Elapraza - instructions for use, dose, side effects, contraindications

Active substanceIdursulfaseIdursulfase

Similar drugsTo uncover

Hunteraz

concentrate d / infusion

NANOLEC, LTD. Russia

Elapraz®

concentrate d / infusion

Shyer Human Rights Genetics Therapies Inc. USA

Dosage form: & nbspConcentrate for the preparation of a solution for infusions

Composition:1 ml of concentrate contains:

active substance: Idursulfase 2.00 mg;

Excipients: sodium chloride 8.00 mg, sodium hydrogen phosphate heptahydrate 0.99 mg, sodium dihydrogen phosphate monohydrate 2.25 mg, polysorbate-20 0.0002 ml, water for injection up to 1.0 ml.

Description:Transparent or slightly opalescent colorless solution

Pharmacotherapeutic group:Preparations for the treatment of diseases of the digestive tract and metabolic disorders - enzymes

ATX: & nbsp

A.16.A.B.09 Idursulfase

Pharmacodynamics:

Hunter syndrome is an X-linked recessive hereditary disease caused by an inadequate level in the body of the lysosomal enzyme iduronate-2-sulfatase. The function of iduronate-2-sulfatase is the catabolism of glycosaminoglycans (GAG) of dermatan sulfate and heparan sulfate by degradation of oligosaccharide-bound sulfate halves. In connection with the absence or presence of a deficient enzyme of iduronate-2-sulfatase in patients with Hunter syndrome, glycosaminoglycans progressively accumulate in the lysosomes of cells, leading to cellular supersaturation, organomegaly, tissue destruction, and organ failure. Idursulfase is the purified form of the lysosomal enzyme iduronate-2-sulfatase obtained on the human cell line providing a glycosylation profile similar to the natural profile of the enzyme. Idursulfase is secreted as a 525-amino acid glycoprotein and contains 8 N-linked glycosylated sites that occupy chains of complex, hybrid oligosaccharides, as well as oligosaccharides with a high content of mannose. The molecular weight of the idursulfase is about 76 kDaltons.

Elapraza®, administered intravenously to patients with Hunter syndrome, provides an exogenous enzyme to the cell lysosomes. Mannose-6-phosphate residues (M6F) on oligosaccharide chains allow the enzyme to specifically bind to the MbP receptors on the cell surface, which leads to internalization of the enzyme targeted at intracellular lysosomes and subsequent catabolism of accumulated GAG. A total of 108 male patients with Hunter syndrome and a wide range of symptoms were included in two randomized, placebo-controlled studies, 106 of whom continued therapy in two open-label advanced studies.

In a randomized, double-blind, placebo-controlled study for 52 weeks, 96 patients aged 5 to 31 years received Elapraz ® in a dose of 0.5 mg / kg once a week (n = 32) or 0.5 mg / kg once in two weeks (n = 32), or placebo (n = 32). Patients with documented deficiency of the activity of the enzyme iduronate-2-sulphatase, a proportion of the predicted forced vital capacity of the lungs (GEL) <80%, and a wide range of clinical severity of the disease were included in the study.

The primary criterion for evaluating efficacy was a two-compartment combined indicator, based on the sum of the ranks of the change from the start to the end of the distance study, traversed in six minutes (6-minute walk test or 6-MT), as an endurance index, and the percentage of predicted forced LEL as an indicator function lungs. This criterion was significantly different in patients treated weekly from that in the placebo group (p = 0.0049).

Additional analysis of clinical efficacy was carried out for individual components of the primary combined test, absolute changes in the ZHEL,changes in the concentration of GAG in urine and liver and spleen sizes, the volume of forced exhalation in the first second (FEV1) and dynamics of left ventricular mass (LVH).

Evaluation Criteria	52 weeks of therapy 0 5 mg / kg once a week
	Marginal weighted (OM) (mean (SE))		Mean change in treatment group compared with placebo group	R- meaning (by comparison of with placebo)
	Idur-sulfase	Placebo	Mean change in treatment group compared with placebo group	R- meaning (by comparison of with placebo)
Combined criteria (6-MT and% ZHEL)	74.5 (4.5)	55.5 (4.5)	19.0 (6.5)	0.0049
6-MT (m)	43.3 (9.6)	8.2(9.6)	35.1 (13.7)	0 0131
% of the projected	4.2(1.6)	-0.04 (1.6)	4.3(2.3)	0.0650
The absolute volume (L)	0.23 (0.04)	0.05 (0.04)	0.19 (0.06)	0,0011
Concentration of GAG in urine (μg GAG / mg creatinine)	-223.3 (20.7)	52.23 (20.7)	-275.5 (30.1)	<0.0001
% change in liver size	-25.7 (1-5)	-0.5(1.6)	-25.2 (2.2)	<0.0001
% change sizes spleen	-25.5 (3.3)	7.7(3.4)	-33.2 (4.8)	<0.0001

Overall, 11 of 31 (36%) patients in the weekly therapy group compared with 5 of 31 (16%) patients in the placebo group had increased FEV1 values by at least 0.02 L at or before the end of the study, indicating dose-dependent reduction of airway obstruction. Patients in the weekly therapy group significantly improved, on average by 15%, FEV1 at the time of completion of the study.

The concentration of GAG in urine decreased below the upper limit of the norm (defined as 126.6 μg GAG / mg creatinine) in 50% of patients receiving weekly therapy.

In 80% (20 patients) of 25 patients with hepatomegaly at the beginning of the study, who received weekly treatment with the drug, there was a decrease in liver size at the end of the study to normal.

Of the 9 patients in the weekly therapy group with initial spleen enlargement in 3 patients, the size of the spleen was restored to normal by the end of the study.

Approximately half of patients from the weekly therapy group (15 of 32, 47%) had left ventricular hypertrophy at the beginning of the study, which was determined by the left ventricular mass index (LVL)> 103 g / m2. Six (40%) of these patients normalized left ventricular mass at the end of the study.

All patients received weekly idursulfase weekly for 3.2 years as part of an additional extended study (TJCT024EXT).

In patients randomized to idursulfase weekly in the study of TCT024, the mean maximum improvement in the distance traversed in six minutes occurred by Month 20, and the mean proportion of the predicted VLP peaked at Month 16.

All patients had a statistically significant mean increase in the distance traveled in 6 minutes,(for patients receiving idursulfase, the beginning of the study was TCT024, and for patients receiving placebo, the beginning was Week 53), while the significant mean and the proportion of increase in walking distance ranged from 13.7 m to 41.5 m and from 64% to 11.7% (maximum to Month 20). At most time points of the definition, patients who initially received weekly therapy in the study of TCT024 improved their walking distance more than in the other two treatment groups.

The median proportion of the predicted HDL significantly increased to Month 16 in all patients, although by Month 36 it was similar to the baseline value. In patients with the most severe lung diseases at the beginning of the study (according to measurements of the proportion of the predicted VTE), a minimal improvement was observed.

Statistically significant increases in the absolute volume of JEL from initiation of therapy were observed during the majority of visits in each previous treatment group in the study of TCT024. Changes in the average values from 0.07 l to 0.31 l and the proportion varied from 6.3% to 25.1% (maximum to Month 30).Changes in mean and proportion at each time point from the start of treatment were greatest in the weekly therapy group in the study of TCT024.

During the last visit in the study of TCT024 in 21/31 patients from the weekly therapy group, 24/32 patients from the treatment group once every two weeks and 18/31 of the placebo group had a final normalization of the GAG concentration in the urine, which was lower the upper limit of the norm.

Changes in the concentration of GAG in urine were the earliest signs of clinical improvement with idursulfase therapy, and the greatest decrease in the concentration of GAG in urine was observed during the first 4 months of therapy in all treatment groups; changes from 4 to 36 months were minor. The higher the concentration of GAG in the urine at the beginning of the study, the more the concentration of GAG in urine decreases during the treatment with idursulfase.

Reductions in liver and spleen sizes observed at the end of the study, TCT024 (Week 53), were preserved during the additional study (TCT024EXT) in all patients, regardless of the previous distribution to the groups. The liver size was restored to normal by 24 months in 73% (52 of 71) patients who had hepatomegaly at the beginning of the study.In addition, liver size on average decreased to the maximum extent to Month 8 in all patients previously treated, with a slight increase in liver size in Month 36. The decrease in liver size did not depend on the age, severity of the disease, the presence of antibodies or neutralizing antibodies. During the study of TCT024, the size of the spleen was restored to normal for Months 12 and 24 in 9.7% of patients with splenomegaly who received weekly therapy.

During the study, TCT024, the mean left ventricular mass index (LVMI) remained stable for 36 months of idursulfase therapy in all treatment groups.

Pharmacokinetics:

The mechanism of absorption of idursulfase is mediated by selective binding to mannose-b-phosphate receptors. Before internalization by cells, it is localized in the cell lysosomes, thereby, obscuring the distribution of the protein. Degradation of idursulfase occurs by protein hydrolysis with the formation of small peptide residues and amino acids, thus, impaired renal or hepatic function does not affect the pharmacokinetic parameters of idursulfase.

Evaluation of pharmacokinetic parameters was performed in 10 patients at the 1st and 27th week after a 3-hour intravenous administration Elaprazy 0.5 mg / kg once a week. After 27 weeks of therapy, no differences in pharmacokinetic parameters were noted.

Table 1. Pharmacokinetic parameters

(mean / standard deviation)

Pharmacokinetic parameters	Week 1	Week 27
FROM_and"(Μg / ml)	1.5 (0.6)	U (0.3)
AUC (min * μg / ml)	206 (87)	169 (55)
T_!/2(min)	44(19)	48 (21)
CI (ml / min / kg)	3,0(1.2)	3.4(1.0)
Vss. (% BW)	21 (8)	25 (9)

Based on the results of standard preclinical safety pharmacology, toxicity after single and repeated administration, reproductive toxicity, and toxic effects on the developing embryo / fetal and impact male fertility is not established specific risk to humans.

Animal studies have found no direct or indirect undue influence of the drug on pregnancy, embryo / fetal development, birth or postnatal development.

In animal studies, excretion of idursulfase into breast milk was not detected.

Indications:Elapraza® is indicated for long-term treatment of patients with Hunter syndrome (Mucopolysaccharidosis type II, IPS II).

Contraindications:

Hypersensitivity to the active substance or any of the excipients.

Use in patients with impaired liver and kidney function

The experience of clinical use of the drug in patients with impaired liver and kidney function is absent.

Application in elderly patients

The experience of using the drug in patients older than 65 years is absent.

Use in children

Children under 5 years of age have no experience with the drug.

Carefully:Patients receiving idursulfase may develop reactions associated with infusion. During clinical trials, the most frequent reactions associated with the administration of idursulfase were skin reactions (rash, itching, urticaria), fever, headache, arterial hypertension, and blood flushes to the skin of the face. Adverse reactions were stopped by reducing the rate of drug administration, stopping infusions or administering antihistamine and antipyretics, low doses of glucocorticosteroids (prednisone and methylprednisolone), or inhalation of beta-agonists. During clinical trials, none of the patients were abolished because of the development of an undesirable reaction associated with drug infusion.

Special precautions are required when administering Elapraz® to patients with severe concomitant airway disease. These patients should limit or closely monitor the use of antihistamines or other sedatives. In some cases, it may be necessary to maintain positive airway pressure.

Elapraz® should be delayed if the patient develops an acute respiratory disease with an increase in body temperature. For patients using oxygen substitution therapy, it is necessary to have a supply of oxygen during the administration of the drug in case of development of an undesirable reaction. In patients who develop antibodies against idursulfase immunoglobulin classes M or G (IgM or IgG), the risk of developing infusion reactions and other undesirable events is increased.

In some patients who received the preparation of Elapraz®, life-threatening anaphylactic reactions. The delayed signs of anaphylactic reactions were observed 24 hours after the initial reaction.With the development of an anaphylactic reaction, the infusion should be stopped immediately, and appropriate treatment and monitoring started. Adhere to the current standards of emergency therapy. Patients with severe or refractory anaphylactic reactions may require prolonged clinical follow-up. Patients who have had anaphylactic reactions to the administration of Elapraz® in the past should be cautioned.

Special precautions are required when administering Elapraz® to pregnant or breast-feeding women.

Pregnancy and lactation:In studies of the reproductive function of male rats, the effects of Elapraz® on the fertility of animals have not been noted.

There are no data on the use of idursulfase in pregnant women. According to the results of studies conducted in animals, there was no direct or indirect adverse effect of the drug on reproductive function. As a precaution, it is preferable to avoid the use of Elapraz® during pregnancy.

It is not known whether idursulfase with breast milk.Data from animals confirmed the excretion of indursulfase into breast milk. It is impossible to exclude the risk for children who are breastfeeding, so the decision to continue breastfeeding or continue taking Elapraz® should be made in the light of the benefits of breastfeeding for the baby and the benefits of Elapraz® for lactating.

Dosing and Administration:

Only for intravenous infusion.

The administration of the drug Elapraz® should be carried out under the supervision of a doctor or other medical professional who has experience in treating patients with type II mucopolysaccharidosis or other hereditary metabolic disorders.

The drug Elapraz® should be administered intravenously for 3 hours at a dose of 0.5 mg / kg body weight once a week. The time of administration can be gradually reduced to 1 hour if unwanted reactions do not develop against the background of infusions.

Children

Children and adolescents should be injected at a dose of 0.5 mg / kg body weight once a week.

In patients with good tolerability of treatment, it is possible to administer an infusion of Elapraz® at home.

Currently, there is no clinical experience with the use of Elapraz ® in patients with renal or hepatic insufficiency, in children under 5 years old, and also in patients older than 65 years.

Side effects:

The adverse reactions noted during the clinical trials of the preparation of Elapraz® were almost always light or moderate in severity. The most frequently observed reactions associated with the administration of the drug, in the form of skin reactions (rash, itching, urticaria), fever, headache and increased blood pressure (BP). As the therapy continued, the incidence of reactions associated with infusion decreased.

The undesirable drug reactions listed below are presented according to the class of the system organ in order of severity and according to the following frequencies: very often (> 1/10), often (> 1 / 100- <1/10). The incidence of adverse events per patient is determined by the number of patients treated. Also included are undesirable drug reactions noted after drug registration (frequency category "unknown").

Immune system disorders: unknown - anaphylactic reaction; Violations from the nervous system: very often - headache; often - dizziness, tremor;

Heart Disease: often - cyanosis, arrhythmia, tachycardia;

Vascular disorders: very often - the elevation of blood pressure, the tides of "blood" to the skin of the face; often - lowering blood pressure;

Respiratory diseases, diseases of the thorax and mediastinum: very often-wheezing, shortness of breath; often - hypoxia, rapid breathing, bronchospasm, cough; Disorders from the gastrointestinal tract: very often - abdominal pain, nausea, dyspepsia; often - swelling of the tongue; Disturbances from the skin and subcutaneous tissues: very often - hives, rashes, itching often - erythema;

Disturbances from the musculoskeletal and connective tissue: very often - chest pain; often - arthralgia;

General disorders and disorders at the site of administration: very often - the reaction associated with the administration of the drug, fever, swelling in the infusion area; often - edema of the face, peripheral edema.

During the study of Elapraz® in 5 patients who received the drug at a dose of 0.5 mg / kg body weight weekly or one week later, serious adverse reactions were noted.Against the backdrop of one or more infusions, 4 patients developed hypoxia, which required the administration of oxygen to three patients with severe obstructive airways disease (2 patients had a tracheotomy before). The most severe infusion reaction, manifested by short-term convulsions, developed in 1 patient against the background of an exacerbation of an infectious respiratory disease, and was accompanied by hypoxia during drug administration. In a fourth patient with a less severe course of the underlying disease, the adverse reaction was spontaneously resolved after discontinuation of the drug administration. Subsequently, using a slower infusion rate and conducting pre-treatment of patients (the appointment of low doses of corticosteroids, antihistamines, inhalations of beta-agonists), these phenomena did not develop again.

In the fifth patient with pre-existing cardiopathy, premature ventricular complexes and pulmonary embolism were recorded during the study.

After the registration of the drug, reports about the development of anaphylactic reactions were received.

In all the studies conducted, 53/107 patients (50%) developed IgG antibodies to idursulfase. In 9 of these patients antibodies to idursulfase of IgM class were also developed, and antibodies of IgA class were detected in 4 patients. The total level of neutralizing antibodies was 26/107 patients (24%). In a 52-week study, seropositivity levels peaked at Week 18-27 and steadily declined throughout the rest of this study.

In general, patients with detected IgG antibodies were more prone to drug-related infusion reactions than those who did not have such antibodies. However, the overall incidence of adverse events associated with infusion of the drug decreased over time, regardless of the level of antibodies. Excretion of GAG with urine was somewhat reduced in patients with antibodies to idursulfase.

Overdose:

There are no known cases of an overdose of Elapraza. Interaction with other medicinal products

There have been no studies of the interaction of Elapraz with other drugs. However, according to the results of drug metabolism studies in cell lysosomes, idursulfase It should not interact with drugs that are metabolized in the body by the cytochrome P450 system.

Special instructions:

special instructions

Each Elaprazis bottle is intended for single use only, and contains 6 mg of idursulfase in 3 ml of concentrate. Before intravenous administration concentrate Elaprazia must be diluted with 0.9% solution of sodium chloride.

- It is necessary to determine the number of vials, the contents of which must be diluted taking into account the body weight of the patient and the recommended dose (0.5 mg / kg body weight).

- It is forbidden to use concentrate in vials if the concentrate has changed color or foreign impurities have been detected.

- It is necessary to extract the calculated volume of Elapraz from the corresponding number of vials and dilute in 100 ml of 0.9% sodium chloride solution.

- After dilution, the solution must be mixed gently, without shaking.

- It is necessary to provide sterile conditions in the preparation of solutions, since Elapraza does not contain preservatives or bacteriostatic substances.

Form release / dosage:Concentrate for the preparation of solution for infusion.

Packaging:

3 ml of the drug in a glass bottle (type 1), closed with a butyl rubber stopper, covered with fluoride resin and covered with an aluminum cap on top with a tear-off lid of blue color.

For 1, 4 or 10 vials together with the instruction for use are placed in a cardboard box.

Storage conditions:

List B.

In the dark place at a temperature of 2 to 8 ° C. Do not freeze.

After dilution the drug is stored at a temperature of 20 to 25 ° C for no more than 8 hours.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-001413/08

Date of registration:06.03.2008

The owner of the registration certificate:Shyer Human Rights Genetics Therapies Inc.Shyer Human Rights Genetics Therapies Inc. USA

Manufacturer: & nbsp

Shire Human Genetic Therapies, Inc. USA

Information update date: & nbsp09.01.2013

Illustrated instructions

Instructions

Elapraz® (Elaprase)