DUPIXENT

Summary of the safety profile The most common adverse reactions in atopic dermatitis, asthma, and CRSwNP are injection site reactions (includes erythema, oedema, pruritus, pain, and swelling), conjunctivitis, conjunctivitis allergic, arthralgia, oral herpes, and eosinophilia.

An additional adverse reaction of injection site bruising was reported in EoE and COPD. Additional adverse reactions of injection site induration, injection site rash, and injection site dermatitis were reported in COPD. 4). Tabulated list of adverse reactions The dupilumab safety data presented in Table 7 were predominantly derived from 12 randomised, placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients.

These studies involved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during the controlled period are representative of the overall safety profile for dupilumab. Listed in Table 7 are adverse reactions observed in clinical trials and/or postmarketing setting presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 7:

List of adverse reactions MedDRA System Organ Class Frequency Adverse Reaction Infections and infestations Common Conjunctivitis* Oral herpes* Blood and lymphatic system disorders Common Eosinophilia Immune system disorders Uncommon Rare Angioedema# Anaphylactic reaction Serum sickness reaction Serum sickness-like reaction Eye disorders Common Uncommon Conjunctivitis allergic* Keratitis*# Rare Blepharitis*† Eye pruritus*† Dry eye*† Ulcerative keratitis*†# Skin and subcutaneous tissue disorders Uncommon Facial rash# Musculoskeletal and connective tissue disorders Common Arthralgia# General disorders and administration site conditions Common Injection site reactions (includes erythema, oedema, pruritus, pain, swelling and bruising) *eye disorders and oral herpes occurred predominately in atopic dermatitis studies.

†the frequencies for eye pruritus, blepharitis, and dry eye were common and ulcerative keratitis was uncommon in atopic dermatitis studies. #from postmarketing reporting. 4). Conjunctivitis and keratitis related events Conjunctivitis and keratitis occurred more frequently in atopic dermatitis patients who received dupilumab compared to placebo in atopic dermatitis studies.

Most patients with conjunctivitis or keratitis recovered or were recovering during the treatment period. In the long-term OLE atopic dermatitis study (AD-1225) at 5 years, the respective rates of conjunctivitis and keratitis remained similar to those in the dupilumab arm in the placebo controlled atopic dermatitis studies.

Among asthma and COPD patients, the frequency of conjunctivitis and keratitis was low and similar between dupilumab and placebo. Among CRSwNP and Prurigo Nodularis (PN) patients the frequency of conjunctivitis was higher in dupilumab than placebo, though lower than that observed in atopic dermatitis patients.

Among patients with EoE and CSU, the frequency of conjunctivitis was low and similar between dupilumab and placebo groups. 4). Eczema herpeticum Eczema herpeticum was reported in < 1 % of the dupilumab groups and in < 1 % of the placebo group in the 16-week atopic dermatitis monotherapy adult studies.

9 % of the placebo + TCS group. These rates remained stable at 5 years in the long-term OLE study (AD-1225). Eosinophilia Dupilumab-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo in the atopic dermatitis, asthma, CRSwNP, and COPD indications.

Eosinophil counts declined to near baseline levels during study treatment and returned to baseline during the asthma open-label extension safety study (TRAVERSE). The mean blood eosinophil levels decreased to below baseline by week 20 and was maintained up to 5 years in the long-term OLE study (AD-1225).

Compared to placebo, no increase in mean blood eosinophil counts was observed in PN (PRIME and PRIME2). Mean and median blood eosinophil counts declined to near baseline or remained below baseline levels in EoE and COPD (BOREAS and NOTUS) during study treatment.

In adult and adolescent subjects with CSU (CUPID Study A, Study B, and Study C) treated with Dupilumab, an increase from baseline in blood eosinophil count was not observed compared to placebo at Week 12 and a slight increase was observed during study treatment.

5 % in placebo-treated patients (SOLO1, SOLO2, AD-1021, DRI12544, QUEST, and VOYAGE; SINUS-24 and SINUS-52; PRIME and PRIME2 studies; TREET Parts A and B studies); BOREAS and NOTUS; CUPID Study A, B and C). 4 % of dupilumab-treated patients and 0 % in placebo-treated patients in study AD-1539, with median eosinophil counts declining below baseline at end of treatment period.

0 % of patients treated with placebo and […]

4. In a clinical study of atopic dermatitis patients, the effects of dupilumab on the pharmacokinetics (PK) of CYP substrates were evaluated. The data gathered from this study did not indicate clinically relevant effects of dupilumab on CYP1A2, CYP3A, CYP2C19, CYP2D6, or CYP2C9 activity.

An effect of dupilumab on the PK of co-administered medicinal products is not expected. Based on the population analysis, commonly co-administered medicinal products had no effect on dupilumab pharmacokinetics on patients with moderate to severe asthma.

1. 4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Acute exacerbations of Asthma or COPD Dupilumab must not be used to treat acute asthma symptoms or acute exacerbations of asthma or COPD.

Dupilumab must not be used to treat acute bronchospasm or status asthmaticus. Corticosteroids It is recommended that systemic, topical, or inhaled corticosteroids should not be discontinued abruptly upon initiation of therapy with dupilumab.

Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Biomarkers of type 2 inflammation may be suppressed by systemic corticosteroid use. 1). Hypersensitivity If a systemic hypersensitivity reaction (immediate or delayed) occurs, discontinue administration of dupilumab immediately and initiate appropriate therapy.

Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported. 8). Eosinophilic conditions Cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (EGPA) have been reported with dupilumab in adult patients who participated in the asthma development program.

Cases of vasculitis consistent with EGPA have been reported with dupilumab and placebo in adult patients with co-morbid asthma in the CRSwNP development program. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients with eosinophilia.

Patients being treated for asthma may present with serious systemic eosinophilia sometimes presenting with clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis, conditions which are often treated with systemic corticosteroid therapy.

These events usually, but not always, may be associated with the reduction of oral corticosteroid therapy. Helminth infection Patients with known helminth infections were excluded from participation in clinical studies. Dupilumab may influence the immune response against helminth infections by inhibiting IL-4/IL-13 signalling.

Patients with pre-existing helminth infections should be treated before initiating dupilumab. If patients become infected while receiving treatment with dupilumab and do not respond to anti-helminth treatment, treatment with dupilumab should be discontinued until infection resolves.

8). Conjunctivitis, dry eye and keratitis related events Conjunctivitis, dry eye and keratitis related events have been reported with dupilumab, predominantly in atopic dermatitis patients. g. 8). Advise patients to promptly report new onset or worsening eye symptoms to their healthcare provider.

Sudden changes in vision or significant eye pain that does not settle warrant urgent review. 8). Patients with comorbid asthma Advise patients on dupilumab who also have comorbid asthma to not adjust or stop their asthma treatments without consultation with their physicians.

Monitor patients with comorbid asthma carefully following discontinuation of dupilumab. Vaccinations Concurrent use of live and live attenuated vaccines with dupilumab should be avoided as clinical safety and efficacy have not been established.

It is recommended that patients should be brought up to date with live and live attenuated immunisations in agreement with current immunisation guidelines prior to treatment with dupilumab. Clinical data are not available to support more specific guidance for live or live attenuated vaccines administration in patients treated with dupilumab.

5). Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg dose, that is to say essentially ‘sodium-free’. 14 mL). Polysorbates may cause allergic reactions.