Dupixent

Dupilumab.

Each single-use pre-filled syringe with needle shield contains 300 mg dupilumab in 2 mL solution.
DUPIXENT is a fully human monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling by specifically binding to the IL-4Rα subunit of the IL-4 and IL-13 receptor complexes. DUPIXENT inhibits IL-4 signaling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα).
Dupilumab is produced by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture.
Dupilumab is a covalent heterotetramer consisting of two disulfide-linked human heavy chains, each covalently linked through a disulfide bond to a human kappa light chain. There is a single N-linked glycosylation site in each heavy chain, located within the CH2 domain of the Fc constant region of the molecule. The DUPIXENT heavy chain has an immunoglobulin (Ig) G4P isotype constant region. IgG4P is an IgG4 constant region with a single amino acid substitution in the hinge region that recreates the IgG1 hinge sequence in order to stabilize IgG4 dimer formation. The variable domains of the heavy and light chains combine to form the IL-4Rα binding site within the antibody.
Dupilumab has a molecular weight of approximately 147 kDa.
Excipients/Inactive Ingredients: Arginine hydrochloride, histidine, polysorbate 80, sodium acetate trihydrate, glacial acetic acid, sucrose, water for injections.

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excluding corticosteroids. ATC code: D11AH05.
Pharmacology: Pharmacodynamics: Mechanism of action: Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling. Dupilumab inhibits IL-4 signaling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). IL-4 and IL-13 are major drivers of human type 2 inflammatory disease, such as atopic dermatitis. Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of the mediators of type 2 inflammation.
Pharmacodynamic effects: In atopic dermatitis clinical trials, treatment with dupilumab was associated with decreases from baseline in concentrations of type 2 immunity biomarkers, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE and allergen-specific IgE in serum. A reduction of lactate dehydrogenase (LDH), a biomarker associated with AD disease activity and severity, was observed with dupilumab treatment.
In asthma clinical trials, dupilumab treatment markedly decreased FeNO and circulating concentrations of eotaxin-3, total IgE, allergen specific IgE, TARC, and periostin in asthma subjects relative to placebo. These reductions in type 2 inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment.
Clinical efficacy and safety in atopic dermatitis: Adults with atopic dermatitis: The efficacy and safety of dupilumab as monotherapy and with concomitant topical corticosteroids were evaluated in three pivotal randomised, double-blind, placebo-controlled studies (SOLO 1, SOLO 2, and CHRONOS) in 2,119 patients 18 years of age and older with moderate to severe atopic dermatitis (AD) defined by Investigator's Global Assessment (IGA) score ≥ 3, an Eczema Area and Severity Index (EASI) score ≥16, and a minimum body surface area (BSA) involvement of ≥10%. Eligible patients enrolled into the three studies had previous inadequate response to topical medication.
In all three studies, patients received an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg once every two weeks (Q2W); an initial dose of 600 mg dupilumab on day 1, followed by 300 mg once weekly (QW); or matching placebo. Dupilumab was administered by subcutaneous (SC) injection in all studies. If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment (which included higher potency topical steroids or systemic immunosuppressants) at the discretion of the investigator. Patients who received rescue treatment were considered non-responders.
SOLO 1 enrolled 671 patients (224 to placebo, 224 to dupilumab 300 mg Q2W, and 223 to dupilumab 300 mg QW) and had a treatment period of 16 weeks.
SOLO 2 enrolled 708 patients (236 to placebo, 233 to dupilumab 300 mg Q2W, and 239 to dupilumab 300 mg QW) and had a treatment period of 16 weeks.
CHRONOS enrolled 740 patients (315 to placebo + topical corticosteroid (TCS), 106 to dupilumab 300 mg Q2W + TCS, and 319 to dupilumab 300 mg QW + TCS) and had a treatment period of 52 weeks. Patients received dupilumab or placebo with concomitant use of TCS starting at baseline using a standardized regimen. Patients were also permitted to use topical calcineurin inhibitors (TCI).
Endpoints: In all three pivotal studies, the co-primary endpoints were the proportion of patients with IGA 0 or 1 ("clear" or "almost clear") with a reduction of ≥ 2 points on a 0-4 IGA scale and the proportion of patients with improvement of at least 75% in EASI (EASI-75) from baseline to week 16. Other evaluated outcomes included the proportion of patients with improvement of at least 50% and 90% in EASI (EASI-50 and EASI-90, respectively), reduction in itch as measured by the peak pruritus Numerical Rating Scale (NRS), and percent change in the SCORing Atopic Dermatitis (SCORAD) scale from baseline to week 16. Additional secondary endpoints included mean change from baseline to week 16 in the Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index(DLQI), and Hospital Anxiety and Depression Scale (HADS) scores. In CHRONOS, efficacy was also evaluated at week 52.
Baseline Characteristics: In the monotherapy studies (SOLO 1 and SOLO 2), across all treatment groups, the mean age was 38.3, the mean weight was 76.9 kg, 42.1% were female, 68.1% were white, 21.8% were Asian, and 6.8% were black. In these studies, 51.6% of patients had a baseline IGA score of 3 (moderate AD), 48.3% of patients had a baseline IGA of 4 (severe AD) and 32.4% of patients had received prior systemic immunosuppressants. The baseline mean EASI score was 33.0, the baseline weekly averaged pruritus NRS was 7.4, the baseline mean SCORAD score was 67.8, the baseline mean POEM score was 20.5, the baseline mean DLQI was 15.0, and the baseline mean HADS total score was 13.3.
In the concomitant TCS study (CHRONOS), across all treatment groups, the mean age was 37.1, the mean weight was 74.5 kg, 39.7% were female, 66.2% were white, 27.2% were Asian, and 4.6% were black. In this study, 53.1% of patients had a baseline IGA score of 3 and 46.9% of patients had a baseline IGA of 4 and 33.6% of patients received prior systemic immunosuppressants. The baseline mean EASI score was 32.5, the baseline weekly pruritus NRS was 7.3, the baseline mean SCORAD score was 66.4, the baseline mean POEM score was 20.1, the baseline mean DLQI was 14.5, and the baseline mean HADS total score was 12.7.
Clinical Response: 16-Week Monotherapy Studies (SOLO 1 and SOLO 2): In SOLO 1 and SOLO 2, from baseline to week 16, a significantly greater proportion of patients randomized to dupilumab achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of ≥4 points on the pruritus NRS compared to placebo (see Table 1).
A significantly greater proportion of patients randomized to dupilumab achieved a rapid improvement in the pruritus NRS compared to placebo (defined as ≥ 4-point improvement as early as week 2; p < 0.01) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period. The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.
Figure 1 and Figure 2 show the mean percent change from baseline in EASI and the mean percent change from baseline in NRS, respectively up to week 16. (See Table 1 and Figures 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

52-Week Concomitant TCS Study (CHRONOS): In CHRONOS, a significantly greater proportion of patients randomized to dupilumab 300 mg Q2W + TCS achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of ≥ 4 points on the pruritis NRS from baseline to week 16 and week 52 compared to placebo + TCS (see Table 2).
A significantly greater proportion of patients randomized to dupilumab + TCS achieved a rapid improvement in the pruritus NRS compared to placebo + TCS (defined as ≥4-point improvement as early as week 2; p < 0.05) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period. The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.
Figure 3 and Figure 4 show the mean percent change from baseline in EASI and the mean percent change from baseline in NRS, respectively, up to week 52 in CHRONOS. (See Table 2 and Figures 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Treatment effects in subgroups (weight, age, gender, race, and background treatment, including immunosuppressants) in CHRONOS were consistent with the results in the overall study population.
Clinical Response in Patients Not Adequately Controlled with, Intolerant to, or for whom Ciclosporin Treatment was Inadvisable (CAFE study): CAFE study evaluated the efficacy of dupilumab compared to placebo during a 16-week treatment period, administered with concomitant TCS, in adult patients with AD who are not adequately controlled with, or are intolerant to, oral ciclosporin, or when this treatment is currently contraindicated or not medically advisable.
A total of 325 patients were enrolled, with 210 patients who were previously exposed to ciclosporin and 115 patients who have never been exposed to ciclosporin because ciclosporin treatment was medically inadvisable. The mean age was 38.4 years, 38.8% were female, the baseline mean EASI score was 33.1, the mean BSA was 55.7, the baseline weekly average pruritis NRS was 6.4, the baseline mean SCORAD score was 67.2, and the baseline mean DLQI was 13.8.
The primary endpoint was the proportion of patients with EASI-75 at week 16.
Primary and secondary endpoints for the 16 week CAFE study are summarized in Table 3. (See Table 3.)

Click on icon to see table/diagram/image

In the subgroup of patients resembling the CAFE study population within the 52 week CHRONOS study, 69.6% of dupilumab 300 mg Q2W-treated patients reached EASI-75 vs 18.0% placebo-treated patients at week 16, and 52.4% of dupilumab 300 mg Q2W-treated vs 18.6% placebo-treated at week 52. In this subset, the percent change of pruritus NRS from baseline was -51.4% vs -30.2% at week 16 and -54.8% vs -30.9% at week 52, for the dupilumab 300 mg Q2W and placebo groups respectively.
Maintenance and Durability of Response (SOLO CONTINUE study): To evaluate maintenance and durability of response, subjects treated with dupilumab for 16 weeks in SOLO 1 and SOLO 2 studies who achieved IGA 0 or 1 or EASI-75 were re-randomized in SOLO CONTINUE study to an additional 36-week treatment of dupilumab or placebo, for a cumulative 52-week study treatment. Endpoints were assessed at weeks 51 or 52.
The co-primary endpoints were the difference between baseline (week 0) and week 36 in percent change in EASI from SOLO 1 and SOLO 2 studies baseline and percentage of patients with EASI-75 at week 36 in patients with EASI-75 at baseline.
Patients who continued on the same dose regimen received in the SOLO 1 and SOLO 2 studies (300 mg Q2W or 300 mg QW) showed the optimal effect in maintaining clinical response while efficacy for other dose regimens diminished in a dose-dependent manner.
Primary and secondary endpoints for the 52 week SOLO CONTINUE study are summarized in Table 4. (See Table 4.)

Click on icon to see table/diagram/image

In SOLO CONTINUE, a trend for increased treatment-emergent ADA positivity with increased dosing intervals was observed. Treatment-emergent ADA: QW: 1.2%; Q2W: 4.3%; Q4W: 6.0%; Q8W: 11.7%. ADA responses lasting more than 12 weeks: QW: 0.0%; Q2W: 1.4%; Q4W: 0.0%; Q8W: 2.6%.
Quality of Life/Patient-Reported Outcomes in Atopic Dermatitis: In both monotherapy studies (SOLO 1 and SOLO 2), both dupilumab 300 mg Q2W and 300 mg QW groups significantly improved patient-reported symptoms and the impact of AD on sleep and health-related quality of life as measured by POEM and DLQI total scores, respectively, at 16 weeks compared to placebo. A significantly larger proportion of patients administered dupilumab groups had clinically meaningful reductions in POEM and DLQI total score (each defined as ≥ 4 points improvement) from baseline to week 16 compared to placebo group. In addition, anxiety and depression symptoms as measured by the HADS total score were significantly reduced in the dupilumab groups compared to placebo at 16 weeks. In a subset of patients with HADS-anxiety or HADS-depression subscale scores ≥ 8 at baseline (the cut-off value for anxiety or depression), a larger proportion of patients in the dupilumab groups achieved HADS-anxiety and HADS-depression scores < 8 at week 16 compared to placebo (See Table 5).

Click on icon to see table/diagram/image

In the concomitant TCS study (CHRONOS), dupilumab 300 mg Q2W + TCS and dupilumab 300 mg QW + TCS improved patient-reported symptoms and the impact of AD on sleep and health-related quality of life as measured by POEM and DLQI total scores, respectively, at 52 weeks compared to placebo + TCS. A larger proportion of patients administered dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS had clinically meaningful reductions in POEM and DLQI total score (each defined as ≥ 4-point improvement) from baseline to week 52 compared to the placebo + TCS. In addition, dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS reduced anxiety and depression as measured by the HADS total score at 52 weeks compared to placebo + TCS. In a post-hoc analysis in a subset of patients with HADS-anxiety or HADS-depression subscale scores ≥8 at baseline (the cut-off value for anxiety or depression), a larger proportion of patients in the dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS groups achieved HADS-anxiety and HADS-depression scores < 8 at week 52 compared to placebo + TCS (See Table 6).

Click on icon to see table/diagram/image

Adolescents with atopic dermatitis: The efficacy and safety of dupilumab monotherapy in adolescent patients was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1526) in 251 adolescent patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD) defined by Investigator's Global Assessment (IGA) score ≥3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area (BSA) involvement of ≥10%. Eligible patients enrolled into this study had previous inadequate response to topical medication.
Patients received an initial dose of 400 mg dupilumab (two 200 mg injections) on day 1, followed by 200 mg once every other week (Q2W) for patients with baseline weight of <60 kg or an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg Q2W for patients with baseline weight of ≥ 60 kg; an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg every 4 weeks (Q4W) regardless of baseline body weight; or matching placebo. Dupilumab was administered by subcutaneous (SC) injection. If needed to control intolerable symptoms, patients were permitted to receive rescue treatment at the discretion of the investigator. Patients who received rescue treatment were considered nonresponders.
In this study, the mean age was 14.5 years, the median weight was 59.4 kg, 41.0% were female, 62.5% were White, 15.1% were Asian, and 12.0% were Black. At baseline 46.2% of patients had a baseline IGA score of 3 (moderate AD), 53.8% of patients had a baseline IGA of 4 (severe AD), the mean BSA involvement was 56.5%, and 42.4% of patients had received prior systemic immunosuppressants. Also at baseline the mean Eczema Area and Severity Index (EASI) score was 35.5, the baseline weekly averaged pruritus Numerical Rating Scale (NRS) was 7.6, the baseline mean SCORing Atopic Dermatitis (SCORAD) score was 70.3, the baseline mean Patient Oriented Eczema Measure (POEM) score was 21.0, and the baseline mean Children Dermatology Life Quality Index (CDLQI) was 13.6. Overall, 92.0% of patients had at least one co-morbid allergic condition; 65.6% had allergic rhinitis, 53.6% had asthma, and 60.8% had food allergies. The co-primary endpoint was the proportion of patients with IGA 0 or 1 ("clear" or "almost clear") least a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least 75% in EASI), from baseline to week 16. Other evaluated outcomes included the proportion of subjects with EASI-50 or EASI-90 (improvement of at least 50% or 90% in EASI from baseline respectively), reduction in itch as measured by the peak pruritus NRS, and percent change in the SCORAD scale from baseline to week 16. Additional secondary endpoints included mean change from baseline to week 16 in the POEM and CDLQI scores.
Clinical Response: The efficacy results at week 16 for adolescent atopic dermatitis study are presented in Table 7. (See Table 7.)

Click on icon to see table/diagram/image

A larger percentage of patients randomised to placebo needed rescue treatment (topical corticosteroids, systemic corticosteroids, or systemic non-steroidal immunosuppressants) as compared to the dupilumab group (58.8% and 20.7%, respectively).
A significantly greater proportion of patients randomised to dupilumab achieved a rapid improvement in the pruritus NRS compared to placebo (defined as >4-point improvement as early as week 4; nominal p<0.001) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period (see Figure 5). The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis. (See Figure 5.)

Click on icon to see table/diagram/image

The dupilumab group significantly improved patient-reported symptoms, the impact of AD on sleep and health-related quality of life as measured by POEM, SCORAD, and CDLQI scores at 16 weeks compared to placebo.
The long-term efficacy of dupilumab in adolescent patients with moderate-to-severe AD who had participated in previous clinical trials of dupilumab was assessed in open-label extension study (AD-1434). Efficacy data from this study suggests that clinical benefit provided at week 16 was sustained through week 52.
Clinical efficacy and safety in asthma: The asthma development program included three randomised, double-blind, placebo-controlled, parallel-group, multi-centre studies (DRI12544, QUEST, and VENTURE) of 24 to 52 weeks in treatment duration which enrolled a total of 2,888 patients (12 years of age and older). Patients were enrolled without requiring a minimum baseline blood eosinophil or other type 2 inflammatory biomarker (e.g. FeNO or IgE) level. Asthma treatment guidelines define type 2 inflammation as eosinophilia ≥ 150 cells/mcL and/or FeNO ≥ 20 ppb. In DRI12544 and QUEST, the pre-specified subgroup analyses included blood eosinophils ≥ 150 and ≥ 300 cells/mcL, FeNO ≥ 25 and ≥ 50 ppb.
DRI12544 was a 24-week dose-ranging study which included 776 patients (18 years of age and older). Dupilumab compared with placebo was evaluated in adult patients with moderate to severe asthma on a medium-to-high dose inhaled corticosteroid and a long acting beta agonist. The primary endpoint was change from baseline to week 12 in FEV1 (L). Annualized rate of severe asthma exacerbation events during the 24-week placebo controlled treatment period was also determined. Results were evaluated in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophils count.
Dupilumab compared with placebo was evaluated in 107 adolescent and 1,795 adult patients with persistent asthma on a medium-to-high dose inhaled corticosteroid (ICS) and a second controller medication. Patients requiring a third controller were allowed to participate in this trial. Patients were randomised to receive either 200 mg (N=631) or 300 mg (N=633) Dupixent every other week (or matching placebo for either 200 mg (N = 317) or 300 mg (N= 321) every other week) following an initial dose of 400 mg, 600 mg or placebo respectively. The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo controlled period and change from baseline in pre-bronchodilator FEV1 at week 12 in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophils and FeNO.
VENTURE was a 24-week oral corticosteroid-reduction study in 210 patients with asthma unrestricted by baseline type 2 biomarker levels who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, patients received 300 mg dupilumab (n=103) or placebo (n=107) once every other week for 24 weeks following an initial dose of 600 mg or placebo. Patients continued to receive their existing asthma medicine during the study; however their OCS dose was reduced every 4 weeks during the OCS reduction phase (week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction in oral corticosteroid dose assessed in the overall population, based on a comparison of the oral corticosteroid dose at weeks 20 to 24 that maintained asthma control with the previously optimized (at baseline) oral corticosteroid dose.
The demographics and baseline characteristics of these 3 studies are provided in Table 8 as follows. (See Table 8.)

Click on icon to see table/diagram/image

Exacerbations: In the overall population in DRI12544 and QUEST subjects receiving either dupilumab 200 mg or 300 mg every other week had significant reductions in the rate of severe asthma exacerbations compared to placebo. There were greater reductions in exacerbations in subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (see Table 9 and Table 10).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In the pooled analysis of DRI12544 and QUEST, hospitalizations and/or emergency room visits due to severe exacerbations were reduced by 25.5% and 46.9% with dupilumab 200 mg or 300 mg every other week, respectively.
Lung Function: Clinically significant increases in pre-bronchodilator FEV₁ were observed at week 12 for DRI12544 and QUEST. There were greater improvements in FEV₁ in the subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 11 and Table 12).
Significant improvements in FEV₁ were observed as early as week 2 following the first dose of dupilumab for both the 200 mg and 300 mg dose strengths and were maintained through week 24 (DRI12544) and week 52 in QUEST (see Figure 6). (See Figure 6 and Tables 11 and 12.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Quality of Life/Patient-Reported Outcomes in Asthma: Pre-specified secondary endpoint of ACQ-5 and AQLQ(S) responder rates were analysed at 24 weeks (DRI12544 and VENTURE) and at 52 weeks (QUEST). The responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-5 and 1-7 for AQLQ(S)). Improvements in ACQ-5 and AQLQ(S) were observed as early as week 2 and maintained for 24 weeks in DRI12544 study and 52 weeks in QUEST study. Similar results were observed in VENTURE. The ACQ-5 and AQLQ(S) responder rate results in patients with elevated baseline biomarkers of type 2 inflammation in QUEST at week 52 are presented in Table 13. (See Table 13.)

Click on icon to see table/diagram/image

Oral Corticosteroid Reduction Study (VENTURE): VENTURE evaluated the effect of dupilumab on reducing the use of maintenance oral corticosteroids. Baseline characteristics are presented in Table 8. All patients were on oral corticosteroids for at least 6 months prior to the study initiation. The baseline mean oral corticosteroid use was 11.75 mg in the placebo group and 10.75 mg in the group receiving dupilumab.
In this 24-week trial, asthma exacerbations (defined as a temporary increase in oral corticosteroid dose for at least 3 days) were reduced by 59% in subjects receiving dupilumab compared with those receiving placebo (annualized rate 0.65 and 1.60 for the dupilumab and placebo group, respectively; rate ratio 0.41 [95% CI 0.26, 0.63]) and improvement in pre-bronchodilator FEV₁ from baseline to week 24 was greater in subjects receiving dupilumab compared with those receiving placebo (LS mean difference for dupilumab versus placebo of 0.22 L [95% CI: 0.09 to 0.34 L]). Effects on lung function, on oral steroid and exacerbation reduction were similar irrespective of baseline levels of type 2 inflammatory biomarkers (e.g. blood eosinophils, FeNO). The ACQ-5 and AQLQ(S) were also assessed in VENTURE and showed improvements similar to those in QUEST.
The results for VENTURE by baseline biomarkers are presented in Table 14. (See Table 14.)

Click on icon to see table/diagram/image

Long-term extension trial (TRAVERSE): The long-term efficacy of Dupilumab in 2282 adults and adolescents with moderate-to-severe asthma, and adults with oral corticosteroid-dependent asthma, who had participated in previous clinical trials of Dupilumab, was assessed in the open-label extension study (TRAVERSE). In this study, the clinical benefit of Dupilumab, including reduction in exacerbations and improvement in lung function, was sustained up to 96 weeks. In the population with oral-corticosteroid-dependent asthma, there was sustained reduction in exacerbations and maintained improvement in lung function, despite continued decrease or discontinuation of oral corticosteroid dose up to 96 weeks. Similar maintenance of effect was also observed for ACQ-5 and AQLQ(S) at week 48 (see Table 15). Consistent results were also observed in the subgroup of patients on high dose ICS. (See Table 15.)

Click on icon to see table/diagram/image

Paediatric population: A total of 107 adolescents aged 12 to 17 years with moderate to severe asthma were enrolled in QUEST study and received either 200 mg (N=21) or 300 mg (N=18) dupilumab (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) every other week. Efficacy with respect to severe asthma exacerbations and lung function was observed in both adolescents and adults. For both the 200 mg and 300 mg every other week doses, significant improvements in FEV₁ (LS mean change from baseline at week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg every other week dose, patients had a reduction in the rate of severe exacerbations that was consistent with adults. Safety and efficacy in paediatric patients (< 12 years of age) with severe asthma have not been established. The adverse event profile in adolescents was generally similar to the adults.
The European Medicines Agency has deferred the obligation to submit the results of studies with dupilumab in one or more subset of the paediatric population in atopic dermatitis and asthma (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: The pharmacokinetics of dupilumab is similar in patients with atopic dermatitis and asthma.
Absorption: After a single subcutaneous (SC) dose of 75-600 mg dupilumab, median times to maximum concentration in serum (t_max) were 3-7 days. The absolute bioavailability of dupilumab following a SC, ranging between 61% and 64%, as determined by a population pharmacokinetics (PK) analysis.
Steady-state concentrations were achieved by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 73.3±40.0 mcg/mL to 79.9±41.4 mcg/mL for 300 mg dose administered every other week.
Distribution: A volume of distribution for dupilumab of approximately 4.6 L was estimated by population PK analysis, indicating that dupilumab is distributed primarily in the vascular system.
Biotransformation: Specific metabolism studies were not conducted because dupilumab is a protein. Dupilumab is expected to degrade to small peptides and individual amino acids.
Elimination: Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable IL-4R α target-mediated elimination predominates.
After the last steady state dose, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, was 10 weeks for the 300 mg Q2W regimen and 13 weeks for the 300 mg QW regimen.
Linearity/non-linearity: Due to nonlinear clearance, dupilumab exposure, as measured by area under the concentration-time curve, increases with dose in a greater than proportional manner following single SC doses from 75-600 mg.
Special populations: Gender: Gender was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis.
Elderly patients: Of the 1,472 patients with atopic dermatitis exposed to dupilumab in a phase 2 dose-ranging study or phase 3 placebo-controlled studies, a total of 67 were 65 years or older. Although no differences in safety or efficacy were observed between older and younger adult atopic dermatitis patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
Age was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis. However, there were only 61 patients over 65 years of age included in this analysis.
Of the 1,977 patients with asthma exposed to dupilumab, a total of 240 patients were 65 years or older and 39 patients were 75 years or older. Efficacy and safety in this age group were similar to the overall study population.
Race: Race was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab by population PK analysis.
Hepatic impairment: Dupilumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of dupilumab.
Renal impairment: Dupilumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of dupilumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of dupilumab. Very limited data are available in patients with severe renal impairment.
Body Weight: Dupilumab trough concentrations were lower in subjects with higher body weight with no meaningful impact on efficacy.
Paediatric population: The pharmacokinetics of dupilumab in paediatric patients (< 12 years of age) with atopic dermatitis has not been studied.
For adolescents 12 to 17 years of age with atopic dermatitis receiving every other week dosing (Q2W) with either 200 mg (<60 kg) or 300 mg (≥60 kg), the mean ±SD steady state trough concentration of dupilumab was 54.5±27.0 mcg/ml.
A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in QUEST study. The mean ±SD steady-state trough concentrations of dupilumab were 107±51.6 mcg/mL and 46.7±26.9 mcg/mL, respectively, for 300 mg or 200 mg administered every other week. No age-related pharmacokinetic difference was observed in adolescent patients after correction for body weight.
The long-term safety and efficacy of Dupilumab was assessed in 89 adolescent patients who were enrolled in an open-label extension study in moderate-to-severe asthma (TRAVERSE). In this study, patients were followed for up to 96 weeks, resulting in 99 patient-years cumulative exposure to Dupilumab. The safety profile of Dupilumab in TRAVERSE was consistent with the safety profile observed in asthma pivotal studies for up to 52 weeks of treatment. No additional adverse reactions were identified. In this study, the clinical benefit of Dupilumab, including reduction in exacerbations and improvement in lung function observed in pivotal asthma studies, was sustained up to 96 weeks
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints) and toxicity to reproduction and development.
The mutagenic potential of dupilumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with dupilumab. An evaluation of the available evidence related to IL-4Rα inhibition and animal toxicology data with surrogate antibodies does not suggest an increased carcinogenic potential for dupilumab.
During a reproductive toxicology study conducted in monkeys, using a surrogate antibody specific to the monkey IL-4Rα, no fetal abnormalities were observed at dosages that saturate the IL-4Rα.
An enhanced pre- and post-natal developmental study revealed no adverse effects in maternal animals or their offspring up to 6 months post-partum/post-birth.
Fertility studies conducted in male and female mice using a surrogate antibody against IL-4Rα showed no impairment of fertility (see Use in Pregnancy & Lactation).

Atopic Dermatitis: DUPIXENT is indicated for the treatment of patients aged 12 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. DUPIXENT can be used with or without topical corticosteroids.
Asthma: DUPIXENT is indicated as add on maintenance treatment in patients aged 12 years and older with moderate to severe asthma with type 2 inflammation (elevated eosinophils or elevated FeNO).

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of conditions for which dupilumab is indicated (see Indications/Uses).
Posology: Atopic dermatitis: Adults: The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week administered as subcutaneous injection.
Adolescents: The recommended dose of dupilumab for adolescent patients 12 to 17 years of age is specified in Table 16. (See Table 16.)

Click on icon to see table/diagram/image

Dupilumab can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas.
Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment for atopic dermatitis. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.
Patients receiving concomitant oral corticosteroids may reduce their steroid dose once clinical improvement with dupilumab has occurred (see Pharmacology: Pharmacodynamics under Actions). Steroid reductions should be accomplished gradually (see Precautions).
Asthma: The recommended dose of dupilumab for adults and adolescents (12 years of age and older) is: An initial dose of 400 mg (two 200 mg injections) followed by 200 mg given every other week.
The dose may be increased to 300 mg every other week based on physician assessment.
An initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week for patients with oral corticosteroids-dependent asthma or with co-morbid moderate-to-severe atopic dermatitis for which dupilumab is indicated.
Missed dose: If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
Special populations: Elderly patients (≥ 65 years): No dose adjustment is recommended for elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is needed in patients with mild or moderate renal impairment. Very limited data are available in patients with severe renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No data are available in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Body weight: No dose adjustment for body weight is recommended for patients with asthma 12 years of age and older or in adults with atopic dermatitis (see Pharmacology: Pharmacokinetics under Actions).
For patients 12 to 17 years of age with atopic dermatitis, the recommended every other week dose is 200 mg (< 60 kg) or 300 mg (≥ 60 kg).
Paediatric patients: The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 12 years have not been established (see Pharmacology: Pharmacokinetics under Actions). No data are available.
The safety and efficacy of dupilumab in children with severe asthma below the age of 12 years have not been established (see Pharmacology: Pharmacokinetics under Actions). No data are available.
Method of administration: Subcutaneous use.
Dupilumab is administered by subcutaneous injection into the thigh or abdomen, except for the 5 cm around the navel. If somebody else administers the injection, the upper arm can also be used.
For atopic dermatitis and asthma patients taking an initial 600 mg dose, administer two 300 mg dupilumab injections consecutively in different injection sites.
For asthma patients taking an initial 400 mg dose, administer two 200 mg dupilumab injections consecutively in different injection sites.
It is recommended to rotate the injection site with each injection. Dupilumab should not be injected into skin that is tender, damaged or has bruises or scars.
A patient may self-inject dupilumab or the patient's caregiver may administer dupilumab if their healthcare professional determines that this is appropriate. Proper training should be provided to patients and/or caregivers on the preparation and administration of dupilumab prior to use according to the Instructions for Use (IFU) section in the package leaflet.

There is no specific treatment for dupilumab overdose. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

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. This should be taken into consideration to determine type 2 status in patients taking oral corticosteroids (see Pharmacology: Pharmacodynamics under Actions).
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.
Hypersensitivity: If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of dupilumab should be discontinued immediately and appropriate therapy initiated. Hypersensitivity reactions, including anaphylaxis, serum sickness or serum sickness-like reactions and angioedema, have been reported (Adverse Reactions).
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 signaling. 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 antihelminth treatment, treatment with dupilumab should be discontinued until infection resolves.
Eosinophilic Conditions: 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. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients with eosinophilia. Cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis have been reported with dupilumab in adult patients who participated in the asthma development program. A causal association between dupilumab and these conditions has not been established.
Acute Asthma Symptoms or Deteriorating Disease: Dupilumab should not be used to treat acute asthma symptoms or acute exacerbations. Do not use dupilumab to treat acute bronchospasm or status asthmaticus.
Reduction of Corticosteroid Dosage: Do not discontinue systemic, topical, or inhaled corticosteroids 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.
Concomitant Atopic Conditions: Safety and efficacy have not been established in allergic or atopic conditions other than atopic dermatitis. Patients with comorbid atopic conditions (such as asthma) should be advised not to adjust their treatment without consultation with their physicians. When discontinuing DUPIXENT consider the potential effects on other atopic conditions.
Conjunctivitis and Keratitis related events: Conjunctivitis and keratitis related events have been reported with Dupilumab, predominantly in atopic dermatitis patients. Some patients reported visual disturbances (e.g. blurred vision) associated with conjunctivitis or keratitis (see Adverse Reactions).
Keratitis was reported in <1% of the DUPIXENT group (1 per 100 subject-years) and in 0% of the placebo group (0 per 100 subject-years) in the 16-week monotherapy trials. In the 52-week DUPIXENT + topical corticosteroids (TCS) trial, keratitis was reported in 4% of the DUPIXENT + TCS group (12 per 100 subject-years) and in 0% of the placebo + TCS group (0 per 100 subject years). Most subjects with keratitis recovered or were recovering during the treatment period (Adverse Reactions).
Advise patients to report new onset or worsening eye symptoms to their healthcare provider.
Patients treated with Dupilumab who develop conjunctivitis that does not resolve following standard treatment or signs and symptoms suggestive of keratitis should undergo ophthalmological examination, as appropriate (see Adverse Reactions).
Vaccinations: Live and live attenuated vaccines should not be given concurrently with dupilumab as clinical safety and efficacy has not been established. Immune responses to TdaP vaccine and meningococcal polysaccharide vaccine were assessed, see Interactions. 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.
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per 300 mg dose, i.e. essentially "sodium-free".
Effects on ability to drive and use machines: Dupilumab has no or negligible influence on the ability to drive or operate machinery.

Pregnancy: There are limited amount of data from the use of dupilumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Dupilumab should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Breast-feeding: It is unknown whether dupilumab is excreted in human milk or absorbed systemically after ingestion. A decision must be made whether to discontinue breast-feeding or to discontinue dupilumab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility: Animal studies showed no impairment of fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Atopic dermatitis: Adult with atopic dermatitis: Summary of the safety profile: The most common adverse reactions were injection site reactions, conjunctivitis, blepharitis, and oral herpes. Very rare cases of serum sickness/serum sickness-like reactions have been reported in the atopic dermatitis development program (see Precautions).
In the monotherapy studies, the proportion of patients who discontinued treatment due to adverse events was 1.9% of the placebo group, 1.9% of the dupilumab 300 mg Q2W group, 1.5% of the dupilumab 300 mg QW group. In the concomitant TCS study, the proportion of patients who discontinued treatment due to adverse events was 7.6% of the placebo + TCS group, 1.8% of the dupilumab 300 mg Q2W + TCS group, and 2.9% of the dupilumab 300 mg QW + TCS group.
Tabulated list of adverse reactions: The safety of dupilumab was evaluated in four randomized, double-blind, placebo-controlled studies and one dose-ranging study in patients with moderate-to-severe atopic dermatitis. In these 5 trials, 1,689 subjects were treated with subcutaneous injections of dupilumab, with or without concomitant topicalcorticosteroids (TCS). A total of 305 patients were treated with dupilumab for at least 1 year.
Listed in Table 17 are adverse reactions observed in atopic dermatitis clinical trials presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 17.)

Click on icon to see table/diagram/image

Adolescents with atopic dermatitis: The safety of dupilumab was assessed in a study of 250 patients 12 to 17 years of age with moderate to severe atopic dermatitis (AD-1526). The safety profile of dupilumab in these patients followed through week 16 was similar to the safety profile from studies in adults with atopic dermatitis.
The long-term safety of dupilumab was assessed in an open-label extension study in patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1434). The safety profile of dupilumab in patients followed through week 52 was similar to the safety profile observed at week 16 in AD-1526 study. The long-term safety profile of dupilumab observed in adolescents was consistent with that seen in adults with atopic dermatitis.
Asthma: Summary of the safety profile: The most common adverse reaction was injection site erythema. Anaphylactic reaction has been reported very rarely in the asthma development program (see Precautions).
In DRI12544 and QUEST studies, the proportion of patients who discontinued treatment due to adverse events was 4.3% of the placebo group, 3.2% of the dupilumab 200 mg Q2W group, and 6.1% of the dupilumab 300 mg Q2W group.
Tabulated list of adverse reactions: A total of 2,888 adult and adolescent patients with moderate-to-severe asthma were evaluated in 3 randomised, placebo-controlled, multicentre trials of 24 to 52 weeks duration (DRI12544, QUEST, and VENTURE). Of these, 2,678 had a history of 1 or more severe exacerbations in the year prior to enrolment despite regular use of medium-to-high dose inhaled corticosteroids plus an additional controller(s) (DRI12544 and QUEST). A total of 210 patients with oral corticosteroid-dependent asthma receiving high-dose inhaled corticosteroids plus up to two additional controllers were enrolled (VENTURE).
Listed in Table 18 are adverse reactions observed in asthma clinical trials presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 18.)

Click on icon to see table/diagram/image

Description of selected Adverse reactions: Hypersensitivity: Hypersensitivity reactions, including anaphylaxis and serum sickness or serum sickness-like reactions, have been reported (see Precautions).
Conjunctivitis and related events: Conjunctivitis occurred more frequently in atopic dermatitis patients who received dupilumab. Most patients with conjunctivitis or keratitis recovered or were recovering during the treatment period.
Among asthma patients frequency of conjunctivitis and keratitis was low and similar between dupilumab and placebo (see Precautions).
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 studies. In the 52-week atopic dermatitis dupilumab + TCS study, eczema herpeticum was reported in 0.2% of the dupilumab + TCS group and 1.9% of the placebo + TCS group.
Eosinophilia: Dupilumab-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo. Eosinophil counts declined to near baseline levels during study treatment. Eosinophil counts continued to decline below baseline during the open-label extension study in asthma patients.
Treatment-emergent eosinophilia (≥ 5,000 cells/mcL) was reported in < 2% of dupilumab-treated patients and < 0.5% in placebo-treated patients.
Infections: No increase was observed in the overall incidence of infections or serious infections with dupilumab compared to placebo in the primary safety pool for atopic dermatitis clinical studies. In the 16-week atopic dermatitis monotherapy clinical studies, serious infections were reported in 1.0% of patients treated with placebo and 0.5% of patients treated with dupilumab. In the 52-week atopic dermatitis CHRONOS study, serious infections were reported in 0.6% of patients treated with placebo and 0.2% of patients treated with dupilumab.
No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for asthma clinical studies. In the 24-week safety pool, serious infections were reported in 1.0% of patients treated with dupilumab and 1.1% of patients treated with placebo. In the 52-week QUEST study, serious infections were reported in 1.3% of patients treated with dupilumab and 1.4% of patients treated with placebo.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity with dupilumab.
Anti-Drug-Antibodies (ADA) responses were not generally associated with impact on dupilumab exposure, safety, or efficacy.
Approximately 6% of patients with atopic dermatitis who received dupilumab 300 mg Q2W for 52 weeks developed ADA to dupilumab; approximately 2% exhibited persistent ADA responses and approximately 2% had neutralizing antibodies.
Approximately 16% of adolescent patients with atopic dermatitis who received dupilumab 300 mg or 200 mg Q2W for 16 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses, and approximately 5% had neutralizing antibodies.
Approximately 9% of patients with asthma who received dupilumab 200 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 4% exhibited persistent ADA responses and approximately 4% had neutralizing antibodies.
Approximately 5% of patients in the placebo groups in the 52 week studies were also positive for antibodies to dupilumab; approximately 2% exhibited persistent ADA response and approximately 1% had neutralizing antibodies.
Less than 0.4% of patients exhibited high titer ADA responses associated with reduced exposure and efficacy. In addition, there was one patient with serum sickness and one with serum sickness-like reaction (< 0.1%) associated with high ADA titers (see Precautions).
Postmarketing Experience: The following additional adverse reactions have been reported during post-approval use of dupilumab. The adverse reactions are derived from spontaneous reports and therefore, the frequency is "not known" (cannot be estimated from the available data).
Immune system disorders: Angioedema.
Musculoskeletal and connective tissue disorders: Arthralgia.
Eye disorders: Keratitis, ulcerative keratitis.

Immune responses to vaccination were assessed in a study in which patients with atopic dermatitis were treated once weekly for 16 weeks with 300 mg of dupilumab. After 12 weeks of dupilumab administration, patients were vaccinated with a Tdap vaccine (T cell-dependent), and a meningococcal polysaccharide vaccine (T cell-independent) and immune responses were assessed 4 weeks later.
Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-treated and placebo-treated patients. No adverse interactions between either of the non-live vaccines and dupilumab were noted in the study.
Therefore, patients receiving dupilumab may receive concurrent inactivated or non-live vaccinations. For information on live vaccines see Precautions.
In a clinical study of AD 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 medications is not expected. Based on the population analysis, commonly co-administered medications had no effect on dupilumab pharmacokinetics on patients with moderate to severe asthma.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: The instructions for the preparation and administration of DUPIXENT in a pre-filled syringe with needle shield are given in the package leaflet.
The solution should be clear to slightly opalescent, colourless to pale yellow. If the solution is cloudy, discoloured or contains visible particulate matter, the solution should not be used.
After removing the 300 mg pre-filled syringe with needle shield from the refrigerator, it should be allowed to reach room temperature by waiting for 45 min before injecting DUPIXENT.
The pre-filled syringe should not be exposed to heat or direct sunlight and should not be shaken.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements. After use, place the pre-filled syringe with needle shield into a puncture-resistant container and discard as required by local regulations. Do not recycle the container.

Store refrigerated at 2°C to 8°C in the original carton to protect from light.
Do not freeze.
Do not expose to heat.
Do not shake.
Shelf-life: 36 months.
If necessary, pre-filled syringe with needle shield may be kept at room temperature up to 25°C for a maximum of 14 days. Do not store above 25°C. If the carton needs to be removed permanently from refrigerator, the date of removal may be recorded on the outer carton. After removal from the refrigerator, Dupixent must be used within 14 days or discarded.

Other Dermatologicals

D11AH05 - dupilumab ; Belongs to the class of agents for atopic dermatitis, excluding corticosteroids. Used in the treatment of atopic dermatitis.

S