Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions were injection site reactions (15.5%) and upper respiratory tract infections (16.4%) (most frequently nasopharyngitis).

Tabulated list of adverse reactions

Adverse reactions from clinical studies and postmarketing reports (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, 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 < 1/1,000); very rare (< 1/10,000).

A total of 8,956 patients have been treated with Taltz in blinded and open-label clinical studies in plaque psoriasis, psoriatic arthritis, axial spondyloarthritis, and other autoimmune conditions. Of these, 6,385 patients were exposed to Taltz for at least one year, cumulatively representing 19,833 adult patient years of exposure and 196 children cumulatively representing 207 patient years of exposure.


Table 1.     List of adverse reactions in clinical studies and postmarketing reports 
System organ class                  Frequency                            Adverse reaction Infections and infestations         Very common                          Upper respiratory tract infection
Common                               Tinea infection,
Herpes simplex
(mucocutaneous)
Uncommon                             Influenza,
Rhinitis,
Oral candidiasis,
Conjunctivitis,
Cellulitis
Rare                                 Oesophageal candidiasis
Blood and lymphatic system          Uncommon                             Neutropenia, disorders                                                                Thrombocytopenia Immune system disorders             Uncommon                             Angioedema Rare                                 Anaphylaxis
Respiratory, thoracic and           Common                               Oropharyngeal pain mediastinal disorders
Gastrointestinal disorders          Common                               Nausea Uncommon                             Inflammatory bowel disease
Skin and subcutaneous               Uncommon                             Urticaria, disorders                                                                Rash, Eczema
General disorders and              Very common                          Injection site reactionsa administration site conditions a
See section description of selected adverse reactions

Description of selected adverse reactions

Injection site reactions
The most frequent injection site reactions observed were erythema and pain. These reactions were predominantly mild to moderate in severity and did not lead to discontinuation of Taltz.
In the adult plaque psoriasis studies, injection site reactions were more common in subjects with a body weight < 60 kg compared with the group with a body weight ≥ 60 kg (25% vs. 14% for the combined Q2W and Q4W groups). In the psoriatic arthritis studies, injection site reactions were more common in subjects with a body weight < 100 kg compared with the group with a body weight ≥ 100 kg (24% vs.
13% for the combined Q2W and Q4W groups). In the axial spondyloarthritis studies, injection site reactions were similar in subjects with a body weight < 100 kg compared with the group with a body weight ≥ 100 kg (14% vs. 9% for the combined Q2W and Q4W groups). The increased frequency of injection site reactions in the combined Q2W and Q4W groups did not result in an increase in discontinuations in either the plaque psoriasis, the psoriatic arthritis or the axial spondyloarthritis studies.

The results described above are obtained with the original formulation of Taltz. In a single-blinded, randomized cross-over study in 45 healthy subjects comparing the original formulation with the revised, citrate-free formulation, statistically significantly lower VAS pain scores were obtained with the citrate- free vs. the original formulation during injection (difference in LS Mean VAS score -21.69) and 10 min after injection (difference in LS Mean VAS score -4.47).


Infections
In the placebo-controlled period of the phase III clinical studies in plaque psoriasis in adults, infections were reported in 27.2% of patients treated with Taltz for up to 12 weeks compared with 22.9% of patients treated with placebo.

The majority of infections were non-serious and mild to moderate in severity, most of which did not necessitate treatment discontinuation. Serious infections occurred in 13 (0.6%) of patients treated with Taltz and in 3 (0.4%) of patients treated with placebo (see section 4.4). Over the entire treatment period infections were reported in 52.8% of patients treated with Taltz (46.9 per 100 patient years). Serious infections were reported in 1.6 % of patients treated with Taltz (1.5 per 100 patient years).

Infection rates observed in psoriatic arthritis and axial spondyloarthritis clinical studies were similar to those observed in the plaque psoriasis studies with the exception of the frequencies of the adverse reactions of influenza and conjunctivitis which were common in patients with psoriatic arthritis.

Laboratory assessment of neutropenia and thrombocytopenia
In plaque psoriasis studies, 9% of patients receiving Taltz developed neutropenia. In most cases, the blood neutrophil count was ≥1,000 cells/mm3. Such levels of neutropenia may persist, fluctuate or be transient.
0.1% of patients receiving Taltz developed a neutrophil count <1,000 cells/mm3. In general, neutropenia did not require discontinuation of Taltz. 3% of patients exposed to Taltz had a shift from a normal baseline platelet value to <150,000 platelet cells/mm3 to ≥75,000 cells/mm3. Thrombocytopenia may persist, fluctuate or be transient.

The frequency of neutropenia and thrombocytopenia in psoriatic arthritis and axial spondyloarthritis clinical studies is similar to that observed in the plaque psoriasis studies.

Immunogenicity
Approximately 9–17% of adult plaque psoriasis patients treated with Taltz at the recommended dosing regimen developed anti-drug antibodies, the majority of which were low titres and not associated with reduced clinical response up to 60 weeks of treatment. However, approximately 1% of patients treated with Taltz had confirmed neutralizing antibodies associated with low drug concentrations and reduced clinical response.

In psoriatic arthritis patients treated with Taltz at the recommended dosing regimen up to 52 weeks, approximately 11% developed anti-drug antibodies, the majority of which were low titre, and approximately 8% had confirmed neutralizing antibodies. No apparent association between the presence of neutralizing antibodies and impact on drug concentration or efficacy was observed.

In radiographic axial spondyloarthritis patients treated with Taltz at the recommended dosing regimen up to 16 weeks, 5.2% developed anti-drug antibodies, the majority of which were low titer, and 1.5% (3 patients) had neutralizing antibodies (NAb). In these 3 patients, NAb-positive samples had low ixekizumab concentrations and none of these patients achieved an ASAS40 response. In non-radiographic axial spondyloarthritis patients treated with Taltz at the recommended dosing regimen for up to 52 weeks, 8.9% developed anti-drug antibodies, all of which were low titer; no patient had neutralizing antibodies; 

and no apparent association between the presence of anti-drug antibodies and drug concentration, efficacy, or safety was observed.

Across all indications, an association between immunogenicity and treatment emergent adverse events has not been clearly established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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