Medicinal Products

ALDURAZYME 100 U / mL

Generic drug of the therapeutic class: Metabolism and nutrition
active ingredients: Laronidase
laboratory: Genzyme Europe BV

Solution for solution for IV infusion
Box of 1 bottle of 5 ml
All forms

Indication

Aldurazyme is indicated as a long-term enzyme replacement therapy in patients with a confirmed diagnosis of mucopolysaccharidosis type I (MPS I, α-L-iduronidase deficiency) to treat non-neurological manifestations of the disease (see section Pharmacodynamic properties ).

Dosage ALDURAZYME 100 U / mL Concentrate for solution for infusion IV Box of 1 vial of 5 ml

Treatment with Aldurazyme should be supervised by a physician experienced in the management of patients with MPS I or other inherited metabolic diseases. The administration of Aldurazyme should be carried out in an appropriate clinical setting with the resuscitation equipment necessary for the treatment of medical emergencies.


Dosage

The recommended dosage regimen for Aldurazyme is 100 U / kg body weight, administered once a week.

Pediatric population

No dosage adjustment is necessary for the pediatric population.

The elderly

The safety and efficacy of Aldurazyme have not been established in patients over 65 years of age. No dosage regimen can be recommended in these patients.

Patients with renal insufficiency or liver failure

The safety and efficacy of Aldurazyme have not been evaluated in patients with

hepatic or renal failure. No dosage regimen can be recommended in these patients.


Administration mode

Aldurazyme should be administered by intravenous infusion.

The initial infusion rate of 2 U / kg / h may be gradually increased every fifteen minutes, if the infusion is well tolerated, up to a maximum of 43 U / kg / h. The total volume of the administration should be delivered in about 3 to 4 hours. For information on premedication, see section Warnings and precautions for use .

For instructions on drug dilution before administration, see section Instructions for use, handling and disposal .

Against indications

Severe hypersensitivity (eg, anaphylactic reaction) to the active substance or to any of the excipients listed under Composition (see sections Warnings and precautions for use and undesirable effects ).

Aldurazyme side effects

Tolerance Profile Summary

The majority of adverse events in the clinical trials were infusion-associated reactions (ADRs), reported in 53% of patients in the Phase 3 study (treated for up to 4 years) and in 35% of patients included in the study dedicated to patients under 5 years of age (up to 1 year of treatment). Some of them were severe in intensity. The number of these reactions has decreased over time. The most commonly reported adverse reactions (AEs) were: headache, nausea, abdominal pain, rash, arthralgia, backache, extremity pain, flushing, pyrexia, infusion site reactions, increased blood pressure, decreased oxygen saturation, tachycardia and chills. The following reactions associated with infusion have been reported post-marketing: cyanosis, hypoxia, tachypnea, fever, vomiting, chills and erythema, some of these reactions being of severe severity.

Table of adverse effects

AEs reported with Aldurazyme during the Phase 3 study and its extension phase in 45 patients aged 5 years and older and over a treatment period of up to 4 years, are categorized below, by following frequency: very common (≥ 1/10); frequent (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10 000 to <1/1000); very rare (<1 / 10, 000) and not known (can not be estimated based on available data). Given the small patient population, an adverse event reported in a single patient is classified as common.

MedDRA Classes of organ systems

Very common

Frequent

Not known frequency

Immune system disorders

anaphylactic reaction

Psychiatric disorders

agitation

Nervous system disorders

headaches

paresthesia, dizziness

Heart conditions

tachycardia

Vascular disorders

congestive puff

hypotension, pallor, coldness of the extremities

Respiratory, thoracic and mediastinal disorders

respiratory distress, dyspnea, cough

cyanosis, hypoxia, tachypnea,

bronchospasm, respiratory arrest

Gastrointestinal disorders

nausea, abdominal pain

vomiting, diarrhea

Skin and subcutaneous tissue disorders

Rashes

angioneurotic edema, swelling of the face, urticaria, pruritus, cold sweats, alopecia, hyperhidrosis

erythema, edema of the face, laryngeal edema, peripheral edema

Musculoskeletal and systemic disorders

arthropathy, arthralgia, back pain, extremity pain

musculoskeletal pain

General disorders and administration site conditions

fever, infusion site reaction

chills, sensations of heat, sensations of cold, fatigue, flu-like syndrome

extravasation

investigations

increase in body temperature, decrease in oxygen saturation


Only one patient with pre-existing airway involvement developed a severe reaction three hours after the start of the infusion (at week 62 treatment), characterized by urticaria and airway obstruction requiring tracheotomy. This patient had IgE antibodies.


In addition, some patients with a history of severe MPS I with pulmonary involvement and upper airway experienced severe reactions such as bronchospasm, respiratory arrest, and facial edema (see Warnings and Precautions section ).


Pediatric population

The adverse reactions reported with Aldurazyme in a phase 2 study in 20 patients <5 years of age, most of whom had a severe phenotype, treated for up to 12 months are shown below. The adverse effects were all mild to moderate in severity.

MedDRA Classes of organ systems

MedDRA Preferred Term

Frequency

Heart conditions

tachycardia

Very common

General disorders and administration site conditions

fever

Very common

chills

Very common

investigations

increase in blood pressure

Very common

decreased oxygen saturation

Very common


In a phase 4 study, 33 patients with MPS I received one of the following 4 regimens: 100 U / kg IV once a week (recommended dose), 200 U / kg IV once a week weekly, 200 U / kg IV every 2 weeks or 300 U / kg IV every 2 weeks. The group receiving the recommended dose had the smallest number of patients with AE and RAP. The observed PCRs were similar to those observed in other clinical studies.


Description of some adverse effects

immunogenicity

Almost all patients developed IgG antibodies against laronidase. The majority of patients experienced seroconversion within three months of starting treatment; however, seroconversion in patients younger than 5 years of age with a more severe phenotype occurred primarily in the first month (26 days on average versus 45 days in patients 5 years and older). At the end of the phase 3 study (or at the time of premature withdrawal from the study), 13/45 patients had no detectable antibody by radioimmunoprecipitation (RIP) test, including 3 patients who had never had seroconversion. Patients with low or no antibody levels showed a sharp decrease in their level of urinary GAGs; conversely, patients with high antibody titers showed a variable reduction in urinary GAG levels. The clinical significance of this finding is unknown as there was no consistent relationship between IgG antibody level and clinical efficacy endpoints.


In addition, 60 patients included in phase 2 and 3 studies were subjected to in vitro tests for neutralizing effects. Four patients (three in the Phase 3 study and one in the Phase 2 study) showed in vitro marginal to mild inhibition of the enzyme activity of laronidase, which did not appear to have an impact on the clinical efficacy and / or reduction of urinary GAGs.


The presence of antibodies did not appear to be related to the incidence of RAPs, although the onset of these usually coincided with the formation of IgG antibodies. The appearance of IgE antibodies has not been fully explored.

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