Optimark - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Optimark 500 micromol/ml solution for injection in pre-filled syringe

Optimark 500 micromol/ml solution for injection in vial

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Pre-filled syringe

1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.

Each 10 ml syringe contains 3309 mg gadoversetamide equivalent to 5 millimol. Each 15 ml syringe contains 4963.5 mg gadoversetamide equivalent to 7.5 millim Each 20 ml syringe contains 6618 mg gadoversetamide equivalent to 10 millimol. Each 30 ml syringe contains 9927 mg gadoversetamide equivalent to 15 millimol.

Excipient(s) with known effect :

20 ml of the solution contain 28.75 mg sodium.

30 ml of the solution contain 43.13 mg sodium.

For the full list of excipients, see section 6.1.

\°

Vial

1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.

Each 10 ml vial contains 3309 mg gadoversetamide equivalent to 5 millimol.

Each 15 ml vial contains 4963.5 mg gadoversetamide equivalent to 7.5 millimol.

Each 20 ml vial contains 6618 mg gadoversetamide equivalent to 10 millimol.

0^

Excipient(s) with known effect:

• 20 ml of the solution contain 28.75 mg sodium.

  For the full list of ex

  
  

ts, see section 6.1.

3. PHARMACEUTICAL FORM

Pre-filled syringe

Solution for injection in pre-filled syringe.

Vial

Solution for injection in vial.

Clear, colourless to pale yellow solution. pH: 6.0 – 7.5

Osmolality (37°C): 1000 – 1200 mOsm/kg

4. CLINICAL PARTICULARS4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

Optimark is indicated for use with magnetic resonance imaging (MRI) of the central nervous system (CNS) and liver. It provides contrast enhancement and facilitates visualization and helps with the characterization of focal lesions and abnormal structures in the CNS and liver in adult patients and in children of two years and older with known or highly suspected pathology.

4.2 Posology and method of administration

Optimark should only be administered by physicians experienced in clinical MRI practice.

To enable immediate action in emergencies, the necessary medicinal products (e.g. epinephrine/ adrenaline, theophylline, antihistamines, corticosteroids and atropines), endotracheal tube and ventilator must be immediately available.

Posology

The agent should be administered as a bolus peripheral intravenous injection at a dose of 0.2 ml/kg (100 micromol/kg) body weight. To ensure complete injection of the contrast medium, the injection should be followed by a 5 ml flush of sodium chloride 9 mg/ml (0.9 %) solution for injection. The imaging procedure should be completed within 1 hour of administration of the contrast medium.

Repeat dose

In cranial MRI, if a strong clinical suspicion of a lesion persists despite a single dose contrast-enhanced MRI or when more accurate information on the number, size or extent of lesions might influence management or therapy of the patient, in subjects with normal renal function, a second bolus injection of 0.2ml/kg (100 micromol/kg) may be administered within 30 minutes of the first injection as it may increase the diagnostic yield of the examination.

The safety of repeat doses has not been established in children and adolescents (2 years and older), in patients with renal impairment, or the elderly. The repeat dose is not recommended in these populations.

Limited data with other gadolinium contrast agents suggests that for the exclusion of additional cranial metastases in a patient with a known solitary resectable metastasis, an MR exam with the injection of the dose of 300 micromol/kg body weight of Optimark may lead to higher diagnostic confidence.

Paediactric population

No dose adjustment is considered necessary in children more than 2 years of age.

Optimark is contraindicated in neonates up to 4 weeks of age (see section 4.3).

Use of Optimark is not recommended in children less than 2 years of age_because the safety, efficacy, and impact of immature kidney function have not been studied in this age group.

Elderly (aged 65 years and above)

No dose adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).

Renal and hepatic impairment

Optimark is contraindicated in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) and/or acute renal injury and in patients who have had liver transplantation or in patients in the perioperative liver transplantation period (see section 4.3). Optimark should only be used after careful risk/benefit evaluation in patients with moderate renal impairment (GFR 30–59 ml/min/1.73m2) at a dose not exceeding 100 micromol/kg body weight (see section 4.4). More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Optimark injections should not be repeated unless the interval between injections is at least 7 days.

Method of administration

The agent should be administered as a bolus peripheral intravenous injection. To ensure complete injection of the contrast medium, the injection should be followed by a 5 ml flush of sodium chloride 9 mg/ml (0.9 %) solution for injection. Insertion of a flexible in-dwelling venous catheter is recommended, see section 4.4.

Optimark must not be administered with an autoinjector to children of 2 to 11 years (see section 4.4).

Precautions to be taken before handling or administering the medicinal product

The container and the solution should be inspected prior to use as described in section 6.6.

4.3 Contraindications

Hypersensitivity to gadoversetamide or to other gadolinium containing products, or to any of the excipients listed in section 6.1.

Optimark is contraindicated

• • in patients with severe renal impairment (GFR <30ml/min/1.73m2) and/or acute kidney injury,

in patients who have had liver transplantation or

in patients in the perioperative liver transplantation period and

in neonates up to 4 weeks of age (see section 4.4).

4.4 Special warnings and precautions for use

As with any paramagnetic contrast agent, enhancement of MRI with gadoversetamide may impair the visualization of existing lesions. Some of these lesions may be seen on unenhanced, non-contrast MRI. Therefore, caution should be exercised when contrast enhanced scan interpretation is made in the absence of a companion unenhanced MRI.

Before the examination, care must be taken that patients are sufficiently hydrated.

Hypersensitivity

Allergoid and other idiosyncratic reactions also may occur with gadoversetamide, which could become manifest in form of cardiovascular, respiratory and skin reactions (see section 4.8). Most of these reactions occur within half an h    fter administering the contrast medium. As with all other

contrast media of the same class, late     ions may occur (after hours or days) in rare cases; however,

none were reported in the completed clinical trials.

If hypersensitivity reactions occur, the administration of the contrast medium must be discontinued immediately and intravenous treatment initiated, if necessary.

During the examination, supervision by a physician is necessary and insertion of a flexible in-dwelling catheter is recommended. To enable immediate action in emergencies, the necessary medicinal products (e.g. epinephrine/a­drenaline, theophylline, antihistamines, corticosteroids and atropines), endotracheal tube and ventilator must be immediately available.

The risk of hypersensitivity reactions is increased in the following cases:

• – patients with allergic predisposition

• – patients with bronchial asthma; in these patients it is especially the risk of bronchospasm which is increased

• – patients with a history of reactions to contrast agents, including a previous history of reaction to iodine-based contrast agents

Before the injection of contrast media, patients should be asked whether they have any allergies (e.g. allergies to seafood or medicinal products, hay fever, urticaria), whether they are hypersensitive to contrast media and whether they have bronchial asthma. Premedication with antihistamines and/or glucocorticoids may be considered.

Patients taking beta-blockers

It should be noted that patients using beta-blockers do not necessarily respond to the beta-agonists usually used for the treatment of hypersensitivity reactions.

Patients with cardiovascular disease

In this group of patients hypersensitivity reactions may be severe. Especially in patients with serious heart diseases (e.g. severe heart failure, coronary artery disease) cardiovascular reactions may deteriorate. However, these were not evident from clinical trials with Optimark.

Central nervous system disorders

In patients suffering from epilepsy or brain lesions the likelihood of convulsions during the examination may be increased. Precautions are necessary when examining these patients (e.g. monitoring of the patient) and the equipment and medicinal products needed for the rapid treatment of possible convulsions should be available.

Patients with impaired renal function

Prior to administration of Optimark, all patients should be screened for renal dysfunction by obtaining laboratory tests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of Optimark and some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR <30ml/min/1.73m2) and/or acute kidney injury. Optimark is contraindicated in these patients (see section 4.3). Patients who have had or are undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. Therefore, Optimark must not be used in patients who have had or are undergoing liver transplantation and in neonates (see section 4.3).

The risk for development of NSF in patients with moderate renal impairment (GFR 30–59 ml/min/1.73 m2) is unknown; therefore Optimark should only be used after careful risk-benefit evaluation in patients with moderate renal impairment.

Gadoversetamide is dialysable. Haemodialysis shortly after Optimark administration may be useful at removing Optimark 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.

In patients with baseline renal impairment, acute kidney injury requiring dialysis has occurred with the use of Optimark. The risk of acute kidney injury may increase with an increased dose of the contrast agent. Administer the lowest dose possible for adequate imaging.

Children and adolescents

Optimark must not be administered with an autoinjector. The required dose should be administered by hand to children of 2 to 11 years to avoid overdosage by mistake.

Neonates and infants.

Optimark should not be used in children below the age of two years. Safety and efficacy have not been studied in this age group.

Elderly

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

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose of up to 17 ml, i.e. it is essentially ‘sodium-free’.

10 ml vials and 15 ml vials contain less than 1 mmol sodium; i.e. they are essentially ‘sodium free‘. Higher doses contain 1 mmol sodium or more, which should be taken into consideration for patients on a controlled sodium diet.

Pre-filled syringe

20 ml of the solution contain 28.75 mg sodium.

30 ml of the solution contain 43.13 mg sodium.

Vial

20 ml of the solution contain 28.75 mg sodium.

Serum iron and zinc

Caution should be exercised because transient decreases in serum iron and zinc parameters have been observed in clinical trials. The clinical significance of this is unknown.

4.5 Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been performed.

Optimark has been shown to cause interference in the measurement of serum calcium using the orthocresolphtha­lein complexone (OCP) colorimetric method. However, the administration of gadoversetamide does not cause a true decrease in serum calcium. In the presence of gadoversetamide, the OCP technique produces an erroneous, low value for plasma calcium. The magnitude of this measurement artefact is proportional to the concentration of gadoversetamide in the blood, and in patients with normal renal clearance accurate values can be obtained approximately 90 minutes following injection. In patients with compromised renal function, clearance of gadoversetamide will be slowed and the interference with calcium determination by OCP prolonged. Gadoversetamide does not affect other methods of measuring serum calcium, such as the arsenazo III colorimetric method, atomic absorption spectroscopy, and inductively coupled plasma mass spectroscopy.

rjp

4.6 Fertility, pregnancy and lactation

Pregnancy                                                *Q-

There are no data from the use of gadoversetamide in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Optimark should not be used during pregnancy unless the clinical condition of the woman requires use of gadoversetamide.

Breast-feeding

It is unknown whether gadoversetamide is excreted in human milk. There is insufficient information

milk. A risk to the suckling child cannot be excluded.

Breast-feeding should be discontinued for at least 24 hours after the administration of Optimark.

Fertility

Non-clinical data did not reveal special hazards for humans based on conventional studies of reproductive toxicity. Clinical studies on fertility have not been performed

Optimark has no or negligible influence on the ability to drive and use machines.

Ambulant patients while driving vehicles or operating machinery should take into account that acute dizziness may uncommonly (>1/1,000 to <1/100) occur (see section 4.8).

4.8 Undesirable Effects

Summary of the safety profile

Most of the adverse reactions were of mild to moderate intensity and transient in nature. The most common adverse reactions were dysgeusia, feeling hot, headache and dizziness.

The majority of adverse reactions observed after the use of gadoversetamide were found to be adverse reactions of the nervous system, followed by general adverse reactions, gastrointestinal disorders/skin and subcutaneous tissue disorders.

Serious adverse reactions have been reported and include anaphylactic reactions, cardiovascular reactions, and allergic respiratory disorders. Treatment should be symptomatic and immediate access to necessary medicinal products and emergency equipment should be available should a serious event occur.

Tabulated list of adverse reactions

The following adverse reactions have been reported from clinical trials and from post-marketing use of gadoversetamide. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class (MedDRA)	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very Rare (<1/10,000)	Not known
Immune System Disorders		Anaphylactic reaction
Metabolism and Nutrition Disorders			Decreased appetite
Psychiatric Disorders			Anxiety, Sleep disorder, Confusion and disorientation (	Y
Nervous System Disorders	Headache, Dysgeusia	Dizziness, Hypoaesthesia, Paraesthesia, Parosmia	Convulsion, Tremor, Somnolence, Burning sensation	Syncope
Eye Disorders			Erythema of eyelid^Eyepain, Vision blurred, Conjunctivitis, Ocular hyperaemia
Ear and Labyrinth Disorders			Tinnitus,Vrtigo
Cardiac Disorders			Palpitations, AV block first degrees Extrasystoles, -Tachycardia, Arrhythmia
Vascular Disorders		Flushing	'Hypotension, Hypertension
Respiratory, Thoracic and Mediastinal Disorders		Nasal congestions Throat irritation	Dyspnoea, Dysphonia, Rhinorrhoea, Throat tightness, Bronchospasm, Cough, Laryngeal/pha­ryngeal oedema, Pharyngitis, Rhinitis, Sneezing
Gastrointestinal Disorders		Nausea, Diarrhoea	Salivary hypersecretion,, Abdominal pain, Constipation, Dry mouth	Vomiting
Skin and Subcutaneous Tissue Disorders		Pruritus, Rash	Urticaria, Cold sweat, Erythema, Hyperhidrosis	Periorbital oedema	Nephrogenic systemic fibrosis (NSF)
Renal and Urinary Disorders			Blood creatinine increased, Haematuria

System Organ Class (MedDRA)	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very Rare (<1/10,000)	Not known
General Disorders and Administration Site Conditions	Feeling hot	Chest discomfort, Chest pain, Feeling cold (including peripheral coldness), Administration site reactions	Chills, Pain, Face oedema, Asthenic conditions including asthenia, fatigue, and malaise, Fever, Oedema peripheral, Feeling abnormal
Investigations		Blood calcium abnormal	ALT increased, Urine analysis ( abnormal, Urine electrolytes abnormal, albumin in urine, CPK Increased, Haemoglobin decreased        JTp	y Electrocardiogram QT prolonged

Local reactions have occurred at the injection site and may lead to local irritation type reactions.

Cases of nephrogenic systemic fibrosis (NSF) have been reported with Optimark (see section 4.4).

Cases of gadolinium associated skin plaques, with demonstrated sclerotic bodies on histology, have been reported with some gadolinium-containing contrast agents in patients who do not otherwise have symptoms or signs of nephrogenic systemic fibrosis.

Paediatric population

Optimark has been studied in children of 2 years and older with a similar safety profile as shown in the adult population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

Gadoversetamide has been tested in humans in doses up to 700 micromol/kg (seven times the standard dose). Clinical consequences of an overdose have not been reported. Acute toxicity symptoms are unlikely to occur in patients with normal renal function. Optimark can be removed by haemodialysis. However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

5.1 Pharmacodynamic propertiesPharmacotherapeutic Group: MRI contrastATC code: V08CA06Gadoversetamide is a chelate containi responsible for the contrast enhance

olinium – which has paramagnetic properties and is t effect in MRI – and the ligand versetamide.

The purpose of an MRI contrast agent is to induce signal intensity changes within the lesion thereby facilitating its recognition from the surrounding normal structures. The use of a contrast agent may therefore reduce the threshold for lesion detection and visualization. Gadolinium containing MRI contrast agents (gadolinium-based chelates) are designed to act indirectly on the local magnetic environment by altering proton T1 (spin-lattice) and T2 (spin-spin) relaxation times and at the usual concentration of 100 micromol/kg, the T1 shortening predominates, and the T2 shortening is not significant using T1-weighted sequences.

Gadoversetamide, an extracellular gadolinium chelate, after intravenous administration, equilibrates rapidly within the extracellular fluid/space and is eliminated primarily by glomerular filtration.

As a result of these characteristics, the timing of the image acquisition after contrast administration is critical in liver imaging. For liver metastases, the signal difference between the tumour and surrounding liver tissue is significantly improved during the first 90 seconds after an extracellular gadolinium contrast agent is administered. Therefore, a rapid imaging sequence should be initiated 20 seconds after bolus injection of the contrast agent when the agent is predominately in the hepatic arteries and then again at 60 seconds after injection during the dominant portal venous phase. Since the hepatic artery and portal venous system supply approximately 20% and 80% of the hepatic blood supply, respectively, the earlier (hepatic arterial phase) images provide optimal lesion conspicuity for hypervascular lesions and the portal venous phase images are useful for hypovascular lesions (most metastatic lesions are relatively hypovascular and are better demonstrated during the portal venous phase, manifesting as areas of lower signal intensity compared with the markedly enhanced liver). Lesion conspicuity of hypo- and hypervascular lesions may be reduced if imaging is delayed more than 3 minutes due to the diffusion of the contrast agent into the interstitial spaces of both the liver parenchyma and lesion (e.g. metastasis) making the lesion isointense with the normal liver parenchyma. Delayed post-contrast or equilibrium images (> 5 minutes after dosing) assist in the characterization of lesions, e.g. the centre of a metastasis may accumulate contrast in the interstitial space of the lesion and become hyperintense to the normal liver. This difference in enhancement pattern is useful in formulating a differential diagnosis based on lesion characterization and diagnostic confidence.

The enhancement of brain tumours using a gadolinium (or iodine) containing contrast agent depends on the disruption of the blood brain barrier (BBB). As a result, these agents have been referred to as markers for sites of abnormal BBB breakdown. When the BBB is disrupted, the gadoversetamide molecules diffuse into the interstitial compartment thereby producing the characteristic paramagnetic effect of T1 and T2 shortening. In general, the addition of contrast to MRI, at the standard clinical dose of 100 micromol/kg, has led to a significantly improved lesion detection, sensitivity and diagnostic accuracy.

5.2 Pharmacokinetic properties

Distribution

The pharmacokinetics of gadoversetamide conforms to a two compartment micromol/kg dose, the mean distribution half life in normal subjects calc residuals in 12 normal volunteers is 13.3 ± 6.8 min. Mean volume of di micromol/kg dose in non-renally impaired patients (including both

CNS or liver pathology) was 158.7 ± 29.0 to 214.3 (range 116.4 t.0) ml/kg. This volume of distribution (approximately 10–15 l for a body weight of 70 kg) is consistent with a medicinal product which distributes into the extracellular fluid. Dose level has no consistent effect on the volume of distribution in any of the studies. Gadoversetamide doe

Elimination

The elimination half life at the 100 micromol/k dose ranges from 1.49 ± 0.15 h in healthy volunteers to 2.11 ± 0.62 h in non-renally impaired patients (including normal subjects and patients with CNS or liver pathology).

The mean plasma clearance of gadoversetamide in healthy subjects (111.0 ± 14.1 ml/min/1­.73m2BSA) is not significantly different from the mean renal clearance. Similar results are obtained in normal subjects and patients with various combinations of liver, CNS and renal dysfunctions with renal clearance of gadoversetamide being approximately 95% of the total plasma clearance. Such results (ratio renal clearance/total plasma clearance close to 1) indicate that gadoversetamide is essentially cleared through the kidneys.

There was no systematic difference in any of the kinetic parameters as a function of dose level (100 to 700 micromol/kg). Therefore, within this dose range, the kinetics of gadoversetamide appear to be linear.

Metabolism

The high accountability for the dose as intact complex in urine suggests that no significant metabolism of gadoversetamide occurs in humans.

Special Populations

Effect of Gender:

Adult male and female subjects were enrolled in two pharmacokinetic studies. No significant differences in pharmacokinetics based on gender were identified.

Effects of Age:

When corrected for body weight, the total body clearance of gadoversetamide is greater in the 2 to 11 year age group (143 ± 27.9 ml/h/kg) than that observed in the 12 to 18 year age group (117 ± 26.1 ml/h/kg) and the two adult populations (82.1 ± 16.8 and 56.5 ± 9.7 ml/h/kg in the 19 to 64 and > 65 year of age groups, respectively).

The elimination half life in the 2 to 11 and 12 to 18 year age groups (1.4 ± 0.3 and 1.6± 0.3 h-1, respectively) is shorter than that observed in the two adult populations (1.9 ± 0.5 and 2.5± 0.5 h-1 in the 19 to 64 and > 65 year of age groups, respectively). The number of elderly patients in whom the pharmacokinetics were determined was limited (over 65 years, N=3).

Effect of Renal Impairment

Gadoversetamide plasma levels increase linearly with decreasing renal function; in patients with severe renal impairment (CrCl<30 ml/min) this even leads to a six-fold decreased gadoversetamide clearance and a corresponding six-fold increased extent of exposure AUC and t>/2. Since gadoversetamide is only administered as a single dose this will lead to a longer and higher exposure for a limited duration. Still, after 72 hours even in patients with severe renal impairment nearly the whole dose is recovered in the urine and in healthy populations up to 500 micromol/kg doses were administered without safety issues. Nevertheless, because of reported cases of NSF that may be associated with renal impairment for other gadolinium containing contrast agents and for gadoversetamide, Optimark should not be used in these patients.

5.3 Preclinical safety data

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute toxicity, reproductive toxicity, local tolerance, antigenicity, and genotoxicity. No carcinogenicity studies were performed.

Repeated-dose toxicity studies in rats and dogs revealed vacuolation of the tubular cells of the kidneys, with strong evidence for reversibility of the effect. No functional impairment was observed.

The elimination of Optimark in dogs younger than 3 months of age was significantly delayed because of immature renal function and resulted in a high systemic exposure to Optimark. Weekly repeated dosing of two to twenty times the clinical dose from one week of age through maturation resulted in extensive mineralization of tissues, which produced localized effects, such as ulcerative dermatitis, compromised circulation and hepatic dysfunction.

Versetamide

Calcium hydroxide

Calcium chloride dihydrate

Sodium hydroxide and/or hydrochloric acid for pH adjustment

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, Optimark should not be mixed with other medicinal products.

• 6.3 Shelf-life

• 3 years.

6.4 Special precautions for storage

Pre-filled syringe

Keep the syringe in the outer carton in order to protect from light.

Vial

Keep the vial in the outer carton in order to protect from light.

Do not refrigerate or freeze.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Pre-filled syringe

Optimark is filled in pre-filled syringes made of polypropylene. Syringe tip cap and piston are made of bromobutyl rubber.

Pre-filled syringes:

Assembly and Inspection

Inspect the syringe for signs of leakage. Do not use if leakage is observed.

After screwing the push rod into the syringe piston, it is important to turn the push rod an additional % turn so that the grey piston rotates freely

Prior to using the syringe, twist off grey tip cap and discard. Syringe is now ready for needle or infusion tubing attachment.

Discard syringe and unused portion of the solution after use.

Any unused product or waste material should be disposed of in accordance with local requirements. The peel-off tracking label on the pre-filled syringes should be stuck onto the patient record to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.

Vial

Optimark should be drawn into the syringe and used immediately.

The product must be examined before use to confirm that all solids are dissolved and that the container and closure are undamaged. If solids remain, the vial must be discarded.

Discard syringe and unused portion of the solution after use.

Any unused product or waste material should be disposed of in accordance with local requirements.

cs

The peel-off tracking label 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. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.

7. MARKETING AUTHORISATION HOLDER

Guerbet

15, rue des Vanesses

93420 Villepinte

France

8. MARKETING AUTHORISATION NUMBER(S)

Pre-filled syringe

1 × 10 ml: EU/1/07/398/007

10 × 10 ml: EU/1/07/398/008

1 × 15 ml: EU/1/07/398/009

10 × 15 ml: EU/1/07/398/010

1 × 20 ml: EU/1/07/398/011

10 × 20 ml: EU/1/07/398/012

1 × 30 ml: EU/1/07/398/013

10 × 30 ml EU/1/07/398/014

Vial

1 × 10 ml: EU/1/07/398/001

10 × 10 ml: EU/1/07/398/002

1 × 15 ml: EU/1/07/398/003

10 × 15 ml: EU/1/07/398/004

1 × 20 ml: EU/1/07/398/005

10 × 20 ml: EU/1/07/398/006

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 23 July 2007

Date of latest renewal: 15 June 2012