ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
VPRIV 200 Units powder for solution for infusion
2.
One vial contains 200 Units* of velaglucerase alfa.
After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.
*An enzyme unit is defined as the amount of enzyme that is required to convert one micromole of
p-nitrophenyl β-D-glucopyranoside to p-nitrophenol per minute at 37ºC.
Velaglucerase alfa is produced in an HT-1080 human fibroblast cell line by recombinant DNA
technology.
Excipients:
One vial contains 6.07 mg sodium.
For a full list of excipients, see section 6.1.
3.
Powder for solution for infusion.
White to off-white powder.
4.
VPRIV is indicated for long-term enzyme replacement therapy (ERT) in patients with type 1 Gaucher
disease.
VPRIV treatment should be supervised by a physician experienced in the management of patients with
Gaucher disease. Home administration under the supervision of a healthcare professional may be
considered only for patients who have received at least three infusions and were tolerating their
infusions well.
Posology
The recommended dose is 60 Units/kg administered every other week.
Dose adjustments can be made on an individual basis based on achievement and maintenance of
therapeutic goals. Clinical studies have evaluated doses ranging from 15 to 60 Units/kg every other
week. Doses higher than 60 Units/kg have not been studied.
Special populations
Current enzyme replacement therapy
Patients currently treated with imiglucerase enzyme replacement therapy for type 1 Gaucher disease
may be switched to VPRIV, using the same dose and frequency.
2
Renal or hepatic impairment
No dosing adjustment is recommended in patients with renal or hepatic impairment based on current
knowledge of the pharmacokinetics and pharmacodynamics of velaglucerase alfa. See section 5.2.
Elderly (≥65 years old)
Four of the 94 patients (5%) who received velaglucerase alfa during clinical studies were age 65 years
or older. The limited data do not indicate a need for a dose adjustment in this age group.
Paediatric population
Twenty of the 94 patients (21%) who received velaglucerase alfa during clinical studies were in the
paediatric and adolescent age range (4 to ≤17 years). The safety and efficacy profiles were similar
between paediatric and adult patients. See section 5.1 for further information.
Method of administration
For intravenous infusion use only.
To be administered as a 60-minute intravenous infusion.
Must be administered through a 0.22 µm filter.
For instructions on reconstitution and dilution of VPRIV, see section 6.6 and the end of the leaflet.
Severe allergic reaction to the active substance or to any of the excipients.
Hypersensitivity
Hypersensitivity reactions have been reported in patients in clinical studies. As with any intravenous
protein medicinal product, hypersensitivity reactions are possible. Therefore, appropriate medical
support should be readily available when velaglucerase alfa is administered. If a severe reaction
occurs, current medical standards for emergency treatment are to be followed.
Treatment should be approached with caution in patients who have exhibited symptoms of
hypersensitivity to other enzyme replacement therapy.
Infusion related-reactions
Infusion-related reactions were the most commonly observed adverse reactions in patients treated in
clinical studies. Most of the infusion-related reactions were mild. The most commonly observed
symptoms of infusion-related reactions were: headache, dizziness, hypotension, hypertension, nausea,
fatigue/asthenia, and pyrexia/body temperature increased. In treatment-naïve patients, the majority of
infusion-related reactions occurred during the first 6 months of treatment.
The management of infusion-related reactions should be based on the severity of the reaction, and
include slowing the infusion rate, treatment with medicinal products such as antihistamines,
antipyretics and/or corticosteroids, and/or stopping and resuming treatment with increased infusion
time.
Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those
cases where symptomatic treatment was required. Patients were not routinely pre-medicated prior to
infusion of velaglucerase alfa during clinical studies.
Immunogenicity
Antibodies may play a role in treatment-related reactions found with the use of velaglucerase alfa. To
further evaluate the relationship, in cases of severe infusion-related reactions and in cases of lack or
loss of effect patients should be tested for the presence of antibodies and the results reported to the
company.
In the clinical trials, one of 94 (1%) patients developed IgG-class antibodies to velaglucerase alfa. In
3
this one event, the antibodies were determined to be neutralising in an
in vitro
assay. No infusion-
related reactions were reported for this patient. No patients developed IgE antibodies to velaglucerase
alfa.
Sodium
This medicinal product contains 6.07 mg sodium per vial. To be taken into consideration by patients
on a controlled sodium diet.
No interaction studies have been performed.
Women of child bearing potential
Patients who have Gaucher disease and become pregnant may experience a period of increased disease
activity during pregnancy and the puerperium. A risk-benefit assessment is required for each
pregnancy. Close monitoring of the pregnancy and clinical manifestations of Gaucher disease is
necessary for the individualisation of therapy.
Pregnancy
There are no data from the use of velaglucerase alfa in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development. Caution should be exercised
when prescribing to pregnant women.
Breast-feeding
There are no data from studies in breast-feeding women. It is not known whether velaglucerase alfa is
excreted in human milk. Because many active substances are excreted in human milk, caution should
be exercised when prescribing to a breast-feeding woman.
Fertility
Animal studies show no evidence of impaired fertility.
VPRIV has no or negligible influence on the ability to drive or use machines.
The data described below reflect exposure of 94 patients with type 1 Gaucher disease who received
velaglucerase alfa at doses ranging from 15 to 60 Units/kg every other week in 5 clinical studies.
Fifty-four patients were naïve to ERT and 40 patients switched from imiglucerase to VPRIV. Patients
were between 4 and 71 years old at the time of first treatment with VPRIV, and included 46 male and
48 female patients.
The most serious adverse reactions in patients in clinical trials were hypersensitivity reactions.
The most common adverse reactions were infusion-related reactions. The most commonly observed
symptoms of infusion-related reactions were: headache, dizziness, hypotension, hypertension, nausea,
fatigue/asthenia, and pyrexia/body temperature increased (see section 4.4 for further information). The
only adverse reaction leading to discontinuation of treatment was an infusion-related reaction.
Adverse reactions reported in patients with type 1 Gaucher disease are listed in Table 1. Information
is presented by system organ class and frequency according to MedDRA convention. Frequency is
defined as very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping,
adverse reactions are presented in order of decreasing seriousness.
4
Table 1: Adverse reactions reported with VPRIV observed in patients with type 1 Gaucher
disease
System organ class
Adverse reaction
Very common
Common
Immune system disorders
hypersensitivity reactions
Nervous system disorders headache, dizziness
Cardiac disorders
tachycardia
Vascular disorders
hypertension, hypotension, flushing
Gastrointestinal disorders
abdominal pain/abdominal pain
upper, nausea
Skin and subcutaneous
tissue disorders
rash, urticaria
Musculoskeletal and
connective tissue
disorders
bone pain, arthralgia, back pain
General disorders and
administration site
conditions
infusion-related reaction,
asthenia/fatigue, pyrexia/body
temperature increased
Investigations
activated partial thromboplastin time
prolonged, neutralizing antibody
positive
Paediatric population
The safety profile of VPRIV in clinical studies involving children and adolescents aged 4 to ≤17 years
was similar to that observed in adult patients.
There is no experience with overdose of velaglucerase alfa. The maximum dose of velaglucerase alfa
in clinical studies was 60 Units/kg. See section 4.4.
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products – enzymes, ATC code:
A16AB10.
Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene which
results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This enzymatic deficiency
causes an accumulation of glucocerebroside primarily in macrophages, giving rise to foam cells or
"Gaucher cells". In this lysosomal storage disorder (LSD), clinical features are reflective of the
distribution of Gaucher cells in the liver, spleen, bone marrow, skeleton, and lungs. The accumulation
of glucocerebroside in the liver and spleen leads to organomegaly. Bone involvement results in
skeletal abnormalities and deformities as well as bone pain crises. Deposits in the bone marrow and
splenic sequestration lead to clinically significant anaemia and thrombocytopenia.
The active substance of VPRIV is velaglucerase alfa, which is produced by gene activation technology
in a human cell line. Velaglucerase alfa is a glycoprotein. The monomer is approximately 63 kDa, has
497 amino acids, and the same amino acid sequence as the naturally occurring human enzyme,
glucocerebrosidase. There are 5 potential N-linked glycosylation sites, four of which are occupied.
5
Velaglucerase alfa is manufactured to contain predominantly high-mannose-type glycans to facilitate
internalisation of the enzyme by the phagocytic target cells via the mannose receptor.
Velaglucerase alfa supplements or replaces beta-glucocerebrosidase, the enzyme that catalyzes the
hydrolysis of glucocerebroside to glucose and ceramide in the lysosome, reducing the amount of
accumulated glucocerebroside and correcting the pathophysiology of Gaucher disease. Velaglucerase
alfa increases haemoglobin concentration and platelet counts and reduces liver and spleen volumes in
patients with type 1 Gaucher disease.
In Studies 025EXT and 034, patients were offered home therapy. In Study 025EXT, 7 of 10 patients
received home therapy at least once during 60 months of treatment. In Study 034, 25 of 40 patients
received home therapy at least once during the 12-month study.
Clinical efficacy and safety
Studies in treatment naïve patients
Study 025 was a 9 month, open-label study in 12 adult (≥18 years) patients who were naïve to ERT
(defined as having not been treated with ERT for at least 12 months prior to study entry). VPRIV was
initially administered in a dose-escalating fashion in the first 3 patients (15, 30, 60 Units/kg) and the 9
remaining patients began treatment with 60 Units/kg.
Clinically meaningful improvements from baseline were observed in haemoglobin concentration and
platelet counts as early as 3 months and in liver and spleen volumes at both 6 months and 9 months
following the initiation of treatment with VPRIV.
Ten patients who completed Study 025 enrolled in an open-label extension study (025EXT). After a
minimum of 12 months of continuous treatment with VPRIV, all patients qualified to have the dose of
VPRIV reduced in a step-wise fashion from 60 to 30 Units/kg after achieving at least 2 of the 4 “Year
1” therapeutic goals of ERT for type 1 Gaucher disease. Patients received doses ranging from 30 to
60 Units/kg (median dose 35 Units/kg) every other week for up to 60 months (5 years). Sustained
clinical activity continued to be demonstrated during 5 years of treatment as observed by
improvements in haemoglobin concentrations and platelet counts and reduced liver and spleen
volumes.
Study 032 was a 12-month, randomized, double-blind, parallel-group efficacy study in 25 patients
aged 2 years and older who were naïve to ERT (defined as having not been treated with ERT for at
least 30 months prior to study entry). Patients were required to have Gaucher disease-related anaemia
and either thrombocytopenia or organomegaly. Patients were randomized to receive VPRIV at a dose
of either 45 Units/kg (N=13) or 60 Units/kg (N=12) every other week.
Velaglucerase alfa 60 Units/kg given IV every other week demonstrated clinically meaningful
increases from baseline in mean haemoglobin concentration (+2.4 g/dl) and platelet count
(+50.9 x 10
9
/l), liver volume was reduced from 1.46 to 1.22 times normal (mean reduction of 17%)
and spleen volume was reduced from 14.0 to 5.75 times normal (mean reduction of 50%). Meaningful
increases from baseline were observed in the 45 Units/kg dose group in haemoglobin concentration
(+2.4 g/dl) and platelet count (+40.9 x 10
9
/l), liver volume was reduced from 1.40 to 1.24 times normal
(mean reduction of 6%) and spleen volume was reduced from 14.5 to 9.50 times normal (mean
reduction of 40%).
Study 039 was a 9-month, randomized, double-blind, non-inferiority, active-comparator (imiglucerase)
controlled, parallel-group efficacy study in 34 patients aged 2 years and older who were naïve to ERT
(defined as having not been treated with ERT for at least 12 months prior to study entry). Patients
were required to have Gaucher disease-related anaemia and either thrombocytopenia or organomegaly.
Patients received either 60 Units/kg of VPRIV (N=17) or 60 Units/kg of imiglucerase (N=17) every
other week.
The mean absolute increase from baseline in haemoglobin concentrations was 1.624 g/dl (±0.223 SE)
6
following 9 months of treatment with VPRIV. This increase in haemoglobin concentration was
demonstrated to be clinically and statistically non-inferior to imiglucerase (mean treatment difference
of change from baseline to 9 months [VPRIV – imiglucerase]: 0.135 g/dl). There were no statistically
significant differences between VPRIV and imiglucerase in changes in platelet counts and liver and
spleen volumes after 9 months of VPRIV treatment, and in the time to first haemoglobin response
(defined as 1 g/dl increase from baseline).
Study in patients switching from imiglucerase treatment to VPRIV
Study 034 was a 12-month, open-label safety study in 40 patients aged 2 years and older who had been
receiving treatment with imiglucerase at doses ranging from 15 to 60 Units/kg for a minimum of 30
consecutive months. Patients were required to have a stable dose of imiglucerase for at least 6 months
prior to study enrolment. Treatment with VPRIV was administered as the same number of units and
regimen as their imiglucerase dose. Haemoglobin concentration and platelet counts were evaluated as
changes from baseline, which was defined as the end of the patient’s treatment with imiglucerase.
In patients who switched from imiglucerase to VPRIV, haemoglobin concentrations and platelet
counts were sustained at therapeutic levels through 12 months of treatment.
Paediatric population
Use in the age group 4 to 17 is supported by evidence from controlled studies in adults and paediatric
[20 of 94 (21%)] patients. The safety and efficacy profiles were similar between paediatric and adult
patients. The studies allowed the inclusion of patients 2 years and older and the safety and efficacy
profiles are expected to be similar down to the age of 2 years. However, no data are available for
children under the age of 4 years.
The European Medicines Agency has waived the obligation to submit the results of studies with
VPRIV in all subsets of the paediatric population with type 2 Gaucher disease and has deferred the
obligation to submit the results of studies with VPRIV in one or more subsets of the paediatric
population in Gaucher disease type 1 and 3, as per the PIP decision.
5.2 Pharmacokinetic properties
Velaglucerase alfa serum concentrations rose rapidly for the first 20 minutes of the 60-minute infusion
before leveling off, and C
max
was typically attained between 40 and 60 minutes after the start of the
infusion. After the end of the infusion, velaglucerase alfa serum concentrations fell rapidly in a
monophasic or biphasic fashion with a mean t
1/2
ranging from 5 to 12 minutes at doses of 15, 30, 45,
and 60 Units/kg.
Velaglucerase alfa exhibited an approximately linear (i.e. first-order) pharmacokinetic profile, and
C
max
and AUC increased approximately proportional to the dose over the dose range 15 to 60 Units/kg.
The steady state volume of distribution was approximately 10% of the body weight. The high
clearance of velaglucerase alfa from serum (mean 6.7 to 7.6 ml/min/kg) is consistent with the rapid
uptake of velaglucerase alfa into macrophages via mannose receptors.
The range of velaglucerase alfa clearance in paediatric patients (N=7, age range 4 to 17 years) was
contained within the range of clearance values in adult patients (N=15, age range 19 to 62 years).
Additionally, there were no apparent pharmacokinetic differences between male and female patients
with type 1 Gaucher disease.
None of the subjects in the pharmacokinetic studies were positive for anti-velaglucerase alfa antibodies
on the days of pharmacokinetic evaluation. Therefore, it was not possible to evaluate the effect of
antibody response on the pharmacokinetic profile of velaglucerase alfa.
7
5.3
Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, and toxicity to reproduction and development.
6.
6.1 List of excipients
Sucrose
Sodium citrate dihydrate (E331)
Citric acid monohydrate (E330)
Polysorbate 20
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
18 months
Reconstituted and diluted solution for infusion:
Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C under
protection from light.
From a microbiological point of view, the medicinal 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
must not exceed 24 hours at 2°C to 8°C.
6.4
Special precautions for storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted and/or diluted medicinal product, see section 6.3.
6.5
Nature and contents of container
200 Units of velaglucerase alfa in a 5 ml vial (type I glass) with a stopper (fluoro-resin coated butyl
rubber), one piece seal, and flip-off cap. Pack sizes of 1, 5 and 25 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
VPRIV requires reconstitution and dilution, and is intended for intravenous infusion only. VPRIV is
for single-use only and is administered through a 0.22 µm filter.
Use aseptic technique.
8
Prepare VPRIV as follows:
1. The number of vials to be reconstituted is determined based on the individual patient’s weight
and the prescribed dose.
2. The required vials are removed from the refrigerator. Each 200 Units vial is reconstituted with
2.2 ml of sterile water for injections.
3. Upon reconstitution, mix vials gently. Do not shake. Each vial will contain an extractable
volume of 2.0 ml (100 Units/ml).
4. Prior to further dilution, visually inspect the solution in the vials; the solution should be clear to
slightly opalescent and colourless; do not use if the solution is discoloured or if foreign
particulate matter is present.
5. The calculated volume of medicinal product is withdrawn from the appropriate number of vials
and the total volume required is diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) solution
for infusion. Mix gently. Do not shake. The infusion should be initiated within 24 hours from
the time of reconstitution.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
8.
EU/1/10/646/001
EU/1/10/646/003
EU/1/10/646/004
9.
Date of first authorisation: 26/08/2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
9
1.
VPRIV 400 Units powder for solution for infusion
2.
One vial contains 400 Units* of velaglucerase alfa.
After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.
*An enzyme unit is defined as the amount of enzyme that is required to convert one micromole of
p-nitrophenyl β-D-glucopyranoside to p-nitrophenol per minute at 37ºC.
Velaglucerase alfa is produced in an HT-1080 human fibroblast cell line by recombinant DNA
technology.
Excipients:
One vial contains 12.15 mg sodium.
For a full list of excipients, see section 6.1.
3.
Powder for solution for infusion.
White to off-white powder.
4.
VPRIV is indicated for long-term enzyme replacement therapy (ERT) in patients with type 1 Gaucher
disease.
VPRIV treatment should be supervised by a physician experienced in the management of patients with
Gaucher disease. Home administration under the supervision of a healthcare professional may be
considered only for patients who have received at least three infusions and were tolerating their
infusions well.
Posology
The recommended dose is 60 Units/kg administered every other week.
Dose adjustments can be made on an individual basis based on achievement and maintenance of
therapeutic goals. Clinical studies have evaluated doses ranging from 15 to 60 Units/kg every other
week. Doses higher than 60 Units/kg have not been studied.
Special populations
Current enzyme replacement therapy
Patients currently treated with imiglucerase enzyme replacement therapy for type 1 Gaucher disease
may be switched to VPRIV, using the same dose and frequency.
10
Renal or hepatic impairment
No dosing adjustment is recommended in patients with renal or hepatic impairment based on current
knowledge of the pharmacokinetics and pharmacodynamics of velaglucerase alfa. See section 5.2.
Elderly (≥65 years old)
Four of the 94 patients (5%) who received velaglucerase alfa during clinical studies were age 65 years
or older. The limited data do not indicate a need for a dose adjustment in this age group.
Paediatric population
Twenty of the 94 patients (21%) who received velaglucerase alfa during clinical studies were in the
paediatric and adolescent age range (4 to ≤17 years). The safety and efficacy profiles were similar
between paediatric and adult patients. See section 5.1 for further information.
Method of administration
For intravenous infusion use only.
To be administered as a 60-minute intravenous infusion.
Must be administered through a 0.22 µm filter.
For instructions on reconstitution and dilution of VPRIV, see section 6.6 and the end of the leaflet.
Severe allergic reaction to the active substance or to any of the excipients.
Hypersensitivity
Hypersensitivity reactions have been reported in patients in clinical studies. As with any intravenous
protein medicinal product, hypersensitivity reactions are possible. Therefore, appropriate medical
support should be readily available when velaglucerase alfa is administered. If a severe reaction
occurs, current medical standards for emergency treatment are to be followed.
Treatment should be approached with caution in patients who have exhibited symptoms of
hypersensitivity to other enzyme replacement therapy.
Infusion related-reactions
Infusion-related reactions were the most commonly observed adverse reactions in patients treated in
clinical studies. Most of the infusion-related reactions were mild. The most commonly observed
symptoms of infusion-related reactions were: headache, dizziness, hypotension, hypertension, nausea,
fatigue/asthenia, and pyrexia/body temperature increased. In treatment-naïve patients, the majority of
infusion-related reactions occurred during the first 6 months of treatment.
The management of infusion-related reactions should be based on the severity of the reaction, and
include slowing the infusion rate, treatment with medicinal products such as antihistamines,
antipyretics and/or corticosteroids, and/or stopping and resuming treatment with increased infusion
time.
Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those
cases where symptomatic treatment was required. Patients were not routinely pre-medicated prior to
infusion of velaglucerase alfa during clinical studies.
Immunogenicity
Antibodies may play a role in treatment-related reactions found with the use of velaglucerase alfa. To
further evaluate the relationship, in cases of severe infusion-related reactions and in cases of lack or
loss of effect patients should be tested for the presence of antibodies and the results reported to the
company.
In the clinical trials, one of 94 (1%) patients developed IgG-class antibodies to velaglucerase alfa. In
11
this one event, the antibodies were determined to be neutralising in an in vitro assay. No infusion-
related reactions were reported for this patient. No patients developed IgE antibodies to velaglucerase
alfa.
Sodium
This medicinal product contains 12.15 mg sodium per vial. To be taken into consideration by patients
on a controlled sodium diet.
No interaction studies have been performed.
Women of child bearing potential
Patients who have Gaucher disease and become pregnant may experience a period of increased disease
activity during pregnancy and the puerperium. A risk-benefit assessment is required for each
pregnancy. Close monitoring of the pregnancy and clinical manifestations of Gaucher disease is
necessary for the individualisation of therapy.
Pregnancy
There are no data from the use of velaglucerase alfa in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development. Caution should be exercised
when prescribing to pregnant women.
Breast-feeding
There are no data from studies in breast-feeding women. It is not known whether velaglucerase alfa is
excreted in human milk. Because many active substances are excreted in human milk, caution should
be exercised when prescribing to a breast-feeding woman.
Fertility
Animal studies show no evidence of impaired fertility.
VPRIV has no or negligible influence on the ability to drive or use machines.
The data described below reflect exposure of 94 patients with type 1 Gaucher disease who received
velaglucerase alfa at doses ranging from 15 to 60 Units/kg every other week in 5 clinical studies.
Fifty-four patients were naïve to ERT and 40 patients switched from imiglucerase to VPRIV. Patients
were between 4 and 71 years old at the time of first treatment with VPRIV, and included 46 male and
48 female patients.
The most serious adverse reactions in patients in clinical trials were hypersensitivity reactions.
The most common adverse reactions were infusion-related reactions. The most commonly observed
symptoms of infusion-related reactions were: headache, dizziness, hypotension, hypertension, nausea,
fatigue/asthenia, and pyrexia/body temperature increased (see section 4.4 for further information). The
only adverse reaction leading to discontinuation of treatment was an infusion-related reaction.
Adverse reactions reported in patients with type 1 Gaucher disease are listed in Table 1. Information is
presented by system organ class and frequency according to MedDRA convention. Frequency is
12
defined as very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping,
adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse reactions reported with VPRIV observed in patients with type 1 Gaucher
disease
System organ class
Adverse reaction
Very common
Common
Immune system disorders
hypersensitivity reactions
Nervous system disorders headache, dizziness
Cardiac disorders
tachycardia
Vascular disorders
hypertension, hypotension, flushing
Gastrointestinal disorders
abdominal pain/abdominal pain upper,
nausea
Skin and subcutaneous
tissue disorders
rash, urticaria
Musculoskeletal and
connective tissue
disorders
bone pain, arthralgia, back
pain
General disorders and
administration site
conditions
infusion-related reaction,
asthenia/fatigue, pyrexia/body
temperature increased
Investigations
activated partial thromboplastin time
prolonged, neutralizing antibody positive
Paediatric population
The safety profile of VPRIV in clinical studies involving children and adolescents aged 4 to ≤17 years
was similar to that observed in adult patients.
There is no experience with overdose of velaglucerase alfa. The maximum dose of velaglucerase alfa
in clinical studies was 60 Units/kg. See section 4.4.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products – enzymes, ATC code:
A16AB10.
Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene which
results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This enzymatic deficiency
causes an accumulation of glucocerebroside primarily in macrophages, giving rise to foam cells or
"Gaucher cells". In this lysosomal storage disorder (LSD), clinical features are reflective of the
distribution of Gaucher cells in the liver, spleen, bone marrow, skeleton, and lungs. The accumulation
of glucocerebroside in the liver and spleen leads to organomegaly. Bone involvement results in
skeletal abnormalities and deformities as well as bone pain crises. Deposits in the bone marrow and
splenic sequestration lead to clinically significant anaemia and thrombocytopenia.
The active substance of VPRIV is velaglucerase alfa, which is produced by gene activation technology
in a human cell line. Velaglucerase alfa is a glycoprotein. The monomer is approximately 63 kDa, has
497 amino acids, and the same amino acid sequence as the naturally occurring human enzyme,
13
glucocerebrosidase. There are 5 potential N-linked glycosylation sites, four of which are occupied.
Velaglucerase alfa is manufactured to contain predominantly high-mannose-type glycans to facilitate
internalisation of the enzyme by the phagocytic target cells via the mannose receptor.
Velaglucerase alfa supplements or replaces beta-glucocerebrosidase, the enzyme that catalyzes the
hydrolysis of glucocerebroside to glucose and ceramide in the lysosome, reducing the amount of
accumulated glucocerebroside and correcting the pathophysiology of Gaucher disease. Velaglucerase
alfa increases haemoglobin concentration and platelet counts and reduces liver and spleen volumes in
patients with type 1 Gaucher disease.
In Studies 025EXT and 034, patients were offered home therapy. In Study 025EXT, 7 of 10 patients
received home therapy at least once during 60 months of treatment. In Study 034, 25 of 40 patients
received home therapy at least once during the 12-month study.
Clinical efficacy and safety
Studies in treatment naïve patients
Study 025 was a 9 month, open-label study in 12 adult (≥18 years) patients who were naïve to ERT
(defined as having not been treated with ERT for at least 12 months prior to study entry). VPRIV was
initially administered in a dose-escalating fashion in the first 3 patients (15, 30, 60 Units/kg) and the
9 remaining patients began treatment with 60 Units/kg.
Clinically meaningful improvements from baseline were observed in haemoglobin concentration and
platelet counts as early as 3 months and in liver and spleen volumes at both 6 months and 9 months
following the initiation of treatment with VPRIV.
Ten patients who completed Study 025 enrolled in an open-label extension study (025EXT). After a
minimum of 12 months of continuous treatment with VPRIV, all patients qualified to have the dose of
VPRIV reduced in a step-wise fashion from 60 to 30 Units/kg after achieving at least 2 of the 4 “Year
1” therapeutic goals of ERT for type 1 Gaucher disease. Patients received doses ranging from 30 to
60 Units/kg (median dose 35 Units/kg) every other week for up to 60 months (5 years). Sustained
clinical activity continued to be demonstrated during 5 years of treatment as observed by
improvements in haemoglobin concentrations and platelet counts and reduced liver and spleen
volumes.
Study 032 was a 12-month, randomized, double-blind, parallel-group efficacy study in 25 patients
aged 2 years and older who were naïve to ERT (defined as having not been treated with ERT for at
least 30 months prior to study entry). Patients were required to have Gaucher disease-related anaemia
and either thrombocytopenia or organomegaly. Patients were randomized to receive VPRIV at a dose
of either 45 Units/kg (N=13) or 60 Units/kg (N=12) every other week.
Velaglucerase alfa 60 Units/kg given IV every other week demonstrated clinically meaningful
increases from baseline in mean haemoglobin concentration (+2.4 g/dl) and platelet count
(+50.9 x 10
9
/l), liver volume was reduced from 1.46 to 1.22 times normal (mean reduction of 17%)
and spleen volume was reduced from 14.0 to 5.75 times normal (mean reduction of 50%). Meaningful
increases from baseline were observed in the 45 Units/kg dose group in haemoglobin concentration
(+2.4 g/dl) and platelet count (+40.9 x 10
9
/l), liver volume was reduced from 1.40 to 1.24 times normal
(mean reduction of 6%) and spleen volume was reduced from 14.5 to 9.50 times normal (mean
reduction of 40%).
Study 039 was a 9-month, randomized, double-blind, non-inferiority, active-comparator (imiglucerase)
controlled, parallel-group efficacy study in 34 patients aged 2 years and older who were naïve to ERT
(defined as having not been treated with ERT for at least 12 months prior to study entry). Patients
were required to have Gaucher disease-related anaemia and either thrombocytopenia or organomegaly.
Patients received either 60 Units/kg of VPRIV (N=17) or 60 Units/kg of imiglucerase (N=17) every
other week.
14
The mean absolute increase from baseline in haemoglobin concentrations was 1.624 g/dl (±0.223 SE)
following 9 months of treatment with VPRIV. This increase in haemoglobin concentration was
demonstrated to be clinically and statistically non-inferior to imiglucerase (mean treatment difference
of change from baseline to 9 months [VPRIV – imiglucerase]: 0.135 g/dl). There were no statistically
significant differences between VPRIV and imiglucerase in changes in platelet counts and liver and
spleen volumes after 9 months of VPRIV treatment, and in the time to first haemoglobin response
(defined as 1 g/dl increase from baseline).
Study in patients switching from imiglucerase treatment to VPRIV
Study 034 was a 12-month, open-label safety study in 40 patients aged 2 years and older who had been
receiving treatment with imiglucerase at doses ranging from 15 to 60 Units/kg for a minimum of
30 consecutive months. Patients were required to have a stable dose of imiglucerase for at least
6 months prior to study enrolment. Treatment with VPRIV was administered as the same number of
units and regimen as their imiglucerase dose. Haemoglobin concentration and platelet counts were
evaluated as changes from baseline, which was defined as the end of the patient’s treatment with
imiglucerase.
In patients who switched from imiglucerase to VPRIV, haemoglobin concentrations and platelet
counts were sustained at therapeutic levels through 12 months of treatment.
Paediatric population
Use in the age group 4 to 17 is supported by evidence from controlled studies in adults and paediatric
[20 of 94 (21%)] patients. The safety and efficacy profiles were similar between paediatric and adult
patients. The studies allowed the inclusion of patients 2 years and older and the safety and efficacy
profiles are expected to be similar down to the age of 2 years. However, no data are available for
children under the age of 4 years.
The European Medicines Agency has waived the obligation to submit the results of studies with
VPRIV in all subsets of the paediatric population with type 2 Gaucher disease and has deferred the
obligation to submit the results of studies with VPRIV in one or more subsets of the paediatric
population in Gaucher disease type 1 and 3, as per the PIP decision.
5.2 Pharmacokinetic properties
Velaglucerase alfa serum concentrations rose rapidly for the first 20 minutes of the 60-minute infusion
before leveling off, and C
max
was typically attained between 40 and 60 minutes after the start of the
infusion. After the end of the infusion, velaglucerase alfa serum concentrations fell rapidly in a
monophasic or biphasic fashion with a mean t
1/2
ranging from 5 to 12 minutes at doses of 15, 30, 45,
and 60 Units/kg.
Velaglucerase alfa exhibited an approximately linear (i.e. first-order) pharmacokinetic profile, and
C
max
and AUC increased approximately proportional to the dose over the dose range 15 to 60 Units/kg.
The steady state volume of distribution was approximately 10% of the body weight. The high
clearance of velaglucerase alfa from serum (mean 6.7 to 7.6 ml/min/kg) is consistent with the rapid
uptake of velaglucerase alfa into macrophages via mannose receptors.
The range of velaglucerase alfa clearance in paediatric patients (N=7, age range 4 to 17 years) was
contained within the range of clearance values in adult patients (N=15, age range 19 to 62 years).
Additionally, there were no apparent pharmacokinetic differences between male and female patients
with type 1 Gaucher disease.
None of the subjects in the pharmacokinetic studies were positive for anti-velaglucerase alfa antibodies
on the days of pharmacokinetic evaluation. Therefore, it was not possible to evaluate the effect of
antibody response on the pharmacokinetic profile of velaglucerase alfa.
15
5.3 P
reclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, and toxicity to reproduction and development.
6.
6.1 List of excipients
Sucrose
Sodium citrate dihydrate (E331)
Citric acid monohydrate (E330)
Polysorbate 20
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
3 years.
Reconstituted and diluted solution for infusion:
Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C under
protection from light.
From a microbiological point of view, the medicinal 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
must not exceed 24 hours at 2°C to 8°C.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted and/or diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
400 Units of velaglucerase alfa in a 20 ml vial (type I glass) with a stopper (fluoro-resin coated butyl
rubber), one piece seal, and flip-off cap. Pack sizes of 1, 5 and 25 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
VPRIV requires reconstitution and dilution, and is intended for intravenous infusion only. VPRIV is
for single-use only and is administered through a 0.22 µm filter.
Use aseptic technique.
16
Prepare VPRIV as follows:
1.
The number of vials to be reconstituted is determined based on the individual patient’s weight
and the prescribed dose.
2.
The required vials are removed from the refrigerator. Each 400 Units vial is reconstituted with
4.3 ml of sterile water for injections.
3.
Upon reconstitution, mix vials gently. Do not shake. Each vial will contain an extractable
volume of 4.0 ml (100 Units/ml).
4.
Prior to further dilution, visually inspect the solution in the vials; the solution should be clear to
slightly opalescent and colourless; do not use if the solution is discoloured or if foreign
particulate matter is present.
5.
The calculated volume of medicinal product is withdrawn from the appropriate number of vials
and the total volume required is diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) solution
for infusion. Mix gently. Do not shake. The infusion should be initiated within 24 hours from
the time of reconstitution.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
8.
EU/1/10/646/002
EU/1/10/646/005
EU/1/10/646/006
9.
Date of first authorisation: 26/08/2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
17
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
18
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Cell Bank manufacture and storage.
Shire Human Genetic Therapies, Inc
700 Main Street, Cambridge, Massachusetts 02139
United States of America
Name and address of the manufacturer responsible for batch release
Shire Human Genetic Therapies AB
Aldermansgata 13
227 64 Lund
Sweden
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription. (See Annex I: Summary of Product
Characteristics, 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 5.10 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 6.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
19
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMA.
20
ANNEX III
LABELLING AND PACKAGE LEAFLET
21
A. LABELLING
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE
PACKAGING
OUTER CARTON – 200 UNITS (single vial pack)
1.
VPRIV 200 Units powder for solution for infusion
velaglucerase alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial contains 200 Units of velaglucerase alfa.
After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.
3.
LIST OF EXCIPIENTS
Sucrose
Sodium citrate dihydrate
Citric acid monohydrate
Polysorbate 20
Contains sodium, see leaflet for further information.
4.
Powder for solution for infusion
1 vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
23
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
EU/1/10/646/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE
PACKAGING
OUTER CARTON – 200 UNITS (5 vial pack)
1.
VPRIV 200 Units powder for solution for infusion
velaglucerase alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial contains 200 Units of velaglucerase alfa.
After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.
3.
LIST OF EXCIPIENTS
Sucrose
Sodium citrate dihydrate
Citric acid monohydrate
Polysorbate 20
Contains sodium, see leaflet for further information.
4.
Powder for solution for infusion
5 vials
Not for individual sale
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
25
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
EU/1/10/646/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND IMMEDIATE
PACKAGING
OUTER CARTON – 200 UNITS (25 vial pack)
1.
VPRIV 200 Units powder for solution for infusion
velaglucerase alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial contains 200 Units of velaglucerase alfa.
After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.
3.
LIST OF EXCIPIENTS
Sucrose
Sodium citrate dihydrate
Citric acid monohydrate
Polysorbate 20
Contains sodium, see leaflet for further information.
4.
Powder for solution for infusion
25 vials
Not for individual sale
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
27
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
EU/1/10/646/004
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
28
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL – 200 UNITS
1.
VPRIV 200 U powder for solution for infusion
velaglucerase alfa
Intravenous use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
200 Units
6.
OTHER
29
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON – 400 UNITS (single vial pack)
1.
VPRIV 400 Units powder for solution for infusion
velaglucerase alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial contains 400 Units of velaglucerase alfa.
After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.
3.
LIST OF EXCIPIENTS
Sucrose
Sodium citrate dihydrate
Citric acid monohydrate
Polysorbate 20
Contains sodium, see leaflet for further information.
4.
Powder for solution for infusion
1 vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
30
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
EU/1/10/646/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON – 400 UNITS (5 vial pack)
1.
VPRIV 400 Units powder for solution for infusion
velaglucerase alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial contains 400 Units of velaglucerase alfa.
After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.
3.
LIST OF EXCIPIENTS
Sucrose
Sodium citrate dihydrate
Citric acid monohydrate
Polysorbate 20
Contains sodium, see leaflet for further information.
4.
Powder for solution for infusion
5 vials
Not for individual sale
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
32
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
EU/1/10/646/005
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
33
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON – 400 UNITS (25 vial pack)
1.
VPRIV 400 Units powder for solution for infusion
velaglucerase alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial contains 400 Units of velaglucerase alfa.
After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.
3.
LIST OF EXCIPIENTS
Sucrose
Sodium citrate dihydrate
Citric acid monohydrate
Polysorbate 20
Contains sodium, see leaflet for further information.
4.
Powder for solution for infusion
25 vials
Not for individual sale
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
34
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
EU/1/10/646/006
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
35
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL – 400 UNITS
1.
VPRIV 400 U powder for solution for infusion
velaglucerase alfa
Intravenous use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
400 Units
6.
OTHER
36
B. PACKAGE LEAFLET
37
PACKAGE LEAFLET: INFORMATION FOR THE USER
VPRIV 200 Units powder for solution for infusion
VPRIV 400 Units powder for solution for infusion
velaglucerase alfa
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1. What VPRIV is and what it is used for
2. Before you use VPRIV
3. How to use VPRIV
4. Possible side effects
5.
How to store VPRIV
6.
Further information
1.
WHAT VPRIV IS AND WHAT IT IS USED FOR
VPRIV is a long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease
Gaucher disease is a genetic disorder caused by a missing or defective enzyme named
glucocerebrosidase. When this enzyme is missing or does not work properly, a substance called
glucocerebroside builds up inside cells in the body. The build-up of this material causes the signs and
symptoms found in Gaucher disease.
VPRIV is designed to replace the missing or defective enzyme, glucocerebrosidase, in patients with
Gaucher disease.
2.
BEFORE YOU USE VPRIV
Do not use VPRIV
-
If you are allergic (hypersensitive) to velaglucerase alfa or any of the other ingredients of
VPRIV.
Take special care with VPRIV
-
If you are treated with VPRIV, you may experience a side effect during or following the
infusion (see section 4, possible side effects). This is known as an infusion-related reaction and
can sometimes be severe.
-
Infusion-related reactions include dizziness, headache, nausea, low or high blood pressure,
tiredness, and fever. If you experience an infusion-related reaction,
you must tell your doctor
immediately
.
-
If you have an infusion-related reaction you may be given additional medicines to treat or help
prevent future reactions. These medicines may include antihistamines, antipyretics, and
corticosteroids.
-
If the infusion-related reaction is severe, your doctor will stop the intravenous infusion
immediately and start giving you appropriate medical treatment.
-
Most of the time you can still be given VPRIV even if you experience an infusion-related
reaction.
38
Tell your doctor if you have previously experienced an infusion-related reaction or allergic reaction
with other ERT for Gaucher disease.
Children
VPRIV should not be used in children under the age of 2 years.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy and breast-feeding
Gaucher disease may become more active in a woman during pregnancy and for a few weeks after
birth. Women with Gaucher disease who are considering pregnancy should talk with their doctor.
VPRIV has not been studied in pregnant women. Studies in animals do not show harmful effects from
VPRIV. Caution should be exercised when using VPRIV in pregnancy.
VPRIV has not been studied in women who are breast-feeding and it is not known whether VPRIV
appears in breast milk. However, VPRIV contains a protein that may be digested by the child.
Cautious use of VPRIV during breast feeding is recommended.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
VPRIV has no or negligible influence on your ability to drive or use machines.
Important information about one of the ingredients of VPRIV
Each 200 Units vial of this medicine contains 6.07 mg sodium. Each 400 Units vial of this medicine
contains 12.15 mg sodium. This should be taken into consideration by patients on a controlled sodium
diet.
3.
HOW TO USE VPRIV
VPRIV is only to be used under appropriate medical supervision of a doctor who is knowledgeable in
the treatment of Gaucher disease. VPRIV is given by a doctor or nurse by intravenous infusion.
Dose
The usual dose is 60 Units/kg given every other week.
If you are currently being treated for Gaucher disease with another ERT and your doctor wants to
change you to VPRIV, you can initially receive VPRIV at the same dose and frequency you had been
receiving the other ERT. In clinical studies, doses ranging from 15 Units/kg to 60 Units/kg have been
used.
Use in children and adolescents
VPRIV may be given to children and adolescents (2 to ≤17 years of age) at the same dose and
frequency as in adults.
Response to treatment
Your doctor will monitor your response to treatment and may change your dose (up or down) over
time.
If you are tolerating your infusions well in the clinic, your doctor or nurse may administer your
infusions at home.
39
Administration
VPRIV is supplied in a vial as a packed powder which is mixed with sterile water and further diluted
in sodium chloride 9 mg/ml (0.9%) solution prior to intravenous infusion.
After preparation, your doctor or nurse will give VPRIV to you through a drip into a vein (by
intravenous infusion) over a period of 60 minutes.
If you use more VPRIV than you should
If you feel ill whilst receiving the infusion, tell your doctor or nurse immediately.
If you forget to have VPRIV
If you have missed an infusion, please contact your doctor.
If you stop using VPRIV
Discuss changes in treatment with your doctor.
If you have any further questions on the use of this medicine, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, VPRIV can cause side effects, although not everybody gets them.
In studies with VPRIV, side effects were mainly seen while patients were being infused with the
medicine or shortly after (infusion-related reactions). These side effects have included headache,
dizziness, decreased blood pressure, increased blood pressure, nausea, tiredness, and fever/body
temperature increased. If you experience any side effect like these, please tell your doctor
immediately. The majority of these side effects were mild in intensity.
However a few patients experienced an allergic skin reaction such as severe rash or itching. A severe
allergic reaction, with difficulty breathing, swelling of the face, lips, tongue or throat occured. If any
of these happen tell your doctor immediately.
The frequency of possible side effects listed below is defined using the following convention:
Very common
affects more than 1 user in 10
Common
affects 1 to 10 users in 100
Uncommon
affects 1 to 10 users in 1,000
Rare
affects 1 to 10 users in 10,000
Very rare
affects less than 1 user in 10,000
Not known
frequency cannot be estimated from the available data.
In studies with VPRIV the following side effects were reported:
The very common side effects are:
-
headache
-
dizziness
-
bone pain
-
joint pain
-
back pain
-
infusion-related reaction
-
weakness/loss of strength/fatigue
-
fever/body temperature increased
The common side effects are:
-
abdominal pain/nausea
-
abnormal blood clotting
-
decreased blood pressure
40
-
increased blood pressure
-
flushing
-
rapid heart beat
-
rash/hives
-
serious allergic reactions
-
developing antibodies to VPRIV
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE VPRIV
Keep out of the reach and sight of children.
Do not use VPRIV after the expiry date which is stated on the outer carton and vial after ‘EXP’. The
expiry date refers to the last day of that month.
Store in the refrigerator (2ºC - 8ºC).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Do not use if the solution is discoloured or if foreign particles are present.
Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What VPRIV contains
-
The active substance is velaglucerase alfa.
One vial of VPRIV 200 Units powder contains 200 Units of velaglucerase alfa.
One vial of VPRIV 400 Units powder contains 400 Units of velaglucerase alfa.
After reconstitution the solution contains 100 Units of velaglucerase alfa per ml.
-
The other ingredients are sucrose, sodium citrate dihydrate, citric acid monohydrate, and
polysorbate 20.
What VPRIV looks like and contents of the pack
VPRIV is a powder for solution for infusion which comes as a white to off-white powder.
VPRIV 200 Units powder is packaged in a 5 ml glass vial, with 1, 5 or 25 vials per carton.
VPRIV 400 Units powder is packaged in a 20 ml glass vial, with 1, 5 or 25 vials per carton.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorization Holder
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
41
Manufacturer
Shire Human Genetic Therapies AB
Aldermansgata 13
227 64 Lund
Sweden
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
.
There are also links to other websites about rare diseases and treatments.
_________________________________________________________________________________
The following information is intended for medical or healthcare professionals only.
VPRIV is a powder for solution for infusion. VPRIV requires reconstitution and dilution and is
intended for intravenous infusion only. VPRIV is for single–use only and is administered through a
0.22 µm filter. Vials are single-use only. Discard any unused solution. VPRIV should not be infused
with other medicines in the same infusion as the compatibility in solution with other medicines has not
been evaluated. The total volume of infusion should be delivered over a period of 60 minutes.
Use aseptic technique.
Prepare VPRIV as follows:
1.
The number of vials to be reconstituted is determined based on the individual patient’s weight and
the prescribed dose.
2.
The required vials are removed from the refrigerator. Each vial is reconstituted using sterile water
for injections:
Vial size
Water for Injections
200 Units
2.2 ml
400 Units
4.3 ml
3.
Upon reconstitution, mix vials gently. Do not shake.
4.
Prior to dilution, visually inspect the solution in the vials; the solution should be clear to slightly
opalescent and colourless; do not use if the solution is discoloured, or if foreign particulate matter
is present.
5.
The calculated volume of medicinal product is withdrawn from the appropriate number of vials.
Some solution will remain in the vial:
Vial size
200 Units
Extractable volume
400 Units
4.0 ml
6.
The total volume required is diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) solution for
infusion. Mix gently. Do not shake. The infusion should be initiated within 24 hours from the
time of reconstitution.
From a microbiological point of view, the medicine should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
must not exceed 24 hours at 2°C to 8°C.
Medicines should not be disposed of via waste water or household waste. Any unused medicine or
waste material should be disposed of in accordance with local requirements
42
2.0 ml
Source: European Medicines Agency
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