Nexviadim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEXVIADYME (NEXVIADYME)

Composition:

Active substance: avalglucosidase alfa;

1 vial contains avalglucosidase alfa 100 mg;

after reconstitution, 1 ml contains avalglucosidase alfa 10 mg;

Excipients: L-histidine; L-histidine hydrochloride monohydrate; glycine; mannitol; polysorbate 80.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical properties: solid product, white to pale yellow.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolic processes. Enzymes. Avalglucosidase alfa.

ATC code A16AB22.

Pharmacological Properties

Pharmacodynamics

Avalglucosidase alfa is human acid α-glucosidase produced in Chinese hamster ovary cells using recombinant DNA technology and subsequently conjugated via approximately 7 hexamannose structures (each containing two terminal moieties of mannose-6-phosphate [M6P]) to oxidized sialic acid residues on the molecule, thereby increasing the bis-M6P level.

Mechanism of action

Avalglucosidase alfa is a recombinant human acid α-glucosidase (rhGAA) that provides an exogenous source of GAA. Avalglucosidase alfa is a modified form of alglucosidase alfa, in which approximately 7 hexamannose structures, each containing two terminal mannose-6-phosphate (bis-M6P) moieties, are conjugated to oxidized sialic acid residues on alglucosidase alfa. Avalglucosidase alfa has 15 times more mannose-6-phosphate (M6P) moieties compared to alglucosidase alfa. Binding to M6P receptors on the cell surface occurs via carbohydrate groups on the GAA molecule, followed by internalization and transport to lysosomes, where proteolytic processing takes place, resulting in increased enzymatic activity for glycogen breakdown.

Clinical efficacy and safety

Clinical trials in patients with late-onset Pompe disease (LOPD). Study 1, EFC14028/COMET, was a multinational, multicenter, randomized, double-blind trial comparing the efficacy and safety of Nexviazyme and alglucosidase alfa in 100 patients with late-onset Pompe disease, aged 16 to 78 years at initiation of treatment. Patients were randomized in a 1:1 ratio stratified by baseline forced vital capacity (FVC), sex, age, and country to receive either 20 mg/kg of Nexviazyme or alglucosidase alfa once every 2 weeks for 12 months (49 weeks).

Study 1 included an open-label extension period, during which all patients from the alglucosidase alfa group were switched to Nexviazyme and continued treatment until at least week 145. Overall, 95 patients entered the open-label extension period (51 from the Nexviazyme group and 44 from the alglucosidase alfa group). One additional pediatric patient was enrolled directly into the Nexviazyme extension period.

The primary endpoint of Study 1 was the change from baseline in percent predicted FVC in the upright position at 12 months (week 49). At week 49, the least squares mean (LS) [standard error (SE)] change in percent predicted FVC was 2.89% (0.88) in patients receiving Nexviazyme and 0.46% (0.93) in those receiving alglucosidase alfa. The clinically relevant LS mean difference in percent predicted FVC of 2.43% (95% CI: –0.13, 4.99) between Nexviazyme and alglucosidase alfa exceeded the pre-specified non-inferiority margin of –1.1 and demonstrated statistical non-inferiority (p = 0.0074). The study did not demonstrate statistical superiority (p = 0.0626), and testing of secondary endpoints was performed without adjustment for multiplicity.

Results for the primary endpoint are presented in Table 1.

In patients switched from alglucosidase alfa to Nexviazyme after week 49, the LS mean change in percent predicted FVC from week 49 to week 145 was 0.81 (1.08) (95% CI: –1.32, 2.95). Stabilization of percent predicted FVC was maintained after switching to Nexviazyme in the alglucosidase alfa group, with values similar to those in the Nexviazyme group at week 145. Patients who continued treatment with Nexviazyme maintained improvement in percent predicted FVC compared to baseline.

Table 1

Change from baseline to week 49 in least squares mean percent predicted FVC in the upright position

MMRM — mixed model for repeated measurements.

a Based on MMRM; the model includes percent predicted FEV1 at baseline (as continuous), sex, age (in years at baseline), treatment group, visit, and the interaction effect between treatment group and visit as fixed effects.

b Non-inferiority margin: –1.1 %.

c Non-inferiority not achieved.

The primary secondary endpoint in Study 1 was the change from baseline to 12 months (Week 49) in the total distance walked during the 6-minute walk test (6MWT). At Week 49, the least squares mean change from baseline in the 6MWT distance was 32.21 m (9.93) for patients receiving Nexviadyme and 2.19 m (10.40) for those receiving alglucosidase alfa. The least squares mean difference was 30.01 m (95 % CI: 1.33, 58.69), indicating a numerically greater improvement with Nexviadyme compared to alglucosidase alfa. 6MWT results are presented in Table 2.

In patients who switched from alglucosidase alfa to Nexviadyme after Week 49, the change in least squares mean 6MWT distance from Week 49 to Week 145 was –2.3 m (10.6), 95 % CI: –23.2, 18.7. At Week 145, stabilization of 6MWT performance was observed after switching from alglucosidase alfa to Nexviadyme. Participants in the Nexviadyme group showed sustained improvement compared to baseline.

Additional secondary endpoints of the study included maximal inspiratory pressure, maximal expiratory pressure, total manual dynamometry score, total score on the quick motor function test, and SF-12 questionnaire scores (health-related quality of life, both physical and mental component scores). Results for these endpoints are provided in Table 2.

In patients with late-onset Pompe disease aged 16 to 78 years who were treatment-naïve and initiated Nexviadyme at a dose of 20 mg/kg every 2 weeks, the change from baseline to Week 49 in the least squares mean percentage of urinary hexose tetrasaccharide (Hex4) was –53.90 % (24.03), which was maintained at Week 145 at –53.35 % (72.73) in patients who continued Nexviadyme treatment. In patients who initiated treatment with alglucosidase alfa at 20 mg/kg every 2 weeks, the change from baseline to Week 49 in the least squares mean percentage of urinary Hex4 was –10.8 % (32.33), with a subsequent decline to –48.04 % (41.97) at Week 145 after switching from alglucosidase alfa to Nexviadyme.

Table 2

Change from baseline to Week 49 in least squares means for additional secondary endpoints

a The LSM for distance at T6XX adjusts the value by the percentage of predicted FEV1 at baseline, baseline T6XX result (distance walked in meters), age (in years at baseline), sex, treatment group, visit, and the treatment-by-visit interaction as fixed effects.

b The mean change from baseline in the 6MWT at weeks 13, 25, and 37 was 18.02 (8.79), 27.26 (9.98), and 28.43 (9.06), respectively, in the avalglucosidase alfa group and 15.11 (9.16), 9.58 (10.41), and 15.49 (9.48), respectively, in the alglucosidase alfa group.

c Post hoc sensitivity analysis excluding 4 patients (2 in each treatment group) with supraphysiological baseline values of maximal inspiratory pressure and maximal expiratory pressure.

d Physical component summary.

e Mental component summary.

In an open-label, uncontrolled study in patients with late-onset Pompe disease, the percentage of predicted FEV1 and 6MWT results indicated maintenance of effect with long-term treatment with avalglucosidase alfa 20 mg/kg every 2 weeks up to 6 years.

Clinical study in patients with infantile-onset Pompe disease (IOPD). Study 2, ACT14132/mini-COMET, was a multicenter, multinational, open-label, phase 2 cohort study with repeated escalating doses of Nexviadyme administered to pediatric patients (1–12 years of age) with IOPD who had either clinical worsening or a suboptimal clinical response to alglucosidase alfa treatment. A total of 22 patients were enrolled in the study; Cohort 1 included 6 patients with clinical worsening who received 20 mg/kg every 2 weeks for 25 weeks, Cohort 2 included 5 patients with clinical worsening who received 40 mg/kg every 2 weeks for 25 weeks, and Cohort 3 included 11 patients with suboptimal response who received either Nexviadyme 40 mg/kg every 2 weeks for 25 weeks (5 patients) or alglucosidase alfa at a stable dose used prior to study initiation (ranging from 20 mg/kg every 2 weeks to 40 mg/kg weekly) for 25 weeks (6 patients).

The primary objective of Study 2 was to evaluate the safety and tolerability of Nexviadyme. A secondary objective was to determine the efficacy of Nexviadyme. Data showed stabilization or improvement in efficacy outcomes as measured by the Gross Motor Function Measure-88 (GMFM-88), Quick Motor Function Test (QMFT), Pompe Pediatric Evaluation of Disability Inventory (Pompe-PEDI), left ventricular mass Z-score, and eyelid position in patients who previously experienced worsening or inadequate control with alglucosidase alfa. The treatment effect was more pronounced with 40 mg/kg every 2 weeks compared to 20 mg/kg every 2 weeks. In two of the six patients receiving Nexviadyme 20 mg/kg every 2 weeks (Cohort 1), further clinical worsening occurred, and their dose was increased from 20 to 40 mg/kg every 2 weeks at week 55 and week 61, respectively. All patients receiving 40 mg/kg every 2 weeks maintained this dose throughout the study without further clinical worsening.

In pediatric patients (<18 years) receiving Nexviadyme 40 mg/kg every 2 weeks who had either clinical worsening (Cohort 2) or suboptimal clinical response (Cohort 3) on alglucosidase alfa, the mean percent change (SD) in urinary hexose tetrasaccharide levels from baseline at 6 months was –40.97% (16.72) and –37.48% (17.16), respectively. In patients who had previously worsened on alglucosidase alfa and were treated with Nexviadyme 20 mg/kg every 2 weeks, the mean percent change (SD) was 0.34% (42.09).

Long-term effects of Nexviadyme were evaluated in 10 patients at week 49, 8 patients at week 73, and 3 patients at week 97. In patients with IOPD who had worsening on alglucosidase alfa, efficacy on specific worsening parameters, including motor function, left ventricular mass, and eyelid position, was maintained up to 2 years.

Pediatric population

Nexviadyme was administered to nineteen pediatric patients aged 1 to 12 years with IOPD who had previously received alglucosidase alfa treatment (see sections "Posology and method of administration" and "Undesirable effects"), as well as to two patients aged 9 and 16 years with late-onset Pompe disease.

The European Medicines Agency has waived the obligation to submit the results of studies with Nexviadyme for the treatment of Pompe disease in one or more subsets of the pediatric population (see section "Posology and method of administration" for use in children).

Pompe disease patient registry

Healthcare professionals and other healthcare workers are encouraged to register patients diagnosed with Pompe disease at www.registrynxt.com. This registry collects anonymized patient data. The goal of the "Pompe Disease Patient Registry" is to improve understanding of Pompe disease, monitor patient status and their response to enzyme replacement therapy over time, and ultimately improve clinical outcomes for these patients.

Pharmacokinetics

Patients with late-onset Pompe disease (LOPD)

The pharmacokinetics of avalglucosidase alfa were evaluated in a population analysis of data from 75 patients with LOPD aged 16 to 78 years who received avalglucosidase alfa at doses ranging from 5 to 20 mg/kg every 2 weeks.

Patients with infantile-onset Pompe disease (IOPD)

The pharmacokinetics of avalglucosidase alfa were characterized in 16 patients aged 1 to 12 years treated with avalglucosidase alfa: 6 patients receiving 20 mg/kg and 10 patients receiving 40 mg/kg every 2 weeks. All patients had previously received treatment.

Absorption

In patients with LOPD receiving a 4-hour intravenous infusion of 20 mg/kg every 2 weeks, the mean values for maximum concentration (Cmax) and area under the concentration-time curve over 2 weeks (AUC2w) were 273 µg/mL (24%) and 1220 µg·h/mL (29%), respectively.

In patients with IOPD receiving a 4-hour intravenous infusion of 20 mg/kg every 2 weeks and a 7-hour intravenous infusion of 40 mg/kg every 2 weeks, mean Cmax ranged from 175 to 189 µg/mL for the 20 mg/kg dose and from 205 to 403 µg/mL for the 40 mg/kg dose. Mean AUC2w ranged from 805 to 923 µg·h/mL for 20 mg/kg and from 1720 to 2630 µg·h/mL for the 40 mg/kg dose.

Distribution

In patients with LOPD, according to a typical population pharmacokinetic model, the predicted volume of distribution of avalglucosidase alfa in the central compartment was 3.4 L.

In patients with IOPD receiving avalglucosidase alfa at 20 mg/kg and 40 mg/kg every 2 weeks, the mean volume of distribution at steady state ranged from 3.5 to 5.4 L.

Elimination

In patients with LOPD, according to a typical population pharmacokinetic model, the predicted linear clearance was 0.87 L/h. After administration of 20 mg/kg every 2 weeks, the mean plasma half-life was 1.55 hours.

In patients with IOPD receiving avalglucosidase alfa at 20 mg/kg and 40 mg/kg every 2 weeks, mean plasma clearance ranged from 0.53 to 0.70 L/h, and mean plasma half-life ranged from 0.60 to 1.19 hours.

Linearity/Non-linearity

Exposure to avalglucosidase alfa increased proportionally with dose from 5 to 20 mg/kg in patients with LOPD and from 20 to 40 mg/kg in patients with IOPD. No accumulation was observed when the drug was administered every 2 weeks.

Immunogenicity

In Study 1, EFC14028/COMET, 95.2% (59 out of 62 patients) of patients treated with Nexviadyme developed anti-drug antibodies (ADAs) during treatment. Due to the variability in ADA formation, no clear trend in peak ADA titer or impact on pharmacokinetics was observed at week 49.

Special patient populations

Population pharmacokinetic analyses of data from patients with late-onset Pompe disease showed that body weight, age, and sex had no significant effect on the pharmacokinetics of avalglucosidase alfa.

Hepatic impairment. The pharmacokinetics of avalglucosidase alfa in patients with hepatic impairment have not been studied.

Renal impairment. A formal study of the effect of renal impairment on the pharmacokinetics of avalglucosidase alfa was not conducted. According to a population pharmacokinetic analysis of data from 75 patients with late-onset Pompe disease receiving 20 mg/kg, including 6 patients with mild renal impairment (baseline glomerular filtration rate of 60–89 mL/min), renal impairment had no significant effect on the exposure of avalglucosidase alfa.

Non-clinical safety data

Non-clinical data revealed no special hazard for humans based on standard repeated-dose toxicity studies, including safety pharmacology endpoints.

Avalglucosidase alfa did not cause adverse effects in a combined fertility study in male and female mice when administered up to 50 mg/kg intravenously every other day (9.4 times higher than the steady-state AUC in humans at the recommended dose of 20 mg/kg every 2 weeks for patients with LOPD) (see section "Pregnancy and lactation").

In an embryofetal toxicity study in mice, administration of avalglucosidase alfa at the highest dose of 50 mg/kg/day (17 times higher than the steady-state AUC in humans at the recommended dose of 20 mg/kg every 2 weeks for patients with LOPD) resulted in increased post-implantation loss and mean number of late fetal resorptions. No adverse effects were observed at 20 mg/kg/day (4.8 times higher than the steady-state AUC in humans at the recommended dose). Avalglucosidase alfa does not cross the placenta in mice, suggesting that the effects on embryo and fetus at 50 mg/kg/day were related to maternal toxicity due to immune response. No developmental abnormalities or developmental deviations were observed.

In an embryofetal toxicity study in rabbits administered avalglucosidase alfa up to 100 mg/kg/day intravenously (91 times higher than the steady-state AUC in humans at the recommended dose of 20 mg/kg every 2 weeks for patients with LOPD), no adverse effects were observed.

In a pre- and postnatal development toxicity study in mice, no adverse effects were observed after administration of avalglucosidase alfa every other day. The no-observed-adverse-effect level for female reproductive function and offspring viability and growth was 50 mg/kg every other day intravenously.

When administered to immature mice, avalglucosidase alfa was generally well tolerated after 9 weeks of administration at doses up to 100 mg/kg every 2 weeks intravenously (approximately 2–5 times higher than the steady-state AUC in humans at the recommended dose of 40 mg/kg every 2 weeks for patients with IOPD). However, the highest dose tested in immature animals was insufficient to exclude potential risk in IOPD patients receiving 40 mg/kg based on exposure margins.

Clinical characteristics

Indications. Nexviadyme (avalglucosidase alfa) is indicated for long-term enzyme replacement therapy in patients with Pompe disease (acid α-glucosidase deficiency).

Contraindications. Life-threatening hypersensitivity to the active substance or to any of the excipients listed in the section "Composition", when re-administration has been unsuccessful (see sections "Special precautions for use" and "Adverse reactions").

Interaction with other medicinal products and other forms of interaction

Interaction studies have not been conducted. Since avalglucosidase alfa is a recombinant human protein, cytochrome P450-mediated interactions with other medicinal products are unlikely.

Special precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded in the patient's medical records.

Hypersensitivity reactions (including anaphylaxis)

Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving Nexviadyme (see section "Adverse reactions").

Appropriate medical support, including equipment for cardiopulmonary resuscitation, should be readily available when administering Nexviadyme, particularly for patients with cardiac hypertrophy and patients with significant respiratory impairment.

In the event of severe hypersensitivity or anaphylaxis, administration of Nexviadyme should be immediately discontinued and appropriate medical treatment initiated. The risks and benefits of re-administering Nexviadyme after anaphylaxis or severe hypersensitivity reaction should be carefully considered. Some patients have been re-challenged with the product at a reduced infusion rate and at a dose lower than the recommended dose. Desensitisation procedures to Nexviadyme may be considered in patients who have experienced severe hypersensitivity. Extreme caution and availability of appropriate resuscitation equipment are required if the decision is made to re-administer the product. If the patient tolerates the infusion, the dose may be increased to achieve the prescribed dose.

If mild or moderate hypersensitivity reactions occur, the infusion rate may be reduced or the infusion temporarily stopped.

Infusion-related reactions

During clinical studies, infusion-related reactions occurred at any time during or within several hours after infusion of Nexviadyme, more frequently at higher infusion rates (see section "Adverse reactions").

Patients with acute underlying illness at the time of Nexviadyme infusion are at increased risk of infusion-related reactions. Patients with late-onset Pompe disease may have cardiac and respiratory dysfunction, increasing the risk of severe complications from infusion reactions.

Antihistamines, antipyretics, and/or corticosteroids may be administered to prevent or reduce infusion-related reactions. However, infusion-related reactions may still occur in patients who have received premedication.

In the event of severe infusion-related reactions, immediate discontinuation of Nexviadyme and appropriate medical treatment may be required. The benefits and risks of re-administering Nexviadyme after severe infusion-related reactions should be carefully considered. Some patients have been re-challenged with the product at a reduced infusion rate and at a dose lower than the recommended dose. If the patient tolerates the infusion, the dose may be increased to achieve the prescribed dose. If mild or moderate infusion-related reactions occur despite premedication, reducing the infusion rate or temporarily stopping the infusion may alleviate symptoms (see section "Adverse reactions").

Immunogenicity

Antidrug antibodies (ADAs) have been reported during treatment in both treatment-naïve patients (95%) and previously treated patients (62%) (see section "Adverse reactions").

Infusion-related reactions and hypersensitivity reactions may occur independently of ADA formation. Most infusion-related and hypersensitivity reactions were mild or moderate in severity and were managed with standard clinical measures. In clinical studies, ADA formation did not impact clinical efficacy (see section "Adverse reactions").

If patients do not respond to therapy, testing for ADAs should be considered. For patients at risk of allergic reactions or who have experienced an anaphylactic reaction to prior alglucosidase alfa administration, immunological testing may be considered upon the occurrence of adverse events, including determination of IgG and IgE type ADAs.

For information regarding the laboratory testing service provided by Sanofi Specialty Care, contact the local Sanofi representative or Sanofi EU Medical Services.

Risk of acute cardiorespiratory failure

Caution should be exercised when administering Nexviadyme to patients predisposed to fluid volume overload and to patients with acute concomitant respiratory illness or cardiac and/or respiratory dysfunction who require fluid restriction. These patients are at risk of serious worsening of cardiac or respiratory function during infusion. Appropriate medical support and monitoring should be available during Nexviadyme infusion, and some patients may require prolonged observation.

Cardiac arrhythmia and sudden death under general anaesthesia during central venous catheter placement

Caution should be exercised when administering general anaesthesia for central venous catheter placement or other surgical procedures in patients with IOPD and cardiac hypertrophy.

Cardiac arrhythmias, including ventricular fibrillation, ventricular tachycardia, and bradycardia, leading to cardiac arrest or fatal outcome or requiring cardiopulmonary resuscitation or defibrillation, have been associated with the use of general anaesthesia in patients with IOPD and cardiac hypertrophy.

Use during pregnancy or breastfeeding

Pregnancy

There are no available data on the use of Nexviadyme in pregnant women. Animal studies did not reveal direct harmful effects on reproductive function. An indirect effect on the foetus in mice was associated with an anaphylactic reaction to avalglucosidase alfa (see section "Non-clinical safety data" above). The potential risk to humans is unknown. It cannot be determined whether Nexviadyme is safe for use during pregnancy. Nexviadyme may be used during pregnancy only if the potential benefit to the mother outweighs the potential risk, including to the foetus.

Breastfeeding

There are no available data on the passage of Nexviadyme into human breast milk or its effects on milk production or the breastfed infant. It cannot be determined whether Nexviadyme is safe for use during breastfeeding. Nexviadyme may be used during breastfeeding only if the potential benefit to the mother outweighs the potential risk, including to the breastfed infant (see section "Non-clinical safety data" above).

Fertility

There are no clinical data on the effect of Nexviadyme on human fertility. Animal studies in mice revealed no impairment of fertility in males or females (see section "Non-clinical safety data" above).

Effect on ability to drive and use machines

Nexviadyme may have a minor influence on the ability to drive and use machines. Adverse reactions such as dizziness, hypotension, and somnolence may affect the ability to drive and use machines on the day of infusion (see section "Adverse reactions").

Method of Administration and Dosage

Nexviazyme should be administered under the supervision of a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular disorders.

Dosage

Patients may be premedicated with antihistamines, antipyretics, and/or corticosteroids to prevent or reduce the incidence of allergic reactions.

The recommended dose of avalglucosidase alfa is 20 mg/kg body weight, administered once every 2 weeks.

Dosage Modification for Patients with Infantile-Onset Pompe Disease (IOPD)

For patients with IOPD who show no improvement or have an inadequate response in cardiac, respiratory, and/or motor function while receiving 20 mg/kg, consideration should be given to increasing the dose to 40 mg/kg administered once every 2 weeks, provided there are no safety concerns (e.g., severe hypersensitivity, anaphylactic reactions, or risk of fluid overload).

If a patient does not tolerate avalglucosidase alfa at a dose of 40 mg/kg once every 2 weeks (e.g., due to severe hypersensitivity, anaphylactic reactions, or risk of fluid overload), dose reduction to 20 mg/kg once every 2 weeks should be considered (see section "Special Warnings and Precautions").

Special Patient Populations

Elderly Patients

Dose adjustment is not required for patients aged >65 years.

Hepatic Impairment

The safety and efficacy of avalglucosidase alfa in patients with hepatic impairment have not been evaluated, and a specific dosing regimen cannot be recommended for these patients.

Renal Impairment

Dose adjustment is not required for patients with mild to moderate renal impairment. The safety and efficacy of avalglucosidase alfa in patients with moderate or severe renal impairment have not been evaluated, and a specific dosing regimen cannot be recommended for these patients (see section "Pharmacokinetics").

Method of Administration

Nexviazyme vials are intended for single use only.

The medicinal product must be administered by intravenous infusion.

The infusion should be administered gradually, depending on the patient's response and comfort.

It is recommended to start the infusion at an initial rate of 1 mg/kg/hour and progressively increase the rate every 30 minutes in the absence of infusion-related reactions, according to Table 3. Vital signs should be monitored at each step before increasing the infusion rate.

Table 3

Infusion Rate Schedule

a At the recommended dose of 20 mg/kg, for patients with a body weight of 1.25–5 kg, a maximum infusion rate of 4.8 mg/kg/hour may be used.

b For patients with Pompe disease who do not show clinical improvement, dose escalation to 40 mg/kg once every 2 weeks is recommended. For patients with a body weight of 1.25–5 kg, a maximum infusion rate of 9.6 mg/kg/hour may be used.

If anaphylaxis, severe hypersensitivity reaction, or severe infusion-related reactions occur, administration of Nexviadyme should be immediately discontinued and appropriate medical treatment initiated. In case of moderate or mild-to-moderate hypersensitivity or infusion-related reactions, the infusion rate may be reduced or the infusion temporarily interrupted and/or appropriate treatment initiated (see section "Special precautions for use").

Symptoms may persist despite temporary interruption of the infusion; therefore, the physician should wait at least 30 minutes before deciding whether to discontinue the infusion for the remainder of the day. If symptoms resolve, the infusion should be resumed at half the rate at which the reaction occurred, or lower, for 30 minutes, followed by a 50% increase in infusion rate over 15–30 minutes. If symptoms do not recur, the infusion rate may be increased to the rate at which the reaction occurred, and further gradual increases in infusion rate may be considered up to the maximum rate.

Home Infusion

Home infusion of Nexviadyme may be considered for patients who tolerate infusions well and have not experienced moderate or severe infusion-related reactions for several months. The decision to transition a patient to home infusions should be made after evaluation of the patient's condition and upon physician recommendation. When assessing the suitability of home infusion, the patient's comorbidities and ability to comply with home infusion procedures should be considered. The following criteria should be taken into account:

• The patient should not have concomitant medical conditions that, in the physician’s opinion, may affect the patient’s ability to tolerate infusions.
• The patient’s condition should be medically stable. A comprehensive medical evaluation must be completed before initiating home infusions.
• Infusions of Nexviadyme should be administered under the supervision of a physician experienced in the treatment of Pompe disease in a hospital or other appropriate outpatient setting for several months. Documentation confirming that infusions were well tolerated without infusion-related reactions or with only mild-to-moderate reactions controlled by premedication is required before initiating home infusions.
• The patient must be willing and able to comply with the requirements for home infusion procedures.
• Appropriate equipment, resources, and procedures for home infusion, including training, must be available for the healthcare provider. The healthcare provider must be present throughout the entire home infusion and for a certain period afterward, depending on the patient’s prior tolerance of infusions in the hospital setting.

If adverse reactions occur during home infusion, the infusion should be immediately stopped and appropriate medical treatment initiated (see section "Special precautions for use").

Subsequent infusions should be administered in a hospital or appropriate outpatient facility until such adverse reactions have resolved. The dose and infusion rate must not be altered without consultation with the responsible physician.

Instructions for reconstitution and dilution of the medicinal product prior to administration

The vials are intended for single use only.

Reconstitution

Aseptic techniques should be followed during reconstitution.

1. Determine the number of vials to reconstitute based on the patient’s body weight and the recommended dose of 20 mg/kg or 40 mg/kg.

Patient body weight (kg) × dose (mg/kg) = patient dose (mg).

Patient dose (mg) divided by 100 mg/vial = number of vials to reconstitute. If the result is not a whole number, round up to the next whole number.

Example 1:

Patient body weight (16 kg) × dose (20 mg/kg) = patient dose (320 mg).

320 mg divided by 100 mg/vial = 3.2 vials; therefore, reconstitute the contents of 4 vials.

Example 2:

Patient body weight (16 kg) × dose (40 mg/kg) = patient dose (640 mg).

640 mg divided by 100 mg/vial = 6.4 vials; therefore, reconstitute the contents of 7 vials.

1. Remove the required number of vials from the refrigerator and allow them to reach room temperature for approximately 30 minutes.
2. Reconstitute the contents of each vial by slowly adding 10.0 mL of water for injection to each vial. Each vial will contain 100 mg/10 mL (10 mg/mL) of avalglucosidase alfa. Avoid forcing the water for injection onto the powder or causing foaming. This is achieved by slowly adding the water for injection drop by drop down the side of the vial, not directly onto the lyophilized powder. To dissolve the lyophilized powder, gently tilt and swirl the vial. Do not invert, shake, or agitate the vial.
3. Immediately inspect the reconstituted solution in the vials for the presence of particulate matter or discoloration. If particles are observed or the solution has changed color, the reconstituted medicinal product must not be used.

The resulting solution should be diluted.

Chemical, physical, and microbiological stability of the reconstituted solution has been demonstrated for 24 hours at 2–8 °C.

From a microbiological standpoint, the reconstituted medicinal product should be used immediately.

If the medicinal product is not used immediately for dilution, the user is responsible for storage conditions and duration prior to dilution—typically not exceeding 24 hours at 2–8 °C.

Dilution

1. Dilute the reconstituted solution with 5% glucose solution in water to a final concentration of 0.5 mg/mL to 4 mg/mL. Table 4 provides the recommended total infusion volume based on patient body weight.
2. Slowly withdraw the required volume of reconstituted solution from each vial (calculated according to patient body weight).
3. Slowly add the reconstituted solution directly to the 5% glucose solution, avoiding foaming or agitation in the infusion bag. Avoid introducing air into the infusion bag.
4. Gently invert or knead the infusion bag to mix the solution. Do not shake.
5. To avoid administration of extraneous particles together with the medicinal product, use of an in-line low protein-binding filter with a pore size of 0.2 µm is recommended.

After completion of the infusion, flush the intravenous administration system with 5% glucose solution in water.

1. Nexviadyme should not be administered through the same intravenous line as other medicinal products.

Table 4

Calculated intravenous infusion volumes of Nexviadyme according to patient body weight at doses of 20 and 40 mg/kg

After reconstitution, the chemical, physical and microbiological stability of the solution has been demonstrated within a concentration range of 0.5 mg/mL to 4 mg/mL for 24 hours at 2–8 °C and subsequently for 9 hours at room temperature (up to 25 °C), allowing for infusion.

Aseptic techniques must be followed.

From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the responsibility for storage conditions and duration lies with the user — typically, storage should not exceed 24 hours at 2–8 °C and subsequently 9 hours at room temperature (up to 25 °C), to allow for infusion.

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

Children

The safety and efficacy of alglucosidase alfa in children under 6 months of age have not been established. Data on use in patients under 6 months of age are lacking.

Overdose

Excessively rapid infusion of Nexviazyme may cause flushing. In clinical studies, pediatric patients received doses up to 40 mg/kg body weight once every 2 weeks, and no specific signs or symptoms were observed following administration of higher doses. For management of adverse reactions, see sections "Special warnings and precautions for use" and "Adverse reactions".

Adverse Reactions

Brief Summary of Safety Profile

Serious adverse reactions reported in patients receiving the medicinal product Nexviadym were: respiratory distress and chills in 1.4% of patients; headache, dyspnea, hypoxia, tongue edema, nausea, pruritus, urticaria, skin color change, chest discomfort, pyrexia, increased or decreased blood pressure, elevated body temperature, increased heart rate, and decreased oxygen saturation in 0.7% of patients. Hypersensitivity reactions were reported in 60.6% of patients, anaphylaxis in 2.8%, and infusion-related reactions in 39.4% of patients. Overall, 4.9% of patients receiving Nexviadym in clinical studies permanently discontinued treatment; 2.8% of patients discontinued treatment due to events considered related to Nexviadym: respiratory distress, chest discomfort, dizziness, cough, nausea, flushing, ocular hyperemia, urticaria, and erythema.

List of Adverse Reactions

The most frequently reported adverse reactions (ARs) (> 5%) were: pruritus (13.4%), nausea (12%), headache (10.6%), rash (10.6%), urticaria (8.5%), chills (7.7%), fatigue (7.7%), and erythema (5.6%).

A pooled analysis of safety data from 4 clinical studies (EFC14028/COMET, ACT14132/mini-COMET, TDR12857/NEO, and LTS13769/NEO-EXT) included data from 142 patients overall [118 adults and 24 children (1 child directly enrolled in the open-label extension period of Study 1)], who received Nexviadym. Adverse reactions from the pooled analysis of clinical studies are presented in Table 5.

Adverse reactions are categorized by system organ classes. Frequency is defined according to the following categories: 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).

Due to the small patient population, an adverse reaction reported in 2 patients is classified as common.

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 5

Adverse reactions observed in patients receiving Nexviadym based on pooled analysis of clinical studies (N = 142)

The treatment-related adverse reactions considered biologically plausible for avalglucosidase alfa are listed in Table 5, according to the prescribing information for alglucosidase alfa.

In the comparative study EFC14028/COMET, 100 patients with late-onset Pompe disease (LOPD), aged 16 to 78 years, who had not previously received enzyme replacement therapy, were treated either with 20 mg/kg of Nexviazyme (n = 51) or 20 mg/kg of alglucosidase alfa (n = 49). During the 49-week double-blind, active-controlled period, serious adverse reactions were reported in 2% of patients receiving Nexviazyme and in 6.1% of patients receiving alglucosidase alfa. Overall, 8.2% of patients receiving alglucosidase alfa discontinued treatment permanently due to adverse reactions; no patient in the Nexviazyme group discontinued treatment permanently. The most commonly reported adverse reactions (>5%) in patients receiving Nexviazyme were headache, nausea, pruritus, urticaria, and fatigue.

Of the 95 patients who entered the open-label extension period of study EFC14028/COMET, 51 patients continued treatment with Nexviazyme and 44 patients switched from alglucosidase alfa to Nexviazyme.

During the open-label extension period, serious adverse reactions were reported in 3 (5.8%) patients who continued treatment with Nexviazyme throughout the study and in 3 (6.8%) patients who switched to treatment with Nexviazyme. The most commonly reported adverse reactions (>5%) in patients who continued treatment with Nexviazyme throughout the study were nausea, chills, erythema, pruritus, and urticaria. The most commonly reported adverse reactions (>5%) in patients who switched to treatment with Nexviazyme were pruritus, rash, headache, nausea, chills, fatigue, and urticaria.

In a pediatric patient who was additionally enrolled directly into the open-label extension period, no adverse reactions or infusion-related reactions were observed.

Description of selected adverse reactions

Hypersensitivity (including anaphylaxis)

In the pooled safety analysis, hypersensitivity reactions were observed in 86/142 (60.6%) patients, including 7/142 (4.9%) patients who reported severe hypersensitivity reactions and 4/142 (2.8%) patients in whom anaphylaxis was observed. Some of the hypersensitivity reactions were IgE-mediated. Signs and symptoms of anaphylaxis included: tongue swelling, hypotension, hypoxia, respiratory distress, chest tightness, generalized edema, generalized flushing, feeling of warmth, cough, dizziness, dysarthria, throat tightness, dysphagia, nausea, redness of palms, lower lip swelling, decreased breath sounds, redness of soles, tongue swelling, pruritus of palms and soles, and decreased blood oxygen saturation (desaturation). Symptoms of severe hypersensitivity reactions included: tongue swelling, respiratory failure, respiratory distress, generalized edema, erythema, urticaria, and rash.

Infusion-related reactions

According to the pooled safety analysis, infusion-related reactions occurred in approximately 56/142 (39.4%) patients receiving avalglucosidase alfa in clinical studies. Severe infusion-related reactions were observed in 6/142 (4.2%) patients, including symptoms of respiratory distress, hypoxia, chest discomfort, generalized edema, tongue swelling, dysphagia, nausea, erythema, urticaria, and increased or decreased blood pressure. Infusion-related reactions reported in more than 1 patient included respiratory distress, chest discomfort, dyspnea, cough, decreased oxygen saturation, throat irritation, dyspepsia, nausea, vomiting, diarrhea, lip swelling, tongue swelling, erythema, erythema of palms, rash, erythematous rash, pruritus, urticaria, hyperhidrosis, skin plaques, eye hyperemia, eyelid edema, facial swelling, increased or decreased blood pressure, tachycardia, headache, dizziness, tremor, burning sensation, pain (including limb pain, upper abdominal pain, oropharyngeal pain, and flank pain), somnolence, lethargy, fatigue, pyrexia, influenza-like illness, chills, flushing, feeling of warmth or cold, cyanosis, and pallor. The severity of most infusion-related reactions was rated as mild to moderate.

In the comparative study EFC14028/COMET, a smaller proportion of patients with late-onset Pompe disease in the avalglucosidase alfa group reported at least 1 infusion-related reaction (13/51 [25.5%]) compared to the alglucosidase alfa group (16/49 [32.7%]). Severe infusion-related reactions were not observed in patients in the avalglucosidase alfa group, while they were reported in 2 patients in the alglucosidase alfa group (dizziness, visual disturbance, hypotension, dyspnea, cold sweat, and chills). The most common infusion-related reactions that occurred during treatment (>2 patients) in the avalglucosidase alfa group were pruritus (7.8%) and urticaria (5.9%), while in the alglucosidase alfa group they were nausea (8.2%), pruritus (8.2%), and flushing (6.1%). Most infusion-related reactions observed in 7 (13.7%) patients in the avalglucosidase alfa group and in 10 (20.4%) patients in the alglucosidase alfa group were of mild severity.

During the open-label extension period, infusion-related reactions were reported in 12 (23.5%) patients who continued treatment with Nexviazyme throughout the study; infusion-related reactions reported in more than 1 patient included: nausea, chills, erythema, pruritus, pyrexia, urticaria, rash, and eye hyperemia. Infusion-related reactions were reported in 22 (50%) patients who switched to treatment with Nexviazyme; infusion-related reactions reported in more than 1 patient included: pruritus, headache, rash, nausea, chills, fatigue, urticaria, respiratory distress, feeling of cold, chest discomfort, erythema, erythematous rash, pruritic rash, skin plaques, burning sensation, and swelling of lips and tongue. The number of infusion-related reactions in both groups decreased over time.

Immunogenicity

The frequency of antibody formation against avalglucosidase alfa in patients with Pompe disease who received Nexviazyme is shown in Table 6. The median time to seroconversion was 8.3 weeks.

In treatment-naïve adult patients, infusion-related reactions occurred in both patients with positive anti-drug antibody (ADA) status and in those with negative ADA status. Increased frequency of infusion-related reactions and hypersensitivity was observed with higher titers of IgG-type ADA. In treatment-naïve patients, there was a trend toward increased frequency of infusion-related reactions with increasing ADA titers, with the highest frequency of infusion-related reactions (69.2%) observed in the range of high peak ADA titers ≥12,800, compared to 33.3% in patients with medium ADA titers of 1,600–6,400, 14.3% in patients with low ADA titers of 100–800, and 33.3% in ADA-negative patients. In adult patients previously treated with enzyme replacement therapy (ERT), the frequency of infusion-related reactions and hypersensitivity was higher in patients who developed antibodies during treatment compared to ADA-negative patients. Anaphylaxis developed in one treatment-naïve patient and in two previously treated patients. The frequency of infusion-related reactions was similar in pediatric patients with positive and negative ADA status. Anaphylaxis occurred in one pediatric patient who had previously received treatment (see section "Special precautions").

In the clinical study EFC14028/COMET, ADA formation was observed in 81 out of 96 (84.4%) patients during treatment. In most patients, ADA titers were in the low to medium range, and high persistent titers of antibodies against Nexviazyme were detected in 7 patients. Assessment of cross-reactivity of ADA at week 49 showed that antibodies in 3 (5.9%) patients were cross-reactive to both alglucosidase alfa and Nexviazyme. Patients with high titers showed variable effects on pharmacokinetic, pharmacodynamic, and efficacy parameters; however, in most patients, there was no clinically significant impact of anti-drug antibodies on efficacy (see section "Pharmacokinetics").

Table 6

Frequency of ADA formation during treatment in patients with late-onset Pompe disease and in patients with infantile-onset Pompe disease

a Two of these patients were pediatric.

b Previously treated patients had received alglucosidase alfa before or during the clinical trial: for 0.9–9.9 years in adult patients and for 0.6–11.8 years in pediatric patients.

c Not established

Pediatric population

Adverse reactions observed in clinical trials in the pediatric population (19 children aged 1 to 12 years with infantile-onset Pompe disease [mean age 6.8 years] and 2 children [9 and 16 years] with late-onset Pompe disease) were similar to those observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

Unopened vials: 4 years.

Reconstituted medicinal product: within 24 hours when stored at 2–8 °C.

Diluted medicinal product: within 24 hours when stored at 2–8 °C and subsequently for up to 9 hours at room temperature (up to 25°C).

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

Incompatibilities. Since compatibility studies have not been conducted, this medicinal product must not be mixed with other medicinal products.

Packaging. No. 1: 100 mg of powder for concentrate for solution for infusion in a vial; 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Genzyme Ireland Limited.

Manufacturer's address and location of its operations. IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland.

Marketing Authorization Holder. Sanofi B.V.

Address of the Marketing Authorization Holder. Paasheuvelweg 25, 1105 BP Amsterdam, the Netherlands.