Agalsidase alfa (Agalsidasum alpha)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Enzymes and antiferments

Included in the formulation
  • Replagal®
    solution d / infusion 
    Shyer Human Rights Genetics Therapies Inc.     USA
    • 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:Fabry disease is a hereditary disease characterized by a deficiency of lysosomal alpha-galactosidase A, resulting in the accumulation of glycosphingolipids, predominantly globotriaosylceramide. Agalsidase alfa (alpha-galactosidase A) catalyzes the hydrolysis of globotriaosylceramide and other neutral glycosphingolipids with the alpha-galactic radical at the end in the cells of the body (including endothelial and parenchymal) to ceramide dihexonide and galactose. The glycosylation profile is similar to that of the natural enzyme, which 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. Distribution in the main tissues and organs is comparable in men and women. Vd - 17% of body weight.
    About 10% of the administered dose is taken up by the liver. Metabolised by peptide hydrolysis.

    The average value of clearance in children (7-11 years), in adolescents (12-18 years) and adults - 4.2 ml / min / kg, 3.1 ml / min / kg and 2.3 ml / min / kg, respectively .

    After 6 months of use the clearance is increased (in connection with the production of antibodies to agalsidase alpha, determined in low titre).

    After a single dose of 0.2 mg / kg, the half-life of men and women from the bloodstream is 91-125 min and 61-117 min, respectively. In children (7-18 years), the drug administered at a dose of 0.2 mg / kg is excreted faster than in adults. Half-life of the tissues is more than 24 hours. Renal elimination is insignificant.
    Indications:
    The disease is Fabry (deficiency of alpha-galactosidase A).

    ICD-10

    IV.E70-E90.E75   Disorders of sphingolipids exchange and other diseases of lipid accumulation

    Contraindications:
    Hypersensitivity to agsidase alpha; lactation period; children under 7 years.

    Carefully:Agalsidazu alfa should be used with caution in pregnancy.
    Pregnancy and lactation:
    The action category for fetus by FDA is B.

    Limited experience in the use of the drug 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 a direct or indirect damaging effect of the drug on the female organism during pregnancy or the development of an embryo / fetus.

    There are no data on the intake of agalsidase alpha in breast milk, therefore, the use during lactation (breastfeeding) is contraindicated.

    Use with caution in pregnancy.
    Dosing and Administration:
    The administration of agalsidase alpha should be performed under the supervision of a physician who has experience in treating patients with Fabry disease or other hereditary metabolic disorders.

    The drug should be administered IV for 40 minutes at a dose of 0.2 mg / kg once every 2 weeks.

    Dissolve the required volume in 100 ml of a 0.9% solution of sodium chloride. When breeding, sterile conditions should be ensured. agalsidase alfa does not contain preservatives or bacteriostatic substances. The solution is gently mixed without shaking.

    The solution for infusion should be administered through an IV system (infusion pump) with a built-in 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.

    Side effects:
    The most frequent undesirable effects were 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 frequent reactions in children were light-flow reactions associated with infusion (chills, fever, hot flashes, headache, nausea, dyspnea).

    Metabolism: often - peripheral edema.
    From the nervous system: very often - headache; often - hypersomnia, dizziness, taste distortion, neuropathic pain, tremor, hypoesthesia, paresthesia; sometimes - parosmia.

    From the sense organs: often - increased lacrimation, decreased corneal reflex, tinnitus or its amplification.

    From the CAS side: very often hot flushes; often - tachycardia, increased blood pressure, palpitations.

    From the respiratory system: often - cough, hoarseness of voice, sore throat, shortness of breath, nasopharyngitis, pharyngitis, rhinorrhea, increased secretion in the oropharynx.

    From the digestive system: very often - nausea; often - diarrhea, vomiting, pain (discomfort) in the abdomen.

    From the skin: often - acne, erythema, rash, itching, reticulum; sometimes - angioedema, hives.

    From the musculoskeletal system: often - a feeling of discomfort in the muscles and bones, myalgia, back pain, pain in the limbs, arthralgia, swelling of the joints; sometimes - a sense of heaviness.

    Local reactions: often a rash at the injection site.

    Other: very often - chills, fever, pain and discomfort, weakness or weakness; often - a feeling of heat or cold, asthenia, pain and a feeling of heaviness in the chest, flu-like syndrome, malaise, peripheral edema; sometimes - a decrease in tissue saturation with oxygen.

    Overdose:There were no reports of cases of an overdose of agalsidase alpha.
    Interaction:
    It should not be administered concomitantly with chloroquine, amiodarone or gentamicin (inhibit the intracellular activity of alpha-galactosidase). Pharmaceutically incompatible with other medicines.

    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, most patients received drugs for the treatment of neuropathic pain (carbamazepine, phenytoin and gabapentin), thus there were no signs of drug interaction with the drug.
    Special instructions:
    It is forbidden to use concentrate in vials, if it has changed color or foreign inclusions have been detected.

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

    The solution for infusion should be administered through an IV system (infusion pump) with a built-in 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.

    Idiosyncratic reactions associated with the administration of the drug

    The most frequent symptoms of idiosyncratic reactions associated with the administration of the drug,
    - chills, headache, nausea, fever, flushes of blood to the skin of the face 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 therapy with the drug. Over time, their frequency and severity decrease. With the development of mild or moderate acute infusion reactions, it is necessary to immediatelysuspend the introduction 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 cancellation of drug treatment. In addition, to prevent the development of these reactions 1-24 hours before the introduction of agalsidase alpha, it is possible to administer either intravenous or intravenous antihistamine or glucocorticosteroid drugs in clinically justified cases.

    With the development of allergic reactions (including severe) it is necessary to immediately stop the drug and start symptomatic therapy.

    Unused medication or its remnants should be disposed of in accordance with accepted requirements.

    On the background of therapy in patients, antibodies of the IgG class to the protein agalsidase alpha can be produced. Approximately 24% of male patients had a low IgG antibody titer 3-12 months after the start of treatment. After 12-54 months of therapy, 17% of patients still showed antibodies, while 7% of patients showed signs of developing immunological tolerance, which was confirmed by the disappearance of IgG antibodies over time.The remaining 76% of patients did not detect antibodies.
    In patients over 65 years of age or with liver failure, efficacy and safety have not been studied.

    There were no clinical studies of the drug 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 trials of the drug in children aged 7-18 years, who received the drug at a dose of 0.2 mg / kg for 6 months, did not reveal any unexpected adverse reactions and currently recommend the recommended regimen for this age group of patients .

    Patients with impaired liver function.

    There were no clinical studies of the drug with patients with liver failure.

    It is not necessary to adjust the dose of the drug 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.
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