Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Allergic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) 
Summary of safety profile
During allergic asthma clinical trials in adult and adolescent patients 12 years of age and older, the most commonly reported adverse reactions were headaches and injection site reactions, including injection site pain, swelling, erythema and pruritus. In clinical trials in children 6 to <12 years of age, the most commonly reported adverse reactions were headache, pyrexia and upper abdominal pain. Most of the reactions were mild or moderate in severity. In clinical trials in patients ≥18 years of age in CRSwNP, the most commonly reported adverse reactions were headache, dizziness, arthralgia, abdominal pain upper and injection site reactions.


Tabulated list of adverse reactions
Table 9 lists the adverse reactions recorded in clinical studies in the total allergic asthma and CRSwNP safety population treated with Xolair by MedDRA system organ class and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as: 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) and very rare (<1/10,000). Reactions reported in the post-marketing setting are listed with frequency not known (cannot be estimated from the available data).

Table 9: Adverse reactions in allergic asthma and CRSwNP

Infections and infestations
Uncommon                                              Pharyngitis
XOL_POW_API_30MAR2022 V3                                         Baesd on EU SmPC DEC21 Rare                                                   Parasitic infection Blood and lymphatic system disorders
Not known                                              Idiopathic thrombocytopenia, including severe cases Immune system disorders
Rare                                                   Anaphylactic reaction, other serious allergic conditions, anti-omalizumab antibody development
Not known                                              Serum sickness, may include fever and lymphadenopathy
Nervous system disorders
Common                                                 Headache*
Uncommon                                               Syncope, paraesthesia, somnolence, dizziness# Vascular disorders
Uncommon                                               Postural hypotension, flushing Respiratory, thoracic and mediastinal disorders
Uncommon                                               Allergic bronchospasm, coughing Rare                                                   Laryngoedema
Not known                                              Allergic granulomatous vasculitis (i.e. Churg-Strauss syndrome)
Gastrointestinal disorders
Common                                                 Abdominal pain upper **# Uncommon                                               Dyspeptic signs and symptoms, diarrhoea, nausea Skin and subcutaneous tissue disorders
Uncommon                                               Photosensitivity, urticaria, rash, pruritus Rare                                                   Angioedema
Not known                                              Alopecia
Musculoskeletal and connective tissue disorders
Common                                                 Arthralgia†
Rare                                                   Systemic lupus erythematosus (SLE) Not known                                              Myalgia, joint swelling General disorders and administration site conditions
Very common                                            Pyrexia**
Common                                                 Injection site reactions such as swelling, erythema, pain, pruritus
Uncommon                                               Influenza-like illness, swelling arms, weight increase, fatigue
*: Very common in children 6 to <12 years of age
**: In children 6 to <12 years of age
#
: Common in nasal polyp trials
†: Unknown in allergic asthma trials


Chronic spontaneous urticaria (CSU)
Summary of safety profile
The safety and tolerability of omalizumab were investigated with doses of 75 mg, 150 mg and 300 mg every four weeks in 975 CSU patients, 242 of whom received placebo. Overall, 733 patients were treated with omalizumab for up to 12 weeks and 490 patients for up to 24 weeks. Of those, 412 patients were treated for up to 12 weeks and 333 patients were treated for up to 24 weeks at the
300 mg dose.

Tabulated list of adverse reactions

XOL_POW_API_30MAR2022 V3                                            Baesd on EU SmPC DEC21 A separate table (Table 10) shows the adverse reactions for the CSU indication resulting from differences in dosages and treatment populations (with significantly different risk factors, comorbidities, co- medications and ages [e.g. asthma trials included children from 6-12 years of age]).

Table 8 lists the adverse reactions (events occurring in ≥1% of patients in any treatment group and ≥2% more frequently in any omalizumab treatment group than with placebo (after medical review)) reported with 300 mg in the three pooled phase III studies. The adverse reactions presented are divided into two groups: those identified in the 12-week and the 24-week treatment periods.

The adverse reactions are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions listed first. The corresponding frequency category for each adverse reaction is based on 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 <1/1000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 10: Adverse reactions from the pooled CSU safety database (day 1 to week 24) at 300 mg omalizumab 
Omalizumab studies 1, 2 and 3 Pooled                  Frequency category 12-Week
Placebo N=242             300 mg N=412
Infections and infestations
Sinusitis                              5 (2.1%)                    20 (4.9%)                     Common Nervous system disorders
Headache                               7 (2.9%)                    25 (6.1%)                     Common Musculoskeletal and connective tissue disorders
Arthralgia                             1 (0.4%)                    12 (2.9%)                     Common General disorder and administration site conditions
Injection site reaction*               2 (0.8%)                    11 (2.7%)                     Common Omalizumab studies 1 and 3 Pooled                  Frequency category  24-Week
Placebo N=163                300 mg N=333
Infections and infestations
Upper respiratory tract                5 (3.1%)                    19 (5.7%)                     Common infection
* Despite not showing a 2% difference to placebo, injection site reactions were included as all cases were assessed causally related to study treatment.

Description of selected adverse reactions

Immune system disorders
For further information, see section 4.4.
Anaphylaxis
Anaphylactic reactions were rare in clinical trials. However, post-marketing data following a cumulative search in the safety database retrieved a total of 898 anaphylaxis cases. Based on an estimated exposure of 566,923 patient treatment years, this results in a reporting rate of approximately 0.20%.

Arterial thromboembolic events (ATE)
In controlled clinical trials and during interim analyses of an observational study, a numerical imbalance of ATE was observed. The definition of the composite endpoint ATE included stroke, transient ischaemic attack, myocardial infarction, unstable angina, and cardiovascular death (including death from unknown cause). In the final analysis of the observational study, the rate of ATE per 1,000 patient years was 7.52 XOL_POW_API_30MAR2022 V3                                             Baesd on EU SmPC DEC21 (115/15,286 patient years) for Xolair-treated patients and 5.12 (51/9,963 patient years) for control patients.
In a multivariate analysis controlling for available baseline cardiovascular risk factors, the hazard ratio was 1.32 (95% confidence interval 0.91-1.91). In a separate analysis of pooled clinical trials, which included all randomised double-blind, placebo-controlled clinical trials lasting 8 or more weeks, the rate of ATE per 1,000 patient years was 2.69 (5/1,856 patient years) for Xolair-treated patients and 2.38 (4/1,680 patient years) for placebo patients (rate ratio 1.13, 95% confidence interval 0.24-5.71).

Platelets
In clinical trials few patients had platelet counts below the lower limit of the normal laboratory range.
None of these changes were associated with bleeding episodes or a decrease in haemoglobin. No pattern of persistent decrease in platelet counts, as observed in non-human primates (see section 5.3), has been reported in humans (patients above 6 years of age), even though isolated cases of idiopathic thrombocytopenia, including severe cases, have been reported in the post-marketing setting.

Parasitic infections
In allergic patients at chronic high risk of helminth infection, a placebo-controlled trial showed a slight numerical increase in infection rate with omalizumab that was not statistically significant. The course, severity, and response to treatment of infections were unaltered (see section 4.4).

Systemic lupus erythematosus
Clinical trial and post-marketing cases of systemic lupus erythematosus (SLE) have been reported in patients with moderate to severe asthma and CSU. The pathogenesis of SLE is not well understood.

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/