Aldazyme

1 ml contains 100 U (approximately 0.58 mg) of laronidase.

Each vial of 5 ml contains 500 U of laronidase.

The activity unit (U) is defined as the hydrolysis of one micromole of substrate (4-MUI) per minute.

Laronidase is a recombinant form of human α-L-iduronidase and is produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.

Excipient(s) with known effect:

Each vial of 5 ml contains 1.29 mmol sodium.

Concentrate for solution for infusion.

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

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.

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.

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

Infusion-associated reactions

Patients treated with Aldurazyme may develop infusion-associated reactions (IARs), defined as any related adverse event occurring during the infusion or until the end of the infusion day. Some of these IARs may be severe (see below).

Patients treated with Aldurazyme should be closely monitored and all cases of infusion-associated reactions, delayed reactions and possible immunological reactions reported. Antibody status should be regularly monitored and reported.

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.

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.

Based on the Phase 3 clinical trial, almost all patients are expected to develop IgG antibodies to laronidase, mostly within 3 months of initiation of treatment.

Patients who have developed antibodies or symptoms of IARs should be treated with caution when administering Aldurazyme.

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.

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.

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.

In case of a mild or moderate IAR, treatment with antihistamines and paracetamol/ibuprofen should be considered and/or a reduction in the infusion rate to half the infusion 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/ibuprofen 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 paracetamol/ibuprofen 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.

As with any intravenous protein product, severe allergic-type hypersensitivity reactions are possible.

If these reactions occur, immediate discontinuation of Aldurazyme is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment are to be observed.

Excipients

This medicinal product contains sodium and is administered in 0.9% sodium chloride intravenous solution. To be taken into consideration by patients on a controlled sodium diet.

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.

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. 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.

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

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.

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.

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.

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 titers showed variable reduction in urinary GAG. The clinical significance of this finding is unknown since there were no consistent relationships between IgG antibody level and clinical efficacy endpoints.

In addition 60 patients in the Phase 2 and 3 studies 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.

The presence of antibodies did not appear to be related to the incidence of IARs, although the onset of IARs typically coincided with the formation of IgG antibodies. The occurrence of IgE antibodies was not fully explored.

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 national reporting system below.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

After intravenous administration of laronidase with an infusion time of 240 minutes and at a dose of 100 U/kg body weight pharmacokinetic properties were measured at Weeks 1, 12 and 26.

C_max showed an increase over time. The volume of distribution decreased with continued treatment, possibly related to antibody formation and/or decreased liver volume.

The pharmacokinetic profile in patients less than 5 years old was similar to that of older and less severely affected patients.

Laronidase is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of laronidase in a clinically significant way. Renal elimination of laronidase is considered to be a minor pathway for clearance.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity and toxicity to reproduction. Genotoxic and carcinogenic potential are not expected.

Unopened vials:

3 years

Diluted solutions:

From a microbiological safety point of view, the product should be used immediately. If not used immediately, in-use storage should not be longer than 24 hours at 2°C - 8°C provided that dilution has taken place under controlled and validated aseptic conditions.

Store in a refrigerator (2°C - 8°C).