Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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).

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 three 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 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, pneumonia a, 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 Stomatitis b, diarrhoea, vomiting
Common           Constipation, nausea, abdominal pain, flatulence, oral pain, gastritis Skin and subcutaneous tissue disorders
Very common Rash c, 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 Amenorrhoea d, menstruation irregular d
Common           Menorrhagia, ovarian cyst, vaginal haemorrhage
Uncommon         Menstruation delayed d



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, potentation 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.

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 (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 studies and post-marketing spontaneous reports, angioedema has been reported with and without concomitant use of ACE inhibitors (see section 4.4).

Paediatric population

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. Two additional clinical trials were conducted with Votubia for other indications: A phase III study which included 101 paediatric patients and a phase II study which included 22 paediatric patients. 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 3/4 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.

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 to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/