Replagal^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Takeda Pharmaceuticals International AG Ireland Branch (Ireland)

Manufactured By

Vetter Pharma-Fertigung, GmbH & Co. KG (Germany)

Labeled By

DHL SUPPLY CHAIN (NETHERLANDS) B.V. (Netherlands)

Quality Control Release

SHIRE PHARMACEUTICALS IRELAND, Limited (Ireland)

ATC Code

A16AB03 (Agalsidase alfa)

Active Substance

Agalsidase alfa (Rec.INN registered by WHO)

Dosage Form

Replagal®

Concentrate for solution for infusion 1 mg/1 ml: 3.5 ml vial 1, 4 or 10 pcs.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion clear, colorless.

Excipients: sodium dihydrogen phosphate monohydrate – 3.5 mg, polysorbate-20 – 0.0002 ml, sodium chloride – 8.8 mg, sodium hydroxide – q.s. to pH 6.0, water for injections – up to 1 ml.

3.5 ml – colorless glass type 1 vials with a capacity of 5 ml (1) – cardboard boxes.
3.5 ml – colorless glass type 1 vials with a capacity of 5 ml (4) – cardboard boxes.
3.5 ml – colorless glass type 1 vials with a capacity of 5 ml (10) – cardboard boxes.

Clinical-Pharmacological Group

Drug for the treatment of hereditary enzymatic deficiency

Pharmacotherapeutic Group

Drugs for the treatment of digestive tract and metabolism disorders – enzymes

Pharmacological Action

Fabry disease is a hereditary disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in the accumulation of glycosphingolipids, primarily globotriaosylceramide.

Agalsidase alfa (alpha-galactosidase A), catalyzes the hydrolysis of globotriaosylceramide and other neutral glycosphingolipids with terminal alpha-galactosyl residues in the body’s cells (including endothelial and parenchymal cells) to ceramide dihexoside and galactose.

The glycosylation profile is similar to that of the natural enzyme, allowing agalsidase alfa 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 major tissues and organs is comparable in men and women. V_d– 17% of body weight.

Approximately 10% of the administered dose is taken up by the liver. It is metabolized via peptide hydrolysis.

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

After 6 months of use, clearance increases (due to the development of antibodies to agalsidase alfa, detected at low titers).

After a single dose of 0.2 mg/kg, the T_1/2 from the bloodstream in men and women 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 eliminated faster than in adults.

T_1/2 from tissues is more than 24 hours.

Renal elimination is negligible.

Indications

Fabry disease (alpha-galactosidase A deficiency).

ICD codes

Dosage Regimen

Administer as an intravenous infusion under the supervision of a physician experienced in the management of patients with Fabry disease or other inherited metabolic disorders.

The recommended dosage for adults and children over 7 years of age is 0.2 mg per kilogram of body weight.

Infuse the total dose over 40 minutes once every two weeks.

Calculate the exact number of vials required based on the patient’s body weight and the vial strength of 3.5 mg per 3.5 ml vial.

Do not administer as an intravenous bolus injection.

Premedicate with antipyretics and/or antihistamines if the patient has experienced prior infusion-associated reactions.

Monitor the patient closely for signs of hypersensitivity during and after the infusion.

In case of a severe infusion reaction, discontinue the infusion immediately and initiate appropriate medical treatment.

No dosage adjustment is required for patients with renal impairment, including those on dialysis or post-kidney transplantation.

Adverse Reactions

Most frequently infusion reactions – fever, chills, tachycardia, nausea, vomiting, urticaria, angioedema.

Nervous system disorders very common – headache; common – hypersomnia, dizziness, taste perversion, neuropathic pain, tremor, hypoesthesia, paresthesia; sometimes – parosmia.

Sensory organ disorders common – increased lacrimation, decreased corneal reflex, tinnitus or its intensification.

Cardiovascular system disorders very common – hot flushes; common – tachycardia, increased blood pressure, palpitations.

Respiratory system disorders common – cough, hoarseness, sore throat, shortness of breath, nasopharyngitis, pharyngitis, rhinorrhea, increased secretion in the oropharynx.

Digestive system disorders very common – nausea; common – diarrhea, vomiting, abdominal pain (discomfort).

Skin and subcutaneous tissue disorders common – acne, erythema, rash, itching, livedo reticularis; sometimes – angioedema, urticaria.

Musculoskeletal and connective tissue disorders: common – muscle and bone discomfort, myalgia, back pain, limb pain, arthralgia, joint swelling; sometimes – feeling of heaviness.

Local reactions common – injection site rash.

General disorders and administration site conditions very common – chills, fever, pain and discomfort, weakness or its intensification; common – sensation of heat or cold, asthenia, chest pain and feeling of heaviness, flu-like syndrome, malaise, peripheral edema; sometimes – decreased tissue oxygen saturation.

Contraindications

Hypersensitivity to agalsidase alfa; lactation period; children under 7 years of age.

With caution pregnancy.

Use in Pregnancy and Lactation

Use with caution during pregnancy.

Contraindicated for use during breastfeeding.

Use in Hepatic Impairment

The efficacy and safety in patients with hepatic impairment have not been studied.

Use in Renal Impairment

In patients with chronic renal failure, including those on dialysis, or after kidney transplantation, dose adjustment is not required.

Pediatric Use

Contraindicated for use in children under 7 years of age.

Geriatric Use

The efficacy and safety in patients over 65 years of age have not been studied.

Special Precautions

Extensive kidney damage may limit their response to enzyme replacement therapy, possibly due to irreversible changes. In such cases, deterioration of renal function is an expected natural progression of the disease.

The efficacy and safety in patients over 65 years of age or with hepatic impairment have not been studied.

If allergic reactions (including severe ones) develop, the administration of this agent must be stopped immediately and symptomatic therapy initiated.

During therapy, patients may develop IgG class antibodies to agalsidase alfa. In 24% of male patients, low titers of IgG class antibodies were detected 3-12 months after the start of treatment. After 12-54 months, 17% still had detectable antibodies, while 7% showed signs of developing immunological tolerance, confirmed by the disappearance of IgG class antibodies over time. No antibodies were detected in the remaining 76% of patients.

Drug Interactions

Should not be administered concomitantly with chloroquine, amiodarone, or gentamicin (they inhibit the intracellular activity of alpha-galactosidase).

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.