4.1. Therapeutic indications

Aldurazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency) to treat the non-neurological manifestations of the disease (see section 5.1).

4.2. Posology and method of administration

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 4.4.

For instruction on dilution of the medicinal product before administration, see section 6.6.

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.

If the patient experiences adverse reactions during the home infusion, the infusion process should be stopped immediately, and appropriate medical treatment should be initiated (see section 4.4). Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient care until no such adverse reaction is present.

4.3. Contraindications

Severe hypersensitivity (e.g. anaphylactic reaction) to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).

4.4. 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.

Hypersensitivity reactions (including anaphylaxis)

Hypersensitivity reactions, including anaphylaxis have been reported in patients treated with Aldurazyme (see section 4.8). 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.

Infusion-associated reactions (IARs)

IARs, defined as any related adverse event occurring during the infusion or until the end of the infusion day were reported in patients treated with Aldurazyme (see section 4.8).

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.

In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and symptomatic treatment (e.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.

In case of a mild or moderate IAR, symptomatic treatment (e.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 IARs should be treated with caution when administering Aldurazyme (see sections 4.3 and 4.8).

Patients treated with Aldurazyme should be closely monitored and all cases of infusion-associated reactions, delayed reactions and possible immunological reactions reported. Antibody status, including IgG, IgE, neutralizing antibodies for enzyme activity or enzyme reuptake, should be regularly monitored and reported.

In clinical studies IARs were usually manageable by slowing the rate of infusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol or ibuprofen), thus enabling the patient to continue treatment.

In patients with clinical decline, assessing urinary GAGs, ADA and neutralising antibodies should be considered (see section 4.8).

Excipients

This medicinal product contains 30 mg sodium per vial, equivalent to 1.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult, and is administered in 0.9% sodium chloride intravenous solution (see section 6.6).

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Based on its metabolism, laronidase is an unlikely candidate for Cytochrome P450 mediated interactions.

Aldurazyme should not be administered simultaneously with chloroquine or procaine due to a potential risk of interference with the intracellular uptake of laronidase.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are inadequate data on the use of Aldurazyme in pregnant women. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/foetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown. Therefore Aldurazyme should not be used during pregnancy unless clearly necessary.

Breast-feeding

Laronidase may be excreted in milk. Because there are no data available in neonates exposed to laronidase via breast milk, it is recommended to stop breast-feeding during Aldurazyme treatment.

Fertility

There are no clinical data on the effects of laronidase on fertility. Preclinical data did not reveal any significant adverse finding (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8. Undesirable effects

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.

Additionally, a few patients who had a prior history of severe MPS I- related upper airway and pulmonary involvement, experienced severe reactions including bronchospasm, respiratory arrest, and facial oedema (see section 4.4).

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

General disorders and administration site conditions

pyrexia

Very common

chills

Very common

Investigations

blood pressure increased

Very common

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 reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Inappropriate administration of laronidase (overdose and/or infusion rate higher than recommended) may be associated with adverse drug reactions. An excessively fast administration of laronidase may result in nausea, abdominal pain, headache, dizziness and dyspnoea.

In such situations and according to the patient's clinical status, the infusion should be stopped or the infusion rate slowed down immediately. If medically appropriate, further intervention may be indicated.