1. Name Of The Medicinal Product
Fabrazyme 35 mg powder for concentrate for solution for infusion
2. Qualitative And Quantitative Composition
Each vial of Fabrazyme contains a nominal value of 35 mg of agalsidase beta. After reconstitution with 7.2 ml water for injections, each vial of Fabrazyme contains 5 mg/ml (35 mg/7 ml) of agalsidase beta. The reconstituted solution must be diluted further (see section 6.6).
Agalsidase beta is a recombinant form of human α-galactosidase A and is produced by recombinant DNA technology using a mammalian Chinese Hamster Ovary (CHO) cell culture. The amino acid sequence of the recombinant form, as well as the nucleotide sequence which encoded it, are identical to the natural form of α-galactosidase.
3. Pharmaceutical Form
Powder for concentrate for solution for infusion.
White to off-white lyophilised cake or powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Fabrazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency).
4.2 Posology And Method Of Administration
Fabrazyme treatment should be supervised by a physician experienced in the management of patients with Fabry disease or other inherited metabolic diseases.
Posology
The recommended dose of Fabrazyme is 1 mg/kg body weight administered once every 2 weeks as an intravenous infusion.
Alternative dosing regimens have been used in clinical studies. In one of these studies, after an initial dose of 1.0 mg/kg every 2 weeks for 6 months, 0.3 mg/kg every 2 weeks may maintain clearance of GL-3 in certain cell types in some patients; however, the long term clinical relevance of these findings has not been established (see section 5.1).
The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise the potential occurrence of infusion-associated reactions. After patient tolerance is established, the infusion rate may be increased gradually with subsequent infusions.
Patients with renal impairment
No dose adjustment is necessary for patients with renal insufficiency.
Patients with hepatic impairment
Studies in patients with hepatic insufficiency have not been performed.
Elderly
The safety and efficacy of Fabrazyme in patients older than 65 years have not been established and no dosage regimen can presently be recommended in these patients.
Paediatric population
Studies in children 0-7 years have not been performed and no dosage regimen can presently be recommended in patients in this paediatric age group as safety and efficacy have not yet been established. No dose adjustment is necessary for children 8-16 years.
Method of administration
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients.
4.4 Special Warnings And Precautions For Use
Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. The majority of patients developed IgG antibodies to r-hαGAL, typically within 3 months of the first infusion with Fabrazyme. Over time, the majority of seropositive patients in clinical trials demonstrated either a downward trend in titers (based on a
Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs), which are defined as any related adverse event occurring on the infusion day. These patients should be treated with caution when re-administering agalsidase beta (See section 4.8). Antibody status should be regularly monitored.
In clinical trials, sixty seven percent (67 %) of the patients experienced at least one infusion-associated reaction (See section 4.8). The frequency of IARs decreased over time. Patients experiencing mild or moderate infusion-associated reactions when treated with agalsidase beta during clinical trials have continued therapy after a reduction in the infusion rate (~0.15 mg/min; 10 mg/hr) and/or pre-treatment with antihistamines, paracetamol, ibuprofen and/or corticosteroids.
As with any intravenous protein medicinal product, allergic-type hypersensitivity reactions are possible.
A small number of patients have experienced reactions suggestive of immediate (Type I) hypersensitivity. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed. With careful rechallenge Fabrazyme has been re-administered to all 6 patients who tested positive for IgE antibodies or had a positive skin test to Fabrazyme in a clinical trial. In this trial, the initial rechallenge administration was at a low dose and a lower infusion rate (1/2 the therapeutic dose at 1/25 the initial standard recommended rate). Once a patient tolerates the infusion, the dose may be increased to reach the therapeutic dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards, as tolerated.
The effect of Fabrazyme treatment on the kidneys may be limited in patients with advanced renal disease.
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, agalsidase beta is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.
Fabrazyme should not be administered with chloroquine, amiodarone, benoquin or gentamycin due to a theoretical risk of inhibition of intra-cellular α-galactosidase activity.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of agalsidase beta in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal development (See section 5.3).
Fabrazyme should not be used during pregnancy unless clearly necessary.
Breast-feeding
Agalsidase beta may be excreted in milk. Because there are no data available on effects in neonates exposed to agalsidase beta via breast milk, it is recommended to stop breast-feeding when Fabrazyme is used.
Fertility
Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility.
4.7 Effects On Ability To Drive And Use Machines
Fabrazyme may have a minor influence on the ability to drive or use machines on the day of Fabrazyme administration because dizziness, somnolence, vertigo and syncope may occur (see section 4.8).
4.8 Undesirable Effects
Adverse drug reactions (ADRs) reported from clinical trials to be related to Fabrazyme administered at a dose of 1mg/kg in a total of 168 patients (154 males and 14 females) treated with Fabrazyme for a minimum of one infusion up to a maximum of 5 years are listed by System Organ Class and frequency (very common
Incidence of Related Adverse Events with Fabrazyme Treatment
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Infusion associated reactions consisted most often of fever and chills. Additional symptoms included mild or moderate dyspnoea, hypoxia (oxygen saturation decreased), throat tightness, chest discomfort, flushing, pruritus, urticaria, face oedema, angioneurotic oedema, rhinitis, bronchospasm, tachypnoea, wheezing, hypertension, hypotension, tachycardia, palpitations, abdominal pain, nausea, vomiting, infusion-related pain including pain at the extremities, myalgia, and headache.
The infusion-associated reactions were managed by a reduction in the infusion rate together with the administration of non-steroidal anti-inflammatory medicinal products, antihistamines and/or corticosteroids. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. The frequency of these reactions decreased over time. The majority of these reactions can be attributed to the formation of IgG antibodies and/or complement activation. In a limited number of patients IgE antibodies were demonstrated (see section 4.4).
Paediatric population
Limited information suggests that the safety profile of Fabrazyme treatment in paediatric patients (above the age of 7) is not different with that seen in adults.
4.9 Overdose
No case of overdose has been reported. In clinical trials doses up to 3 mg/kg body weight were used.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. ATC code: A16AB04.
Fabry disease is an inherited heterogeneous and multisystemic progressive disease, that affects both males and females. It is characterised by the deficiency of α-galactosidase. Reduced or absent α-galactosidase activity results in the accumulation of GL-3 in the lysosomes of many cell types including the endothelial and parenchymal cells, ultimately leading to life-threatening clinical deteriorations as a result of renal, cardiac and cerebrovascular complications. The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to clear the accumulating substrate in the organ tissues; thereby, preventing, stabilizing or reversing the progressive decline in function of these organs before irreversible damage has occurred.
After intravenous infusion, agalsidase beta is rapidly removed from the circulation and taken up by vascular endothelial and parenchymal cells into lysosomes, likely through the mannose-6 phosphate, mannose and asialoglycoprotein receptors.
Efficacy and safety of Fabrazyme was evaluated in one study with children, one dose-finding study, two double-blind placebo-controlled studies, and one open-label extension study in both male and female patients.
In the dose finding study, the effects of 0.3, 1.0 and 3.0 mg/kg once every 2 weeks and 1.0 and 3.0 mg/kg once every 2 days were evaluated. A reduction in GL-3 was observed in kidney, heart, skin and plasma at all doses. Plasma GL-3 was cleared in a dose dependent manner, but was less consistent at the dose of 0.3 mg/kg. In addition, infusion-associated reactions were dose dependent.
In the first placebo-controlled clinical trial, Fabrazyme was effective in clearing GL-3 from the vascular endothelium of the kidney after 20 weeks of treatment. This clearance was achieved in 69% (20/29) of the Fabrazyme treated patients, but in none of the placebo patients (p<0.001). This finding was further supported by a statistically significant decrease in GL-3 inclusions in kidney, heart and skin combined and in the individual organs in patients treated with agalsidase beta compared to placebo patients (p<0.001). Sustained clearance of GL-3 from kidney vascular endothelium upon agalsidase beta treatment was demonstrated further in the open label extension of this trial. This was achieved in 47 of the 49 patients (96%) with available information at month 6, and in 8 of the 8 patients (100%) with available information at the end of the study (up to a total of 5 years of treatment). Clearance of GL-3 was also achieved in several other cell types from the kidney. Plasma GL-3 levels rapidly normalised with treatment and remained normal through 5 years.
Renal function, as measured by glomerular filtration rate and serum creatinine, as well as proteinuria, remained stable in the majority of the patients. However, the effect of Fabrazyme treatment on the kidney function was limited in some patients with advanced renal disease.
Although no specific study has been conducted to assess the effect on the neurological signs and symptoms, the results also indicate that patients may achieve reduced pain and enhanced quality of life upon enzyme replacement therapy.
Another double-blind, placebo-controlled study of 82 patients was performed to determine whether Fabrazyme would reduce the rate of occurrence of renal, cardiac, or cerebrovascular disease or death. The rate of clinical events was substantially lower among Fabrazyme-treated patients compared to placebo-treated patients (risk reduction = 53% intent-to-treat population (p=0.0577); risk reduction = 61 % per-protocol population (p=0.0341)). This result was consistent across renal, cardiac and cerebrovascular events.
The results of these studies indicate that Fabrazyme treatment at 1 mg/kg every other week provides clinical benefit on key clinical outcomes in patients with early and advanced Fabry disease. Because this condition is slowly progressive, early detection and treatment is critical to achieve the best outcomes.
In an additional study, 21 male patients were enrolled to follow GL3 clearance in kidney and skin tissues at an alternative dosing regimen. Following treatment with 1 mg/kg every other week for 24 weeks, a dose regimen of 0.3 mg/kg every 2 weeks for 18 months was able to maintain the clearance of cellular GL-3 in the capillary endothelium of the kidney, other kidney cell types and skin (superficial skin capillary endothelium) in the majority of patients. However, at the lower dose, IgG antibodies may play a role with respect to GL-3 clearance in some patients. Due to the limitations of the study design (small number of patients), no definitive conclusion regarding the dose maintenance regimen can be drawn, but these findings suggest that, after an initial debulking dose of 1.0 mg/kg every 2 weeks, 0.3 mg/kg every 2 weeks may be sufficient in some patients to maintain clearance of GL-3.
In the postmarketing setting, experience was gained in patients who initiated treatment at a dose of 1 mg/kg every 2 weeks and subsequently received a reduced dose for an extended period. In some of these patients, an increase of some of the following symptoms was spontaneously reported: pain, paraesthesia and diarrhoea, as well as cardiac, central nervous system and renal manifestations. These reported symptoms resemble the natural course of Fabry disease.
Paediatric population
In the open-label paediatric study, sixteen patients with Fabry disease (8-16 years old; 14 males, 2 females) had been treated for one year. Clearance of GL-3 in the superficial skin vascular endothelium was achieved in all patients who had accumulated GL-3 at baseline. The 2 female patients had little or no GL-3 accumulation in the superficial skin vascular endothelium at baseline, making this conclusion applicable in male patients only.
5.2 Pharmacokinetic Properties
Following an intravenous administration of agalsidase beta to adults at doses of 0.3 mg, 1 mg and 3 mg/kg body weight, the AUC values increased more than dose proportional, due to a decrease in clearance, indicating a saturated clearance. The elimination half-life was dose dependent and ranged from 45 to 100 minutes.
After intravenous administration of agalsidase beta to adults with an infusion time of approximately 300 minutes and at a dose of 1 mg/kg body weight, biweekly, mean Cmax plasma concentrations ranged from 2000-3500 ng/ml, while the AUCinf ranged from 370-780 μg·min/ml. Vss ranged from 8.3-40.8 l, plasma clearance from 119-345 ml/min and the mean elimination half-life from 80-120 minutes.
Agalsidase beta 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 agalsidase beta in a clinically significant way. Renal elimination of agalsidase beta is considered to be a minor pathway for clearance.
Paediatric population
Fabrazyme pharmacokinetics was also evaluated in 15 paediatric patients (8.5 to 16 years old weighing 27.1 to 64.9 kg). Agalsidase clearance was not influenced by weight in this population. Baseline clearance was 77 ml/min with a volume of distribution at steady-state (Vss) of 2.6 l; half-life was 55 min. After IgG seroconversion, clearance decreased to 35 ml/min, Vss increased to 5.4 l, and half-life increased to 240 min. The net effect of these changes after seroconversion was an increase in exposure of 2- to 3-fold based on AUC and Cmax. No unexpected safety issues were encountered in patients with an increase in exposure after seroconversion.
5.3 Preclinical Safety Data
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, single dose toxicity, repeated dose toxicity and embryonal/foetal toxicity. Studies with regard to other stages of the development have not been carried out. Genotoxic and carcinogenic potential are not expected.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Mannitol
Sodium phosphate monobasic, monohydrate
Sodium phosphate dibasic, heptahydrate
6.2 Incompatibilities
In the absence of compatibility studies, Fabrazyme must not be mixed with other medicinal products in the same infusion.
6.3 Shelf Life
3 years.
Reconstituted and diluted solutions
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage and conditions prior to use are the responsibility of the user. The reconstituted solution cannot be stored and should be promptly diluted; only the diluted solution can be held for up to 24 hours at 2 °C-8 °C.
6.4 Special Precautions For Storage
Store in a refrigerator (2 °C – 8 °C).
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
Fabrazyme 35 mg is supplied in clear Type I glass 20 ml vials. The closure consists of a siliconised butyl stopper and an aluminium seal with a plastic flip-off cap.
Package sizes: 1, 5 and 10 vials per carton.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
The powder for concentrate for solution for infusion has to be reconstituted with water for injections, diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous infusion. Use Aseptic Technique
1. Determine the number of vials to be reconstituted based on the individual patient's weight and remove the required vials from the refrigerator in order to allow them to reach room temperature (in approximately 30 minutes). Each vial of Fabrazyme is intended for single use only.
Reconstitution
2. Reconstitute each vial of Fabrazyme 35 mg with 7.2 ml water for injections. Avoid forceful impact of the water for injections on the powder and avoid foaming. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilized cake. Roll and tilt each vial gently. Do not invert, swirl or shake the vial.
3. The reconstituted solution contains 5 mg agalsidase beta per ml, and appears as a clear colourless solution. The pH of the reconstituted solution is approximately 7.0. Before further dilution, visually inspect the reconstituted solution in each vial for particulate matter and discoloration. Do not use the solution if foreign particles are observed or if the solution is discoloured.
4. After reconstitution it is recommended to promptly dilute the vials, to minimize protein particle formation over time.
5. Any unused product or waste material should be disposed of in accordance with local requirements.
Dilution
6. Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it is recommended to remove an equal volume of 0.9% sodium chloride intravenous solution, from the infusion bag.
7. Remove the airspace within the infusion bag to minimize the air/liquid interface.
8. Slowly, withdraw 7.0 ml (equal to 35 mg) of the reconstituted solution from each vial up to the total volume required for the patient dose. Do not use filter needles and avoid foaming.
9. Then slowly inject the reconstituted solution directly into the 0.9% sodium chloride intravenous solution (not in any remaining airspace) to a final concentration between 0.05 mg/ml and 0.7 mg/ml. Determine the total volume of sodium chloride 0.9% solution for infusion (between 50 and 500 ml) based on the individual dose. For doses lower than 35 mg use a minimum of 50 ml, for doses 35 to 70 mg use a minimum of 100 ml, for doses 70 to 100 mg use a minimum of 250 ml and for doses greater than 100 mg use only 500 ml. Gently invert or lightly massage the infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion bag.
Administration
10. It is recommended to administer the diluted solution through an in-line low protein-binding 0.2 µm filter to remove any protein particles which will not lead to any loss of agalsidase beta activity. The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise the potential occurrence of infusion-associated reactions. After patient tolerance is established, the infusion rate may be increased gradually with subsequent infusions.
7. Marketing Authorisation Holder
Genzyme Europe B.V., Gooimeer 10, NL-1411DD Naarden, The Netherlands
8. Marketing Authorisation Number(S)
EU/1/01/188/001-003
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 03/08/2001
Date of last renewal: 03/08/2006
10. Date Of Revision Of The Text
06/2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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