Xenpozyme

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XENPOZYME® (XENPOZYME®)

Composition:

Active substance: olipudase alfa;

1 vial contains 20 mg of olipudase alfa;

after reconstitution, 1 ml contains 4 mg of olipudase alfa;

Excipients: sodium dihydrogen phosphate monohydrate; disodium hydrogen phosphate heptahydrate; sucrose; L-methionine.

Pharmaceutical form. Powder for preparation of a concentrate for solution for infusion.

Main physicochemical properties: lyophilized powder, white to almost white.

Pharmacotherapeutic group. Drugs affecting the digestive tract and metabolism. Enzymes. ATC code A16AB25.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Olipudase alfa is a recombinant human acid sphingomyelinase that reduces sphingomyelin (SM) accumulation in organs of patients with acid sphingomyelinase deficiency (ASMD).

Clinical efficacy and safety

The efficacy of XENPOZYME was evaluated in 3 clinical studies (the ASCEND study in adult patients, the ASCEND-Peds study in pediatric patients, and an open-label extension study in both adult and pediatric patients), involving a total of 61 patients with ASMD.

Clinical study in adult patients

The ASCEND study was a multicenter, randomized, double-blind, placebo-controlled phase II/III trial with repeat dosing in adult patients with ASMD type A/B and B. A total of 36 patients were randomized in a 1:1 ratio to receive either XENPOZYME or placebo. Treatment was administered intravenously once every 2 weeks in both groups. In patients receiving XENPOZYME, the dose was titrated from 0.1 mg/kg to the target dose of 3 mg/kg. The study consisted of two sequential periods: a randomized, placebo-controlled, double-blind primary analysis period (PAP) lasting up to week 52, followed by a treatment extension period (TEP) lasting up to 4 years.

Patients randomized to the placebo group in the PAP transitioned to active treatment in the TEP, achieving the target dose of 3 mg/kg, while patients initially assigned to the XENPOZYME group continued treatment.

Patients enrolled in the study had a diffusing capacity of the lungs for carbon monoxide (DLco) ≤ 70% of the predicted normal value, spleen volume ≥ 6 times the normal value as measured by magnetic resonance imaging (MRI), and a spleen score ≥ 5 on the splenomegaly scale. Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median age of patients was 30 years (range 18–66 years). The mean age (standard deviation [SD]) at diagnosis of ASMD was 18 (18.4) years. At baseline, neurological manifestations were observed in 9 of 36 adult patients (25%), consistent with a clinical diagnosis of ASMD type A/B. The remaining 27 patients had a clinical diagnosis of ASMD type B.

This study had two separate primary efficacy endpoints: the percentage change from baseline to week 52 in DLco (% of predicted normal) and in spleen volume (multiples of normal), measured by MRI.

Secondary efficacy endpoints included the percentage change from baseline to week 52 in liver volume (multiples of normal) and platelet count. Pharmacodynamic parameters (levels of ceramide and lysosphingomyelin [deacylated form of SM]) were also assessed.

Significant improvement in mean percentage change (%) of predicted DLco (p = 0.0004) and spleen volume (p < 0.0001), as well as in mean liver volume (p < 0.0001) and platelet count (p = 0.0185), was observed in the XENPOZYME group compared to the placebo group during the 52-week primary analysis period. Significant improvement in mean percentage change (%) of predicted DLco, spleen volume, liver volume, and platelet count was observed as early as week 26, the first assessment point after dose initiation.

Results from the PAP at week 52 are presented in Table 1.

Table 1

Mean values (SD) of efficacy endpoints at baseline and mean percentage change (MPC) from baseline to week 52 by least squares (LS) method

* Statistical significance after multiplicity adjustment.

N/A – not applicable.

In addition, lyso-sphingomyelin, the level of which is significantly elevated in blood plasma of patients with ASMD, decreased substantially, reflecting a reduction in sphingomyelin content in tissues. The least squares mean percentage change from baseline to Week 52 (SE) in plasma lyso-sphingomyelin levels prior to infusion was 77.7% (3.9) in the Xenpozyme-treated group compared with 5.0% (4.2) in the placebo group. Hepatic sphingomyelin content, as assessed by histopathological evaluation, decreased by 92.0% (SE 8.1) from baseline to Week 52 in the Xenpozyme treatment group (compared with +10.3% (SE 7.8) in the placebo group).

17 out of 18 patients previously receiving placebo and 18 out of 18 patients previously receiving Xenpozyme for 52 weeks (PPA) initiated or continued treatment with Xenpozyme during the period up to 4 years. The sustained effect of Xenpozyme on efficacy endpoints up to Week 104 is presented in Figures 1 and 2 and Table 2.

Figure 1. Least squares mean (95% CI) percentage change in DLco (% predicted) from baseline to Week 104, mITT population (modified intent-to-treat: randomized patients who received at least one infusion, partially or fully)

Vertical bars represent 95% CI for least squares means.

Least squares means and 95% CI are based on a mixed model for repeated measures approach using data up to Week 104.

Patients in the placebo/Xenpozyme group received placebo until Week 52 and then switched to Xenpozyme.

Figure 2. Least squares mean (95% CI) percentage change in spleen volume (multiples of normal) from baseline to Week 104, mITT population (modified intent-to-treat: randomized patients who received at least one infusion, partially or fully)

Vertical bars represent 95% CI for least squares means.

Least squares means and 95% CI are based on a mixed model for repeated measures approach using data up to Week 104.

Patients in the placebo/Xenpozyme group received placebo until Week 52 and then switched to Xenpozyme.

Table 2

Least squares mean percentage change (SE) from baseline to Week 104 in liver volume (multiples of normal) and platelet count (10⁹/L) in patients treated with Xenpozyme for 104 weeks

N – number of patients

Extended study involving adult patients

Five adult patients with MPS I who participated in the open-label dose-escalation study continued treatment in an open-label extension study and received Xynzyme for a period of up to >7 years.

During the study, sustained improvements were observed in adult patients in % predicted DLco, spleen and liver volumes, and platelet counts compared to baseline (see Table 3).

Table 3

Mean percentage change (MPC) in efficacy parameters from baseline to month 78

N – number of patients

Children

The ASCEND-Peds study (a phase 1/2 clinical trial) was a multicenter, open-label, repeat-dose study evaluating the safety and tolerability of Xenpozyme administered for 64 weeks in children (aged < 18 years) with ASMD (types A/B and B). Additionally, exploratory efficacy endpoints related to organomegaly, lung and liver function, and linear growth were assessed at week 52.

A total of 20 patients (4 children aged 12 to < 18 years, 9 children aged 6 to < 12 years, and 7 children aged < 6 years) received Xenpozyme using a dose-escalation regimen from 0.03 mg/kg to the target dose of 3 mg/kg. Treatment was administered as an intravenous infusion once every 2 weeks for up to 64 weeks. Patients enrolled in the study had spleen volume ≥ 5 times the upper limit of normal, as measured by MRI. Patients were distributed across age groups from 1.5 to 17.5 years, with both sexes equally represented. The mean age (SD) at diagnosis of ASMD was 2.5 (2.5) years. At baseline, neurological manifestations were observed in 8 out of 20 pediatric patients (40%), consistent with a clinical diagnosis of ASMD type A/B. The other 12 patients had a clinical diagnosis of ASMD type B.

Treatment with Xenpozyme resulted in improvement in mean percent change from baseline in % predicted DLco, spleen and liver volumes, platelet counts, and progression of linear growth (measured by height Z-score) at week 52 compared to baseline (see Table 4).

Table 4

Mean percent change (SE) or change (SD) from baseline to week 52 in efficacy parameters (all age groups)

* DLco was assessed in 9 children aged ≥ 5 years who were able to perform the test; change in height Z-score was assessed in 19 children.

Additionally, mean least squares (LS) plasma levels of ceramide and lysosphingomyelin measured pre-infusion decreased by 57% (SE: 5.1) and 87.2% (SE: 1.3), respectively, from baseline levels after 52 weeks of treatment.

The effect of the medicinal product XENPOZYME on spleen and liver volume, platelet count, and height Z-score was observed across all pediatric age groups included in the study.

Open-label extension study in pediatric patients

Twenty pediatric patients who participated in the ASCEND-Peds study continued treatment in an open-label extension study and received XENPOZYME for up to >5 years.

In children, sustained improvements in efficacy parameters (% predicted DLco, spleen and liver volume, platelet count, height Z-score, and bone age) were observed throughout the study up to 48 months (see Table 5).

Table 5

Mean percentage change or change (SE) from baseline to Month 48 (all age groups) in efficacy parameters

N – number of patients.

The European Medicines Agency has deferred the obligation to submit the results of studies on the use of the medicinal product XENPOZYME in one or several subgroups of the paediatric population for the treatment of acid sphingomyelinase deficiency (see section "Posology and method of administration" for information on use in paediatrics).

Pharmacokinetics

The pharmacokinetics (PK) of olipudase alfa were evaluated in 49 adult patients with ASMD who participated in all clinical trials involving single or multiple dosing. At a dose of 3 mg/kg administered once every 2 weeks, the mean (percentage coefficient of variation, %CV) maximum concentration (Cmax) and area under the concentration-time curve over the dosing interval at steady state (AUC0-τ) were 30.2 µg/mL (17%) and 607 µg·h/mL (20%), respectively.

Absorption

Absorption is absent, as XENPOZYME is administered intravenously.

Distribution

The estimated mean (CV%) volume of distribution of olipudase alfa is 13.1 L (18%).

Metabolism

Olipudase alfa is a recombinant human enzyme and is expected to be eliminated via proteolytic degradation into small peptides and amino acids.

Elimination

The mean (CV%) clearance of olipudase alfa is 0.331 L/h (22%). The mean terminal half-life (t1/2) ranges from 31.9 to 37.6 hours.

Linearity/Non-linearity

Olipudase alfa exhibited linear pharmacokinetics over the dose range of 0.03 to 3 mg/kg. Following administration of a dose escalation regimen from 0.1 mg/kg to a maintenance dose of 3 mg/kg once every 2 weeks, minimal accumulation of olipudase alfa in plasma was observed.

Special patient populations

No clinically significant differences in the pharmacokinetics of olipudase alfa were observed according to sex.

Population pharmacokinetic analysis demonstrated that exposure in Mongoloid race subjects (n = 2) and patients of other races (n = 2) was within the range of exposures observed in Caucasian patients.

Elderly patients (≥ 65 years)

Population pharmacokinetic analysis did not demonstrate differences in exposure in elderly patients (only 2 patients aged 65 to 75 years were included in the XENPOZYME clinical trials).

Children

The PK of olipudase alfa was evaluated in 20 paediatric patients, including 4 children aged 12 to < 18 years, 9 children aged 6 to < 12 years, and 7 children aged < 6 years (Table 6). Exposure to olipudase alfa was lower in the paediatric population compared to adult patients. However, these differences were not considered clinically significant.

Table 6

Mean (CV%) pharmacokinetic parameters of olipudase alfa after administration of 3 mg/kg every 2 weeks in children aged 12 to < 18 years, children aged 6 to < 12 years, and children aged < 6 years with ASMD

Descriptive statistics are a post hoc assessment of steady-state exposure using population pharmacokinetic analysis.

AUC0-τ – area under the plasma concentration-time curve during the dosing interval; Cmax – maximum plasma concentration; n – total number of patients.

Hepatic impairment

Olipudase alfa is a recombinant protein and is expected to be eliminated via proteolytic degradation. Therefore, hepatic impairment is not expected to affect the pharmacokinetics of olipudase alfa.

Renal impairment

Four patients (11.1%) with mild renal impairment (60 mL/min ≤ creatinine clearance < 90 mL/min) were included in the ASCEND study. No clinically relevant differences in the pharmacokinetics of olipudase alfa were observed in patients with mild renal impairment. The effect of moderate or severe renal impairment on the pharmacokinetics of olipudase alfa is unknown. Olipudase alfa is not expected to be excreted renally. Therefore, renal impairment is not expected to affect the pharmacokinetics of olipudase alfa.

Preclinical safety data

Preclinical data revealed no special hazard for humans based on pharmacological safety, single-dose toxicity, and repeat-dose toxicity studies conducted in wild-type animals (mice, rats, rabbits, dogs, and monkeys) at doses 10 times the maximum recommended human dose (MRHD). Studies on mutagenic and carcinogenic potential of olipudase alfa have not been conducted.

In acid sphingomyelinase knockout (ASMKO) mice (a disease model for ASMD), death occurred after intravenous bolus injection of single doses of olipudase alfa at doses ≥ 3.3 times the MRHD. However, repeat-dose studies demonstrated that administration of olipudase alfa using a dose-escalation regimen did not result in drug-related mortality and reduced the severity of other toxic effects up to the highest tested dose, which was 10 times the MRHD.

An increased incidence of exencephaly was observed in pregnant mice following daily administration of olipudase alfa at exposure levels lower than those in humans at the recommended maintenance therapeutic dose and dosing frequency. This incidence was slightly higher than historical control data. The relevance of this finding to humans is unknown. Daily intravenous administration of olipudase alfa to pregnant rabbits did not result in fetal malformations or developmental variations at exposure levels substantially exceeding those in humans at the recommended maintenance therapeutic dose and dosing frequency.

In mice administered 3 mg/kg of olipudase alfa on postpartum day 7, olipudase alfa was detected in milk two days after administration.

Clinical characteristics.

Indications.

Xenpozyme is indicated as an enzyme replacement therapy for children and adults for the treatment of manifestations of acid sphingomyelinase deficiency (ASMD) type A/B or B, excluding manifestations of the central nervous system (CNS).

Contraindications.

Life-threatening hypersensitivity (anaphylactic reaction) to olipudase alfa or to any of the excipients of the medicinal product (see sections "Composition", "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Drug interaction studies have not been conducted. Since olipudase alfa is a recombinant human protein, drug interactions mediated by cytochrome P450 are not expected.

Special precautions for use.

Traceability

To facilitate the traceability of biological medicinal products, the full name and batch number of the administered medicinal product should be clearly recorded in the patient's medical records.

Lack of passage across the blood-brain barrier

Xenpozyme is not expected to cross the blood-brain barrier or modulate manifestations of the disease in the central nervous system (CNS).

Infusion reactions (IR)

In clinical studies, IRs were observed in approximately 58 % of patients receiving Xenpozyme. These IRs included hypersensitivity reactions and acute-phase reactions (see section "Adverse reactions"). The most common IRs were headache, urticaria, pyrexia, nausea, and vomiting (see section "Adverse reactions"). IRs usually occurred from the start of infusion up to 24 hours after completion of the infusion.

Hypersensitivity/anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been observed in patients receiving Xenpozyme (see section "Adverse reactions"). In clinical studies, hypersensitivity reactions were reported in 7 (17.5 %) adult patients and 9 (45 %) paediatric patients, including one child who experienced anaphylaxis.

Patient management

Patients require careful monitoring during and for an appropriate period after the infusion, depending on clinical assessment. Patients should be informed about the potential symptoms of hypersensitivity/anaphylaxis and instructed to seek immediate medical attention if symptoms occur. Management of patients with IRs should be based on the severity of signs and symptoms and may include temporary interruption of the Xenpozyme infusion, reduction of the infusion rate, and/or appropriate medical treatment.

In the event of severe hypersensitivity or anaphylaxis, administration of Xenpozyme should be immediately discontinued and appropriate medical treatment initiated. One patient who developed anaphylaxis during a clinical study was successfully re-challenged with an individualised desensitisation regimen, allowing the patient to resume long-term treatment with Xenpozyme at the recommended maintenance dose. The prescribing physician should evaluate the risks and benefits of re-initiating Xenpozyme after anaphylaxis or a severe hypersensitivity reaction. If re-initiation of Xenpozyme after anaphylaxis is being considered, the prescribing physician should contact the local Sanofi representative for consultation regarding re-initiation of treatment. When re-initiating Xenpozyme, extreme caution should be exercised, and appropriate resuscitation measures must be readily available.

In the case of mild or moderate IRs, the infusion rate may be slowed or temporarily interrupted, the duration of each step of the individual infusion may be extended, and/or the dose of Xenpozyme may be reduced. If dose reduction is required, subsequent dose escalation should follow the dose escalation scheme described in Table 7 and Table 8 for adult and paediatric patients, respectively (see section "Dosage and administration").

Premedication with antihistamines, antipyretics, and/or corticosteroids may be administered to patients to prevent or reduce allergic reactions.

Immunogenicity

During clinical studies in adult and paediatric patients, anti-drug antibodies (ADAs) to the medicinal product were reported (see section "Adverse reactions"). IRs and hypersensitivity reactions may occur independently of ADA development. Most IRs and hypersensitivity reactions were mild or moderate and manageable with standard clinical interventions.

Testing for IgE ADAs may be considered in patients experiencing a severe hypersensitivity reaction to olipudase alfa.

Although loss of efficacy was not reported in clinical studies, testing for IgE ADAs may be considered in the event of loss of response to treatment.

Transient elevation of transaminases

During the dose-escalation phase of Xenpozyme in clinical studies, transient elevations in transaminase levels (alanine aminotransferase (ALT) or aspartate aminotransferase (AST)) were reported within 24–48 hours after infusions (see section "Adverse reactions"). These elevated transaminase levels typically returned to pre-infusion levels by the time of the next scheduled infusion.

Transaminase levels (ALT and AST) should be measured within 1 month prior to initiating treatment with Xenpozyme (see section "Dosage and administration"). During dose escalation or resumption of treatment after missed doses, transaminase levels should be measured within 72 hours prior to the next scheduled Xenpozyme infusion. If baseline or pre-infusion transaminase levels exceed the upper limit of normal (ULN) by more than 2 times during dose escalation, additional transaminase measurements should be performed within 72 hours after the end of the infusion. If pre-infusion transaminase levels are elevated above baseline and exceed the ULN by more than 2 times, the dose of Xenpozyme may be adjusted (repeat the previous dose or reduce) or treatment may be temporarily withheld, depending on the degree of transaminase elevation (see section "Dosage and administration").

Once the recommended maintenance dose is reached, transaminase levels may be monitored as part of routine clinical management of patients with ASMD.

Sodium content

This medicinal product contains 3.02 mg of sodium per vial, equivalent to 0.15 % of the World Health Organization (WHO) recommended maximum daily intake of 2 g sodium for adults and ≤ 0.38 % of the maximum daily sodium intake allowed for children up to 16 years of age.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Women of childbearing potential are advised to use effective contraception during treatment and for 14 days after the last dose if treatment with Xenpozyme is discontinued.

Pregnancy

There are no data on the use of olipudase alfa in pregnant women. Reproductive toxicity was observed in animal studies (see section "Preclinical safety data"). Xenpozyme is not recommended during pregnancy and in women of childbearing potential who are not using effective contraception, unless the potential benefit to the pregnant woman outweighs the potential risks, including to the fetus.

Breastfeeding

There is no information on the excretion of olipudase alfa in human breast milk. Olipudase alfa was detected in the milk of lactating mice (see section "Preclinical safety data"). A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue treatment with Xenpozyme, taking into account the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Fertility

There are no data on the effect of olipudase alfa on fertility in men or women. Animal studies do not indicate a direct or indirect adverse effect on fertility (see section "Preclinical safety data").

Ability to affect the speed of reactions when driving or operating machinery.

Due to reports of arterial hypotension in clinical studies, Xenpozyme may have a minor influence on the ability to drive or operate machinery (see section "Adverse reactions").

Method of Administration and Dosage

Treatment with XENPOZYME must be conducted under the supervision of a healthcare professional experienced in the management of ASMD or other inherited metabolic disorders. Infusion of the medicinal product XENPOZYME must be administered only by a healthcare professional with immediate access to appropriate medical resources and life-supporting equipment necessary for managing potential severe reactions, such as serious systemic hypersensitivity reactions.

Dosage

Rapid metabolism of accumulated sphingomyelin (SM) by olipudase alfa leads to the formation of pro-inflammatory degradation products, which may cause infusion reactions and/or transient elevations in liver enzymes. A dose-escalation regimen may minimize most of these adverse events (see section "Non-clinical Safety Data").

The dosage of XENPOZYME is based on actual body weight for patients with a body mass index (BMI) ≤ 30 or on ideal body weight for patients with BMI > 30 (see below "Patients with BMI > 30").

Adult Patients

Dose-Escalation Phase

The recommended initial dose of XENPOZYME is 0.1 mg/kg* for adult patients (additional instructions are provided in the section on missed doses). The dose should then be increased according to the regimen outlined in Table 7.

Table 7

Dose-Escalation Regimen for Adult Patients

* Actual body weight is used for patients with BMI ≤ 30. For patients with BMI > 30, ideal body weight should be used, as described below.

Maintenance phase

The recommended maintenance dose of XENPOZYME is 3 mg/kg* every 2 weeks.

* Actual body weight is used for patients with BMI ≤ 30. For patients with BMI > 30, ideal body weight should be used, as described below.

Children

Titration phase

The recommended initial dose of XENPOZYME is 0.03 mg/kg* for pediatric patients, followed by dose escalation according to the schedule presented in Table 8.

Table 8

Dose escalation schedule in pediatric patients

* Actual body weight is used for patients with BMI ≤ 30. For patients with BMI > 30, ideal body weight is used, as described below.

Maintenance Phase

The recommended maintenance dose of XENPOZYME is 3 mg/kg* every 2 weeks.

* Actual body weight is used for patients with BMI ≤ 30. For patients with BMI > 30, ideal body weight is used, as described below.

Patients with BMI > 30

The body weight value used to calculate the dose of XENPOZYME for adult and pediatric patients with body mass index (BMI) > 30 is determined using the method described below (for both the dose escalation and maintenance phases).

Body weight (kg) used for dose calculation = 30 × (actual height in meters)².

Example:

For a patient with:

BMI 38

body weight 110 kg

height 1.7 m

The dose to be administered is calculated using a body weight value of 30 × 1.7² = 86.7 kg.

Missed Doses

A dose is considered missed if it is not administered within 3 days of the scheduled date. If a dose of XENPOZYME is missed, the next dose should be administered as soon as possible, as described below. Subsequently, the drug should be administered every 2 weeks from the date of the last administration.

During the Dose Escalation Phase

• If 1 infusion is missed, administer the last tolerated dose before resuming dose escalation according to the schedule for adults (Table 7) or for pediatric patients (Table 8).
• If 2 consecutive infusions are missed, administer a dose one level lower than the last tolerated dose (using a minimum dose of 0.3 mg/kg) before resuming dose escalation according to Table 7 or Table 8.
• If 3 or more consecutive infusions are missed, restart dose escalation at the 0.3 mg/kg level according to Table 7 or Table 8.

At the next scheduled infusion following a missed dose, if the dose to be administered is 0.3 or 0.6 mg/kg, this dose should be administered twice according to Table 7 and Table 8.

During the Maintenance Phase

• If 1 maintenance infusion is missed, administer the maintenance dose and adjust the treatment schedule accordingly.
• If 2 consecutive maintenance infusions are missed, administer 1 dose lower than the maintenance dose (i.e., 2 mg/kg). Then, for subsequent infusions, administer the maintenance dose (3 mg/kg) every 2 weeks.
• If 3 or more consecutive maintenance infusions are missed, restart dose escalation at the 0.3 mg/kg level according to Table 7 or Table 8.

Monitoring of Transaminase Levels

Transaminase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) should be measured prior to initiation of treatment and monitored at each dose escalation step (see section "Special Instructions for Use"). If transaminase levels prior to infusion exceed the baseline level and are more than 2 times the upper limit of normal (ULN), the dose of XENPOZYME may be adjusted (repeat the previous dose or reduce) or treatment may be temporarily interrupted depending on the degree of transaminase elevation. If dose adjustment or treatment interruption is required, reinitiation of treatment should follow the dose escalation schedule described in Table 7 and Table 8 for adults and pediatric patients, respectively, and in accordance with recommendations for missed doses (see section on missed doses information).

Special Patient Populations

Elderly Patients

Dose adjustment is not recommended for patients aged 65 years and older (see section "Pharmacokinetics").

Hepatic Impairment

Dose adjustment is not recommended for patients with hepatic impairment (see section "Pharmacokinetics").

Renal Impairment

Dose adjustment is not recommended for patients with renal impairment (see section "Pharmacokinetics").

Administration Method

XENPOZYME is intended for intravenous use only. Vials are for single use only. Infusions should be administered gradually, preferably using an infusion pump.

Instructions for Reconstitution and Dilution of the Medicinal Product Prior to Administration

Preparation of the Dosed Solution

The powder for concentrate for solution for infusion must be reconstituted with sterile water for injection, then diluted with 9 mg/ml (0.9%) sodium chloride solution for injection, and administered by intravenous infusion.

Reconstitution and dilution steps must be performed under aseptic conditions. At no time during the preparation of the infusion solution should filter devices be used. Formation of foam during reconstitution and dilution should be avoided.

1. Determine the number of vials to reconstitute based on the patient's body weight and prescribed dose.

Patient body weight (kg) × dose (mg/kg) = patient dose (mg). Patient dose (mg) divided by 20 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.

2. Remove the required number of vials from the refrigerator and allow them to reach room temperature for approximately 20–30 minutes.
3. Reconstitute each vial by adding 5.1 mL of sterile water for injection to the vial, using a slow, dropwise addition down the inner wall of the vial.
4. Gently tilt and swirl the vial. Each vial will contain 4 mg/mL of a clear, colorless solution.
5. Visually inspect the reconstituted solution in the vials for presence of particulate matter and discoloration. The XENPOZYME solution must be clear and colorless. Do not use vials containing opaque particles or showing discoloration.
6. Withdraw the volume of reconstituted solution corresponding to the prescribed dose from the appropriate number of vials and dilute with 9 mg/mL (0.9%) sodium chloride solution for injection in a syringe or infusion bag depending on the infusion volume (see Table 9 for recommended total infusion volume based on patient age and/or body weight).

Table 9

Recommended Infusion Volumes

• For variable final infusion volumes based on body weight in children (see Table 9):
  • Prepare an infusion solution of 0.1 mg/mL by withdrawing 0.25 mL (1 mg) of the reconstituted solution prepared in Step 3 and 9.75 mL of sodium chloride solution 9 mg/mL (0.9%) for injection into an empty 10 mL syringe.
  • Calculate the volume (mL) required to achieve the patient's dose (mg).

Example: 0.3 mg ÷ 0.1 mg/mL = 3 mL

• Dilution instructions for a total volume from ≥ 5 mL to ≤ 20 mL using a syringe.
  • Slowly inject the required volume of reconstituted solution along the inner wall of an empty syringe.
  • Slowly add sufficient sodium chloride solution 9 mg/mL (0.9%) for injection to achieve the required total infusion volume (avoid foaming inside the syringe).
• Dilution instructions for a total volume ≥ 50 mL using an infusion bag.
  • Empty infusion bag:
    • Slowly inject the required volume of reconstituted solution prepared in Step 3 into a sterile infusion bag of appropriate size.
    • Slowly add sufficient sodium chloride solution 9 mg/mL (0.9%) for injection to achieve the required total infusion volume (avoid foaming inside the bag).
  • Pre-filled infusion bag:
    • Remove from the pre-filled infusion bag containing sodium chloride solution 9 mg/mL (0.9%) for injection a volume equal to that of the reconstituted solution to be added, so that the final volume corresponds to that indicated in Table 9.
    • Slowly add the required volume of reconstituted solution prepared in Step 3 to the infusion bag (avoid foaming inside the bag).
      1. Gently invert the syringe or infusion bag to mix. Do not shake. As this is a protein solution, slight flocculation may occasionally occur after dilution (described as fine semi-transparent fibers).
      2. During administration, the diluted solution must be filtered through a low-protein-binding in-line filter of 0.2 μm.
      3. After completion of the infusion, flush the infusion line with sodium chloride solution 9 mg/mL (0.9%) for injection, using the same infusion rate as for the final part of the infusion.

Disposal

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

After reconstitution and dilution, the solution is administered as an intravenous infusion. The infusion rate should be gradually increased during the infusion only in the absence of infusion-related reactions (recommendations for managing infusion reactions are provided in section "Special precautions"). The infusion rate and duration of infusion (+/- 5 minutes) for each infusion step are detailed in Table 10 and Table 11.

Table 10

Infusion rate and duration of infusion for adult patients

N/A – not applicable.

Table 11

Infusion rate and duration of infusion for pediatric patients

N/A – not applicable.

During infusion, monitor for signs and symptoms of infusion reactions (IRs), such as headache, urticaria, pyrexia, nausea and vomiting, as well as other signs or symptoms of hypersensitivity. Depending on the severity of symptoms, the infusion may be slowed, interrupted, or discontinued, and appropriate medical treatment should be initiated if necessary.

In case of severe hypersensitivity and/or anaphylactic reaction, treatment with XENPOZYME should be immediately discontinued (see section "Special precautions").

At the end of the infusion (once the syringe or infusion bag is empty), flush the infusion line with 9 mg/ml (0.9%) sodium chloride solution for injection, using the same infusion rate as for the final portion of the infusion.

Home infusion during the maintenance dose phase

Home infusions under the supervision of a healthcare professional may be considered for patients receiving the maintenance dose who tolerate infusions well. The decision to transition patients to home infusions should be made by the physician who prescribed the treatment, following patient assessment and in accordance with their recommendations.

When administering XENPOZYME, appropriate medical supplies and life-support equipment must be available; personnel must be trained in emergency medical care. If anaphylactic or other acute reactions occur, immediately discontinue the infusion of XENPOZYME, initiate appropriate medical treatment, and seek medical assistance. In the event of severe hypersensitivity reactions, subsequent infusions should only be administered under conditions where resuscitation equipment is readily available. The dose and infusion rate must remain unchanged during home administration and should not be modified without the intervention of the prescribing physician. In case of missed or delayed doses, contact the prescribing physician.

Children.

Administer to children according to the information provided in section "Dosage and administration".

Overdose.

There is no known specific antidote for overdose with XENPOZYME. For management of patients experiencing adverse reactions associated with XENPOZYME, see sections "Special precautions" and "Adverse reactions".

Adverse Reactions

Summary of Safety Profile

Serious adverse reactions reported in patients receiving the medicinal product XENPOZYME were extrasystoles on a background of cardiomyopathy in 1 (2.5%) adult patient, and anaphylactic reaction, urticaria, rash, hypersensitivity, and increased alanine aminotransferase levels in 1 (5%) child. The frequency of serious infusion reactions related to hypersensitivity was higher in children compared to adult patients.

The most commonly reported adverse reactions with XENPOZYME were headache (31.7%), pyrexia (25%), urticaria (21.7%), nausea (20%), vomiting (16.7%), abdominal pain (15%), myalgia (11.7%), pruritus (10%), and increased C-reactive protein levels (10%).

Tabulated List of Adverse Reactions

A combined safety analysis from 4 clinical studies (a tolerability study in adult patients, ASCEND, ASCEND-Peds, and an extension study in adult patients and children) included a total of 60 patients (40 adult patients and 20 children) who received XENPOZYME at doses up to 3 mg/kg every 2 weeks.

Adverse reactions reported in the combined safety analysis of clinical studies are listed in Table 12 by system organ class and are categorized by frequency: 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 not known (frequency cannot be estimated from the available data).

Table 12

Adverse reactions in patients treated with XENPOZYME based on the combined analysis of clinical studies results

Description of individual adverse reactions

Infusion reactions (IRs), including hypersensitivity/anaphylactic reactions

IRs were reported in 55% of adult patients and 65% of pediatric patients. The most common IR symptoms in adult patients were headache (22.5%), nausea (15%), urticaria (12.5%), arthralgia (10%), myalgia (10%), pyrexia (10%), pruritus (7.5%), vomiting (7.5%), and abdominal pain (7.5%). The most common IR symptoms in pediatric patients were pyrexia (40%), urticaria (35%), vomiting (30%), headache (20%), nausea (20%), and rash (15%). IRs typically occurred from the start of infusion up to 24 hours after completion of the infusion.

In clinical studies, hypersensitivity-related IRs, including anaphylaxis, were observed in 26.7% of patients: in 17.5% of adult patients and in 45% of pediatric patients. The most common symptoms of hypersensitivity-related IRs were urticaria (20%), pruritus (6.7%), erythema (6.7%), and rash (5%).

One pediatric patient enrolled in clinical studies experienced a severe anaphylactic reaction. Additionally, outside the clinical study program, two anaphylactic reactions were observed in a 16-month-old child with type A Niemann-Pick disease who was receiving XENPOZYME. Both patients tested positive for IgE antibodies to olipudase alfa.

In 2 adult patients and 3 pediatric patients, IR symptoms were associated with changes in laboratory parameters (specifically C-reactive protein and ferritin), indicating an acute-phase reaction.

Elevated transaminase levels

Transient elevations in transaminase levels (ALT or AST) within 24–48 hours after infusion were observed in some patients receiving XENPOZYME during the dose-escalation phase of clinical studies. Elevated transaminase levels typically returned to pre-infusion levels by the next scheduled infusion.

Overall, after 52 weeks of treatment with XENPOZYME, mean ALT levels decreased by 45.9% and mean AST levels decreased by 40.2% compared to baseline. Among adult patients, ALT levels normalized in all 16 patients who had elevated baseline ALT levels, and AST levels normalized in 10 out of 12 patients who had elevated baseline AST levels.

Immunogenicity

Overall, anti-drug antibodies (ADAs) developed in 16 out of 40 (40%) adult patients and in 13 out of 20 (65%) pediatric patients receiving XENPOZYME during treatment. The median time from first infusion of XENPOZYME to seroconversion was approximately 33 weeks in adults and 10 weeks in pediatric patients. Most ADA-positive patients (11 out of 16 adults and 8 out of 13 pediatric patients) had low ADA response (≤ 400) or reverted to ADA-negative status. Neutralizing antibodies (NAbs) that inhibited the activity of olipudase alfa were detected in 4 out of 16 ADA-positive adult patients and in 5 out of 13 ADA-positive pediatric patients. In six patients, NAbs were detected at a single time point, and in three patients, intermittent responses were observed. In one pediatric patient, treatment intensified the ADA response. In another pediatric patient, an anaphylactic reaction occurred, and IgE and IgG ADAs were detected with a peak titer of 1600.

No impact of ADAs on the pharmacokinetics or efficacy of XENPOZYME was observed in adult or pediatric patients. However, a higher percentage of patients experienced IRs (including hypersensitivity reactions) during treatment among those who developed ADAs compared to those who did not (75.9% vs. 41.9%).

Pediatric patients

Except for a higher frequency of hypersensitivity-related IRs in pediatric patients compared to adults, the safety profile of XENPOZYME in pediatric and adult patients was similar.

Long-term use

Overall, the nature of adverse events in adult and pediatric patients during long-term use was consistent with that observed during the first year of treatment.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life

Unopened vials

60 months.

Reconstituted medicinal product

After reconstitution with sterile water for injection, chemical, physical, and microbiological stability has been demonstrated for up to 24 hours at 2–8 °C or 6 hours at room temperature (up to 25 °C).

From a microbiological standpoint, the reconstituted medicinal product should be used immediately. If not used immediately for dilution, the responsibility for storage time and conditions prior to dilution lies with the user, and it should generally not exceed 24 hours at 2–8 °C.

Diluted medicinal product

After dilution with 9 mg/mL (0.9%) sodium chloride solution for injection, chemical, physical, and microbiological stability has been demonstrated for solutions ranging from 0.1 mg/mL to 3.5 mg/mL for up to 24 hours at 2–8 °C and up to 12 hours (including infusion time) at room temperature (up to 25 °C).

From a microbiological standpoint, the diluted medicinal product should be used immediately. If not used immediately after dilution, the responsibility for storage time and conditions lies with the user, and it should generally not exceed 24 hours at 2–8 °C, followed by up to 12 hours (including infusion time) at room temperature (up to 25 °C).

Storage conditions

Store in a refrigerator (2–8 °C). Keep out of reach of children.

Incompatibilities

Due to lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Packaging

No. 1: 20 mg powder for concentrate for solution for infusion in a vial; 1 vial in a cardboard box.

Prescription category

Prescription only.

Manufacturer

Genzyme Ireland Limited.

Manufacturer's address and location of operations

IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland.

Marketing Authorization Holder

Sanofi B.V.

Address of the Marketing Authorization Holder and/or its representative

Paasheuvelweg 25, 1105 BP Amsterdam, the Netherlands.