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 trisodium equivalent to 4.54g of gadofosveset.

This medicinal product contains 6.3 mmol sodium (or 145 mg) per dose. For a full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

Posology and method of administration

This medicinal product should only be used by physicians experienced in the field of diagnostic imaging.

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).

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.

Use is not recommended in neonates, infants, children and adolescents. No clinical experience is yet available for patients younger than 18.

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.

Contraindications

Special warnings and precautions for use

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.

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.

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 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.

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.

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.

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.

This medicine contains 6.3 mmol sodium (or 145 mg) per dose. To be taken into consideration by patients on a controlled sodium diet.

Interaction with other medicinal products and other forms of interaction

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.

In clinical trials using Ablavar, no specific trends were observed that would signify a potential interaction of the medicinal product with laboratory test methods.

Fertility, pregnancy and lactation

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.

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.

Effects on ability to drive and use machines

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

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.

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 Appetite decreased
Psychiatric disorders		Anxiety Confusion	Hallucination Abnormal dreams

Medicinal product no longer authorised

System Organ Class (MedDRA)	Common ( 1/100)	Uncommon ( 1/1,000 to 1/100)	Rare ( 1/10,000 to 1/1,000)

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
Skin and subcutaneous tissue disorders	Pruritus	Urticaria Rash Erythema Sweating increased	Swelling face Clamminess
System Organ Class (MedDRA)	Common ( 1/100)	Uncommon ( 1/1,000 to 1/100)	Rare ( 1/10,000 to 1/1,000)

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

Medicinal product no longer authorised

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.

Overdose

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

PHARMACOLOGICAL PROPERTIES

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-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.

Pharmacokinetic properties

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 (t1/2 ) 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.

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

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.

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

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.

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.

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.

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.

PHARMACEUTICAL PARTICULARS

List of excipients

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life

Special precautions for storage

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.

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.

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION