Agalsidase Alfa

Registered South African indications:

• Fabry disease

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
  - Extensive renal damage (eGFR<60ml/min/1.73m²)
• Hepatic impairment
• Elderly
• IgE antibody positivity
  (See additional prescribing points)
• Pre-existing cardiac manifestations of Fabry disease

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

Treatment should be supervised by a physician experienced in the management of patients with Fabry disease or other inherited metabolic diseases

Fabry disease (α-galactosidase A deficiency)
- Long-term enzyme replacement therapy in those with a confirmed diagnosis of Fabry disease

• IV: 0.2mg/kg, as an infusion over 40min, administered once every other week

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Infusion of agalsidase alfa at home may be considered for patients who are tolerating their infusions well

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Administration directions (See additional prescribing points)

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

Treatment should be supervised by a physician experienced in the management of patients with Fabry disease or other inherited metabolic diseases

Fabry disease (α-galactosidase A deficiency)
- Long-term enzyme replacement therapy in those with a confirmed diagnosis of Fabry disease

Between 0-6 years

• Not established for use

Between 7-18 years

• See adult dosage

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Infusion of agalsidase alfa at home may be considered for patients who are tolerating their infusions well

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Administration directions (See additional prescribing points)

Pregnancy

South African manufacturer recommendations

• Caution; no evidence of risk in studies
• Caution should be exercised when prescribing to pregnant women
• Very limited clinical data on pregnancies exposed to agalsidase alfa (n=4) have shown no adverse effects on the mother and newborn child

International manufacturer recommendations

• Caution; no evidence of risk in studies
• Caution should be exercised when prescribing to pregnant women
• There is very limited data on pregnancies exposed to agalsidase alfa
• Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryonic/ fetal development when exposed during organogenesis
• Reproduction toxicity studies in female rats and rabbits have shown no effect on pregnancy or the developing foetus
• No studies have been conducted with respect to parturition or peri/ post-natal development
• It is not known whether agalsidase alfa crosses the placenta

Breastfeeding

• Caution 
• Caution should be exercised when prescribing to breastfeeding women
• It is not known whether agalsidase alfa is excreted in human milk

Fertility

South African manufacturer recommendations

• No information available

International manufacturer recommendations

• No effects on male fertility were seen in reproductive studies in male rats

Renal Impairment

• Caution: No dose adjustment recommended 
  No dose adjustment is necessary in patients with renal impairment
  Limited data are available in patients on dialysis or post renal transplantation, no dose adjustment is recommended
  The presence of extensive renal damage (eGFR<60ml/min/1.73m²) may limit the renal response to enzyme replacement therapy, possibly due to underlying irreversible pathological changes. In such cases, the loss of renal function remains within the expected range of the natural progression of disease

Hepatic Impairment

• Caution; no information available 
  No studies have been performed in patients with hepatic impairment

Elderly

• Caution; no information available 
  Studies in patients >65 years have not been performed and no dosage regimen can presently be recommended in these patients as safety and efficacy have not yet been established

Porphyria Information

• Not porphyrinogenic (NP) 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Neuropathic pain
• Tremor
• Hypoesthesia
• Paraesthesia
• Pain
• Fatigue
  - Aggravated fatigue
• Discomfort
• Hypersomnia

Cardiovascular Disorders

• Palpitations
• Chest pain
• Tachycardia
• Atrial fibrillation
• Tachyarrhythmia
• Hypertension
• Hypotension
• Flushing
• Chest tightness
• Myocardial ischaemia
• Heart failure
• Ventricular extrasystoles

Respiratory Disorders

• Dyspnoea
• Cough
• Nasopharyngitis
• Pharyngitis
• Hoarseness
• Throat tightness
• Rhinorrhoea
• Decreased oxygen saturation
• Increased throat secretion

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea
• Abdominal discomfort

Musculoskeletal Disorders

• Arthralgia
• Pain in limb
• Myalgia
• Back pain
• Musculoskeletal discomfort
• Peripheral swelling
• Joint swelling
• Sensation of heaviness

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria
• Erythema
• Pruritus
• Acne
• Hyperhidrosis
• Livedo reticularis
• Injection site rash

Immune, Blood and Lymphatic System Disorders

• Peripheral oedema
• Pyrexia
• Rigors
• Hypersensitivity
• Influenza-like illness
• Anaphylactic reaction
• Angioneurotic oedema
• Idiosyncratic infusion-related reactions
  (See additional prescribing points)
• Formation of IgG antibodies

Sensory Disorders

• Tinnitus
• Aggravated tinnitus
• Increased lacrimation
• Decreased corneal reflex
• Dysgeusia
• Parosmia

Others

• Feeling hot
• Feeling cold

• Chloroquine
• Amiodarone
• Benoquin
• Gentamicin

None routine

Additional observations

• Signs and symptoms of infusion-related reactions
  - Fever
  - Rigors
  - Tachycardia
  - Hypertension
  - Hypotension
  - Dyspnoea

Method of administration

• Calculate the dose and number of agalsidase alfa vials needed
• Dilute the total volume of agalsidase alfa concentrate required in 100ml of 9mg/ml (0.9%) sodium chloride solution for infusion
• Care must be taken to ensure the sterility of the prepared solutions since agalsidase alfa does not contain any preservative or bacteriostatic agent; aseptic technique must be observed
• Once diluted, the solution should be mixed gently but not shaken
• Since no preservative is present, it is recommended that administration is started as soon as possible after dilution
• The solution should be inspected visually for particulate matter and discolouration prior to administration
• For single use only. Any unused product or waste material should be disposed of in accordance with local requirements
• In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products and should not be infused concomitantly in the same intravenous line with other agents
• Administer the infusion solution over a period of 40 minutes using an intravenous line with an integral filter

Traceability

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

Idiosyncratic infusion related reactions

•  A review of cardiac events showed that infusion reactions may be associated with hemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease
• The onset of infusion related reactions has generally occurred within the first 2-4 months after initiation of treatment with agalsidase alfa although later onset (after 1 year) has been reported as well. These effects have decreased with time
• If mild or moderate acute infusion reactions occur, medical attention must be sought immediately and appropriate actions instituted
• The infusion can be temporarily interrupted (5-10 minutes) until symptoms subside and the infusion may then be restarted
• Mild and transient effects may not require medical treatment or discontinuation of the infusion. In addition, oral or intravenous pre-treatment with antihistamines and/or corticosteroids, from 1-24 hours prior to infusion may prevent subsequent reactions in those cases where symptomatic treatment was required

Antibodies to the protein

• As with all protein pharmaceutical agents, patients may develop antibodies to the protein
• A low titre IgG antibody response has been observed in approximately 24% of the male patients treated with agalsidase alfa
• Based on limited data this percentage has been found to be lower (7%) in the male paediatric population
• These IgG antibodies appeared to develop following approximately 3-12 months of treatment
• After 12-54 months of therapy, 17% of agalsidase alfa treated patients were still antibody positive whereas 7% showed evidence for the development of immunologic tolerance, based on the disappearance of IgG antibodies over time. The remaining 76% were antibody negative throughout
• In paediatric patients >7 years of age, 1/16 male patients tested positive for IgG anti-agalsidase alfa antibodies during the study. No increase in the incidence of adverse events was detected for this patient
• In paediatric patients <7 years of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies
• IgE antibody positivity not associated with anaphylaxis has been reported in clinical trials in a very limited number of patients

Agalsidase alfa is used to treat Fabry disease. Fabry disease is a glycosphingolipid storage disorder that is caused by deficient activity of the lysosomal enzyme α-galactosidase A, resulting in accumulation of globotriaosylceramide (Gb3 or GL- 3, also known as ceramidetrihexoside (CTH)), the glycosphingolipid substrate for this enzyme. Agalsidase alfa catalyses the hydrolysis of Gb3, cleaving a terminal galactose residue from the molecule. Treatment with the enzyme has been shown to reduce accumulation of Gb3 in many cell types including endothelial and parenchymal cells. Agalsidase alfa has been produced in a human cell line to provide for a human glycosylation profile that can influence uptake by mannose-6-phosphate receptors on the surface of target cells.

Infusion (per ml) 1mg

• Replagal (Takeda) originator