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

Active substanceIdursulfaseIdursulfase

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Hunteraz

concentrate d / infusion

NANOLEC, LTD. Russia

Elapraz®

concentrate d / infusion

Shyer Human Rights Genetics Therapies Inc. USA

Dosage form: & nbspconcentrate for solution for infusion

Composition:

Composition per 1 bottle:

Active substance: Idursulfase Beta - 6.00 mg

Excipients:

sodium dihydrogen phosphate monohydrate - 6.75 mg

sodium phosphate dibasic heptahydrate - 2.97 mg

Sodium Chloride 24.00 mg

polysorbate 20 - 0.66 mg

water for injection - up to 3 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:

Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is a rare X-linked recessive hereditary disease caused by a deficiency in the patient's body of the lysosomal enzyme iduronate-2-sulfatase. Iduronat-2-sulfase is involved in the first stage of catabolism of glycosaminoglycans (GAG) - heparan and dermatan sulfate. As a result of inadequate activity of iduronate-2-sulfatase, the accumulation of glycosaminoglycans (GAG) -heparan and dermatan sulfate in lysosomes of virtually all cell types of various tissues and organs occurs, which leads to cellular supersaturation, organomegaly,destruction of tissues and impaired function of organs.

Idursulfase beta is a purified form of the lysosomal enzyme iduronate-2-sulfatase - recombinant human idoronate-2-sulphatase (rCIDC). rHIDC is produced by recombinant DNA technology using the Chinese hamster ovary (CHO) cell line (host cell: CHO DG44 / expression vector: ID pJK dhfr ABOUTr2).

Idursulfase beta is a glycoprotein with 525 amino acids with a molecular weight of about 78 KDa, which contains eight asparagine-linked glycosylation sites occupied by complex oligosaccharide structures and two disulfide bonds. The enzymatic activity of Idursulfase Beta depends on the post-translational modification of the specific cysteine in formylglycine. Intravenous administration to patients with Hunter's syndrome of idursulfase beta provides an exogenous enzyme to the cell lysosomes. Mannose-6-phosphate residues (M6F) on oligosaccharide chains allow the enzyme to specifically bind to M6P receptors on the cell surface, which leads to internalization of the enzyme targeted at intracellular lysosomes and subsequent catabolism of accumulating GAG.

The efficacy and safety of Hunteraz was confirmed in two clinical studies in male patients with Hunter syndrome aged 38 months to 35 years in 24 to 52 weeks.

The effectiveness of treatment was assessed based on the percentage change from the baseline GAG level in the patients urine, the distance traveled by the patients in 6 minutes, the indicators of the forced vital capacity of the lungs, the volume of the liver, the size and function of the heart, joint mobility, growth and development of patients.

The pharmacodynamic effect of Hunterazy on GAG accumulation was evaluated in animal studies. The use of Hunteraz resulted in a significant reduction in GAG levels in the urine and tissues of animals, thereby demonstrating the therapeutic efficacy of the drug.

Pharmacokinetics:

Information on the pharmacokinetic parameters of Hunteraz was obtained in a clinical study of patients with Hunter syndrome.

Based on the results of the analysis, the curve of the dependence of the serum concentration of Idursulfase Beta on time showed the curve of an apparent two-phase excretion. Apparent terminal half-life (t1/2, z) was 7.3-9.1 hours.In the group of patients who received Hunteraz in a dose of 0.5 mg / kg Cmah was 1024.9 ng / ml, a AUC_last - 2724 ng / ml, In the group of patients who received Hunteraz in a dose of 1.0 mg / kg, C_m_Oh was 2045.2 ng / ml, a AUC_last - 7804 ng / ml.

Within the dose range of 0.5-1.0 mg / kg C_m_Oh and AUC_last showed a tendency to increase exposure, while the apparent final half-life (t1/2, z) did not show significant differences.

Degradation of glycoproteins occurs by protein hydrolysis with the formation of small peptide residues and amino acids, and therefore, impairment of renal or hepatic function does not affect the pharmacokinetic parameters of idursulfase beta.

Mutations in the gene IDS, responsible for the occurrence of Hunter syndrome, occur regardless of race and geographic region, therefore, due to the nature and rarity of the disease, such internal factors as sex, race, height, body weight, age can not have a significant effect on the pharmacokinetic parameters of idursulfase beta. External factors (eg, drug interactions, diet, smoking or alcohol use) are also recognized as not affecting the exposure of intravenous protein preparations.

According to the results of preclinical animal safety studies, when assessing the toxicity after a single and repeated intravenous administration of Hunteraz, reproductive toxicity, effects on male fertility, no specific risk has been established for humans. Animal studies have not identified cardiovascular effects, respiratory parameters, the central nervous system and histopathological changes in the brain and nervous systems.

Indications:

Hunteraz is indicated for long-term treatment of patients with Hunter syndrome (type II mucopolysaccharidosis, MPS II).

Contraindications:

Clinically expressed or life-threatening patients are hypersensitive to the active substance or any of the excipients in cases where the symptoms are not eliminated by appropriate treatment.

Pregnancy,

Use in patients with impaired hepatic and renal function

Experience in the clinical use of the drug in patients with impaired there is no liver or kidney function.

Application in elderly patients

The experience of using the drug in patients older than 35 years is absent.

Use in children

Children under 38 months of age have no experience with the drug.

Carefully:

The drug should be administered with caution to patients with severe concomitant diseases of the respiratory tract.

Pregnancy and lactation:

Pregnancy

Data on the use of Hunteraz in pregnant women are absent. Within the preclinical studies of reproductive function, no changes were observed in animals in such parameters as pre- and post-implantation losses. As a precaution, it is preferable to avoid the use of Hunteras during pregnancy.

Breastfeeding period

There is no data on the use of Hunteraz during breastfeeding.

It is not known whether idursulfase beta with breast milk. It is impossible to exclude the risk for children receiving breastfeeding, so the decision to continue taking Hunteraz should be taken in consideration of the benefits of breastfeeding for the baby and the benefits of Hunteraz for the nursing drug.

Fertility

The effect of Hunteraz on human fertility has not been studied. Studies of idursulfase beta on animals have not revealed a negative impact of non-fertility.

Dosing and Administration:

The drug is intended for intravenous infusion (see subsection "Preparation of a solution for infusions").

Introduction Hanteraza preparation should be carried out under the supervision of a physician or other healthcare professional who has experience in treating patients with mucopolysaccharidosis type II or other inherited metabolic disorders.

Hanteraza The drug should be administered intravenously over a period of from 1 to 3 hours in a dose of 0.5 mg / kg body weight once weekly. Patients may require lengthening infusion time due to the adverse reactions on the background of infusion, however, infusion duration should not exceed 8 hours. The initial infusion rate should be 8 mL / h for the first 15 minutes. If tolerated by the patient the infusion satisfactorily, it is possible to increase the speed of injection of 8 ml / h every 15 minutes, taking the total to 40 ml / hour - until the end of drug administration. The infusion rate should not exceed 100 ml / h.If unwanted reactions occur against the background of infusion, then, according to clinical manifestations, the infusion rate can be reduced and / or temporarily suspended or discontinued. Hunteraz should not be given concomitantly with other drugs through a common infusion catheter.

Children

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

Preparation of a solution for infusions

Hunteraz is a concentrate for the preparation of a solution for infusion in a vial containing 2 mg / ml of idursulfase beta. The vials of Hunteraz preparation do not contain antimicrobial preservatives and are intended only for single use.

Before intravenous administration, the contents of the vial must be diluted

0.9% solution of sodium chloride for injection in accordance with the rules of asepsis as follows:

1. Determine the number of vials of Hunteraz preparation required for the patient for 1 administration, which must be diluted taking into account the patient's body weight and the recommended dose (0.5 mg / kg body weight).

Weight of the patient (kg) x 0.5 mg / kg of idursulfase beta + 2 mg / ml = Total amount (ml) of Hunteraz preparation.

Total amount (ml) of Hunteraz preparation - 3 ml / fl = Total number of vials of Hunteras preparation.

The total number of vials of Hunteras preparation should be rounded to an integer value.

2. Conduct a visual inspection of each vial to ensure that the solution is colorless or slightly opalescent, with no visible particles.

3. Extract the calculated volume of the Hunteraz product from the appropriate number of vials and dissolve in 0.9 ml 0.9% sodium chloride solution for injection with the observance of aseptic rules. It is recommended to use a system for infusions equipped with a filter with a pore diameter of 0.2 micrometers. After diluting the solution for infusion, the infusion system or container must be gently mixed without shaking.

4. From the standpoint of microbiological safety, after dilution, the ready-to-use infusion solution should be used immediately. In case of impossibility of immediate use, the responsibility for the time and storage conditions is assigned to the consumer, and in this case it is allowed to store the diluted solution for infusions in the refrigerator at a temperature of 2 to 8 ° C not more than 48 hours,in the case of storing the diluted solution at room temperature, it should be used within 8 hours.

Side effects:

The adverse reactions noted in the clinical trials of the Hunteraz product were almost all light or moderate in severity.

The most frequent reactions associated with the administration of the drug were skin reactions (urticaria, rashes and itching). All unwanted reactions

were minor and minimized by regulating the rate of infusion and the use of appropriate drug therapy. Possible adverse reactions that occurred while taking the drug, presented below, are listed by organ systems according to the frequency of occurrence: Often (≥1/10), often (≥1/100-< 1/10).

Infectious and parasitic diseases:

very often - infections of the upper respiratory tract, bronchitis, sinusitis, otitis media

middle ear, pharyngotongsilit;

often - infection of the eyes (barley), pneumonia *.

Disorders from the rut and subcutaneous tissues:

very often - hives, itchy skin, dermatitis, fungal lesions of the trunk,

often - erythematous rash, atopic dermatitis, eczema, spots, fungal lesions of the foot.

Disturbances from the respiratory system, chest and mediastinal organs:

very often - cough, rhinorrhea, allergic rhinitis;

often - rhinitis, bronchial asthma, epistaxis, productive cough *, stopping respiratory movements during sleep.

Disorders from the gastrointestinal tract:

very often - diarrhea, gastroenteritis, enteritis;

often - nausea, vomiting, constipation, fissure of the anus, lesion of the anorectal region, dyspepsia, stomatitis, dental disease.

General disorders and disorders at the injection site:

very often - fever;

often - deterioration of the general condition.

Disturbances from the musculoskeletal and connective tissue:

often - muscle spasms, myalgia.

Disorders from the side of the organ of vision:

often - conjunctivitis, dry keratoconjunctivitis *.

Trauma, intoxication and complications of manipulation:

often swelling in the infusion area.

Violations of the genitals and mammary glands:

often - balanoposthitis *.

Undesirable reactions recorded in clinical studies in the 1.0 mg / kg group of Hunteraz

It is impossible to exclude the possibility of anaphylactic reactions (cf.section "Special instructions").

In patients with complete absence (deletion) or a significant change in gene sequences (rearrangement) the risk of reactions related to the infusion, the drug increased (see. Section "Special instructions").

Immunogenicity

In all patients after the administration of Hunteras in clinical trials, no antibodies were detected during the observation period.

Children

The adverse reactions observed in children, by nature and frequency of occurrence, did not differ from the corresponding reactions in adult patients.

Overdose:

There is no experience of overdose of Hunteraz in humans.

Interaction:

Studies of the interaction of Hunteraz with other medicinal products were not carried out.

Special instructions:

Reactions associated with infusion administration of the drug

Patients treated with idursulfase beta may develop reactions associated with infusion administration of the drug, such as respiratory distress, hypoxia, hypotension, apoplexy and (or) angioedema. Adverse reactions can be stopped by decrease in the rate of drug administration, discontinuation of infusions or administration of antihistamines, glucocorticosteroids.

Special precautions are required when administering Hunterazy to patients with severe concomitant airway disease. It may be necessary to hospitalize patients in a specialized department for the infusion of the drug and monitor the clinical condition. 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.

It is necessary to postpone the administration of Hunteraz if the patient develops an acute respiratory disease with an increase in 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.

Anaphylactic reactions

Some patients may have life-threatening anaphylactic reactions. The delayed signs of anaphylactic reactions can be observed even 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 Hunteras in the past, prescribe the drug again with caution, during the introduction of the drug, the presence of specially trained medical personnel and the availability of equipment for resuscitation. Heavy and life-threatening reactions Hypersensitivity in cases where the patient's condition is not amenable control, is a contraindication for repeated use of the drug (see the section "Contraindications").

Features of the drug at the first admission

Features of the drug at the first reception was not observed.

Dilute infusion solution

Each bottle of Hunteraz is intended for single use only.

The remaining diluted solution for infusion should be disposed of after use.

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

Does not affect the ability to drive vehicles and perform work that requires an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Concentrate for solution for infusion 2 mg / ml.

Packaging:

For 3.0 ml of the drug in 6.0 ml vials of colorless glass type I, sealed with butyl rubber plugs with Teflon coating, and rolled up with aluminum caps with a plastic detachable lid of violet color.

On 1 bottle together with the instruction on application place in a pack from a cardboard.

Storage conditions:

At a temperature of 2 to 8 ° C in a dark place. Do not freeze!

Keep out of the reach of children!

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004673

Date of registration:25.01.2018

Expiration Date:25.01.2023

The owner of the registration certificate:NANOLEC, LTD. NANOLEC, LTD. Russia

Manufacturer: & nbsp

Green Cross Corporation The Republic of Korea

Representation: & nbspNANOLEC, LTD.NANOLEC, LTD.

Information update date: & nbsp26.03.2018

Illustrated instructions

Instructions

Hunteraz (Hunteraza)