Taltz prefilled syringe

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.

Contraindications

Clinically important active infections.

Incompatibilities

Not applicable.

Undesirable effects

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).

Tabulated list of adverse reactions

ADRs from clinical studies and postmarketing reports (Table 1) 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 Taltz Prefilled Syringe in blinded and open-label clinical studies in plaque psoriasis, psoriatic arthritis, and other autoimmune conditions. Of these, 4,500 patients were exposed to Taltz Prefilled Syringe 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 Taltz Prefilled Syringe 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 Taltz Prefilled Syringe 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 Taltz Prefilled Syringe 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.

Table 1. List of adverse reactions in clinical studiesa and postmarketing reports

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 Taltz Prefilled Syringe.

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 Taltz Prefilled Syringe 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 Prefilled Syringe 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 Taltz Prefilled Syringe (46.9 per 100 patient years). Serious infections were reported in 1.6 % of patients treated with Taltz Prefilled Syringe (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 Taltz Prefilled Syringe 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 Prefilled Syringe developed a neutrophil count < 1,000 cells/mm3. In general, neutropenia did not require discontinuation of Taltz Prefilled Syringe.

3 % of patients exposed to Taltz Prefilled Syringe 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 Taltz Prefilled Syringe 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 Prefilled Syringe had confirmed neutralising antibodies associated with low drug concentrations and reduced clinical response.

In psoriatic arthritis patients treated with Taltz Prefilled Syringe 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.

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 Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: [email protected], or United Kingdom: Yellow Card Scheme; Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Preclinical safety data

Non-clinical data from cynomolgus monkeys revealed no special hazards for humans based on repeat-dose toxicity studies, safety pharmacology evaluations, and reproductive and developmental toxicity studies.

Ixekizumab administration to cynomolgus monkeys for 39 weeks at subcutaneous doses up to 50 mg/kg weekly produced no organ toxicity or undesirable effects on immune function (e.g. T-cell dependent antibody response and NK cell activity). A weekly subcutaneous dose of 50 mg/kg to monkeys is approximately 19 times the 160 mg starting dose of Taltz Prefilled Syringe and in monkeys results in exposure (AUC) that is at least 61-fold higher than the predicted mean steady-state exposure in humans administered the recommended dose regimen.

Non-clinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ixekizumab.

No effects on reproductive organs, menstrual cycles or sperm were observed in sexually mature cynomolgus monkeys that received ixekizumab for 13 weeks at a weekly subcutaneous dose of 50 mg/kg.

In developmental toxicity studies, ixekizumab was shown to cross the placenta and was present in the blood of offspring for up to 6 months of age. A higher incidence of postnatal mortality occurred in the offspring of monkeys given ixekizumab compared to concurrent controls. This was related primarily to early delivery or maternal neglect of offspring, common findings in nonhuman primate studies, and considered clinically irrelevant.

Therapeutic indications

Plaque psoriasis

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

Psoriatic arthritis

Taltz Prefilled Syringe, 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.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC13

Mechanism of action

Ixekizumab is an IgG4 monoclonal antibody that binds with high affinity (< 3 pM) and specificity to interleukin 17A (both IL-17A and IL-17A/F). Elevated concentrations of IL-17A have been implicated in the pathogenesis of psoriasis by promoting keratinocyte proliferation and activation, as well as in the pathogenesis of psoriatic arthritis. Neutralisation of IL-17A by ixekizumab inhibits these actions. Ixekizumab does not bind to ligands IL-17B, IL-17C, IL-17D, IL-17E or IL-17F.

In vitro binding assays confirmed that ixekizumab does not bind to human Fcγ receptors I, IIa, and IIIa or to complement component C1q.

Pharmacodynamic effects

Ixekizumab modulates biological responses that are induced or regulated by IL-17A. Based on psoriatic skin biopsy data from a phase I study, there was a dose-related trend towards decreased epidermal thickness, number of proliferating keratinocytes, T cells, and dendritic cells, as well as reductions in local inflammatory markers from baseline to day 43. As a direct consequence treatment with ixekizumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.

Taltz Prefilled Syringe has been shown to lower (within 1 week of treatment) levels of C-reactive protein, which is a marker of inflammation.

Clinical efficacy and safety

Plaque psoriasis

The efficacy and safety of Taltz Prefilled Syringe were assessed in three randomised, double-blind, placebo-controlled phase III studies in adult patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy (UNCOVER-1, UNCOVER-2, and UNCOVER-3). The efficacy and safety of Taltz Prefilled Syringe were also evaluated versus etanercept (UNCOVER-2 and UNCOVER-3). Patients randomised to Taltz Prefilled Syringe who were sPGA (0,1) responders (static Physicians Global Assessment) at Week 12 were re-randomised to receive placebo or Taltz Prefilled Syringe for an additional 48 weeks (UNCOVER-1 and UNCOVER-2); patients randomised to placebo, etanercept or Taltz Prefilled Syringe who were sPGA (0,1) non-responders received Taltz Prefilled Syringe for up to 48 weeks.

Of the 3,866 patients enrolled in these placebo-controlled studies, 64 % had received prior systemic therapy (biologic, conventional systemic or psoralen and ultraviolet A (PUVA)), 43.5 % had received prior phototherapy, 49.3 % had received prior conventional systemic therapy, and 26.4 % had received prior biologic therapy for the treatment of psoriasis. Of all patients, 14.9 % had received at least one anti-TNF alpha agent, and 8.7 % had received an anti-IL-12/IL-23. 23.4 % of patients had a history of psoriatic arthritis at baseline.

In all three studies, the co-primary endpoints were the proportion of patients who achieved a PASI 75 response (Psoriasis Area and Severity Index) and an sPGA of 0 (“clear”) or 1 (“minimal”) response at Week 12 versus placebo. Patients in all treatment groups had a median baseline PASI score ranging from 17.4 to 18.3; 48.3 % to 51.2 % of patients had a baseline sPGA score of severe or very severe, and mean baseline itch Numeric Rating Scale (itch NRS) ranging from 6.3 to 7.1.

Clinical response at 12 weeks

UNCOVER-1 enrolled 1,296 patients. Patients were randomised (1:1:1) to receive either placebo or Taltz Prefilled Syringe (80 mg every two or four weeks [Q2W or Q4W] following a 160 mg starting dose) for 12 weeks.

Table 2. Efficacy results at Week 12 in UNCOVER-1

Abbreviations: N = number of patients in the intent-to-treat population

Note: patients with missing data were counted as non-responders

a p < 0.001 compared with placebo

b Patients with Itch NRS >= 4 at baseline: placebo N = 374, Taltz Prefilled Syringe 80 mg Q4W N = 379, Taltz Prefilled Syringe 80 mg Q2W N = 391

UNCOVER-2 enrolled 1,224 patients. Patients were randomised (1:2:2:2) to receive either placebo, or Taltz Prefilled Syringe (80 mg every two or four weeks [Q2W or Q4W] following a 160 mg starting dose) or etanercept 50 mg twice weekly for 12 weeks.

Table 3. Efficacy results at Week 12 in UNCOVER-2

Abbreviations: N = number of patients in the intent-to-treat population

Note: patients with missing data were counted as non-responders.

a p < 0.001 compared with placebo

b p < 0.001 compared with etanercept

c p < 0.01 compared with placebo

d Patients with Itch NRS > = 4 at baseline: placebo N = 135, Taltz Prefilled Syringe 80 mg Q4W N = 293, Taltz Prefilled Syringe 80 mg Q2W N = 303, Etanercept N = 306

UNCOVER-3 enrolled 1,346 patients. Patients were randomised (1:2:2:2) to receive either placebo, or Taltz Prefilled Syringe (80 mg every two or four weeks [Q2W or Q4W] following a 160 mg starting dose) or etanercept 50 mg twice weekly for 12 weeks.

Table 4. Efficacy results at Week 12 in UNCOVER-3

Abbreviations: N = number of patients in the intent-to-treat population

Note: patients with missing data were counted as non-responders

a p < 0.001 compared with placebo

b p < 0.001 compared with etanercept

c Patients with Itch NRS >= 4 at baseline: placebo N = 158, Taltz Prefilled Syringe 80 mg Q4W N = 313, Taltz Prefilled Syringe 80 mg Q2W N = 320, Etanercept N = 312

Taltz Prefilled Syringe was associated with a fast onset of efficacy with > 50 % reduction in mean PASI by Week 2 (Figure 1). The percentage of patients achieving PASI 75 was significantly greater for Taltz Prefilled Syringe compared with placebo and etanercept as early as Week 1. Approximately 25 % of patients treated with Taltz Prefilled Syringe achieved a PASI score < 5 by Week 2, more than 55 % achieved the PASI score < 5 by Week 4, and increased to 85 % by Week 12 (compared to 3 %, 14 % and 50 % for etanercept). Significant improvements in itch severity were seen at Week 1 in patients treated with Taltz Prefilled Syringe.

Figure 1. PASI score, percent improvement at each post baseline visit (mBOCF)) in the Intent-to-Treat Population during the Induction Dosing Period - UNCOVER-2 and UNCOVER-3

The efficacy and safety of Taltz Prefilled Syringe was demonstrated regardless of age, gender, race, body weight, PASI baseline severity, plaques location, concurrent psoriatic arthritis, and previous treatment with a biologic. Taltz Prefilled Syringe was efficacious in systemic treatment-naive, biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients.

Efficacy in Non-Responders to Etanercept: For patients identified as an sPGA (0,1) non-responder to etanercept at Week 12 in UNCOVER-2 (N = 200) and who were switched to Taltz Prefilled Syringe 80 mg Q4W after a 4 week washout period, 73 % and 83.5 % of patients were able to achieve sPGA (0,1) and PASI 75, respectively, after 12 weeks of being treated with Taltz Prefilled Syringe.

In the 2 clinical studies that included an active comparator (UNCOVER-2 and UNCOVER-3), the rate of serious adverse events was 1.9 % for both etanercept and for Taltz Prefilled Syringe, and the rate of discontinuation due to adverse events was 1.2 % for etanercept and 2.0 % for Taltz Prefilled Syringe. The rate of infections was 21.5 % for etanercept and 26.0 % for Taltz Prefilled Syringe, with the majority of the events mild to moderate in severity. The rate of serious infections was 0.4 % for etanercept and 0.5 % for Taltz Prefilled Syringe.

Maintenance of Response at Week 60

Patients originally randomised to Taltz Prefilled Syringe and who were responders at Week 12 (i.e., sPGA score of 0,1) in UNCOVER-1 and UNCOVER-2 were re-randomised to an additional 48 weeks of one of the following treatment regimens: placebo, or Taltz Prefilled Syringe (80 mg every four or twelve weeks [Q4W or Q12W]).

Table 5. Maintenance of Response and Efficacy at Week 60

(Studies UNCOVER-1 and UNCOVER-2)

Abbreviations: N = number of patients in the analysis population

Note: patients with missing data were counted as non-responders

a p < 0.001 compared with placebo

Taltz Prefilled Syringe was efficacious in the maintenance of response in systemic treatment-naive, biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients.

For sPGA (0,1) responders at Week 12 re-randomised to treatment withdrawal (i.e., placebo), the median time to relapse (sPGA > 3) was 164 days in integrated UNCOVER-1 and UNCOVER-2 studies. Among these patients, 71.5 % regained at least an sPGA (0,1) response within 12 weeks of restarting treatment with Taltz Prefilled Syringe 80 mg Q4W.

Significantly greater improvements at Week 12 from baseline compared to placebo and etanercept were demonstrated in nail psoriasis (as measured by the Nail Psoriasis Severity Index [NAPSI]), in scalp psoriasis (as measured by Psoriasis Scalp Severity Index [PSSI]) and in palmoplantar psoriasis (as measured by Psoriasis Palmoplantar Severity Index [PPASI]). These improvements in nail, scalp and palmoplantar psoriasis were maintained at Week 60 in patients treated with Taltz Prefilled Syringe who were sPGA (0,1) responders at Week 12.

Quality of Life/Patient-Reported Outcomes

At Week 12 and across studies, Taltz Prefilled Syringe was associated with statistically significant improvement in Health-related Quality of Life as assessed by mean decrease ranges from baseline in the Dermatology Life Quality Index (DLQI) (Taltz Prefilled Syringe 80 mg Q2W from -10.2 to -11.1, Taltz Prefilled Syringe 80 mg Q4W from -9.4 to -10.7, etanercept from -7.7 to -8.0 and placebo -1.0 to -2.0). A significantly greater proportion of patients treated with Taltz Prefilled Syringe achieved a DLQI 0 or 1. Across studies, Taltz Prefilled Syringe was associated with statistically significant improvement of itching severity assessed by the Itch NRS score. A significantly greater proportion of patients treated with Taltz Prefilled Syringe achieved a reduction of Itch NRS > 4 points at week 12 (84.6 % for Taltz Prefilled Syringe Q2W, 79.2 % for Taltz Prefilled Syringe Q4W and 16.5 % for placebo) and the benefit was sustained over time up to Week 60 in patients treated with Taltz Prefilled Syringe who were sPGA (0 or 1) responders at Week 12. There was not any evidence of worsening of depression up to 60 weeks treatment with Taltz Prefilled Syringe as assessed by the Quick Inventory of Depressive Symptomatology Self Report.

Postmarketing Phase 3b, direct comparative study

Efficacy and safety of ixekizumab was also investigated in a double-blind study compared to ustekinumab with ixekizumab being superior on the primary study objective (PASI 90 response at week 12, Table 6). Onset of response was superior on PASI 75 as early as week 2 (p < 0.001) and on PASI 90 and PASI 100 by week 4 (p < 0.001). Superiority of ixekizumab versus ustekinumab was also demonstrated in the subgroups stratified by weight.

Table 6.PASI-Response Rates from comparative study ixekizumab versus ustekinumab

* Ixekizumab 160 mg was given as a loading dose followed by 80 mg at week 2,4,6,8,10 and 12, and 80 mg Q4W thereafter

** Weight based dosing: Patients treated with ustekinumab received 45 mg or 90 mg at Weeks 0 and 4, then every 12 weeks until Week 52 (dosed by weight as per approved posology)

§p < 0.001 versus ustekinumab (p value only provided for primary endpoint)

Psoriatic arthritis

The safety and efficacy of Taltz Prefilled Syringe were assessed in two randomised, double-blind, placebo-controlled phase III studies in 780 patients with active psoriatic arthritis (> 3 swollen and > 3 tender joints). Patients in these studies had a diagnosis of psoriatic arthritis (Classification Criteria for Psoriatic Arthritis [CASPAR] criteria) for a median of 5.33 years. Randomised patients also had current plaque psoriasis skin lesions (94.0 %) or a documented history of plaque psoriasis, with 12.1 % of patients with moderate to severe plaque psoriasis at baseline. Over 58.9 % and 22.3 % of the psoriatic arthritis patients had enthesitis and dactylitis at baseline, respectively. For both studies, the primary endpoint was American College of Rheumatology (ACR) 20 response at Week 24.

In Psoriatic Arthritis Study 1 (SPIRIT-P1), patients naive to biologic therapy with active psoriatic arthritis were randomised to subcutaneous injections of placebo, adalimumab 40 mg once every 2 weeks (active control reference arm), Taltz Prefilled Syringe 80 mg once every 2 weeks (Q2W), or 80 mg once every 4 weeks (Q4W). Both Taltz Prefilled Syringe regimens included a 160 mg starting dose. 85.3 % of patients in this study had received prior treatment with > 1 cDMARD. 53 % of patients had concomitant use of MTX at a mean weekly dose of 15.8 mg. 67 % of patients who had concomitant use of MTX had a dose of 15 mg or greater. Patients in all treatment groups with an inadequate response at week 16 received rescue therapy (modification to background therapy). Patients on Taltz Prefilled Syringe Q2W or Q4W remained on their originally assigned dose of Taltz Prefilled Syringe. Patients receiving adalimumab or placebo were re-randomised 1:1 to Taltz Prefilled Syringe Q2W or Q4W at week 16 or 24 based on responder status.

Psoriatic Arthritis Study 2 (SPIRIT-P2) enrolled patients who were previously treated with an anti-TNF agent and discontinued the anti-TNF agent for either lack of efficacy or intolerance (anti-TNF-IR patients). Patients were randomised to subcutaneous injections of placebo, Taltz Prefilled Syringe 80 mg once every 2 weeks (Q2W), or 80 mg once every 4 weeks (Q4W). Both Taltz Prefilled Syringe regimens included a 160 mg starting dose. 56 % and 35 % of patients were inadequate responders to 1 anti-TNF or 2 anti-TNF, respectively. SPIRIT-P2 evaluated 363 patients, of whom 41 % had concomitant use of MTX at a mean weekly dose of 16.1 mg. 73.2 % of patients who had concomitant use of MTX had a dose of 15 mg or greater. Patients in all treatment groups with an inadequate response at week 16 received rescue therapy (modification to background therapy). Patients in Taltz Prefilled Syringe Q2W or Q4W remained on their originally assigned dose of Taltz Prefilled Syringe. Patients receiving placebo were re-randomised 1:1 to Taltz Prefilled Syringe Q2W or Q4W at week 16 or 24 based on responder status.

Signs and symptoms

Treatment with Taltz Prefilled Syringe resulted in significant improvement in measures of disease activity compared to placebo at Week 24 (see Table 7).

Table 7. Efficacy results in SPIRIT-P1 and SPIRIT-P2 at week 24

Pharmacokinetic properties

Absorption

Following a single subcutaneous dose of ixekizumab in patients with psoriasis, mean peak concentrations were achieved within 4 to 7 days, across a dose range of 5 to 160 mg. The mean (SD) maximum plasma concentration (Cmax) of ixekizumab, after the 160 mg starting dose, was 19.9 (8.15) µg/ml.

After the 160 mg starting dose, steady state was achieved by Week 8 with the 80 mg Q2W dosing regimen. Mean (SD) Cmax,ss, and C trough,ss estimates are 21.5 (9.16) µg/ml, and 5.23 (3.19) µg/ml.

After switching from the 80 mg Q2W dosing regimen to the 80 mg Q4W dosing regimen at Week 12, steady state would be achieved after approximately 10 weeks. Mean (SD) Cmax,ss, and Ctrough,ss estimates are 14.6 (6.04) µg/ml, and 1.87 (1.30) µg/ml.

The average bioavailability of ixekizumab after subcutaneous administration was 54 % to 90 % across analyses.

Distribution

From population pharmacokinetic analyses, the mean total volume of distribution at steady state was 7.11 L.

Biotransformation

Ixekizumab is a monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous immunoglobulins.

Elimination

In the population PK analysis, mean serum clearance was 0.0161 L/hr. Clearance is independent of dose. The mean elimination half-life, as estimated from population pharmacokinetic analysis, is 13 days in patients with plaque psoriasis.

Linearity/non-linearity

Exposure (AUC) increased proportionally over a dose range of 5 to 160 mg given as a subcutaneous injection.

Psoriatic arthritis

The pharmacokinetic properties of Taltz Prefilled Syringe observed in psoriatic arthritis patients were similar to those displayed in plaque psoriasis patients. The bioavailability of Taltz Prefilled Syringe in psoriatic arthritis patients was in the range of 61-84 % on the basis of the population pharmacokinetic model.

Elderly

Of the 4,204 plaque psoriasis patients exposed to Taltz Prefilled Syringe in clinical studies, a total of 301 were 65 years of age or older and 36 patients were 75 years of age or older. Of the 1,118 psoriatic arthritis patients exposed to Taltz Prefilled Syringe in clinical studies, a total of 122 patients were 65 years of age or older and 6 patients were 75 years of age or older.

Based on population pharmacokinetic analysis with a limited number of elderly patients (n = 94 for age > 65 years and n = 12 for age > 75 years), clearance in elderly patients and patients less than 65 years of age was similar.

Renal or hepatic impairment

Specific clinical pharmacology studies to evaluate the effects of renal impairment and hepatic impairment on the PK of ixekizumab have not been conducted. Renal elimination of intact ixekizumab, an IgG MAb, is expected to be low and of minor importance; similarly, IgG MAbs are mainly eliminated via intracellular catabolism and hepatic impairment is not expected to influence clearance of ixekizumab.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Infections

Treatment with Taltz Prefilled Syringe is associated with an increased rate of infections such as upper respiratory tract infection, oral candidiasis, conjunctivitis, and tinea infections.

Taltz Prefilled Syringe should be used with caution in patients with clinically important chronic infection. If such an infection develops, monitor carefully and discontinue Taltz Prefilled Syringe if the patient is not responding to standard therapy or the infection becomes serious. Taltz Prefilled Syringe should not be resumed until the infection resolves.

Taltz Prefilled Syringe must not be given to patients with active tuberculosis (TB). Consider anti-TB therapy prior to initiation of Taltz Prefilled Syringe in patients with latent TB.

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 Prefilled Syringe should be discontinued immediately and appropriate therapy initiated.

Inflammatory Bowel Disease

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

Immunisations

Taltz Prefilled Syringe 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.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per 80 mg dose, i.e., essentially “sodium-free”.

Effects on ability to drive and use machines

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

Dosage (Posology) and method of administration

Taltz Prefilled Syringe is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which Taltz Prefilled Syringe is indicated.

Posology

Plaque psoriasis

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

Psoriatic arthritis

The recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg (one injection) 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.

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.

Elderly (> 65 years)

No dose adjustment is required.

There is limited information in subjects aged > 75 years.

Renal or hepatic impairment

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

Paediatric population

The safety and efficacy of Taltz Prefilled Syringe in children and adolescents aged 6 to 18 years in the treatment of moderate to severe plaque psoriasis have not yet been established. No data are available.

There is no relevant use of Taltz Prefilled Syringe in children below the age of 6 years in the treatment of moderate to severe plaque psoriasis.

The safety and efficacy of Taltz Prefilled Syringe 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 Prefilled Syringe in children below 2 years for the indication of psoriatic arthritis.

Method of administration

Subcutaneous use.

Taltz Prefilled Syringe 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/pen must not be shaken.

After proper training in subcutaneous injection technique, patients may self-inject Taltz Prefilled Syringe 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.

Special precautions for disposal and other handling

Instructions for use

Pre-filled syringe

The instructions for using the syringe, included with the package leaflet, must be followed carefully.

The pre-filled syringe is for single use only.

Taltz Prefilled Syringe should not be used if particles appear or if the solution is cloudy and/or distinctly brown.

Taltz Prefilled Syringe that has been frozen must not be used.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Pre-filled pen

The instructions for using the pen, included with the leaflet, must be followed carefully.

The pre-filled pen is for single use only.

Taltz Prefilled Syringe should not be used if particles appear or if the solution is cloudy and/or distinctly brown.

Taltz Prefilled Syringe that has been frozen must not be used.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.