Aldurazim - instructions for use, dosage, side effects, contraindications

Active substanceLaronidaseLaronidase

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concentrate d / infusion

Dosage form: & nbspconcentrate for solution for infusion

Composition:

Each 5 ml bottle contains:

Active substance: laronidase - 500 ED (+ excess of filling 30 units); Excipients: sodium chloride; sodium dihydrogen phosphate monohydrate; sodium hydrogen phosphate heptahydrate; polysorbate-80; water for injections.

Description:

Transparent or slightly opalescent colorless or light yellow liquid.

Pharmacotherapeutic group:The digestive tract and metabolic products are enzymes

ATX: & nbsp

A.16.A.B Enzyme preparations

A.16.A.B.05 Laronidase

Pharmacodynamics:

The reason for the accumulation of mucopolysaccharides is the inadequacy of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). MPS-1 (mucopolysaccharidosis I) is heterogeneous and affects various organs and systems with a disease characterized by alpha deficiency-L-iduronidase, lysosomal hydralase, which catalyzes the hydrolysis of terminal residues of alpha-L-duronic acid dermatan sulfate and heparan sulfate. Reduction or absence of alpha activity-L- Iduronidase leads to the accumulation of GAG (dermatan sulfate and heparan sulfate) in different types of cells and tissues.

Fermento-replacement therapy is designed to restore the level of enzymatic activity, sufficient for the hydrolysis of accumulated substrates and to prevent their further accumulation. After intravenous administration laronidase quickly leaves systemic blood flow and is absorbed by the cells, entering their lysosomes, apparently through mannose-6-phos- phate receptors.

Purified laronidase is a glycoprotein with a molecular weight of about 83 kilodaltons. After cleavage of laronidase by N-in the end, 628 amino acid residues are found in its composition. Its molecule contains 6 sites (sites) that bind through the amino group (Ngroup) with oligosaccharides of different structures.

Three clinical trials were conducted with Aldurazim to prove its effectiveness and safety. Two clinical studies focused mainly on the evaluation of the effect of Aldurazim on such systemic manifestations of MPS 1 as hepatomegaly, restriction of joint mobility, restrictive lung injury, upper airway obstruction and ocular pathology.The aim of the study in patients under five years of age was mainly to study the safety and pharmacokinetics of Aldurasim, but also a safety assessment was conducted. At the moment, clinical data showing a beneficial effect of the drug on the neurological manifestations of this disease, are absent.

The safety and efficacy of Aldurasim was evaluated in a randomized, double-blind, placebo-controlled clinical trial, Phase 3, conducted in 45 patients aged 6 to 43 years. Although the study included patients presenting the full spectrum of this disease, most of the patients entering it had an intermediate phenotype, and only one patient had a severe phenotype. In the study included patients with FVC (forced vital capacity of the lungs) less than 80% of the calculated normal FVC value (calculated based on the patient's growth), able to stand for 6 minutes and pass 5 meters.

Patients received either Aldurasim weekly at a dose of 100 U / kg body weight or placebo for a total of 26 weeks. The main endpoint (index) of effectiveness were changes in the percentage of FVC from the calculated normal FVC and absolute distance,overcome during the test with a six-minute walk. At the conclusion of the Phase 3 clinical trial, all patients were sequentially included in the open follow-up of this clinical trial, during which they all received Aldurazim weekly at a dose of 100 U / kg body weight.

After 26 weeks of treatment, the Aldurasim group of patients had an improvement in respiratory function by an average of 5.6 percent, as measured by a change in the percentage of FVC from the calculated normal FVC.

With regard to the walking ability assessed by the six-minute walk test, an increase in distance traveled by an average of 38.1 meters was observed compared with the group of patients treated with placebo.

The subsequent 50 weeks of treatment within the framework of the open continuation of this study improved the FVC. A further increase in walking ability was demonstrated: in comparison with the outcome, the distance traveled in 6 minutes increased by an average of 42.9 meters.

	Clinical Phase 3 study, 26 weeks of treatment Compared with placebo				Continuation of phase 3 clinical trial, total 50 weeks of treatment Compared with placebo
			Value	Confidence Interval			Value	Confidence Interval
				(95%)				(95%)
FVC (percent)	Average	5,6	-		Average	5,9	0,003	2,59-9,28
FVC (percent)	Median	3,0	0,009	0,9-8,6	Median	3,4
Test with a six-minute walk (meters)	Average	38,1	-		Average	42,9	0,005	16,27-69,53
Test with a six-minute walk (meters)	Median	38,5	0,066	-2,0-79,0	Median	48,0

In 80% of patients who had an increase in liver size in the outcome, normalization of its size was observed. There was a rapid (in the first 4 weeks) decrease in GAG release in the urine, which persisted throughout the remaining time of the study. By the 50th week, there was a decrease in the content of GAG in urine by an average of 64.8%.

During the study, there was no significant improvement in the quality of life indicators used. These indicators were not specially adapted for patients with MPS 1.

AT ITT (intent-to-treat) -populations (in the group of patients allocated to receive treatment and received at least one dose of the study drug), there was no significant improvement in the index of apnea-hypopnea and the volume of movements in the joints. However, this was not powerful enough (by the number of patients) to detect "the reliability of differences in these secondary efficacy variables, and besides, many patients had normal values of the outcome in the outcome.

Phase 2 of the open one-year study was conducted primarily to assess the safety and pharmacokinetics of Aldurasim in 20 patients under the age of 5 years at the time of treatment (16 patients had a severe form of the disease, while the 4th form had an average severity). All patients received Aldurazim at a dosage of 100 Units per kg weekly by infusions for 52 weeks, except for 4 patients for whom the dose was increased to 200 Units per kg starting from the 26th week of the study. The study was carried out to the end on 18 patients, 2 patients died as a result of heart failure and respiratory arrest, respectively, which was not associated with treatment.

A sharp drop in the GAG level in urine was registered by the 13th week of the study, after which the level was restored. The average decline rate was 61.3%. The volume of the liver of all patients in the evaluation of the clinical examination was classified as much higher than the average. In 9 patients out of 18 who underwent examination, liver volume was reduced to the normal level by week 52, the remaining patients showed a decrease in liver volume.Echocardiography showed a slight decrease in left ventricular mass (in 10 patients with an average degree of left ventricular hypertrophy, in 7 patients the norm returned to 52 weeks of treatment), but the average level of fractional ejection also decreased, remaining nonetheless within normal limits. Some valve changes were recorded. In younger patients with severe form of MPS 1 and in patients with moderate severity, there was an increase in the numbers (height and weight) that approached the norms, and there was also an improvement in the mental development of adaptive behavior. In turn, in older patients with a more severe form of MPS 1, no improvement was observed.

Pharmacokinetics:

The determination of pharmacokinetic parameters was carried out at the 1st, 12th and 26th week after intravenous administration of laronidase at a dose of 100 U / kg of body weight with an infusion time of 240 minutes.

Index	Infusion 1 Average ± SD (standard deviation)	Infusion 12 Average ± SD (standard deviation)	Infusion 26 Average ± SD (standard deviation)
FROM_max (U / ml)	0,197 ± 0,052	0,210 ± 0,079	0,302 ± 0,089
AUC ∞ (hours * Units/ml)	0,930 ± 0,214	0,913 ± 0,445	1,191 ± 0,451
CL (ml / mmin/ kg)	1,96 ± 0,495	2,31 ± 1,13	1,68 ±0,763
Vz (l / kg)	0,604 ± 0,172	0,307 ± 0,143	0,239 ± 0,128
Vss (l / kg)	0,440 ± 0,125	0,252 ± 0,079	0,217 ± 0,081
t1 / 2 (hours)	3,61 ± 0,894	2,02 ± 1,26	1,94 ± 1,09

Over time, there was an increase in C_m_Oh (maximum plasma concentration). As the treatment continued, the volume of distribution decreased, apparently related to the formation of antibodies and / or a decrease in liver size. The pharmacokinetic profile of patients younger than 5 years was consistent with the profile of older patients with a lower severity of the disease.

Larnonidase is a protein, so it is expected that it will be metabolically degraded with a pathway of peptide hydrolysis. In this regard, it is not expected that a violation of liver function will affect the pharmacokinetics of laronidase in a clinically significant degree. Isolation of laronidase by the kidneys is considered as an insignificant pathway, excretion. See "Dosage regimen and method of use".

Indications:

Aldurazim is indicated for long-term enzyme replacement therapy in patients with confirmed diagnosis of mucopolysaccharidosis 1 (MPS-1, deficiency of alpha-L-iduronidase) for the treatment of non-neurological manifestations of this disease (see the section "Pharmacodynamics").

Contraindications:

Severe hypersensitivity reactions (such as anaphylactic reactions) on the active substance or any additional ingredient in the drug (see "Special instructions and precautions" and "Side effects").

Pregnancy and lactation:

There are no data on the use of Aldurasim in pregnant women. Studies in animals have not revealed direct or indirect adverse effects on pregnancy, embryonic / fetal development, childbirth and. postnatal development (see section "Pre-clinical data"). A potential risk to a person is not known.

Aldurazim should not be used during pregnancy without obvious need. Laronidase can be excreted with human milk. Since there is no available data on newborns receiving laronidase with mother's milk, it is recommended that during the treatment with Aldurazim, stop breastfeeding.

Dosing and Administration:

Treatment with Aldurazim should be performed under the supervision of a physician experienced in the treatment of patients with MPS-1 or with other hereditary metabolic diseases. The introduction of Aldurasim should be carried out in an appropriate clinical setting, with equipment,necessary for emergency medical care.

Recommended Aldurasim Dosing regimen: weekly administration in a dose of 100 U / kg of body weight as an intravenous infusion. The initial injection rate of 2 U / kg / hour, with good tolerability, can. gradually increase every fifteen minutes, to a maximum of 43 units / kg / hour. All the required volume of solution should be entered approximately within 3-4 hours. For information about conducting premedication, see the "Special instructions and precautions" section, and for more instructions see the "Instructions for use and handling of the drug".

The safety and efficacy of Aldurasim in patients over 65 years of age have not been determined, and therefore recommendations for dosing regimens can not be given for patients of these age groups.

The safety and effectiveness of Aldurasim in patients with renal and hepatic insufficiency have not been determined, and therefore recommendations on the dosage regimen in such patients can not be given.

Side effects:

In clinical trials, most adverse reactions (HP) were classified as infusion-related reactions (SIR). HP 53% of patients in the 3-phase study (received treatment less than 4 years) and 35% of patients in 5 studies (received therapy less than 1 year) were observed. Some SIRs were heavy. Over time, the number of these reactions decreased. The most common HP were: headache, nausea, abdominal pain, rash, arthralgia, pain in the back, pain in the limbs, "hot flashes", an increase in body temperature, a reaction at the injection site, an increase in blood pressure, a decrease in saturation blood oxygen, tachycardia and chills. Postmarketing data collection on CIR revealed reports of the development of cyanosis, hypoxia, tachypnea (rapid breathing), fever, vomiting, chills and erythema, some of which were severe.

The following undesirable reactions to the drug Aldurazim, identified in a total of 45 patients aged 5 years and older, the duration of treatment of which was up to 4 years, when conducting and extending the clinical Phase 3 studies. The frequency was determined as follows: very often (> 1/10), often (from ≥ 1/10 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (from ≥ 1/10000 to <1/1000), very rarely (<1/10000) and it is not known (it is impossible to assess according to available data).Due to a small number of patients participating in the study HP, revealed in one patient, was considered as frequent.

System-Organic grade MedDRA	Highly often	Often	Unknown
Immune system disorders		Anaphylactic reaction
Disorders of the psyche		Restless state
Disturbances from the nervous system	Headache	Paresthesia, dizziness
Heart Disease		Tachycardia
Vascular disorders	"Tides"	Decrease HELL, pallor, cold snap peripheral body parts
Disturbances from respiratory system, bodies thoracic cells and organs of the mediastinum		Respiratory distress syndrome, dyspnoea, cough	Cyanosis, hypoxia, tachypnea (faster breathing), bronchospasm, respiratory arrest
Disorders from the gastrointestinal tract	Nausea, stomach ache	Vomiting, diarrhea
Disturbances from the skin and subcutaneous tissues	Rash	Angioedema swelling, swelling of the face, urticaria, itching, cold sweat, alopecia, hyperhidrosis	Erythema, facial edema, laryngeal edema, peripheral edema
Violations from hand musculoskeletal and connective fabrics	Arthropathy, arthralgia, back pain, pain in the extremities	Musculoskeletal pain
General violations and violations at the site of introduction	Increase temperatures body, reaction at the site of administration	Chills, sensation heat, cold sensation, fatigue, flu-like condition	extravasation
Based on research results		Increase temperatures body, decrease oxygenation of the blood

Have a single patient with a previous borne disease respiratory system developed a severe reaction to the administration of the drug three hours after the start of infusion (at the 62nd week of treatment): urticaria and airway obstruction, requiring tracheostomy. On examination, this patient had a positive reaction to IgE.

In addition, several patients with severe MPS-1 with upper respiratory tract and lung disease developed severe reactions:

bronchospasm, stopping breathing and swelling of the face.

Application in pediatrics. Below are the HP (mild and moderate severity), identified in 2 phase studies in a total of 20 patients under 5 years of age with a severe form of the IPS-1 phenotype, when duration of treatment Aldurazim was up to 12 months.

The system-organ class MedDRA	The preferred term MedDRA	Frequency
Heart Disease	Tachycardia	Often
Are common violations and violations at the site of administration	Increased body temperature	Often
	Chills	Often
Based on research results	Increased blood pressure	Often
Based on research results	Decreased oxygen saturation	Often

In the 4th phase of the study, 4 dosing regimens were used in 33 patients with IPS-1: 100 units / kg iv once a week (recommended dose), 200 units / kg IV once every two weeks and 300 units / kg IV once every two weeks.

In patients who received Aldurazim in the recommended dose, the frequency HP and the CIR was the smallest. The type of SIR detected in this study did not differ from the type of SIR recorded in other clinical trials.

Overdose:

No case of overdose has been reported.

Interaction:

No studies on the interaction with this drug have been conducted. Based on the metabolism of laronidase, it is an unlikely candidate for interactions mediated through cytochrome P450.

Aldurazim should not be administered concomitantly with chloroquine or procaine, as there is a potential risk of intracellular absorption of laronidase.

Incompatibilities

Due to the lack of compatibility studies, this drug should not be mixed with other drugs, except as indicated in the section "Instructions for use and handling of the drug."

Special instructions:Patients receiving Aldurasim treatment may develop infusion-related reactions (SIRs) defined as any infusion-related undesirable event occurring either during infusion or during the day of the infusion (see "Side Effects" section). Some infusion-related reactions can be severe (see below).

Patients receiving Aldurazim treatment should be under constant medical supervision and should report all cases of the occurrence of infusion-related reactions, deferred reactions and possible immunological reactions. The presence of antibodies should be regularly determined and the results of these studies reported.

Patients with anamnesis history of previous severe upper respiratory tract infections have experienced severe infusion-related reactions (SIR), and therefore, the condition of these patients should be closely monitored,and the introduction of Aldurasim to such patients should be carried out in an appropriate clinical setting, with the equipment necessary to provide emergency medical care.

According to the Phase 3 clinical study, almost all patients developed antibody class IgG to laronidase, mainly during the first three months from the start of treatment. Patients with antibodies or symptoms of infusion-related reactions should be treated with caution (see "Contraindications" and "Side effects").

In a phase 3 clinical trial, the infusion-related reactions were usually leveled by reducing the infusion rate and providing patients with premedication with antihistamines and / or antipyretics (paracetamol or ibuprofen), which allowed the patient to continue treatment.

Due to the small experience of resuming treatment after a long break in such cases, care should be taken in connection with the increased risk of developing hypersensitivity reactions.

When starting treatment with Aldurazim or when resuming interrupted treatment, it is recommended thatpremedication (antihistamines and / or antipyretics) approximately 60 minutes before the infusion to minimize the possibility of related with infusion reactions. In the presence of clinical indications, the question of medication premedication with subsequent infusion of Aldurasim may be considered.

In the case of mild or moderate infusion-related reactions, treatment with antihistamines and paracetamol / ibuprofen should be considered and / or the infusion rate reduced by half, compared to the infusion rate at which the reaction occurred.

If a single severe infusion-related reaction develops, the infusion should be stopped before the symptoms are resolved and the question of treatment with antihistamines and paracetamol / ibuprofen should be considered. This infusion can be resumed with a reduction in the rate of administration to 1/2 to 1/4 of the rate of administration at which this reaction occurred.

In the case of a re-emergence of a moderately expressed infusion-related reaction or a provocative test after a single severe infusion-related reactionshould consider premedication (antihistamines and paracetamol / ibuprofen or corticosteroids), and the infusion rate should be reduced to 1/2 - 1/4 of the infusion rate at which the previous reaction occurred.

As with intravenous administration of any other protein preparation, it is possible to develop severe hypersensitivity reactions of the allergic type.

When these reactions appear, immediate discontinuation of Aldurasim is recommended and appropriate treatment should be started, in which it is necessary to follow modern standards of emergency medical care.

Studies in patients with renal and hepatic insufficiency have not been conducted.

Instructions for use and handling of the drug

Each Aldurasim bottle is for single use only. To prepare the infusion solution concentrate, must be diluted in accordance with the rules of asepsis Infusion solution of sodium chloride 9 mg / ml (0.9%). Management of diluted Aldurasim solution is recommended through a system for intravenous infusions with a line-mounted filter with a pore diameter of 0.2 μm.

Preclinical safety data

Preclinical data obtained with the help of studies on the pharmacology of safety, single dose toxicity, repeated dose toxicity and reproductive toxicity, did not reveal a particular danger to humans. It is not expected that the drug has genotoxic or carcinogenic effects.

Instructions for preparing the infusion (follow the rules of asepsis)

- Determine the number of bottles required for dilution, based on the individual weight of the patient. Extract the required number of vials from the refrigerator approximately 20 minutes earlier so that they can reach room temperature.

- Before the dilution, visually check each vial for the presence of solid particles or change in the color of the solution. A clear or slightly opalescent, colorless or pale yellow solution should not contain visible solids. Do not use vials containing solid particles or having a discolored solution.

- Determine the total amount of infusion based on the individual weight of the patients making up or 100 ml (if the patient's body weight is less than or equal to 20 kg) or 250 ml (if the patient's body weight is more than 20 kg) infusion solution of sodium chloride 9 mg / ml (0.9% ).

- Remove from the vial and dispose of the volume of sodium chloride 9 mg / ml (0.9%), equal to the total volume of Aldurasim, which should be added.

- Extract the required volumes from Aldurasim vials, combining the extracted volumes.

- Add the combined volumes of Aldurasim to the infusion solution of sodium chloride 9 mg / ml (0.9%).

- Carefully mix the infusion solution.

- Visually check the solution for presence of solids before use. Only transparent and colorless solutions that do not contain visible solid particles should be used.

Any quantities of unused product or consumables must be destroyed in accordance with the requirements available in the country.

Effect on the ability to drive transp. cf. and fur:

There have been no studies on the impact on the ability to drive and use machinery.

Form release / dosage:Concentrate for solution for infusion, 100 units / ml.

Packaging:

For 5 ml of concentrate in bottles of transparent colorless glass type I (F. USA / EF), closed with siliconeized butyl rubber stoppers under aluminum rolling, which are covered with plastic caps from polypropylene.For 1, 10 or 25 vials, together with the instructions for use are placed in a cardboard box.

Storage conditions:Store at a temperature of 2 to 8 ° C.

Shelf life:

Unopened vials: 3 years

Diluted solutions:

From the point of view of microbiological safety the preparation should be used immediately after preparation. If the preparation has not been used immediately after preparation, it can be stored for no more than 24 hours at a temperature of 2 ° C to 8 ° C, provided that the preparation has been diluted in controlled and validated aseptic conditions.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003818/08

Date of registration:19.05.2008 / 01.10.2014

Expiration Date:Unlimited

The owner of the registration certificate:Genzyme Europe BVGenzyme Europe BV Netherlands

Manufacturer: & nbsp

GENZYME, Ltd. United Kingdom

Representation: & nbspJENZAIM RUS LLCJENZAIM RUS LLCRussia

Information update date: & nbsp16.07.2017

Illustrated instructions

Instructions

Aldurazim® (Aldurazyme®)