Taltz ® (ixekizumab)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information.For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).

Taltz® (ixekizumab): Is Injection Site Pain Common?

Pain was statistically significantly (p<.0001) reduced in patients who received citrate-free ixekizumab compared with the original ixekizumab formulation.

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UK_cFAQ_IXE401_INJECTION_SITE_PAIN_PsO_PsA_axSpA_CITRATE_FREE
en-GB

Does the Patient Need to Discontinue Ixekizumab Because of Injection Site Pain?

The severity of injection site pain was predominantly mild to moderate and did not lead to discontinuation of ixekizumab.1 The prescribing physician decides how to manage injection site pain using his best clinical judgment.  

What Can the Patient Do to Reduce Injection Site Pain?

  • The patient may alternate injection sites and, if possible, should avoid areas of the skin that show psoriasis.2
  • The patient can wait 30 minutes to let the pre-filled pen or syringe warm to room temperature before using it. It is NOT allowed to use any heat sources to warm the medicine, for example: a microwave, hot water, or direct sunlight.2 
  • The package leaflet and the user manual give further instructions for administration.

Trials of Citrate-Free Ixekizumab in Healthy Participants

The original commercial formulation of ixekizumab was used in clinical trials conducted in patients with moderate-to-severe plaque psoriasis, active psoriatic arthritis, ankylosing spondylitis (AS), and nonradiographic axial spondyloarthritis (nr-axSpA). This information is available in Clinical Trials of Original Ixekizumab Formulation with Psoriasis, Psoriatic Arthritis, Axial Spondyloarthritis .

Citrate-free ixekizumab was studied in clinical trials conducted in healthy participants. This information is available in Injection Site Pain Reduction With Citrate-Free Ixekizumab.

Rationale for Citrate-Free Formulation of Ixekizumab

Ixekizumab has an established efficacy and safety profile which has been demonstrated across clinical trials conducted in patients with psoriasis (including pediatric psoriasis), psoriatic arthritis, and axial spondyloarthritis (including ankylosing spondylitis/radiographic axial spondyloarthritis and nonradiographic axial spondyloarthritis) with 22,698.7 patient-years (PY) of exposure to ixekizumab as of March 2022.3-11

Injection site reactions (ISRs) were one of the most common treatment-emergent adverse events reported with ixekizumab treatment in clinical trials. The incidence rate of ISRs was between 15 and 22 per 100 PY over the first year of ixekizumab administration.12

In the ISRs reported with ixekizumab, injection site pain and injection site erythema were among the most frequent.12 Postapproval reports and customer insights have shown that injection site pain is a concern and problem for some patients, thus the rationale for evaluating an alternate formulation to help reduce injection site pain and improve the patient's experience.10,13 

Additionally, preliminary studies conducted in healthy volunteers identified citrate, as buffer in the matrix, and sodium chloride, as the tonicity agent, were the main causes of injection site pain.13

Injection Site Pain Reduction With Citrate-Free Ixekizumab

Incidence and severity of adverse events were found to be similar between the citrate-free formulation and the original commercial formulation of ixekizumab in the new formulation clinical development program conducted in healthy subjects with the exception of less injection site pain with the citrate-free formulation. No new safety signals were identified.10,13

In the injection site pain study, pain measurements were quantified using a visual analog scale (VAS) pain score for all subjects. The VAS assessed injection site pain using a 100-mm line anchored by verbal descriptors “no pain” (score of 0) and “worst possible pain” (score of 100).13

Immediately following injection, pain VAS scores in least squares mean (LSM) were 3.52 for the citrate-free ixekizumab formulation compared with 25.21 for the original ixekizumab formulation. Pain was statistically significantly (p<.0001) reduced with a -21.69 difference in LSM in pain VAS scores.13

Pain Visual Analog Scale Score for Original Commercial and Citrate-Free ixekizumab Formulation in Trial RHCS13

Figure 1 description: The visual analog scale pain score immediately following injection was 25.21 for the original commercial ixekizumab formulation and 3.52 for the citrate-free ixekizumab formulation.

Abbreviations: IXE = ixekizumab; LSM = least squares mean; VAS = visual analog scale.

***p<.0001 vs original ixekizumab formulation.

Ten minutes after injection, pain VAS scores in LSM were 0.68 for the citrate-free ixekizumab formulation compared with 5.15 for the original commercial ixekizumab formulation. Pain was statistically significantly (p<.0001) reduced with the use of citrate-free ixekizumab with a -4.47 difference in LSM in pain VAS scores.10

Most participants reported mild-to-moderate pain immediately after injection (Visual Analog Scale Pain Score Immediately After Injection).10

Visual Analog Scale Pain Score Immediately After Injection10

Treatment-Emergent Adverse Events

Original Commercial IXE
(N=61)

Citrate-Free IXE
(N=63)

Pain severity, n (%)

No pain (VAS=0)

5 (8.2)

26 (41)

Mild (VAS ≤30)

36 (59)

36 (57)

Moderate (>30 VAS ≤70)

16 (26)

1 (1.6)

Severe (VAS >70)

4 (6.6)

0

 Abbreviations: IXE = ixekizumab; VAS = visual analog scale.

A higher incidence of ISRs from solicited assessments was reported following administration of the original commercial ixekizumab formulation than citrate-free ixekizumab.10

By 10 minutes post injection, the majority of participants reported no pain to mild pain for both formulations. Approximately twice as many participants reported mild pain at 10 minutes following the original commercial ixekizumab formulation compared with citrate-free ixekizumab.10

By 30 minutes post injection, nearly all participants reported no pain or mild pain for both formulations, and the proportion of participants that reported pain overall had decreased. One participant still reported moderate pain at 30 minutes following administration with the original commercial ixekizumab formulation.10

Eli Lilly and Company will continue to monitor any potential new safety signals via postmarketing surveillance activities.13

Clinical Trials of Original Ixekizumab Formulation with Psoriasis, Psoriatic Arthritis, Axial Spondyloarthritis 

Please note that multiple, different dosing regimens, including unapproved doses, are included in this response.

Psoriasis Clinical Trials

What Was the Incidence of Injection Site Pain For All Patients in the Psoriasis Clinical Trials?

Of all adult patients treated with ixekizumab across 17 psoriasis clinical trials as of a data cutoff of March 2022 [n=6892 accounting for 18,025.7 patient-years (PYs) of exposure], injection site pain, as a separate event, was spontaneously reported by 1.7% of patients (n=117).10,14

Detailed Data From Pivotal Psoriasis Clinical Trials

Most ISRs (≥95%) were mild-to-moderate in severity. Of patients who reported an ISR, 0.2% discontinued ixekizumab due to ISR.3,15

During the 12-week induction periods of UNCOVER-1, -2, and -3, injection site pain was spontaneously reported in

  • 28 patients (2.4%) in the ixekizumab every 2 weeks (Q2W) dosing group 
  • 17 patients (1.5%) in the ixekizumab every 4 weeks (Q4W) dosing group, and 
  • 14 patients (1.8%) in the placebo group.10,16

Injection site pain resulted in discontinuation of study drug for 1 patient in the ixekizumab Q4W treatment group.10

Injection site pain was typically reported to occur during injection in the 12-week induction period.

16.9% of patients who received ixekizumab Q2W spontaneously reported an ISR (n=197/1167).16

  • 51% of patients who reported an ISR experienced pain.
    • Most patients (>90%) reported mild-to-moderate pain.16

Maximal Pain of ISRs in Patients Treated With Ixekizumab Every 2 Weeks During UNCOVER-1, -2, and -3 Psoriasis Clinical Trials (N=197) shows maximal pain of the ISRs reported using a follow-up questionnaire.

Maximal Pain of ISRs in Patients Treated With Ixekizumab Every 2 Weeks During UNCOVER-1, -2, and -3 Psoriasis Clinical Trials (N=197)16

Figure 1 description. Of the patients with psoriasis treated with ixekizumab every 2 weeks, 49% experienced no injection site pain, 32% experienced mild injection site pain, 16% experienced moderate injection site pain, and 3% experienced severe injection site pain during the first 12 weeks.

Abbreviation: ISRs = Injection site reactions.
Note: Denominator for percentages in figure is 197, or the number of patients who reported an ISR of any type in UNCOVER-1, -2, and -3.

No clear association between the presence of antidrug antibodies and safety, including ISR, has been established.16

Original Commercial Formulation - Treatment-Emergent Adverse Events With Autoinjector and Prefilled Syringe

UNCOVER-A was a study conducted primarily to evaluate the effect of drug delivery device, either by autoinjector or prefilled syringe, on the pharmacokinetics of ixekizumab.17 Efficacy and safety were also assessed throughout the clinical trial.

During the treatment period, 10 (9.8%) patients in the prefilled syringe group and 16 patients (15.7%) in the autoinjector group reported an ISR TEAE.10 Treatment-emergent adverse events reported by the investigator as possibly related to device included 1 in the prefilled syringe group and 10 in the autoinjector group device.17

In UNCOVER-A, injection site pain, as a separate event, was reported by approximately 2% of patients in the autoinjector group and 2% of patients in the prefilled syringe group.10

Psoriatic Arthritis Clinical Trials

What Was the Incidence of Injection Site Pain For All Patients in the Psoriatic Arthritis Clinical Trials?

Of all patients treated with ixekizumab across 4 psoriatic arthritis clinical trials as of March 2022 (n=1401 patients accounting for 2247.7 PYs of exposure to ixekizumab), injection site pain, as a separate event, was spontaneously reported by 1.6% of patients (n=22).10,18

Detailed Data From Pivotal Psoriatic Arthritis Clinical Trials

During the 24-week double-blind, placebo-controlled periods of SPIRIT-P1 and SPIRIT-P2, injection site pain was spontaneously reported in

  • 2 patients (0.9%) in the ixekizumab Q4W dosing group
  • 2 patients (0.9%) in the ixekizumab Q2W dosing group, and
  • 5 patients (2.2%) in the placebo group.10

Injection site pain resulted in discontinuation of study drug in 1 patient in the placebo group, and no patients in the ixekizumab treatment groups.10

The information below consists of solicited data from a follow-up questionnaire completed by 40 patients treated with ixekizumab 80 mg Q4W who reported an ISR (MedDRA high-level term) of any type during the placebo-controlled treatment period of SPIRIT-P1 and SPIRIT-P2.10

The follow-up form suggested that among patients who experienced an ISR of any type, 13 patients experienced pain, out of which only 3 were moderate-to-severe (Maximal Pain of ISRs in Patients Treated With Ixekizumab Every 4 Weeks During SPIRIT-P1 and SPIRIT-P2 Psoriatic Arthritis Clinical Trials (N=40)).10

Maximal Pain of ISRs in Patients Treated With Ixekizumab Every 4 Weeks During SPIRIT-P1 and SPIRIT-P2 Psoriatic Arthritis Clinical Trials (N=40)10

Figure 2 description. Of the patients with psoriatic arthritis treated with ixekizumab every 4 weeks, 68% experienced no injection site pain, 25% experienced mild injection site pain, 5% experienced moderate injection site pain, and 2.5% experienced severe injection site pain during the first 24 weeks.

Abbreviation: ISRs = injection site reactions.
Note: Denominator for percentages in figure is 40, or the number of patients who reported an ISR of any type in SPIRIT-P1 and SPIRIT-P2.

axSpA Clinical Trials

What Was the Incidence of Injection Site Pain For All Patients in the axSpA Clinical Trials?

Injection site pain as a separate event was reported by 12 (1.3%) patients across 4 axSpA clinical trials as of March 2022 (COAST-V and COAST-W AS/r-axSpA trials, COAST-X nr-axSpA trial, and the COAST-Y long-term extension study in patients with axSpA) (N=932 patients accounting for 2097.7 PYs of ixekizumab exposure).10

Detailed Data From Pivotal AS/r-axSpA Trials

Most ISRs were mild or moderate in severity.7,9 Of patients who reported an ISR, 1 patient (0.5%) in the ixekizumab Q4W group and 3 patients (1.7%) in the ixekizumab Q2W group discontinued due to ISR.7,9

During the 16-week double-blind, placebo-controlled periods of COAST-V and COAST-W, injection site pain was spontaneously reported in

  • 4 patients (2.1%) in the ixekizumab Q4W dosing group
  • 5 patients (2.8%) in the ixekizumab Q2W dosing group, and
  • 4 patients (2.1%) in the placebo group.10

Injection site pain resulted in discontinuation of study drug for 1 patient in the ixekizumab Q4W group.10

The information below consists of solicited data from a follow-up questionnaire completed by 12 patients treated with ixekizumab 80 mg Q4W who reported an ISR (MedDRA high-level term) of any type during the placebo-controlled treatment period of COAST-V and COAST-W.10

The follow-up form suggested that among the 12 patients who experienced an ISR of any type, 8 patients treated with ixekizumab Q4W experienced pain, of whom, 4 experienced moderate pain (Maximal Pain of ISRs in Patients Treated With Ixekizumab Every 4 Weeks During COAST-V and COAST-W AS/r-axSpA Clinical Trials (N=12)).10

Maximal Pain of ISRs in Patients Treated With Ixekizumab Every 4 Weeks During COAST-V and COAST-W AS/r-axSpA Clinical Trials (N=12)10

Figure 3 description. About 33% of patients with radiographic axial spondyloarthritis experienced no injection site pain, mild injection site pain, and moderate injection site pain, respectively. No patients experienced severe injection site pain during the first 16 weeks. 

Abbreviations: AS/r-axSpA = ankylosing spondylitis/radiographic axial spondyloarthritis; ISRs = Injection site reactions.
Note: Denominator for percentages in figure is 12, or the number of patients who reported an ISR of any type in COAST-V and COAST-W.

Data From Nonradiographic Axial Spondyloarthritis Trial

During the 52 weeks of COAST-X, injection site pain was spontaneously reported in 1 patient each in both

  • the ixekizumab treatment groups and
  • in the placebo group (1.0% of patients in each group).10

Injection site pain resulted in discontinuation of study drug for

  • 1 patient in the placebo group, and
  • no patients in the ixekizumab treatment groups.10

This data includes cases of injection site pain reported prior to any switch to open-label ixekizumab Q2W, which was allowed at the investigator's discretion from week 16 of COAST-X.8,10

Background Information

Unsolicited adverse event (AE) data were reported spontaneously in psoriasis, psoriatic arthritis, and axial spondyloarthritis clinical trials to investigators during study visits and were later coded using Medical Dictionary for Regulatory Activities (MedDRA) terms. Solicited AE data were collected using a standardized questionnaire only if patients initially reported an ISR of any type.16 Preferred terms that are included in the high-level group term of ISRs include, but are not limited to

  • injection site bruising
  • injection site erythema
  • injection site mass
  • injection site pain
  • injection site pruritus
  • injection site rash
  • injection site reaction
  • injection site swelling
  • injection site urticaria, and
  • injection site warmth.10

Data in this response include

  • unsolicited ISR TEAEs reported in clinical trials, and
  • solicited data from follow-up questionnaire completed by patients reporting an ISR of any type (questionnaire used in phase 3 trials only).10

References

1Taltz [summary of product characteristics]. Eli Lilly and Company (Ireland) Limited, Ireland

2Taltz 80 mg solution for injection in pre-filled pen [Instructions for use]. Eli Lilly and Company (Ireland) Limited, Ireland

3Gordon KB, Blauvelt A, Papp KA, et al; UNCOVER-1, UNCOVER-2, and UNCOVER-3 Study Groups. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356. http://dx.doi.org/10.1056/NEJMoa1512711

4Paller AS, Seyger MMB, Magariños GA, et al; IXORA-PEDS Study Group. Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS). Br J Dermatol. 2020;183(2):231-241. https://doi.org/10.1111/bjd.19147

5Mease PJ, van der Heijde D, Ritchlin CT, et al; SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79-87. http://dx.doi.org/10.1136/annrheumdis-2016-209709

6Nash P, Kirkham B, Okada M, et al; SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389(10086):2317-2327. http://dx.doi.org/10.1016/S0140-6736(17)31429-0

7van der Heijde D, Cheng-Chung Wei J, Dougados M, et al; COAST-V Study Group. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392(10163):2441-2451. http://dx.doi.org/10.1016/s0140-6736(18)31946-9

8Deodhar A, van der Heijde D, Gensler LS, et al; COAST-X Study Group. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395(10217):53-64. http://dx.doi.org/10.1016/S0140-6736(19)32971-X

9Deodhar A, Poddubnyy D, Pacheco-Tena C, et al; COAST-W Study Group. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol. 2019;71(4):599-611. http://dx.doi.org/10.1002/art.40753

10Data on file, Eli Lilly and Company and/or one of its subsidiaries.

11Deodhar A, Blauvelt A, Schwartzman S, et al. Long-term safety of ixekizumab in adult patients with psoriasis, psoriatic arthritis, and axial spondyloarthritis. Poster presented at: American College of Rheumatology/ARP - 2022 Annual Scientific Meeting; November 10-14, 2022; Philadelphia, Pennsylvania.

12Genovese MC, Mysler E, Tomita T, et al. Safety of ixekizumab in adult patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis: data from 21 clinical trials. Rheumatology (Oxford). 2020;59(12):3834-3844. https://doi.org/10.1093/rheumatology/keaa189

13Chabra S, Gill BJ, Gallo G, et al. Ixekizumab citrate-free formulation: results from two clinical trials. Adv Ther. 2022;39(6):2862-2872. https://doi.org/10.1007/s12325-022-02126-0

14Griffiths CEM, Gooderham M, Colombel JF, et al. Safety of ixekizumab in adult patients with moderate-to-severe psoriasis: data from 17 clinical trials with over 18,000 patient-years of exposure. Dermatol Ther (Heidelb). 2022;12(6):1431-1446. https://doi.org/10.1007/s13555-022-00743-9

15Griffiths CEM, Reich K, Lebwohl M, et al; UNCOVER-2, UNCOVER-3 Investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993):541-551. https://doi.org/10.1016/S0140-6736(15)60125-8

16Shear NH, Paul C, Blauvelt A, et al. Safety and tolerability of ixekizumab: integrated analysis of injection-site reactions from 11 clinical trials. J Drugs Dermatol. 2018;17(2):200-206. http://jddonline.com/articles/dermatology/S1545961618P0200X

17Duffin KC, Bagel J, Bukhalo M, et al. Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A). J Eur Acad Dermatol Venereol. 2017;31(1):107-113. https://doi.org/10.1111/jdv.13768

18Deodhar AA, Combe B, Accioly AP, et al. Safety of ixekizumab in patients with psoriatic arthritis: data from four clinical trials with over 2000 patient-years of exposure. Ann Rheum Dis. 2022;81(7):944-950. https://doi.org/10.1136/annrheumdis-2021-222027

Date of Last Review: 25 October 2025


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