Drugs List

Therapeutic Indications

Uses

Enzyme replacement therapy - Fabry disease

Contraindications

Children under 7 years
Patients over 65 years

Precautions and Warnings

Breastfeeding
Pregnancy

Allergic disposition: consider prophylactic antihistamine & corticosteroid
Treatment to be initiated and supervised by a specialist
Administer reconstituted solution immediately
Slow infusion and treat non life threatening allergic reactions accordingly
Monitor patient for infusion-associated reactions (IARs)
Antibodies to ingredient may develop
Discontinue if serious allergic or anaphylactic reaction occurs

Patient may develop IgG antibodies to agalsidase alfa. Antibodies typically develop after 3 to 12 months of treatment. After 12 to 54 months, some cases of immune tolerance (disappearance of the antibody over time) have been reported.
Borderline IgE antibody positivity not associated with anaphylaxis has been reported in clinical trials in a very limited number of patients.
Antibodies to agalsidase alfa have not been shown to be associated with any clinically significant effects on safety (e.g. infusion reactions) or efficacy.

A review of cardiac effects showed that infusion reactions may be associated with haemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease.

Infusion reactions may generally occur within the first 2 to 4 months after initiation of treatment, although later onset (after 1 year) have also been reported. The infusion can be temporarily interrupted (5 to 10 minutes) until symptoms subside and the infusion may be restarted.
Infusion related reactions can be minimised by pre-treatment with antihistamines and/or corticosteroids from 1 to 24 hours prior to infusion.

Pregnancy and Lactation

Pregnancy

Agalsidase alfa should be used with caution during pregnancy.

Very limited clinical data exists and is not known whether agalsidase alfa crosses the placenta. No adverse effects on mother and newborn child have been seen in the small number of exposed pregnancies.
The animal data, involving only one species, suggests low risk, but the near absence of human pregnancy experience prevents a more complete assessment of the embryofetal risk. However, Fabry disease is a debilitating condition that can be markedly improved by the use of enzyme replacement therapy. Thus, Briggs concludes that if a woman requires enzyme replacement therapy and gives informed consent, this formulation should not be withheld because of pregnancy.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Agalsidase alfa should be used with caution during breastfeeding.

It is not known whether agalsidase alfa is excreted in breast milk. The molecular weight of the enzyme (about 100,000) and short plasma elimination half life (45-102 minutes) suggest that it will not be excreted into breast milk. Even if excretion does occur, the enzyme probably would be digested in the nursing infant's gut (Briggs, 2011).

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acne
Altered temperature sensation
Angioedema
Angioneurotic oedema
Arthralgia
Asthenia
Atrial fibrillation
Back pain
Bradycardia
Cardiac failure
Chest pain
Chest tightness
Corneal reflex decreased
Cough
Diarrhoea
Dizziness
Dysgeusia
Dyspnoea
Ear pain
Erythema
Fatigue
Flushing
Headache
Hoarseness
Hyperhidrosis
Hypersensitivity reactions including anaphylaxis
Hypersomnia
Hypertension
Hypoesthesia
Hypotension
Increased oropharyngeal secretions
Influenza-like symptoms
Injection site reactions
Joint swelling
Lacrimation disorder
Limb pain
Livedo reticularis
Malaise
Musculoskeletal pain
Myalgia
Myocardial ischaemia
Nasopharyngitis
Nausea
Neuropathy
Oxygen saturation decreased
Pain - generalised
Palpitations
Paraesthesia
Parosmia
Peripheral oedema
Pharyngitis
Pruritus
Pyrexia
Rash
Rhinorrhoea
Rigors
Sensation of heaviness
Skin discolouration
Syncope
Tachyarrhythmia
Tachycardia
Throat tightness
Tinnitus
Tremor
Urticaria
Ventricular extrasystoles
Vomiting

Presentation

Infusions of agalsidase alfa.
Agalsidase alfa is a recombinant form of alfa-galactosidase A produced in a human cell line by genetic engineering technology.

Drugs List

Therapeutic Indications

Uses

Enzyme replacement therapy - Fabry disease

Dosage

Adults

Elderly

Children

Patients with Renal Impairment

Contraindications

Children under 7 years
Patients over 65 years

Precautions and Warnings

Breastfeeding
Pregnancy

Allergic disposition: consider prophylactic antihistamine & corticosteroid
Treatment to be initiated and supervised by a specialist
Administer reconstituted solution immediately
Slow infusion and treat non life threatening allergic reactions accordingly
Monitor patient for infusion-associated reactions (IARs)
Antibodies to ingredient may develop
Discontinue if serious allergic or anaphylactic reaction occurs

Patient may develop IgG antibodies to agalsidase alfa. Antibodies typically develop after 3 to 12 months of treatment. After 12 to 54 months, some cases of immune tolerance (disappearance of the antibody over time) have been reported.
Borderline IgE antibody positivity not associated with anaphylaxis has been reported in clinical trials in a very limited number of patients.
Antibodies to agalsidase alfa have not been shown to be associated with any clinically significant effects on safety (e.g. infusion reactions) or efficacy.

A review of cardiac effects showed that infusion reactions may be associated with haemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease.

Infusion reactions may generally occur within the first 2 to 4 months after initiation of treatment, although later onset (after 1 year) have also been reported. The infusion can be temporarily interrupted (5 to 10 minutes) until symptoms subside and the infusion may be restarted.
Infusion related reactions can be minimised by pre-treatment with antihistamines and/or corticosteroids from 1 to 24 hours prior to infusion.

Pregnancy and Lactation

Pregnancy

Agalsidase alfa should be used with caution during pregnancy.

Very limited clinical data exists and is not known whether agalsidase alfa crosses the placenta. No adverse effects on mother and newborn child have been seen in the small number of exposed pregnancies.
The animal data, involving only one species, suggests low risk, but the near absence of human pregnancy experience prevents a more complete assessment of the embryofetal risk. However, Fabry disease is a debilitating condition that can be markedly improved by the use of enzyme replacement therapy. Thus, Briggs concludes that if a woman requires enzyme replacement therapy and gives informed consent, this formulation should not be withheld because of pregnancy.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Agalsidase alfa should be used with caution during breastfeeding.

It is not known whether agalsidase alfa is excreted in breast milk. The molecular weight of the enzyme (about 100,000) and short plasma elimination half life (45-102 minutes) suggest that it will not be excreted into breast milk. Even if excretion does occur, the enzyme probably would be digested in the nursing infant's gut (Briggs, 2011).

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acne
Altered temperature sensation
Angioedema
Angioneurotic oedema
Arthralgia
Asthenia
Atrial fibrillation
Back pain
Bradycardia
Cardiac failure
Chest pain
Chest tightness
Corneal reflex decreased
Cough
Diarrhoea
Dizziness
Dysgeusia
Dyspnoea
Ear pain
Erythema
Fatigue
Flushing
Headache
Hoarseness
Hyperhidrosis
Hypersensitivity reactions including anaphylaxis
Hypersomnia
Hypertension
Hypoesthesia
Hypotension
Increased oropharyngeal secretions
Influenza-like symptoms
Injection site reactions
Joint swelling
Lacrimation disorder
Limb pain
Livedo reticularis
Malaise
Musculoskeletal pain
Myalgia
Myocardial ischaemia
Nasopharyngitis
Nausea
Neuropathy
Oxygen saturation decreased
Pain - generalised
Palpitations
Paraesthesia
Parosmia
Peripheral oedema
Pharyngitis
Pruritus
Pyrexia
Rash
Rhinorrhoea
Rigors
Sensation of heaviness
Skin discolouration
Syncope
Tachyarrhythmia
Tachycardia
Throat tightness
Tinnitus
Tremor
Urticaria
Ventricular extrasystoles
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: February 2015.

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press. Accessed on 18 February 2015.

Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications. Accessed on 18 February 2015.

Summary of Product Characteristics: Replagal 1mg/ml concentrate for solution for infusion. Shire Human Genetic Therapies. Revised 27 July 2014.