Abatacept

Registered South African indications:

• Rheumatoid arthritis
• Juvenile idiopathic arthritis

Contraindications

South African recommendations

• Known hypersensitivity to abatacept or any of its excipients
• Active or dormant untreated tuberculosis
• Pregnancy, or if a woman plans to become pregnant
• Mothers who are breastfeeding their infants

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Severe and uncontrolled infections such as sepsis and opportunistic infections

Cautions

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions) 
• Renal impairment
• Hepatic impairment
• Elderly
• Porphyria
• History of recurrent infections
• Underlying conditions predisposing patient to infections
• Latent tuberculosis
• Viral hepatitis
• Efficacy of live vaccines within 3 months of discontinuation of abatacept (See additional prescribing points)
• Children requiring immunization
• Autoimmune disorders (See additional prescribing points)
• Known malignancies
• Risk factors for skin cancer
• Blood glucose monitoring (IV) (see additional prescribing points)
• Sodium controlled diet (IV)
• May impair the ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: inf, pfs

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Rheumatoid arthritis (Additional agent may be required)
- For reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with active rheumatoid arthritis, as monotherapy or concomitantly with DMARDs (disease modifying antirheumatic drugs) other than tumour necrosis factor (TNF) blocking agents

125mg solution for subcutaneous injection

• SC: 125mg, weekly regardless of weight with or without an IV loading dose

Initiating therapy with an IV loading dose

• IV: Loading dose: Single IV infusion: Followed by: SC: First 125mg, within a day of the IV infusion; Thereafter: SC: 125mg once a week; If switching from IV therapy to SC administration, administer the first SC dose in place of the next scheduled IV dose

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See additional prescribing points for preparation and administration instructions for SC administration of abatacept 125mg

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250mg solution for infusion

• IV: Given as an infusion over 30min, utilising the weight range-based dosing specified in the table below; Following initial admin.: Give the next doses at 2 and 4 weeks after the first infusion; Thereafter: Admin. every 4 weeks

Body weight	Dose	Number of vials*
<60kg	500mg	2
60-100kg	750mg	3
>100kg	1000mg	4

*Each vial provides 250mg of abatacept

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Any unused portions in the vials must be immediately discarded

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For both the 125mg solution for subcutaneous injection and 250mg solution for infusion: Methotrexate, other non-biologic DMARDs, corticosteroids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be used during treatment with abatacept

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Abatacept should not be used with siliconised syringes
See additional prescribing points for method of administration

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

Paed. dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Juvenile idiopathic arthritis (JIA)
- Reducing signs and symptoms in paediatric patients with moderately to severely active polyarticular juvenile idiopathic arthritis and may be used as an adjunct therapy with other antirheumatic agents

250mg solution for infusion

Younger than 6 years

• Not established for use

Between 6-17 years

• <75kg: IV: 10mg/kg, based on the patient’s body weight at each admin. given as an infusion over 30min; Following initial admin.: Give the next doses at 2 and 4 weeks after the first infusion; Thereafter: Admin. every 4 weeks
• >75kg: IV: Given as an infusion over 30min, utilising the weight range-based dosing specified in the table below; Following initial admin.: Give the next doses at 2 and 4 weeks after the first infusion; Thereafter: Admin. every 4 weeks; Max: 1000mg/dose

Body weight	Dose	Number of vials*
60-100kg	750mg	3
>100kg	1000mg	4

*Each vial provides 250mg of abatacept

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Abatacept should not be administered concomitantly with TNF antagonists. Abatacept is not recommended for use concomitantly with other biologic rheumatoid arthritis therapy such as anakinra

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Methotrexate, other non-biologic DMARDs, corticosteroids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be used during treatment with abatacept

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Abatacept should not be used with siliconised syringes
See additional prescribing points for method of administration

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The safety and efficacy of abatacept solution for subcutaneous administration in children below 18 years of age have not been established. No data are available

Pregnancy

South African recommendations

• Contraindicated
• There are no studies in pregnant women
• Abatacept should not be used during pregnancy, or if a woman is planning to become pregnant
• Abatacept may cross the placenta into the serum of infants born to women treated with abatacept during pregnancy. Consequently, these infants may be at increased risk for infection
• The safety of administering live vaccines to infants exposed to abatacept in utero is unknown
• Administration of live vaccines to infants exposed to abatacept in utero is not recommended for 10 weeks following the mother's last exposure to abatacept during pregnancy

Recommendations in other jurisdictions

• Caution
• There is no adequate data from the use of abatacept in pregnant women. In pre-clinical embryo-foetal development studies, no undesirable effects were observed at doses up to 29-fold a human 10mg/kg dose based on AUC. In a pre- and postnatal development study in rats, limited changes in immune function were observed at 11-fold higher than a human 10 mg/kg dose based on AUC
• Abatacept should not be used in pregnant women unless clearly necessary. Women of childbearing potential should use effective contraception during treatment with abatacept and up to 14 weeks after the last dose of abatacept treatment
• Abatacept may cross the placenta into the serum of infants born to women treated with abatacept during pregnancy. Consequently, these infants may be at increased risk of infection. The safety of administering live vaccines to infants exposed to abatacept in utero is unknown. Administration of live vaccines to infants exposed to abatacept in utero is not recommended for 14 weeks following the mother's last exposure to abatacept during pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• Abatacept has been shown to be present in rat milk. It is not known whether abatacept is excreted in human milk
• Mothers should be instructed not to breastfeed if they are receiving abatacept

Recommendations in other jurisdictions

• Caution; not recommended
• Abatacept has been shown to be present in rat milk. It is not known whether abatacept is excreted in human milk. A risk to the newborns/infants cannot be excluded
• Breastfeeding should be discontinued during treatment with abatacept and for up to 14 weeks after the last dose of abatacept treatment

Fertility

• Formal studies of the potential effect of abatacept on human fertility have not been conducted
• In rats, abatacept had no undesirable effects on male or female fertility

Renal Impairment

• Caution; no information available

Hepatic Impairment

• Caution; no information available

Elderly

• Caution; no dose adjustment recommended 

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Immunosuppressive therapy increases infection risk and may trigger acute cases of porphyria

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Anxiety
• Sleep disorder
• Insomnia
• Headache
• Dizziness
• Paraesthesia
• Migraine
• Asthenia

Cardiovascular Disorders

• Palpitations
• Tachycardia
• Bradycardia
• Hypertension
• Hypotension
• Hot flush
• Vasculitis

Respiratory Disorders

• Upper respiratory tract infection
• Tracheitis
• Nasopharyngitis
• Sinusitis
• Lower respiratory tract infection
• Bronchitis
• Rhinitis
• Pneumonia
• Influenza
• Tuberculosis
• Malignant lung neoplasm
• Cough
• Bronchospasm
• Wheezing
• Dyspnoea
• Throat tightness
• Exacerbation of chronic obstructive pulmonary disease

Gastrointestinal Disorders

• Tooth infection
• Gastrointestinal infection
• Abdominal pain
• Diarrhoea
• Nausea and vomiting
• Dyspepsia
• Mouth ulceration
• Aphthous stomatitis
• Gastritis

Genitourinary Disorders

• Urinary tract infection
• Pyelonephritis
• Pelvic inflammatory disease
• Haematuria (in children)

Hepatobiliary Disorders

• Abnormal hepatic function tests

Endocrine and Metabolic Disorders

• Amenorrhoea
• Menorrhagia
• Increased weight

Musculoskeletal Disorders

• Arthralgia
• Musculoskeletal infections
• Pain in extremities

Skin and Subcutaneous Tissue Disorders

• Onychomycosis
• Skin abscess
• Basal cell and squamous cell carcinoma
• Skin papilloma
• Rash
• Alopecia
• Pruritus
• Increased tendency to bruise
• Dry skin
• Urticaria
• Psoriasis
• Acne
• Erythema
• Hyperhidrosis
• Flushing
• Infusion site extravasation
• Infusion site pain
• Infusion site swelling

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Leukopenia
• Thrombocytopenia
• Lymphoma
• Herpes infections
  - Herpes simplex
  - Oral herpes
  - Herpes zoster
• Sepsis
• Bacteraemia
• Influenza-like illness

Sensory Disorders

• Conjunctivitis
• Dry eye
• Reduced visual acuity
• Vertigo
• Ear infection

• Tumour necrosis factor inhibitors
• Biologic immunosuppressive agents
• Immunomodulatory agents
• Anakinra
• Rituximab
• Live vaccines

• Hepatitis screening
• Tuberculosis screening
• Skin examination

Specific cases may require

• Signs and symptoms of infection

Preparation and administration instructions for subcutaneous administration

• Abatacept 125mg solution for subcutaneous injection is not intended for IV infusion
• Abatacept solution for subcutaneous injection is intended for use under the guidance of a medical practitioner or healthcare practitioner
• After proper training in subcutaneous injection technique, a patient may self-inject with abatacept solution for subcutaneous injection if a doctor determines that it is appropriate
• Patients should be instructed to follow the detailed "Instructions for preparing and giving a subcutaneous injection of abatacept" provided at the end of the patient information leaflet (PIL)
• Abatacept should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit
• Do not use abatacept prefilled syringes exhibiting particulate matter or discolouration
• Abatacept solution for subcutaneous injection should be clear to slightly opalescent and colourless to pale yellow
• Any leftover product remaining in the prefilled syringe should not be used
• Patients using abatacept solution for subcutaneous injection should be instructed to inject the full amount in the syringe (1.0ml), which provides 125mg of abatacept, according to the directions provided in the PIL
• Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard

Method of administration (250mg solution for infusion)

• Use aseptic technique
• Abatacept is provided as a lyophilised powder in preservative-free, single-use vials
• Each vial of abatacept must be reconstituted with 10ml of sterile water for injection
• Immediately after reconstitution, the product must be further diluted to 100ml with 0.9% sodium chloride injection
• The infusion of the fully diluted abatacept solution must be completed within 24 hours of reconstitution of the abatacept vials
• The fully diluted abatacept solution may be stored at room temperature (up to 25°C) or refrigerated at 2°C to 8 °C before use
• Each abatacept vial provides 250mg of abatacept for administration
• Reconstitute the abatacept powder in each vial with 10ml of sterile water for injection using the silicone-free disposable syringe provided with each vial and an 18-21 gauge needle
• Remove the flip-top from the vial and wipe the top with an alcohol swab
• Insert the syringe needle into the vial through the centre of the rubber stopper and direct the stream of sterile water for injection to the glass wall of the vial
• Do not use the vial if the vacuum is not present
• To minimise foam formation, gently swirl the vial until the contents are completely dissolved
• Avoid prolonged or vigorous agitation. DO NOT SHAKE. Upon complete dissolution of the lyophilised powder, the vial should be vented with a needle to dissipate any foam that may be present
• The solution should be clear and colourless to pale yellow
• Do not use if opaque particles, discolouration, or other foreign particles are present
• After reconstitution, the concentration of abatacept in the vial will be 25mg/ml
• The reconstituted abatacept solution must be further diluted to 100ml with 0.9% sodium chloride injection. From a 100ml infusion bag or bottle, withdraw a volume of 0.9% sodium chloride injection equal to the volume of the reconstituted abatacept vials (for 2 vials remove 20ml, for 3 vials remove 30ml, for 4 vials remove 40ml)
• Slowly add the reconstituted abatacept solution to the infusion bag or bottle using a silicone-free disposable syringe provided with each vial and gently mix
• Do not shake the bag or bottle
• The concentration of the fully diluted abatacept solution in the infusion bag or bottle will depend on the number of vials used
• Any unused portions in the vials must be immediately discarded
• Prior to administration, visually inspect the abatacept solution for particulate matter and discolouration
• Discard the solution if any particulate matter or discolouration is observed
• Administer the entire, fully diluted abatacept solution over a period of 30 minutes
• Administer the solution with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2-1.2µm)
• Abatacept should not be infused concomitantly in the same intravenous line with other agents
• No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of abatacept with other agents

Autoimmune processes

• There is a theoretical concern that treatment with abatacept might increase the risk for autoimmune processes in adults and children, for example, deterioration of multiple sclerosis
• In the placebo-controlled clinical trials, abatacept treatment did not lead to increased autoantibody formation, such as antinuclear and anti-dsDNA antibodies, relative to placebo treatment

Blood glucose testing

• Parenteral medicinal products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ)
• The GDH-PQQ based glucose monitoring systems may react with the maltose present in abatacept, resulting in falsely elevating blood glucose readings on the day of infusion
• When receiving abatacept, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods

Vaccinations

• Patients treated with abatacept may receive concurrent vaccinations, except for live vaccines
• Live vaccines should not be given concurrently with abatacept or within 3 months of its discontinuation
• Medicinal products that affect the immune system, including abatacept, may blunt the effectiveness of some immunisations
• It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating abatacept therapy

Traceability

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

Abatacept selectively modulates a key costimulatory signal required for full activation of T lymphocytes expressing CD28. Full activation of T lymphocytes requires two signals provided by antigen presenting cells: recognition of a specific antigen by a T cell receptor (signal 1) and a second, costimulatory signal. A major costimulatory pathway involves the binding of CD80 and CD86 molecules on the surface of antigen presenting cells to the CD28 receptor on T lymphocytes (signal 2). Abatacept selectively inhibits this costimulatory pathway by specifically binding to CD80 and CD86. Studies in vitro and in animal models demonstrate that abatacept modulates T lymphocyte-dependent antibody responses and inflammation. In vitro, abatacept attenuates human T lymphocyte activation as measured by decreased proliferation and cytokine production. Abatacept decreases antigen specific TNFα, interferon-γ, and interleukin-2 production by T lymphocytes.

Injection (per 1ml) 125mg

• Orencia pre-filled (Bristol-Myers Squibb) originator

Injection (per 10ml) 250mg

• Orencia (Bristol-Myers Squibb) originator