Aldurazyme is indicated as a long-term enzymatic replacement therapy in patients with a confirmed diagnosis of Type I mucopolysaccharidosis (MPS I, deficiency of α-L-iduronidase), in order to treat non-neurological manifestations Of the disease (see section 5.1 Pharmacodynamic properties).
Treatment with Aldurazyme should be supervised by a physician experienced in the management of patients with MPS I or other heritable metabolic diseases. The administration of Aldurazyme should be carried out in an appropriate clinical setting, equipped with the resuscitation equipment, necessary for the treatment of emergencies, medical

Dosage

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


No dose adjustment is required for the population, pediatric.

Elderly people

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 a
Hepatic or renal insufficiency. No dosage regimen can be recommended in these patients.

Mode of administration

Aldurazyme should be administered by intravenous infusion.

The initial perfusion 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. Administered in about 3 to 4 hours. For information on premedication, see section 4.4 Precautionary statements and precautions for use.
For instructions on dilution of the drug before administration, see section Instructions for use, handling, and disposal.
Solution transparent to slightly opalescent and colorless to pale yellow.

Pharmacotherapeutic class

Enzymes. ATC code A16AB05.

MPS I

The storage disorders of mucopolysaccharides are due to a deficiency in specific lysosomal enzymes necessary for catabolism, glycosaminoglycans (GAGs). MPS I is a heterogeneous and multivisceral disease characterized by a deficiency of α-L-iduronidase, hydrolase, lysosomal which acts as a catalyst for the hydrolysis of α-L-iduronic residues, terminal dermatan sulfate and Of the heparan sulfate The reduced or zero activity of α-L-iduronidase results in an accumulation of GAGs, dermatan sulphate and heparan sulphate, in many cell types and tissues. Br>

Mechanism of Action

The objective of enzymatic replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyze the substrate, accumulate and prevent further accumulation.After intravenous infusion laronidase is rapidly removed from the circulation and captured by The cells in the lysosomes, probably by the receptors of mannose-6 phosphate.

The purified laronidase is a glycoprotein of molecular weight about 83 kD. Laronidase is composed of 628 amino acids after cleavage of the N-terminus. The molecule contains 6 modification sites: N-linked oligosaccharides

Clinical efficacy and tolerance

Three clinical trials have been conducted with Aldurazyme to evaluate its efficacy and tolerability. One clinical study focused on evaluating the effect of Aldurazyme on systemic manifestations of MPS I such as low endurance, restrictive syndrome, airway obstruction, upper Decreased amplitude of movements, joint, hepatomegaly and visual disorders. One study mainly evaluated the safety and pharmacokinetics of Aldurazyme in patients under 5 years of age, but some measures of efficacy were also included. The third study was conducted to evaluate the pharmacodynamics and safety of several Aldurazyme regimens. To date, no clinical data show any benefit on the neurological manifestations of the disease

Tolerance and efficacy of Aldurazyme were evaluated in a randomized, double-blind, placebo-controlled Phase 3 study of 45 patients aged 6-43 years. Although recruited patients represent all degrees of severity of the disease, the majority of patients were intermediate phenotype, one patient with severe phenotype. Patients were recruited with a Forced Vital Capacity (FVC), less than 80% of the expected value, and were able to remain standing for 6 minutes and walk a distance of 5 meters. Patients received 100 U / kg of Aldurazyme or placebo every week for a total of 26 weeks. The main criteria for evaluating efficacy were the CVF variation, predicted from the theoretical value, and the absolute distance traveled during the six-minute walk test (TM6M). All patients were subsequently included in the extension of the Phase 3 open-label study where they all received 100 U / kg of Aldurazyme each week for 3.5 years (182 weeks) Additional.

After 26 weeks of treatment, patients treated with Aldurazyme showed an improvement in their respiratory function and their ability to walk to the placebo group as shown below.

Phase 3 26 weeks of treatment versus placebo

Value p

Confidence Interval (95%)

Percentage: expected CVF (percentage point)

Average

5.6

-

Median

3.0

0.009

0.9 - 8.6

TM6M; (meters)

Average

38.1

-

Median

38,5

0.066

-2.0 - 79.0

During the extension of the open-label study, improvement and / or maintenance of these effects were observed up to 208 weeks in the Aldurazyme / Aldurazyme group and 182 weeks in the placebo / Aldurazyme group, as As indicated in the table below.

Aldurazyme / Aldurazyme

Placebo / Aldurazyme

A 208; weeks

A 182 weeks

Change from the initial pre-processing visit

CVF predicted in%, (%) 1

- 1.2

- 3.3

TM6M; (meters)

+ 39,2

+ 19.4

Index of apnea / hypopnea (AHI)

- 4,0

- 4.8

Amplitude of shoulder flexion movements (degrees)

+ 13,1

+ 18,3

Disability Index, CHAQ / HAQ 2

- 0.43

- 0.26

1: The decrease (expressed as a percentage) of the predicted FVC is not clinically significant within this timeframe, the absolute lung volumes continued to increase in proportion to the size changes in the pediatric patients during the period Of growth.

2: Both groups exceeded the minimum clinically significant difference (-0.24)

Of the 26 patients with abnormal liver volume, during the initial pretreatment visit, 22 (85%) had normal liver volume at the end of the study. There was a rapid reduction in urinary excretion of GAGs (μg / mg, creatinine) during the first 4 weeks, with this trend remaining throughout the remainder of the study. Urinary GAG levels decreased by 77% and 66%, respectively, in Placebo / Aldurazyme and Aldurazyme / Aldurazyme groups. At the end of the study, one-third of the patients (15 out of 45) had normal urinary GAG levels.
To cope with the heterogeneity of the manifestation of the disease in patients, a composite evaluation criterion was summarized, summarizing clinically significant changes over five, efficacy variables (normal CVF predicted in Percentage, TM6M walking test, amplitude of shoulder flexion movements, apnea / hypopnea index (AHI) and visual acuity). The overall response was an improvement in 26 patients (58%), none in 10 patients (22%) and in 9 patients (20%).

A 1-year Phase 2 open-label study was conducted to evaluate mainly the safety and pharmacokinetics of Aldurazyme in 20 patients under 5 years of age at recruitment (16 patients with severe phenotype and 4 An intermediate phenotype). Patients were to receive 100 U / kg of Aldurazyme per weekly infusions for a total of 52 weeks. Four patients received a dose of up to 200 U / kg in the past 26 weeks due to high GAG levels during Week 22. Eighteen patients participated in the study up to Aldurazyme was well tolerated at both dosages The mean rate of urinary GAGs decreased by 50% at week 13 and by 61% at the end of the study. At the end of the study, all patients had decreases in hepatomegaly and 50% (9/18) had normal liver size. The proportion of patients with mild left ventricular hypertrophy increased from 53% (10/19) to 17% (3/18), the mean left ventricular mass relative to the body surface decreased by 0.9% -score (n '= 17). Several patients had growth in size (n '= 7) and weight (n' = 3) for their age (z score). Patients, the youngest with severe phenotype (
The European Medicines Agency will re-evaluate each year any new information that may be available, and if necessary this CPR will be updated.
Hypersensitivity, severe (eg, anaphylactic reaction), to the active substance or to any of the excipients mentioned in section Composition (see sections 4.4 and 4.4) Br>

Reactions associated with perfusion

Patients treated with Aldurazyme may develop perfusion-associated reactions (PERs), defined as any adverse effects associated with perfusion, occurring during infusion or before the end of the infusion day (see Effects; Undesirable effects). Some of these HBPs may be severe (see below).
Patients treated with Aldurazyme should be closely monitored and all cases of reactions associated with infusion, delayed reactions or possible immunological reactions should be reported. Immunological status (presence of antibodies) should be monitored and reported regularly

Serious reactions associated with perfusion have been reported in patients with severe preexisting upper airways. It will therefore be necessary to continue to monitor these patients in particular, in whom the administration of Aldurazyme will be carried out only in an appropriate clinical setting with the equipment necessary for the treatment of emergencies, >

Patients with acute underlying disease at the time of administration of the Aldurazyme perfusion appear to be more likely to develop HBP. Particular attention should be paid to the clinical condition of the patient before administration of Aldurazyme


Patients who have developed antibodies or symptoms of RAP should be treated with caution when administering Aldurazyme (see sections 4.3 and 4.4). >

In clinical studies it has generally been possible to control the PCR by reducing the perfusion velocity and a (pre) treatment of the patient with antihistamines and / or antipyretics (paracetamol or ibuprofen) So the patient to continue the treatment.

Because of limited experience in resuming treatment, after a prolonged break it is advisable to exercise extreme caution because of the increased theoretical risk of a reaction, hypersensitivity following the interruption Of the processing.

For initial administration of Aldurazyme or for resumption of administration, after discontinuation of therapy, it is recommended that premedication (antihistamines and / or antipyretics) be administered to patients approximately 60 minutes prior to onset Of the infusion, in order to minimize the possible occurrence of PCR. The administration of a premedication should be considered for subsequent infusions of Aldurazyme if the clinical situation so requires.

In the case of mild or moderate HBP, treatment with antihistamines and paracetamol / ibuprofen should be considered and / or a reduction in infusion rate up to half the rate at which the reaction occurred .

In the case of a single HBP, severe, the infusion should be discontinued until the symptoms disappear and treatment with antihistamines and paracetamol / ibuprofen should be considered. The infusion may be resumed with a reduction in the rate of infusion up to half or a quarter of the rate at which the reaction occurred. >
In the event of recurrence, a moderate PCR or a new administration, after a single severe PCR, premedication should be considered (antihistamines and paracetamol / ibuprofen and / or corticosteroids) as well as a reduction in velocity Perfusion rate up to half or a quarter of the rate at which the reaction occurred.

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

If such reactions occur, it is advisable to discontinue the administration of Aldurazyme immediately and appropriate medical treatment begun. The current medical standards for emergency treatment must be observed.

Excipients

This medicinal product contains sodium and is administered in an intravenous solution of 0.9% sodium chloride (see section Instructions for use, handling and disposal). Patients on a controlled sodium diet.

No interaction studies have been performed. Because of its metabolism, laronidase is unlikely to interact with cytochrome P450.

Aldurazyme should not be administered concomitantly with chloroquine or procaine because of a potential risk of interference with intracellular laronidase uptake
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In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products except those mentioned in the section Instructions for use, handling and disposal; Solution for infusion of 9 mg / ml sodium chloride (0.9%)

No cases of overdose have been reported.

Pregnancy

Data on the use of Aldurazyme in pregnant women are insufficient. Studies in animals have not shown direct or indirect deleterious effects on pregnancy, embryonic or fetal development, childbirth and postnatal development (see section Safety data, preclinical) . The potential clinical risk is unknown. Therefore, Aldurazyme should not be used during pregnancy unless absolutely necessary.


Laronidase is susceptible to excretion in milk. Since no data are available in newborns exposed to laronidase through breast milk, it is advisable to discontinue breast-feeding during treatment with Aldurazyme
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Fertility

There is no clinical data on the effect of laronidase on fertility. Preclinical data did not reveal any significant effects on fertility (see section Preclinical safety data).

Summary of the tolerance profile

The majority of adverse reactions in clinical trials were infusion-associated reactions (RAP), reported in 53% of patients in the Phase 3 study (treated over a period of time Up to 4 years), and in 35% of the patients included in the study, dedicated to patients younger than 5 years (up to 1 year of treatment). Some of them were severe in intensity. The most frequently reported adverse reactions (AEs) were headache, nausea, abdominal pain, rash, arthralgia, back pain, aches and pains; Pyrexia, perfusion site reactions, increase in blood pressure, decrease in oxygen saturation, tachycardia and chills. The following reactions associated with the infusion have been reported after marketing: cyanosis, hypoxia, tachypnea, fever, vomiting, chills and erythema, some of these reactions being of severe intensity

Table of undesirable effects

The AIs reported with Aldurazyme during the Phase 3 study and its extension phase in 45 patients aged 5 years and over and over a treatment period of up to 4 years are classified as follows (≥ 1/10), frequent (≥ 1/100 to