Dupixent^® (Solution) Instructions for Use

Marketing Authorization Holder

Sanofi Winthrop Industrie (France)

Manufactured By

Sanofi Winthrop Industrie (France)

Or

Cook Pharmica LLC (USA)

Labeled By

SANOFI WINTHROP INDUSTRIE (France)

Or

SANOFI VOSTOK, JSC (Russia)

Or

COOK PHARMIKA, LLC (USA)

Quality Control Release

SANOFI-AVENTIS DEUTSCHLAND, GmbH (Germany)

Or

SANOFI WINTHROP INDUSTRIE (France)

Or

SANOFI VOSTOK, JSC (Russia)

Contact Information

SANOFI

ATC Code

D11AH05 (Dupilumab)

Active Substance

Dupilumab (Rec.INN registered by WHO)

Dosage Forms

	Dupixent®	Solution for subcutaneous injection 150 mg/1 ml: 2 ml syringes 1, 2 or 6 pcs.
		Solution for subcutaneous injection 175 mg/1 ml: 1.14 ml syringes 1, 2 or 6 pcs.

Dosage Form, Packaging, and Composition

Solution for subcutaneous injection clear or slightly opalescent, colorless or yellowish in color.

Excipients : L-histidine and L-histidine hydrochloride monohydrate – 3.1 mg^c, L-arginine hydrochloride – 4.35 mg^d, sodium acetate trihydrate and glacial acetic acid – 0.75 mg^f, sucrose – 50 mg^g, polysorbate 80 – 2 mg^h, water for injections – up to 1 ml.

2 ml – disposable syringes (1) – cardboard packs with sealed valves^×.
2 ml – disposable syringes (2) – cardboard packs with sealed valves^×.
2 ml – disposable syringes (2) – intermediate cardboard packages (3) – cardboard packs with sealed valves^×.
2 ml – syringes with a protection system made of transparent glass (type I) (1) – cardboard packs with sealed valves^×.
2 ml – syringes with a protection system made of transparent glass (type I) (2) – cardboard packs with sealed valves^×.
2 ml – syringes with a protection system made of transparent glass (type I) (2) – intermediate cardboard packages (3) – cardboard packs with sealed valves^×.

Solution for subcutaneous injection clear or slightly opalescent, colorless or yellowish in color.

Excipients : L-histidine and L-histidine hydrochloride monohydrate – 3.1 mg^c, L-arginine hydrochloride – 10.51 mg^e, sodium acetate trihydrate and glacial acetic acid – 0.75 mg^f, sucrose – 49.88 mg^g, polysorbate 80 – 2 mg^h, water for injections – up to 1 ml.

1.14 ml – disposable syringes with a protection system made of transparent glass (type I) (1) – cardboard packs with sealed valves^×.
1.14 ml – disposable syringes with a protection system made of transparent glass (type I) (2) – cardboard packs with sealed valves^×.
1.14 ml – disposable syringes with a protection system made of transparent glass (type I) (2) – intermediate cardboard packages (3) – cardboard packs with sealed valves^×.

^× Each cardboard pack has an anti-counterfeit sticker applied.

^a Based on 2 ml of the drug.
^b Based on 1.14 ml of the drug.
^c The content of L-histidine and L-histidine hydrochloride is given in terms of L-histidine (M=155.16 g/mol), based on the total histidine concentration in the drug of 20 mM.
^d The content of L-arginine hydrochloride is given in terms of L-arginine (M=174.2 g/mol), based on the molar concentration of L-arginine in the drug of 25 mM. The nominal content of L-arginine hydrochloride (M=210.66 g/mol) in one syringe is 10.5 mg.
^e The content of L-arginine hydrochloride is given in terms of L-arginine (M=174.2 g/mol), based on the molar concentration of L-arginine in the drug of 50 mM. The nominal content of L-arginine hydrochloride (M=210.66 g/mol) in one syringe is 9.93 mg.
^f The content of sodium acetate trihydrate and glacial acetic acid is given, based on the total concentration of acetate ion in the drug of 12.5 mM.
^g The sucrose content is given in terms of milligrams, based on the mass-volume concentration of sucrose in the drug of 5%.
^h The polysorbate 80 content is given in terms of milligrams, based on the mass-volume concentration of polysorbate 80 in the drug of 0.2%.

Clinical-Pharmacological Group

Interleukin inhibitor

Pharmacotherapeutic Group

Interleukin inhibitor

Pharmacological Action

Mechanism of action

The drug Dupixent^® is a recombinant human monoclonal antibody (IgG4) that blocks interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit common to the IL-4 and IL-13 receptor complexes. The drug Dupixent^® blocks IL-4 signaling through type I receptors (IL-4Rα/γc) and shared IL-4 and IL-13 signaling through type II receptors (IL-4Rα/IL-13Rα). IL-4 and IL-13 are key type 2 inflammatory cytokines (including those produced by Th2 lymphocytes) involved in the pathogenesis of atopic diseases.

Type 2 inflammation plays an important role in the pathogenesis of many atopic diseases, including bronchial asthma, contributes to airflow limitation and increases the risk of exacerbations. IL-4 and IL-13 act as key drivers of type 2 inflammation, activating multiple cell types (e.g., mast cells, lymphocytes, eosinophils, neutrophils, macrophages) and inducing multiple mediators (e.g., immunoglobulin E, histamine, eicosanoids, leukotrienes, chemokines and cytokines, including eotaxin/CCL11, TARC/CCL17 and IL-5) involved in type 2 inflammation. Blocking the IL-4/IL-13 signaling pathway with dupilumab in patients reduces the concentrations of many of these type 2 inflammatory markers, including immunoglobulin E, periostin and multiple pro-inflammatory cytokines and chemokines (e.g., eotaxin, TARC), and also reduces the fractional exhaled nitric oxide (FeNO) level – a marker of lung inflammation. It has been shown that blocking the IL-4/IL-13 signaling pathway with dupilumab in humanized animal models prevents the subsequent actions of these cytokines and chemokines, including goblet cell hyperplasia, airway smooth muscle hyperreactivity, eosinophilic inflammation in the lungs, other inflammatory processes in the lungs, and prevents impaired lung function; while the reduction in the severity of eosinophilic inflammation in the lungs occurs independently of normal or elevated blood eosinophil levels.

Dupilumab is produced using recombinant DNA technology in a suspension culture of Chinese hamster ovary cells.

Dupilumab has a molecular mass of approximately 147 kDa.

Pharmacodynamics

Atopic Dermatitis

In clinical studies, treatment with Dupixent^® led to a reduction in serum concentrations of biomarkers associated with type 2 inflammatory cytokines, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum immunoglobulin E and allergen-specific immunoglobulin E. A reduction in LDH activity, a biomarker associated with the severity and activity of atopic dermatitis, was also observed. Dupixent^® caused suppression of TARC chemokine as early as the beginning of the 2nd week of treatment compared to placebo, with a trend of continued reduction to maximum and sustained suppression by the 12th week of treatment.

In patients receiving Dupixent^® at a dose of 300 mg every 2 weeks and at a dose of 300 mg once a week, total serum immunoglobulin E decreased by -74.8% and -73.9% (median change from baseline), respectively, by week 52 of therapy, compared to -0% in the placebo group. Similar trends were observed for antigen-specific immunoglobulins E, including Staphylococcus aureus (S. aureus) enterotoxin A-specific, grass and tree allergens.

Bronchial Asthma

In accordance with the inhibition of IL-4 and IL-13 signaling, treatment with dupilumab markedly reduced FeNO levels and concentrations of eotaxin-3, total immunoglobulin E, allergen-specific immunoglobulin E, TARC and periostin in patients with bronchial asthma compared to placebo. These reductions in inflammatory biomarker levels were comparable for the 200 mg every 2 weeks and 300 mg every 2 weeks dosing regimens and were near maximal suppression by 2 weeks of treatment, except for immunoglobulin E, which decreased more slowly. The described effects were sustained during treatment.

Chronic Rhinosinusitis with Nasal Polyps

In study participants with chronic rhinosinusitis with nasal polyps (CRSwNP), treatment with dupilumab also resulted in a reduction in urinary leukotriene E4 (LTE4) levels, a marker associated with mast cell, basophil and eosinophil activation.

Clinical Efficacy

Atopic Dermatitis

The efficacy and safety of Dupixent^® as monotherapy or in combination with topical corticosteroids were evaluated in three main randomized, double-blind, placebo-controlled studies (SOLO1, SOLO2 and CHRONOS) involving 2119 patients aged 18 years and older with moderate to severe atopic dermatitis.

16-week monotherapy studies (SOLO1 and SOLO2)

An Investigator’s Global Assessment (IGA) score of 0 or 1 (“clear” or “almost clear skin”) by week 16 of treatment in the SOLO1 clinical study was achieved by 37.9% of patients receiving Dupixent^® at a dose of 300 mg every 2 weeks, and 37.2% of patients receiving Dupixent^® at a dose of 300 mg once a week, versus 10.3% of patients in the placebo group, and in the SOLO2 study – 36.1% and 36.4% versus 8.5% of patients, respectively.

Improvement of at least 75% from baseline in the Eczema Area and Severity Index (EASI-75) by week 16 of treatment in the SOLO1 study was achieved by 51.3% of patients receiving Dupixent^® at a dose of 300 mg every 2 weeks, and 52.5% of patients receiving Dupixent^® at a dose of 300 mg once a week, versus 14.7% of patients in the placebo group, and in the SOLO2 study – 44.2% and 48.1% versus 11.9%, respectively.

A reduction in itch of at least 4 points on the peak pruritus Numerical Rating Scale (NRS) by week 16 of treatment in the SOLO1 study was achieved by 40.8% of patients receiving Dupixent^® at a dose of 300 mg every 2 weeks, and 40.3% of patients receiving Dupixent^® at a dose of 300 mg once a week, versus 12.3% of patients in the placebo group, and in the SOLO2 study – 36.0% and 39.0% of patients versus 9.5%, respectively. A significantly greater percentage of patients receiving Dupixent^® achieved rapid improvement on the pruritus NRS compared to patients in the placebo group (defined as ≥4-point improvement as early as week 2), and the percentage of patients who experienced a reduction in pruritus severity on the NRS continued to increase throughout the treatment period.

Treatment effects in subgroups (with subgrouping by body weight, age, gender, race and concomitant therapy, including the use of immunosuppressants) in the SOLO1 and SOLO2 studies were generally consistent with the results obtained in the overall study population.

52-week clinical study with concomitant use of topical corticosteroids (CHRONOS)

IGA 0 or 1 by week 16 of treatment was achieved by 38.7% of patients receiving Dupixent^® 300 mg every 2 weeks + topical corticosteroids, and 39.2% of patients receiving Dupixent^® 300 mg once a week + topical corticosteroids, versus 12.4% of patients in the placebo group, and by week 52 – 36.0% and 40.0% versus 12.5% of patients, respectively.

EASI-75 by week 16 of treatment was achieved by 68.9% of patients receiving Dupixent^® 300 mg every 2 weeks + topical corticosteroids, and 63.9% of patients receiving Dupixent^® 300 mg once a week + topical corticosteroids, versus 23.2% of patients in the placebo + topical corticosteroids group, and by week 52 – 65.2% and 64.1% versus 21.6% of patients, respectively.

An improvement of at least 4 points on the pruritus NRS by week 16 of treatment was achieved by 58.8% of patients receiving Dupixent^® 300 mg every 2 weeks + topical corticosteroids, and 50.8% of patients receiving Dupixent^® 300 mg once a week + topical corticosteroids, versus 19.7% of patients in the placebo + topical corticosteroids group, and by week 52 – 51.2% and 39.0% versus 12.9% of patients, respectively. A more significant percentage of patients receiving Dupixent^® + topical corticosteroids achieved rapid improvement on the pruritus NRS compared to patients in the placebo + topical corticosteroids group (defined as > 4-point improvement as early as week 2; p <0.05), and the proportion of patients who experienced a reduction in pruritus severity on the NRS continued to increase throughout the treatment period.

Treatment effects in subgroups (with subgrouping by body weight, age, gender, race and concomitant therapy, including the use of immunosuppressants) in the CHRONOS study were generally consistent with the results obtained in the overall study population.

Clinical efficacy in patients for whom cyclosporine treatment was not recommended

In patients for whom cyclosporine treatment was not recommended or was ineffective, monotherapy with Dupixent^® in both treatment groups led to a significant improvement in the signs and symptoms of atopic dermatitis compared to placebo. A greater percentage of patients receiving Dupixent^® compared to the placebo group achieved IGA 0 or 1 and a reduction from baseline of ≥2 points by week 16 (29.5% vs. 6.8%), EASI-75 by week 16 (38% vs. 11.4%), and a reduction of at least 4 points in the pruritus index from baseline by week 16 (34.9% compared to 8%) (p <0.001 for all 3 endpoints). Similar results were observed in patients receiving Dupixent^® concomitantly with topical corticosteroids. The efficacy of the combination of Dupixent^® + topical corticosteroids was maintained up to 52 weeks of therapy.

Adolescents aged 12 to 17 years

The efficacy and safety of Dupixent^® monotherapy in patients were evaluated in a multicenter, randomized, double-blind, placebo-controlled study (AD-1536) involving 251 patients aged 12 to 17 years with moderate to severe atopic dermatitis. Eligible patients enrolled in this study demonstrated an inadequate response to prior topical therapy.

Patients received: an initial dose of 400 mg of Dupixent^® (2 injections of 200 mg) followed by 200 mg every 2 weeks for patients with a baseline body weight of less than 60 kg or an initial dose of Dupixent^® 600 mg (2 injections of 300 mg) followed by 300 mg every 2 weeks for patients with a baseline body weight of 60 kg or more; or an initial dose of Dupixent^® 600 mg (2 injections of 300 mg) followed by 300 mg every 4 weeks regardless of body weight; or placebo.

Dupixent^® is administered subcutaneously. If necessary to control unacceptable symptoms, patients were allowed to receive rescue treatment at the investigator’s discretion. Patients who received such treatment were assessed as non-responders to Dupixent^® therapy.

In this study, the mean age of patients was 14.5 years, mean weight 59.4 kg, 41.0% of patients were female, 62.5% were White, 15.1% were Asian and 12.0% were Black. Overall, 92.0% of patients had at least one comorbid allergic condition; 65.5% of patients had allergic rhinitis; 53.6% of patients had bronchial asthma and 68% of patients had food allergy.

Clinical response

An Investigator’s Global Assessment (IGA) score of 0 or 1 (“clear” or “almost clear skin”) by week 16 of treatment in the AD-1526 study was achieved by 24.4% of patients receiving Dupixent^® 300 mg every 2 weeks (≥ 60 kg) or 200 mg every 2 weeks (< 60 kg) versus 2.4% of patients in the placebo group.

Improvement of at least 75% from baseline in the Eczema Area and Severity Index (EASI-75) by week 16 was achieved by 41.5% of patients receiving Dupixent^® versus 8.2% of patients in the placebo group.

A reduction in itch of at least 4 points on the peak pruritus Numerical Rating Scale (NRS) by week 16 of treatment in the study was achieved by 36.6% of patients receiving Dupixent^®, versus 4.8% of patients in the placebo group. A significantly greater percentage of patients receiving Dupixent^® achieved rapid improvement on the pruritus NRS compared to patients in the placebo group (defined as ≥ 4-point improvement as early as week 2), and the percentage of patients who experienced a reduction in pruritus severity on the NRS continued to increase throughout the treatment period.

A significantly greater proportion of patients randomized to Dupixent^® therapy achieved rapid improvement on the pruritus NRS compared to placebo (improvement of more than 4 times as early as week 4; nominal p-value <0.001) and the proportion of patients responding to therapy on the NRS was observed in conjunction with improvement in objective signs of atopic dermatitis.

Long-term studies of the efficacy of Dupixent^® therapy in adolescent patients with moderate to severe atopic dermatitis who participated in previous clinical studies of Dupixent^® were evaluated in an open-label extension study (AD-1434). The efficacy data obtained in this study suggest that the clinical benefit achieved at week 16 of therapy is stable over 52 weeks of therapy.

Children aged 6 to 11 years

The efficacy and safety of Dupixent^® in pediatric patients in combination with topical corticosteroids were studied in a multicenter randomized double-blind placebo-controlled study (AD-1652) involving 367 patients aged 6 to 11 years with atopic dermatitis characterized by IGA scores ≥4 (on a scale of 0 to 4), EASI ≥21 (on a scale of 0 to 72), and a minimum affected body surface area of ≥15%. Eligible patients enrolled in this study had previously had an inadequate response to topical medications. Patients were stratified based on baseline body weight (<30 kg, ≥30 kg).

Patients in the group receiving Dupixent^® every 2 weeks + topical corticosteroids with a baseline body weight <30 kg received an initial dose of the drug of 200 mg/day and then 100 mg every 2 weeks from week 2 to week 14, and patients with a baseline body weight ≥30 kg received an initial dose of Dupixent^® of 400 mg/day and then 200 mg every 2 weeks from week 2 to week 14. Patients in the group receiving Dupixent^® every 4 weeks + topical corticosteroids received an initial dose of the drug of 600 mg/day and then 300 mg every 4 weeks from week 4 to week 12, regardless of body weight. Patients were allowed to receive rescue therapy at the investigator’s discretion. Patients who received rescue therapy were considered non-responders to Dupixent^® therapy.

In this study, the mean age was 8.5 years, the mean body weight was 29.8 kg, 50.1% of patients were female, 69.2% were White, 16.9% were Black, and 7.6% were Asian.

Overall, 91.7% of patients had at least one comorbid allergic condition; 64.4% had a food allergy, 62.7% had other allergies, 60.2% had allergic rhinitis, and 46.7% of patients had asthma.

Clinical Response

An Investigator’s Global Assessment (IGA) score of 0 or 1 (“clear” or “almost clear skin”) by Week 16 of treatment in the AD-1652 study was achieved by 29.5% of patients with a body weight less than 30 kg receiving Dupixent^® 300 mg every 4 weeks, compared to 13.1% in the placebo group; 39.0% of patients with a body weight of 30 kg or more receiving Dupixent^® 200 mg every 2 weeks, compared to 9.7% in the placebo group.

Improvement of at least 75% from baseline in the Eczema Area and Severity Index (EASI-75) by Week 16 of treatment in the AD-1652 study was achieved by 75.4% of patients with a body weight less than 30 kg receiving Dupixent^® 300 mg every 4 weeks, compared to 27.9% in the placebo group; 74.6% of patients with a body weight of 30 kg or more receiving Dupixent^® 200 mg every 2 weeks, compared to 25.8% in the placebo group.

A reduction of at least 4 points in peak pruritus on the Numerical Rating Scale (NRS) by Week 16 of treatment in the AD-1652 study was achieved by 54.1% of patients with a body weight less than 30 kg receiving Dupixent^® 300 mg every 4 weeks, compared to 11.7% in the placebo group; 61.4% of patients with a body weight of 30 kg or more receiving Dupixent^® 200 mg every 2 weeks, compared to 12.9% in the placebo group.

A significantly greater percentage of patients treated with Dupixent^® achieved rapid improvement in the pruritus NRS compared to patients in the placebo group (defined as ≥4-point improvement as early as Week 2), and the percentage of patients who experienced a reduction in pruritus NRS continued to increase throughout the treatment period.

A significantly greater percentage of patients randomized to therapy with Dupixent^® in combination with topical corticosteroids achieved rapid improvement in the pruritus NRS compared to placebo (improvement of ≥4 points at Week 4).

The long-term efficacy of therapy with Dupixent^® in combination with topical corticosteroids in pediatric patients with atopic dermatitis who participated in previous clinical studies of Dupixent^® in combination with topical corticosteroids was studied in an ongoing open-label extension study (AD-1434). Efficacy data from this study suggest that the clinical improvement observed at Week 16 was maintained through 52 weeks of therapy.

Asthma

Three randomized, double-blind, placebo-controlled, parallel-group, multicenter studies (DRI12544, QUEST, and VENTURE) ranging from 24 to 52 weeks in duration were conducted in 2888 patients (aged 12 years and older). Patients were enrolled in all three studies regardless of minimum baseline eosinophil levels or other type 2 inflammatory biomarkers (e.g., FeNO or immunoglobulin E levels).

Asthma Exacerbations

The DRI12544, QUEST, and VENTURE studies evaluated the rate of severe asthma exacerbations regardless of minimum eosinophil count or any other type 2 inflammatory biomarkers (e.g., FeNO or immunoglobulin E) at study start. In the overall population, regardless of eosinophil count and other type 2 inflammatory biomarkers, patients receiving Dupixent^® 200 mg or 300 mg every 2 weeks experienced a significant reduction in the rate of severe asthma exacerbations compared to the placebo group. In the DRI12544 and QUEST studies, the rate of severe exacerbations with Dupixent^® 200 mg every 2 weeks was reduced by 70% and 48%, respectively; and with the 300 mg every 2 weeks dose by 70% and 46%, respectively; and by 59% in the VENTURE study.

In a pooled analysis of the DRI12544 and QUEST studies, the rate of severe exacerbations leading to hospitalization and/or emergency department visits was reduced by 25.5% and 46.9% with Dupixent^® 200 mg or 300 mg every 2 weeks, respectively.

The cumulative mean number of severe exacerbations was lower in patients treated with Dupixent^® compared to placebo in the DRI12544, QUEST, and VENTURE studies (in the overall population and in the population with baseline eosinophils ≥150 cells/µL or FeNO ≥25 ppb) over the 24- or 52-week treatment period for both dosing regimens.

In the QUEST study, patients receiving medium-dose inhaled corticosteroids had a similar reduction in the rate of severe asthma exacerbations compared to patients receiving high-dose inhaled corticosteroids.

Lung Function

A clinically significant increase in pre-bronchodilator forced expiratory volume in 1 second (FEV1) was observed at Week 12 in the overall population regardless of eosinophil levels or other type 2 inflammatory biomarkers (e.g., FeNO or immunoglobulin E). In the DRI12544, QUEST, and VENTURE studies, compared to placebo, greater improvement in FEV1 was also observed in patients with FeNO ≥25 ppb. Improvement in FEV1 was similar regardless of whether patients received medium-dose inhaled corticosteroids, high-dose inhaled corticosteroids, or oral corticosteroids.

Significant improvements in FEV1 were observed as early as the second week (DRI12544, QUEST, and VENTURE) after the first injection of Dupixent^® at both the 200 mg and 300 mg doses and were maintained for 24 weeks (DRI12544 and VENTURE) and 52 weeks (QUEST).

The adjusted mean difference in absolute FEV1 was 0.20 L and 0.14 L in the groups receiving Dupixent^® 200 mg every 2 weeks compared to placebo; 0.16 L and 0.13 L in the groups receiving 300 mg every 2 weeks compared to placebo, in the DRI12544 and QUEST studies, respectively. The corresponding percent change in FEV1 ranged from 9.2% to 11.9% for the 200 mg every 2 weeks dose and from 9.4% to 11.7% for the 300 mg every 2 weeks dose. The adjusted mean difference in absolute pre-bronchodilator FEV1 from baseline to Week 24 (sufficient time to achieve maximum oral corticosteroid dose reduction) in the VENTURE study was 0.22 L in the Dupixent^® group compared to placebo, corresponding to a 15.1% improvement from baseline.

Furthermore, patients treated with Dupixent^® had significantly improved post-bronchodilator FEV1 from baseline at Weeks 12 and 52 compared to placebo, indicating that Dupixent^® improves fixed airway obstruction. In the Dupixent^® group, no decline in lung function was observed over one year of follow-up based on post-bronchodilator FEV1 values.

Reduction of Oral Corticosteroid Use

The VENTURE study evaluated the effect of Dupixent^® on reducing maintenance oral corticosteroid use. The baseline mean oral corticosteroid dose was 11.75 mg in the placebo group and 10.75 mg in the Dupixent^® group. Compared to placebo, patients receiving Dupixent^® had a greater reduction in the daily oral corticosteroid dose while maintaining asthma control. The mean overall reduction in the daily oral corticosteroid dose while maintaining asthma control was 70.1% from baseline in patients receiving Dupixent^® and 41.9% in the placebo group.

Patient-Reported Outcomes

Additionally, in all 3 studies, Dupixent^® provided clinically significant improvement in asthma control measures in the overall population compared to the placebo group, as evidenced by ACQ-5 scores and corresponding improvement in quality of life measured by the AQLQ(S). Improvements in ACQ-5 and AQLQ(S) were observed as early as 2 weeks, and this improvement was maintained for 24 weeks in the DRI12544 study and 52 weeks in the QUEST study. In the overall population of the QUEST study, the proportion of responders, defined as achieving the minimal clinically important difference in ACQ-5 and AQLQ(S), was significantly higher by Week 52 in the group receiving both doses of Dupixent^®.

Long-Term Extension Study (TRAVERSE)

The long-term efficacy of Dupixent^® was evaluated in 2282 adults and adolescents with moderate-to-severe asthma, and in adult patients with corticosteroid-dependent asthma who participated in previous clinical trials of Dupixent^®, in an open-label extension study (TRAVERSE). In this Dupixent^® study, improvement in clinical outcomes, including reduction in exacerbation rates and improvement in lung function, was maintained for 96 weeks. In patients with corticosteroid-dependent asthma, despite ongoing reduction or discontinuation of oral corticosteroids, a reduction in exacerbation rates and sustained improvement in lung function were observed over 96 weeks.

The severe exacerbation rate over 96 weeks was 0.3 and 0.27; and the improvement in FEV1 from baseline was 0.33 L (21.1%) and 0.42 L (27.3%) in patients with blood eosinophils ≥150 cells/µL and ≥300 cells/µL, respectively. Similar maintenance of effect was observed for ACQ-5 and AQLQ(S) parameters. Similar results were observed in the subgroup of patients receiving high-dose inhaled corticosteroids.

Chronic Rhinosinusitis with Nasal Polyps

The clinical development program for Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) included two randomized, double-blind, multicenter, placebo-controlled, parallel-group studies (SINUS-24 and SINUS-52) involving 724 patients aged 18 years and older receiving background therapy with intranasal corticosteroids. These studies included patients with severe CRSwNP despite previous sinus surgery or treatment with systemic corticosteroids within the last 2 years. Treatment with systemic corticosteroids or surgery was permitted during the study at the investigator’s discretion. In the SINUS-24 study, a total of 276 patients were randomized to either Dupixent^® 300 mg (n=143) or placebo (n=133), administered every 2 weeks for 24 weeks. In the SINUS-52 study, a total of 448 patients were randomized to either Dupixent^® 300 mg every 2 weeks for 52 weeks (n=150), or Dupixent^® 300 mg every 2 weeks for 24 weeks, then 300 mg every 4 weeks until Week 52 (n=145), or placebo (n=153). All patients had reduced sinus opacification on computed tomography, assessed by the Lund-Mackay CT score (LMS), with 73-90% of patients having opacification of all sinuses. Patients were stratified based on history of surgery and asthma/aspirin-exacerbated respiratory disease (AERD). Previous sinus surgery had been performed in 63% of patients, with a mean of 2.0 surgeries; 74% of participants had received systemic corticosteroids within the last 2 years, with a mean of 1.6 courses in the last 2 years. 59% of patients had comorbid asthma, and 28% had AERD.

The co-primary endpoints were the change from baseline in the nasal polyp score (NPS, range 0-8) assessed by endoscopy at Week 24 (centralized, masked reading) and the change from baseline in the patient-reported nasal congestion/obstruction score (NC, range 0-3) averaged over 28 days at Week 24, based on daily diary entries. In both studies, secondary endpoints at Week 24 included changes from baseline in: Lund-Mackay CT score, Total Symptom Score (TSS), University of Pennsylvania Smell Identification Test (UPSIT), daily sense of smell score, and the 22-item Sino-Nasal Outcome Test (SNOT-22). A pooled analysis assessed the reduction in the proportion of patients requiring urgent systemic corticosteroid use and/or sinus surgery, as well as improvement in FEV1 in the subgroup of patients with asthma. Statistically and clinically significant efficacy was observed for the improvement in NPS at Week 24 in SINUS-24 (adjusted mean difference -2.06 compared to placebo) and in SINUS-52 at Weeks 24 and 52 with further progressive improvement (adjusted mean difference -1.8 and -2.4 compared to placebo for Dupixent^® 300 mg every 2 weeks, at Weeks 24 and 52, respectively). Patients treated with Dupixent^® had a significant reduction in nasal congestion/obstruction compared to placebo at Week 24 in SINUS-24 (adjusted mean difference -0.89 compared to placebo) and at Weeks 24 and 52 in SINUS-52 (adjusted mean difference -0.87 and -0.98 compared to placebo for Dupixent^® 300 mg every 2 weeks, at Weeks 24 and 52, respectively). In both studies, a significant improvement from baseline in NC score and daily sense of smell score was observed as early as the first assessment at Week 4. A significant reduction in the Lund-Mackay CT score was observed at Week 24 in SINUS-24 (adjusted mean difference -7.44 compared to placebo) and in SINUS-52 at Week 24 with further improvement by Week 52 (adjusted mean difference -5.13 and -6.94 compared to placebo for Dupixent^® 300 mg every 2 weeks, at Weeks 24 and 52, respectively). A pooled analysis demonstrated a 74% reduction in the proportion of patients requiring urgent systemic corticosteroid courses and an 83% reduction in those requiring sinus surgery with Dupixent^® compared to placebo. In the subgroup of patients with comorbid asthma, a significant improvement in pre-bronchodilator FEV1 was observed at Week 24 of Dupixent^® treatment regardless of baseline eosinophil levels: the adjusted mean change from baseline in FEV1 at Week 24 for the Dupixent^® 300 mg every 2 weeks dose was 0.14 L versus -0.07 L in the placebo group, a difference of 0.21 L. Efficacy for the co-primary endpoints – change from baseline in NPS and NC score at Week 24 – and the key secondary endpoint (Lund-Mackay CT score) in patient subgroups with comorbid asthma or AERD was similar to the overall CRSwNP population.

Pharmacokinetics

The pharmacokinetics of dupilumab are similar in patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyps.

Absorption

Following a single subcutaneous administration of 75-600 mg of dupilumab, the median time to reach maximum serum concentration (T_max) was 3-7 days. The absolute bioavailability of dupilumab after subcutaneous administration is similar between patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyps and is 61-64% (established by population pharmacokinetic analysis).

Administration of a single loading dose on day one leads to rapid attainment of clinically effective concentrations within 2 weeks.

With the 200 mg or 300 mg every 2 weeks regimen, starting with a 400 mg or 600 mg loading dose, steady-state concentrations (C_ss) of dupilumab are typically reached on average by Week 16 of treatment. At steady state, the mean trough concentration before the next dose was 39 mg/L with 200 mg every 2 weeks and 70-80 mg/L with 300 mg every 2 weeks.

With weekly subcutaneous administration of 300 mg of Dupixent^®, starting with a 600 mg loading dose, steady-state concentrations are typically reached on average after 13 weeks of treatment. At steady state, the mean trough concentration before the next dose was 189 mg/L.

Dose Linearity

Due to nonlinear clearance, the systemic exposure of dupilumab, as determined by AUC, increases faster than dose-proportionally after a single subcutaneous administration of doses ranging from 75 mg to 600 mg.

Distribution

The volume of distribution (V_d) of dupilumab is approximately 4.6 L, indicating that it is distributed primarily within the vascular system.

Metabolism

As dupilumab is a protein, no specific metabolism studies were conducted. Dupilumab is expected to be degraded into small peptides and individual amino acids.

Elimination

Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is largely via a non-saturable proteolytic pathway, while at lower concentrations, elimination is predominantly via nonlinear saturable binding to the IL-4Rα target.

Following the last dose at steady state, the median time to non-quantifiable dupilumab concentrations is 9 weeks for the 200 mg every 2 weeks regimen, 10-12 weeks for the 300 mg every 2 weeks regimen, and 13 weeks for the 300 mg weekly regimen.

Pharmacokinetics in Special Patient Populations

Gender did not affect the pharmacokinetics of Dupixent^®.

Age of patients did not affect the pharmacokinetics of Dupixent^®.

Elderly Patients. According to population pharmacokinetic analysis, patient age did not affect the efficacy and safety of Dupixent^®.

Pediatric Patients. The safety and efficacy of Dupixent^® have been established in patients 6 years of age and older with moderate-to-severe atopic dermatitis. Safety and efficacy were comparable between children, adolescents, and adults. The safety and efficacy in children under 6 years of age with atopic dermatitis have not been studied.

Asthma. The long-term safety and efficacy of Dupixent^® were evaluated in 89 adolescent patients with moderate-to-severe asthma who were enrolled in an open-label extension study (TRAVERSE). In this study, follow-up continued for 96 weeks, resulting in 99 patient-years of cumulative Dupixent^® exposure. The safety profile of Dupixent^® in the TRAVERSE study was consistent with the safety profile reported in the base asthma studies over 52 weeks of therapy. No additional adverse reactions were identified. In this study, the clinical benefit of Dupixent^®, including reduction in exacerbation rates and improvement in lung function observed in the base asthma studies, was maintained through Week 96.

The safety and efficacy of the drug in children under 12 years of age with bronchial asthma have not been studied. The adverse reaction profile in adolescents is comparable to that in adults (see the “Adverse Reactions” section).

Chronic rhinosinusitis with nasal polyps. Chronic rhinosinusitis with nasal polyps is not usually seen in children. The pharmacokinetics of dupilumab have not been studied in children (patients under 18 years of age) with chronic rhinosinusitis with nasal polyps.

Race. According to the results of a population pharmacokinetic analysis, race did not affect the pharmacokinetic parameters of Dupixent^®.

Hepatic impairment. Dupilumab is a monoclonal antibody, so it is not expected to undergo significant hepatic elimination. Clinical studies to evaluate the effect of hepatic impairment on the pharmacokinetics of dupilumab have not been conducted.

Renal impairment. Dupilumab is a monoclonal antibody, so it is not expected to undergo significant renal elimination. Clinical studies to evaluate the effect of renal impairment on the pharmacokinetics of dupilumab have not been conducted. Results from population pharmacokinetic analyses showed that mild to moderate renal impairment does not significantly affect the systemic exposure of dupilumab. There are no data on the use of dupilumab in patients with severe renal impairment.

Body weight. No dose adjustment based on body weight is required for patients with bronchial asthma aged 12 years and older and adult patients with atopic dermatitis.

For patients aged 6-17 years with atopic dermatitis, the recommended dose is 300 mg every 4 weeks (with a body weight of 15-<30 kg), 200 mg every 2 weeks (with a body weight of 30-<60 kg), and 300 mg every two weeks (with a body weight of more than 60 kg).

Indications

• Moderate to severe atopic dermatitis in patients 6 years of age and older with an inadequate response to topical therapy or when such therapy is not advisable. Dupixent^® can be used as monotherapy or concomitantly with topical medicinal products;
• As an add-on maintenance therapy for moderate to severe asthma in patients aged 12 years and older with an eosinophilic phenotype or in patients with oral corticosteroid-dependent asthma;
• As an add-on maintenance therapy for adult patients with poorly controlled severe chronic rhinosinusitis with nasal polyps.

ICD codes

Dosage Regimen

Dupixent^® is administered subcutaneously.

Atopic dermatitis

The recommended dose of Dupixent^® for adult patients

• Initial dose – 600 mg (2 injections of 300 mg), then – 300 mg every 2 weeks. Depending on the individual therapeutic response, the dose may be increased to 300 mg weekly.

The recommended dose of Dupixent^® for patients aged 6-17 years

• For patients with a body weight from 15 to <30 kg initial dose – 600 mg (2 injections of 300 mg), then 300 mg every 4 weeks;
• For patients with a body weight from 30 to <60 kg initial dose – 400 mg (2 injections of 200 mg), then 200 mg every 2 weeks;
• For patients with a body weight of 60 kg and more initial dose – 600 mg (2 injections of 300 mg), then 300 mg every 2 weeks.

Bronchial asthma

The recommended dose of Dupixent^® for adult patients and children (12 years and older)

• Initial dose – 400 mg (2 injections of 200 mg), then – 200 mg every 2 weeks. Depending on the individual therapeutic response, the dose may be increased to 300 mg every 2 weeks;
• Initial dose – 600 mg (2 injections of 300 mg), then – 300 mg every 2 weeks for patients with glucocorticosteroid-dependent asthma or concomitant moderate or severe atopic dermatitis for which Dupixent^® is indicated.

Chronic rhinosinusitis with nasal polyps

If a dose is missed, the patient should receive the injection as soon as possible and then continue treatment according to the prescribed administration schedule.

Special patient groups

The safety and efficacy of Dupixent^® in children under 6 years of age and adolescents with atopic dermatitis, bronchial asthma, and in patients with chronic rhinosinusitis with nasal polyps under 18 years of age have not been established.

No dose adjustment is required for elderly patients.

There are no data on the use of the drug in patients with hepatic impairment.

No dose adjustment is required for patients with mild or moderate renal impairment. There are no data on the use of the drug in patients with severe renal impairment.

No dose adjustment based on body weight is required for patients with asthma over 12 years of age and adult patients with atopic dermatitis and chronic rhinosinusitis with nasal polyps.

For patients 6-17 years of age with atopic dermatitis, the recommended dose is 300 mg every 4 weeks (with a body weight of 15-<30 kg), 200 mg every 2 weeks (with a body weight of 30-<60 kg) and 300 mg every 2 weeks (with a body weight of more than 60 kg).

Method of administration

Before administration, the drug should be inspected for the presence of particulate matter or discoloration. If the drug contains particulate matter or the solution is discolored, do not administer the drug.

The solution in the pre-filled syringe with a safety system or the pre-filled syringe must be allowed to reach room temperature before injecting Dupixent^®. It is recommended to leave it at room temperature for 45 minutes (for the 300 mg dosage) or 30 minutes (for the 200 mg dosage).

If necessary, the pre-filled syringe can be stored at room temperature (up to 25°C (77°F)) for a maximum of 14 days. The drug should not be stored at temperatures above 25°C (77°F). After removal from the refrigerator, Dupixent^® should be used within 14 days or discarded.

Syringes should be protected from heat and direct sunlight.

If the initial dose is 600 mg, two 300 mg injections should be administered at different injection sites.

If the initial dose is 400 mg, two 200 mg injections should be administered at different injection sites.

Treatment with Dupixent^® should be carried out under medical supervision. The injection can be administered by the patient themselves or by a caregiver.

Before starting treatment with Dupixent^®, patients and/or their caregivers must be trained in the preparation and administration of the Dupixent^® injection, according to the instructions in the “Instructions for preparation and administration of the Dupixent^® injection, 300 mg in a pre-filled single-use syringe with a safety system”, “Instructions for preparation and administration of the Dupixent^® injection, 300 mg in a pre-filled single-use syringe” and “Instructions for preparation and administration of the Dupixent^® injection, 200 mg in a pre-filled single-use syringe with a safety system”.

Dupixent^® can be self-administered subcutaneously using a pre-filled single-use syringe into the thigh or abdomen, except for the area within a 5 cm diameter directly around the navel. If the injection is administered by another person, the drug can also be administered into the upper arm.

It is recommended to rotate injection sites with each administration.

The Dupixent^® injection should not be administered into areas of painful or damaged skin, or into areas with bruising or scarring.

All unused drug residues and consumables must be disposed of in accordance with local regulations.

Instructions for preparation and administration of the Dupixent^® 300 mg injection in a pre-filled single-use syringe with a safety system

Before starting to use Dupixent^® in a pre-filled single-use syringe with a safety system, read these instructions carefully.

The components of the pre-filled single-use syringe with a safety system are shown in the figure below.

This device is a pre-filled single-use syringe with a safety system (hereinafter referred to as the “syringe”). It contains a solution for subcutaneous administration containing 300 mg of Dupixent^®.

Important information

• Do not attempt to self-inject or have someone else inject you until your doctor or healthcare professional has taught you the correct technique for subcutaneous injection.
• Read the usage information carefully before using the syringe.
• Ask your doctor how often you need to inject Dupixent^®.
• Ask your doctor or healthcare professional to show you how to use the syringe correctly before you self-inject Dupixent^® for the first time.
• It is recommended to rotate the injection site with each administration.
• Do not use the syringe if it has been dropped on a hard surface or is damaged.
• Do not use the syringe if the needle cap is missing or was not securely attached.
• Do not touch the plunger rod until you are ready to inject.
• Do not inject through clothing.
• Do not attempt to remove air bubbles from the syringe.
• To reduce the risk of accidental needle sticks, each pre-filled single-use syringe is equipped with a safety device with a protection system that automatically activates, covering the needle, after the injection has been administered.
• Do not pull the plunger rod back.
• The syringe is not reusable.

How to store the syringe

• Keep syringes out of the reach of children.
• Store unused syringes in the original carton in the refrigerator at a temperature between 2°C (35.6°F) and 8°C (46.4°F).
• After removal from the refrigerator, the syringe should be left at room temperature for 45 minutes and allowed to warm up before injecting Dupixent^®.
• Syringes can be stored at room temperature for no more than 14 days.
• Do not shake the syringe.
• Do not expose the syringe to heat.
• Do not freeze the syringe.
• Do not expose the syringe to direct sunlight.

Step 1. Removing the syringe from the packaging

Remove the syringe from the carton by holding it by the middle of the body.

Do not remove the needle cap until you are ready to inject.

Do not use the syringe if it has been dropped on a hard surface or is damaged.

Step 2. Preparation

Make sure you have everything you need for the injection

• Pre-filled syringe;
• 1 alcohol wipe*;
• 1 cotton ball or gauze pad*;
• A puncture-resistant container* (see Step 12).

* Not included in the carton.

Check the labeling carefully

• Check the expiration date;
• Make sure you have the correct drug and the correct dose.

Do not use the syringe after the expiration date on the label.

Step 3. Inspection

Inspect the solution through the syringe viewing window: check if the solution is clear, colorless or has a light yellow tint.

Note: You may see air bubbles, this is normal.

Do not use the syringe if the liquid has changed color or become cloudy, or if it has visible flakes or particles.

Step 4. Wait 45 minutes

Place the syringe on a flat surface for at least 45 minutes, let the syringe warm up to room temperature.

Do not heat the syringe.

Do not expose the syringe to direct sunlight.

The syringe must not be stored at room temperature for more than 14 days.

Step 5. Selecting the injection site

Choose the injection site

• You can inject into the outer thigh or the front of the abdomen, except for the area within a 5 cm diameter directly around the navel;
• If the injection is given by another person, the skin area on the upper arm can also be used for injection.

Dupixent^® injections should not be given into areas of painful or damaged skin, or into areas with bruising or scarring.

Step 6. Preparing the injection site

• Wash your hands.
• Wipe the skin area intended for injection with an alcohol wipe.
• Let the skin dry before injecting.

Do not touch the prepared skin area with your hands or blow on it before injecting.

Step 7. Removing the needle cap

Hold the syringe by the middle of the body, with the needle pointing away from you; remove the needle cap.

Do not put the needle cap back on.

Do not touch the needle.

The drug must be administered immediately after removing the needle cap.

Step 8. Pinching the skin

Pinch the skin at the injection site as shown in the figure.

Step 9. Inserting the needle

Insert the needle completely into the pinched skin at an angle of approximately 45°.

Step 10. Injecting the solution

Release the pinched skin.

Slowly and continuously press the plunger rod to inject the entire solution until the syringe is empty.

Note: You will feel some resistance. This is normal.

Step 11. Completing the injection and removing the needle

Lift your thumb, releasing pressure on the plunger rod, the needle will retract into the needle guard; then remove the syringe from the injection site.

Gently press a cotton ball or gauze pad to the injection site if you see blood.

Do not put the needle cap back on the needle.

Do not rub the skin after the injection.

Step 12. Disposal

After use, place the syringe and needle cap in a puncture-resistant container.

Do not put the needle cap back on the needle.

Keep the container out of the reach of children.

Instructions for preparation and administration of the Dupixent^® 300 mg injection in a pre-filled single-use syringe

Before starting to use Dupixent^® in a pre-filled single-use syringe, read these instructions carefully.

The components of the pre-filled syringe are shown in the figure below.

*The syringe may have a rigid or soft needle cap.

This device is a pre-filled single-use syringe (hereinafter referred to as the “syringe”). It contains a solution for subcutaneous administration containing 300 mg of Dupixent^®.

Important information

• Do not attempt to self-inject or have someone else inject you until your doctor or healthcare professional has taught you the correct technique for subcutaneous injection.
• Read the usage information carefully before using the syringe.
• Ask your doctor how often you need to inject Dupixent^®.
• Ask your doctor or healthcare professional to show you how to use the syringe correctly before you self-inject Dupixent^® for the first time.
• It is recommended to rotate the injection site with each administration.
• Do not use the syringe if it is damaged.
• Do not use the syringe if the needle cap is missing or was not securely attached.
• Do not touch the plunger rod until you are ready to inject.
• Do not inject through clothing.
• Do not attempt to remove air bubbles from the syringe.
• Do not pull the plunger rod back.
• The syringe is not reusable.

How to store the syringe

• Keep syringes out of the reach of children.
• Store unused syringes in the original carton in the refrigerator at a temperature between 2°C (35.6°F) and 8°C (46.4°F).
• After removal from the refrigerator, the syringe should be left at room temperature for 45 minutes and allowed to warm up before injecting Dupixent^®.
• Syringes can be stored at room temperature for no more than 14 days.
• Do not shake the syringe.
• Do not expose the syringe to heat;
• Do not freeze the syringe.
• Do not expose the syringe to direct sunlight.

Step 1. Removing the syringe from the packaging

Remove the syringe from the carton by holding it by the middle of the body.

Do not remove the needle cap until you are ready to inject.

Do not use the syringe if it has been damaged.

Step 2. Preparation

Make sure you have everything you need for the injection

• Pre-filled syringe;
• 1 alcohol wipe*;
• 1 cotton ball or gauze pad*;
• A puncture-resistant container* (see Step 12).

* Not included in the carton.

Check the labeling carefully

• Check the expiration date;
• Make sure you have the correct drug and the correct dose.

Do not use the syringe after the expiration date on the label.

Step 3. Inspection

Inspect the solution in the syringe: check if the solution is clear, if the liquid is colorless or has a light yellow tint.

Note: You may notice air bubbles; this is normal.

Do not use the syringe if the liquid has changed color or become cloudy, or if it contains visible flakes or particles.

Step 4. Wait 45 min

Place the syringe on a flat surface for at least 45 minutes; allow the syringe to warm up to room temperature.

Do not heat the syringe.

Do not expose the syringe to direct sunlight.

The syringe must not be stored at room temperature for more than 14 days.

Step 5. Injection site selection

Select the injection site.

You can inject into the outer thigh or the front of the abdomen, except for the area within a 5 cm diameter directly around the navel.

If the injection is administered by another person, the skin area on the upper arm can also be used for injection.

Dupixent^® injections should not be administered into areas with painful or damaged skin, bruising, or scarring.

Step 6. Injection site preparation

Wash your hands.

Wipe the skin area intended for injection with an alcohol wipe.

Allow the skin to dry before injection.

Do not touch the prepared skin area with your hands or blow on it before injection.

Step 7. Needle cap removal

Hold the syringe by the middle of the barrel, with the needle pointing away from you; remove the needle cap.

Do not recap the needle.

Do not touch the needle.

The medication must be administered immediately after removing the needle cap.

Step 8. Skin pinch formation

Pinch the skin at the injection site as shown in the picture.

Step 9. Needle insertion

Insert the needle completely into the pinched skin at an angle of approximately 45°.

Step 10. Solution administration

Release the skin pinch.

Slowly and continuously press the plunger rod to inject the entire solution until the syringe is empty.

Note: You will feel some resistance. This is normal.

Step 11. Needle withdrawal

Withdraw the needle from the skin at the same angle it was inserted.

Do not recap the needle.

Gently press a cotton ball or gauze pad on the injection site if you notice blood.

Do not rub the skin after injection.

Step 12. Disposal

After use, place the syringe and needle cap into a puncture-resistant container.

Do not recap the needle.

Keep the container out of the reach of children.

Instructions for preparation and administration of Dupixent^® 200 mg injection in a single-dose pre-filled syringe with a safety system

Before starting to use Dupixent^® in a single-dose pre-filled syringe with a safety system, read these instructions carefully.

The components of the single-dose pre-filled syringe with a safety system are shown in the figure below.

This device is a single-dose pre-filled syringe with a safety system (hereinafter referred to as the “syringe”). It contains a solution for subcutaneous injection containing 200 mg of Dupixent^®.

Important information

Do not attempt to self-inject or have someone else inject you until your doctor or healthcare professional has trained you in the correct technique for subcutaneous injection.

Before using the syringe, read the usage information carefully.

Ask your doctor how often you need to administer Dupixent^® injections.

Ask your doctor or healthcare professional to show you how to use the syringe correctly before self-administering your first Dupixent^® injection.

It is recommended to rotate the injection site with each administration.

Do not use the syringe if it has been dropped on a hard surface or is damaged.

Do not use the syringe if the needle cap is missing or was not securely attached.

Do not touch the plunger rod until you are ready to inject.

Do not inject through clothing.

Do not attempt to remove air bubbles from the syringe.

To reduce the risk of accidental needle sticks, each single-dose pre-filled syringe is equipped with a safety device with a protective system that is automatically activated, covering the needle, after you have completed the injection.

Do not pull the plunger rod back.

The syringe is for single use only.

How to store the syringe

Keep syringes out of the reach of children.

Store unused syringes in the original carton in the refrigerator at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

After removal from the refrigerator, the syringe should be left at room temperature for 30 minutes and allowed to warm up before injecting Dupixent^®.

Syringes can be stored at room temperature for no more than 14 days.

Do not shake the syringe.

Do not expose the syringe to heat.

Do not freeze the syringe.

Do not expose the syringe to direct sunlight.

Step 1. Removing the syringe from the packaging

Remove the syringe from the carton by holding it by the middle of the barrel.

Do not remove the needle cap until you are ready to inject.

Do not use the syringe if it has been dropped on a hard surface or is damaged.

Step 2. Preparation

Make sure you have everything you need for the injection.

Pre-filled syringe.

1 alcohol wipe*.

1 cotton ball or gauze pad*.

Puncture-resistant container* (see Step 12).

* Not included in the carton.

Check the labeling carefully.

Check the expiration date.

Make sure you have the correct medication and the correct dose.

Do not use the syringe after the expiration date printed on the label.

Step 3. Inspection

Inspect the solution through the syringe viewing window: check if the solution is clear, if the liquid is colorless or has a light yellow tint.

Note: You may notice air bubbles; this is normal.

Do not use the syringe if the liquid has changed color or become cloudy, or if it contains visible flakes or particles.

Step 4. Wait 30 min

Place the syringe on a flat surface for at least 30 minutes; allow the syringe to warm up to room temperature.

Do not heat the syringe.

Do not expose the syringe to direct sunlight.

The syringe must not be stored at room temperature for more than 14 days.

Step 5. Injection site selection

Select the injection site.

You can inject into the outer thigh or the front of the abdomen, except for the area within a 5 cm diameter directly around the navel.

If the injection is administered by another person, the skin area on the upper arm can also be used for injection.

Dupixent^® injections should not be administered into areas with painful or damaged skin, bruising, or scarring.

Step 6. Injection site preparation

Wash your hands.

Wipe the skin area intended for injection with an alcohol wipe.

Allow the skin to dry before injection.

Do not touch the prepared skin area with your hands or blow on it before injection.

Step 7. Needle cap removal

Hold the syringe by the middle of the barrel, with the needle pointing away from you; remove the needle cap.

Do not recap the needle.

Do not touch the needle.

The medication must be administered immediately after removing the needle cap.

Step 8. Skin pinch formation

Pinch the skin at the injection site as shown in the picture.

Step 9. Needle insertion

Insert the needle completely into the pinched skin at an angle of approximately 45°.

Step 10. Solution administration

Release the skin pinch.

Slowly and continuously press the plunger rod to inject the entire solution until the syringe is empty.

Note: You will feel some resistance. This is normal.

Step 11. Completing the injection and needle withdrawal

Lift your thumb, releasing pressure from the plunger rod, the needle will retract into the needle guard, and then remove the syringe from the injection site.

Gently press a cotton ball or gauze pad on the injection site if you notice blood.

Do not recap the needle.

Do not rub the skin after injection.

Step 12. Disposal

After use, place the syringe and needle cap into a puncture-resistant container.

Do not recap the needle.

Keep the container out of the reach of children.

Adverse Reactions

Atopic Dermatitis

The following classification is used to describe the frequency of adverse reactions: very common (≥10%); common (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); frequency not known (cannot be estimated from the available data).

Table 1. Adverse reactions observed in clinical trials in patients with atopic dermatitis^a

* Post-marketing data.

Description of selected adverse reactions

Conjunctivitis and keratitis related events

Conjunctivitis and keratitis were most frequently observed in atopic dermatitis patients treated with Dupixent^®. In most patients, conjunctivitis or keratitis resolved completely or partially during the treatment period. Among asthma patients, the frequency of conjunctivitis and keratitis was low and similar between the Dupixent^® and placebo groups. In chronic rhinosinusitis with nasal polyposis patients, the frequency of conjunctivitis was low, although the frequency in the Dupixent^® group was higher than in the placebo group. No cases of keratitis were reported in the clinical trial program in patients with chronic rhinosinusitis with nasal polyposis (see “Special Precautions” section).

Eczema herpeticum and Herpes zoster

In clinical trials in atopic dermatitis patients, the frequency of eczema herpeticum was similar between the groups receiving Dupixent^® and the placebo group. Based on 16-week monotherapy studies, Herpes zoster was reported in <0.1% of patients in the Dupixent^® group (<1 per 100 patient-years) and <1% in the placebo group (1 per 100 patient-years). In the 52-week clinical trial with concomitant topical corticosteroids (CHRONOS), Herpes zoster was reported in 1% of patients in the Dupixent^® + topical corticosteroids group (1 per 100 patient-years) and in 2% in the placebo group (2 per 100 patient-years). In clinical trials in asthma patients, the frequency of Herpes zoster was similar between the groups receiving Dupixent^® or placebo.

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis and serum sickness or serum sickness-like reactions, have been reported (see “Contraindications” and “Special Precautions” sections).

Eosinophils

Patients treated with Dupixent^® had a higher mean initial increase from baseline in eosinophils compared to patients receiving placebo. Eosinophil counts decreased to near baseline levels during the study. In the open-label extension study in asthma patients, eosinophil counts continued to decrease below baseline.

The frequency of treatment-emergent eosinophilia (≥500 cells/μL) was similar between patients receiving Dupixent^® and placebo. Treatment-emergent eosinophilia (≥5000 cells/μL) was reported in less than 2% of patients receiving Dupixent^® and less than 0.5% of patients receiving placebo.

Infections

The number of serious infections in patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis was comparable between patients taking Dupixent^® and placebo.

In the primary safety clinical trials of atopic dermatitis patients, no increase in the overall frequency of infections or serious infections was observed during treatment with Dupixent^® compared to placebo. In the 16-week primary safety clinical trials, which involved Dupixent^® monotherapy, serious infections were reported in 0.5% of patients receiving Dupilumab and in 1.0% of patients receiving placebo. In the 52-week CHRONOS study, serious infections were reported in 0.2% of patients receiving Dupixent^® and in 0.6% of patients receiving placebo.

In clinical trials in asthma patients, no increase in the overall frequency of infections or serious infections was observed during treatment with Dupixent^® compared to placebo. In the 24-week clinical trial, serious infections were reported in 1.0% of patients receiving Dupilumab and in 1.1% of patients receiving placebo. In the 52-week QUEST study, serious infections were reported in 1.3% of patients receiving Dupilumab and in 1.4% of patients receiving placebo.

In clinical trials in patients with chronic rhinosinusitis with nasal polyposis, no increase in the overall frequency of infections was observed. In the 24-week clinical trial, serious infections were reported in 0.7% of patients receiving Dupixent^® and in 1.1% of patients receiving placebo.

During the 52-week SINUS-52 study, infections were reported in 1.3% of patients receiving Dupilumab and in 1.3% of patients receiving placebo.

Cardiovascular events

In the 1-year placebo-controlled trial in asthma patients (QUEST), cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 case (0.2%) in the group of patients receiving Dupixent^® 200 mg every 2 weeks; in 4 cases (0.6%) in the group of patients receiving Dupixent^® 300 mg every 2 weeks and in 2 cases (0.3%) in the placebo group. In the 1-year placebo-controlled trial in atopic dermatitis patients (CHRONOS), cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 case (0.9%) in the group of patients receiving Dupixent^® 300 mg every 2 weeks + topical corticosteroids; in 0 cases (0.0%) in the group of patients receiving Dupixent^® 300 mg every week + topical corticosteroids and in 1 case (0.3%) in the placebo + topical corticosteroids group.

Immunogenicity

As with all therapeutic proteins, Dupixent^® has the potential for immunogenicity.

Approximately 5% of atopic dermatitis, asthma, or chronic rhinosinusitis with nasal polyposis patients who received Dupixent^® at a dose of 300 mg every 2 weeks for 52 weeks developed anti-duplimab antibodies (ADA); approximately 2% of patients had persistent ADA and approximately 2% had neutralizing antibodies. Similar results were observed in pediatric patients (6 to 11 years) with atopic dermatitis who received Dupixent^® at a dose of 200 mg every 2 weeks or 300 mg every 4 weeks for 16 weeks.

Approximately 16% of adolescents with atopic dermatitis treated with Dupixent^® at a dose of 300 mg or 200 mg every 2 weeks for 16 weeks developed antibodies to dupilumab; approximately 3% had a persistent ADA response, and approximately 5% of patients had neutralizing antibodies.

Approximately 9% of asthma patients who received Dupixent^® at a dose of 200 mg every 2 weeks for 52 weeks developed antibodies to dupilumab; approximately 4% had persistent ADA and approximately 4% had neutralizing antibodies.

Regardless of age and population, approximately 2-4% of patients in the placebo groups in the 52-week studies had antibodies to dupilumab; approximately 2% had persistently positive antibodies and approximately 1% had neutralizing antibodies.

The antibody response generally did not affect the systemic exposure, safety, or efficacy of Dupixent^®. Less than 1% of patients receiving Dupixent^® at the registered dose had high titers of anti-drug antibodies associated with reduced systemic exposure and efficacy. Additionally, one patient had serum sickness and another had a serum sickness-like reaction (<0.1%), associated with high antibody titers (see "Special Precautions" section).

The observed incidence of persistent ADA and neutralizing activity is highly dependent on the sensitivity and specificity of the assay used. Furthermore, the observed incidence of ADA positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease status in each individual case. For these reasons, comparison of the incidence of antibodies to dupilumab with the incidence of antibodies to other products may be misleading.

Contraindications

Hypersensitivity to dupilumab or to any of the excipients.

Children under 6 years of age with moderate-to-severe atopic dermatitis and moderate-to-severe asthma due to unestablished efficacy and safety.

Children under 12 years of age with moderate-to-severe asthma due to unestablished efficacy and safety.

With caution

During pregnancy (only if the expected benefit outweighs the potential risk to the fetus).

Use in Pregnancy and Lactation

Pregnancy

There are limited data on the use of dupilumab in pregnant women. In animal studies, no direct or indirect adverse effects regarding reproductive toxicity were found. Dupixent^® should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding Period

It is not known whether Dupilumab is excreted in human breast milk. Considering the benefits of breastfeeding for the child and the advantages of continued use of the drug for the mother, a decision should be made to either discontinue breastfeeding or discontinue Dupixent^® during the breastfeeding period.

Use in Hepatic Impairment

No data are available on the use of the drug in patients with hepatic impairment.

Use in Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment. There are no data on the use of the drug in patients with severe renal impairment.

Pediatric Use

Contraindications: children under 6 years of age in patients with moderate-to-severe atopic dermatitis and moderate-to-severe asthma due to unestablished efficacy and safety; children under 12 years of age in patients with moderate-to-severe asthma due to unestablished efficacy and safety.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Hypersensitivity

If a systemic hypersensitivity reaction occurs, treatment with Dupixent^® should be discontinued immediately and appropriate therapy initiated.

In clinical studies with Dupixent^® in atopic dermatitis, one case of serum sickness-like reaction and one case of serum sickness after drug administration were reported (both adverse reactions were considered serious). In a study with the drug in asthma, one case of anaphylaxis following administration of Dupixent^® was reported (see section “Adverse Reactions”).

Conjunctivitis and Keratitis-related Conditions

Conjunctivitis and keratitis-related conditions were more common in patients with atopic dermatitis treated with Dupixent^®. Some patients experienced visual disturbances (e.g., blurred vision) associated with conjunctivitis or keratitis (see section “Adverse Reactions”). Patients should report the first appearance or worsening of eye symptoms to their healthcare provider. Patients receiving Dupixent^® treatment who develop conjunctivitis that does not resolve after standard treatment or signs and symptoms of keratitis should undergo appropriate ophthalmological examination (see section “Adverse Reactions”).

Eosinophilic Conditions

In patients with asthma, serious systemic eosinophilia may develop, sometimes presenting with clinical signs of eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis, which are often treated with systemic corticosteroids. These events, generally but not always, may be associated with the reduction of oral corticosteroid use. Physicians should be vigilant for vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy occurring in their patients with eosinophilia. Cases of eosinophilic pneumonia and vasculitis consistent with eosinophilic granulomatosis with polyangiitis were reported with the use of Dupixent^® in adult patients who participated in a clinical trial of the drug for asthma. A causal relationship between the use of Dupixent^® and these conditions has not been established.

Symptoms of Asthma Exacerbation or Worsening Condition

Dupixent^® should not be prescribed for the treatment of acute worsening or exacerbations of asthma. Dupixent^® is not used to treat acute bronchospasm or status asthmaticus.

Corticosteroid Dose Reduction

The use of systemic, topical, or inhaled corticosteroids should not be abruptly discontinued after initiation of therapy with Dupixent^®. Corticosteroid dose reduction, if necessary, should be gradual and performed under the direct supervision of a physician. Corticosteroid dose reduction may be accompanied by systemic withdrawal symptoms and/or manifestation of conditions that were previously not apparent due to systemic corticosteroid therapy.

Helminth Infections

Patients with identified helminth infections were not included in clinical studies. It is not known whether Dupixent^® can affect the immune response to helminth infections. Patients with existing helminth infections should be treated prior to initiating treatment with Dupixent^®. If a patient becomes infected with helminths during treatment with Dupixent^® and anti-helminth drugs are ineffective, treatment with Dupixent^® should be discontinued until the parasitic infection is resolved.

Concomitant Atopic Conditions

Patients with atopic dermatitis or CRSwNP and concomitant asthma should be advised not to change their treatment without consulting their healthcare provider. When discontinuing treatment with Dupixent^®, potential effects on the course of other atopic conditions should be taken into account.

Effect on Ability to Drive and Use Machines

Dupixent^® has no or negligible influence on the ability to drive and operate machinery.

Overdose

In clinical studies, no safety concerns were identified with single intravenous administration at doses up to 12 mg/kg.

Treatment There is no specific antidote for overdose with Dupixent^®. In case of overdose, the patient’s condition should be monitored for the timely detection of signs and symptoms of adverse events, and appropriate symptomatic treatment should be initiated immediately.

Drug Interactions

Live Vaccines

The use of Dupixent^® with live vaccines has not been studied. Vaccination with live vaccines should not be administered during treatment with Dupixent^®.

Non-live (Inactivated) Vaccines

Immune responses to vaccination were studied in a trial where patients with atopic dermatitis received Dupixent^® 300 mg weekly for 16 weeks. After 12 weeks of dupilumab therapy, patients were vaccinated with Tdap vaccine (T-cell dependent, Adacel^®) and meningococcal polysaccharide vaccine (T-cell independent, Menomune^®), and immune responses were assessed after 4 weeks. In patients receiving both dupilumab and placebo, antibody response rates to tetanus and meningococcal polysaccharide vaccines were similar. No undesirable interactions between either of these non-live vaccines and dupilumab were found in this study.

Interaction with CYP450 Isoenzyme Substrates

In a clinical study conducted in patients with atopic dermatitis, the effects of dupilumab on the pharmacokinetics of CYP isoenzyme substrates were evaluated. Data from this study do not indicate a clinically significant effect of dupilumab on the activity of CYP1A2, CYP3A, CYP2C19, CYP2D6, or CYP2C9 isoenzymes.

Interaction with Other Drugs for Asthma Treatment

An effect of dupilumab on the pharmacokinetics of co-administered drugs is not expected. Data from a population analysis do not indicate an effect of co-administered drugs on the pharmacokinetics of dupilumab in patients with moderate-to-severe asthma.

Storage Conditions

The drug should be stored out of the reach of children, in the original package to protect from light, at a temperature between 2°C (35.6°F) and 8°C (46.4°F); do not freeze.

Shelf Life

Shelf life is 36 months. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.