Ixekizumab

Ixekizumab should not be used with live vaccines. No data are available on the response to live vaccines; there are insufficient data on response to inactive vaccines.

Serious hypersensitivity reactions, including some cases of anaphylaxis, angioedema, urticaria and, rarely, late (10-14 days following injection) serious hypersensitivity reactions including widespread urticaria, dyspnea and high antibody titres have been reported. If a serious hypersensitivity reaction occurs, administration of ixekizumab should be discontinued immediately and appropriate therapy initiated.

Cases of new or exacerbations of Crohn’s disease and ulcerative colitis have been reported. Caution should be exercised when prescribing ixekizumab to patients with inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, and patients should be monitored closely.

There is a limited amount of data from the use of ixekizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or post-natal development. As a precautionary measure, it is preferable to avoid the use of ixekizumab during pregnancy.

It is not known whether ixekizumab is excreted in human milk or absorbed systemically after ingestion. However, ixekizumab is excreted at low levels in the milk of cynomolgus monkeys. A decision should be made whether to discontinue breast-feeding or to discontinue ixekizumab taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential

Women of childbearing potential should use an effective method of contraception during treatment and for at least 10 weeks after treatment.

Fertility

The effect of ixekizumab on human fertility has not been evaluated. Animal studies do not indicate direct or indirect harmful effects with respect to fertility.

Ixekizumab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) were injection site reactions and upper respiratory tract infections (most frequently nasopharyngitis).

List of adverse reactions

ADRs from clinical studies and postmarketing reports are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each ADR 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 7,339 patients have been treated with ixekizumab in blinded and open-label clinical studies in plaque psoriasis, psoriatic arthritis, and other autoimmune conditions. Of these, 4,500 patients were exposed to ixekizumab for at least one year, cumulatively representing 13,645.6 patient years of exposure.

In plaque psoriasis, three placebo-controlled phase III studies were integrated to evaluate the safety of ixekizumab in comparison to placebo up to 12 weeks after treatment initiation. A total of 3,119 patients were evaluated (1,161 patients on 80 mg every 4 weeks (Q4W), 1,167 patients on 80 mg every 2 weeks (Q2W) and 791 patients on placebo).

In psoriatic arthritis, two placebo-controlled phase III studies were integrated to evaluate the safety of ixekizumab in comparison to placebo up to 24 weeks after treatment initiation. A total of 678 patients were evaluated (229 patients on 80 mg every 4 weeks (Q4W), 225 patients on 80 mg every 2 weeks (Q2W) and 224 patients on placebo). The safety profile observed in patients with psoriatic arthritis treated with ixekizumab is consistent with the safety profile in plaque psoriasis with the exception of the frequencies of the adverse reactions of influenza and conjunctivitis which were common in patients with psoriatic arthritis.

List of adverse reactions in clinical studies^a and postmarketing reports:

Infections and infestations

Very Common: Upper respiratory tract infection^b

Common: Tinea infection, Herpes simplex (mucocutaneous)^c

Uncommon: Influenzaⁱ, Rhinitis, Oral candidiasis^d, Conjunctivitisⁱ, Cellulitis^e

Blood and lymphatic system disorders

Uncommon: Neutropenia^g, Thrombocytopenia^g

Immune system disorders

Uncommon: Angioedema

Rare: Anaphylaxish

Respiratory, thoracic and mediastinal disorders

Common: Oropharyngeal pain

Gastrointestinal disorders

Common: Nausea

Skin and subcutaneous disorders

Uncommon: Urticaria, Rash, Eczema,

General disorders and administration site conditions

Very common: Injection site reactions^f

^a Placebo-controlled clinical studies (phase III) in moderate to severe plaque psoriasis patients exposed to ixekizumab 80 mg Q2W, ixekizumab 80 mg Q4W or placebo for up to 12 weeks of treatment duration, or in active psoriatic arthritis patients exposed to ixekizumab 80 mg Q2W, ixekizumab 80 mg Q4W or placebo for up to 24 weeks of treatment duration.
^b Upper respiratory tract infection includes nasopharyngitis and upper respiratory tract infection.
^c Herpes simplex (mucocutaneous) is defined as events with the preferred terms Oral herpes, Herpes simplex, Genital herpes, Herpes dermatitis, and Genital herpes simplex.
^d Oral candidiasis defined as events with the preferred terms oral candidiasis and oral fungal infection .
^e Cellulitis includes staphylococcal and external ear cellulitis, and erysipelas.
^f In the 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). 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 or the psoriatic arthritis studies.
^g Based on reported adverse events.
^h Based on postmarketing reports.
ⁱ Adverse drug reactions in patients treated with ixekizumab in the plaque psoriasis and psoriatic arthritis clinical trials were similar with the exception of the frequencies of influenza (common) and conjunctivitis (common) in the psoriatic arthritis clinical trials.

Description of selected adverse reactions

(Based on adverse reactions data from 4,204 patients with moderate to severe plaque psoriasis [4,729.7 patient years] and 1,117 patients with active psoriatic arthritis [1,050.6 patient years] who have received at least 1 dose of ixekizumab.)

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 ixekizumab.

Infections

In the placebo-controlled period of the phase III clinical studies in plaque psoriasis, infections were reported in 27.2% of patients treated with ixekizumab 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 ixekizumab and in 3 (0.4%) of patients treated with placebo. Over the entire treatment period infections were reported in 52.8% of patients treated with ixekizumab (46.9 per 100 patient years). Serious infections were reported in 1.6% of patients treated with ixekizumab (1.5 per 100 patient years).

Infection rates observed in psoriatic arthritis 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 ixekizumab 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 ixekizumab developed a neutrophil count <1000 cells/mm³. In general, neutropenia did not require discontinuation of ixekizumab. 3% of patients exposed to ixekizumab 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 clinical studies is similar to that observed in the plaque psoriasis studies.

Immunogenicity

Approximately 9–17% of plaque psoriasis patients treated with ixekizumab 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 ixekizumab had confirmed neutralising antibodies associated with low drug concentrations and reduced clinical response.

In psoriatic arthritis patients treated with ixekizumab 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 neutralising antibodies. No apparent association between the presence of neutralising antibodies and impact on drug concentration or efficacy was observed.

An association between immunogenicity and treatment emergent adverse events has not been clearly established.