Eléliso

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELELYSO (ELELYSO®)

Composition:

Active substance: taliglucerase alfa;

1 vial contains taliglucerase alfa 200 units;

Excipients: mannitol (E 421), polysorbate 80, sodium citrate (as trisodium salt dihydrate), citric acid anhydrous.

Pharmaceutical form. Lyophilized powder for solution for infusion.

Main physicochemical properties: white or almost white powder, may form a cake.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolism. Enzyme preparations. ATC code A16AB11.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Gaucher disease is an autosomal recessive disorder caused by mutations in the human glucocerebrosidase gene, leading to reduced activity of the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. Enzyme deficiency results in the accumulation of the substrate glucocerebroside primarily within the lysosomal compartments of macrophages, leading to the formation of foamy cells or Gaucher cells, which accumulate in the liver, spleen, and bone marrow.

Eliglustat, an enzyme replacement therapy product, is a recombinant analog of human lysosomal glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside into glucose and ceramide, thereby reducing the accumulated glucocerebroside. Cellular uptake of the drug into lysosomes is mediated by binding of the oligosaccharide mannose chains of Eliglustat to specific mannose receptors on the cell surface, resulting in internalization and subsequent transport of the drug to lysosomes.

Pharmacokinetics

The pharmacokinetics of taliglucerase alfa were evaluated in 38 patients (29 adults and 9 children) who received intravenous infusions of the drug Elelyso at doses of 30 units/kg (50% of the recommended dose) or 60 units/kg (recommended dose) (see section "Dosage and Administration") every two weeks. Pharmacokinetic parameters for adults and children are presented in Table 1.

In adult patients with type 1 Gaucher disease receiving Elelyso at doses of 30 units/kg (50% of the recommended dose) or 60 units/kg (recommended dose) (see section "Dosage and Administration") (N = 29) every two weeks as initial therapy, pharmacokinetics were assessed after the first dose and at week 38 of treatment. In this dose-ranging study, the pharmacokinetics of taliglucerase alfa were found to be nonlinear, with greater-than-dose-proportional increases in exposure.

With repeated dosing of 30 units/kg (50% of the recommended dose) or 60 units/kg (recommended dose) (see section "Dosage and Administration") administered every two weeks, no significant accumulation or changes in the pharmacokinetics of taliglucerase alfa were observed between week 1 and week 38 of treatment. Given the limited data available, no significant differences in pharmacokinetic parameters between male and female patients were observed in this study.

The pharmacokinetics of taliglucerase alfa were evaluated in 9 children aged 4 to 17 years with type 1 Gaucher disease who received Elelyso treatment for 10 to 27 months. Six of the 9 patients were treatment-naïve, while 3 patients had switched from imiglucerase therapy. In both dose groups (30 units/kg [50% of the recommended dose] and 60 units/kg [recommended dose]) (see section "Dosage and Administration"), clearance values in children were similar to those observed in adult patients. AUC values in children were lower than those in adults due to body weight-dependent dosing and lower body weight in children.

Table 1. Pharmacokinetic parameters of taliglucerase alfa following repeated dosing in adults and children with type 1 Gaucher disease

Parameters	Children (N = 9) Median (range)		Adults at week 38 (N = 29) Median (range)
	30 units/kga n = 5	60 units/kg n = 4	30 units/kga n = 14	60 units/kg n = 15
Age, years	15 (10, 17)	11 (4, 16)	35 (19, 74)	33 (19, 58)
Body weight, kg	44.3 (22.8; 71.0)	28.6 (16.5; 50.4)	72.5 (51.5; 99.5)	73.5 (58.5; 87.0)b
AUC0–∞, ng*hr/mLc	1416 (535; 1969)	2984 (1606; 4273)	2007 (1007; 10092)	6459 (2548; 21020)b
T1/2, min	37.1 (22.5; 56.8)	32.5 (18.0; 42.9)	18.9 (9.20; 57.9)	28.7 (11.3; 104)b
CL, L/hr	30.5 (17.4; 37.8)	15.8 (11.7; 24.9)	30.5 (6.79; 68.0)	18.5 (6.20; 37.9)b
Vss, L	14.9 (10.1; 35.6)	8.80 (3.75; 21.4)	11.7 (2.3; 22.7)	10.7 (1.4; 18.5)b

a30 units/kg is 50% of the recommended dose.

b n = 14

c Values based on parameters with concentrations expressed in ng/mL.

Immunogenicity

The frequency of antibody detection (including neutralizing antibodies) depends largely on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparison of antibody detection frequencies to drugs in the studies described below with those in other studies, including studies of the drug Elelyso or other taliglucerase alfa products.

Antibodies to the drug

In Studies 1, 2, and 3, the majority of patients who developed antibodies during treatment with Elelyso experienced hypersensitivity reactions compared to those who did not develop antibodies to the drug (see sections "Adverse Reactions" and "Special Warnings and Precautions for Use").

In Study 1 (adult patients with Gaucher disease who had not previously received treatment) (see section "Clinical Studies"), antibodies to the drug developed in 17 (53%) of 32 patients during treatment with Elelyso. Additionally, 2 (6%) patients tested positive for antibodies at baseline prior to starting treatment with Elelyso.

In Study 2 (children with Gaucher disease who had not previously received treatment) (see section "Clinical Studies"), antibodies to the drug developed in 2 (22%) of 9 patients with type 1 Gaucher disease. Additionally, 1 patient tested positive for antibodies prior to starting treatment with Elelyso.

In Study 3 (switching from imiglucerase to Elelyso) involving 31 patients (26 adults and 5 children) (see section "Clinical Studies"), antibodies to the drug developed in 6 adults (23% of adult patients) and did not develop in any of the children. Additionally, 3 (10%) patients tested positive for antibodies prior to starting treatment with Elelyso. There is insufficient information available to characterize the reaction to Elelyso antibodies and the impact of antibodies on the pharmacokinetics, pharmacodynamics, or efficacy of taliglucerase alfa products.

Neutralizing antibodies

In Studies 1, 2, and 3, with a total of 72 patients, 30 of 31 patients (adults and children) who developed antibodies during treatment with Elelyso or who tested positive for antibodies at baseline were evaluated for neutralizing antibody activity using a mannose receptor binding assay and an enzymatic activity assay. Nineteen (63%) of the 30 patients had neutralizing antibodies capable of inhibiting in vitro binding of Elelyso to mannose receptors. Eight (42%) of these 19 patients had neutralizing antibodies capable of inhibiting in vitro enzymatic activity of Elelyso.

Although efficacy was quantitatively lower (less reduction in spleen and liver volume) in patients receiving Elelyso who developed neutralizing antibodies compared to those who did not develop neutralizing antibodies, the data were insufficient to fully assess whether these neutralizing antibodies reduce treatment efficacy.

Other antibodies

Antibodies to specific plant glycans in Elelyso also developed in nine (29%) of 31 patients (adults and children) who developed antibodies to Elelyso during treatment or who tested positive for antibodies at baseline.

Clinical Studies.

1. Clinical study of Elelyso as initial therapy.

Clinical study in adult patients.

The safety and efficacy of the drug were evaluated in adult patients with type 1 Gaucher disease. This was a 9-month, multicenter, double-blind, randomized study (Study 1) involving 31 adult patients with spleen enlargement (>8 times normal) related to Gaucher disease and thrombocytopenia (<120,000/mm³). At baseline, 16 patients had spleen enlargement and 10 patients had anemia. All patients had not previously received enzyme replacement therapy. Patients with severe neurological symptoms were excluded from the study.

Patients were randomized to receive either Elelyso at a dose of 30 units/kg (n = 15) (50% of the recommended dose) or 60 units/kg (recommended dose) (see section "Dosage and Administration") (n = 16) every two weeks. After 9 months, 26 of the 31 patients continued to participate in an open-label extension study with a total treatment duration of up to 24 months, receiving the same intravenous dose every two weeks. Twenty-three of the 26 patients who continued Elelyso treatment (30 or 60 units/kg administered intravenously every two weeks) continued in an open-label phase for an additional 12 months (total duration of Elelyso treatment was 36 months).

Baseline demographics

In Study 1, patients were aged 19 to 74 years (mean age 36 years), 48% were male, 97% were Caucasian, and 29% and 71% were Hispanic/Latino and non-Hispanic/non-Latino, respectively.

Efficacy results

Table 2 presents baseline values and mean changes in clinical parameters (spleen volume, liver volume, platelet count, and hemoglobin) after 9 months of treatment with Elelyso in Study 1. Liver and spleen volumes were measured by MRI and reported as percentages of body weight and multiples of normal. The observed reduction in spleen volume compared to baseline (primary endpoint) was considered clinically meaningful in the context of the natural history of untreated Gaucher disease.

Table 2. Mean changes (standard deviation) in clinical parameters from baseline to 9 months in adult patients with type 1 Gaucher disease who had not previously received enzyme replacement therapy, treated with Elelyso (N = 31) (Study 1)

Parameters	Clinical parameter	30 units/kg* (n = 15)	60 units/kg (n = 16)
		Mean value (standard deviation)	Mean value (standard deviation)
Spleen volume (% body weight)	Baseline	3.1 (1.5)	3.3 (2.7)
	9th month	2.2 (1.3)	2.1 (1.9)
	Change	–0.9 (0.4)	1.3 (1.1)
Spleen volume (multiple of normal)	Baseline	15.4 (7.7)	16.7 (13.4)
	9th month	11.1 (6.3)	10.4 (9.4)
	Change	4.5 (2.1)	6.6 (5.4)
Liver volume (% body weight)	Baseline	4.2 (0.9)	3.8 (1.0)
	9th month	3.6 (0.7)	3.1 (0.7)
	Change	0.6 (0.5)	0.6 (0.4)
Liver volume (multiple of normal)	Baseline	1.7 (0.4)	1.5 (0.4)
	9th month	1.4 (0.3)	1.2 (0.3)
	Change	0.2 (0.2)	0.3 (0.2)
Platelet count (mm³)	Baseline	75,320 (40,861)	65,038 (28,668)
	9th month	86,747 (50,989)	106,531 (53,212)
	Change	11,427 (20,214)	41,494 (47,063)
Hemoglobin (g/dL)	Baseline	12.2 (1.7)	11.4 (2.6)
	9th month	14.0 (1.4)	13.6 (2.0)
	Change	1.6 (1.4)	2.2 (1.4)

*The recommended dose of Eleliso for patients who have not previously received enzyme replacement therapy is 60 units/kg every two weeks. The dose of 30 units/kg every two weeks of Eleliso is not the recommended dose of the medicinal product (see section "Dosage and administration").

Data corresponding to changes in clinical parameters from baseline to 24 months (including a 9-month initial period and a 15-month first long-term extension) were obtained in the dosing groups of 30 units/kg (n = 12) (50% of the recommended dose) and 60 units/kg (recommended dose) (see section "Dosage and administration") (n = 14), respectively: mean spleen volume (standard deviation) (% body weight) decreased by 1.4 (0.6) and 2.0 (2.0), as multiples of normal – by 6.8 (3.0) and 10.2 (9.8); hemoglobin level increased by 1.3 (1.7) g/dL and 2.4 (2.3) g/dL; liver volume (% body weight) decreased by 1.1 (0.5) and 1.0 (0.7), as multiples of normal – by 0.4 (0.2) and 0.4 (0.3); platelet count increased by 28,433 (31,996)/mm³ and 72,029 (68,157)/mm³.

Clinical study in pediatric patients up to 16 years of age inclusive.

The safety and efficacy of Eleliso were evaluated in pediatric patients with type 1 Gaucher disease in a 12-month, multicenter, double-blind, randomized study (Study 2) involving 9 treatment-naïve patients. Patients were randomized to receive Eleliso either at a dose of 30 units/kg (n = 4) (50% of the recommended dose) or 60 units/kg (recommended dose) (see section "Dosage and administration") (n = 5) every two weeks. After 12 months, all 9 patients entered the blinded long-term extension phase of the study (24 months of total treatment), during which they continued receiving Eleliso at the same dose every two weeks.

Baseline Demographics

In Study 2, patients were aged 2 to 13 years (mean age 8.1 years), 67% were male, 89% were Caucasian, and 44% and 56% were Hispanic/Latino and non-Hispanic/non-Latino, respectively.

Efficacy Results

The following data from Study 2 represent changes (mean (Q1, Q3)) in clinical parameters from baseline to 12 months in the group receiving 60 units/kg (n = 5): spleen volume decreased from 18.4 (14.2; 35.1) MN (multiples of normal) to 11.0 (8.3; 14.5) MN; hemoglobin increased from 11.1 (9.2; 11.3) g/dL to 11.7 (11.5; 12.9) g/dL; liver volume decreased from 2.1 (2.0; 2.3) MN to 1.6 (1.5; 1.9) MN; platelet count increased from 80,000 (79,000; 87,000)/mm³ to 131,000 (119,000; 215,000)/mm³.

The following data represent changes (mean (Q1, Q3)) in clinical parameters from baseline to 24 months in the group receiving 60 units/kg (n = 5): spleen volume decreased by 19.0 (8.3; 41.2) MN; hemoglobin increased by 2.5 (1.9; 3.0) g/dL; liver volume decreased by 0.8 (0.6; 1.1) MN; and platelet count increased by 76,000 (67,000; 100,000)/mm³.

1. Clinical studies in patients who switched from imiglucerase to Eleliso therapy.

The safety and efficacy of the product were evaluated in 31 patients (26 adults and 5 children) with type 1 Gaucher disease who switched from imiglucerase to Eleliso (Study 3). Study 3 was a 9-month, multicenter, open-label, single-arm study in patients who had previously received imiglucerase at doses ranging from 9.5 units/kg to 60 units/kg every two weeks for at least 2 years. Key eligibility criteria included stable clinical status and having received a stable dose of imiglucerase every two weeks for at least 6 months prior to enrollment. Imiglucerase therapy was discontinued, and treatment with Eleliso was initiated every two weeks at the same dose (in units) previously received by each patient (from 9.5 units/kg to 60 units/kg administered intravenously every two weeks). Dose adjustments were permitted if necessary to maintain clinical parameters (i.e., hemoglobin level, platelet count, spleen and liver volumes).

• 18 of the 26 adult patients who completed the 9-month clinical study continued Eleliso treatment (from 9.5 units/kg to 60 units/kg administered intravenously every two weeks) in an open-label extension study for an additional 27 months (total treatment period of 36 months).
• 5 pediatric patients who completed the 9-month clinical study continued open-label treatment with Eleliso (from 9.5 units/kg to 60 units/kg administered intravenously every two weeks) for an additional 24 months (total treatment period of 33 months).

Baseline Demographics

In Study 3, patients were aged 6 to 66 years (mean age 42 years, including pediatric patients), 55% were male, 97% were Caucasian, and 16% and 84% were Hispanic/Latino and non-Hispanic/non-Latino, respectively.

Efficacy Results

In Study 3, at baseline, spleen volume was 5.2 (4.5) (multiples of normal), liver volume was 1.0 (0.3) (multiples of normal), platelet count was 161,137 (73,387)/mm³, and hemoglobin was 13.5 (1.4) g/dL. After 9 months of Eleliso treatment, spleen volume was 4.8 (4.6) (multiples of normal), liver volume was 1.0 (0.2) (multiples of normal), platelet count was 161,167 (80,820)/mm³, and hemoglobin was 13.4 (1.5) g/dL. The dose remained unchanged in 30 out of 31 patients. One patient required a dose increase (from 9.5 units/kg to 19 units/kg) at week 24 due to a platelet count of 92,000/mm³ at week 22, with a subsequent rise to 170,000/mm³ by month 9.

Over the 36-month period, 18 adult patients receiving Eleliso showed stable clinical parameters (spleen volume, liver volume, platelet count, and hemoglobin); however, only 10 of these 18 adult patients completed the 27-month Eleliso treatment in the extension study, and spleen and liver volumes were assessed at 36 months in only 7 patients.

Over the 33-month period, 5 pediatric patients receiving Eleliso demonstrated stability in these clinical parameters.

Clinical characteristics.

Indications.

Elelyso is indicated for the treatment of patients aged 4 years and older with a confirmed diagnosis of Type 1 Gaucher disease.

Contraindications.

Severe allergic reactions to taliglucerase alfa or any other components of the product in medical history.

Interaction with other medicinal products and other forms of interaction.

Not established.

Special precautions for use.

Hypersensitivity reactions, including anaphylaxis.

Life-threatening hypersensitivity reactions, including anaphylaxis, have occurred in patients receiving enzyme replacement therapy, including Elelyso. During clinical trials (patients who did not routinely receive premedication with antihistamines and/or corticosteroids prior to Elelyso infusions in clinical trials):

• In 2 of 72 (3%) patients receiving Elelyso treatment, signs and symptoms of anaphylaxis occurred, including urticaria, hypotension, flushing, wheezing, chest tightness, nausea, vomiting, and dizziness. These reactions occurred during Elelyso infusion.
• In 21 of 72 (29%) patients receiving Elelyso treatment, hypersensitivity reactions occurred, including signs and symptoms of anaphylaxis in 2 patients. Signs and symptoms of hypersensitivity reactions included pruritus, angioedema, flushing, erythema, rash, vomiting, cough, chest tightness, and throat irritation. These reactions occurred within 3 hours of starting the infusion (see section "Adverse Reactions").

Anaphylaxis has occurred during early courses of enzyme replacement therapy and after prolonged duration of therapy. Administration of Elelyso should be supervised by a healthcare professional experienced in managing hypersensitivity reactions, including anaphylaxis. Treatment with Elelyso should be initiated in a healthcare setting equipped with appropriate medical monitoring and support, including access to cardiopulmonary resuscitation equipment. Patients should be closely monitored for 3 hours following the start of each infusion.

In patients treated with Elelyso who developed antibodies to taliglucerase alfa (so-called anti-drug antibodies), a higher incidence of hypersensitivity reactions was generally observed compared to those without anti-drug antibodies (see section "Adverse Reactions"). Close observation for hypersensitivity reactions is recommended in patients who develop anti-drug antibodies.

Management of hypersensitivity reactions, depending on the severity, may include slowing or temporarily stopping the infusion and/or administration of antihistamines, antipyretics, and/or corticosteroids for mild reactions. Premedication with antihistamines and/or corticosteroids may prevent the occurrence of hypersensitivity reactions. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, Elelyso infusion should be stopped immediately and appropriate treatment initiated, including administration of epinephrine. Patients should be informed about the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and the need to seek immediate medical attention if such symptoms occur.

The benefits and risks of re-administering Elelyso to patients who have experienced a severe hypersensitivity reaction related to the drug should be carefully considered. Caution should be exercised when re-administering the drug (see section "Adverse Reactions").

Sodium content.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose. Patients on a low-sodium diet may be advised that this medicinal product can be considered essentially sodium-free.

Use in the elderly.

During clinical trials, 8 patients aged 65 years and older received Elelyso treatment. The clinical trials of Elelyso did not include a sufficient number of patients aged 65 years and older to determine whether their response to treatment differs from that of younger patients.

Use during pregnancy or breastfeeding.

Pregnancy.

Limited available data on the use of Elelyso in pregnant women are insufficient to inform the risk associated with its use. However, clinical considerations are available (see subsection "Clinical considerations"). In reproductive studies in animals, intravenous administration of taliglucerase alfa at doses 5 times the recommended clinical dose did not show evidence of embryofetal toxicity. The estimated background risk of major congenital malformations and miscarriage for this population is unknown. In the general U.S. population, the estimated background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical considerations

Risk to the mother and embryo/fetus associated with the disease.

Women with type 1 Gaucher disease have an increased risk of miscarriage if symptoms of the disease are not treated and controlled before conception and during pregnancy. Pregnancy may exacerbate existing symptoms of type 1 Gaucher disease or lead to new manifestations. Manifestations of type 1 Gaucher disease may lead to adverse pregnancy outcomes, including hepatosplenomegaly, which may interfere with normal fetal growth, and thrombocytopenia, which may lead to postpartum hemorrhage and bleeding requiring blood transfusion.

Breastfeeding.

There are no data on the presence of taliglucerase alfa in human breast milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for Elelyso treatment and any potential adverse effects on the breastfed infant from Elelyso or from the underlying maternal condition.

Ability to affect reaction speed when driving or operating machinery.

Since dizziness has been reported during clinical trials with taliglucerase alfa, patients should be aware of their individual response to Elelyso before driving or operating machinery.

Administration and Dosage

Recommendations prior to administration of Eleliso.

Administration of Eleliso should be supervised by a healthcare professional experienced in the management of hypersensitivity reactions, including anaphylaxis (see section "Special precautions").

Eleliso therapy should be initiated in a healthcare setting equipped with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment (see section "Special precautions").

To reduce the risk of hypersensitivity reactions, premedication with antihistamines and/or corticosteroids should be considered (see section "Special precautions").

Recommended dosage for patients aged 4 years and older.

Treatment of patients aged 4 years and older who have not previously received enzyme replacement therapy.

The recommended dose of Eleliso is 60 units/kg (based on actual body weight) administered every 2 weeks as a 60–120-minute intravenous infusion.

Treatment of patients aged 4 years and older transitioning from imiglucerase.

When switching from a stable dose of imiglucerase to Eleliso, intravenous administration of Eleliso (infusion duration 60 to 120 minutes) should be initiated at the same dose (units/kg) as imiglucerase, followed by administration of Eleliso once every 2 weeks. Dose adjustments should be made based on achieving and maintaining therapeutic goals for each individual patient.

Preparation instructions.

Eleliso should be reconstituted, diluted, and administered under the supervision of a healthcare professional.

Eleliso should be prepared under aseptic conditions following the steps below:

1. Determine the number of vials required based on the patient’s body weight in kg and the recommended dose (see section "Recommended dosage for patients aged 4 years and older"). Round the number of vials up to the next whole number.
2. Remove the required number of vials from the refrigerator. Do not leave vials at room temperature for more than 24 hours prior to reconstitution. Vials must not be heated or warmed in a microwave oven.
3. Reconstitute each vial of Eleliso with 5.1 mL of sterile water for injection to obtain a reconstituted solution concentration of 40 units/mL and a withdrawable volume of 5 mL.
   • After reconstitution, gently mix the contents of the vials. DO NOT SHAKE.
     • Visually inspect the solution in the vials before further dilution; the solution should be clear and colorless. Do not use the solution if it has changed color or contains particulate matter.
4. The reconstituted product must be further diluted with 0.9% sodium chloride injection solution to a final volume of 100–200 mL before intravenous infusion. Unused solution should be discarded.
   • For children aged 4 years and older, a final volume of 100–120 mL should be used.
     • For adults, a final volume of 130–150 mL may be used. However, if the volume of reconstituted solution alone is 130–150 mL or more, the final volume should not exceed 200 mL.
5. Gently mix. DO NOT SHAKE. As this is a protein solution, slight flocculation (appearing as translucent fibers) may occasionally occur after reconstitution.
6. Discard any unused solution.

Storage and handling of reconstituted and diluted solution.

If the vial of reconstituted Eleliso is not used immediately, it may be stored in the refrigerator for up to 24 hours at 2–8°C (protected from light) or at room temperature for up to 4 hours at 20–25°C (without protection from light).

If the diluted solution is not used immediately, it may be stored in the refrigerator for up to 24 hours at 2–8°C (protected from light).

The total storage time for reconstituted and diluted solution must not exceed 24 hours. Any unused product or diluent must be discarded after 24 hours from the start of preparation. Do not freeze.

Administration instructions.

After reconstitution and dilution, the prepared solution should be administered as an intravenous infusion lasting at least 60 minutes and filtered through a low protein-binding filter with a pore size of 0.2 µm.

• For pediatric patients based on body weight (actual body weight):
  • Less than 30 kg: infusion rate should be 1 mL/min.
  • 30 kg and above: initial infusion rate should be 1 mL/min. After establishing tolerability of Eleliso, the infusion rate may be increased, but not above the recommended maximum of 2 mL/min.
• For adults: initial infusion rate should be 1.2 mL/min. After establishing tolerability of Eleliso, the infusion rate may be increased, but not above the recommended maximum of 2.2 mL/min.

Pediatric population.

The safety and efficacy of Eleliso in pediatric patients aged 4 years and older with confirmed type 1 Gaucher disease have been established. The use of Eleliso is supported by demonstrated efficacy in adults from adequate and well-controlled studies, as well as additional pharmacodynamic data from 5 pediatric patients and pharmacokinetic data from 9 pediatric patients included in clinical trials (see section "Pharmacokinetics"). Data from 14 pediatric patients were included in the safety evaluation (see section "Adverse reactions"). There is insufficient data to recommend dosing of Eleliso in children under 4 years of age.

Vomiting during Eleliso administration was observed more frequently in pediatric patients than in adults (4 out of 9 treatment-naïve pediatric patients), which may represent a hypersensitivity reaction. The incidence of other adverse reactions was similar in pediatric and adult patients (see section "Adverse reactions").

Overdose.

There is no experience with overdose of Eleliso.

Adverse Reactions

Clinical trial experience

Because the conditions under which clinical trials are conducted vary widely, the adverse reaction rates observed in the clinical trials of one medicinal product cannot be directly compared with those of another medicinal product, and may not reflect the rates observed in clinical practice.

Adverse reactions from the Elizyme clinical trial in which the drug was administered as initial therapy

• Clinical trial in adult patients

The safety of Elizyme administered at doses of 30 units/kg (n = 16) (50% of the recommended dose) (see section "Dosage and administration") or 60 units/kg (n = 16) intravenously every two weeks was evaluated during a 9-month, double-blind, randomized clinical trial in 32 adult patients (aged 19 to 74 years) with type 1 Gaucher disease who had not previously received enzyme replacement therapy (Study 1) (see section "Clinical trials"). Table 3 lists adverse reactions in patients who received Elizyme treatment.

Table 3. Adverse reactions occurring in ≥ 5% of adult patients treated with Elizyme who had not previously received enzyme replacement therapy.

Adverse reactions	Number of treatment-naïve adult patients (N = 32), n (%)
Headache	6 (19)
Arthralgia	4 (13)
Increased fatigue	3 (9)
Nausea	3 (9)
Dizziness	3 (9)
Abdominal pain	2 (6)
Pruritus	2 (6)
Hyperemia	2 (6)
Vomiting	2 (6)
Urticaria	2 (6)

Clinical study in pediatric patients up to 16 years of age, inclusive.

The safety of Eleliso administered at doses of 30 units/kg (n = 4) (50% of the recommended dose) (see section "Posology and method of administration") or 60 units/kg (n = 5), given intravenously every two weeks, was evaluated during a 12-month randomized clinical study in 9 children (aged 2 to 13 years) with type 1 Gaucher disease who had not previously received enzyme replacement therapy (Study 2) (see section "Clinical studies").

The most common adverse reaction (≥10%) was vomiting, which occurred in 4 out of 9 patients. Two patients experienced hypersensitivity reactions; one patient developed severe vomiting and gastrointestinal inflammation, while the other experienced mild throat irritation and chest discomfort. Both patients improved after treatment with antihistamines and continued Eleliso therapy.

Adverse reactions from the clinical study in patients switched from imiglucerase to Eleliso.

The safety of Eleliso was evaluated in 31 patients (26 adults and 5 children), aged 6 to 66 years, with type 1 Gaucher disease who had previously been treated with imiglucerase for at least 2 years (Study 3). Eleliso was administered intravenously every two weeks for 9 months at a dose (units/kg) equal to each patient’s previous imiglucerase dose. Table 4 lists these adverse reactions observed in patients treated with Eleliso.

Table 4. Adverse reactions in ≥10% of patients switched from imiglucerase to Eleliso (after 9 months of therapy)

Adverse Reactions	Adults and children switched from imiglucerase treatment (N = 31*) n (%)
Arthralgia	4 (13)
Headache	4 (13)
Limb pain	3 (10)

Immunogenicity: adverse reactions associated with neutralizing antibodies

In Studies 1, 2, and 3, patients with type 1 Gaucher disease who were treatment-naïve and those with prior enzyme replacement therapy experience were evaluated (see section "Clinical studies"). Hypersensitivity reactions occurred in 36% (9/25) of patients with type 1 Gaucher disease treated with elosulfase alfa who developed antibodies during the treatment period, compared to 15% (6/41) of patients who did not develop antibodies during treatment (see section "Special precautions for use" and "Pharmacological properties"). Among the 9 patients treated with elosulfase alfa who experienced hypersensitivity reactions, antibody testing was positive; 2 patients experienced anaphylaxis, and 1 additional patient discontinued elosulfase alfa due to hypersensitivity reactions.

Post-marketing experience.

The following adverse reactions have been reported during post-marketing use of elosulfase alfa. Because these reactions are reported voluntarily from an uncertain population size and additional information beyond that collected during post-marketing surveillance may be unavailable, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders: vomiting, diarrhea.

General disorders and administration site conditions: fatigue.

Immune system disorders: anaphylaxis (see section "Special precautions for use"), immune-mediated localized drug eruption of type III.

Musculoskeletal and connective tissue disorders: back pain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store at 2–8 °C in the original packaging to protect from light.

Packaging. 1 vial containing 200 IU of the medicinal product in a cardboard box.

Prescription status. Prescription-only.

Manufacturer.

Pharma & Upjohn Company LLC.

Manufacturer's address and location of operations.

7000 Portage Road, Kalamazoo, Michigan (MI) 49001, USA.