough level 2 weeks after discontinuation of one of multiple strong CYP3A4 inducers. If all potent inducers are discontinued, consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme de-induction) before the Votubia dose is returned to the dose used prior to initiation of the co-administration. The everolimus trough concentrations should be assessed 2 to 4 weeks later since the natural degradation time of the induced enzymes has to be taken into account (see sections 4.2 and 4.4). |
| Dexamethasone | Not studied. Decreased exposure expected. | |
| Antiepileptics (e.g. 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 |
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).
In EXIST-3 (Study CRAD001M2304), everolimus increased pre-dose concentrations of the antiepileptics carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about 10%. The increase in the pre-dose concentrations of these antiepileptics may not be clinically significant but dose adjustments for antiepileptics with a narrow therapeutic index, e.g carbamazepine, may be considered. Everolimus had no impact on pre-dose concentrations of antiepileptics that are substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide).
Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (see section 4.4).
The effect of a ketogenic diet may be mediated through mTOR inhibition. In the absence of clinical data, the possibility of an additive effect on adverse events cannot be excluded when everolimus is given in conjunction with a ketogenic diet.
The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Votubia. The use of live vaccines should be avoided during treatment with Votubia. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.
Potentiation of radiation treatment toxicity has been reported in patients receiving everolimus (see sections 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-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.
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.
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.
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 (see also section 5.3 for preclinical observations on the male and female reproductive systems). Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus (see section 5.3).
Votubia 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 Votubia.
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.
Table 4 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 4. Adverse reactions reported in TSC studies:
| Infections and infestations | |
| Very common | Nasopharyngitis, upper respiratory tract infection, pneumoniaa, urinary tract infection, sinusitis, pharyngitis |
| Common | Otitis media, cellulitis, pharyngitis streptococcal, gastroenteritis viral, gingivitis |
| Uncommon | Herpes zoster, sepsis, bronchitis viral |
| Blood and lymphatic system disorders | |
| Common | Anaemia, neutropenia, leucopenia, thrombocytopenia, lymphopenia |
| Immune system disorders | |
| Common | Hypersensitivity |
| Metabolism and nutrition disorders | |
| Very common | Decreased appetite, hypercholesterolaemia |
| Common | Hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, hyperglycaemia |
| Psychiatric disorders | |
| Common | Insomnia, aggression, irritability |
| Nervous system disorders | |
| Very common | Headache |
| Uncommon | Dysgeusia |
| Vascular disorders | |
| Very common | Hypertension |
| Common | Lymphoedema |
| Respiratory, thoracic and mediastinal disorders | |
| Very common | Cough |
| Common | Epistaxis, pneumonitis |
| Gastrointestinal disorders | |
| Very common | Stomatitisb, diarrhoea, vomiting |
| Common | Constipation, nausea, abdominal pain, flatulence, oral pain, gastritis |
| Skin and subcutaneous tissue disorders | |
| Very common | Rashc, acne |
| Common | Dry skin, acneiform dermatitis, pruritus, alopecia |
| Uncommon | Angioedema |
| Musculoskeletal and connective tissue disorders | |
| Uncommon | Rhabdomyolysis |
| Renal and urinary disorders | |
| Common | Proteinuria |
| Reproductive system and breast disorders | |
| Very common | Amenorrhoead, menstruation irregulard |
| Common | Menorrhagia, ovarian cyst, vaginal haemorrhage |
| Uncommon | Menstruation delayedd |
| General disorders and administration site conditions | |
| Very common | Pyrexia, fatigue |
| Investigations | |
| Common | Blood lactate dehydrogenase increased, blood luteinising hormone increased, weight decreased |
| Uncommon | Blood follicle stimulating hormone increased |
| Injury, poisoning and procedural complications | |
| Not knowne | Radiation recall syndrome, potentiation of radiation reaction |
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.
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 (see section 4.4).
In clinical studies, everolimus has been associated with haemorrhage events. On rare occasions, fatal outcomes were observed in the oncology setting (see section 4.4). 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 (see section 4.4).
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 trials and post-marketing spontaneous reports, angioedema has been reported with and without concomitant use of ACE inhibitors (see section 4.4).
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.
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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