4.1. Therapeutic indications

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

4.2. Posology and method of administration

Nexviadyme treatment should be supervised by a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular diseases.

Posology

Patients may be pre-treated with antihistamines, antipyretics, and/or corticosteroids to prevent or reduce allergic reactions.

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

Dose modification for IOPD patients

For IOPD (infantile-onset Pompe disease) patients who experience lack of improvement or insufficient response in cardiac, respiratory, and/or motor function while receiving 20 mg/kg, a dose increase to 40 mg/kg every other week should be considered in the absence of safety concerns (e.g., severe hypersensitivity, anaphylactic reactions, or risk of fluid overload).

In patients who do not tolerate avalglucosidase alfa at 40 mg/kg every other week (e.g., severe hypersensitivity, anaphylactic reactions, or risk of fluid overload), consider decreasing the dose to 20 mg/kg every other week. (see section 4.4).

Special populations

Elderly patients

No dose adjustment is required in patients >65 years.

Hepatic impairment

The safety and efficacy of avalglucosidase alfa in patients with hepatic impairment have not been evaluated and no specific dose regimen can be recommended for these patients.

Renal impairment

No dose adjustment is required in patients with mild renal impairment. The safety and efficacy of avalglucosidase alfa in patients with moderate or severe renal impairment have not been evaluated and no specific dose regimen can be recommended for these patients. (see section 5.2).

Paediatric population (patients 6 months of age and younger)

The safety and efficacy of avalglucosidase alfa in children 6 months of age and younger have not yet been established. There are no data available in patients 6 months of age and younger.

Method of administration

Nexviadyme vials are for single use only and the medicinal product should be administered as an intravenous infusion.

The infusion should be administered incrementally as determined by patient response and comfort.

It is recommended that the infusion begins at an initial rate of 1 mg/kg/hour and is gradually increased every 30 minutes if there are no signs of infusion-associated reactions (IARs), in accordance with Table 1. Vital signs should be obtained at each step, before increasing the infusion rate.

Table 1 – Infusion rate schedule

Recommended Dose

Infusion rate (mg/kg/hour)

Approximate duration (h)

step 1

step 2

step 3

step 4

step 5

20 mg/kg

1

3

5a

7a

NA

4 to 5

IOPD40 mg/kg

4-step process

1

3

5

7

NA

7

5-step processb

1

3

6

8

10b

5

a For patients with a recommended dose of 20 mg/kg and body weight of 1.25-5 kg a maximum infusion rate of 4.8 mg/kg/hour can be applied.

b For IOPD patients who experience lack of improvement a dose increase to 40 mg/kg every other week is recommended. For a body weight of 1.25-5 kg a maximum infusion rate of 9.6 mg/kg/hour can be applied.

In the event of anaphylaxis or severe hypersensitivity reaction or severe IARs, administration of Nexviadyme should be immediately discontinued and appropriate medical treatment should be initiated. In the event of mild to moderate hypersensitivity reactions or IARs, the infusion rate may be slowed or temporarily stopped and/or appropriate medical treatment initiated (see section 4.4).

Symptoms may persist despite temporarily stopping the infusion; therefore, the treating physician should wait at least 30 minutes for symptoms of the reactions to resolve before deciding to stop the infusion for the remainder of the day. If symptoms subside, infusion rate should be resumed for 30 minutes at half the rate, or less, of the rate at which the reactions occurred, followed by an increase in infusion rate by 50% for 15 to 30 minutes. If symptoms do not recur, the infusion rate should be increased to the rate at which the reactions occurred and consider continuing to increase the rate in a stepwise manner until the maximum rate is achieved.

Home infusion

Infusion of Nexviadyme at home may be considered for patients who are tolerating their infusions well and have no history of moderate or severe IARs for a few months. The decision to have a patient move to home infusion should be made after evaluation and upon recommendation by the treating physician. A patient's underlying co-morbidities and ability to adhere to the home infusion requirements need to be taken into account when evaluating the patient for eligibility to receive home infusion. The following criteria should be considered:

• The patient must have no ongoing concurrent condition that, in the opinion of the physician, may affect patient's ability to tolerate the infusion.

• The patient is considered medically stable. A comprehensive evaluation must be completed before the initiation of home infusion.

• The patient must have received Nexviadyme infusions supervised by a physician with expertise in management of Pompe patients for a few months that could be in a hospital or in another appropriate setting of outpatient care. Documentation of a pattern of well-tolerated infusions with no IARs, or mild IARs that have been controlled with premedication, is a prerequisite for the initiation of home infusion.

• The patient must be willing and able to comply with home infusion procedures.

• Home infusion infrastructure, resources, and procedures, including training, must be established and available to the healthcare professional. The healthcare professional should be available at all times during the home infusion and a specified time after infusion, depending on patient's tolerance prior to starting home infusion.

If the patient experiences adverse reactions during the home infusion, the infusion process should be stopped immediately, and appropriate medical treatment should be initiated (see section 4.4). Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient care until no such adverse reaction is present. Dose and infusion rate must not be changed without consulting the responsible physician.

For instructions on reconstitution and dilution of medicinal product before administration, see section 6.6.

4.3. Contraindications

Life-threatening hypersensitivity to the active substance or to any of the excipients listed in section 6.1 when re-challenge was unsuccessful. (see sections 4.4 and 4.8)

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity reactions (including anaphylaxis)

Hypersensitivity reactions, including anaphylaxis, have been reported in Nexviadyme-treated patients (see section 4.8).

Appropriate medical support measures, including cardiopulmonary resuscitation equipment especially for patients with cardiac hypertrophy and patients with significantly compromised respiratory function, should be readily available when Nexviadyme is administered.

If severe hypersensitivity or anaphylaxis occur, Nexviadyme should be discontinued immediately, and appropriate medical treatment should be initiated. The risks and benefits of re-administering Nexviadyme following anaphylaxis or severe hypersensitivity reaction should be considered. Some patients have been re-challenged using slower infusion rates at a dose lower than the recommended dose. In patients with severe hypersensitivity, desensitization procedure to Nexviadyme may be considered. If the decision is made to re-administer the medicinal product, extreme caution should be exercised, with appropriate resuscitation measures available. Once a patient tolerates the infusion, the dose may be increased to reach the approved dose.

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

Infusion-associated reactions (IARs)

In clinical studies, IARs were reported to occur at any time during and/or within a few hours after the infusion of Nexviadyme and were more likely with higher infusion rates (see section 4.8).

Patients with an acute underlying illness at the time of Nexviadyme infusion appear to be at greater risk for IARs. Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from IARs. Antihistamines, antipyretics, and/or corticosteroids can be given to prevent or reduce IARs. However, IARs may still occur in patients after receiving pre-treatment.

If severe IARs occur, immediate discontinuation of the administration of Nexviadyme should be considered and appropriate medical treatment should be initiated. The benefits and risks of re-administering Nexviadyme following severe IARs should be considered. Some patients have been re-challenged using slower infusion rates at a dose lower than the recommended dose. Once a patient tolerates the infusion, the dose may be increased to reach the approved dose. If mild or moderate IARs occur regardless of pre-treatment, decreasing the infusion rate or temporarily stopping the infusion may ameliorate the symptoms (see section 4.8).

Immunogenicity

Treatment emergent anti-drug antibodies (ADA) were reported in both treatment naïve (95%) and treatment-experienced patients (62%) (see section 4.8).

IARs and hypersensitivity reactions may occur independent of the development of ADA. The majority of IARs and hypersensitivity reactions were mild or moderate and were managed with standard clinical practices. In clinical studies, the development of ADA did not impact clinical efficacy (see section 4.8).

ADA testing may be considered if patients do not respond to therapy. Adverse-event-driven immunologic testing, including IgG and IgE ADA, may be considered for patients who have risk for allergic reaction or previous anaphylactic reaction to alglucosidase alfa.

Contact your local Sanofi representative or Sanofi EU Medical Services for information on the Sanofi Speciality Care testing services.

Risk of acute cardiorespiratory failure

Caution should be exercised when administering Nexviadyme to patients susceptible to fluid volume overload or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusion. Appropriate medical support and monitoring measures should be readily available during Nexviadyme infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.

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

Caution should be used when administering general anaesthesia for the placement of a central venous catheter or for other surgical procedures in patients with IOPD with cardiac hypertrophy.

Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia, and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation, have been associated with the use of general anaesthesia in IOPD patients with cardiac hypertrophy.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Because it is a recombinant human protein, avalglucosidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no available data on the use of Nexviadyme in pregnant women. Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. Indirect foetal effects in mice were considered related to an anaphylactic response to avalglucosidase alfa (see section 5.3). The potential risk for humans is unknown. No conclusions can be drawn regarding whether or not Nexviadyme is safe for use during pregnancy. Nexviadyme should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the foetus.

Breast-feeding

There are no available data on the presence of Nexviadyme in human milk or the effects of Nexviadyme on milk production or the breast-fed infant. No conclusions can be drawn regarding whether or not Nexviadyme is safe for use during breast-feeding. Nexviadyme should be used during breast-feeding only if the potential benefits to the mother outweigh the potential risks, including those to the breast-fed child (see section 5.3).

Fertility

There are no clinical data on the effects of Nexviadyme on human fertility. Animal studies in mice showed no impairment of male or female fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Nexviadyme may have a minor influence on the ability to drive and use machines. Because dizziness, hypotension and somnolence have been reported as IARs, this may affect the ability to drive and use machines on the day of the infusion (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

Serious adverse reactions reported in patients treated with Nexviadyme were respiratory distress and chills in 1.4% of patients and in 0.7% of patients each were headache, dyspnoea, hypoxia, tongue oedema, nausea, pruritus, urticaria, skin discoloration, chest discomfort, pyrexia, blood pressure increased or decreased, body temperature increased, heart rate increased, and oxygen saturation decreased. Hypersensitivity reactions were reported in 60.6% of patients, anaphylaxis in 2.8%, and IARs in 39.4% in patients. A total of 4.9% of patients receiving Nexviadyme in clinical studies permanently discontinued treatment; 2.8% of patients each discontinued the treatment because of the following events considered to be related to Nexviadyme: respiratory distress, chest discomfort, dizziness, cough, nausea, flushing, ocular hyperaemia, urticaria, and erythema.

The most frequently reported adverse drug reactions (ADRs) (>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%).

The pooled safety analysis from 4 clinical studies (EFC14028/COMET, ACT14132/mini-COMET, TDR12857/NEO, and LTS13769/NEO-EXT) included a total of 142 patients (118 adult and 24 paediatric patients (1 paediatric patient directly enrolled in the open-label extension period of Study 1)) treated with Nexviadyme. ADRs reported in patients treated with Nexviadyme in the pooled analysis of clinical studies are listed in Table 2.

Tabulated list of adverse reactions

Adverse reactions per System Organ Class, presented by frequency 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 not known (cannot be estimated from the available data).

Due to the small patient population, an adverse reaction reported in 2 patients is classified as common. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 – Adverse reactions occurring in patients treated with Nexviadyme in a pooled analysis of clinical studies (N=142)

System organ class

Frequency

Preferred term

Infections and infestations

Uncommon

Conjunctivitis

Immune Disorders

Very common

Common

Hypersensitivity

Anaphylaxis

Nervous system disorders

Very common

Common

Common

Common

Common

Uncommon

Headache

Dizziness

Tremor

Somnolence

Burning sensation

Paraesthesia

Eye Disorders

Common

Common

Common

Common

Uncommon

Ocular hyperaemia

Conjunctival hyperaemia

Eye pruritus

Eyelid oedema

Lacrimation increased

Cardiac Disorders

Common

Uncommon

Tachycardia

Ventricular extrasystoles

Vascular Disorders

Common

Common

Common

Common

Common

Common

Hypertension

Flushing

Hypotension

Cyanosis

Hot flush

Pallor

Respiratory, thoracic, and mediastinal disorders

Common

Common

Common

Common

Common

Uncommon

Uncommon

Cough

Dyspnoea

Respiratory distress

Throat irritation

Oropharyngeal pain

Tachypnoea

Laryngeal oedema

Gastrointestinal disorders

Very common

Common

Common

Common

Common

Common

Common

Common

Uncommon

Uncommon

Uncommon

Nausea

Diarrhoea

Vomiting

Lip swelling

Swollen tongue

Abdominal pain

Abdominal pain upper

Dyspepsia

Hypoaesthesia oral

Paraesthesia oral

Dysphagia

Skin and subcutaneous tissue disorders

Very common

Very common

Common

Common

Common

Common

Common

Common

Common

Uncommon

Uncommon

Pruritus

Rash

Urticaria

Erythema

Palmer erythema

Hyperhidrosis

Rash erythematous

Rash pruritic

Skin plaque

Angioedema

Skin discolouration

Musculoskeletal and connective tissue disorders

Common

Common

Common

Common

Muscle spasms

Myalgia

Pain in extremity

Flank pain

General disorders and administration site conditions

Common

Common

Common

Common

Common

Common

Common

Common

Common

Common

Common

Common

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

Uncommon

Fatigue

Chills

Chest discomfort

Pain

Influenza-like illness

Infusion site pain

Pyrexia

Asthenia

Face oedema

Feeling cold

Feeling hot

Sluggishness

Facial pain

Hyperthermia

Infusion site extravasation

Infusion site joint pain

Infusion site rash

Infusion site reaction

Infusion site urticaria

Localized oedema

Peripheral swelling

Investigation

Common

Common

Common

Uncommon

Uncommon

Uncommon

Uncommon

Blood pressure increased

Oxygen saturation decreased

Body temperature increase

Heart rate increased

Breath sounds abnormal

Complement factor increased

Immune complex level increased

Table 2 includes treatment related adverse events that are considered biologically plausibly related to avalglucosidase alfa based on the alglucosidase alfa SmPC.

In a comparative study, EFC14028/COMET, 100 LOPD (late-onset Pompe disease) patients aged 16 to 78 naïve to enzyme replacement therapy were treated either with 20 mg/kg of Nexviadyme (n=51) or 20 mg/kg of alglucosidase alfa (n=49). During the double-blind active-controlled period of 49 weeks, serious adverse reactions were reported in 2% of patients treated with Nexviadyme and 6.1% of those treated with alglucosidase alfa. A total of 8.2% patients receiving alglucosidase alfa in the study permanently discontinued treatment due to adverse reactions; none of the patients from the Nexviadyme group permanently discontinued the treatment. The most frequently reported ADRs (>5%) in patients treated with Nexviadyme were headache, nausea, pruritus, urticaria, and fatigue.

The 95 patients who entered open-label extension period of EFC14028/COMET consisted of 51 patients who continued treatment with Nexviadyme and 44 patients who switched from alglucosidase alfa to Nexviadyme.

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

No adverse reaction or IAR was reported by the additional paediatric patient directly enrolled in the open-label extension period.

Description of selected adverse reactions

Hypersensitivity (including anaphylaxis)

In a pooled safety analysis, 86/142 (60.6%) patients experienced hypersensitivity reactions including 7/142 (4.9%) patients who reported severe hypersensitivity reactions and 4/142 (2.8%) patients who experienced anaphylaxis. Some of the hypersensitivity reactions were IgE mediated. Anaphylaxis signs and symptoms included tongue oedema, hypotension, hypoxia, respiratory distress, chest pressure, generalised oedema, generalised flushing, feeling hot, cough, dizziness, dysarthria, throat tightness, dysphagia, nausea, redness on palms, swollen lower lip, decreased breath sounds, redness on feet, swollen tongue, itchy palms and feet, and oxygen desaturation. Symptoms of severe hypersensitivity reactions included tongue oedema, respiratory failure, respiratory distress, generalized oedema, erythema, urticaria, and rash.

Infusion-associated reactions (IARs)

In a pooled safety analysis, IARs were reported in approximately 56/142 (39.4%) of patients treated with avalglucosidase alfa in clinical studies. Severe IARs were reported in 6/142 (4.2%) of patients including symptoms of respiratory distress, hypoxia, chest discomfort, generalized oedema, tongue oedema, dysphagia, nausea, erythema, urticaria, and increased or decreased blood pressure. IARs reported in more than 1 patient included respiratory distress, chest discomfort, dyspnoea, cough, oxygen saturation decreased, throat irritation, dyspepsia, nausea, vomiting, diarrhoea, lip swelling, swollen tongue, erythema, palmar erythema, rash, rash erythematous, pruritus, urticaria, hyperhidrosis, skin plaque, ocular hyperaemia, eyelid oedema, face oedema, increased or decreased blood pressure, tachycardia, headache, dizziness, tremor, burning sensation, pain (including pain in extremity, abdominal pain upper, oropharyngeal pain, and flank pain), somnolence, sluggishness, fatigue, pyrexia, influenza like illness, chills, flushing, feeling hot or cold, cyanosis, and pallor. The majority of IARs were assessed as mild to moderate.

In the comparative study EFC14028/COMET study, fewer LOPD patients in the avalglucosidase alfa group reported at least 1 IAR (13/51 [25.5%]) in comparison to the alglucosidase alfa group (16/49 [32.7%]). Severe IARs were not reported in patients in the avalglucosidase alfa group and reported in 2 patients in the alglucosidase alfa group (dizziness, visual impairment, hypotension, dyspnoea, cold sweat, and chills). The most frequently reported treatment-emergent IARs (>2 patients) in the avalglucosidase alfa group were pruritus (7.8%) and urticaria (5.9%) and in the alglucosidase alfa group were nausea (8.2%), pruritus (8.2%), and flushing (6.1%). The majority of IARs reported in 7 (13.7%) patients were of mild severity in the avalglucosidase alfa group and 10 (20.4%) patients in the alglucosidase alfa group.

During the open-label extension period, IARs were reported in 12 (23.5%) patients continuing Nexviadyme treatment throughout the study; IARs reported in more than 1 patient were nausea, chills, erythema, pruritus, pyrexia, urticaria, rash, and ocular hyperaemia. IARs were reported in 22 (50%) patients who switched to Nexviadyme; IARs reported in more than 1 patient were pruritis, headache, rash, nausea, chills, fatigue, urticaria, respiratory distress, feeling cold, chest discomfort, erythema, rash erythematous, rash pruritic, skin plaque, burning sensation, lip swelling, and swollen tongue. The number of IARs in both groups decreased over time.

Immunogenicity

The incidence of ADA response to avalglucosidase alfa in Nexviadyme-treated patients with Pompe disease is shown in Table 3. The median time to seroconversion was 8.3 weeks.

In treatment-naïve adult patients, the occurrence of IARs was observed in both ADA-positive and ADA-negative patients. Increase in the incidence of IARs and hypersensitivity were observed with higher IgG ADA titres. In treatment-naïve patients, a trend for increases in the incidence of IARs was observed with increasing ADA titres, with the highest incidence of IARs (69.2%) reported in the high ADA peak titre range ≥12,800, compared with an incidence of 33.3% in patients with intermediate ADA titre 1,600-6,400, an incidence of 14.3% in those with low ADA titre 100-800 and an incidence of 33.3% in those who were ADA negative. In enzyme replacement therapy (ERT) experienced adult patients, the occurrences of IARs and hypersensitivity were higher in patients who developed treatment emergent ADA compared to patients who were ADA negative. One (1) treatment naïve patient and 2 treatment-experienced patients developed anaphylaxis. The occurrences of IARs were similar between paediatric patients with ADA positive and negative status. One treatment-experienced paediatric patient developed anaphylaxis (see section 4.4).

In clinical study EFC14028/COMET, 81 of 96 (84.4%) patients developed treatment-emergent ADA. Majority of patients developed ADA titre in the low to intermediate range, with 7 patients reported High Sustained Antibody Titres (HSAT) to Nexviadyme. Evaluation of ADA cross-reactivity at week 49 showed that three (5.9%) patients generated antibodies that were cross-reactive to alglucosidase alfa and Nexviadyme. Variable impact on PK, PD, and efficacy measures were observed among high titre patients, however, in most patients there was no clinically significant effect of ADA on efficacy (see section 5.2).

Table 3 – Treatment emergent ADA incidence in LOPD and IOPD patient population

Nexviadyme

Treatment-naïve patients Avalglucosidase alfa ADAa

Treatment-experienced patientsb

Avalglucosidase alfa ADA

Adults

20 mg/kg every other week

Adults

20 mg/kg every other week

Paediatric

20 mg/kg every other week

Paediatric

40 mg/kg every other week

(N=62)

N (%)

(N=58)

N (%)

(N=6)

N (%)

(N=16)

N (%)

ADA at baseline

2 (3.3)

43 (74.1)

1 (16.7)

2 (12.5)

Treatment emergent ADA

59 (95.2)

36 (62.1)

1 (16.6)

9 (56.3)

Neutralizing antibody

Both NAb types

14 (22.6)

5 (8.6)

0

0

Inhibition enzyme activity, only

5 (8.1)

6 (10.3)

0

0

Inhibition of enzyme uptake, only

12 (19.4)

15 (25.9)

0

2 (12.5%)

a Includes two paediatric patients

b Treatment-experienced patients received alglucosidase alfa treatment before or during the clinical study within a range of 0.9-9.9 years for adult patients and 0.6-11.8 years for paediatric patients.

c Not determined

Paediatric population

Adverse drug reactions reported from clinical studies in the paediatric population (19 paediatric patients with IOPD between 1-12 years of age (mean age of 6.8) and two paediatric patients (9 and 16 years old) with LOPD) were similar to those reported in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Excessive infusion rate of Nexviadyme may result in hot flush. In a clinical study, paediatric patients received doses up to 40 mg/kg of body weight once every 2 weeks and no specific signs and symptoms were identifies following the higher doses. For management of adverse reactions, see sections 4.4 and 4.8.