Health Articles

 

Microsoft word - 47cd8c65-4106-28a417.doc

FABRAZYME®
Physician Information Leaflet
NAME OF THE MEDICINAL PRODUCT

Fabrazyme 5 mg, powder for concentrate for solution for infusion.
Fabrazyme 35 mg, powder for concentrate for solution for infusion.
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of Fabrazyme 35 mg 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).
Each vial of Fabrazyme 5 mg contains a nominal value of 5 mg of agalsidase beta. After reconstitution
with 1.1 ml water for injections, each vial of Fabrazyme contains 5 mg/ml of agalsidase beta. The
reconstituted solution must be diluted further (see section 6.6).
Agalsidase beta is a recombinant form of α-galactosidase A and is produced by recombinant DNA
technology using 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.
For excipients, see section 6.1.

3. PHARMACEUTICAL

Powder for concentrate for solution for infusion.
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.
The recommended dose of Fabrazyme is 1mg/kg body weight administered once every 2 weeks as an
intravenous infusion. For further instructions see section 6.6.
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.
No dose adjustment is necessary for patients with renal insufficiency.
Studies in patients with hepatic insufficiency have not been performed.

The safety and efficacy of Fabrazyme in children below the age of 16 years and in patients older than
65 years have not been established and no dosage regimen can presently be recommended in these
patients.
4.3 Contraindications

Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients.
4.4
Special warnings and special precautions for use

Almost all patients are expected to develop IgG antibodies to agalsidase beta using the advised starting
dose, mostly within 3 months of initiation of treatment.
After up to 2 years of therapy, 63% of patients who were antibody positive show a significant reduction
in antibody titer over time.
The remaining 37% of patients demonstrated a plateau in their antibody titer.
In a limited number of patients IgE antibodies were demonstrated. Two of these patients were
subsequently rechallenged uneventfully with Fabrazyme and continue to receive treatment.
Patients with antibodies to agalsidase beta have a higher risk of infusion-associated reactions defined as
any related adverse event occurring during the infusion or until the end of the infusion day. (See section
4.8).
These patients should be treated with caution when re-administering agalsidase beta.
Initially, approximately half of the patients experienced infusion-associated reactions (See section 4.8).
In the phase 3 clinical study and its extension, infusion-associated reactions were managed by slowing
the rate of infusion and by pre-treating the patients with antihistamines, paracetamol, ibuprofen and/or
corticosteroids.
As with any intravenous protein product, allergic-type hypersensitivity reactions are possible.
Patients experiencing mild or moderate hypersensitivity reactions when treated with agalsidase beta
during clinical trials have continued therapy after a reduction in the rate of infusion ( 0.15 mg/min; 10
mg/hr) and pre-treatment with antihistamines, paracetamol, ibuprofen and/or corticosteroids.
If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of the administration
of Fabrazyme should be considered and an appropriate treatment has to be initiated. The current
medical standards for emergency treatment are to be observed.
The effect of Fabrazyme treatment on the kidneys may be limited in patients with advanced renal
disease.
Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility.
4.5 Interaction with other medicinal products and other forms of interaction
No in vitro metabolism studies have been carried out. 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
There are no adequate data from the use of agalsidase beta in pregnant women.
Animal studies do not indicate direct or indirect harmful effects on embryonal/foetal development (See
section 5.3).
Fabrazyme should not be used during pregnancy unless clearly necessary.
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 nursing when Fabrazyme is used.

4.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been conducted with Fabrazyme.
4.8 Undesirable effects

Adverse drug reactions (ADRs) reported to be related to Fabrazyme administered at a dose of 1mg/kg in
a total of 58 patients treated up to 12 months are listed by system organ class and frequency (very
common: > 10%, common: 5-10%) in the table below. ADRs were mostly mild to moderate in severity:
Body as a whole – general disorders
Rigors, temperature changed sensation, fever, pain at the extremities Chest pain, fatigue, back pain, pallor, pain, leg pain, asthenia, malaise Respiratory system disorders Very common Rhinitis, dyspnoea Common Bronchospasm, throat tightness Gastro-intestinal system disorders Very common: Nausea, vomiting Common: Abdominal Central and peripheral nervous system Very common: Headache, tremor Common: Paraesthesia, Cardiovascular disorders, general Very common: Oedema of the extremities, hypertension Musculo-skeletal system disorders Heart rate and rhythm disorders Common: Tachycardia, Psychiatric disorders Common: Somnolence Skin and appendages disorders Common: Pruritus Urinary system disorders Common: Albuminuria Vascular (extracardiac) disorder Common: Flushing Vision disorders Common: Vision Abnormal, Lacrimation abnormal Initially, approximately half of the patients experienced infusion-associated reactions. These reactions
consisted most often of fever/chills. Additional symptoms included mild to moderate dyspnoea, throat
tightness, chest tightness, flushing, pruritus, urticaria, rhinitis, bronchial constriction, tachypnea and/or
wheezing; moderate hypertension, 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 rate of infusion together with the
administration of non-steroidal anti-inflammatory medicinal products, antihistamines and/or
corticosteroids. After up to 2 years less than 37% of the patients experienced infusion-associated
reactions. 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. Two of these
patients were subsequently rechallenged uneventfully with Fabrazyme and continue to receive treatment.
4.9 Overdose
No case of overdose has been reported. In clinical trials doses up to 3mg/kg body weight were used.
5. PHARMACOLOGICAL
PROPERTIES

5.1 Pharmacodynamic
properties

Pharmacotherapeutic group: Alimentary tract and metabolism products – enzymes.
ATC code: A16AB04 agalsidase beta.
Fabry disease is a heterogeneous and multisystemic disorder, characterised by the deficiency of
α-galactosidase, a lysosomal hydrolase which catalyses the hydrolysis of glycosphingolipids, in
particular of globotriaosylceramide (GL-3), to terminal galactose and ceramide dihexoside. Reduced or
absent α-galactosidase activity results in the accumulation of GL-3 in many cell types including the
endothelial and parenchymal cells.
The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to
hydrolyse the accumulated substrate.
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.

In a phase 1/2 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 significant 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 a placebo controlled clinical trial Fabrazyme was effective in clearing GL-3 from the vascular
endothelium of the kidney after 20 weeks of treatment, as assessed by light microscopy. 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 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).
These results were confirmed by an interim analysis of an open label extension of the placebo controlled
trial in which patients from both randomisation groups are scheduled to receive Fabrazyme for an
additional 18 months. Clearance of GL-3 in the vascular endothelium of the kidney was achieved in
98% of patients for whom information is available.
Results of histological evaluation performed in various other cell types confirmed that GL-3 is cleared,
although longer treatment periods may be required to obtain complete clearance in some cell types.

Clinical and laboratory efficacy analyses in the placebo controlled clinical trial and its extension
included kidney function, pain assessment (Short Form McGill), quality of life questionnaire (SF-36),
and plasma GL-3. The average renal function, as measured by glomerular filtration rate and serum
creatinine, remained stable during two years of agalsidase beta treatment.
Although improvement in the pain score was seen in the first six months, this was seen both in the
placebo and active treated groups. Therefore, no conclusions on the effect of enzyme replacement
therapy on pain can be drawn.
Quality of life scores improved numerically but not statistically during treatment over a period for up to
two years. No conclusions on the effect of enzyme replacement therapy on quality of life can be drawn.
Replacement therapy has no effect on the neurological signs and symptoms of the disease, but no
systematic studies have been conducted.
Plasma GL-3 levels rapidly normalised with treatment.
A retrospective analysis of ECG's to evaluate the PR-interval duration was performed on patients
enrolled in the placebo controlled clinical trial and its extension. In those patients with a PR-interval of
<130 msec, an increase of the PR-duration (p<0.05) was demonstrated after treatment for 18 months in
those who received agalsidase beta in the double blind phase. In those who received placebo in the
double-blind phase, after treatment with agalsidase beta for 18 months, there was no change in PR
interval.
5.2 Pharmacokinetic
properties

Following an intravenous administration of agalsidase beta 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 with an infusion time of ca. 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 0.12-0.57 l/kg, plasma
clearance from 1.7-4.9 ml/min/kg 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.
5.3 Preclinical safety data

Preclinical 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

2 years.

6.4 Special precautions for storage
Store at 2 °C – 8 °C (in a refrigerator).
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 and would not be longer than
24 hours at 2 °C-8 °C.

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.

Fabrazyme 5 mg is supplied in clear Type I glass 5 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 Instructions for use and handling, and disposal
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.
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.
Each vial of Fabrazyme is intended for single use only.
Use Aseptic Technique
Reconstitution

Fabrazyme 35 mg
Reconstitute each vial of Fabrazyme 35 mg with 7.2 ml water for injections; avoid forceful impact of
water for injections on the powder and avoid foaming of the solution by mixing gently. The
reconstituted volume is 7.4 ml containing 5 mg enzyme/ml, and appears as a clear colourless solution.
The pH of the reconstituted solution is approximately 7.0.
Fabrazyme 5 mg
Reconstitute each vial of Fabrazyme 5 mg with 1.1 ml water for injections; avoid forceful impact of
water for injections on the powder and avoid foaming of the solution by mixing gently. The
reconstituted volume contains 5 mg enzyme/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 vials exhibiting particulates or discoloration. After reconstitution it is
recommended to promptly dilute the vials.
Any unused product or waste material should be disposed of in accordance with local requirements.
Dilution

The reconstituted solution contains 5 mg agalsidase beta per ml. Withdraw 7.0 ml (equal to 35 mg)
from the Fabrazyme 35 mg vial or 1.0 ml (equal to 5 mg) from the Fabrazyme 5 mg vial, of the
reconstituted solution from each vial and combine the withdrawn volumes. Then dilute the combined
volumes with 0.9% sodium chloride intravenous solution to a recommended final volume of 500 ml.
Mix the infusion solution gently.
Administration

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.


Manufacturer :
Genzyme Corporation, MA USA
Importer and License Holder:
Genzyme Israel Ltd.
P.O. Box 1188, Kfar-Saba, 44111 Israel
Tel: 1-800-412222; 09-7666640
License number:
Fabrazyme 35 mg: 124.94.30313.00
Fabrazyme 5 mg: xxx.xxx.31079.00

Source: http://www.genzyme.co.il/uploadimages/FabrazymePhysicianLeaflet.pdf