Dupilumab

Registered South African indications:

• Atopic dermatitis - moderate to severe
  - When the disease is not adequately controlled with topical corticosteroid therapies or when those therapies are not advisable
  - Used with or without additional topical corticosteroids therapy
• Asthma - moderate to severe
  - With type 2 inflammation characterised by elevated blood eosinophils and/or elevated fractional exhaled nitric oxide (FeNO)
  - Indicated as maintenance therapy to improve lung function
  - Indicated as maintenance therapy for oral corticosteroid-dependent asthma irrespective of baseline levels of type 2 inflammatory biomarkers
• Inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP) - severe
  - Indicated as an add-on maintenance treatment
  - Indicated to reduce the need for surgery and systemic corticosteroid
  - As an add-on maintenance treatment of co-morbid asthma
• Prurigo nodularis (PN)
  - Used with or without topical corticosteroids

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients 

Cautions

South African recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Hepatic impairment
• Pre-existing helminth infections
• Pre-existing conjunctivitis or keratitis
• Concomitant atopic conditions (See additional prescribing points)
• Sucrase-isomaltase intolerance

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Hepatic impairment
• Acute asthma symptoms or acute exacerbations
• Acute bronchospasm
• Status asthmaticus
• Abrupt discontinuation of systemic, topical, or inhaled corticosteroid upon initiation
• Reduction in corticosteroid dose (See additional prescribing points)
• Type 2 status in patients taking oral corticosteroids
• Pre-existing helminth infections
• Pre-existing conjunctivitis or keratitis
• Comorbid asthma in atopic dermatitis or chronic rhinosinusitis with nasal polyposis patients (See additional prescribing points)

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Atopic dermatitis - moderate to severe (Additional agent(s) may be required)
- When the disease is not adequately controlled with topical corticosteroid therapies or when those therapies are not advisable
- Used with or without additional topical corticosteroids therapy

• SC: Initial: 600mg (two 300mg injections); Maintenance: 300mg, every other week; May be increased to 300mg, weekly based on individual therapeutic response

Asthma - moderate to severe
- With type 2 inflammation characterised by elevated blood eosinophils and/or elevated fractional exhaled nitric oxide (FeNO)
- Indicated as maintenance therapy to improve lung function
- Indicated as maintenance therapy for oral corticosteroid-dependent asthma irrespective of baseline levels of type 2 inflammatory biomarkers

Usual dose

• SC: Initial: 400mg (two 200mg injections); Maintenance: 200mg, every other week; May be increased to 300mg, every other week based on prescriber assessment

Oral corticosteroid-dependent asthma or with co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severe chronic rhinosinusitis with nasal polyposis

• SC: Initial: 600mg (two 300mg injections); Maintenance: 300mg, every other week

Inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP) - severe (Additional agents required)
- Indicated as an add-on maintenance treatment
- Indicated to reduce the need for surgery and systemic corticosteroid
- As an add-on maintenance treatment of co-morbid asthma

• SC: Initial: 300mg; Maintenance: 300mg, every other week

Prurigo nodularis (PN)
- Used with or without topical corticosteroids

• SC: Initial: 600mg (two 300mg injections); Maintenance: 300mg, every other week

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Missed dose
If a weekly dose is missed, administer dose as soon as possible. Thereafter, resume dosing at the regular scheduled time
If an every other week dose is missed, administer within 7 days from the missed dose and then resume patient's original schedule
If the missed dose is not administered within 7 days, wait until next dose on the original schedule
If an every 4 week dose is missed, administer the injection within 7 days from the missed dose and then resume patient's original schedule
If the missed dose is not administered within 7 days, administer the dose, starting a new schedule based on this date

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Method of administration
Subcutaneous use under the guidance of a health care professional. A patient may self-inject dupilumab, or the patient’s caregiver may administer dupilumab
Atopic dermatitis, asthma and prurigo nodularis patients: Initial 600mg dose, the two 300mg injections should be administered at two different injection sites
Atopic dermatitis and asthma patients: Initial 400mg dose, the two 200mg injections should be administered at two different injection sites

Patients and/or caregivers should be properly trained on the preparation and administration of dupilumab prior to use according to the INSTRUCTIONS FOR USE
Allow the 200mg pre-filled syringe with a needle shield to reach room temperature by waiting for 30 minutes before injecting. The 300mg pre-filled syringe with a needle shield or pre-filled syringe should be allowed to reach room temperature by waiting for 45 minutes before injecting

Dupilumab is self-administered by subcutaneous injection into the thigh or abdomen, except for the 5 cm around the navel, using a single-use pre-filled syringe. If somebody else administers the injection, the upper arm can also be used. 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

Paed. forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Atopic dermatitis - moderate to severe (Additional agent(s) may be required)
- When the disease is not adequately controlled with topical corticosteroid therapies or when those therapies are not advisable
- Used with or without additional topical corticosteroids therapy

Younger than 6 months

• Not established for use

Between 6 months to 5 years

• See table below

Table: Dose of dupilumab for subcutaneous administration in paediatric patients 6 months to 5 years of age with atopic dermatitis

Body weight	Initial dose	Subsequent doses
5 to < 15kg	200mg (one 200mg injection)	200mg, every 4 weeks (Q4W)
15 to < 30kg	300mg (one 300mg injection)	300mg, every 4 weeks (Q4W)

Between 6-17 years

• See table below

Table: Dose of dupilumab for subcutaneous administration in paediatric and adolescent patients 6 to 17 years of age with atopic dermatitis

Body weight	Initial dose	Subsequent doses
15 to < 30kg	600mg (two 300mg injections)	300 mg every 4 weeks (Q4W)
30 to < 60kg	400mg (two 200mg injections)	200 mg every other week (Q2W)
≥ 60kg	600mg (two 300mg injections)	300 mg every other week (Q2W)

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Safety and efficacy in paediatric patients with atopic dermatitis younger than 6 months have not been established

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Asthma - moderate to severe
- With type 2 inflammation characterised by elevated blood eosinophils and/or elevated fractional exhaled nitric oxide (FeNO)
- Indicated as maintenance therapy to improve lung function
- Indicated as maintenance therapy for oral corticosteroid-dependent asthma irrespective of baseline levels of type 2 inflammatory biomarkers

Younger than 6 years

• Not established for use

Between 6-11 years

Usual dose

• See below table

Table: Dose of dupilumab for subcutaneous administration in paediatric patients 6 to 11 years of age with asthma

Body weight	Initial and subsequent doses
15 to < 30kg	300mg every 4 weeks (Q4W)
30 to < 60kg	200mg every other week (Q2W) or 300mg every 4 weeks (Q4W)
≥ 60kg	200mg every other week (Q2W)

Asthma and co-morbid moderate-to-severe atopic dermatitis

Table: Dose of dupilumab for subcutaneous administration in paediatric and adolescent patients 6 to 11 years of age with asthma and co-morbid moderate-to-severe atopic dermatitis

Body weight	Initial dose	Subsequent doses
15 to < 30kg	600mg (two 300mg injections)	300 mg every 4 weeks (Q4W)
30 to < 60kg	400mg (two 200mg injections)	200 mg every other week (Q2W)
≥ 60kg	600mg (two 300mg injections)	300 mg every other week (Q2W)

12 years and older

• See adult dosage

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Safety and efficacy in paediatric patients with asthma younger than 6 years have not been established

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Chronic rhinosinusitis with nasal polyposis (CRSwNP) does not normally occur in children. Safety and efficacy in paediatric patients with CRSwNP younger than 18 years have not been established

Prurigo nodularis (PN) rarely occurs in children. Safety and efficacy in paediatric patients with PN younger than 18 years have not been established

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Missed dose
If a weekly dose is missed, administer dose as soon as possible. Thereafter, resume dosing at the regular scheduled time
If an every other week dose is missed, administer within 7 days from the missed dose and then resume patient's original schedule
If the missed dose is not administered within 7 days, wait until next dose on the original schedule
If an every 4 week dose is missed, administer the injection within 7 days from the missed dose and then resume patient's original schedule
If the missed dose is not administered within 7 days, administer the dose, starting a new schedule based on this date

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Method of administration
Subcutaneous use under the guidance of a health care professional. A patient may self-inject dupilumab, or the patient’s caregiver may administer dupilumab

Atopic dermatitis, asthma and prurigo nodularis patients: Initial 600mg dose, the two 300mg injections should be administered at two different injection sites
Atopic dermatitis and asthma patients: Initial 400mg dose, the two 200mg injections should be administered at two different injection sites
In children 12 years of age and older, it is recommended that dupilumab be administered by or under supervision of an adult. In children 6 months to less than 12 years of age, dupilumab should be given by a caregiver

Patients and/or caregivers should be properly trained on the preparation and administration of dupilumab prior to use according to the INSTRUCTIONS FOR USE
Allow the 200mg pre-filled syringe with a needle shield to reach room temperature by waiting for 30 minutes before injecting. The 300mg pre-filled syringe with a needle shield or pre-filled syringe should be allowed to reach room temperature by waiting for 45 minutes before injecting

Dupilumab is self-administered by subcutaneous injection into the thigh or abdomen, except for the 5 cm around the navel, using a single-use pre-filled syringe. If somebody else administers the injection, the upper arm can also be used. 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

Pregnancy

South African recommendations

• Caution; not recommended
• Safety in pregnancy has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.  Due to the lack of data, the use of dupilumab is not recommended during pregnancy

Recommendations in other jurisdictions

• Caution; no evidence of risk in studies
• 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
• Dupilumab should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus

Breastfeeding

South African recommendations

• Caution; not recommended 
• It is unknown whether dupilumab is excreted in human milk. Because many antibodies are excreted in  human milk, mothers receiving dupilumab are advised not to breastfeed their infants

Recommendations in other jurisdictions

• Caution; not recommended 
• It is unknown whether dupilumab is excreted in human milk or absorbed systemically after ingestion
• A decision must be made whether to discontinue breastfeeding or to discontinue dupilumab therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• Animal studies showed no impairment of fertility

Renal Impairment

• Mild to moderate: No dose adjustment recommended 
• Severe: Caution; no information available 

Hepatic Impairment

• Caution; no information available 

Elderly

• No dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Gastrointestinal Disorders

• Oral herpes

Musculoskeletal Disorders

• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Injection site reactions
  - Erythema
  - Oedema
  - Pruritis
  - Pain
  - Swelling
• Eczema herpeticum

Immune, Blood and Lymphatic System Disorders

• Anaphylactic reaction
• Angioedema

• Serum sickness reaction
  - Serum sickness-like reaction
• Eosinophilia
• Immunogenicity
  - Anti-drug-antibodies

Sensory Disorders

• Conjunctivitis
  - Allergic
• Eye pruritus
• Blepharitis
• Keratitis
  - Ulcerative keratitis

• Live vaccine
• Live attenuated vaccine
  (See additional prescribing points)

None routine. Specific cases may require

• Pulmonary function
• Rheumatological evaluation

Additional observations

• Signs and symptoms of:
  - Arthralgia
  - Hypersensitivity reactions
  - Ocular adverse effects (unresolved conjunctivitis)
• Signs of infection

Reductions in corticosteroid dose

• Should be gradual and performed under the direct supervision of a physician
• May be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy

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

Helminth infections

• 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 anti-helminth treatment, treatment with dupilumab should be discontinued until infection resolves

Vaccinations

• Live and live attenuated vaccines should not be given concurrently with dupilumab as clinical safety and efficacy has not been established
• It is recommended that patients should be brought up to date with live and live attenuated immunisations in agreement with current immunisation guidelines prior to treatment with dupilumab

Recommendations in other jurisdictions

Atopic dermatitis or chronic rhinosinusitis with nasal polyposis patients (CRSwNP) with comorbid asthma

• Patients on dupilumab for moderate to severe atopic dermatitis or severe CRSwNP who also have co-morbid asthma should not adjust or stop their asthma treatments without consultation with their physicians
• Patients with comorbid asthma should be monitored carefully following discontinuation of dupilumab

South African recommendations

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 medical practitioner
• When discontinuing dupilumab consider the potential effects on the other atopic conditions

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.

Injection (per 2ml) 300mg

• Dupixent (Sanofi Aventis) originator