Agalsidaz beta - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Enzymes and antiferments

Included in the formulation

Fabrazym®

lyophilizate d / infusion

Genzyme Europe BV Netherlands

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

M.09.A.B Enzyme preparations

Pharmacodynamics:

A remedy for enzyme replacement therapy for Fabry disease. Agalcidase beta - recombinant human alpha-galactosidase A - an enzyme in which the amino acid sequence is the same as in the endogenous enzyme. Obtained using recombinant DNA technology on Chinese hamster cells.

Fabry disease is a heterogeneous and polysystemic disease characterized by a deficiency of alpha-galactosidase - a lysosomal hydrolase, which catalyzes the hydrolysis of glycosphingolipids, in particular globotrioosilceramide.

The decrease or absence of alpha-galactosidase activity causes the accumulation of GL-3 in lysosomes of many cell types, including endothelial and parenchymal cells, which ultimately leads to life-threatening clinical manifestations as a result of lesions of the kidneys, heart and brain vessels.

After in / in introduction of agalsidase beta is quickly removed from the systemic blood flow and is captured by the vascular endothelium and parenchymal cells, including in the lysosomes, probably via mannose-6-phosphate, mannose, and asialoglycoprotein receptors.

Enzyme replacement therapy is aimed at restoring the level of enzymatic activity sufficient to remove the substrate accumulating in the tissues of the organs, thereby preventing, stabilizing or completely restoring the progressive decline in the function of these organs before irreversible changes develop.

Pharmacokinetics:

After iv administration of agalsidase beta to adults at a dose of 0.3, 1 and 3 mg / kg, the AUC ("area under the curve" - "area under the curve ") increase in proportion to the dose due to reduced clearance, which indicates the saturation clearance.

The half-life is a dose-dependent quantity and ranges from 45 to 100 min. After intravenous administration of agalsidase beta to adults for approximately 300 min at a dose of 1 mg / kg every 2 weeks, the mean Cmax values were 2000 to 3500 ng / ml, while the AUC_{in / in}were from 370 to 780 μg · min / ml. Vss was 8.3-40.8 liters, plasma clearance - 119-345 ml / min, and an average half-life of 80-120 minutes.

In children, the body weight does not affect the clearance of agalsidase. The initial clearance is 77 ml / min, half elimination- 55 min. After IgG seroconversion, the clearance is reduced to 35 ml / min, and half eliminationincreases to 240 min.The overall effect of these changes after seroconversion is a 2-3-fold increase in action.

Agalsidase beta is a protein, therefore it is believed that its metabolism is carried out by peptide hydrolysis. Accordingly, the effect of liver function abnormalities on the pharmacokinetics of agalsidase beta in a clinically significant degree is unlikely. It is believed that excretion through the kidneys is an insignificant part of the clearance of agalsidase beta.

Indications:

Prolonged enzyme replacement therapy in patients with confirmed diagnosis of Fabry disease (insufficiency of alpha-galactosidase A).

ICD-10

IV.E70-E90.E75.2 Other sphingolypidosis

Contraindications:

Hypersensitivity (anaphylactic reaction) to the active substance or any ingredient in the preparation.

Carefully:

The safety of the use of agalsidase beta in children is not established. In patients with impaired cardiac activity, a predisposition to a higher risk of developing severe complications of infusion reactions is possible. Studies in patients with hepatic insufficiency have not been conducted.

Pregnancy and lactation:

The action category for fetus by FDA is B.

Agalsidaz beta should not be used during pregnancy, except in cases of obvious need, when the expected benefit of therapy for the mother exceeds the potential risk to the fetus. It is not known whether agalsiadza beta is excreted in human breast milk. If it is necessary to use during lactation, the expected benefit of therapy for the mother and the potential risk for the infant should be carefully weighed.

Dosing and Administration:

The treatment of Fabry's disease should be performed under the supervision of a physician with experience in managing patients with Fabry's disease or other congenital metabolic diseases.

The recommended dose of the drug is 1 mg / kg every 2 weeks as an intravenous infusion. The rate of infusion depends on the patient's body weight. The duration of treatment is determined individually.

In clinical trials, alternative dosing regimens were used. One study found that after an initial dose of 1 mg / kg every 2 weeks for 6 months, a dose of 0.3 mg / kg every 2 weeks could maintain GL-3 clearance in certain cell types in some patients, but the significance of these data in the long-term period is not established.

To reduce the potential for the development of reactions associated with infusion, the initial infusion rate should not exceed 0.25 mg / min (15 mg / h).

After establishing the tolerance for subsequent infusions, the infusion rate can be gradually increased.

In patients with renal insufficiency and in children aged 8-16 years, dose adjustment is not required.

Side effects:

Infusion reactions. Infusion reactions of severe course are rare and manifest 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 therapy with the drug. Over time, their frequency and severity decrease. Reactions associated with the administration of the drug, and increased pain in children developed more often.

The most serious reactions are: allergic and anaphylactic reactions.

Common reactions: chills, fever, heat or cold feeling, hot flashes, pain in the extremities, chest pain, sensation of a lump in the throat, peripheral swelling, back pain, pallor, face swelling, myalgia, muscle spasms.

Infections: upper respiratory tract infections, lower respiratory tract infections, sinusitis, nasopharyngitis, rhinitis, pharyngitis, fungal infections, viral infections, local infections.

From the respiratory system: shortness of breath, a feeling of stuffy nose, stagnant phenomena in the respiratory system.

From the digestive system: nausea, vomiting, abdominal pain, diarrhea, toothache, dry mouth.

From the side of the central nervous system and the peripheral nervous system: headache, paresthesia, weakness, dizziness, drowsiness, burning sensation.

From the cardiovascular system: arterial hypertension, tachycardia, arterial hypotension, bradycardia, thinning of the ventricular wall.

Musculoskeletal and connective tissue system: pain in the extremities, muscle pain, back pain, muscle spasms, arthralgia, muscle stiffness, musculoskeletal stiffness.

Dermatological reactions: itching, hives, rash.

Body of sight: increased lachrymation, itching in the eyes, hyperemia of the eyes.

The organ of hearing and balance: tinnitus, dizziness, puffiness of the external ear, pain in the ears.

Other: increased incidence of injuries.

Overdose:

No cases of drug overdose have been reported. In clinical studies, doses up to 3 mg / kg were used.

Interaction:

There have been no laboratory studies on the metabolism of the drug, it is unlikely that cytochrome P450 will influence the interaction of drugs with each other.

Agalsidazu beta should not be used concomitantly with chloroquine, amiodarone, benoquinone or gentamicin because of the theoretical risk of a decrease in the activity of agalsidase beta.

Due to the lack of compatibility studies, agalsidase beta Do not mix with other drugs in the same infusion.

Special instructions:

Infusion should be made in conditions that allow for emergency therapy.

It is recommended that a 0.2 μm filter with a low level of protein binding be introduced to remove any protein particles and avoid any loss of agalsidase beta activity. The initial infusion rate should be no more than 0.25 mg / min (15 mg / h) in order to minimize the possible development of RSI. After determining the tolerability of the drug by the patient, the infusion rate can be gradually increased with subsequent infusions.

With the development of allergic and anaphylactic reactions, immediately stop the infusion and begin emergency therapy.

When re-used in patients with anaphylactic or severe allergic reactions to the introduction of agalsidase beta in the history, the expected benefit and potential risk should be weighed. In such cases, the introduction should be carried out with extreme caution.

If there is a risk of developing infusion reactions, premedication should be performed with antipyretic and antihistamine.

With the development of infusion reactions, the rate of infusion should be reduced, the infusion temporarily suspended and / or the additional administration of antipyretic, antihistamines and / or corticosteroids commenced. If the infusion reactions persist, stop the infusion and immediately begin the appropriate therapy. In case of a risk of developing infusion reactions, repeated administration of agalsidase beta should be performed with caution.

In patients with impaired cardiac activity, a predisposition to a higher risk of developing severe complications of infusion reactions is possible.

As agalsidase beta (r-hαGAL) is a recombinant protein, the formation of IgG antibodies is expected in patients with little or no enzymatic activity. Most patients developed IgG antibodies to r-hαGAL usually within 3 months after the first infusion. Over time, the majority of seropositive patients in clinical trials demonstrated either a reduction in titers (40% of patients) or no response (antibodies were not detected, as confirmed by 2 consecutive radioimmunoprecipitation (RIP) -14% of patients) or demonstrated a continuous antibody titer (35% patients).

With the normal tolerability of the infusion, the dose can be increased to a therapeutic dose of 1 mg / kg, and the infusion rate can be gradually increased as the drug is tolerated.

There were no studies of the effect of the drug on reproductive function.

Instructions

Agalsidase beta (Agalsidasum beta)