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

Elfabrio 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 Elfabrio is administered to patients who have not had treatment before, or who have experienced severe hypersensitivity reactions to Elfabrio in the past.

Pre-treatment with antihistamines and/or corticosteroids may be advisable for patients who had previously experienced hypersensitivity reactions to Elfabrio 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.

For instructions on reconstitution, see section 6.6.

Patients switching treatment from agalsidase alfa or beta

For the initial 3 months (6 infusions) of treatment with Elfabrio, pre-treatment regimen should be preserved with stepwise discontinuation of pre-treatment based on appropriate tolerability of the patients.

Special populations

Renal or hepatic impairment

No dose adjustment is needed in patients with renal or hepatic impairment.

Elderly (≥ 65 years old)

Safety and efficacy of Elfabrio 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 Elfabrio 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.

Elfabrio 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 μ m 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 Elfabrio before administration, see section 6.6.

Home administration

Infusion of Elfabrio at home may be considered if the patient is tolerating his infusions well and have 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 Elfabrio

*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.

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

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.

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, and nasal congestion. If a severe allergic or anaphylactic-type reactions occur, immediate discontinuation of Elfabrio is recommended and current medical standards for emergency treatment are to be followed.

In patients who have experienced severe hypersensitivity reactions during Elfabrio 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 Elfabrio, 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 Elfabrio 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 Elfabrio treatment should be monitored.

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

Glomerulonephritis membranoproliferative

Depositions of immune complexes can potentially occur during treatment with ERTs, as a manifestation of immunological response to the product. A single case of glomerulonephritis membranoproliferative was reported during the clinical development of Elfabrio, 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.

Excipients of known effect

This medicinal product contains 48 mg sodium per vial, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

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

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 Elfabrio 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 Elfabrio 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 Elfabrio 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).

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

Summary of the safety profile

The most common adverse reactions were infusion-related reactions reported in 6.3% of patients, followed by hypersensitivity and asthenia reported each by 5.6% of patients.

In clinical studies, 5 patients (3.5%) experienced a serious reaction that was considered related to Elfabrio. Four of these reactions were confirmed IgE-mediated hypersensitivity (bronchospasm, hypersensitivity) that occurred at the first infusion of Elfabrio 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 Elfabrio 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 6 years.

Adverse reactions are listed in Table 2. 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 2: Adverse reactions reported during treatment with Elfabrio

* 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 32 patients (22%): 26 patients (23%) treated with 1 mg/kg every two weeks and 6 patients (20%) 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 symptom was pain. 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 Elfabrio 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 Elfabrio every two weeks and 0 out of 30 patients treated with 2 mg/kg Elfabrio every four weeks developed treatment-induced anti-drug antibodies (ADAs).

Glomerulonephritis membranoproliferative

During the clinical development of Elfabrio, one patient out of 136 reported a severe event of glomerulonephritis membranoproliferative 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.

There are no reports of overdose of Elfabrio during clinical studies. The maximum dose of Elfabrio 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.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code: A16AB20.

Mechanism of action

The active substance of Elfabrio is pegunigalsidase alfa. Pegunigalsidase alfa is a pegylated recombinant form of human α -galactosidase-A. The amino acid sequence of the recombinant form is similar to the naturally occurring human enzyme.

Pegunigalsidase alfa supplements or replaces α -galactosidase-A, the enzyme that catalyses the hydrolysis of the terminal α -galactosyl moieties of oligosaccharides and polysaccharides in the lysosome, reducing the amount of accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3).

Clinical efficacy and safety

Efficacy

The efficacy and safety of pegunigalsidase alfa were evaluated in 142 patients (94 males and 48 females), of which 112 receiving pegunigalsidase alfa 1 mg/kg every other week (EOW).

Disease substrate

Analyses of kidney biopsies from naï ve patients treated with pegunigalsidase alfa in a phase 1/2 study exhibited a reduction of the globotriaosylceramide (Gb3) substrate from the renal peritubular capillaries, measured with BLISS (Barisoni Lipid Inclusion Scoring System) of 68% in the overall population (including females, classic males and non-classic males exposed to different tested doses; n=13) after 6 months of treatment. Additionally, 11 out of 13 subjects with available biopsies had substantial reduction (≥ 50%) in their BLISS score following 6 months of treatment. Plasma Lyso-Gb3 decreased by 49% after 12 months of treatment (n=16) and by 83% after 60 months of treatment (n=10). In a phase 3 study, where patients were switching from agalsidase beta to pegunigalsidase alfa, plasma Lyso-Gb3 values stayed stable after 24 months of treatment (+3.3 nM mean value, n=48).

Renal function

The renal function was evaluated through the estimated glomerular filtration rate (eGFR – CKD-EPI equation) and its annualised measurement slope was the primary endpoint for efficacy in two phase 3 studies in previously ERT-treated adult Fabry patients: BALANCE (main study), a randomized, double blinded, head-to-head comparison with agalsidase beta, after switch from agalsidase beta at month 12 (primary analysis) and month 24, and an open label single arm study, after switch from agalsidase alfa, both followed by a long-term extension study.

No final conclusion on non-inferiority over agalsidase beta as measured by the annualised eGFR can be retrieved from the main study given that the data for the primary endpoint comparison at month 12 was not on its own sufficiently informative due to the design and size of the trial. Nevertheless, the median eGFR slopes from baseline to month 24 of pegunigalsidase and the comparator agalsidase beta appeared close. At month 12, the mean slopes for eGFR were -2.507 mL/min/1.73 m² /year for the pegunigalsidase alfa arm and -1.748 for the agalsidase beta arm (difference -0.749 [-3.026, 1.507]. At month 24, the median slopes for eGFR were - 2.514 [-3.788; - 1.240] mL/min/1.73 m² /year for the pegunigalsidase alfa arm and -2.155 [-3.805; - 0.505] for the agalsidase beta arm (difference -0.359 [-2.444 ; 1.726]).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Elfabrio in one or more subsets of the paediatric population in the treatment of Fabry disease (see section 4.2 for information on paediatric use).

Plasma pharmacokinetic (PK) profiles of pegunigalsidase alfa were characterized during the course of the clinical development at 0.2, 1, and 2 mg/kg administered every two weeks in adult patients with Fabry disease. The pharmacokinetic results for all three dose levels demonstrated that the enzyme was available throughout the 2-week intervals with a plasma half-life (t_1/2) ranging from 53-134 hours across dose groups and visit day. The mean value for AUC_0-∞ increased with increasing dose on Day 1 and throughout the study. Mean values for dose-normalized AUC_0-2wk were similar for all dose levels, indicating linear dose-proportionality. For patients who received 1 and 2 mg/kg Elfabrio, there were increases in mean t_1/2 and AUC_0-∞ with increasing duration of treatment and corresponding decreases in Cl and V_z, suggesting a saturated clearance.

Pegunigalsidase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of Elfabrio in a clinically significant way. The molecular weight of pegunigalsidase alfa is ~116 KDa, which is twice the cut-off value for glomerular filtration, thus excluding filtration and/or proteolytic degradation in kidneys.

There are no animal studies to assess the carcinogenic or mutagenic potential of Elfabrio.

In the 6-month chronic toxicity study in mice, an increased incidence and/or mean severity of multifocal nephropathy and interstitial lymphocytic infiltration in the kidneys, hepatocytic vacuolation and hepatocyte necrosis in the liver, were confined to males and females administered the high-dose of 40 mg/kg/injection (3.2-fold human exposure, in terms of AUC, following a dose of 1 mg/kg); in monkeys, an increased incidence of Kupffer cell hypertrophy was noted in the liver (7.6-fold above AUC reached in humans following a dose of 1 mg/kg) all findings resolved during the recovery period.

Animal studies demonstrated low systemic exposure in foetus (between 0.005 and 0.025% of dams' systemic exposure) and suckling pups (maximum 0.014% compared to mother's systemic exposure) following repeated treatment of the dams or mothers with pegunigalsidase alfa. Fertility and embryofoetal developmental toxicity studies did not show evidence of impaired fertility, embryotoxicity or teratogenicity. However, prenatal and postnatal developmental toxicity studies were not performed with pegunigalsidase alfa and the risks for foetus and pups during the late pregnancy and lactation are unknown.

Sodium citrate tribasic dihydrate

Citric acid

Sodium chloride

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

4 years.

Diluted solution for infusion

Chemical and physical in use stability has been demonstrated for 72 hours both at 2 ° C-8 ° C and below 25 ° C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours in the refrigerator (2 ° C-8 ° C) or 8 hours if stored below 25 ° C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2 ° C-8 ° C).

For storage conditions after dilution of the medicinal product, see section 6.3.

10 mL vial (15R clear glass) closed with coated rubber stopper and sealed with aluminium flip off cap.

Pack sizes of 1, 5 or 10 vials.

Not all pack sizes may be marketed.

Elfabrio is for intravenous infusion only. Aseptic technique to be used.

Vials are for single use only.

If contamination is suspected, the vial has not to be used. Shaking or agitating this medicinal product must be avoided.

Filter needles do not have to be used during the preparation of the infusion.

The number of vials to be diluted should be determined based on the individual patient's weight and the required vials should be removed from the refrigerator in order to allow them to reach room temperature (in approximately 30 minutes).

Dilution

1) Determine the total number of vials required for the infusion.

The number of vials required is based on the total dose required for each individual patient and requires calculation for weight-based dosing.

An example calculation for total dose in an 80 kg patient prescribed 1 mg/kg is as follows:

- Patient weight (in kg) ÷ 2 = Volume of dose (in mL)

- Example: 80 kg patient ÷ 2 = 40 mL (volume to be withdrawn).

- Given that 10 mL can be withdrawn from each vial, 4 vials are needed in this example.

2) Allow the required number of vials to reach room temperature prior to dilution (approximately 30 minutes).

Visually inspect the vials. Do not use if cap is missing or broken. Do not use if there is particulate matter or if it is discoloured.

Avoid shaking or agitating the vials.

3) Remove and discard the same volume as calculated in step 1 of sodium chloride 9 mg/mL (0.9%) solution for infusion from the infusion bag.

4) Withdraw the required volume of Elfabrio solution from the vials, and dilute with sodium chloride 9 mg/mL (0.9%) solution for infusion, to a total volume based on patient weight specified in Table 4 below.

Table 4: Minimum total infusion volume for patients by body weight

Inject the Elfabrio solution directly into the infusion bag.

Do NOT inject in the airspace within the infusion bag.

Gently invert the infusion bag to mix the solution, avoiding vigorous shaking and agitation.

The diluted solution should be administered using an inline low protein binding 0.2 μ m filter.

Disposal

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