ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Ablavar 0.25 mmol/ml solution for injection
2.
1 ml Ablavar solution for injection contains gadofosveset equivalent to 244 mg (0.25 mmol)
gadofosveset trisodium.
Each vial of 10 ml solution contains a total of 2.44 g (2.50 mmol) of gadofosveset trisodium.
Each vial of 15 ml solution contains a total of 3.66 g (3.75 mmol) of gadofosveset trisodium.
Each vial of 20 ml solution contains a total of 4.88 g (5.00 mmol) of gadofosveset trisodium.
Excipient
This medicinal product contains 6.3 mmol sodium (or 145 mg) per dose.
For a full list of excipients, see section 6.1.
3.
Solution for injection.
Clear, colourless to pale yellow liquid.
4.
This medicinal product is for diagnostic use only.
Ablavar is indicated for contrast-enhanced magnetic resonance angiography (CE-MRA) for
visualisation of abdominal or limb vessels in adults only, with suspected or known vascular disease.
This medicinal product should only be used by physicians experienced in the field of diagnostic
imaging.
Posology
Adults: 0.12 ml/kg body weight (equivalent to 0.03 mmol/kg)
Imaging time points
Dynamic imaging begins immediately upon injection. Steady state imaging can begin after the
dynamic scan has been completed. In clinical trials, imaging was completed up to approximately one
hour following injection.
No clinical information is available about repeated use of this medicinal product.
Special populations
Elderly (aged 65 years and above)
No dose adjustment is considered necessary. Caution should be exercised in elderly patients (see
section 4.4).
2
Renal impairment
Use of Ablavar should be avoided in patients with severe renal impairment
(GFR < 30 ml/min/1.73 m
2
) and in patients in the perioperative liver transplantation period unless the
diagnostic information is essential and not available with non-contrast enhanced magnetic resonance
imaging (MRI) (see section 4.4). If use of Ablavar cannot be avoided, the dose should not exceed
0.03 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack
of information on repeated administration, Ablavar injections should not be repeated unless the
interval between injections is at least 7 days.
Hepatic impairment
Dose adjustments in hepatic impairment are not necessary (see section 5.2).
Paediatric population
Use is not recommended in neonates, infants, children and adolescents. No clinical experience is yet
available for patients younger than 18.
Method of administration
This medicinal product should be administered as a single intravenous bolus injection, manually, or
by magnetic resonance injector (MR injector) over a period of time up to 30 seconds followed by a
25-30 ml normal saline flush.
Hypersensitivity to the active substance or to any of the excipients.
Diagnostic procedures involving the use of MRI contrast agents should be carried out under the
supervision of a physician with the prerequisite training and a thorough knowledge of the procedure
to be performed. Appropriate facilities should be available for coping with any complication of the
procedure, as well as for emergency treatment of potential severe reactions to the contrast agent itself.
The usual safety precautions for magnetic resonance imaging must be observed, e.g., exclusion of
cardiac pacemakers and ferromagnetic implants.
As with other contrast enhanced diagnostic procedures, post-procedure observation of the patient is
recommended, in particular in patients with a history of allergy, renal insufficiency, or adverse
reaction.
Hypersensitivity warning
The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid, or
cardiovascular reactions, or other idiosyncratic reactions should always be considered especially in
those patients with a known clinical hypersensitivity, previous reaction of contrast media, a history of
asthma, or other allergic disorders. Experience with other contrast media shows that the risk of
hypersensitivity reactions is higher in those patients. Delayed reactions may occur (after hours to
days).
Caution should also be exercised in the following cases:
Hypersensitivity reactions
If hypersensitivity reactions occur (see section 4.8), administration of the contrast medium must be
discontinued immediately and - if necessary - specific therapy instituted via a venous access. It is
therefore advisable to use a flexible indwelling cannula for intravenous contrast medium
administration. Due to the possibility of severe hypersensitivity reactions after intravenous contrast
administration, preparedness for institution of emergency measures is necessary, e.g., appropriate
medicinal products, an endotracheal tube, and a respirator should be at hand.
3
Renal impairment
Since gadofosveset is cleared from the body primarily by urinary excretion, caution should be
exercised in patients with impaired renal function (see section 4.2 and 5.2).
Prior to administration of Ablavar, it is recommended that all patients are screened for renal
dysfunction by obtaining laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some
gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment
(GFR < 30 ml/min/1.73 m
2
). Patients undergoing liver transplantation are at particular risk since the
incidence of acute renal failure is high in this group. As there is a possibility that NSF may occur with
Ablavar, it should therefore be avoided in patients with severe renal impairment and in patients in the
perioperative liver transplantation period unless the diagnostic information is essential and not
available with non-contrast enhanced MRI.
Haemodialysis shortly after Ablavar administration may be useful at removing Ablavar from the body.
There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in
patients not already undergoing haemodialysis.
Elderly
As the renal clearance of gadofosveset may be impaired in the elderly, it is particularly important to
screen patients aged 65 years and older for renal dysfunction.
Haemodialysis shortly after Ablavar administration in patients currently receiving haemodialysis may
be useful at removing Ablavar from the body. In a clinical trial it was shown that gadofosveset can
effectively be removed from the body by dialysis using high flux filters.
There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in
patients not already undergoing haemodialysis.
Electrocardiographic changes
Elevated levels of gadofosveset (e.g. repeated use in the short term [within 6-8 hours], or an
inadvertent overdose
>
0.05 mmol/kg) may be associated with mild QT prolongation (8.5 msec by
Fridericia correction). In the situation of elevated levels of gadofosveset or underlying QT
prolongation the patient should be carefully observed including cardiac monitoring.
Vascular stents
It has been shown in published studies that MRA in the presence of metallic stents causes artefacts.
The reliability of lumen visualisation in a stented vessel with Ablavar has not been evaluated.
Sodium
This medicine contains 6.3 mmol sodium (or 145 mg) per dose.
To be taken into consideration by patients on a controlled sodium diet.
Because gadofosveset is bound to albumin, an interaction with other plasma protein bound active
substances (e.g., ibuprofen and warfarin) is generally possible, i.e., a competition for the protein
binding site can occur. However, in a series of
in vitro
drug interaction studies (in 4.5 % human serum
albumin and human plasma), gadofosveset demonstrated no adverse interaction with digitoxin,
propranolol, verapamil, warfarin, phenprocoumon, ibuprofen, diazepam, ketoprofen, naproxen,
diclofenac and piroxicam at clinically relevant concentrations.
In vitro
studies using human liver
microsomes did not indicate any potential to inhibit the cytochrome P 450 enzyme system.
4
In a clinical study, it was shown that gadofosveset does not affect the unbound fraction of warfarin in
plasma. The anticoagulant activity of warfarin was not altered and the efficacy of the medicinal
product was not influenced.
Laboratory test interactions
In clinical trials using Ablavar, no specific trends were observed that would signify a potential
interaction of the medicinal product with laboratory test methods.
Pregnancy
There are no data from the use of Ablavar in pregnant women. Animal studies have shown
reproductive toxicity at repeated high doses (see section 5.3). Ablavar should not be used during
pregnancy unless the clinical condition of the woman requires use of the medicinal product.
Breast-feeding
Gadolinium containing contrast agents are excreted into breast milk in very small amounts (see
section 5.3). At clinical doses, no effects on the infant are anticipated due to the small amount
excreted in milk and poor absorption from the gut. Continuing breastfeeding or discontinuing Ablavar
for a period of 24 hours after administration should be at the discretion of the physician and breast-
feeding mother.
No studies on the effects on the ability to drive and use machine have been performed. Uncommonly,
dizziness or vision problems may occur with this medicine. If a patient experiences these effects
he/she should not drive or use machines
The most common adverse reactions were pruritus, paresthesia, headache, nausea, vasodilatation,
burning sensation and dysgeusia. Most of the adverse reactions were mild to moderate in intensity.
Most of the adverse reactions (80%) occurred within 2 hours. Delayed reactions (after hours to days)
may occur.
Clinical trial data
Based on clinical trial experience in more than 1,800 patients, the following adverse reactions have
been observed.
The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
System Organ
Class (MedDRA)
Common
(
1/100)
Uncommon
(
1/1,000 to
1/100)
Rare
(
1/10,000 to
1/1,000)
Infections and
infestations
Nasopharyngitis
Cellulitis
Urinary tract infection
Immune system
disorders
Hypersensitivity
Metabolism and
nutrition disorders
Hyperglycaemia
Electrolyte imbalance (incl.
Hypocalcemia)
Hyperkalemia
Hypokalemia
Hypernatremia
5
System Organ
Class (MedDRA)
Common
(
1/100)
Uncommon
(
1/1,000 to
1/100)
Rare
(
1/10,000 to
1/1,000)
Appetite decreased
Psychiatric
disorders
Anxiety
Confusion
Hallucination
Abnormal dreams
Nervous system
disorders
Headache
Paraesthesia
Dysgeusia
Burning sensation
Dizziness (excl. Vertigo)
Tremor
Hypoesthesia
Parosmia
Ageusia
Muscle contractions
involuntary
Eye disorders
Vision abnormal
Lacrimation increased
Abnormal sensation in eye
Asthenopia
Ear and labyrinth
disorders
Ear pain
Cardiac disorders
Atrioventricular block first
degree,
Electrocardiogram QT
prolonged,
Tachycardia
Electrocardiogram abnormal
Cardiac flutter
Myocardial ischaemia
Bradycardia
Atrial fibrillation
Palpitations
Electrocardiogram ST
segment depression,
Electrocardiogram T wave
amplitude decreased
Vascular disorders
Vasodilatation
(incl. Flushing)
Phlebitis
Hypertension
Peripheral coldness
Anaphylactoid reaction
Hypotension
Arteriosclerosis
Respiratory,
thoracic and
mediastinal
disorders
Dyspnea
Cough
Respiratory depression
Gastrointestinal
disorders
Nausea
Vomiting
Retching
Diarrhea
Abdominal pain
Pharyngolaryngeal pain
Abdominal discomfort
Flatulence
Hypoesthesia lips
Salivary hypersecretion
Dyspepsia
Dry mouth
Pruritus ani
6
System Organ
Class (MedDRA)
Common
(
1/100)
Uncommon
(
1/1,000 to
1/100)
Rare
(
1/10,000 to
1/1,000)
Skin and
subcutaneous
tissue disorders
Pruritus
Urticaria
Rash
Erythema
Sweating increased
Swelling face
Clamminess
Musculoskeletal
and connective
tissue disorders
Pain in limb
Neck pain
Muscle cramps
Muscle spasms
Muscle tightness
Sensation of heaviness
Renal and urinary
disorders
Haematuria,
Microalbuminuria,
Glycosuria
Micturition urgency
Renal pain
Urinary frequency
Reproductive
system and breast
disorders
Genital pruritus,
Genital burning sensation
Pelvic pain
General disorders
and administration
site conditions
Feeling cold
Pain,
Chest pain
Groin pain
Fatigue
Feeling abnormal
Feeling hot
Injection site pain, Injection
site erythema, Injection site
coldness
Pyrexia
Rigors
Weakness
Chest pressure sensation
Injection site thrombosis
Injection site bruising
Injection site inflammation
Injection site burning
Injection site extravasation
Injection site haemorrhage
Injection site pruritus
Sensation of pressure
Injury, poisoning
and procedural
complications
Phantom limb pain
Cases of nephrogenic systemic fibrosis (NSF) have been reported with other gadolinium-containing
contrast agents (see section 4.4).
As with other intravenous contrast agents, this medicinal product can be associated with
anaphylactoid / hypersensitivity reactions characterised by cutaneous, respiratory and/or
cardiovascular manifestations which may lead to shock.
Ablavar can be removed by haemodialysis. However, there is no evidence that haemodialysis is
suitable for prevention of nephrogenic systemic fibrosis (NSF).
5.
7
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Contrast media, paramagnetic contrast media, ATC code: V08CA.
Ablavar is a formulation of a stable gadolinium diethylenetriaminepentaacetic acid (GdDTPA) chelate
substituted with a diphenylcyclohexylphosphate group (gadofosveset trisodium), for use in magnetic
resonance imaging (MRI).
Gadofosveset binds reversibly to human serum albumin. Protein binding enhances T1 relaxivity of
gadofosveset up to 10 fold compared to non-protein bound gadolinium chelates. In human studies,
gadofosveset substantially shortens blood T1 values for up to 4 hours after intravenous bolus
injection. Relaxivity in plasma was measured to be 33.4 to 45.7 mM
-1
s
-1
over the dose range of up to
0.05 mmol/kg at 20 MHz. High resolution MRA scans of vascular structures are obtained up to one
hour after administration of the medicinal product. The extended vascular imaging window for
gadofosveset is attributed to enhanced relaxivity and extended residence in vascular space resulting
from its plasma protein binding. No comparative studies with extracellular gadolinium contrast agents
have been conducted.
The safety and effectiveness of Ablavar in patients under 18 years of age have not been established.
5.2
Pharmacokinetic properties
Distribution
The plasma concentration-time profile of intravenously administered gadofosveset conforms to a two-
compartment open model. After intravenous administration of 0.03 mmol/kg dose the mean half-life
of the distribution phase (t
1/2
) was 0.48 ± 0.11 hours and the volume of distribution at steady state
was 148 ± 16 ml/kg, roughly equivalent to that of extracellular fluid. Plasma protein binding was in a
range 80% to 87% for up to the first 4 hours after injection.
Biotransformation
The results from various evaluations of plasma and urine samples indicated that gadofosveset does not
undergo measurable metabolism.
Elimination
In healthy volunteers, gadofosveset was predominantly eliminated in the urine with 84% (range 79 –
94%) of the injected dose (0.03 mmol/kg) excreted in the urine in 14 days. Ninety-four percent (94%)
of the urinary excretion occurred in the first 72 hours. A small portion of gadofosveset dose was
recovered in the faeces (4.7%, range 1.1 – 9.3%), indicating a minor role of biliary excretion in the
disposition of gadofosveset. After intravenous administration of 0.03 mmol/kg dose renal clearance
(5.51 ± 0.85 ml/h/kg) and total clearance (6.57 ± 0.97 ml/h/kg) were similar, and mean terminal
elimination half-life was 18.5 ± 3.0 hours.
Characteristics in patients
Renal
impairment
In patients with moderate to severe renal impairment the half-life is markedly prolonged and the AUC
increased by 2-3fold.
Hemodialysis patients
Gadofosveset can be removed from the body by hemodialysis. After bolus intravenous administration
of 0.05 mmol/kg dose in patients requiring three times a week haemodialysis using high-flux filter, at
the end of third dialysis session, the plasma concentration had declined to less than 15 % of the Cmax.
During the dialysis sessions the mean half-life of plasma concentration decline was in the range
5-6 hours. The mean dialysis clearance was between the range of 16-32 ml/h/kg. The high-flux
dialysis filter was more efficient compared to the low-flux filter, therefore, use of a high-flux dialysis
filter is recommended.
8
Hepatic impairment
Plasma pharmacokinetics and protein binding of gadofosveset were not significantly influenced by
moderate hepatic impairment (Child Pugh B). A slight decrease in faecal elimination of gadofosveset
was seen for the hepatic impaired subjects (2.7%) compared to normal subjects (4.8%). In one subject
with moderate hepatic impairment and abnormally low serum albumin, total clearance and half-life of
gadofosveset was indicative of faster clearance compared to subjects with moderate hepatic
impairment and normal serum albumin levels.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, acute toxicity, local tolerance, contact-sensitising potential, and genotoxicity.
No carcinogenicity studies were performed.
Repeated dose toxicity
Repeated-dose toxicity studies revealed vacuolation of the tubular cells of the kidneys, with strong
evidence for reversibility of the effect. No functional impairment was observed and electron
microscopic investigations of the rat kidneys indicated that the observed vacuolation was primarily a
storage phenomenon. Effects were of higher severity in rats than in monkeys, probably because of the
higher renal clearance in rats. In monkeys, no renal effects were observed after single use even at a
dose 100-times higher than the clinical dose.
Reproduction toxicity
In rabbits, an increased number of early resorptions and a slight but significant increase in the number
of foetal anomalies (in particular hydrocephalus and malrotated limbs) were observed at doses at
which no or slight maternal toxicity was observed (exposure was 2 and 5 times the expected human
exposure, respectively). In an animal study, it was shown that less than 1% of the dose of
gadofosveset administered enters breast milk.
6.
6.1 List of excipients
Fosveset
Sodium hydroxide
Hydrochloric acid
Water for injections
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.
After first opening: the medicinal product should be used immediately.
6.4 Special precautions for storage
Keep the injection vial in the outer carton in order to
protect from light.
9
6.5 Nature and contents of container
10 and 20 ml colourless type I glass vials with chloro- or bromobutyl elastomer stopper and
aluminium bordered cap (plastic disk).
Pack sizes
:
1, 5, or 10 vials 10 ml (in 10-ml glass vial)
1, 5, or 10 vials 15 ml (in 20-ml glass vial)
1, 5, or 10 vials 20 ml (in 20-ml glass vial)
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
This medicinal product is supplied ready to use as a clear, colourless to pale yellow aqueous solution.
Contrast media should not be used in case of severe discolouration, the occurrence of particulate
matter, or defective container.
Vials are not intended for the withdrawal of multiple doses. The rubber stopper should never be
pierced more than once. After withdrawal of the solution from the vial, it should be used immediately.
The peel-off tracking label included with the vials should be stuck onto patient record to enable
accurate recording of the gadolinium contrast agent used.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
TMC Pharma Services Ltd., Finchampstead, Berkshire RG40 4LJ, UK
8.
EU/1/05/313/001 - 009
9.
Date of first authorisation: 3 October 2005
Date of latest renewal:
Detailed information on this product is available on the website of the European Medicines Agency
10
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
11
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Bayer Schering Pharma AG
D – 13342 Berlin
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medicinal prescription (See Annex 1: Summary of Product
Characteristics, section 4.2)
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 2.0 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation 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, any
updated RMP should be submitted at the same time as the following 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
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
PSURs
The MAH will continue to submit yearly PSURs unless otherwise specified by the CHMP.
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER PACKAGING - BOX
1.
Ablavar 0.25 mmol/ml solution for injection
Gadofosveset
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml Ablavar solution for injection contains gadofosveset equivalent to 244 mg (0.25 mmol)
gadofosveset trisodium.
Each vial of 10 ml solution contains 2.44 g (2.50 mmol) of gadofosveset trisodium,
Each vial of 15 ml solution contains 3.66 g (3.75 mmol) of gadofosveset trisodium.
Each vial of 20 ml solution contains 4.88 g (5.00 mmol) of gadofosveset trisodium.
3.
LIST OF EXCIPIENTS
Excipients: fosveset, sodium hydroxide, hydrochloric acid, water for injections
See the leaflet for further information.
4.
Solution for injection
1 vial
5 vials
10 vials
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use and diagnostic use only.
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
The peel-off tracking label included with the vials should have the dose recorded on it and be stuck
onto patient record
15
8.
EXPIRY DATE
EXP
After first opening use immediately.
9.
SPECIAL STORAGE CONDITIONS
Keep the injection 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
Discard any unused medium after each investigation.
TMC Pharma Services Ltd., Finchampstead, Berkshire, RG40 4LJ, UK
EU/1/05/313/001 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-10 ml-1
vial
EU/1/05/313/002 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-10ml-5
vials
EU/1/05/313/003 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-10ml-10
vials
EU/1/05/313/004 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-15ml-1
vial
EU/1/05/313/005 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-15ml-5
vials
EU/1/05/313/006 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-15ml-10
vials
EU/1/05/313/007 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-20ml-1
vial
EU/1/05/313/008 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-20ml-5
vials
EU/1/05/313/009 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-20ml-10
vials
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
17
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
Vial 15 and 20ml
1.
Ablavar 0.25 mmol/ml solution for intravenous use
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml Ablavar solution contains gadofosveset equivalent to 244 mg (0.25 mmol) gadofosveset
trisodium.
Each vial of 15 ml solution contains 3.66 g (3.75 mmol) of gadofosveset trisodium.
Each vial of 20 ml solution contains 4.88 g (5.00 mmol) of gadofosveset trisodium.
3.
LIST OF EXCIPIENTS
Fosveset
Sodium hydroxide
Hydrochloric acid
Water for injection
4.
Solution for injection.
15 ml
20 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Ablavar should be administered as a single intravenous bolus injection, manually, or by magnetic
resonance injector over a period of time up to 30 seconds followed by a 25-30 ml normal saline flush.
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
After first opening use immediately
18
9.
SPECIAL STORAGE CONDITIONS
Keep the injection 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
Discard any unused medium after each investigation.
TMC Pharma Services Ltd., Finchampstead, Berkshire, RG40 4LJ, UK
EU/1/05/313/004 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-15ml-1
vial
EU/1/05/313/005 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-15ml-5
vials
EU/1/05/313/006 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-15ml-10
vials
EU/1/05/313/007 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-20ml-1
vial
EU/1/05/313/008 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-20ml-5
vials
EU/1/05/313/009 Ablavar-0.25 mmol/ml-Solution for injection-Intravenous use-Vial (glass)-20ml-10
vials
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
19
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
10 ML
1.
Ablavar 0.25 mmol/ml solution for injection
Gadofosveset
Intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
After first opening: the medicinal product should be used immediately.
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 ml
6.
OTHER
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ablavar 0.25 mmol/ml solution for injection
Gadofosveset
Read all of this leaflet carefully before you are given this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have further questions, please ask the doctor giving you Ablavar (the radiologist) or the
hospital/MRI-centre personnel
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or radiologist.
In this leaflet
:
1. What Ablavar is and what it is used for
2. Before you are given Ablavar
3. How to use Ablavar
4. Possible side effects
5.
How to store Ablavar
6.
Further information
1.
WHAT ABLAVAR IS AND WHAT IT IS USED FOR
Ablavar is an injectable contrast medium for making a diagnostic image of the body's blood vessels in
the abdomen or limb clearer. It is for use in adults only.
Ablavar is for diagnostic use only. It is used to help detect changes in the blood vessels which are
known or suspected to be abnormal. The diagnosis can be made with greater accuracy than without
using this medicine.
This medicine, a contrast agent with magnetic properties, helps to visualise the passage of blood
through the vessels by brightening the blood for an extended period. This medicine is used together
with an imaging technique called magnetic resonance imaging (MRI).
If you have any questions or are not sure about something, ask the doctor or MRI-centre personnel.
2.
BEFORE YOU ARE GIVEN ABLAVAR
Do not use Ablavar
You must not be given Ablavar if you
are allergic (hypersensitive) to gadofosveset or any of the
other ingredients of this medicine (see section 6 of this leaflet).
Take special care with Ablavar
You will need special medical attention if
allergy-like reactions
occur. Tell your doctor
immediately
if you notice itching, a feeling of mild swelling in your throat or tongue, which might be
a first sign of some allergy-like reaction. Your doctor will be mindful of other signs as well.
Tell your doctor if:
you have a cardiac pacemaker
or
any ferromagnetic implant
or a metallic stent in your
body
you suffer from allergy (e.g. hay fever, hives) or asthma
you had any reactions to previous injections of contrast media
your kidneys do not work properly
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you have recently had, or soon expect to have, a liver transplant
If any of these apply to you, your doctor will decide whether the intended examination is possible or
not.
Your doctor may decide to take a blood test to check how well your kidneys are working before
making the decision to use this medicine, especially if you are 65 years of age or older.
Children
or adolescents under 18 years
This medicine should not be used in children or adolescents under 18 year of age.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Your doctor will advise you what to do.
Pregnancy and breast-feeding
Ask your doctor for advice before taking any medicine.
You must tell your doctor if you think you are or might become pregnant.
It has not been proven that this medicine is safe to use during pregnancy. Your doctor or radiologist
will consider this with you. This medicine must not be used in pregnant women unless strictly
necessary.
Tell your doctor if you are breast-feeding or about to start breast-feeding. Your doctor will discuss
whether you should continue breast-feeding or interrupt breast-feeding for a period of 24 hours after
you receive this medicine.
Driving and using machines
There are no studies on the effects on the ability to drive and use machines.
This medicine can uncommonly cause dizziness or vision problems. If you get these effects you
should not drive or use machines
Important information about some of the ingredients of Ablavar
This medicine contains 6.3 mmol sodium (or 145 mg) per dose. To be taken into consideration by
patients on a controlled sodium diet.
3.
HOW TO USE ABLAVAR
You will be asked to lie down on the MRI scanning bed. Scanning may start immediately after the
Ablavar injection. After the injection you will be observed in case there might be any initial side
effects.
The usual dose
The dose of this medicine varies depending on your weight. The doctor will decide how much
medicine is needed for your examination. The dose is: 0.12 ml/kg body weight (equivalent to
0.03 mmol/kg of body weight).
Further information regarding the administration and handling of this medicine is given at the end of
the leaflet.
Method of administration
This medicine is given as a rapid injection into a vein by a medical professional only. The usual
injection site is the back of your hand or just in front of your elbow.
Dose in special patient groups
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The use of this medicine is not recommended in patients with severe kidney problems and patients
who have recently had, or soon expect to have, a liver transplant. However if use is required you
should only receive one dose of this medicine during a scan and you should not receive a second
injection for at least 7 days.
Elderly
It is not necessary to adjust your dose if you are 65 years of age or older but you may have a blood test
to check how well your kidneys are working.
If you receive more Ablavar than you should have received:
If you think you may have had an overdose talk to your doctor immediately. Your doctor will treat
you should overdose occur. If necessary, this medicine can be removed from the body by
haemodialysis using high-flux filters.
If you have any further questions
on the use of this medicine, please consult your doctor, the
radiologist or MRI-centre personnel.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Ablavar can cause side effects, although not everybody gets them.
If you have any of the following symptoms you should tell a doctor immediately:
Ablavar can be associated with allergy-like reactions (anaphylactoid / hypersensitivity reactions)
characterised by:-
skin reactions, (cutaneous reactions)
breathing difficulties and/or heart/ pulse-rate/ blood pressure disturbances which may lead
to consciousness disorders respiratory reactions, and /or cardiovascular manifestations
which may lead to shock).
Most of the side effects were mild to moderate in intensity. Most of the side effects (80%) occurred
within 2 hours. Delayed effects (after hours to days) may occur.
Below are listed the reported/experienced side effects by frequency): 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.
The following is a list of side-effects observed in clinical trials:
Common:
Headache
Tingling or numbness of the hands or feet
Change of taste in mouth
Burning sensation
Warm feeling (vasodilatation) including flushing
Nausea
Itching
Feeling cold.
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Uncommon:
Runny nose
Sore throat
Feeling anxious
Confusion
Allergy-like reaction
Impairment of taste
Dizziness
Shaking
Decreased feeling or sensitivity (especially of the skin)
Sense of smell distortion
Involuntary muscle contractions
Abnormal vision
Tear secretion increased
Disturbed nerve signals in the heart (first degree)
Fast heart beat
Problems with the electrical rhythm of the heart (long QT)
High blood pressure
Swelling and clotting in a vein
Coldness in the fingers and toes
Shortness of breath
Cough
Vomiting
Attempting to vomit
Diarrhoea
Stomach discomfort
Stomach pain
Pain in the throat
Indigestion
Dry mouth
Wind
Decreased feeling or sensitivity of the lips
Increased production of saliva
Anal itching
Hives
Reddening of the skin
Rash
Sweating increased
Muscle cramps
Muscle spasms
Neck pain
Pain in arms or legs
Genital itching
Genital burning sensation
Pain
Chest pain
Tiredness
Feeling abnormal
Groin pain
Feeling hot
Injection site pain
Injection site coldness
Reddening of skin at the injection site
Blood in the urine
Proteins in the urine
Sugar in the urine
25
High sugar levels in the blood
Low calcium levels in the blood
Unusual amount of salt in the body.
Rare:
Inflammation of the skin
Urinary tract infection
Abnormal dreams
Seeing, feeling or hearing things that is not there
Appetite decreased
Eyesight disorders
Abnormal eye sensation
Ear pain
Heartbeat irregularity/disturbed heart-chamber contractions (cardiac flutter, atrial fibrillation)
problems with the electrical rhythm of the heart (ST segment/T wave abnormalities)
Chest pain
Slow heart beat
Palpitations
Thickening of the arteries due to cholesterol deposits
Low blood pressure
Shallow breathing
Face swelling
Sweatiness
Muscle tightness
Sensation of heaviness
Urge to pass urine
Kidney pain
Passing urine frequently
Lower abdominal pain
Fever
Shivering
Weakness
Chest pressure sensation
Injection site blood clot
Injection site bruising
Injection site inflammation
Injection site burning
Fluid escaping from injection site into the surrounding tissue
Injection site bleeding
Injection site itching
Sensation of pressure
Phantom pain in the arms or legs
Low or high potassium levels in the blood
High sodium levels in the blood.
There have been reports of nephrogenic systemic fibrosis (which causes hardening of the skin and
may affect also soft tissue and internal organs) associated with use of other gadolinium-containing
contrast agents.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or radiologist.
5.
HOW TO STORE ABLAVAR
Keep out of the reach and sight of children.
26
Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date
refers to the last day of the month.
Keep the injection vial in its outer carton in order to
protect from light
.
After first opening, the medicine should be used immediately.
Do not use this medicine if you notice severe
discolouration, the occurrence of particulate matter or a
defective container.
Medicines should not be disposed of via wastewater 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 Ablavar contains
- The active substance is gadofosveset equivalent to 244 mg/ml gadofosveset trisodium
corresponding to 0.25 mmol/millilitre.
10 ml solution contains 2.44 g, 15 ml solution contains 3.66 g and 20 ml solution contains 4.88 g
of gadofosveset trisodium in a vial.
-
The other ingredients are fosveset, sodium hydroxide, hydrochloric acid, and water for injections.
What Ablavar looks like and contents of the pack
Ablavar is a clear, colourless to pale yellow liquid supplied in a rubber stoppered glass vial, with an
aluminium seal, in individual cartons. The contents of the packs are:
1, 5 or 10 injection vials with 10 ml solution for injection (in 10-ml glass vial)
1, 5 or 10 injection vials with 15 ml solution for injection (in 20-ml glass vial)
1, 5 or 10 injection vials with 20 ml solution for injection (in 20-ml glass vial)
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
TMC Pharma Services Ltd., Finchampstead, Berkshire RG40 4LJ , UK
Tel:01252 842255
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
<-----------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Prior to administration of Ablavar it is recommended that all patients are screened for renal
dysfunction by obtaining laboratory tests.
There have been reports of nephrogenic systemic fibrosis
(NSF) associated with use of some
gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment
27
(GFR< 30 ml/min /1.73 m
2
). Patients undergoing liver transplantation are at particular risk since the
incidence of acute renal failure is high in this group. As there is a possibility that NSF may occur with
Ablavar, it should therefore be avoided in patients with severe renal impairment and in patients in the
perioperative liver transplantation period unless the diagnostic information is essential and not
available with non-contrast enhanced MRI. If use of Ablavar cannot be avoided, the dose should not
exceed 0.03 mmol/kg body weight. More than one dose should not be used during a scan. Because of
the lack of information on repeated administration, Ablavar injections should not be repeated unless
the interval between injections is at least 7 days.
As the renal clearance of gadofosveset may be impaired in the elderly, it is particularly important to
screen patients aged 65 years and older for renal dysfunction.
Haemodialysis shortly after Ablavar administration may be useful at removing Ablavar from the body.
There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in
patients not already undergoing haemodialysis.
Ablavar should not be used during pregnancy unless the clinical condition of the woman requires use
of gadofosveset.
Continuing breast feeding or discontinuing Ablavar for a period of 24 hours after administration,
should be at the discretion of the doctor and lactating mother.
The peel-off tracking label included on the vials should be stuck onto the patient record to enable
accurate recording of the gadolinium contrast agent used. The dose used should also be recorded.
Ablavar is supplied ready to use as a clear, colourless to pale yellow aqueous solution.
Contrast media should not be used in case of severe discolouration, the occurrence of particulate
matter, or defective container.
Vials containing Ablavar are not intended for the withdrawal of multiple doses. The rubber stopper
should never be pierced more than once. After withdrawal of the solution from the vial, this medicinal
product should be used immediately.
Any remaining solution not used in one examination must be discarded.
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Source: European Medicines Agency
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