Medicines Healthcare Products Regulatory Agency
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][foot