Ustekinumab

Registered South African indications:

• Plaque psoriasis
• Psoriatic arthriitis
• Crohn's disease

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Clinically important, active infection

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Active tuberculosis

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Chronic infection or history of recurrent infections
• Latent infections
• Past history of latent or active tuberculosis
• Risk factors for or history of malignancy
  - >60 years of age
  - Medical history of prolonged immunosuppressant therapy
  - History of PUVA treatment
• Coadministration with other immunosuppressive agents or when transitioning from other biologic agents
• Controlled sodium diet

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Clinical important, active infections
• Chronic infection or history of recurrent infections
• Latent infections
• Past history of latent or active tuberculosis
• Risk factors for or history of malignancy
  - >60 years of age
  - Medical history of prolonged immunosuppressant therapy
  - History of PUVA treatment
• Diabetes mellitus
• Administration of some live vaccines to household contacts
• Current or prior coadministration with allergy immunotherapy particularly for anaphylaxis
• Coadministration with other immunosuppressive agents or when transitioning from other biologic agents
• Latex allergy
• Fructose intolerance
• Glucose-galactose malabsorption
• Sucrose-isomaltase insufficiency

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

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Crohn's disease - moderate to severe
- Where an inadequate response with, loss of response to, or intolerance to either conventional therapy or a TNFα antagonist or medical contraindications to such therapies
Ulcerative colitis - moderate to severe
- Where an inadequate response with, loss of response to, or intolerance to either conventional therapy or a biologic or medical contraindications to such therapies

Initial single IV dosing

Body weight of patient at the time of dosing	Recommended dosea	Number of 130mg ustekinumab vials
≤55kg	260mg	2
>55kg-≤85kg	390mg	3
>85kg	520mg	4
aApproximately 6mg/kg

Maintenance dosing

• SC: Given at week 8 after IV dose: 90mg, Then: 90mg, every 12 weeks

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Patients who have not shown adequate response at 8 weeks after the first SC dose, may receive a second SC dose at this time. Patients who lose response on dosing every 12 weeks may benefit from an increase in dosing frequency to every 8 weeks

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Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment. Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit 16 weeks after the IV induction dose or 16 weeks after switching to the 8-weekly maintenance dose

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Immunomodulators and/or corticosteroids may be continued during treatment with ustekinumab. In patients who have responded to treatment with ustekinumab, corticosteroids may be reduced or discontinued in accordance with standard of care

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In Crohn's disease or Ulcerative Colitis, if therapy is interrupted, resumption of treatment with subcutaneous dosing every 8 weeks is safe and effective

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Plaque psoriasis - moderate to severe
- After failure to respond to, or a contraindication to, or intolerance to other systemic therapies including ciclosporin, methotrexate (MTX) or PUVA (psoralen and ultraviolet A)
Psoriatic arthritis (Additional agent may be required)
- When the response to previous non-biological disease-modifying antirheumatic drug (DMARD) therapy has been inadequate

• SC: Initial: 45mg at week 0 and 4; Maintenance: 45mg, every 12 weeks
  OR
• SC: >100kg: Initial: 90mg at week 0 and 4; Maintenance: 90mg, every 12 weeks

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In these patients, 45mg was also shown to be efficacious. However, 90mg resulted in greater efficacy

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Consideration should be given to discontinuing treatment in patients who have shown no response up to 28 weeks of treatment

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South African manufacturer recommendations

Plaque psoriasis - moderate to severe
- In candidates for phototherapy or systemic therapy
Psoriatic arthritis - moderate to severe (Additional agent may be required)
- As second line treatment, when the response to previous disease-modifying antirheumatic drug (DMARDS) was inadequate

• SC: Initial: 45mg at week 0 and 4; Maintenance: 45mg, 12 weekly
  OR
• SC: >100kg: Initial: 90mg at week 0 and 4; Maintenance: 90mg, 12 weekly

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For patients with psoriasis, who inadequately respond to dosing every 12 weeks, consideration may be given to treating every 8 weeks

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Consideration should be given to discontinuing treatment in patients who have shown no response up to 28 weeks of treatment

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Re-treatment: For patients with psoriasis, re-treatment with a dosing regimen of weeks 0 and 4 after interruption of therapy has been shown to be safe and effective

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Crohn’s disease - moderate to severe
- Where an inadequate response with, loss of response to, or intolerance to either conventional therapy or a TNFα antagonist or medical contraindications to such therapies 

Initial single IV dosing

Body weight of patient at the time of dosing	Recommended dosea	Number of 130mg ustekinumab vials
≤55kg	260mg	2
>55kg-≤85kg	390mg	3
>85kg	520mg	4
aApproximately 6mg/kg

Maintenance dosing

• SC: Given at week 8 after IV dose: 90mg, Then: 90mg, every 8 weeks
  OR
• SC: Given at week 8 after IV dose: 90mg, Then: 90mg, every 12 weeks

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Patients who inadequately respond to 90mg subcutaneous dosing every 12 weeks may benefit from an increase in dosing frequency to every 8 weeks

---

Immunomodulators and/or corticosteroids may be continued during treatment with ustekinumab. In patients who have responded to treatment with ustekinumab, corticosteroids may be reduced or discontinued in accordance with standard of care. If therapy is interrupted, treatment may be resumed with subcutaneous dosing every 8 weeks

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

Paed. dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Plaque psoriasis - moderate to severe
- When inadequately controlled by, or intolerant to, other systemic therapies or phototherapies

Younger than 6 years

• Not established for use

6 years and older

• <60kg: SC: Initial: 0.75mg/kg at week 0 and 4; Maintenance: 0.75mg/kg, every 12 weeks
• ≥60kg-≤100kg: SC: Initial: 45mg at week 0 and 4; Maintenance: 45mg, every 12 weeks
• >100kg:  SC: Initial: 90mg at week 0 and 4; Maintenance: 90mg, every 12 weeks

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To calculate the volume of injection (mL) for patients <60kg, use the following formula: body weight (kg) x 0.0083 (mL/kg)
The calculated volume should be rounded to the nearest 0.01mL and administered using a 1mL graduated syringe. A 45 mg vial is available for paediatric patients who need to receive less than the full 45mg dose

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Consideration should be given to discontinuing treatment in patients who have shown no response up to 28 weeks of treatment

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Not established for use in children below 18 years in psoriatic arthritis, Crohn's disease or ulcerative colitis

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South African manufacturer recommendations

• Not established for use in children below 18 years

Pregnancy

International manufacturer recommendations

• Caution; not recommended 
• There are no adequate data from the use of ustekinumab in pregnant women
• Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development
• As a precautionary measure, it is preferable to avoid the use of ustekinumab in pregnancy
• Women of childbearing potential should use effective methods of contraception during treatment and for at least 15 weeks after treatment

South African manufacturer recommendations

• Caution; not recommended
• The safety of ustekinumab has not been established during pregnancy
• Ustekinumab should not be given to a pregnant woman except if the benefit clearly outweighs the risk

Breastfeeding

International manufacturer recommendations

• Caution; not recommended 
• It is unknown whether ustekinumab is excreted in human breast milk
• Animal studies have shown excretion of ustekinumab at low levels in breast milk. It is not known if ustekinumab is absorbed systemically after ingestion
• Because of the potential for adverse reactions in breastfeeding infants from ustekinumab, a decision on whether to discontinue breastfeeding during treatment and up to 15 weeks after treatment or to discontinue therapy with ustekinumab must be made taking into account the benefit of breastfeeding to the child and the benefit of ustekinumab therapy to the woman

South African manufacturer recommendations

• Caution; not recommended
• The safety of ustekinumab has not been established during breastfeeding
• It is unknown whether ustekinumab is excreted in human breast milk. Women are advised against breastfeeding while receiving ustekinumab

Fertility

International manufacturer recommendations

• The effect of ustekinumab on human fertility has not been evaluated

South African manufacturer recommendations

• No information available

Renal Impairment

• Caution; no information available 

Hepatic Impairment

• Caution; no information available 

Elderly

International manufacturer recommendations

Caution; no dose adjustment recommended 

South African manufacturer recommendations

• No dose adjustment recommended 

Porphyria Information

• Probably not porphyrinogenic (PNP)
  There is an increased risk of infection in patients on immunosuppressive therapy
  Monitor for signs and symptoms of infections or symptoms of porphyric attack

Drugs in Sport

Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Facial palsy
• Depression
• Fatigue

Respiratory Disorders

• Nasopharyngitis
• Upper respiratory tract infection (including viral)
• Sinusitis
• Lower respiratory tract infection
• Oropharyngeal pain
• Nasal congestion
• Allergic alveolitis
• Eosinophilic pneumonia
• Organising pneumonia

Gastrointestinal Disorders

• Dental infections
• Diarrhoea
• Nausea and vomiting

Genitourinary Disorders

• Vulvovaginal mycotic infection

Musculoskeletal Disorders

• Back pain
• Myalgia
• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity vasculitis
• Cellulitis
• Pruritus
• Pustular psoriasis
• Skin exfoliation
• Acne
• Exfoliative dermatitis
• Injection site erythema
• Injection site pain
• Injection site reactions
  - Haemorrhage
  - Haematoma
  - Induration
  - Swelling
  - Pruritus

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Rash
  - Urticaria
• Anaphylaxis
• Angioedema
• Herpes zoster

• Live viral vaccines
• Live bacterial vaccines
• Bacillus of Calmette and Guérin (BCG) vaccine

• Tuberculosis screening
• Full blood count with differential
• Complete metabolic panel
• Hepatitis C virus/hepatitis B virus (HBV) screening
• HIV screening
• Ustekinumab-antibody formation

Additional observations

• Signs or symptoms of:
  - Infection
  - Posterior reversible encephalopathy syndrome
  - Squamous cell skin carcinoma
• Active tuberculosis

Traceability

• In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded

Vaccinations

• It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin (BCG)) should not be given concurrently with ustekinumab
• Specific studies have not been conducted in patients who had recently received live viral or live bacterial vaccines
• No data are available on the secondary transmission of infection by live vaccines in patients receiving ustekinumab
• Before live viral or live bacterial vaccination, treatment with ustekinumab should be withheld for at least 15 weeks after the last dose and can be resumed at least 2 weeks after vaccination
• Patients receiving ustekinumab may receive concurrent inactivated or non-live vaccinations
• Long term treatment with ustekinumab does not suppress the humoral immune response to pneumococcal polysaccharide or tetanus vaccines

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the shared p40 protein subunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits the bioactivity of human IL-12 and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptor protein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that is already bound to IL-12Rβ1 cell surface receptors. Thus, ustekinumab is not likely to contribute to complement- or antibody-mediated cytotoxicity of cells with IL-12 and/or IL-23 receptors. IL-12 and IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells, such as macrophages and dendritic cells, and both cytokines participate in immune functions; IL-12 stimulates natural killer (NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype, IL-23 induces the T helper 17 (Th17) pathway. However, abnormal regulation of IL 12 and IL 23 has been associated with immune mediated diseases, such as psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis. By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis through interruption of the Th1 and Th17 cytokine pathways, which are central to the pathology of these diseases.

Injection (per 0.5ml) 45mg

• Stelara (Janssen) originator