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Ablavar (Vasovist) (gadofosveset trisodium) – Summary of product characteristics - V08CA

Updated on site: 05-Oct-2017

Medication nameAblavar (Vasovist)
ATC CodeV08CA
Substancegadofosveset trisodium
ManufacturerTMC Pharma Services Ltd.
Medicinal product no longer authorised

1. NAME OF THE MEDICINAL PRODUCT

Ablavar 0.25 mmol/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml Ablavar solution for injection contains 244 mg (0.25 mmol) gadofosveset trisodium equivalent to 227 mg gadofosveset.

Each vial of 10 ml solution contains a total of 2.44 g (2.50 mmol) of gadofosveset trisodium equivalent to 2.27 g of gadofosveset

Each vial of 15 ml solution contains a total of 3.66 g (3.75 mmol) of gadofosveset trisodium equivalent to 3.41g of gadofosveset.

Each vial of 20 ml solution contains a total of 4.88 g (5.00 mmol) of gadofosveset trisod um equivalent to 4.54g of gadofosveset.

Excipient

 

 

 

This medicinal product contains 6.3 mmol sodium (or 145 mg) per dose.

For a full list of excipients, see section 6.1.

 

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authorised

 

 

3.

PHARMACEUTICAL FORM

 

 

Solution for injection.

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Clear, colourless to pale yellow liquid.

 

 

 

4.

CLINICAL PARTICULARS

 

 

 

 

 

4.1

Therapeutic indications

 

 

 

 

product

 

 

 

This medicinal product is for diagn stic use only.

Ablavar is indicated for contrast-enhanced magnetic resonance angiography (CE-MRA) for

Medicinal

visualisation of abdominal or limb vessels in adults only, with suspected or known vascular disease.

4.2 Posology

method of administration

This med c nal 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).

Renal impairment

Use of Ablavar should be avoided in patients with severe renal impairment

(GFR < 30 ml/min/1.73 m2) 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

authorised

 

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 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.

4.3

Contraindications

 

Hypersensitivity to the active substance or to any of the excipients.

4.4

Special warnings and precautions for use

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Diagnostic procedures involvingproductthe 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 sho ld 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 f magnetic resonance imaging must be observed, e.g., exclusion of cardiac pacemakers and fer omagnetic implants.

As with other contrast enhanced diagnostic procedures, post-procedure observation of the patient is Medicinalrecommended, in particu ar in patients with a history of allergy, renal insufficiency, or adverse reaction.

Hypersensitiv ty war ing

The possib l ty 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 oth r all rgic disorders. Experience with other contrast media shows that the risk of hypersensitivity reactions is higher 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.

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 m2). 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

As the renal clearance of gadofosveset may be impaired in the elderly, it isauthorisedp rticularly important to screen patients aged 65 years and older for renal dysfunction.

perioperative liver transplantation period unless the diagnostic information essential and not available with non-contrast enhanced MRI.

Haemodialysis shortly after Ablavar administration may be useful at removing Ablavar f om the body.

There is no evidence to support the initiation of haemodialysis for prevention treatment of NSF in patients not already undergoing haemodialysis.

Elderly

Haemodialysis shortly after Ablavar administration in patients curr ntly 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 haem dialysis for prevention or treatment of NSF in

patients not already undergoing haemodialysis.

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Electrocardiographic changes

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Elevated levels of gadofosveset (e.g. repeated use in the short term [within 6-8 hours], or an

product

 

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

Medi4.5 Int cinalraction with other medicinal products and other forms of interaction

It has been shown in pub ished 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 med

ne ontains 6.3 mmol sodium (or 145 mg) per dose.

To be taken

nto 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.

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.

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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.

4.6 Fertility, pregnancy and lactation

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

authorised

 

 

Gadolinium containing contrast agents are excreted into breast milk in very small amounts (s

ction

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.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machine have b en performed. Uncommonly, dizziness or vision problems may occur with this medicine. If a pati nt xperiences these effects he/she should not drive or use machines

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4.8 Undesirable effects

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.

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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).

 

product

 

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

 

 

 

System Organ

Common

Uncommon

Rare

Class (MedDRA)

( 1/100)

( 1/1,000 to 1/100)

( 1/10,000 to 1/1,000)

 

 

 

 

Inf ctions and

 

Nasopharyngitis

Cellulitis

inf stations

 

 

Urinary tract infection

 

 

 

 

Immune system

 

Hypersensitivity

 

Medicinal

 

 

 

disorders

 

 

 

Metabolism and

 

Hyperglycaemia

Hyperkalemia

nutrition disorders

 

Electrolyte imbalance (incl.

Hypokalemia

 

 

Hypocalcemia)

Hypernatremia

 

 

 

Appetite decreased

Psychiatric

 

Anxiety

Hallucination

disorders

 

Confusion

Abnormal dreams

 

 

 

 

System Organ

Common

Uncommon

 

Rare

Class (MedDRA)

( 1/100)

( 1/1,000 to 1/100)

( 1/10,000 to 1/1,000)

 

 

 

 

 

 

 

 

Nervous system

Headache

Dizziness (excl. Vertigo)

 

disorders

Paraesthesia

Tremor

 

 

 

Dysgeusia

Hypoesthesia

 

 

Burning sensation

Parosmia

 

 

 

 

Ageusia

 

 

 

 

Muscle contractions

 

 

 

involuntary

 

 

 

 

 

 

Eye disorders

 

Vision abnormal

Abnormal sensat on in eye

 

 

Lacrimation increased

Asthenopia

 

 

 

 

 

Ear and labyrinth

 

 

 

Ear pain

disorders

 

 

 

 

Cardiac disorders

 

Atrioventricular block first

C rdiac flutter

 

 

degree,

 

Myocardial ischaemia

 

 

Electrocardiogram QT

Bradycardiaauthorised

 

 

prolonged,

 

Atrial fibrillation

 

 

Tachycardia

 

Palpitations

 

 

Electrocardiogram ab ormal

Electrocardiogram ST

 

 

 

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segment depression,

 

 

 

Electrocardiogram T wave

 

 

 

amplitude decreased

 

 

 

 

Vascular disorders

Vasodilatation

Phlebitis

 

Anaphylactoid reaction

 

(incl. Flushing)

Hypertensionno

Hypotension

 

 

Peripheral coldness

Arteriosclerosis

 

 

 

 

 

Respiratory,

product

Dyspnea

 

Respiratory depression

thoracic and

Cough

 

 

mediastinal

 

 

 

disorders

 

 

 

Gastrointestinal

N usea

Vomiting

 

 

disorders

 

Retching

 

 

Medicinal

 

Diarrhea

 

 

 

Abdominal pain

 

 

Pharyngolaryngeal pain

 

 

Abdominal discomfort

 

 

Flatulence

 

 

 

Hypoesthesia lips

 

 

Salivary hypersecretion

 

 

Dyspepsia

 

 

 

 

 

 

 

 

Dry mouth

 

 

 

 

Pruritus ani

 

 

 

 

 

 

 

Skin and

Pruritus

Urticaria

 

Swelling face

subcutaneous tissue

 

Rash

 

Clamminess

disorders

 

Erythema

 

 

 

 

Sweating increased

 

 

 

 

 

 

System Organ

Common

Uncommon

Rare

Class (MedDRA)

( 1/100)

( 1/1,000 to 1/100)

( 1/10,000 to 1/1,000)

Musculoskeletal

 

Pain in limb

 

Muscle tightness

and connective

 

Neck pain

 

Sensation of heaviness

tissue disorders

 

Muscle cramps

 

 

 

Muscle spasms

 

 

 

 

 

 

Renal and urinary

 

Haematuria,

 

Micturition urgency

disorders

 

Microalbuminuria,

Renal pain

 

 

Glycosuria

 

Urinary frequency

 

 

 

 

Reproductive

 

Genital pruritus,

Pelvic pain

system and breast

 

Genital burning sensation

 

disorders

 

 

 

 

General disorders

Feeling cold

Pain,

 

Pyrexia

and administration

Chest pain

 

Rigors

site conditions

 

Groin pain

 

We kness

 

 

Fatigue

 

Chest pressure sensation

 

 

Feeling abnormal

Injectionauthorisedsite thrombosis

 

 

Feeling hot

 

Injection site bruising

 

 

Injection site pain, Injection

Injection site inflammation

 

 

site erythema, I jection site

Injection site burning

 

 

coldness

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Injection site extravasation

 

 

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Injection site haemorrhage

 

 

Injection site pruritus

 

 

Sensation of pressure

 

 

 

 

 

 

 

Injury, poisoning

 

 

 

Phantom limb pain

and procedural

 

 

 

 

complications

 

 

 

 

Cases of nephrogenic systemic fib

sis (NSF) have been reported with other gadolinium-containing

contrast agents (see section 4.4).

 

 

 

As with other intravenous contrastproductagents, this medicinal product can be associated with

anaphylactoid / hypersensitivity reactions characterised by cutaneous, respiratory and/or

cardiovascular ma

festations which may lead to shock.

 

4.9 Over ose

 

 

 

 

Medicinal

 

 

 

Ablavar can be removed by haemodialysis. However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

5. PHARMACOLOGICAL PROPERTIES

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).

Characteristics in patients

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-1s-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 confo ms to a two- compartment open model. After intravenous administration of 0.03 mmol/kg dose the mean half-life of the distribution phase (t1/2) was 0.48 ± 0.11 hours and the volume of distribu ion at steady state was 148 ± 16 ml/kg, roughly equivalent to that of extracellular fluid. Plasma protein binding was in range 80% to 87% for up to the first 4 hours after injection.

The results from various evaluations of plasma and urinelongersampl s indicated that gadofosveset does not undergo measurable metabolism.

Biotransformation

authorised

 

Elimination

In healthy volunteers, gadofosveset was predominant y iminated 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 noh urs. A small portion of gadofosveset dose was

recovered in the faeces (4.7%, range 1.1 – 9.3%), i dicating a minor role of biliary excretion in the disposition of gadofosveset.productAfter intravenous administration of 0.03 mmol/kg dose renal clearance

(5.51 ± 0.85 ml/h/kg) and total clearan e (6.57 ± 0.97 ml/h/kg) were similar, and mean terminal elimination half-life was 18.5 ± 3.0 ho rs.

Renal impairment

Hemodialysis pat ts

In patients with moderate to severe renal impairment the half-life is markedly prolonged and the AUC increasedMedicinalby 2-3fold.

Gadofosveset an 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 nd 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.

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 expected human

exposure, respectively). In an animal study, it was shown that less than 1% of the dose of gadofosveset

administered enters breast milk.

 

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6.

PHARMACEUTICAL PARTICULARS

 

6.1

List of excipients

 

 

Fosveset

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Sodium hydroxide

 

 

 

Hydrochloric acid

 

 

Water for injections

 

 

 

 

 

 

6.2 Incompatibilities

 

 

product

In the absence of compatibility stu ies, this medicinal product must not be mixed with other medicinal

products.

 

6.3

Shelf life

 

Medicinal

 

3 years.

 

After first open g: the medicinal product should be used immediately.

6.4

Special precautions for storage

Ke p the injection vial the outer carton in order to protect from light.

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.

MARKETING AUTHORISATION HOLDER

authorised

TMC Pharma Services Ltd., Finchampstead, Berkshire RG40 4LJ, UK

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/05/313/001 - 009

 

 

 

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 3 October 2005

 

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Date of latest renewal:

 

 

 

 

 

10. DATE OF REVISION OF THE TEXT

 

 

http://www.ema.europa.eu product

no

 

 

Detailed information on this duct is available on the website of the European Medicines Agency Medicinal

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