Laronidase
Adverse Effects, Treatment, and Precautions
Infusion reactions have been reported in patients given laronidase. Common symptoms include flushing, fever, rigors, headache, and rash; symptoms reported less commonly include cough, bronchospasm, dyspnoea, vomiting urticaria, angioedema, and pruritus. Antihistamines and/or antipyretics (e.g. paracetamol or ibuprofen) may relieve symptoms. A reduction in the rate of infusion to half the rate at which the reaction occurred should also be considered for mild reactions; for severe reactions, the infusion should be stopped until symptoms have subsided, and then restarted at one-half to one-quarter the rate at which the reaction occurred. Adrenaline should be used with caution because there is a greater incidence of coronary artery disease in patients with mucopolysaccharidosis I. Pre-treatment with antihistamines and/or antipyretics about 60 minutes before infusion is recommended to prevent reactions. IgG antibodies to laronidase are expected to develop within 3 months of starting treatment in the majority of patients, although the effect of this on safety and efficacy is not clear. However, such patients may be at increased risk of hypersensitivity reactions and should be treated with caution. Injection site reactions have also been reported.
Interactions
Licensed product information for laronidase recommends that it should not be given with chloroquine or procaine because of the potential risk of interference with the intracellular uptake of the enzyme.
Uses and Administration
Laronidase is recombinant human ?-l-iduronidase and is used as enzyme replacement therapy for the treatment of the non-neurological manifestations of mucopolysaccharidosis I .For patients 5 years of age and older, it is given by intravenous infusion in a dose of 100 units/kg each week. The initial infusion rate should be 2 units/kg per hour, increased every 15 minutes during the first hour, as tolerated, to a maximum of 43 units/kg per hour such that the infusion is completed in about 3 to 4 hours (but see also under Adverse Effects, Treatment, and Precautions ). In some countries, the dose is expressed as mg/kg: 100 units is equivalent to about 0.58 mg of laronidase.
Mucopolysaccharidosis I.
Mucopolysaccharidosis I is a progressive disorder characterised by deficiency of the enzyme ?-l-iduronidase, which is necessary to catalyse the hydrolysis of terminal ?-l-iduronic residues of the glycosaminoglycans, dermatan sulfate and heparan sulfate. This results in their accumulation in tissues, with many clinical manifestations including hepatomegaly, skeletal abnormalities, pulmonary disease, eye disease, and progressive deterioration of the CNS. Mucopolysaccharidosis I has traditionally been classified into three main forms based on clinical symptoms and severity: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome. Hurler syndrome is the most severe form with a life expectancy of less than 10 years. However, there is a degree of overlap between the syndromes and they are indistinguishable by routine enzyme or urine tests.
Treatment was previously limited to symptomatic management but other options to halt disease progression are now available. Haematopoietic stem-cell transplantation using bone marrow or umbilical cord blood is of benefit in systemic disease and can prevent (but not usually reverse) CNS deterioration. However, substantial adverse effects limit its use to patients with severe disease. Enzyme replacement therapy with laronidase has been reported to confer benefit on the systemic manifestations of the disease, but since it does not cross the blood-brain barrier in appreciable amounts, beneficial effect on CNS symptoms is again predicted to be unlikely. However, the improvements conferred by enzyme replacement therapy might make haematopoietic stem-cell transplantation easier to tolerate.