Adverse reactions : תופעות לוואי

4.8       Undesirable effects
Oncology patients
Summary of safety profile
The safety profile is based on pooled data from 2,879 patients treated with Afinitor in eleven clinical studies, consisting of five randomized, double-blind, placebo controlled phase III studies and six open- label phase 1 and phase II studies related to the approved indications in oncology.
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, anemia, dysgeusia, pneumonitis, oedema peripheral, hyperglycemia, asthenia, pruritus, weight decreased, hypercholesterolemia, epistaxis, cough and headache.
The most frequent Grade 3-4 adverse reactions (incidence ≥1/100 to <1/10) were stomatitis, anemia, hyperglycemia, infections, fatigue, diarrhea, pneumonitis, asthenia, thrombocytopenia, neutropenia, dyspnea, proteinuria, lymphopenia, hemorrhage, hypophosphatemia, 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 in oncology
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.



AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Table 3             Adverse reactions reported in oncology clinical studies 

Infections and infestations
Very common            Infections a, *
Blood and lymphatic system disorders
Very common            Anemia
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, hyperglycemia, hypercholesterolemia Common                 Hypertriglyceridemia, hypophosphatemia, diabetes mellitus, hyperlipidemia, hypokalemia, 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                 Hemorrhage b, hypertension, lymphoedemag
Uncommon               Flushing, deep vein thrombosis
Respiratory, thoracic and mediastinal disorders
Very common            Pneumonitis c, epistaxis, cough
Common                 Dyspnea
Uncommon               Hemoptysis, pulmonary embolism
Rare                   Acute respiratory distress syndrome


AFI API SEP22 V11                                                REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Gastrointestinal disorders
Very common        Stomatitis d, diarrhea, 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 disorder, 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           Amenorrhea 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 


AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 *     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.


Tuberous sclerosis complex (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 Afinitor (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 Afinitor (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 Afinitor and 45.0 weeks (range 9 to 115) for those receiving placebo. The cumulative median duration of exposure to Afinitor (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 Afinitor and 46.6 weeks (range 14 to 88) for those receiving placebo. The cumulative median duration of exposure to Afinitor (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).


AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 The adverse events considered to be associated with the use of Afinitor (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 3-1 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 3-1       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, hyperglycemia Psychiatric disorders
Common                Insomnia, aggression, irritability
Nervous system disorders

AFI API SEP22 V11                                                 REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 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         Amenorrhea d, menstruation irregular d
Common              Menorrhagia, ovarian cyst, vaginal hemorrhage
Uncommon            Menstruation delayed d

General disorders and administration site conditions
Very common         Pyrexia, fatigue

Investigations
Common              Blood lactate dehydrogenase increased, blood luteinizing hormone increased, weight decreased
Uncommon            Blood follicle stimulating hormone increased


AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 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 generalized, rash maculo-papular, rash macular d
Frequency is 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 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 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 for TSC indications, 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 for oncology indications 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).

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 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 3/4 infections, AFI API SEP22 V11                                               REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 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 patients

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/