NEXVIADYME Powder for solution for infusion Ref.[50122] Active ingredients: Avalglucosidase alfa

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 readministering Nexviadyme following severe IARs should be considered. Some patients have been rechallenged 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 (49%) (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 Genzyme representative or Sanofi Genzyme EU Medical Services for information on the Sanofi Genzyme 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.

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.

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).

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).

Summary of the safety profile

Serious adverse reactions reported in patients treated with Nexviadyme were chills in 1.4% of patients and in 0.7% of patients each were headache, dyspnoea, respiratory distress, nausea, skin discoloration, chest discomfort, pyrexia, blood pressure increased, body temperature increased, heart rate increased, and oxygen saturation decreased. Hypersensitivity reactions were reported in 43.5% of patients, anaphylaxis in 1.4%, and IARs in 26.1% in patients. A total of 2.9% patients receiving Nexviadyme in clinical studies permanently discontinued treatment; 0.7% 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, and erythema.

The most frequently reported adverse drug reactions (ADRs) (>5%) were pruritus (9.4%), rash (8%), headache (7.2%), urticaria (6.5%), fatigue (6.5%), nausea (5.8%), and chills (5.1%).

The pooled safety analysis from 4 clinical studies (EFC14028/COMET, ACT14132/mini-COMET, TDR12857/NEO, and LTS13769/NEO-EXT) included a total of 138 patients (118 adult and 20 paediatric patients) 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 (reported in at least 3 patients) 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=138):

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 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). 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%) were headache, nausea, pruritus, urticaria, and fatigue.

Description of selected adverse reactions

Hypersensitivity (including anaphylaxis)

In a pooled safety analysis, 60/138 (43.5%) patients experienced hypersensitivity reactions including 6/138 (4.3%) patients who reported severe hypersensitivity reactions and 2/138 (1.4%) patients who experienced anaphylaxis. Some of the hypersensitivity reactions were IgE mediated. Anaphylaxis symptoms included respiratory distress, chest pressure, generalised flushing, cough, dizziness, 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 respiratory failure, respiratory distress, and rash.

Infusion-associated reactions (IARs)

In a pooled safety analysis, IARs were reported in approximately 42/138 (30.4%) of patients treated with avalglucosidase alfa in clinical studies. Severe IARs were reported in 3/138 (2.2%) of patients including symptoms of chest discomfort, nausea, and increased blood pressure. IARs reported in more than 1 patient included chills, cough, diarrhoea, erythema, fatigue, headache, influenza-like illness, nausea, ocular hyperaemia, pain in extremity, pruritus, rash, rash erythematous, tachycardia, urticaria, vomiting, chest discomfort, dizziness, hyperhidrosis, lip swelling, oxygen saturation decreased, pain, palmar erythema, swollen tongue and tremor. 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 TEAEs (>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).

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 IAR was observed in both ADA-positive and ADA-negative patients. Increase in the incidence of IAR 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 (61.5%) reported in the high ADA peak titre range ≥12,800, compared with an incidence of 17.2% in patients with intermediate ADA titre 1,600-6,400, an incidence of 7.1% 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 1 treatment-experienced patient developed anaphylaxis. The occurrences of IARs were similar between paediatric patients with ADA positive and negative status. There were no paediatric patients who developed anaphylactic reactions (see section 4.4).

In clinical study EFC14028/COMET, 2 patients reported High Sustained Antibody Titres (HSAT) to Nexviadyme but this was not associated with a loss of efficacy. ADA cross-reactivity studies showed that the majority of patients generate antibodies that are cross-reactive to alglucosidase alfa. At week 49, antibodies specific to Nexviadyme were detected in 3 (5.9%) patients. ADA did not impact measures of efficacy while limited impacts on PK and PD were observed primarily with high titre patients (see section 5.2).

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

^a Includes one paediatric patient
^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 0.5-11.7 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 one 16-year-old paediatric patient 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 national reporting system listed in Appendix V.*

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.