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): General Safety Information in Ankylosing Spondylitis/Radiographic Axial Spondyloarthritis Clinical Trials

Safety information from the ixekizumab prescribing information and clinical trials are available in this response.

Ixekizumab Label Information Related to Safety

Contraindications

Ixekizumab is contraindicated in patients with serious hypersensitivity to the active substance or to any of the excipients.1

Ixekizumab is contraindicated in patients with clinically important active infections (e.g. active tuberculosis).1

Warnings and Precautions

Treatment with ixekizumab is associated with an increased rate of infections such as upper respiratory tract infection, oral candidiasis, conjunctivitis, and tinea infections. Ixekizumab 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.1

If an infection develops,

  • patients should be carefully monitored and 

  • ixekizumab discontinued if

    • the patient is not responding to standard therapy or if

    • the infection becomes serious.1

Ixekizumab should not be resumed until the infection resolves.1

Ixekizumab must not be given to patients with active tuberculosis (TB).1

  • Anti-TB therapy prior to initiation of ixekizumab in patients with latent TB should be considered.1

Serious hypersensitivity reactions, including some cases of

  • anaphylaxis,

  • angioedema,

  • urticaria

  • and, rarely, late (10-14 days following injection) serious hypersensitivity reactions including

    • widespread urticaria,

    • dyspnea and

    • high antibody titres

have been reported.

If a serious hypersensitivity reaction occurs, administration of ixekizumab should be discontinued immediately and appropriate therapy initiated.1

Cases of new or exacerbations of inflammatory bowel disease have been reported with ixekizumab. 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. 1

Ixekizumab should not be used with live vaccines. No data are available on the response to live vaccines; there are insufficient data on response to inactive vaccines.1

Adverse Drug Reactions

Adverse drug reactions are listed in Table 1.

Table 1. List of adverse reactions in clinical studies and postmarketing reports1

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 

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,  

General disorders and administration site conditions

Very common

Injection site reactionsa

a See section description of selected adverse reactions

Adverse drug reactions in patients treated with ixekizumab (80 mg or 160 mg at week 0) by subcutaneous injection followed by 80 mg every 4 weeks in the AS/r-axSpA clinical trials were similar to the frequencies noted in Table 1 above with the exception of the frequency of inflammatory bowel disease and rhinitis (both common, defined as occurring at a frequency of ≥1% and <10%).2

Safety Information in AS/r-axSpA Clinical Trials

Treatment-Emergent Adverse Events Reported in AS/r-axSpA Trials

Treatment-emergent adverse events were evaluated using MedDRA terms.

Treatment-emergent adverse events were defined as events that first occurred or worsened in severity, relative to baseline, at any time during a clinical study. Treatment-emergent adverse events reported during the studies are not always attributed to study medications and the frequencies do not reflect investigator assessment of causality.2

Serious Adverse Event Definition

In ixekizumab clinical trials, an SAE was defined as any AE that resulted in

  • death

  • initial or prolonged inpatient hospitalization

  • a life-threatening experience (that is, immediate risk of dying)

  • persistent or significant disability/incapacity,

  • congenital anomaly/birth defect, and

  • considered significant by the investigator for any other reason.3

Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious adverse drug events when, based upon appropriate medical judgement, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.3

Treatment-Emergent Adverse Events Reported in Double-Blind Treatment Period of COAST-V

Most TEAEs for both ixekizumab 80 mg Q2W and ixekizumab 80 mg Q4W dosing regimens were mild to moderate in severity. The frequency of TEAEs were similar for both ixekizumab dosing regimens.4

The most common TEAEs (defined as occurring in ≥5% of patients receiving ixekizumab) were nasopharyngitis and upper respiratory tract infection. Adverse events during the double-blind treatment period are summarized in Table 2.4

Table 2. Adverse Events During the 16-Week Double-Blind Treatment Period of COAST-V4

 

PBO
N=86
n (%)

ADA Q2W
N=90
n (%)

IXE Q2W
N=83
n (%)

IXE Q4W
N=81
n (%)

TEAEs

34 (40)

44 (49)

36 (43)

34 (42)

Mild

22 (26)

28 (31)

28 (34)

22 (27)

Moderate

11 (13)

14 (16)

6 (7)

12 (15)

Severe

1 (1)

2 (2)

2 (2)

0

Discontinuation due to AE

0

1 (1)

3 (4)

0

Serious AE2

0

3 (3)a

1 (1)b

1 (1)c

Death

0

0

0

0

Common Adverse Eventsd

Nasopharyngitis

6 (7)

6 (7)

5 (6)

6 (7)

Upper respiratory tract infection

4 (5)

2 (2)

4 (5)

7 (9)

Adverse events of special interest

Neutropeniae

Grade 1

2 (2)

18 (20)

8 (10)

6 (8)

Grade 2

1 (1)

3 (3)

3 (4)

2 (3)

Grade 3

1 (1)

0

0

Grade 4

0

0

0

0

Hepatic

1 (1)

2 (2)

1 (1)

1 (1)

Infections

13 (15)

19 (21)

17 (20)

16 (20)

Serious infectionsf

0

1 (1)

1 (1)

1 (1)

Candida infections

0

1 (1)

0

0

Reactivated TB

0

0

0

0

Injection site reactions 

4 (5)

7 (8)

11 (13)

3 (4)

Allergic reactions and hypersensitivities

1 (1)

4 (4)

3 (4)

3 (4)

Potential anaphylaxis

0

0

0

0

Cerebrocardiovascular events

0

0

0

1 (1)

Malignancies

0

0

0

0

IBD

0

0

1 (1)g

0

Depression

0

1 (1)

0

0

Abbreviations: ADA = adalimumab 40 mg every 2 weeks; AE = adverse event; IBD = inflammatory bowel disease; IXE Q2W = ixekizumab 80 mg every 2 weeks after a 160 mg or 80 mg starting dose; IXE Q4W = ixekizumab 80 mg every 4 weeks after a 160 mg starting dose; NSAID = nonsteroidal anti-inflammatory drug; PBO = placebo; SAE = serious adverse event; TEAEs = treatment-emergent adverse events.

a One patient each reported appendicitis, ankle fracture, and adnexal torsion.

b Four SAEs were reported in 1 patient: Crohn’s disease, dyspepsia, erythema multiforme, and gastroenteritis. This patient was adjudicated as having “probable” Crohn’s disease.

c Urinary tract infection.

d Common TEAEs were defined as those that occurred at a frequency of at least 5% for patients receiving IXE (both dosing regimens combined).

e Neutropenia percentages are calculated for patients with a baseline and at least one postbaseline value.

f Reported serious infections were: gastroenteritis (n=1, IXE Q2W group); urinary tract infection (n=1, IXE Q4W group), and appendicitis (n=1, ADA Q2W group).

g Patient had a previous history of NSAID-induced colitis (endoscopically confirmed) and gastroenteritis, and was using NSAIDs as a concomitant therapy during the study. The event was considered serious and occurred after the study drug was discontinued because of gastrointestinal symptoms. This event was adjudicated by the clinical events committee as probable Crohn's disease.

Note: The dosing schedule IXE Q2W is not consistent with the approved dosing schedule for axial spondyloarthritis. Please refer to the Taltz Summary of Product Characteristics for approved dosing.1

Treatment-Emergent Adverse Events Reported in Double-Blind Treatment Period of COAST-W

Most TEAEs for both ixekizumab 80 mg Q2W and Q4W dosing regimens were mild-to-moderate in severity. The frequency of TEAEs were similar for both ixekizumab dosing regimens.5

The most common TEAEs (defined as occurring in ≥5% of patients receiving ixekizumab) were upper respiratory tract infections and injection site reactions. Adverse events reported during the double-blind treatment period are summarized in Table 3.5

Table 3. Adverse Events During the Double-Blind Treatment Period of COAST-W5

 

PBO
N=104

IXE Q2W
N=98

IXE Q4W
N=114

TEAE

51 (49.0)

59 (60.2)

73 (64.0)

Mild

18 (17.3)

23 (23.5)

34 (29.8)

Moderate

26 (25.0)

32 (32.7)

35 (30.7)

Severe

7 (6.7)

4 (4.1)

4 (3.5)

Discontinuation due to AE

2 (1.9)

3 (3.1)

4 (3.5)

Serious AE2

5 (4.8)a

3 (3.1)b

4 (3.5)c

Deathd

0

1 (1.0)

0

Common TEAEse

Upper respiratory tract infection

3 (2.9)

4 (4.1)

9 (7.9)

Injection site reaction

1 (1.0)

8 (8.2)

3 (2.6)

TEAEs of special interest

Hepatic

2 (1.9)

1 (1.0)

5 (4.4)

Cytopenia

0

2 (2.0)

0

Grade 1 neutropeniaf

1 (1.0)

8 (8.2)

10 (8.8)

Grade 2 neutropeniag

0

1 (1.0)

1 (0.9)

Grade 3 neutropeniah

0

0

0

Grade 4 neutropeniai

0

0

1 (0.9)

Infections

10 (9.6)

23 (23.5)

34 (29.8)

Mild

5 (4.8)

14 (14.3)

20 (17.5)

Moderate

5 (4.8)

9 (9.2)

13 (11.4)

Severe

0

0

1 (0.9)

Serious

0

0

2 (1.8)

Candida (genital)

0

1 (1.0)

0

Candida (esophageal)

0

1 (1.0)

0

Herpes zoster

0

0

1 (0.9)

Reactivated TB

0

0

0

Allergic reactions/hypersensitivities

1 (1.0)

6 (6.1)

3 (2.6)

Potential anaphylaxis

0

0

0

Injection site reactionsj

6 (5.8)

16 (16.3)

9 (7.9)

Cerebrocardiovascular eventsk

1 (1.0)

1 (1.0)

0

Malignancies

0

0

1 (0.9)

Depression

5 (4.8)

2 (2.0)

0

Anterior uveitisl

0

3 (3.1)

2 (1.8)

Inflammatory bowel disease

1 (1.0)

0

3 (2.6)

Interstitial lung disease

0

0

0

Abbreviations: AE = adverse event; IXE Q2W = ixekizumab 80 mg every 2 weeks after a 160 mg or 80 mg starting dose; IXE Q4W = ixekizumab 80 mg every 4 weeks after a 160 mg or 80 mg starting dose; PBO = placebo; TB = tuberculosis; TEAE = treatment-emergent adverse event.

a Serious adverse events were reported in 5 patients as follows: inflammatory bowel disease (adjudicated as “probable” Crohn’s disease); femur fracture; inguinal hernia; vasculitis; arthritis.

b Serious adverse events were reported in 3 patients as follows: One serious adverse event was a death caused by suicide; 1 patient reported 2 serious adverse events of depression and atrial tachycardia; increased blood creatine phosphokinase was reported in 1 patient.

c Serious adverse events were reported in 4 patients as follows: pharyngitis; Crohn’s disease (adjudicated as “probable” Crohn’s disease); Peritonitis; fracture pain.

d Cause of death was suicide. The event was judged by the blinded principal investigator to be unrelated to the investigational product. The patient had a documented prior history of depression of about 1 year (reported as mild at study entry).

e Common TEAEs defined as those that occurred at a frequency of ≥5% for patients receiving ixekizumab (both treatment groups combined).

f Grade 1 neutropenia defined as ≥1.5 to <2.0 x 109 cells/L.

g ≥1.0 to <1.5 x 109 cells/L.

h ≥0.5 to <1.0 x 109 cells/L.

i <0.5 x 109 cells/L.

j Injection site reactions high level term includes injection site pain, erythema, dermatitis, hypersensitivity, pruritus, bruising, rash, paresthesia, or reaction (unspecified).

k Confirmed events only.

l Not a prespecified AE of special interest but included in prespecified analyses.

Note: The dosing schedule IXE Q2W is not consistent with the approved dosing schedule for axial spondyloarthritis. Please refer to the Taltz Summary of Product Characteristics for approved dosing.1

Integrated Safety Analysis of COAST-V and COAST-W

The integrated safety data set includes data through March 2020 from 4 clinical trials in patients with axSpA, including phase 3 trials COAST-V, COAST-W (AS/r-axSpA), COAST-X (nr-axSpA), and COAST-Y (long-term extension trial for eligible patients completing COAST-V, COAST-W, or COAST-X) (N=932 accounting for 1849 PY of total ixekizumab exposure).6

The majority of the most common TEAEs were mild-to-moderate in severity. The most common TEAEs were

  • nasopharyngitis (IR, 8.8; 95% CI, 7.5-10.2)

  • upper respiratory tract infection (IR, 6.0; 95% CI, 5.0-7.2), and

  • unspecified injection site reactions (IR, 5.0; 95% CI, 4.1-6.1).6

Table 5 shows the incidence rate of TEAEs, SAEs, death, and discontinuations due to an AE as of March 2020. The IRs for TEAEs, SAEs, and infections decreased over time.6

The incidence rates of TEAEs of special interest as of March 2020 are shown in Table 4. The IRs for

  • serious infections

  • malignancy, and 

  • iridocyclitis were low and stable over time.6

The IRs for ISRs and allergic reactions/hypersensitivities decreased over time. The IRs for adjudicated IBD were low and decreased over time.6

Table 4. Treatment-Emergent Adverse Events of Special Interest in All axSpA Ixekizumab Exposures Integrated Analysis Set6,7

Event, n (%) [IR]

Pooled IXE 
(N=932; 1849 PY)
a

Infections 

511 (54.8) [27.6]

Serious infections

20 (2.1) [1.1]

Opportunistic infectionsb

17 (1.8) [0.9]

Candidiasis

5 (0.5) [0.3]

Tuberculosis

0

Herpes zosterc

12 (1.3) [0.6]

Neutropenia grade ≥1d

156 (16.7) [8.4]

Injection site reactions

155 (16.6) [8.4]

Allergic reactions/hypersensitivity 

86 (9.2) [4.7]

Depression

19 (2.0) [1.0]

MACE

4 (0.4)  [0.2]

Malignancies

7 (0.8) [0.4]

Iridocyclitise

52 (5.6) [2.8]

Adjudicated inflammatory bowel diseasef

17 (1.8) [0.9]

Ulcerative colitis

10 (1.1) [0.5]

Crohn's disease

7 (0.8) [0.4]

Abbreviations: axSpA  = axial spondyloarthritis; IBD = inflammatory bowel disease; IR = incidence rate; IXE = ixekizumab; MACE = major adverse cardiovascular event; PY = patient-year.

a Data through March 2020.

b Opportunistic infections included oral candidiasis, hepatitis B reactivation, herpes simplex (invasive), and herpes zoster.

c 4 of 12 patients with herpes zoster were Asian.

d Neutropenia grade ≥3, n (IR)=3 (0.2).

e Among the 52 patients with iridocyclitis, 37 (71%) had a history of iridocyclitis and 2 (3.8%) patients discontinued due to iridocyclitis.

f Of the 17 patients with adjudicated IBD, 5 patients had a history of IBD, 6 discontinued due to IBD, and 7 events resolved.

Table 5. Treatment-Emergent Adverse Events and Serious Adverse Events in All axSpA Ixekizumab Exposures Integrated Analysis Set6

Event, n (%) [IR]a

Pooled IXE
(N=932; 1849.0 PY)
b

Patients with ≥1 TEAE

775 (83.2) [41.9]

Patients with ≥1 SAE

90 (9.7) [4.9]

Deathsc

3 (0.3) [0.2]

Discontinuations due to AE

62 (6.7) [3.4]

Abbreviations: AE = adverse event; axSpA = axial spondyloarthritis; IR = incidence rate; IXE = ixekizumab; PY = patient-year; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

a IR per 100 PYs.

b Data through March 2020.

c Deaths occurred due to suicide (n=1), sepsis (n=1), and general disorders (homicide) (n=1). The suicide event was judged by the blinded principal investigator to be unrelated to the study drug. The patient had a documented history of mild depression. The sepsis event was judged by the investigator to be related to the study drug.

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. Gordon 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

4. van 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

5. Deodhar 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

6. Schwartzman S, Sandoval D, Kronbergs A, et al. Long-term safety profile of ixekizumab treatment on patients with axial spondyloarthritis. Poster presented at: American College of Rheumatology/ARP 2020 Annual Scientific Meeting (Virtual); November 5-9, 2020.

7. Schwartzman S, Sandoval D, Kronbergs A, et al. Long-term safety profile of ixekizumab treatment on patients with axial spondyloarthritis. Abstract presented at: American College of Rheumatology/ARP 2020 Annual Scientific Meeting (Virtual); November 5-9, 2020.

8. Deodhar 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

9. A long term extension study of ixekizumab (LY2439821) in participants with axial spondyloarthritis. ClinicalTrials.gov identifier: NCT03129100. Updated November 4, 2020. Accessed January 20, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03129100

Glossary

AE = adverse event

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

axSpA = axial spondyloarthritis

bDMARD = biologic disease-modifying antirheumatic drug

IBD = inflammatory bowel disease

IR = incidence rate

ISR = injection site reaction

MedDRA = Medical Dictionary for Regulatory Activities

nr-axSpA = nonradiographic axial spondyloarthritis

PY = patient-years

Q2W = every 2 weeks

Q4W = every 4 weeks

SAE = serious adverse event

TB = tuberculosis

TEAE = treatment-emergent adverse event

TNF = tumor necrosis factor

Appendix: Brief Clinical Trial Descriptions

Axial Spondyloarthritis Trials

  • 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.4

  • 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.5

  • 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.8

  • COAST-Y (N=750) is a phase 3, 104-week, long-term extension trial including a double-blind, placebo-controlled 40-week randomized withdrawal-retreatment period in patients with axial spondyloarthritis who have completed the final study visit in COAST-V, COAST-W, or COAST-X.9

Date of Last Review: October 23, 2020


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