Taltz® ▼ (ixekizumab)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. Please refer to the link for full prescribing information: Taltz Summary of Product Characteristics (SmPC)

Taltz® (ixekizumab): How Frequent is Injection Site Pain in Adults?

The most frequent injection site reactions observed were erythema and pain.

General Information

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.1

  • Ixekizumab is for subcutaneous injection.1

  • The Taltz pen or Taltz syringe contains ixekizumab (active substance) and sodium citrate, citric acid anhydrous, sodium chloride, polysorbate 80, and water for injections as excipients.1

  • The ixekizumab solution has a target pH of 5.3-6.1.2

  • Injection sites may be alternated. If possible, areas of the skin that show psoriasis should be avoided as injection sites.1

  • Comprehensive instructions for administration are given in the package leaflet and the user manual.1

The specific cause(s) of injection site pain with ixekizumab is undetermined.3 No clear association between the presence of anti-drug antibodies and safety, including ISR, has been established.1,3 Management of injection site pain should be made at the discretion of the prescribing physician using their best clinical judgment.

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

Further Label Information on Injection Site Reactions

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 ≥60kg (25% vs. 14% for the combined Q2W and Q4W groups).1

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).1

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).1

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 or the axial spondyloarthritis studies.1

Injection Site Pain in Psoriasis, Psoriatic Arthritis, Axial Spondyloarthritis Clinical Trials

Unsolicited AE data were reported spontaneously in psoriasis, psoriatic arthritis, and axial spondyloarthritis clinical trials to investigators during study visits and were later coded using MedDRA terms. Brief descriptions of the designs of the trials included in this response are available in Appendix: Brief Clinical Trial Descriptions. Solicited AE data were collected using a standardized questionnaire only if patients initially reported an ISR of any type.3 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.2

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).2

Injection Site Pain Data from Psoriasis Clinical Trials

Integrated All Psoriasis Exposures Data Set 

Of all patients treated with ixekizumab across 16 psoriasis clinical trials as of data cutoff of March 2020, injection site pain, as a separate event, was spontaneously reported by 1.9% of patients (n=6645).2

Data from Placebo-controlled, Double-blind Treatment Periods of Pivotal Psoriasis Clinical Trials UNCOVER-1, -2, and -3

Most ISRs (≥95%) were mild-to-moderate in severity. Of patients who reported an ISR, 0.2% discontinued ixekizumab due to ISR.4,5

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 Q2W dosing group 

  • 17 patients (1.5%) in the ixekizumab Q4W dosing group, and 

  • 14 patients (1.8%) in the placebo group.2,3

Injection site pain resulted in discontinuation of study drug for 1 patient in the ixekizumab Q4W treatment group.2

The information below consists of solicited data from a follow-up questionnaire completed by patients who reported an ISR of any type (N=197). During the 12-week induction period of UNCOVER-1, -2, and -3, injection site pain was typically reported to occur during injection.3

The follow-up form completed by patients who reported an ISR (MedDRA high-level term) of any type during the induction period (first 12 weeks) of UNCOVER-1, -2, and -3, suggested 51% of patients treated with IXE Q4W experienced pain (Figure 1). A majority of patients (>90%) reported mild-to-moderate pain.3

Of the ISRs of any type spontaneously reported in psoriasis clinical trials (16.9% of patients reported an ISR; n=197/1167) by patients who received ixekizumab Q2W in UNCOVER-1, -2, and -3, maximal pain of the ISRs reported using the follow-up questionnaire is shown in Figure 1.3

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

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.3

The specific cause(s) of injection site pain with ixekizumab is undetermined.3 Management of injection site pain should be made at the discretion of the prescribing physician using their best clinical judgment.

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.6 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.2 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.6

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.2

Injection Site Pain Data from Psoriatic Arthritis Clinical Trials

Integrated All Psoriatic Arthritis Exposures Data Set

Of all patients treated with ixekizumab across 4 psoriatic arthritis clinical trials as of March 2020 (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).2

Placebo-controlled, Double-blind Treatment Periods of Pivotal Psoriatic Arthritis Clinical Trials SPIRIT-P1 and SPIRIT-P2

Most ISRs (>95%) were mild-to-moderate in severity.2,7 Of patients who reported an ISR, 1.1% discontinued ixekizumab due to ISR.7,8

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.2

Injection site pain resulted in discontinuation of study drug for 1 patient in the placebo group, and no patients in the ixekizumab treatment groups.2

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-P2.2

The follow-up form suggested that, among patients that experienced an ISR of any type, 13 patients experienced pain, out of which only 3 were moderate-to-severe (Figure 2).2

Figure 2. Maximal Pain of ISRs in Patients Treated with Ixekizumab Every 4 Weeks During SPIRIT-P1 and SPIRIT-P2 Psoriatic Arthritis Clinical Trials (N=40)2

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.

Injection Site Pain Data from 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 2020 (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 1849 PYs of ixekizumab exposure).2

16-Week Double-blind, Placebo-Controlled Treatment Periods of Pivotal AS/r-axSpA Trials

Most ISRs were mild or moderate in severity.9,10 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.9,10

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.2

Injection site pain resulted in discontinuation of study drug for 1 patient in the ixekizumab Q4W group.2

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.2

The follow-up form suggested that, among the 12 patients that experienced an ISR of any type, 8 patients treated with IXE Q4W experienced pain, out of which 4 were moderate (Figure 3).2

Figure 3. 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)2

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.

52-Week Double-blind, Placebo-Controlled Treatment Period of Nonradiographic Axial Spondyloarthritis Trial

During the 52-week double-blind, placebo controlled period of COAST-X, injection site pain was spontaneously reported in 1 patient each in both ixekizumab treatment groups and the placebo group (1.0% of patients in each group). 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.2,11

Injection site pain resulted in discontinuation of study drug for 1 patient in the placebo group, and no patients in the ixekizumab treatment groups.2

References

1. Taltz [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

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

3. Shear 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

4. Griffiths CE, Reich K, Lebwohl M, et al. 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. http://dx.doi.org/10.1016/S0140-6736(15)60125-8

5. Gordon KB, Blauvelt A, Papp KA, et al. 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

6. Duffin 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

7. Mease PJ, van der Heijde D, Ritchlin CT, et al. 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

8. Nash P, Kirkham B, Okada M, et al. 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

9. Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. 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

10. van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. 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

11. Deodhar A, van der Heijde D, Gensler LS, et al. 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

Glossary

AE = adverse event

AS/r-axSpA = ankylosing spondylitis/radiographic axial spondyloarthritis

axSpA = axial spondyloarthritis

bDMARD = biologic disease-modifying antirheumatic drug

ISR = injection site reaction

MedDRA = Medical Dictionary for Regulatory Activities

nr-axSpA = nonradiographic axial spondyloarthritis

PsA = psoriatic arthritis

PY = patient-years

Q2W = every 2 weeks

Q4W = every 4 weeks

TEAE = treatment-emergent adverse event

TNF = tumor necrosis factor

Appendix: Brief Clinical Trial Descriptions

  • UNCOVER-1, -2, and -3 (N=3866) phase 3 trials in moderate-to-severe plaque psoriasis were integrated to evaluate the safety of ixekizumab in comparison to placebo up to 12 weeks after treatment initiation.

  • The phase 3 trials examined the efficacy and safety of ixekizumab compared with placebo and etanercept (UNCOVER-2 and -3) during induction treatment and vs placebo in maintenance (UNCOVER-1 and -2).5

  • SPIRIT-P1 (N=417) is a phase 3, 24-week double-blind, placebo-controlled trial with an active reference arm in patients with active PsA who are naïve to bDMARDs with an extension period of up to 3 years.7

  • SPIRIT-P2 (N=363) is a phase 3, 24-week double-blind, placebo-controlled trial in patients with active PsA and an inadequate response or intolerance to TNF inhibitor, with an extension period of up to 3 years.8

  • COAST-V (N=341) is a phase 3, 16-week double-blind, placebo-controlled trial with an active reference arm and a dose-double blind extension period to 52 weeks in patients with active AS/r-axSpA who are naive to bDMARDs.10

  • COAST-W (N=316) is a phase 3, 16-week double-blind, placebo-controlled trial with a dose-double blind extension period to 52 weeks in patients with active AS/r-axSpA and an inadequate response or intolerance to 1 or 2 TNF inhibitors.9

  • COAST-X (N=303) is a phase 3, 52-week double-blind, placebo-controlled trial in patients with nr-axSpA who are naive to bDMARDs.11

Date of Last Review: July 21, 2020


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