Vimizim

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIMIZIM®

Composition:

Active substance: elosulfase alfa;

1 ml of solution contains 1 mg of elosulfase alfa; 1 vial contains 5 mg of elosulfase alfa;

Excipients: sodium acetate trihydrate; sodium dihydrogen phosphate monohydrate; L-arginine hydrochloride; sorbitol (E 420); polysorbate 20; water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: solution from clear to slightly opalescent, from colorless to pale yellow.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolism. Enzymes. ATC code A16AB12.

Pharmacological Properties

Pharmacodynamics

Elosulfase alfa is a recombinant form of human N-acetylgalactosamine-6-sulfatase (rhGALNS), produced in Chinese hamster ovary cell culture by recombinant DNA technology.

Mechanism of Action

Mucopolysaccharidosis is a group of lysosomal storage disorders caused by deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). Mucopolysaccharidosis type IVA (MPS IVA) is characterized by absent or markedly reduced activity of N-acetylgalactosamine-6-sulfatase. Deficient sulfatase activity leads to accumulation of GAG substrates—keratan sulfate (KS) and chondroitin-6-sulfate (C6S)—in lysosomal compartments of cells throughout the body. This accumulation results in generalized cellular, tissue, and organ dysfunction. The intended role of elosulfase alfa is to provide exogenous N-acetylgalactosamine-6-sulfatase enzyme, which is taken up by lysosomes and enhances the catabolism of GAGs (KS and C6S). Enzyme uptake into lysosomes occurs via cation-independent mannose-6-phosphate receptors, thereby restoring GALNS activity and clearance of KS and C6S.

Clinical Efficacy and Safety

The impact of treatment with Vimizim® on systemic manifestations of mucopolysaccharidosis type IVA (MPS IVA) was evaluated across multiple domains—including endurance, respiratory function, growth velocity, mobility, and urinary keratan sulfate (KS) levels—in several clinical studies.

A total of 235 patients with MPS IVA participated in and received Vimizim® across six clinical studies.

The safety and efficacy of Vimizim® were assessed in a randomized, double-blind, placebo-controlled phase 3 clinical study involving 176 patients with MPS IVA aged 5 to 57 years. Most patients had short stature, reduced endurance, and musculoskeletal symptoms. To be eligible for the study, patients had to be able to walk more than 30 meters (m) but less than 235 m in the 6-minute walk test (6 MWT) at baseline.

Patients received elosulfase alfa at 2 mg/kg weekly (n = 58) or 2 mg/kg every two weeks (n = 59), or placebo (n = 59), for a total of 24 weeks. Prior to each infusion, all patients received antihistamines. The primary endpoint was the change from baseline in distance walked during the 6 MWT at week 24 compared to placebo. Secondary endpoints included changes from baseline in performance on the 3-minute stair climb test (MSCT) and urinary KS levels at week 24. A total of 173 patients were sequentially enrolled into an extension study, in which patients continued to receive either 2 mg/kg elosulfase alfa weekly or every two weeks, after which all patients were transitioned to weekly administration of 2 mg/kg, based on assessments at week 24.

Primary and secondary endpoints were evaluated at week 24 (see Table 1). The modeled treatment effect on distance walked during the 6-minute walk test compared to placebo was 22.5 m (95% CI: 4.0, 40.9; p = 0.0174) for patients receiving elosulfase alfa at 2 mg/kg weekly. The modeled treatment effect on the number of steps climbed per minute compared to placebo was 1.1 steps/minute (95% CI: -2.1, 4.4; p = 0.4935) for patients receiving weekly treatment. The modeled treatment effect on the percentage change in urinary KS levels compared to placebo was -40.7% (95% CI: -49.0, -32.4; p < 0.0001) for patients receiving weekly treatment. The greatest differences between groups were observed between the placebo and weekly treatment groups across all endpoints. Results in the group receiving the investigational product every two weeks were comparable to those in the placebo group with respect to distance walked in 6 minutes and number of steps climbed per minute.

Table 1
Results from the placebo-controlled clinical study with administration of the investigational product at 2 mg/kg weekly

* One patient in the Vimizim® group withdrew after the first infusion.

‡ Mean value calculated based on the model comparing Vimizim® and placebo, adjusted for baseline levels.

In additional extension studies, in patients who received weekly intravenous infusions of elosulfase alfa at a dose of 2 mg/kg, maintenance of initial improvements in endurance and sustained reduction in urinary keratan sulfate (KS) levels were observed over a period of up to 156 weeks.

Children

It is important to initiate treatment as early as possible.

The majority of patients who received Vimizim® in clinical trials were within the pediatric age range (5 to 17 years of age). In an open-label study, 15 children with mucopolysaccharidosis type IVA (MPS IVA) aged under 5 years (9 months – < 5 years) received 2 mg/kg of Vimizim® once weekly for 52 weeks. Patients continued treatment for at least another 52 weeks in an observational long-term follow-up study. The total duration of treatment was 104 weeks. Safety and pharmacodynamic results in these patients were consistent with those observed during the first 52 weeks (see section «Adverse reactions»). At baseline, the mean (±SD) normalized standing height z-score was -1.6 (±1.61). After the first 52 weeks of treatment, the normalized standing height z-score was -1.9 (±1.62). At week 104 of treatment, the normalized standing height z-score was -3.1 (±1.13). Information on the use of the medicinal product in children is provided in section «Dosage and administration».

Pharmacokinetics.

Pharmacokinetic parameters of elosulfase alfa were evaluated in 23 patients with mucopolysaccharidosis type IVA (MPS IVA) who received weekly intravenous infusions of 2 mg/kg elosulfase alfa over approximately 4 hours for 22 weeks, with parameters compared at week 0 and week 22. At week 22, mean AUC0–t and Cmax values increased by 181% and 192%, respectively, compared to week 0.

Table 2

Pharmacokinetic properties

1 AUC0-t – area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration;

2 Cmax – maximum observed plasma concentration;

3 CL – total clearance of elosulfase alfa after intravenous administration;

4 t1/2 – elimination half-life;

5 Tmax – time from zero to maximum plasma concentration.

Biotransformation

Elosulfase alfa is a protein expected to be metabolically degraded via peptide hydrolysis. Therefore, hepatic impairment is not anticipated to influence the pharmacokinetics of elosulfase alfa.

Elimination

Renal elimination of elosulfase alfa is considered a negligible metabolic clearance pathway. The mean elimination half-life (t1/2) increased from 7.52 minutes at week 0 to 35.9 minutes at week 22. At week 22, male and female patients had comparable elosulfase alfa clearance, with no trends related to age or body weight. The impact of antibodies on the pharmacokinetics of elosulfase alfa was assessed. No clear relationship was observed between total antibody titer and elosulfase clearance. However, in patients with neutralizing antibodies, overall clearance (CL) values were lower and t1/2 was longer. Despite changes in the pharmacokinetic profile, the presence of neutralizing antibodies did not affect the pharmacodynamics, efficacy, or safety of the drug in patients receiving elosulfase alfa treatment. No significant accumulation of elosulfase alfa in plasma was observed following weekly administration.

Clinical characteristics.

Indications.

Treatment of mucopolysaccharidosis type IVA (Morquio A syndrome, MPS IVA) in patients of any age.

Contraindications.

Life-threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

No studies on interactions have been conducted.

Special precautions for use.

Anaphylaxis and severe allergic reactions

Cases of anaphylaxis and severe allergic reactions have been observed in clinical trials. Therefore, appropriate medical support must be readily available during administration of elosulfase alfa. If such reactions occur, the infusion must be stopped immediately and appropriate treatment initiated. Current medical standards for emergency therapy should be followed. Particular caution is required when re-administering the medication to patients who have experienced allergic reactions during infusion.

Infusion reactions

Infusion reactions (IR) were the most common adverse events observed in clinical trials. IR may include allergic reactions. Patients should receive antihistamines with or without antipyretics prior to infusion (see section "Instructions for use and dosage"). Management of IR depends on the severity of the reaction and may include slowing or temporarily stopping the infusion and/or administering additional antihistamines, antipyretics, and/or corticosteroids. If a severe IR occurs, the infusion must be stopped immediately and appropriate treatment initiated. Re-administration of the drug after a severe reaction should be performed cautiously and under close physician supervision.

Spinal cord/cervical spinal cord compression

Spinal cord/cervical spinal cord compression was observed in clinical trials in patients receiving treatment with Vimizym® as well as in those receiving placebo. Patients should be monitored for symptoms of spinal cord/cervical spinal cord compression (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence), and appropriate clinical management should be provided.

Sodium-restricted diet

This medicinal product contains 8 mg of sodium per vial, which corresponds to 0.4% of the WHO recommended daily intake of sodium (2 g) for adults. It is administered diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion (see section "Instructions for use and dosage"). This should be taken into account for patients on a sodium-restricted diet.

Sorbitol (E 420)

This medicinal product contains 100 mg of sorbitol per vial, equivalent to 40 mg/kg. Patients with rare hereditary conditions such as hereditary fructose intolerance should not take this product unless clearly necessary.

In infants and young children (under 2 years of age), hereditary fructose intolerance may be undiagnosed. Intravenous administration of medicinal products containing sorbitol/fructose may be life-threatening. The benefit of treatment for the child versus the associated risks should be carefully considered before initiating therapy.

A detailed patient history regarding symptoms of hereditary fructose intolerance must be obtained before initiating treatment with this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of Vimizym® in pregnant women.

Animal studies have not shown any direct or indirect harmful effects of the drug on pregnancy or embryofetal development. However, these studies have limited relevance. As a precautionary measure, it is advisable to avoid using Vimizym® during pregnancy, except when absolutely necessary.

Breastfeeding

Animal reproductive toxicity studies have shown that elosulfase alfa is excreted in milk. It is unknown whether elosulfase alfa is excreted in human breast milk, but systemic exposure via breast milk is not expected. Due to the lack of human data, Vimizym® should be used in breastfeeding women only if the potential benefit justifies the potential risk to the infant.

Fertility

No effects on fertility were observed in preclinical studies with elosulfase alfa.

Effect on ability to drive and use machines.

The effect of Vimizym® on the ability to drive or operate machinery is considered negligible. Dizziness has been observed during Vimizym® infusions; if dizziness occurs after infusion, it may affect the ability to drive or operate machinery.

Administration and Dosage

Treatment with Vimizim® should be conducted under the supervision of a physician experienced in managing patients with mucopolysaccharidosis type IVA (MPS IVA) or other inherited metabolic disorders. Administration of Vimizim® should be performed by a properly trained healthcare professional capable of providing emergency medical care. For patients who tolerate infusions well, administration at home under the supervision of a properly trained healthcare professional may be considered.

Dosage

The recommended dose of elosulfase alfa is 2 mg/kg body weight administered once weekly. The total infusion volume should be given over approximately 4 hours (see Table 3).

Due to the potential for hypersensitivity reactions to elosulfase alfa, patients should receive antihistamines with or without antipyretics 30–60 minutes prior to the start of infusion (see section "Special Warnings and Precautions for Use").

Special Populations

Elderly Patients (≥ 65 years of age)

The safety and efficacy of Vimizim® in patients aged 65 years and older have not been established; therefore, no alternative dosing recommendations can be made for these patients. It is unknown whether elderly patients respond differently from younger patients.

Pediatric Patients

The dosage for pediatric patients is the same as for adults. Available data are presented in the sections "Pharmacological Properties" and "Undesirable Effects".

Method of Administration

For intravenous infusion only.

For patients with body weight less than 25 kg, the solution should be administered in a total volume of 100 mL. If the drug is diluted in 100 mL, the initial infusion rate should be 3 mL/hour. If the patient tolerates the infusion well, the rate may be increased every 15 minutes according to the following scheme: first increase the rate to 6 mL/hour, then increase by 6 mL/hour every 15 minutes until the maximum rate of 36 mL/hour is reached.

For patients with body weight of 25 kg or more, the solution should be administered in a total volume of 250 mL. If the drug is diluted in 250 mL, the initial infusion rate should be 6 mL/hour. If the patient tolerates the infusion well, the rate may be increased every 15 minutes according to the following scheme: first increase the rate to 12 mL/hour, then increase by 12 mL/hour every 15 minutes until the maximum rate of 72 mL/hour is reached.

Table 3

Recommended infusion volume and rate*

* The infusion rate may be increased if the patient tolerates it well.

Instructions for dilution of the medicinal product prior to administration are provided below (see section "Preparation of Vimizyme® infusion").

Each Vimizyme® vial is intended for single use only. Vimizyme® must be diluted with 9 mg/ml (0.9%) sodium chloride solution for infusion, under aseptic conditions. The diluted solution is administered to the patient using an infusion set. An infusion set equipped with an integrated 0.2 µm pore size filter may be used.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Preparation of Vimizyme® infusion

Aseptic techniques must be followed.

Vimizyme® must be diluted prior to administration.

The number of vials to be diluted depends on the patient's body weight. The recommended dose is 2 mg/kg.

1. The number of vials to be diluted, based on the patient's body weight and the recommended dose of 2 mg/kg, is determined using the following calculation:
   • Patient's body weight (kg) multiplied by 2 (mg/kg) = patient's dose (mg).
   • Patient's dose (mg) divided by 1 (mg/ml concentration of Vimizyme® concentrate) = total milliliters of Vimizyme®.
   • Total volume (ml) of Vimizyme® divided by 5 ml per vial = total number of vials.
2. The calculated total number of vials should be rounded up to the next whole number. Remove the required number of vials from the refrigerator. Do not heat the vials or treat them in a microwave oven. Do not shake the vials.
3. An infusion container containing 9 mg/ml (0.9%) sodium chloride solution for infusion is considered suitable for intravenous administration of the drug. The total infusion volume depends on the patient's body weight.
   • For patients with body weight less than 25 kg, the solution should be administered in a total volume of 100 ml.
   • For patients with body weight of 25 kg or more, the solution should be administered in a total volume of 250 ml.
4. Before withdrawing Vimizyme® from the vial, inspect the vial contents for the presence of particulate matter and discoloration. Since this is a protein solution, slight flocculation (formation of clumps of fine transparent fibers) may occur. The Vimizyme® solution should be clear or slightly opalescent and colorless or pale yellow. Do not use the product if the solution has changed color or if particulate matter is present.
5. Remove and discard from the infusion container a volume of 9 mg/ml (0.9%) sodium chloride solution for infusion equal to the volume of Vimizyme® concentrate to be added (100 ml or 250 ml, depending on the patient's body weight).
6. Withdraw the calculated volume of Vimizyme® from the appropriate number of vials slowly and carefully to avoid excessive foaming.
7. Add Vimizyme® slowly and carefully into the infusion container, avoiding foaming.
8. Gently rotate the infusion container to ensure uniform distribution of Vimizyme®. Do not shake the solution.
9. The diluted solution is administered to the patient using an infusion set. An infusion set equipped with an integrated 0.2 µm pore size filter may be used.

Diluted solutions: Chemical and physical in-use stability has been demonstrated for 24 hours at 2–8 °C, followed by up to 24 hours at 23–27 °C.

From a microbiological standpoint, the diluted solution should be used immediately. If not used immediately, the user is responsible for the storage conditions and duration; generally, the product should be stored for no longer than 24 hours at 2–8 °C, followed by up to 24 hours at 23–27 °C during administration.

Children.

Vimizyme® is used for the treatment of children. For information on pediatric use, see section "Dosage and administration". Current available data are described in sections "Pharmacological properties" and "Adverse reactions".

Overdose.

In clinical studies, doses of elosulfase alfa up to 4 mg/kg per week were administered; no specific signs or symptoms after administration of higher doses were observed. No differences in safety profiles were noted. Management of adverse reactions is described in sections "Special precautions" and "Adverse reactions".

Adverse Reactions

Overview of Safety Profile

The assessment of adverse reactions is based on treatment experience in 176 patients with Mucopolysaccharidosis Type IVA (MPS IVA), aged 5 to 57 years, who received either 2 mg/kg elosulfase alfa once weekly (n = 58), 2 mg/kg elosulfase alfa every two weeks (n = 59), or placebo (n = 59) in a randomized, double-blind, placebo-controlled study.

Most adverse reactions observed in clinical studies were infusion-related reactions (IRs), defined as reactions occurring after the start of infusion and up to the end of the day of infusion. Serious IRs were observed in clinical studies, including anaphylaxis, hypersensitivity, and vomiting. The most common symptoms of IRs (observed in ≥ 10% of patients treated with Vimizim® and at least 5% more frequently than with placebo) were headache, nausea, vomiting, fever, chills, and abdominal pain. Most IRs were mild or moderate in severity and occurred more frequently during the first 12 weeks of treatment, with a tendency for frequency to decrease over time.

The adverse reactions observed during clinical studies in patients treated with Vimizim® are described below.

The frequency of occurrence is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Immune system disorders:
Common – hypersensitivity reactions;
Uncommon – anaphylaxis.

Nervous system disorders:
Very common – headache, dizziness.

Respiratory, thoracic and mediastinal disorders:
Very common – dyspnea.

Gastrointestinal disorders:
Very common – diarrhea, vomiting, oropharyngeal pain, upper abdominal pain, abdominal pain, nausea.

Musculoskeletal and connective tissue disorders:
Very common – chills;
Common – myalgia.

General disorders and administration site conditions:
Very common – pyrexia (fever).

Description of Selected Adverse Reactions

Immunogenicity

In clinical studies, all patients developed antibodies to elosulfase alfa. Approximately 80% developed neutralizing antibodies capable of inhibiting the binding of elosulfase alfa to the cation-independent mannose-6-phosphate receptor. Despite the presence of antibodies to elosulfase alfa, sustained improvements in efficacy parameters and reductions in urinary keratan sulfate (KS) levels were observed over time across all studies. No correlation was observed between higher antibody titers or positivity for neutralizing antibodies and reduced efficacy, or increased frequency of anaphylaxis or other hypersensitivity reactions. IgE antibodies to elosulfase alfa were detected in ≤ 10% of treated patients and were not always associated with anaphylaxis or other hypersensitivity reactions and/or discontinuation of treatment.

Pediatric Population

In patients aged < 5 years, the overall safety profile of Vimizim® at a dose of 2 mg/kg/week was consistent with the safety profile observed in older children.

Reporting of Suspected Adverse Reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf Life.

3 years.

Storage Conditions.

Store in a refrigerator at 2 °C to 8 °C. Do not freeze. Store in the original packaging to protect from light. Keep out of reach of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except 9 mg/mL (0.9%) sodium chloride solution for infusion.

Packaging.

5 mL of solution in a clear glass vial (Type I), stoppered with a butyl rubber stopper and sealed with an aluminum flip-off cap with a plastic overcap. One vial per cardboard carton.

Prescription Category.
Prescription only.

Manufacturer.

BioMarin International Limited.

Manufacturer's Address and Place of Business.

Shanbally, Ringaskiddy, P43 R298, Ireland.