ALDURAZYME

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

Posology The recommended dosage regimen of Aldurazyme is 100 U/kg body weight administered once every week. Paediatric population No dose adjustment is necessary for the paediatric population. Elderly The safety and efficacy of Aldurazyme in patients older than 65 years have not been established and no dosage regimen can be recommended in these patients.

Renal and hepatic impairment The safety and efficacy of Aldurazyme in patients with renal or hepatic insufficiency have not been evaluated and no dosage regimen can be recommended in these patients. Method of administration Aldurazyme is to be administered as an intravenous infusion.

The initial infusion rate of 2 U/kg/h may be incrementally increased every fifteen minutes, if tolerated, to a maximum of 43 U/kg/h. The total volume of the administration should be delivered in approximately 3-4 hours. For information on pre-treatment, see section

Summary of the safety profile The majority of the related adverse events in the clinical trials were classified as infusion-associated reactions (IARs), experienced by 53% of the patients in the Phase 3 study (treated for up to 4 years) and 35% of the patients in the under 5 study (up to 1 year of treatment).

Some of the IARs were severe. Over time the number of these reactions decreased. The most frequent adverse drug reactions (ADRs) were: headache, nausea, abdominal pain, rash, arthralgia, backpain, pain at extremity, flushing, pyrexia, infusion site reactions, blood pressure increased, oxygen saturation decreased, tachycardia and chills.

Post-marketing experience of infusion-associated reactions revealed reporting of cyanosis, hypoxia, tachypnoea, pyrexia, vomiting, chills and erythema, in which some of these reactions were severe. Tabulated list of adverse reactions ADRs to Aldurazyme reported during the Phase 3 study and its extension in a total of 45 patients age 5 years and older and treated up to 4 years are listed below using the following categories of frequency: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Due to the small patient population, an ADR reported in a single patient is classified as common. MedDRA System Organ Class Very common Common Not known Immune system disorders Anaphylactic reaction Hypersensitivity Psychiatric disorders Restlessness Nervous system disorders Headache Paraesthesia, dizziness Cardiac disorders Tachycardia Bradycardia Vascular disorders Flushing Hypotension, pallor, peripheral coldness Hypertension Respiratory, thoracic and mediastinal disorders Respiratory distress, dyspnoea, cough Cyanosis, hypoxia, tachypnoea, bronchospasm, respiratory arrest, laryngeal oedema, respiratory failure, pharyngeal swelling, stridor, obstructive airways disorder Gastrointestinal disorders Nausea, abdominal pain Vomiting, diarrhoea Lip swelling, swollen tongue Skin and subcutaneous tissue disorders Rash Angioedema, swelling face, urticaria, pruritus, cold sweat, alopecia, hyperhidrosis Erythema, facial oedema Musculoskeletal and connective tissue disorders Arthropathy, arthralgia, back pain, pain in extremity Musculoskeletal pain General disorders and administration site conditions Pyrexia, infusion site reaction* Chills, feeling hot, feeling cold, fatigue, influenza like illness, injection site pain Extravasation, oedema peripheral Investigations Body temperature increased, oxygen saturation decreased Drug specific antibody, neutralizing antibodies, blood pressure increased * During clinical trials and post-marketing experience, infusion/injection site reactions notably included: swelling, erythema, oedema, discomfort, urticaria, pallor, macule, and warmth.

A single patient with pre-existing airway compromise developed a severe reaction three hours from the start of the infusion (at week 62 of treatment) consisting of urticaria and airway obstruction, requiring tracheostomy. This patient tested positive for IgE.

4). Paediatric population ADRs to Aldurazyme reported during a Phase 2 study in a total of 20 patients, under 5 years of age and mainly of the severe phenotype, treated up to 12 months are listed below. ADRs were all mild to moderate in severity.

MedDRA System Organ Class MedDRA Preferred term Frequency Cardiac disorders tachycardia Very common pyrexia Very commonGeneral disorders and administration site conditions chills Very common blood pressure increased Very common Investigations oxygen saturation decreased Very common In a phase 4 study 33 MPS I patients received 1 of 4 dose regimens: 100 U/kg IV every week (recommended dose), 200 U/kg IV every week, 200 U/kg IV every 2 weeks or 300 U/kg IV every 2 weeks.

The recommended dose group had the fewest number of patients who experienced ADRs and IARs. The type of IARs was similar to those seen in other clinical studies. Description of selected adverse reactions Immunogenicity Almost all patients developed IgG antibodies to laronidase.

Most patients seroconverted within 3 months of initiation of treatment; although seroconversion in patients under 5 years old with a more severe phenotype occurred mostly within 1 month (mean 26 days versus 45 days in patients 5 years and older).

By the end of the Phase 3 study (or at time of early study withdrawal), 13/45 patients had no detectable antibodies by radioimmunoprecipitation (RIP) assay, including 3 patients that had never seroconverted. Patients with absent to low antibody levels showed a robust reduction in urinary GAG level, whereas patients with high antibody titres showed variable reduction in urinary GAG.

In addition, higher ADA titres were also observed in MPS I Registry patients with severe disease. Patients with persistently high ADA titres tended to have less reduction in urinary GAG. In the Phase 2 and 3 studies, 60 patients were tested for in-vitro neutralising effects.

Four patients (three in the Phase 3 study and one in the Phase 2 study) showed marginal to low level in vitro inhibition of laronidase enzymatic activity, which did not appear to impact clinical efficacy and/or urinary GAG reduction.

In patients with clinical decline, assessing urinary GAGs, ADA and neutralising antibodies should be considered. The presence of antibodies was not consistently related to the incidence of IARs, although the onset of IARs typically coincided with the formation of IgG antibodies.

Clinical trials and observational studies show only a small number of patients have tested positive for IgE antibodies. The development of IgE antibodies may be associated with hypersensitivity or anaphylactic […]

4. 6. Home Infusion Infusion of Aldurazyme at home may be considered for patients who are tolerating their infusions well and have no history of moderate or severe IARs for a few months. The decision to have a patient move to home infusion should be made after evaluation and upon recommendation by the treating physician.

Home infusion infrastructure, resources, and procedures, including training, must be established and available to the healthcare professional. Home infusion should be supervised by a healthcare professional who should be always available during the home infusion and for a specified time after infusion.

Appropriate information should be given by the treating physician and/or nurse to the patient and/or caregiver prior to initiation of home infusion. Dose and infusion rate should remain constant while at home, and not be changed without supervision of a healthcare professional.

4). Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient care until no such adverse reaction is present. g. 8). 4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

8). Some of these reactions were life threatening and included respiratory failure/distress, stridor, obstructive airways disorder, hypoxia, hypotension, bradycardia, and urticaria. Appropriate medical support measures, including cardiopulmonary resuscitation equipment should be readily available when Aldurazyme is administered.

If anaphylaxis or other severe hypersensitivity reactions occur, the infusion of Aldurazyme should be discontinued immediately. Caution should be exercised if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients.

In patients with severe hypersensitivity, desensitization procedure to Aldurazyme may be considered. If the decision is made to re-administer the product, extreme care should be exercised, with appropriate resuscitation measures available.

If mild or moderate hypersensitivity reactions occur, the infusion rate may be slowed or temporarily stopped. Once a patient tolerates the infusion, the dose may be increased to reach the approved dose. 8). Patients with an acute underlying illness at the time of Aldurazyme infusion appear to be at greater risk for IARs.

Careful consideration should be given to the patient’s clinical status prior to administration of Aldurazyme. With initial administration of Aldurazyme or upon re-administration following interruption of treatment, it is recommended that patients be administered pre-treatment medicines (antihistamines and/or antipyretics) approximately 60 minutes prior to the start of the infusion, to minimise the potential occurrence of IARs.

If clinically indicated, administration of pre-treatment medications with subsequent infusions of Aldurazyme should be considered. As there is little experience on resumption of treatment following prolonged interruption, use caution due to the theoretical increased risk of hypersensitivity reaction after treatment interruption.

Severe IARs have been reported in patients with pre-existent severe underlying upper airway involvement and therefore specifically these patients should continue to be closely monitored and only be infused with Aldurazyme in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available.

g. with antihistamines and antipyretics/anti-inflammatories) should be considered. The benefits and risk of re-administering Aldurazyme following severe IARs should be considered. The infusion can be restarted with a reduction of the infusion rate to 1/2 – 1/4 the rate of the infusion 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 antipyretics/anti-inflammatories and/or corticosteroids) and a reduction of the infusion rate to 1/2 – 1/4 the rate of the infusion at which the previous reaction occurred.

g. with antihistamines and antipyretics/anti-inflammatories) should be considered and/or a reduction in the infusion rate to half the infusion rate at which the reaction occurred. Once a patient tolerates the infusion, the dose may be increased to reach the approved dose.

Immunogenicity Based on the randomized, double-blind, placebo-controlled Phase 3 clinical trial, almost all patients are expected to develop IgG antibodies to laronidase, mostly within 3 months of initiation of treatment. As with any intravenous protein medicinal product, severe allergic-type hypersensitivity reactions are possible.

IARs and hypersensitivity reactions may occur independently of the development of anti-drug antibodies (ADAs). Patients who have developed antibodies or symptoms of […]

g. 8).