Replagal - instructions for use, doses, side effects, contraindications

Active substanceAgalsidase alfaAgalsidase alfa

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Replagal®

solution d / infusion

Shyer Human Rights Genetics Therapies Inc. USA

Dosage form: & nbspconcentrate for solution for infusion

Composition:

1 ml of concentrate contains:

active substance: agalsidase alpha 1 mg;

Excipients: sodium dihydrogen phosphate monohydrate, polysorbate-20, sodium chloride, sodium hydroxide, water for injection.

Description:

A clear, colorless solution.

Pharmacotherapeutic group:Enzyme agent

ATX: & nbsp

M.09.A.B Enzyme preparations

Pharmacodynamics:

Fabry's disease belongs to the group of X-linked recessive lysosomal accumulation diseases that develop as a result of the deficiency of lysosomal alpha-galactosidase A. Agalsidase alfa catalyzes the hydrolysis of glycosphingolipids (globotriyaosilceramide, which is also referred to as Gb3), splitting off terminal galactose residues from the molecule. Deficiency of the enzyme leads to a disruption in the metabolism of glycosphingolipids, which accumulate in the walls of the vessels and tissues of many organs, causing a violation of their structure and function. The replacement therapy with agalsidaz alfa leads to a decrease in accumulation Gb3 in many cells, including endothelial and parenchymal cells.

Agalsidase alpha is produced on the human cell line.The glycosylation profile, similar to the natural profile of the enzyme, allows agsidase alpha to specifically bind to mannose-6-phosphate receptors on the surface of target cells.

Pharmacokinetics:

Pharmacokinetic parameters do not differ significantly between men and women. The periods of half-life of agalsidase alpha from the bloodstream of men after intravenous, single dose at a dose of 0.2 mg / kg were 108 ± 17 minutes, in women 89 ± 28 minutes, the volume of distribution was approximately 17% of the body weight of patients of both sexes. Given the similarity of pharmacokinetic properties of agalsidase alfa in patients of both sexes, the distribution in the main tissues and organs is also comparable in men and women. In children (aged 7-18 years), Replagal, administered at a dose of 0.2 mg / kg, is excreted from the bloodstream faster than in adult patients. The average Replagal clearance in children aged 7-11 years, in adolescents aged 12-18 years, and in adult patients was 4.2 ml / min / kg, 3.1 ml / min / kg and 2.3 ml / min / kg, respectively. After 6 months of using Replalag, the pharmacokinetic parameters changed - the clearance clearly increased. These changes are associated with the production of antibodies to aggalidase alpha, determined in a low titer. It did not have clinical significance for safety and effectiveness of Repplagal.

The half-life of the drug from the tissues exceeds 24 hours, and approximately 10% of the administered dose is absorbed by the liver.

Agalsidase alpha is metabolized by peptide hydrolysis, so it is unlikely that this drug will interact with other drugs.

Renal elimination is insignificant, therefore, impaired renal function does not affect the pharmacokinetic parameters of the drug.

Impaired liver function has no significant effect on the pharmacokinetics agalsidazy alpha, taking into account the peculiarities of its metabolism (peptide hydrolysis).

Indications:

Replagal is indicated for the long-term enzyme replacement therapy in patients with confirmed diagnosis of Fabry disease (deficiency of alpha-galactosidase A).

Contraindications:

Hypersensitivity to the active ingredient or any of the excipients.

Children under 7 years of age (lack of clinical data).

Pregnancy and lactation:

The limited experience of using Repplagal in pregnant women indicates that there is no adverse effect of the drug on the mother and newborn baby.Animal studies also confirm the absence of direct or indirect damaging effect on Replagala female body during pregnancy and the development of the embryo / fetus.

There is no data on the intake of agalsidase alpha in breast milk, therefore it is recommended to abstain from breastfeeding.

Dosing and Administration:

Introduction Replalag need to be carried out under the supervision of a doctor who has experience in treating patients with Fabry disease or other hereditary metabolic disorders.

Replagal should be administered intravenously for 40 minutes at a dose of 0.2 mg / kg body weight once every 2 weeks.

It is necessary to calculate the necessary dose and the number of vials of Replagal.

Dilute the required volume of Replagal in 100 ml of a 0.9% solution of sodium chloride. It is necessary to provide sterile conditions in the preparation of solutions, since Replagal does not contain preservatives or bacteriostatic substances. After reconstitution, the solution must be mixed gently, without shaking.

infusion solution should be administered through the system for intravenous administration (infusion pump) with integrated filter for 40 minutes.Since the drug does not contain preservatives, it is recommended to begin its infusion no later than 3 hours after dilution.

Patients aged 65 years and over

There were no clinical studies of Repplagal in patients over the age of 65 years. Thus, the safety and effectiveness of the drug for this category of patients has not yet been determined.

Patients with impaired liver function

There were no clinical studies of Repplagal with patients with hepatic insufficiency.

Patients with impaired renal function

It is not necessary to adjust the dose of Repplal in patients with renal insufficiency. If renal function is impaired (glomerular filtration rate <60 ml / min), a renal response to enzyme replacement therapy may be limited. It is not recommended to adjust the dose of the drug for patients who are on dialysis or after kidney transplantation.

Children

There were no clinical studies of Repplagal in patients aged 0-6 years, so the safety and effectiveness of the drug for this category of patients has not yet been determined. Results of Clinical Studies of Repplagala in children aged 7-18 years,who received the drug at a dose of 0.2 mg / kg for 6 months, did not reveal unexpected undesirable reactions and currently recommend the recommended treatment regimen for this age group of patients.

Side effects:

The most frequent undesirable effects in the use of Repplagal were the reactions associated with the administration of the drug. Most adverse events were mild or moderate in severity.

System of organs	Undesirable drug reaction (preferred term)
Metabolic disorders Often:	Peripheral edema
Violations from the nervous
systems
Often:	Headache
Often:	Dizziness, perversion of taste, neuropathic pain, tremor, hypersomnia,
Infrequently:	hypesthesia, paresthesia Parosmia
Visual disturbances Often:	Increased lacrimation
Hearing and vestibular disorders
disorders Often:	Noise in the ears, increased tinnitus
Disorders from the cardiovascular system Often: Often:	"Tides" of blood to the skin of the face Tachycardia, increased blood pressure,palpitation
Disturbances from the respiratory organs Often:	Cough, hoarseness of voice, sore throat, shortness of breath, nasopharyngitis, pharyngitis, rhinorrhea,increased secretion in the oropharynx
Disturbances from the respiratory organs Often:
Disorders from the gastrointestinal tract Often: Often:	Nausea Diarrhea, vomiting, abdominal pain / discomfort
Disturbances from the skin and subcutaneous tissue Often: Infrequently:	Acne, erythema, rash, itching, reticulared liver Angioedema, urticaria
Disturbances from the musculoskeletal system Often: Infrequently:	The feeling of "discomfort" in the muscles and bones, myalgia, back pain, pain in the limbs, arthralgia, swelling of the joints The feeling of "heaviness"
General reactions and reactions at the injection site Often: Often:	Chills, fever, pain and discomfort, weakness, increased weakness Sensation of "heat", a feeling of "cold", asthenia, chest pain, a feeling of "heaviness" in the chest, flu-like syndrome, a rash at the injection site, malaise, peripheral edema
Other Often: Infrequently:	Reduction of corneal reflex Reduction of tissue saturation with oxygen

Very often> 1/10; often> 1/100, but <1/10; infrequently> 1/1000, but <1/100;

In patients with renal insufficiency of the last stage, the frequency and spectrum of undesirable drug reactions were the same as in the general population of patients.

Undesirable drug reactions noted in children and adolescents did not differ with those in adult patients. However, the reactions associated with the administration of the drug, and increased pain, developed in children more often. The most frequent reactions in children were light-flow reactions associated with infusion, in the form of chills, fever, "hot flashes", headache, nausea and dyspnea.

Overdose:

There were no reports of cases of reparagal overdose.

Interaction:

Do not inject replalag at the same time as chloroquine, amiodarone or gentamicin, as these drugs inhibit the intracellular activity of alpha-galactosidase.

Taking into account the enzymatic nature of alpha-galactosidase, its interaction with drugs that are metabolized in the body through the cytochrome P450 system is unlikely. In clinical trials, the majority of patients received drugs for the treatment of neuropathic pain (carbamazepine, phenytoin and gabapentin), while there were no signs of drug interaction with Repplagal.

Special instructions:

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

- It is forbidden to inject Replagal together with other drugs through the same system for intravenous administration.

- Unused product or residues should be disposed of in accordance with local regulations.

Idiosyncratic reactions associated with the administration of the drug

The most common symptoms of these reactions are chills, headache, nausea, fever, "hot flashes" of blood to the face skin and fatigue. Infusion reactions of severe course are rare and occur in the form of fever, chills, tachycardia, nausea / vomiting, urticaria, angioedema. Usually, such reactions develop in the first 2-4 months after the beginning of Replagal therapy. Over time, their frequency and severity decrease. With the development of mild or moderate acute infusion reactions, it is necessary to immediately stop the injection of the drug, provide the patient with medical care, and then, if possible, resume the introduction of the drug. Light and short-term reactions do not require drug therapy and the abolition of Replagal treatment. In addition, to prevent the development of these reactions within 1-24 hours before the administration of Replagal, it is possible to administer either intravenous or intravenous antihistaminic orglucocorticosteroid drugs in clinically justified cases.

Allergic reactions

With intravenous injection of Replagal, it is possible to develop allergic reactions, including severe ones. In such cases it is necessary to immediately stop the introduction of Repplagal and begin symptomatic therapy.

Development of antibodies of immunoglobulin class G (IgG)

On the background of Replagal therapy, patients can develop antibodies of the class IgG to the protein agalsidase alfa. In approximately 24% of male patients, 3 to 12 months after initiation of Replagal treatment, a low class antibody titer was detected IgG. After 12-54 months of Replagal therapy, antibodies were still detected in 17% of patients, while in 7% of the patients there were signs of development of immunological tolerance, which was confirmed by the disappearance of antibodies of the class IgG over time. The remaining 76% of patients did not detect antibodies.

Patients with impaired renal function

A widespread renal injury may limit their response to enzyme replacement therapy, possibly due to irreversible changes. In such cases, impairment of renal function is an expected natural progression of the disease.

Form release / dosage:

Concentrate for the preparation of a solution for infusions 1 mg / ml.

Packaging:

For 3.5 ml of the drug in a vial of colorless glass type 1 (Ph Eur, USP) a 5 ml volume, sealed with a butyl rubber stopper, coated with fluoride resin, and an aluminum top cap sealed on top with a detachable plastic lid.

For 1, 4 or 10 bottles together with the instructions for use in a cardboard pack.

Storage conditions:

At a temperature of 2 to 8 ° C.

Do not freeze.

Keep out of the reach of children.

Shelf life:

Shelf life 2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000551/09

Date of registration:29.01.2009

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

Representation: & nbspSchayer Pharmaceutical Contracts LimitedSchayer Pharmaceutical Contracts LimitedRussia

Information update date: & nbsp14.01.2013

Illustrated instructions

Instructions

Replagal® (Replagal®)