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): Safety in Patients from Plaque Psoriasis Clinical Trials

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

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UK_cFAQ_IXE027_Y1_GENERAL_SAFETY_PsO
en-GB

Short Summary

  • Ixekizumab is contraindicated in patients with clinically important active infections (e.g. active tuberculosis).1
  • Based in an analysis of 7 psoriasis clinical trials 54.4% and 6.3% of ixekizumab treated patients presented ≥1 TEAE and ≥1 SAE, respectively.2,3
  • In patients treated with ixekizumab in psoriasis clinical trials adverse reactions occurred, such as
    • injection site reaction (very common ≥10%),
    • upper respiratory tract infection (very common ≥10%), and other infections as
    • tinea infection (common ≥1% and <10%),
    • oral candidiasis and conjunctivitis (uncommon ≥ 0.1% and <1%).4
  • An integrated analysis of 5898 patients (16,313 PY) who received ixekizumab across 13 psoriasis clinical trials found that 101 patients (1.7%) reported treatment-emergent LTBI. No cases of reactivation of TB were reported.5
  • Across 15 adult and 1 pediatric pooled psoriasis trials (N=6645, accounting for 17,902 PY of total ixekizumab exposure) as of the March 19, 2020 database lock, the IR of
    • infections was 23.4 per 100 PY,
    • serious infection was 1.3 per 100 PY,
    • Candida infections was 1.9 per 100 PY of exposure,
    • ISRs was 5.6 per 100 PY of exposure,
    • malignancies was 0.8 per 100 PY of exposure,
    • adjudicated IBD was 0.2 per 100 PY of exposure.6
  • The IRs of select TEAEs did not increase with longer ixekizumab exposure.6
  • In psoriasis studies, 9% and 3% of patients receiving ixekizumab developed neutropenia and thrombocytopenia, respectively.1

Detailed Safety Information from Label and Plaque Psoriasis Clinical Trials

Contraindications

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

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

Infections

Overall

Treatment with ixekizumab is associated with an increased rate of infections such as

  • upper respiratory tract infection
  • oral candidiasis
  • conjunctivitis, and
  • tinea infections.1

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

Across 15 adult and 1 pediatric pooled psoriasis trials (N=6645, accounting for 17,902 PY of total ixekizumab exposure) as of the March 19, 2020 database lock, the IR of infections was 23.4 per 100 PY.6

Serious Infections

If an infection becomes serious, discontinue ixekizumab. Ixekizumab should not be resumed until the infection resolves.1

Across 15 adult and 1 pediatric pooled psoriasis trials (N=6645, accounting for 17,902 PY of total ixekizumab exposure) as of the March 19, 2020 database lock, the IR of serious infections was 1.3 per 100 PY.6

Tuberculosis

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

An integrated analysis of 5898 patients (16,313 PY) who received ixekizumab across 13 psoriasis clinical trials found that 101 patients (1.7%) reported treatment-emergent LTBI. No cases of reactivation of TB were reported.5

Candida Infections

The frequency of Candida infections during the first 12 weeks of UNCOVER-1, -2, and -3 was 1.4% (n=16) in the ixekizumab 80 mg Q2W group compared with 0.5% (n=4) in the placebo group. The IR of Candida infections was 3.7 per 100 PYs of ixekizumab exposure during weeks 0 to 60.7

Most Candida events were mild or moderate in severity and were not recurrent, and none of those reported as of the database lock on April 9, 2015 had led to treatment discontinuation. In the overall safety database (as of April 9, 2015, N=4209 accounting for 6480 PY of ixekizumab exposure), the IR of Candida infections was 2.5 per 100 PY of exposure and 5 Candida-related events were assessed as severe by the investigator. Additionally, there were 8 reported cases of esophageal candidiasis with 2 cases being SAEs. These patients received oral antifungal treatments and the events were considered resolved.2

Dose-dependent oral candidiasis was observed with ixekizumab during the first 12 weeks of treatment. Oral candidiasis was reported in 0.8% of patients with ixekizumab 80 mg Q2W (p<.05 vs Q4W), 0.2% with ixekizumab 80 mg Q4W, 0.1% with etanercept (studies UNCOVER-2 and -3), and 0.0% with placebo.3

Across 15 adult and 1 pediatric pooled psoriasis trials (N=6645, accounting for 17,902 PY of total ixekizumab exposure) as of the March 19, 2020 database lock, the IR of Candida infections was 1.9 per 100 PY of exposure.6

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 ixekizumab should be discontinued immediately and appropriate therapy initiated.1

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 ixekizumab.1

Across 15 adult and 1 pediatric pooled psoriasis trials (N=6645, accounting for 17,902 PY of total ixekizumab exposure) as of the March 19, 2020 database lock, the IR of ISRs was 5.6 per 100 PY of exposure.6

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

Malignancies

Across 15 adult and 1 pediatric pooled psoriasis trials (N=6645, accounting for 17,902 PY of total ixekizumab exposure) as of the March 19, 2020 database lock, the IR of malignancies was 0.8 per 100 PY of exposure.6

Inflammatory Bowel Disease

Cases of new or exacerbations of inflammatory bowel disease have been reported with ixekizumab. Ixekizumab is not recommended in patients with inflammatory bowel disease.1

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

Across 15 adult and 1 pediatric pooled psoriasis trials (N=6645, accounting for 17,902 PY of total ixekizumab exposure) as of the March 19, 2020 database lock, the IR of adjudicated IBD was 0.2 per 100 PY of exposure.6

Laboratory Assessments of Neutropenia and Thrombocytopenia

In plaque psoriasis studies,

  • 9% of patients receiving ixekizumab 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 ixekizumab developed a neutrophil count <1,000 cells/mm3.1

In general, neutropenia did not require discontinuation of ixekizumab.1

3% of patients exposed to ixekizumab had a shift from a normal baseline platelet value to <150,000 platelet cells/mm3 to ≥75,000 cells/mm3.1

  • Thrombocytopenia may persist, fluctuate or be transient.1

Treatment-Emergent Adverse Events Reported in Psoriasis 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.4

 Adverse Reactions Occurring in Patients Treated with Ixekizumab in Psoriasis Clinical Trials lists treatment-emergent adverse events reported as uncommon (infrequent), common, and very common.

 Adverse Reactions Occurring in Patients Treated with Ixekizumab in Psoriasis Clinical Trials4

Adverse Reactions

Very Common
≥10%

Common 
≥1% and <10%

Uncommon (Infrequent)
≥0.1% and <1%

Gastrointestinal disorders

 

 

 

Nausea

 

X

 

Inflammatory bowel diseasea



X

General disorders and administration site conditions 

 

 

 

Injection site reactions

X

 

 

Infections and infestations

 

 

 

Upper respiratory tract infectionb

X

 

 

Tinea infection

 

X

 

Influenza 



X

Rhinitis



X

Oral candidiasis



X

Conjunctivitis



X

Respiratory, thoracic, and mediastinal disorders




Oropharyngeal pain


X


Skin and subcutaneous tissue disorders




Urticaria



X

aInflammatory bowel disease includes Crohn’s disease and ulcerative colitis.

bUpper respiratory tract infection includes nasopharyngitis and upper respiratory tract infection.

Summary of Common Treatment-Emergent Adverse Events Reported in 7 Psoriasis Clinical Trials includes commonly reported TEAEs reported within the overall safety database across all ixekizumab-psoriasis exposures (as of April 9, 2015).2 Please see Appendix and footnotes for details regarding the cutoff rates used for reporting TEAEs in this data set.

Serious Adverse Events Reported in Psoriasis Trials

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.7

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.7

Induction Period (Weeks 0 to 12)

Serious adverse events reported by more than 1 patient treated with ixekizumab during the 12-week induction period are listed in Serious Adverse Events That Were Reported by >1 Patient Treated With Ixekizumab (Total IXE Group) Through Week 12 of the UNCOVER Clinical Trials.

Serious Adverse Events That Were Reported by >1 Patient Treated With Ixekizumab (Total IXE Group) Through Week 12 of the UNCOVER Clinical Trials4,8

 

IXE 80 mg

Q2W

(N=1167)

n (%)

IXE 80 mg

Q4W

(N=1161)

n (%)

Total

IXE

(N=2328)

n (%)

PBO

(N=791)

n (%)

Patients with ≥ 1 SAE (any)

20 (1.7)

26 (2.2)

46 (2.0)

12 (1.5)

Cellulitis

1 (0.1)

2 (0.2)

3 (0.1)

1 (0.1)

Appendicitis

2 (0.2)

0

2 (0.1)

0

Depression

2 (0.2)

0

2 (0.1)

0

COPD

1 (0.1)

1 (0.1)

2 (0.1)

1 (0.1)

Crohn's disease

1 (0.1)

1 (0.1)

2 (0.1)

0

Suicide attempta

1 (0.1)

1 (0.1)

2 (0.1)

0

Erysipelas

0

2 (0.2)

2 (0.1)

0

Other (n=1 each for all other events)

21 (1.8)

22 (1.9)

43 (1.8)

14 (1.8)

Abbreviations: COPD = chronic obstructive pulmonary disease; IXE = ixekizumab; PBO = placebo; Q2W = every 2 weeks; Q4W = every 4 weeks; SAE = serious adverse event.

aIn both cases, important psychosocial triggers preceded the attempt and the suicide attempts were not thought to be related to study drug. One patient had a history of previous suicide attempts that was not disclosed to the investigator in a screening interview.

The dosing schedule IXEQ2W mentioned below is not consistent with the approved dosing schedule for plaque psoriasis in the Taltz summary of product characteristics. Please refer to the Taltz summary of product characteristics for approved dosing.1

Longer Term (Up to 5 Years)

Summary of Serious Treatment-Emergent Adverse Events in Psoriasis Clinical Trials consists of TEAEs that were reported as serious within the overall safety database across all ixekizumab-psoriasis exposures (as of April 9, 2015).2

The IR for SAEs was 5.4 per 100 PY across 15 adult and 1 pediatric psoriasis clinical trials for all patients exposed to ixekizumab (N=6645, accounting for 17,902 PY of total ixekizumab exposure) as of the March 19, 2020 database lock.6

Deaths Among Patients With Psoriasis

As of March 19, 2020, there were 35 fatalities among all patients with psoriasis in the overall safety database (including phase 1, 2, 3, and 4 clinical trials).6 No deaths occurred during the induction period. The majority of deaths were from cardiovascular events in patients with prior risk factors, and none were due to suicide.9-11

Integrated Safety Data Across 14 Psoriasis Clinical Trials

Incidence Rates of Select Categories of Adverse Events at 1-Year Intervals, All Psoriasis Program Patients Exposed to Ixekizumab With Up To 5 Years of Treatment presents the IRs for select TEAEs across 15 adult and 1 pediatric pooled psoriasis trials (N=6645 accounting for 17,902 PY of total ixekizumab exposure) through March 19, 2020. The IRs of select TEAEs did not increase with longer ixekizumab exposure.6

Incidence Rates of Select Categories of Adverse Events at 1-Year Intervals, All Psoriasis Program Patients Exposed to Ixekizumab With Up To 5 Years of Treatment6

Abbreviations: IBD = inflammatory bowel disease; IR = incidence rate; IXE = ixekizumab; MACE = major adverse cerebro-cardiovascular events; PY = patient-years; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Note: Inflammatory bowel disease IR summarized here is unadjudicated events.

References

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

2Strober B, Leonardi C, Papp KA, et al. Short- and long-term safety outcomes with ixekizumab from 7 clinical trials in psoriasis: etanercept comparisons and integrated data. J Am Acad Dermatol. 2017;76(3):432-440.e17. http://dx.doi.org/10.1016/j.jaad.2016.09.026

3Strober B, Papp KA, Leonardi C, et al. Integrated safety of ixekizumab in patients with moderate-to-severe psoriasis: results from a pooled analysis of 7 clinical trials. Poster presented at: 74th Annual Meeting of the American Academy of Dermatology; March 4-8, 2016; Washington, DC.

4Data on file, Eli Lilly and Company and/or one of its subsidiaries.

5Mrowietz U, Riedl E, Winkler S, et al. No reactivation of tuberculosis in patients with latent tuberculosis infection receiving ixekizumab: a report from 16 clinical studies of patients with psoriasis or psoriatic arthritis. J Am Acad Dermatol. 2020;83(5):1436-1439. https://doi.org/10.1016/j.jaad.2020.06.012

6Griffiths CEM, Reich K, Gooderham M, et al. Long-term safety of ixekizumab in patients with moderate-to-severe psoriasis up to 5 years: pooled data from 16 clinical trials. Poster presented at: 29th Annual Meeting of the European Academy of Dermatology and Venereology (EADVirtual); October 29-31, 2020.

7Gordon 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

8Griffiths 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

9Genovese MC, Kameda H, Rahman P, et al. Safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis and psoriatic arthritis: integrated analysis of 18 clinical trials. Poster presented at: American College of Rheumatology/ARP; November 8-13, 2019; Atlanta, GA.

10Genovese 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). Published online May 25, 2020. https://doi.org/10.1093/rheumatology/keaa189

11Armstrong A, Agada N, Xu W, Gallo G. An update on the long-term safety experience of ixekizumab: results from the psoriasis clinical development program with more than 3 years of follow-up from 12 clinical trials and more than 15000 patient-years of exposure to ixekizumab. Poster presented at: 27th Congress of the European Academy of Dermatology and Venereology; September 12-16, 2018; Paris, France.

Glossary

IBD = inflammatory bowel disease

IR = incidence rate

LTBI = latent tuberculosis infection

MedDRA = Medical Dictionary for Regulatory Activities

PBO = placebo

PY = patient-years

Q2W = every 2 weeks

Q4W = every 4 weeks

SAE = serious adverse event

TB = tuberculosis

TEAE = treatment-emergent adverse event

Appendix

Summary of Common Treatment-Emergent Adverse Events Reported in 7 Psoriasis Clinical Trials2

 

Overall Safety Database of 7 Clinical Trials
All IXE Exposures
N=4209; 6480 PY
n [IR]

Patients with ≥1 TEAE

3523 [54.4]

TEAEs with adjusted incidence ≥1.3 (PT)

Nasopharyngitis

911 [14.1]

Upper respiratory tract infection

512 [7.9]

Injection-site reaction

441 [6.8]

Headache

313 [4.8]

Arthralgia

270 [4.2]

Sinusitis

225 [3.5]

Back pain

209 [3.2]

Bronchitis

202 [3.1]

Diarrhea

189 [2.9]

Hypertension

172 [2.7]

Urinary tract infection

179 [2.8]

Influenza

161 [2.5]

Pharyngitis

160 [2.5]]

Oropharyngeal pain

147 [2.3]

Cough

145 [2.2]

Pruritus

143 [2.2]

Injection-site erythema

139 [2.1]

Psoriasis

135 [2.1]

Blood creatine phosphokinase increased

124 [1.9]

Gastroenteritis

114 [1.8]

Nausea

113 [1.7]

Fatigue

94 [1.5]

Eczema

92 [1.4]

Laceration

91 [1.4]

Vulvovaginal candidiasisa

30 [1.5]

Folliculitis

90 [1.4]

Myalgia

84 [1.3]

Rhinitis

84 [1.3]

Tinea pedis

83 [1.3]

Abbreviations: IR = incidence rate per 100 patient-years; IXE = ixekizumab; PT = preferred term; PY = patient-years; TEAE = treatment-emergent adverse event.

aDenominator adjusted because of gender-specific event for females.

Summary of Serious Treatment-Emergent Adverse Events in Psoriasis Clinical Trials3

 

Overall Safety Database of 7 Clinical Trials
All IXE Exposures
N=4209; 6480 PY
n [IR]

Patients with ≥1 SAE

411 [6.3]

SAEs occurring at a frequency of exposure adjusted rate of ≥0.1 (PT)

Cellulitis

17 [0.3]

Fall

13 [0.2]

Myocardial infarction

11 [0.2]

Osteoarthritis

11 [0.2]

Acute myocardial infarction

9 [0.1]

Chronic obstructive pulmonary disease

8 [0.1]

Nephrolithiasis

8 [0.1]

Suicide attempt

8 [0.1]

Coronary artery disease

7 [0.1]

Depression

6 [0.1]

Inguinal hernia

6 [0.1]

Intervertebral disc protrusion

6 [0.1]

Pneumonia

6 [0.1]

Angina pectoris

5 [0.1]

Angina unstable

5 [0.1]

Appendicitis

5 [0.1]

Cholelithiasis

5 [0.1]

Cholecystitis

5 [0.1]

Diverticulitis

5 [0.1]

Prostate cancera 

5 [0.1]

Pulmonary embolism

5 [0.1]

Urinary tract infection

5 [0.1]

Type 2 diabetes mellitus

5 [0.1]

Deep vein thrombosis

4 [0.1]

Dyspnea

4 [0.1]

Hand fracture

4 [0.1]

Road traffic accident

4 [0.1]

Sleep apnea syndrome

4 [0.1]

Abbreviations: IR = incidence rate per 100 patient-years; IXE = ixekizumab; PT = preferred term; PY = patient-years; SAE = serious adverse event.

aDenominator adjusted for male gender-specific event.

Date of Last Review: October 14, 2020


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