Dupilumab (Dupixent▼): risk of ocular adverse reactions and need for prompt management

Healthcare professionals prescribing dupilumab should be alert to the risks of ocular reactions. New onset or worsening ocular symptoms require prompt review. Referral for ophthalmological examination should be made as appropriate.

From:
Medicines and Healthcare products Regulatory Agency
Published
29 November 2022
Therapeutic area:
Dermatology, Ophthalmology, Paediatrics and neonatology, Respiratory disease and allergy

Advice for healthcare professionals:

  • dupilumab is commonly associated with cases of conjunctivitis and allergic conjunctivitis, eye pruritus, blepharitis, and dry eye and with infrequent cases of keratitis and ulcerative keratitis, especially in patients with atopic dermatitis
  • be alert to the risks of ocular reactions and promptly review new onset or worsening ocular symptoms, referring patients for ophthalmological examination as appropriate
  • sudden changes in vision or significant eye pain that does not settle warrant urgent review
  • discuss with patients or caregivers the potential for, and symptoms of, ocular side effects at initiation of dupilumab, including symptoms of conjunctivitis and dry eye (which can also include paradoxical eye watering), keratitis and ulcerative keratitis
  • advise patients to promptly report new-onset or worsening eye symptoms to their healthcare professional so that appropriate treatment can be initiated – advise patients not to self-manage ocular symptoms
  • ensure that patients who develop conjunctivitis or dry eye that does not resolve following initial treatment, or patients with signs and symptoms suggestive of keratitis (especially eye pain and vision changes), undergo ophthalmological examination, as appropriate
  • a UK expert consensus-based guidance on the management of people with dupilumab-related ocular surface disorders is currently being developed by relevant national specialty organisations
  • we remind healthcare professionals that tralokinumab (Adtralza▼), another interleukin-13 inhibitor recently licenced for use in atopic dermatitis, is also associated with common cases of conjunctivitis and allergic conjunctivitis as well as uncommon cases of keratitis, and that patients treated with tralokinumab who develop conjunctivitis that does not resolve following standard treatment should undergo ophthalmological examination
  • report any suspected adverse drug reactions associated with dupilumab or tralokinumab on a Yellow Card

Advice for healthcare professionals to give to patients or parents and caregivers:

  • dupilumab has been linked to side effects affecting the eye, especially in patients with atopic eczema (atopic dermatitis)
  • most side effects of the eye are mild, but some can become serious if they are not managed properly. Do not attempt to self-manage new or worsening eye problems – seek medical help
  • talk to your doctor or another healthcare professional promptly if you have any new or worsening eye problems, such as watering, itching, redness, swelling, eye dryness, a feeling of gritty eyes, or a sensation of a foreign body in the eye
  • if you experience significant eye pain that does not settle, or changes in your vision, it is important to speak to your doctor without delay

Review of the risk of ocular reactions

Dupilumab is a monoclonal antibody that inhibits interleukin-4 and interleukin-13 signalling and is used in moderate to severe atopic dermatitis in adults and adolescents 12 years and older.

Dupilumab is also used in children aged 6 years and older with severe atopic dermatitis or severe asthma, and in adults with severe asthma (see background section for detailed indication).

The potential for adverse reactions affecting the eye with dupilumab was established in the initial clinical trials. Further ocular adverse reactions have been identified during post-marketing clinical use. Although most ocular reactions are mild, some can become serious. We have received a small number of Yellow Card reports of ulcerative keratitis with serious corneal damage associated with dupilumab treatment.

We recently reviewed the risk of dry eye and also serious ocular side effects associated with dupilumab. We sought independent advice from the Gastroenterology, Rheumatology, Immunology and Dermatology Expert Advisory Group to the Commission on Human Medicines, as well as ophthalmology expertise.

The review recommended that updates should be made to the product information for dupilumab to include the adverse drug reaction ‘dry eye’ and also to emphasise the need for prompt and appropriate management of any potential ocular reactions.

It is not currently possible to predict who may experience the rarer and most serious ocular adverse reactions, such as ulcerative keratitis. It is therefore important, with all ocular reactions, for patients to receive prompt care, with treatment provided as appropriate to prevent or minimise damage to the eye.

We are also alerting healthcare professionals prescribing tralokinumab. Tralokinumab, an antibody that inhibits interleukin-13 signalling, has more recently been licenced in the UK for moderate-to-severe atopic dermatitis in adult patients. To date, there is very limited UK clinical experience with its use. Clinical trial data have indicated that keratitis, conjunctivitis and allergic conjunctivitis are associated with tralokinumab use. We are advising healthcare professionals prescribing dupilumab and tralokinumab to discuss with patients the potential for side effects affecting the eye and to ensure any reactions are managed promptly, especially in a patient experiencing eye pain or changes to their vision.

Frequency of ocular adverse reactions

Dupilumab was first licensed in the UK in September 2017. In the past year it is estimated that the usage of dupilumab in the UK was approximately 6,940 patient years.[footnote 1]

Based on combined data from all indications studied in the development of dupilumab, the product information lists conjunctivitis and allergic conjunctivitis with a frequency of common (affecting up to 1 in 10 patients); dry eye, blepharitis, eye pruritus and keratitis as uncommon (affecting up to 1 in 100); and ulcerative keratitis as rare (affecting up to 1 in 1,000). Based on studies of patients with atopic dermatitis, the frequencies listed for eye pruritus, dry eye, and blepharitis in this group are common and uncommon for ulcerative keratitis.

Up to 7 September 2022, the MHRA has received 479 UK reports which included suspected ocular side effects with dupilumab. 111 of these reports were considered serious.[footnote 2] 9 reports of ulcerative keratitis were received, representing 5 cases (for some individual cases, the MHRA received more than one report from different sources). 2 of these cases involved corneal perforation. 18 reports involved children ranging from 6 to 17 years of age.

With regards to the ocular events listed for dupilumab, the table below summarises the number of UK reports received by the MHRA up to 7 September 2022.[footnote 3]

Adverse drug reaction (ADR) term Number of UK reports received by MHRA
Dry eye 151
Conjunctivitis 114
Eye pruritus 99
Blepharitis 22
Conjunctivitis allergic 9
Ulcerative keratitis 9
Keratitis 2

Tralokinumab was first licenced in the UK in June 2021, with NICE recommendation in August 2022. So far in the UK, it has been used at very low levels. Up to 7 September 2022 the MHRA has received no ocular related reports regarding tralokinumab.[footnote 3]

The product information for tralokinumab lists conjunctivitis and conjunctivitis allergic with a frequency of common (affecting up to 1 in 10 patients) and keratitis with a frequency of uncommon (affecting up to 1 in 100) based on information from clinical trials.

Characteristics of ocular adverse reactions

Patients with atopic dermatitis commonly present with ocular surface diseases such as allergic conjunctivitis, blepharitis, and keratitis, as well as infectious conjunctivitis and keratoconus (changes to the shape of the cornea).

The mechanisms by which dupilumab or tralokinumab increase the occurrence of, or exacerbate, ocular adverse events are not fully understood.

Publications, including individual case reports about patients experiencing suspected ocular side effects with dupilumab, show variability in timing of onset and progression, presentation, and sequelae of ocular adverse reactions.[footnote 4][footnote 5][footnote 6][footnote 7][footnote 8][footnote 9][footnote 10] In most reports received by the MHRA where patients have experienced ocular adverse reactions with dupilumab, the reactions have not been considered to be serious by the reporter.[footnote 2] However, the MHRA has received 9 reports of 5 patients who experienced ulcerative keratitis with dupilumab, and, where the information was provided, treatment required corneal gluing or tectonic keratoplasty.[footnote 3] The details of some of the serious reports, and expert advice, indicate that early review and intervention are beneficial to the patient.

Expert ophthalmology and dermatology advice provided to the MHRA indicated that in the UK clinical experience, most ocular reactions seen with dupilumab are mild and can be managed. However, it is not currently possible to predict who may experience the rarer and most severe ocular adverse reactions, such as ulcerative keratitis.

It is therefore important, with all ocular reactions, for patients to receive prompt care, with treatment provided as appropriate to prevent or minimise damage to the eye. It is important to recognise ‘red flags’ for urgent ophthalmological consultation, such as eye pain, vision loss, and an increase in ocular pressure.

Treatment pathways and UK Expert Consensus for ocular adverse reactions

UK clinical experience is that dupilumab treatment does not usually need to be discontinued in the event of ocular reactions. It is important for the patient to receive timely advice and intervention with appropriate care and management of ocular reactions, and for patients and healthcare professionals to recognise serious reactions, and when ophthalmological referral is necessary.

Consult local treatment pathways to outline the spectrum of differential diagnoses that should be considered and the monitoring and treatment of patients who experience ocular side effects while treated with dupilumab. A UK expert consensus-based guidance on the management of people with dupilumab-related ocular surface disorders is currently being developed by relevant national specialty organisations.

Refer to these guidelines and local treatment pathways to guide management of dupilumab or tralokinumab associated adverse ocular reactions. Prompt referral for ophthalmological examination should be made where appropriate.

Background

Dupilumab

Dupilumab, tradename Dupixent, is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signalling. It was first licenced in the UK in September 2017.

For adults and adolescents older than 12 years, it is licensed for use in moderate to severe atopic dermatitis and as add-on maintenance treatment for severe asthma. For adults, it is also licensed as an add-on therapy with intranasal corticosteroids for severe chronic rhinosinusitis with nasal polyposis (see full indication details in the Summary of Product Characteristics).

For children aged 6 years to 11 years, dupilumab is licensed for severe atopic dermatitis and as add-on maintenance treatment for severe asthma.

UK Technology Appraisal Guidance recommendations on dupilumab for treating moderate to severe atopic dermatitis were published in August – September 2018 (for example, see NICE guidance). Usage of dupilumab in the UK up to 2022 has predominantly been for patients with atopic dermatitis.

UK Technology Appraisal Guidance recommendations on dupilumab for treating severe asthma with type 2 inflammation that is inadequately controlled in people 12 years and over were published in 2021.

Tralokinumab

Tralokinumab, tradename Adtralza, is a fully human IgG4 monoclonal antibody that inhibits interleukin-13 signalling.

Tralokinumab was first licenced in the UK in June 2021 for use in adults with moderate to severe atopic dermatitis (see full indication details in Summary of Product Characteristics). On 3 August 2022, NICE published recommendations on tralokinumab for treating moderate to severe atopic dermatitis.

Report any suspected reactions on a Yellow Card

Dupilumab and tralokinumab are black triangle medicines and all suspected adverse drug reactions should be reported to the Yellow Card scheme.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting suspected adverse drug reactions, please provide as much information as possible, including information about medical history, any concomitant medication, onset timing, and treatment dates. When reporting for a biological medicine or vaccine, please ensure that you provide the brand name (or product licence number and manufacturer), and the specific batch number.

Report suspected side effects to medicines, vaccines, medical device and test kit incidents used in coronavirus (COVID-19) testing and treatment using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 16, issue 4: November 2022: 1.

  1. Based on internal analysis by MHRA from the following source: IQVIA MIDAS® Quarterly Sales Audit from Q3 2017 to Q2 2022 reflecting estimates of real-world activity. Copyright IQVIA. All rights reserved. The patient years estimate is based on the WHO Defined Daily Dose of 21.4mg ↩

  2. Under the CIOMS / ICH E2D case level definition of serious (results in death; is life-threatening; requires inpatient hospitalisation or results in prolongation of existing hospitalisation; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction) ↩ ↩2

  3. In interpreting these data, caution should be exercised as the data may not be complete, and many factors can influence the reporting rates and the information provided within the reports. Reporters are asked to submit a Yellow Card report even if they only have a suspicion that the medicine may have caused the adverse drug reaction. ↩ ↩2 ↩3

  4. Popiela MZ and others. ‘Dupilumab-associated ocular surface disease: presentation, management and long-term sequelae’, Eye, 2021, published online 28 January 2021. ↩

  5. Felfeli T and others. ‘Prevalence and Characteristics of Dupilumab-Induced Ocular Surface Disease in Adults With Atopic Dermatitis’. Cornea, 2022, volume 41, pages 1242 to 1247. ↩

  6. Faiz S and others. ‘Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort’. Journal of the American Academy of Dermatology, 2019, volume 81, pages 143 to 151. ↩

  7. Phylactou M and others. ‘Corneal Perforation in Patients Under Treatment With Dupilumab for Atopic Dermatitis’. Cornea, 2022, volume 41, pages 981 to 985. ↩

  8. Woolf RT and others. ‘Real-world effectiveness and tolerability of dupilumab in adult atopic dermatitis: a single centre, prospective 1-year observational cohort study of the first 100 patients treated’. British Journal of Dermatology 2021 volume 184, pages 742 to 774. ↩

  9. Akinlade B and others. ‘Conjunctivitis in dupilumab clinical trials’. British Journal of Dermatology 2019, volume 181, pages 459 to 473. ↩

  10. Ivert LU and others. ‘Eye Complications During Dupilumab Treatment for Severe Atopic Dermatitis’. Acta Dermato-Venereologica, 2019, volume 99, pages 375 to 378 ↩

Published 29 November 2022
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