4.1. Therapeutic indications

Plaque psoriasis

Taltz is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy.

Paediatric plaque psoriasis

Taltz is indicated for the treatment of moderate to severe plaque psoriasis in children from the age of 6 years and with a body weight of at least 25 kg and adolescents who are candidates for systemic therapy.

Psoriatic arthritis

Taltz, alone or in combination with methotrexate, is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drug (DMARD) therapies (see section 5.1).

Axial spondyloarthritis

Ankylosing spondylitis (radiographic axial spondyloarthritis)Taltz is indicated for the treatment of adult patients with active ankylosing spondylitis who have responded inadequately to conventional therapy.

Non-radiographic axial spondyloarthritisTaltz is indicated for the treatment of adult patients with active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs).

4.2. Posology and method of administration

This medicinal product is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which it is indicated.

Posology

Plaque psoriasis in adults

The recommended dose is 160 mg by subcutaneous injection at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then maintenance dosing of 80 mg every 4 weeks (Q4W).

Paediatric plaque psoriasis (age 6 years and above)

Efficacy and safety data is not available in children below the age of 6 years (see section 5.1). Available data do not support a posology below a body weight of 25 kg.

The recommended dose given by subcutaneous injection in children is based on the following weight categories:

Children's body weight

Recommended starting dose (week 0)

Recommended dose every 4 weeks (Q4W) thereafter

Greater than 50 kg

160 mg

80 mg

25 to 50 kg

80 mg

40 mg

For children prescribed 80 mg, Taltz can be used directly from the pre‑filled syringe.

If the 40 mg pre-filled syringe is not available, doses less than 80 mg must be prepared by a healthcare professional. For instructions on preparation of ixekizumab doses of 40 mg, see section 6.6.

Taltz is not recommended for use in children with a body weight below 25 kg. Paediatric body weights must be recorded and regularly re‑checked prior to dosing.

Psoriatic arthritis

The recommended dose is 160 mg by subcutaneous injection at week 0, followed by 80 mg every 4 weeks thereafter. For psoriatic arthritis patients with concomitant moderate to severe plaque psoriasis, the recommended dosing regimen is the same as for plaque psoriasis.

Axial spondyloarthritis (radiographic and non-radiographic)

The recommended dose is 160 mg by subcutaneous injection at week 0, followed by 80 mg every 4 weeks (see section 5.1 for further information).

For all indications (plaque psoriasis in adults and children, psoriatic arthritis, axial spondyloarthritis) consideration should be given to discontinuing treatment in patients who have shown no response after 16 to 20 weeks of treatment. Some patients with initially partial response may subsequently improve with continued treatment beyond 20 weeks.

Special populations

Elderly

No dose adjustment is required in subjects aged ≥ 65 years (see section 5.2).

There is limited information in subjects aged ≥ 75 years.

Renal or hepatic impairment

Taltz has not been studied in these patient populations. No dose recommendations can be made.

Paediatric population

Paediatric plaque psoriasis (below a body weight of 25 kg and below the age of 6 years)

There is no relevant use of Taltz in children below a body weight of 25 kg and below the age of 6 years in the treatment of moderate to severe plaque psoriasis.

Paediatric psoriatic arthritis

The safety and efficacy of Taltz in children and adolescents aged 2 to less than 18 years in the treatment of psoriatic arthritis (a category of juvenile idiopathic arthritis) have not yet been established. No data are available.

There is no relevant use of Taltz in children below 2 years for the indication of psoriatic arthritis.

Method of administration

Subcutaneous use.

Taltz is for subcutaneous injection. Injection sites may be alternated. If possible, areas of the skin that show psoriasis should be avoided as injection sites. The solution/the syringe must not be shaken.

After proper training in subcutaneous injection technique, patients may self-inject Taltz if a healthcare professional determines that it is appropriate. However, the physician should ensure appropriate follow‑up of patients. Comprehensive instructions for administration are given in the package leaflet and the user manual.

If the 40 mg pre-filled syringe is not available, doses less than 80 mg which require dose preparation should only be administered by a healthcare professional.

For instructions on preparation of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Serious hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important active infections (e.g. active tuberculosis, see section 4.4).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infections

Treatment with Taltz is associated with an increased rate of infections such as upper respiratory tract infection, oral candidiasis, conjunctivitis, and tinea infections (see section 4.8).

Taltz should be used with caution in patients with clinically important chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If an infection develops, patients should be carefully monitored and Taltz discontinued if the patient is not responding to standard therapy or if the infection becomes serious. Taltz should not be resumed until the infection resolves.

Taltz must not be given to patients with active tuberculosis (TB). Anti‑TB therapy prior to initiation of Taltz in patients with latent TB should be considered.

Hypersensitivity

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 Taltz should be discontinued immediately and appropriate therapy initiated.

Inflammatory bowel disease (including Crohn's disease and ulcerative colitis)

Cases of new or exacerbations of inflammatory bowel disease have been reported with ixekizumab (see section 4.8). Ixekizumab is not recommended in patients with inflammatory bowel disease. If a patient develops signs and symptoms of inflammatory bowel disease or experiences an exacerbation of pre‑existing inflammatory bowel disease, ixekizumab should be discontinued and appropriate medical management should be initiated.

Immunisations

Taltz 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 (see section 5.1).

Excipients with known effect

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 40 mg dose and per 80 mg dose, that is to say essentially “sodium-free”.

Polysorbate

This medicinal product contains 0.15 mg of polysorbate 80 in each 40 mg pre-filled syringe which is equivalent to 0.30 mg/mL. This medicinal product contains 0.3 mg of polysorbate 80 in each 80 mg pre-filled syringe which is equivalent to 0.30 mg/mL. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

In plaque psoriasis studies, the safety of Taltz in combination with other immunomodulatory agents or phototherapy has not been evaluated.

In population pharmacokinetic analyses, clearance of ixekizumab was not affected by concomitant administration of oral corticosteroids, NSAIDs, sulfasalazine, or methotrexate.

Cytochrome P450 substrates

Results from an interaction study in patients with moderate-to-severe psoriasis determined that 12 weeks of administration of ixekizumab with substances metabolised by CYP3A4 (i.e., midazolam), CYP2C9 (i.e., warfarin), CYP2C19 (i.e., omeprazole), CYP1A2 (i.e., caffeine) or CYP2D6 (i.e., dextromethorphan) does not have a clinically significant impact on the pharmacokinetics of these substances.

4.6. Fertility, pregnancy and lactation

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.

Pregnancy

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 (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Taltz during pregnancy.

Breast-feeding

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 Taltz taking into account the benefit of breast‑feeding for the child and the benefit of therapy for the woman.

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 (see section 5.3).

4.7. Effects on ability to drive and use machines

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

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 post-marketing 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 post-marketing 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 disorders

Uncommon

Neutropenia,

Thrombocytopenia

Immune system disorders

Uncommon

Angioedema

Rare

Anaphylaxis

Respiratory, thoracic and mediastinal disorders

Common

Oropharyngeal pain

Gastrointestinal disorders

Common

Nausea

Uncommon

Inflammatory bowel disease

Skin and subcutaneous disorders

Uncommon

Urticaria,

Rash,

Eczema

Dyshidrotic eczema

Rare

Exfoliative dermatitis

General disorders and administration site conditions

Very common

Injection site reactionsa

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, randomised cross-over study in 45 healthy subjects comparing the original formulation with the revised, citrate-free formulation, statistically significantly lower Visual Analogue Scale (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 neutralising 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 neutralising antibodies. No apparent association between the presence of neutralising antibodies and impact on drug concentration or efficacy was observed.

In paediatric psoriasis patients treated with Taltz at the recommended dosing regimen up to 12 weeks, 21 patients (18%) developed anti‑drug antibodies, approximately half were low titer and 5 patients (4%) had confirmed neutralizing antibodies associated with low drug concentrations. There was no association with clinical response or adverse events.

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 neutralising 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 neutralising 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.

Paediatric population

The safety profile observed in children with plaque psoriasis treated with Taltz every 4 weeks is consistent with the safety profile in adult patients with plaque psoriasis with the exception of the frequencies of conjunctivitis, influenza, and urticaria which were common. Inflammatory bowel disease was also more frequent in paediatric patients, although it was still uncommon. In the paediatric clinical study, Crohn's disease occurred in 0.9% of patients in the Taltz group and 0% of patients in the placebo group during the 12‑week, placebo‑controlled period. Crohn's disease occurred in a total of 4 Taltz treated subjects (2.0%) during the combined placebo‑controlled and maintenance periods of the paediatric clinical study.

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 via the Yellow Card Scheme; Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Doses up to 180 mg have been administered subcutaneously in clinical trials without dose‑limiting toxicity. Overdoses up to 240 mg, subcutaneously, as a single administration in clinical trials, have been reported without any serious adverse events.

In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.