Vpriv^® (Lyophilisate) 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

TAKEDA PHARMACEUTICALS INTERNATIONAL AG IRELAND BRANCH (Ireland)

ATC Code

A16AB10 (Velaglucerase alfa)

Active Substance

Velaglucerase alfa (Rec.INN registered by WHO)

Dosage Form

Vpriv®

Lyophilizate for the preparation of solution for infusion 400 IU: fl. 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of solution for infusion in the form of a white or almost white lyophilized powder or porous mass; reconstituted solution is a colorless transparent or slightly opalescent liquid.

Excipients: sucrose – 200 mg, sodium citrate dihydrate – 51.76 mg, citric acid monohydrate – 5.04 mg, polysorbate 20 – 0.44 mg.

400 IU – glass vials with a capacity of 20 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of hereditary enzymatic deficiency

Pharmacotherapeutic Group

Other agents for the treatment of gastrointestinal diseases and metabolic disorders; enzymes

Pharmacological Action

Gaucher disease is an autosomal recessive disorder caused by a mutation in the glucocerebrosidase (GBA) gene, leading to a deficiency of the lysosomal enzyme beta-glucocerebrosidase.

The deficiency of the lysosomal enzyme causes the accumulation of glucocerebroside, primarily in macrophages, leading to their engorgement and the growth of foam cells or “Gaucher cells”.

The disease belongs to the group of lysosomal storage diseases (LSDs), clinical manifestations are due to the distribution of Gaucher cells in organs and tissues, and include hepatomegaly, splenomegaly, bone marrow involvement, skeletal bones and lungs.

Accumulation of glucocerebroside in the liver and spleen leads to organomegaly. Bone tissue involvement is accompanied by deformation and abnormalities of the skeletal bones, as well as bone crises. Accumulation of cells in the bone marrow and spleen leads to clinically significant anemia and thrombocytopenia.

Velaglucerase alfa is produced in the human fibroblast HT-1080 cell line using recombinant DNA technology. Velaglucerase alfa is a glycoprotein.

The monomer has a molecular weight of 63 kDa, includes 497 amino acids, the sequence of which is analogous to the natural enzyme glucocerebrosidase. It contains 5 potential sites for N-glycosaminoglycan binding, 4 of which are not free.

Velaglucerase alfa contains predominantly glycosaminoglycans with a high mannose content, which promote the internalization of the enzyme by target phagocytic cells via mannose receptors.

Velaglucerase alfa replaces or enhances the action of the enzyme beta-glucocerebrosidase, which accelerates the hydrolysis of glucocerebroside to form glucose and ceramide in lysosomes, reducing the concentration of accumulated glucocerebroside and thus has a beneficial effect on the pathogenetic mechanisms of Gaucher disease.

The use of velaglucerase alfa is accompanied by an increase in hemoglobin concentration and total platelet count in the blood in patients with type I Gaucher disease, as well as a reduction in the severity of hepatomegaly and splenomegaly.

Pharmacokinetics

After intravenous administration, the concentration of velaglucerase alfa in blood plasma increases significantly during the first 20 minutes, C_max is usually reached after 40-60 minutes.

After completion of velaglucerase alfa administration at doses of 15, 30, 45 and 60 IU/kg, the enzyme concentration decreases rapidly along a monophasic or biphasic curve, T_1/2 averages from 5 to 12 minutes.

The pharmacokinetic parameters of velaglucerase alfa have a linear or near-linear profile, C_max and the area under the concentration-time curve (AUC) increase with increasing dose from 15 to 60 IU/kg.

Equilibrium state is achieved at a volume of distribution that is about 10% of body weight. The high clearance of velaglucerase alfa (6.7-7.6 ml/min/kg) persists and is accompanied by rapid uptake of the enzyme by macrophages via mannose receptors.

The clearance of velaglucerase alfa in children (aged 4 to 17 years) does not differ from that in adults (aged 19 to 62 years). No significant differences in pharmacokinetic parameters were noted in patients with type I Gaucher disease of both sexes.

During the study of pharmacokinetics, no cases of antibody development to velaglucerase were noted. Thus, it is impossible to assess the effect of antibodies on the pharmacokinetic profile of velaglucerase alfa.

Preclinical safety data

Preclinical studies have not established any adverse effects of the drug in terms of pharmacological safety, including the absence of toxic effects both with single and repeated dosing, as well as in studies of reproductive and embryotoxicity.

Indications

• For long-term treatment of patients with type I Gaucher disease.

ICD codes

Dosage Regimen

For intravenous infusion.

Vpriv^® should be used under the supervision of a physician experienced in the treatment of patients with Gaucher disease. In patients who have received the drug 3 times or more, provided good treatment tolerance, further use of the drug may be continued at home under the supervision of medical personnel.

Doses

The recommended dose is 60 IU/kg once every 2 weeks.

The dose can be adjusted individually, based on achieving the expected effect and its maintenance. In clinical studies, drug doses from 15 to 60 IU/kg once every 2 weeks were used. The use of doses higher than 60 IU/kg has not been studied.

Ongoing enzyme replacement therapy

For patients receiving imiglucerase for enzyme replacement therapy for type I Gaucher disease, therapy with Vpriv^® can be started immediately after discontinuation of previous therapy; the drug is prescribed at the same dose and with the same frequency of use.

Hepatic and renal impairment

Dose adjustment is not required in patients with hepatic and renal impairment, considering the pharmacokinetic and pharmacodynamic features of velaglucerase alfa.

Use in children

In clinical studies, 20 out of 94 patients (21%) were children (aged 4 to 17 years). The efficacy and safety profiles in adults and children were similar.

In the elderly (over 65 years)

Dose adjustment is not required.

Method of administration

For intravenous infusion only!

Duration of infusion administration – 60 minutes. Vpriv^® must be diluted, the drug is intended only for intravenous infusion. The contents of the vial are for single use only. The drug should be administered only through a 0.22 µm filter.

Aseptic technique must be observed.

Instructions for reconstitution and dilution of Vpriv^®

1. Determine the number of vials to be diluted, taking into account the patient’s body weight and the recommended dose.

2. Remove the required number of vials from the refrigerator.

• Dilution of 400 IU/ml vials. Add 4.3 ml of Sterile Water for Injections to each vial;
• Dilution of 200 IU/ml vials. Add 2.2 ml of Sterile Water for Injections to each vial.

3. After dilution, gently invert the vials. Do not shake. The 400 IU vial will contain an extractable volume of 4.0 ml (100 IU/ml) or the 200 IU vial will contain 2.0 ml (100 IU/ml).

4. Before further dilution, inspect the contents of the vial – the solution should be slightly clear and colorless (see “Description”); do not use the drug if the solution has changed color or if foreign particles are found in it.

5. Withdraw the calculated volume of the drug from the corresponding number of vials and dilute in 100 ml of 0.9% sodium chloride solution. Gently mix. Do not shake.

Administration of the drug should be started within 24 hours after dilution.

Adverse Reactions

Data on adverse reactions include information from 5 clinical studies on the use of the drug in 94 patients aged 4-71 years (46 men and 48 women) with type I Gaucher disease, who received velaglucerase alfa at doses from 15 to 60 IU/kg once every 2 weeks.

In 54 patients, treatment was initiated for the first time, and 40 had previously received imiglucerase.

The most serious adverse reactions in patients in clinical studies were hypersensitivity reactions.

The most frequent adverse reactions were infusion-related reactions.

The following symptoms associated with the infusion of the drug were most frequently noted: headache, dizziness, decreased BP, increased BP, nausea, fatigue/asthenia, and fever/increased body temperature.

The drug was discontinued only due to adverse reactions associated with the infusion.

Adverse reactions noted in more than 1 patient with type I Gaucher disease are listed below. Information is presented in accordance with the MedDRA convention by system organ class and by frequency of occurrence: very common (≥ 1/10) and common (≥ 1/100 to <1/10). Within each group, adverse reactions are presented in order of decreasing severity.

Immune system disorders: common – hypersensitivity reactions.

Nervous system disorders: very common – headache, dizziness.

Cardiac and vascular disorders: common – tachycardia, increased BP, decreased BP, flushing.

Gastrointestinal disorders: common – abdominal pain/upper abdominal pain, nausea.

Skin and subcutaneous tissue disorders: common – rash, urticaria.

Musculoskeletal and connective tissue disorders: very common – bone pain, joint pain, back pain.

General disorders and administration site conditions: very common – infusion-related reactions, fatigue/asthenia, fever/increased body temperature.

Laboratory and instrumental data: common – increased activated partial thromboplastin time (aPTT), positive test for neutralizing antibodies.

In children

The tolerability profile of the drug in children 4-17 years old did not differ from the corresponding observations in adults.

Contraindications

• Severe allergic reactions to the active substance or to any of the excipients.

Use in Pregnancy and Lactation

Pregnancy

There are currently no data on the use of Vpriv^® in pregnant women. Preclinical studies do not indicate direct or indirect adverse effects on pregnancy, embryonic/fetoplacental and postnatal development of the fetus, and the process of childbirth. Caution should be exercised when prescribing the drug to pregnant women.

Breastfeeding

There are no data on the use of the drug in women during breastfeeding. It is not known whether Velaglucerase alfa passes into breast milk. Since many drugs can pass into breast milk, the use of the drug during breastfeeding is recommended with caution.

Use in women of childbearing age

In women of childbearing age with Gaucher disease, the course of the disease may worsen during pregnancy. A benefit/risk assessment should be performed in each case of pregnancy. An individual approach to pregnancy management and patient monitoring, as well as to treatment efficacy assessment, is necessary.

Effect on reproductive ability

Experimental studies revealed no signs of impaired reproductive ability. No adverse effects of the drug were established in studies of pharmacology, toxicity with single and repeated dosing, in tests of reproductive toxicity and fetal development assessment; studies in animals did not confirm adverse effects on reproductive ability.

Use in Hepatic Impairment

Considering the pharmacokinetic and pharmacodynamic features of velaglucerase alfa, no dose adjustment of the drug is required in patients with hepatic impairment.

Use in Renal Impairment

Considering the pharmacokinetic and pharmacodynamic features of velaglucerase alfa, no dose adjustment of the drug is required in patients with renal impairment.

Pediatric Use

In clinical studies, 20 out of 94 patients (21%) were children (aged 4 to 17 years). The efficacy and safety profiles in adults and children were similar.

Geriatric Use

In elderly patients, no dose adjustment is required.

Special Precautions

Hypersensitivity

When administering a drug containing protein by infusion, hypersensitivity reactions may develop. During treatment with Vpriv^®, if necessary, the patient should be provided with adequate medical care. In case of life-threatening anaphylactic reactions, emergency therapy measures are carried out.

The drug should be used with caution in patients with a history of hypersensitivity symptoms when using other enzyme replacement therapy drugs.

Infusion-related reactions

During clinical studies, infusion-related reactions were most frequently noted. The severity of reactions was mostly assessed as mild. In patients receiving treatment for the first time, a greater number of reactions were noted within 6 months.

Treatment of infusion-related reactions depends on the severity of the reactions and includes, along with reducing the infusion rate, the use of drugs such as antihistamines and antipyretics, low doses of corticosteroids, and temporary discontinuation of drug administration followed by resumption of infusion is also recommended.

In some cases, when patients require symptomatic therapy, antihistamines and/or corticosteroids are used. Premedication was generally not performed in clinical studies.

Immunogenicity

In clinical studies, one out of 94 patients (1% of patients) developed IgG class antibodies against velaglucerase alfa, and in vitro analysis established that they were neutralizing. This patient did not have any intravenous infusion-related reactions. No IgE class antibodies to velaglucerase were detected.

Sodium

Since the drug contains 12.15 mg of sodium in the vial containing 400 IU and 6.07 mg of sodium in the vial containing 200 IU, this circumstance must be taken into account in patients who require a sodium-restricted diet.

Special precautions for disposal of unused drug

Unused medicinal product or its residues must be disposed of in accordance with local requirements.

Reconstituted and diluted infusion solution

The chemical and physical stability of the drug has been confirmed when stored for 24 hours at a temperature of 2 to 8°C (46.4°F) protected from light.

From a microbiological point of view, the drug should be used immediately after dilution. If the drug is used later, the shelf life of the diluted solution under the specified storage conditions should not exceed 24 hours; the consumer is responsible for non-compliance with storage requirements.

Effect on ability to drive vehicles and mechanisms

Vpriv^® does not adversely affect the ability to drive a car or other mechanisms.

Overdose

No cases of drug overdose are known. The maximum dose is 60 IU/kg.

Drug Interactions

No interaction studies have been conducted. Patients should be advised to inform doctors about the occurrence of any symptoms when using Vpriv^® concomitantly with other drugs. It is strictly forbidden to mix and administer Vpriv^® with other drugs in the same vial.

Storage Conditions

At a temperature of 2 to 8°C (46.4°F). Do not freeze. Store the vial in the original packaging, protected from light. Keep out of reach of children.

Shelf Life

Shelf life – 1.5 years (200 IU), 3 years (400 IU).

Dispensing Status

By prescription.

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.