4.1. Therapeutic indications

Elfabrio is indicated for long-term enzyme replacement therapy in adult patients with a confirmed diagnosis of Fabry disease (deficiency of alpha-galactosidase).

4.2. Posology and method of administration

Pegunigalsidase alfa treatment must be managed by a physician experienced in the treatment of patients with Fabry disease.

Appropriate medical support measures should be readily available when pegunigalsidase alfa is administered to patients who have not had treatment before, or who have experienced severe hypersensitivity reactions to pegunigalsidase alfa in the past.

Pre-treatment with antihistamines and/or corticosteroids may be advisable for patients who had previously experienced hypersensitivity reactions to pegunigalsidase alfa or to another enzyme replacement therapies (ERT) treatment (see section 4.4).

Posology

The recommended dose of pegunigalsidase alfa is 1 mg/kg of body weight administered once every two weeks.

The treatment can be also administered at the dose of 2 mg/kg of body weight once every four weeks in patients stable with an ERT treatment (see section 4.4 Treatment monitoring).

For instructions on reconstitution, see section 6.6.

Patients switching treatment from agalsidase alfa or beta

For the initial 3 months of treatment with pegunigalsidase alfa, pre-treatment regimen should be preserved with stepwise discontinuation of pre-treatment based on appropriate tolerability of the patients.

Special populations

Hepatic impairment

No dose adjustment is needed in patients with hepatic impairment.

Renal impairment

No dose adjustment is needed in patients with renal impairment.

Renal function should be evaluated regularly during pegunigalsidase alfa treatment (see section 4.4).

Elderly (≥ 65 years old)

Safety and efficacy of pegunigalsidase alfa in patients older than 65 years have not been evaluated and no alternative dose regimens can be recommended for these patients. Elderly patients may be treated with the same dose as other adult patients, see section 5.1.

Paediatric population

The safety and efficacy of pegunigalsidase alfa in children and adolescents aged 0-17 years have not yet been established. No data are available.

Method of administration

For intravenous infusion use only.

Pegunigalsidase alfa must not be infused in the same intravenous line with other products.

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

After preparation, the dilution should be administered via intravenous infusion and filtered through an in-line low protein-binding 0.2 μm filter.

The patient should be observed for infusion-related reactions (IRRs) for two hours after the infusion; see section 4.4.

Further details on how to handle pegunigalsidase alfa before administration, see section 6.6.

Home administration

Infusion of pegunigalsidase alfa at home may be considered if the patient is tolerating infusions well and has no history of moderate or severe IRRs for a few months.

The decision to move to home infusion should be made after evaluation and recommendation by the treating physician. The patient should be medically stable. Home infusion infrastructure, resources, and procedures, including training, must be established and available to the healthcare professional in charge of home infusion.

The healthcare professional should be available at all times during the home infusion and for a specified time after infusion.

Appropriate training should be given by the treating physician and/or nurse to the patient and/or caregiver prior to initiation of home infusion. The dose and infusion rate used in the home setting should remain the same as was used in the hospital setting; they should be changed only under the supervision of the treating physician.

Infusion rate and duration of infusion

Table 1: Recommended dose and infusion time for intravenous administration of 1 mg/kg of body weight of pegunigalsidase alfa every 2 weeks

Initial infusion 1 mg/kg of body weight every 2 weeks

Body weight (Kg)

Total volume (ml)

Infusion time

Infusion rate*

<70

150 ml

≥ 3 hours

0.83 ml/min (50 ml/hr)

70-100

250 ml

≥ 3 hours

1.39 ml/min (83.33 ml/hr)

> 100

500 ml

≥ 3 hours

2.78 ml/min (166.67 ml/hr)

Maintenance infusion

The target infusion duration can be achieved pending patient's tolerability. The increase in the infusion rate should be achieved gradually starting from the rate given at the first infusion.

1 mg/kg of body weight every 2 weeks

Body weight (Kg)

Total volume (ml)

Infusion time

Infusion rate*

<70

150 ml

≥ 1.5 hours

1.68 ml/min (100 ml/hr)

70-100

250 ml

≥ 1.5 hours

2.78 ml/min (166.67 ml/hr)

> 100

500 ml

≥ 1.5 hours

5.56 ml/min (333.33 ml/hr)

*infusion rate may be adjusted in case of infusion reaction (see section 4.4)

Table 2: Recommended dose and infusion time for intravenous administration of 2 mg/kg of body weight of pegunigalsidase alfa every 4 weeks

Initial infusion 2 mg/kg of body weight every 4 weeks

Body weight (Kg)

Total volume (ml)

Infusion time

Infusion rate*

< 70

150 ml

≥ 4.5 hours

0.56 ml/min (33.33 ml/hr)

70-100

250 ml

≥ 4.5 hours

0.93 ml/min (55.56 ml/hr)

> 100

500 ml

≥ 6 hours

1.39 ml/min (83.33 ml/hr)

Maintenance infusion

The target infusion duration can be achieved pending patient's tolerability. The increase in the infusion rate should be achieved gradually starting from the rate given at the first infusion.

2 mg/kg of body weight every 4 weeks

Body weight (Kg)

Total volume (ml)

Infusion time

Infusion rate*

< 70

150 ml

≥ 2 hours

1.25 ml/min (75 ml/hr)

70-100

250 ml

≥ 2 hours

2.08 ml/min (125 ml/hr)

> 100

500 ml

≥ 3 hours

2.78 ml/min (166.67 ml/hr)

*infusion rate may be adjusted in case of infusion reaction (see section 4.4)

If patients experience infusion-related reactions, including hypersensitivity reactions or anaphylactic reactions during the infusion, the infusion must be immediately stopped and appropriate medical treatment should be initiated (see section 4.4).

Any patients experiencing adverse events during the home infusion need to immediately stop the infusion process and seek the attention of a healthcare professional. Subsequent infusions may need to occur in a clinical setting.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

Treatment monitoring

For patients switched to pegunigalsidase alfa 2 mg/kg body weight once every 4 weeks, regular monitoring (e.g.: after 3, 6, 12, 18 and 24 months) should be performed. Monitoring should include at least the evaluation of lyso-Gb3, renal (eGFR, proteinuria), cardiac (LVMi, NT-proBNP, troponin or ECG), and biochemical parameters. A change in any individual parameter should be interpreted in the context of the patient's overall clinical status, and clinically relevant deterioration should prompt re-evaluation of the treatment regimen.

Infusion related reactions

Infusion-related reactions (IRRs), defined as any related adverse events with onset after start of infusion and up to 2 hours after end of infusion have been reported (see section 4.8). The most commonly observed symptoms of IRRs were hypersensitivity, itching, nausea, dizziness, chills and muscular pain.

The management of IRRs must be based on the severity of the reaction, and include slowing the infusion rate and treatment with medicinal products such as antihistamines, antipyretics and/or corticosteroids, for mild to moderate reactions. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those cases where symptomatic treatment was required, although IRRs occurred in some patients after receiving pre-treatment (see section 4.2).

Hypersensitivity

Hypersensitivity reactions have been reported in patients in clinical studies (see section 4.8). As with any intravenous protein product, allergic-type hypersensitivity reactions may manifest and can include localised angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalised urticaria, dysphagia, rash, dyspnoea, flushing, chest discomfort, pruritus, nausea, chills and nasal congestion. If a severe allergic or anaphylactic-type reactions occur, immediate discontinuation of pegunigalsidase alfa is recommended and current medical standards for emergency treatment are to be followed.

In patients who have experienced severe hypersensitivity reactions during pegunigalsidase alfa infusion, caution should be exercised upon re-challenge and appropriate medical support should be readily available. Moreover, for patients who experienced severe hypersensitivity reactions with ERT infusion including pegunigalsidase alfa, appropriate medical support should be readily available.

Immunogenicity

In clinical studies, treatment-induced anti-drug antibodies (ADA) development has been observed (see section 4.8).

The presence of ADAs to pegunigalsidase alfa may be associated with a higher risk of infusion-related reactions, and severe IRRs are more likely to occur in ADA positive patients. Patients who develop infusion or immune reactions with pegunigalsidase alfa treatment should be monitored.

Additionally, patients who are ADA positive to other enzyme replacement therapies, who have experienced hypersensitivity reactions to pegunigalsidase alfa and patients who are switching to pegunigalsidase alfa should be monitored.

Membranoproliferative glomerulonephritis

Depositions of immune complexes can potentially occur during treatment with ERTs, as a manifestation of immunological response to the product. A single case of membranoproliferative glomerulonephritis was reported during the clinical development of pegunigalsidase alfa, due to immune depositions in the kidney (see section 4.8). This event led to a temporary decline in renal function, which improved upon discontinuation of the medicinal product.

Patients with renal impairment

The presence of extensive renal damage (eGFR < 60 ml/min) may limit the renal response to enzyme replacement therapy, possibly due to underlying irreversible pathological changes. In such cases, the loss of renal function remains within the expected range of the natural progression of disease. Regular evaluation of changes in the estimated glomerular filtration rate (eGFR) during pegunigalsidase alfa treatment is recommended.

Excipients of known effect

This medicinal product contains 46 mg sodium per 10 mL vial, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 11.5 mg sodium per 2.5 mL vial, equivalent to 1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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

No interaction studies and no in vitro metabolism studies have been performed. Based on its metabolism, pegunigalsidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

Pegunigalsidase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of pegunigalsidase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of pegunigalsidase alfa during pregnancy unless clearly necessary.

Breast-feeding

It is unknown whether pegunigalsidase alfa/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of pegunigalsidase alfa in milk (for details see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from pegunigalsidase alfa therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no studies assessing the potential effect of pegunigalsidase alfa on fertility in humans.

Animal studies show no evidence of impaired fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Dizziness, syncope or vertigo were observed in some patients following pegunigalsidase alfa administration. These patients should refrain from driving or the use of machines until symptoms have subsided.

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions were infusion-related reactions reported in 7.8% of patients, followed by nausea and asthenia, both reported in 5.6% of patients and headache, reported in 4.2% of patients.

In clinical studies, 5 patients (3.5%) experienced a serious reaction that was considered related to pegunigalsidase alfa. Four of these reactions were confirmed IgE-mediated hypersensitivity (bronchospasm, hypersensitivity) that occurred at the first infusion of pegunigalsidase alfa and resolved within the day after occurrence.

Tabulated summary of adverse reactions

The data described below reflects data from 141 patients with Fabry disease who received pegunigalsidase alfa in 8 clinical studies, following the posology of 1 mg/kg every two weeks or 2 mg/kg every four weeks for a minimum of 1 infusion up to 7 years.

Adverse reactions are listed in Table 3. Information is presented by system organ class. Frequencies are defined as: 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); frequency not known (cannot be estimated from available data).

Table 3: Adverse reactions reported during treatment with pegunigalsidase alfa

System organ class

Frequency

Common

Uncommon

Immune system disorders

hypersensitivity*

type I hypersensitivity*

Psychiatric disorders

agitation*

insomnia

Nervous system disorders

paraesthesia*

dizziness*

headache*

restless legs syndrome

peripheral neuropathy

neuralgia

burning sensation

tremor*

syncope*

Ear and labyrinth disorders

vertigo

Vascular disorders

flushing

hypotension*

hypertension*

lymphoedema

Respiratory, thoracic and mediastinal disorders

bronchospasm*

sneezing*

nasal congestion*

dyspnoea*

throat irritation*

throat tightness

Gastrointestinal disorders

nausea*

abdominal pain*

diarrhoea

vomiting*

gastrooesophageal reflux disease

gastritis

dyspepsia

flatulence

Skin and subcutaneous issue disorders

rash*

erythema*

pruritus*

hypohidrosis

Musculoskeletal and connective tissue disorders

arthralgia

musculoskeletal pain*

Renal and urinary disorders

membranoproliferative glomerulonephritis

chronic kidney disease

proteinuria

Reproductive system and breast disorders

nipple pain

General disorders and administration site conditions

asthenia*

chills*

chest pain*

pain*

influenza-like illness

infusion site extravasation

infusion site pain

oedema

Investigations

body temperature increased*

urine protein/creatinine ratio increased

white blood cells urine positive

blood uric acid increased

weight increased

Injury, poisoning and procedural complications

infusion related reaction*

Cardiac disorders

supraventricular extrasystoles

The following preferred terms have been grouped in Table 3:

• hypersensitivity includes: drug hypersensitivity

• agitation includes: nervousness

• abdominal pain includes: abdominal discomfort

• rash includes: rash maculo-papular and rash pruritic

• musculoskeletal stiffness recorded as musculoskeletal pain includes: myalgia

• asthenia includes: malaise and fatigue

• chest pain includes: chest discomfort and non-cardiac chest pain

• pain includes: pain in extremity

• oedema peripheral recorded as oedema

* Preferred terms considered as IRR as described in the section below.

Description of selected adverse reactions

Infusion related reactions (adverse reactions within 2 hours of infusion)

IRRs were reported in a total of 36 patients (25%): 26 patients (23%) treated with 1 mg/kg every two weeks and 10 patients (34%) treated with 2 mg/kg every four weeks. The most commonly reported symptoms associated with IRRs reported for 1 mg/kg dosage were: hypersensitivity, chills, dizziness, rash and itching. For the 2 mg/kg dose the most commonly reported symptoms were pain, headache and nausea. IRRs were mostly mild or moderate in intensity and resolved with continuous treatment; however, 5 patients (all male, 1 mg/kg dose) experienced 5 severe IRRs. These 5 IRRs were also serious. Four of these events were confirmed type I hypersensitivity reactions and 3 led to the discontinuation from the study. Another patient was later withdrawn from the study, after the occurrence of another moderate IRR. All 5 patients however recovered within the day after of occurrence with appropriate treatment. IRRs predominantly occurred within the first year of treatment with pegunigalsidase alfa and no serious IRR was observed during the second year and beyond.

Immunogenicity

In clinical studies, 17 out of 111 of patients (16%) treated with 1 mg/kg pegunigalsidase alfa every two weeks and 1 out of 30 patients (3.4%) treated with 2 mg/kg pegunigalsidase alfa every four weeks developed treatment-induced anti-drug antibodies (ADAs).

Membranoproliferative glomerulonephritis

During the clinical development of pegunigalsidase alfa, one patient out of 141 reported a severe event of membranoproliferative glomerulonephritis after receiving treatment for more than 2 years. The patient was ADA positive at the start of the infusions. The event led to a transitory reduction in the eGFR and an increase on the level of proteinuria, with no additional signs or symptoms. A biopsy revealed the immune-complex mediated nature of this event. Upon discontinuation of the treatment, the eGFR values stabilised and the glomerulonephritis was reported as resolving.

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: Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There are no reports of overdose of pegunigalsidase alfa during clinical studies. The maximum dose of pegunigalsidase alfa studied was 2 mg/kg body weight every two weeks and no specific signs and symptoms were identified following the higher doses. The most common adverse reactions reported were infusion related reaction and pain in extremity. If overdose is suspected, seek emergency medical attention.