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Dupixent

Dupixent

dupilumab

Manufacturer:

sanofi-aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Dupilumab.
Description
Each 300 mg pre-filled syringe delivers 300 mg dupilumab in 2 mL which also contains L-arginine hydrochloride (10.5 mg), L-histidine (6.2 mg), polysorbate 80 (4 mg), sodium acetate (2 mg), sucrose (100 mg), and water for injection, pH 5.9.
Each 200 mg pre-filled syringe delivers 200 mg dupilumab in 1.14 mL which also contains L-arginine hydrochloride (12 mg), L-histidine (3.5 mg), polysorbate 80 (2.3 mg), sodium acetate (1.2 mg), sucrose (57 mg), and water for injection, pH 5.9.
Dupilumab, an interleukin-4 receptor alpha antagonist, is a human monoclonal antibody of the IgG4 subclass that binds to the IL-4Rα subunit and inhibits IL-4 and IL-13 signaling.
Dupilumab has an approximate molecular weight of 147 kDa.
Dupilumab is produced by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture.
DUPIXENT (dupilumab) Injection is supplied as a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for subcutaneous injection. DUPIXENT is provided as a single-dose pre-filled syringe with needle shield in a siliconized Type-1 clear glass syringe. The needle cap is not made with natural rubber latex.
Action
Pharmacology: Mechanism of Action: Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor.
Inflammation is an important component in the pathogenesis of atopic dermatitis. Multiple cell types that express IL-4Rα (e.g., mast cells, eosinophils, macrophages, lymphocytes, epithelial cells, goblet cells) and inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines, chemokines) are involved in inflammation.
Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced responses, including the release of proinflammatory cytokines, chemokines and IgE.
Pharmacodynamics: Consistent with receptor blockade, serum levels of IL-4 and IL-13 were increased following dupilumab treatment. The relationship between the pharmacodynamic activity and the mechanism(s) by which dupilumab exerts its clinical effects is unknown.
Clinical Studies: Atopic Dermatitis: Adults with Atopic Dermatitis: Three randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3; NCT02277743, 02277769, and 02260986 respectively) enrolled a total of 2119 subjects 18 years of age and older with moderate-to-severe atopic dermatitis (AD) not adequately controlled by topical medication(s). Disease severity was defined by an 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 involvement of ≥10%. At baseline, 59% of subjects were male, 67% were white, 52% of subjects had a baseline IGA score of 3 (moderate AD), and 48% of subjects had a baseline IGA of 4 (severe AD). The baseline mean EASI score was 33 and the baseline weekly averaged peak pruritus Numeric Rating Scale (NRS) was 7 on a scale of 0-10.
In all three trials, subjects in the DUPIXENT group received subcutaneous injections of DUPIXENT 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the monotherapy trials (Trials 1 and 2), subjects received DUPIXENT or placebo for 16 weeks.
In the concomitant therapy trial (Trial 3), subjects received DUPIXENT or placebo with concomitant topical corticosteroids (TCS) and as needed topical calcineurin inhibitors for problem areas only, such as the face, neck, intertriginous and genital areas for 52 weeks.
All three trials assessed the primary endpoint, the change from baseline to Week 16 in the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement. Other endpoints included the proportion of subjects with EASI-75 (improvement of at least 75% in EASI score from baseline), and reduction in itch as defined by at least a 4-point improvement in the peak pruritus NRS from baseline to Week 16.
Clinical Response at Week 16 (Trials 1, 2, and 3): The results of the DUPIXENT monotherapy trials (Trials 1 and 2) and the DUPIXENT with concomitant TCS trial (Trial 3) are presented in Table 1. (See Table 1 and Figure 1.)

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In Trial 3, of the 421 subjects, 353 had been on study for 52 weeks at the time of data analysis. Of these 353 subjects, responders at Week 52 represent a mixture of subjects who maintained their efficacy from Week 16 (e.g., 53% of DUPIXENT IGA 0 or 1 responders at Week 16 remained responders at Week 52) and subjects who were non-responders at Week 16 who later responded to treatment (e.g., 24% of DUPIXENT IGA 0 or 1 non-responders at Week 16 became responders at Week 52). Results of supportive analyses of the 353 subjects in the DUPIXENT with concomitant TCS trial (Trial 3) are presented in Table 2. (See Table 2.)

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Treatment effects in subgroups (weight, age, gender, race, and prior treatment, including immunosuppressants) in Trials 1, 2, and 3 were generally consistent with the results in the overall study population.
In Trials 1, 2, and 3, a third randomized treatment arm of DUPIXENT 300 mg QW did not demonstrate additional treatment benefit over DUPIXENT 300 mg Q2W.
Subjects in Trials 1 and 2 who had an IGA 0 or 1 with a reduction of ≥2 points were re-randomized into Trial 5. Trial 5 evaluated multiple DUPIXENT monotherapy dose regimens for maintaining treatment response. The study included subjects randomized to continue with DUPIXENT 300 mg Q2W (62 subjects) or switch to placebo (31 subjects) for 36 weeks. IGA 0 or 1 responses at Week 36 were as follows: 33 (53%) in the Q2W group and 3 (10%) in the placebo group.
Adolescents with Atopic Dermatitis: The efficacy and safety of DUPIXENT monotherapy in adolescent subjects was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (Trial 6; NCT03054428) in 251 adolescent subjects 12 to 17 years of age, with moderate-to-severe AD defined by an IGA score ≥3 (scale of 0 to 4), an EASI score ≥16 (scale of 0 to 72), and a minimum BSA involvement of ≥10%. Eligible subjects enrolled into this trial had previous inadequate response to topical medication.
Subjects in the DUPIXENT group with baseline weight of <60 kg received an initial dose of 400 mg at Week 0, followed by 200 mg Q2W for 16 weeks. Subjects with baseline weight of ≥60 kg received an initial dose of 600 mg at Week 0, followed by 300 mg Q2W for 16 weeks. Subjects were permitted to receive rescue treatment at the discretion of the investigator. Subjects who received rescue treatment were considered non-responders.
In Trial 6, the mean age was 14.5 years, the median weight was 59.4 kg, 41% of subjects were female, 63% were White, 15% were Asian, and 12% were Black. At baseline 46% of subjects had an IGA score of 3 (moderate AD), 54% had an IGA score of 4 (severe AD), the mean BSA involvement was 57%, and 42% had received prior systemic immunosuppressants. Also, at baseline the mean EASI score was 36, and the weekly averaged Peak Pruritus NRS was 8 on a scale of 0-10. Overall, 92% of subjects had at least one co-morbid allergic condition; 66% had allergic rhinitis, 54% had asthma, and 61% had food allergies.
The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement from baseline to Week 16. Other evaluated outcomes included the proportion of subjects with EASI-75 or EASI-90 (improvement of at least 75% or 90% in EASI from baseline, respectively), and reduction in itch as measured by the Peak Pruritus NRS (≥4-point improvement).
The efficacy results at Week 16 for Trial 6 are presented in Table 3. (See Table 3.)

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A greater proportion of subjects randomized to DUPIXENT achieved an improvement in the Peak Pruritus NRS compared to placebo (defined as ≥4-point improvement at Week 4). See Figure 2.

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Pharmacokinetics: Absorption: Following an initial subcutaneous (SC) dose of 600 mg or 400 mg, dupilumab reached peak mean ±SD concentrations (Cmax) of 70.1±24.1 mcg/mL or 41.8±12.4 mcg/mL, respectively, by approximately 1 week post dose.
Steady-state concentrations were achieved by Week 16 following the administration of 600 mg starting dose and 300 mg dose either weekly (twice the recommended dosing frequency) or every Q2W, or 400 mg starting dose and 200 mg dose Q2W. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 60.3±35.1 mcg/mL to 79.9±41.4 mcg/mL for 300 mg administered Q2W, from 173±75.9 mcg/mL to 193±77.0 mcg/mL for 300 mg administered weekly, and from 29.2±18.7 to 36.5±22.2 mg/L for 200 mg administered Q2W.
The bioavailability of dupilumab following a SC dose is estimated to be 64%.
Distribution: The estimated total volume of distribution was approximately 4.8±1.3 L.
Elimination: The metabolic pathway of dupilumab has not been characterized. As a human monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. After the last steady-state dose of 300 mg Q2W, 300 mg QW, or 200 mg Q2W dupilumab, the median times to non-detectable concentration (<78 ng/mL) are 10-11, 13, and 9 weeks, respectively.
Dose Linearity: Dupilumab exhibited nonlinear target-mediated pharmacokinetics with exposures increasing in a greater than dose-proportional manner. The systemic exposure increased by 30-fold when the dose increased 8-fold following a single dose of dupilumab from 75 mg to 600 mg (i.e., 0.25-times to 2-times the recommended dose).
Weight: Dupilumab trough concentrations were lower in subjects with higher body weight.
Age: Based on population pharmacokinetic analysis, age did not affect dupilumab clearance.
Immunogenicity: Development of antibodies to dupilumab was associated with lower serum dupilumab concentrations. A few subjects who had high antibody titers also had no detectable serum dupilumab concentrations.
Specific Populations: Geriatric Patients: In subjects who are 65 years and older, the mean ±SD steady-state trough concentrations of dupilumab were 69.4±31.4 mcg/mL and 166±62.3 mcg/mL, respectively, for 300 mg administered Q2W and weekly, and 39.7±21.7 mcg/mL for 200 mg administered Q2W.
Pediatric Patients: Atopic Dermatitis: 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.
Renal or Hepatic Impairment: No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of dupilumab was conducted.
Drug Interaction Studies: 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 DUPIXENT pharmacokinetics in patients with moderate-to-severe asthma.
Cytochrome P450 Substrates: The effects of dupilumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), metoprolol (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in a study with 12-13 evaluable subjects with atopic dermatitis (a SC loading dose of 600 mg followed by 300 mg SC weekly for six weeks). No clinically significant changes in AUC were observed. The largest effect was observed for metoprolol (CYP2D6) with an increase in AUC of 29%.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of dupilumab.
No effects on fertility parameters such as reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature mice that were subcutaneously administered a homologous antibody against IL-4Rα at doses up to 200 mg/kg/week.
Indications/Uses
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.
Dosage/Direction for Use
DUPIXENT is administered by subcutaneous injection.
Dosing in Adults: The recommended dose of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week.
Dosing in Adolescents: The recommended dose of DUPIXENT for patients 12 to 17 years of age is specified in Table 4. (See Table 4.)

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Concomitant Topical Therapies: DUPIXENT 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.
Important Administration Instructions: DUPIXENT is intended for use under the guidance of a healthcare provider. A patient may self-inject DUPIXENT after training in subcutaneous injection technique using the pre-filled syringe. Provide proper training to patients and/or caregivers on the preparation and administration of DUPIXENT prior to use according to the "Instructions for Use under Patient Counselling Information".
For the initial 600 mg dose, administer each of the two DUPIXENT 300 mg injections at different injection sites.
For the initial 400 mg dose, administer each of the two DUPIXENT 200 mg injections at different injection sites.
Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.
Rotate the injection site with each injection. DO NOT inject DUPIXENT into skin that is tender, damaged, bruised, or scarred.
If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
The DUPIXENT "Instructions for Use under Patient Counselling Information" contains more detailed instructions on the preparation and administration of DUPIXENT [Instructions for Use under Patient Counselling Information].
Preparation for Use of Dupixent Pre-filled Syringe With Needle Shield: Before injection, remove DUPIXENT pre-filled syringe from the refrigerator and allow DUPIXENT to reach room temperature (45 minutes for the 300 mg/2 mL pre-filled syringe and 30 minutes for the 200 mg/1.14 mL pre-filled syringe) without removing the needle cap.
Inspect DUPIXENT visually for particulate matter and discoloration prior to administration. DUPIXENT is a clear to slightly opalescent, colorless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discolored or cloudy (other than clear to slightly opalescent, colorless to pale yellow). DUPIXENT does not contain preservatives; therefore, discard any unused product remaining in the pre-filled syringe.
Overdosage
There is no specific treatment for DUPIXENT overdose. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.
Contraindications
DUPIXENT is contraindicated in patients who have known hypersensitivity to dupilumab or any of its excipients [see Hypersensitivity under Precautions].
Special Precautions
Hypersensitivity: Hypersensitivity reactions, including generalized urticaria, rash, erythema nodosum and serum sickness or serum sickness-like reactions, were reported in less than 1% of subjects who received DUPIXENT in clinical trials. Two subjects in the atopic dermatitis development program experienced serum sickness or serum sickness-like reactions that were associated with high titers of antibodies to dupilumab [see Immunogenicity under Adverse Reactions]. If a clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue DUPIXENT [see Clinical Trials Experience and Immunogenicity under Adverse Reactions].
Conjunctivitis and Keratitis: Conjunctivitis and keratitis occurred more frequently in atopic dermatitis subjects who received DUPIXENT. Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis recovered or were recovering during the treatment period [see Clinical Trials Experience under 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 atopic dermatitis monotherapy trials. In the 52-week DUPIXENT + topical corticosteroids (TCS) atopic dermatitis 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 [see Clinical Trials Experience under Adverse Reactions].
Advise patients to report new onset or worsening eye symptoms to their healthcare provider.
Reduction of Corticosteroid Dosage: Do not discontinue systemic or topical corticosteroids abruptly upon initiation of therapy with DUPIXENT. 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.
Atopic Dermatitis Patients with Comorbid Asthma: Advise patients with comorbid asthma not to adjust or stop their asthma treatments without consultation with their physicians.
Parasitic (Helminth) Infections: Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if DUPIXENT will influence the immune response against helminth infections.
Treat patients with pre-existing helminth infections before initiating therapy with DUPIXENT. If patients become infected while receiving treatment with DUPIXENT and do not respond to antihelminth treatment, discontinue treatment with DUPIXENT until the infection resolves.
Use in Children: Atopic Dermatitis: The safety and efficacy of DUPIXENT have been established in pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis. A total of 251 adolescents ages 12 to 17 years old with moderate-to-severe atopic dermatitis were enrolled in Trial 6. The safety and efficacy were generally consistent between adolescents and adults [see Clinical Trials Experience under Adverse Reactions and Pharmacology: Pharmacodynamics: Clinical Studies: Atopic Dermatitis under Actions]. Safety and efficacy in pediatric patients (<12 years of age) with atopic dermatitis have not been established.
Use in Elderly: Of the 1472 subjects with atopic dermatitis exposed to DUPIXENT in a dose-ranging study and placebo-controlled trials, 67 subjects were 65 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects [see Pharmacology: Pharmacokinetics under Actions].
Use In Pregnancy & Lactation
Pregnancy: Risk Summary: Available data from case reports and case series with DUPIXENT use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, DUPIXENT may be transmitted from the mother to the developing fetus. In an enhanced pre- and post-natal developmental study, no adverse developmental effects were observed in offspring born to pregnant monkeys after subcutaneous administration of a homologous antibody against interleukin-4-receptor alpha (IL-4Rα) during organogenesis through parturition at doses up to 10-times the maximum recommended human dose (MRHD) [see Data as follows]. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data: Animal Data: In an enhanced pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of homologous antibody against IL-4Rα up to 10 times the MRHD (on a mg/kg basis of 100 mg/kg/week) from the beginning of organogenesis to parturition. No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age.
Lactation: Risk Summary: There are no data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal and limited systemic exposure to dupilumab on the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DUPIXENT and any potential adverse effects on the breastfed child from DUPIXENT or from the underlying maternal condition.
Adverse Reactions
The following adverse reactions are discussed in greater detail as follows: Hypersensitivity [see Hypersensitivity under Precautions], Conjunctivitis and Keratitis [see Conjunctivitis and Keratitis under Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults with Atopic Dermatitis: Three randomized, double-blind, placebo-controlled, multicenter trials (Trials 1, 2, and 3) and one dose-ranging trial (Trial 4) evaluated the safety of DUPIXENT in subjects with moderate-to-severe atopic dermatitis. The safety population had a mean age of 38 years; 41% of subjects were female, 67% were white, 24% were Asian, and 6% were black; in terms of comorbid conditions, 48% of the subjects had asthma, 49% had allergic rhinitis, 37% had food allergy, and 27% had allergic conjunctivitis. In these 4 trials, 1472 subjects were treated with subcutaneous injections of DUPIXENT, with or without concomitant topical corticosteroids (TCS).
A total of 739 subjects were treated with DUPIXENT for at least 1 year in the development program for moderate-to-severe atopic dermatitis.
Trials 1, 2, and 4 compared the safety of DUPIXENT monotherapy to placebo through Week 16. Trial 3 compared the safety of DUPIXENT + TCS to placebo + TCS through Week 52.
Weeks 0 to 16 (Trials 1 to 4): In DUPIXENT monotherapy trials (Trials 1, 2, and 4) through Week 16, the proportion of subjects who discontinued treatment because of adverse events was 1.9% in both the DUPIXENT 300 mg Q2W and placebo groups.
Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% in the DUPIXENT 300 mg Q2W monotherapy groups, and in the DUPIXENT + TCS group, all at a higher rate than in their respective comparator groups during the first 16 weeks of treatment. (See Table 5.)

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Safety through Week 52 (Trial 3): In the DUPIXENT with concomitant TCS trial (Trial 3) through Week 52, the proportion of subjects who discontinued treatment because of adverse events was 1.8% in DUPIXENT 300 mg Q2W + TCS group and 7.6% in the placebo + TCS group. Two subjects discontinued DUPIXENT because of adverse reactions: atopic dermatitis (1 subject) and exfoliative dermatitis (1 subject).
The safety profile of DUPIXENT + TCS through Week 52 was generally consistent with the safety profile observed at Week 16.
Adolescents with Atopic Dermatitis: The safety of DUPIXENT was assessed in a trial of 250 subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (Trial 6). The safety profile of DUPIXENT in these subjects through Week 16 was similar to the safety profile from studies in adults with atopic dermatitis.
The long-term safety of DUPIXENT was assessed in an open-label extension study in subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (Trial 7). The safety profile of DUPIXENT in subjects followed through Week 52 was similar to the safety profile observed at Week 16 in Trial 6. The long-term safety profile of DUPIXENT observed in adolescents was consistent with that seen in adults with atopic dermatitis.
Specific Adverse Reactions: Conjunctivitis: During the 52-week treatment period of concomitant therapy atopic dermatitis trial (Trial 3), conjunctivitis was reported in 16% of the DUPIXENT 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years) [see Conjunctivitis and Keratitis under Precautions].
Eczema Herpeticum and Herpes Zoster: The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups in the atopic dermatitis trial.
Herpes zoster was reported in <0.1% of the DUPIXENT groups (<1 per 100 subject-years) and in <1% of the placebo group (1 per 100 subject-years) in the 16-week atopic dermatitis monotherapy trials. In the 52-week DUPIXENT + TCS atopic dermatitis trial, herpes zoster was reported in 1% of the DUPIXENT + TCS group (1 per 100 subject-years) and 2% of the placebo + TCS group (2 per 100 subject-years).
Hypersensitivity Reactions: Hypersensitivity reactions were reported in <1% of DUPIXENT-treated subjects. These included serum sickness reaction, serum sickness-like reaction, and generalized urticaria, rash, erythema nodosum, and anaphylaxis[see Contraindications, Hypersensitivity under Precautions, and Immunogenicity under Adverse Reactions].
Eosinophils: DUPIXENT-treated subjects had a greater mean initial increase from baseline in eosinophil count compared to subjects treated with placebo. In subjects with atopic dermatitis, the mean and median increases in blood eosinophils from baseline to Week 4 were 100 and 0 cells/mcL respectively.
The incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in DUPIXENT and placebo groups. Treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in <2% of DUPIXENT-treated patients and <0.5% in placebo-treated patients. Blood eosinophil counts declined to near baseline levels during study treatment [see Reduction of Corticosteroid Dosage under Precautions].
Cardiovascular: In the 1-year placebo controlled trial in subjects with atopic dermatitis (Trial 3), cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 (0.9%) of the DUPIXENT + TCS 300 mg Q2W group, 0 (0.0%) of the DUPIXENT + TCS 300 mg QW group, and 1 (0.3%) of the placebo + TCS group.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to dupilumab in the studies described as follows with the incidence of antibodies in other studies or to other products may be misleading.
Approximately 6% of subjects with atopic dermatitis who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 2% exhibited persistent ADA responses, and approximately 2% had neutralizing antibodies.
Approximately 16% of adolescent subjects with atopic dermatitis who received DUPIXENT 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 4% of adolescent subjects with atopic dermatitis in the placebo group were positive for antibodies to DUPIXENT; approximately 1% exhibited persistent ADA responses, and approximately 1% had neutralizing antibodies.
The antibody titers detected in both DUPIXENT and placebo subjects were mostly low. In subjects who received DUPIXENT, development of high titer antibodies to dupilumab was associated with lower serum dupilumab concentrations [see Pharmacology: Pharmacokinetics under Actions].
Two subjects who experienced high titer antibody responses developed serum sickness or serum sickness-like reactions during DUPIXENT therapy [see Hypersensitivity under Precautions].
Drug Interactions
Live Vaccines: Avoid use of live vaccines in patients treated with DUPIXENT.
Non-Live Vaccines: Immune responses to vaccination were assessed in a study in which subjects with atopic dermatitis were treated once weekly for 16 weeks with 300 mg of dupilumab (twice the recommended dosing frequency). After 12 weeks of DUPIXENT administration, subjects were vaccinated with a Tdap vaccine (Adacel) and a meningococcal polysaccharide vaccine (Menomune). Antibody responses to tetanus toxoid and serogroup C meningococcal polysaccharide were assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-treated and placebo-treated subjects. Immune responses to the other active components of the Adacel and Menomune vaccines were not assessed.
Storage
DUPIXENT is sterile and preservative-free. Discard any unused portion.
Store refrigerated at 2°C to 8°C in the original carton to protect from light.
If necessary, pre-filled syringes may be kept at room temperature up to 25°C for a maximum of 14 days. Do not store above 25°C. After removal from the refrigerator, DUPIXENT must be used within 14 days or discarded.
Do not expose the syringe to heat or direct sunlight.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Do NOT freeze. Do NOT shake.
Patient Counseling Information
Administration Instructions: Provide proper training to patients and/or caregivers on proper subcutaneous injection technique, including aseptic technique, and the preparation and administration of DUPIXENT prior to use. Advise patients to follow sharps disposal recommendations [see Instructions for Use as follows].
Hypersensitivity: Advise patients to discontinue DUPIXENT and to seek immediate medical attention if they experience any symptoms of systemic hypersensitivity reactions [see Hypersensitivity under Precautions].
Conjunctivitis and Keratitis: Advise patients to consult their healthcare provider if new onset or worsening eye symptoms develop [see Conjunctivitis and Keratitis under Precautions].
Eosinophilic Conditions: Advise patients to notify their healthcare provider if they present with clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis [see Reduction of Corticosteroid Dosage under Precautions].
Reduction in Corticosteroid Dosage: Inform patients to not discontinue systemic corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy [see Parasitic (Helminth) Infections under Actions].
Atopic Dermatitis Patients with Comorbid Asthma: Advise atopic dermatitis patients with comorbid asthma not to adjust or stop their asthma treatment without talking to their physicians [see Atopic Dermatitis Patients with Comorbid Asthma under Precautions].
Instructions for Use: Read this Instructions for Use before using the DUPIXENT Pre-filled Syringe. Do not inject yourself or someone else until you have been shown how to inject DUPIXENT. In adolescents 12 years of age and older, it is recommended that DUPIXENT be administered by or under supervision of an adult. Your healthcare provider can show you or your caregiver how to prepare and inject a dose of DUPIXENT before you try to do it yourself the first time. Keep these instructions for future use. Call your healthcare provider if you have any questions.
This device is a Single-Dose Pre-filled Syringe (called "DUPIXENT Syringe" in these instructions). It contains 200 mg of DUPIXENT for injection under the skin (subcutaneous injection).
Important Information: Read all of the instructions carefully before using the DUPIXENT Syringe.
Ask your healthcare provider how often you will need to inject the medicine.
Rotate the injection site each time you inject.
Do not use the DUPIXENT Syringe if it has been damaged.
Do not use the DUPIXENT Syringe if the Needle Cap is missing or not securely attached.
Do not touch the Plunger Rod until you are ready to inject.
Do not inject through clothes.
Do not get rid of any air bubbles in the DUPIXENT Syringe.
To reduce the risk of accidental needle sticks, each pre-filled syringe has a Needle Shield that is automatically activated to cover the needle after you have given your injection.
Do not pull back on the Plunger Rod at any time.
Do not remove the Needle Cap until just before you give the injection.
Throw away (dispose of) the used DUPIXENT Single-Dose Pre-filled Syringe right away after use. See "Step 13: Dispose" as follows.
Do not re-use a DUPIXENT Single-Dose Pre-filled Syringe.
How should I store DUPIXENT? Store DUPIXENT Syringes in the refrigerator between 2°C and 8°C.
Store DUPIXENT Syringes in the original carton to protect it from light.
DUPIXENT Syringes can be stored at room temperature up to 25°C up to 14 days. Throw away (dispose of) any DUPIXENT Syringes that have been left at room temperature for longer than 14 days.
Do not shake the DUPIXENT Syringe.
Do not heat the DUPIXENT Syringe.
Do not freeze the DUPIXENT Syringe.
Do not put the DUPIXENT Syringe into direct sunlight.
Step 1: Remove: Remove the DUPIXENT Syringe from the carton by holding the middle of the Syringe Body.
Do not pull off the Needle Cap until you are ready to inject.
Do not use the DUPIXENT Syringe if it has been dropped on a hard surface or damaged.
Step 2: Prepare: Ensure you have the following: the DUPIXENT Pre-filled Syringe, 1 alcohol wipe*, 1 cotton ball or gauze*, a sharps disposal container* (See Step 13).
*Items not included in the carton.
Step 3: Check: When you receive your DUPIXENT Syringes, always check to see that: you have the correct medicine and dose, the expiration date on the Single-Dose Pre-filled Syringe has not passed.
Do not use the DUPIXENT Syringe if the expiration date has passed.
Step 4: Inspect: Look at the medicine through the viewing window on the DUPIXENT Syringe: Check to see if the liquid is clear and colorless to pale yellow.
Note: You may see an air bubble, this is normal.
Do not use the DUPIXENT Syringe if the liquid is discolored or cloudy, or if it contains visible flakes or particles.
Step 5: Wait 30 minutes: Lay the DUPIXENT Syringe on a flat surface and let it naturally warm to room temperature for at least 30 minutes.
Do not heat the DUPIXENT Syringe.
Do not put the DUPIXENT Syringe into direct sunlight.
Do not keep DUPIXENT Syringes at room temperature for more than 14 days. Throw away (dispose of) any DUPIXENT Syringes that have been left at room temperature for longer than 14 days.
Step 6: Choose your injection site: You can inject into your thigh or stomach, except for the 2 inches (5 cm) around your belly button (navel).
If a caregiver injects your dose, they can also use the outer area of the upper arm.
Choose a different site each time you inject DUPIXENT.
Do not inject into skin that is tender, damaged, bruised or scarred.
Step 7: Clean: Wash your hands.
Clean the injection site with an alcohol wipe.
Let your skin dry before injecting.
Do not touch the injection site again or blow on it before the injection.
Step 8: Remove Needle Cap: Hold the DUPIXENT Syringe in the middle of the Syringe Body with the Needle pointing away from you and pull off the Needle Cap.
Do not put the Needle Cap back on.
Do not touch the Needle.
Inject your medicine right away after removing the Needle Cap.
Step 9: Pinch: Pinch a fold of skin at the injection site (thigh or stomach, except 2 inches around your belly button, or outer area of the upper arm if injected by your caregiver).
Step 10: Insert: Insert the Needle completely into the fold of the skin at about a 45° angle.
Step 11: Push: Relax the pinch.
Push the Plunger Rod down slowly and steadily as far as it will go until the DUPIXENT Syringe is empty.
Note: You will feel some resistance. This is normal.
Step 12: Release and Remove: Lift your thumb to release the Plunger Rod until the Needle is covered by the Needle Shield and then remove the Syringe from the injection site.
Lightly press a cotton ball or gauze on the injection site if you see any blood.
Do not put the Needle Cap back on.
Do not rub your skin after the injection.
Step 13: Dispose: Put your used Needles, DUPIXENT Syringes, and Needle Caps in a sharps disposal container right away after use.
Do not dispose of (throw away) Needles, DUPIXENT Syringes, and Needle Caps in your household trash.
If you do not have a sharps disposal container, you may use a household container that is: made of a heavy-duty plastic; can be closed with a tightfitting, puncture-resistant lid, without sharps being able to come out; upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used Needles and Syringes.
Do not dispose your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
Do not put the Needle Cap back on.
ATC Classification
D11AH05 - dupilumab ; Belongs to the class of agents for atopic dermatitis, excluding corticosteroids. Used in the treatment of atopic dermatitis.
Presentation/Packing
Soln for inj (clear to slightly opalescent, colorless to pale yellow in pre-filled syringe) 200 mg/1.14 mL x 2's. 300 mg/2 mL x 2's.
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