Alimentary tract and metabolism products - enzymes

Galsulfase

Concentrate for solution for infusion. A clear to slightly opalescent, and colourless to pale yellow solution.

ach ml of solution contains 1 mg galsulfase. One vial of 5 ml contains 5 mg galsulfase. Galsulfase is a recombinant form of human N-acetylgalactosamine 4-sulfatase and is produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.

Naglazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Mucopolysaccharidosis VI (MPS VI; N-acetylgalactosamine 4-sulfatase deficiency; Maroteaux-Lamy syndrome).

As for all lysosomal genetic disorders, it is of primary importance, especially in severe forms, to initiate treatment as early as possible, before appearance of non-reversible clinical manifestations of the disease. A key issue is to treat young patients aged <5 years suffering from a severe form of the disease, even though patients <5 years were not included in the pivotal phase 3 study.

Naglazyme treatment should be supervised by a physician experienced in the management of patients with MPS VI or other inherited metabolic diseases. Administration of Naglazyme should be carried out in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available.

The recommended dosage regimen for galsulfase is 1 mg/kg body weight administered once every week as an intravenous infusion over 4 hours. The initial infusion rate is adjusted so that approximately 2.5% of the total solution is infused during the first hour, with infusion of the remaining volume (approximately 97.5%) over the next 3 hours.

Hypersensitivity to the active substance or to any of the excipients.

Caution must be exercised in the management and treatment of patients with compromised airways by limitation or careful monitoring of antihistamine and other sedative medication use. Institution of positive–airway pressure during sleep as well as potential tracheostomy in clinically appropriate situations should also be considered. Consider delaying Naglazyme infusions in patients who present with an acute febrile or respiratory illness. The safety and efficacy of Naglazyme in children below the age of 5 years and in patients older than 65 years have not been established. The safety and efficacy of Naglazyme in patients with renal or hepatic insufficiency have not been evaluated.

Patients treated with Naglazyme have developed infusion-associated reactions (IARs), defined as any drug-related adverse event occurring during the infusion or until the end of the infusion day. Based on data obtained during Naglazyme clinical trials, the majority of patients are expected to develop IgG antibodies to galsulfase within 4-8 weeks of treatment initiation. In the Naglazyme clinical trials, IARs were usually manageable by interrupting or slowing the rate of infusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol), thus enabling the patient to continue treatment. As there is little experience on resumption of treatment following prolonged interruption, caution is to be used due to the theoretical increased risk of hypersensitivity reaction. With administration of Naglazyme it is recommended that patients be administered pre-treatment medications (antihistamines with or without antipyretics) approximately 30-60 minutes prior to the start of the infusion, to minimize the potential occurrence of IARs.

In case of a mild or moderate IAR, treatment with antihistamines and paracetamol should be considered and/or a reduction in the infusion rate to half the rate at which the reaction occurred. In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and treatment with antihistamines and paracetamol should be considered. The infusion can be restarted with a reduction of the infusion rate to 50% – 25% of the rate at which the reaction occurred. In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pre-treatment should be considered (antihistamines and paracetamol and/or corticosteroids) and a reduction of the infusion rate to 50% – 25% of the rate at which the previous reaction occurred.

As with any intravenous protein product, severe allergic-type hypersensitivity reactions are possible. If these reactions occur, immediate discontinuation of Naglazyme is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment are to be observed.

No interaction studies have been performed. Pregnancy and lactation For Naglazyme, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryo-foetal development. Naglazyme should not be used during pregnancy unless clearly necessary.

It is not known whether galsulfase is excreted in milk, therefore breast-feeding should be stopped during Naglazyme treatment.

Infusion reactions, characterized by a recurring pattern of symptoms occurring during Naglazyme infusion, were observed in 30 (56%) of the 54 patients treated with Naglazyme across all clinical studies. Reactions began as early as Week 6 and as late as Week 55 of study drug treatment, and occurred during multiple infusions though not always in consecutive weeks.

The most common symptoms of these infusion reactions included fever, chills/rigors, rash, and urticaria, although hypotension, nausea, vomiting, dyspnoea, bronchospasm, retrosternal pain, abdominal pain, headache, malaise, respiratory stress, angioneurotic oedema and joint pain were also reported. 52/54 patients (96%) treated with Naglazyme across studies were positive for antibodies to galsulfase. The clinical significance of antibodies to galsulfase is not known.

BioMarin Europe Limited

(POM)