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 millimol. 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 of sodium. 30 ml of the solution contain 43.13 mg sodium. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe. Clear, colourless to pale yellow solution. pH: 6.0 - 7.5 Osmolality (37degC): 1000 - 1200 mOsm/kg

CLINICAL PARTICULARS

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.

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.

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.

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.

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

Optimark is contraindicated in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) 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.

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).

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

Contraindications

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

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.

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 hour after administering the contrast medium. As with all other contrast media of the same class, late reactions 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:

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.

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.

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.

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.

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). 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.

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.

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

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.

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 1mmol sodium; i.e. they are essentially sodium free. Higher doses contain 1 mmol of sodium or more, which should be taken into consideration for patients on a controlled sodium diet. 20 ml of the solution contain 28.75 mg of sodium. 30 ml of the solution contain 43.13 mg sodium.

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.

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 ortho- cresolphthalein 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.

Fertility, pregnancy and lactation

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.

It is unknown whether gadoversetamide is excreted in human milk. There is insufficient information on the excretion of gadoversetamide in animal 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.

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

Effects on ability to drive and use machines

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).

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
Nervous System Disorders	Headache, Dysgeusia	Dizziness, Hypoaesthesia, Paraesthesia, Parosmia	Convulsion, Tremor, Somnolence, Burning sensation	Syncope
Eye Disorders			Erythema of eyelid, Eye pain, Vision blurred, Conjunctivitis, Ocular hyperaemia
Ear and Labyrinth Disorders			Tinnitus, Vertigo
Cardiac Disorders			Palpitations, AV block first degree, Extrasystoles, Tachycardia, Arrhythmia
Vascular Disorders		Flushing	Hypotension, Hypertension
Respiratory, Thoracic and Mediastinal Disorders		Nasal congestion, 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	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).

Paediatric population

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

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).

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic Group: MRI contrast media, ATC code: V08CA06 Gadoversetamide is a chelate containing gadolinium - which has paramagnetic properties and is responsible for the contrast enhancement 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.

Pharmacokinetic properties

The pharmacokinetics of gadoversetamide conforms to a two compartment open-model. At the 100 micromol/kg dose, the mean distribution half life in normal subjects calculated by the method of residuals in 12 normal volunteers is 13.3 +- 6.8 min. Mean volume of distribution at the 100 micromol/kg dose in non-renally impaired patients (including both normal subjects and patients with CNS or liver pathology) was 158.7 +- 29.0 to 214.3 (range 116.4 to 295.0) 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 does not undergo protein binding in vitro.

The elimination half life at the 100 micromol/kg 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/1.73m2 BSA) 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.

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

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 t1/2. 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.

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.

PHARMACEUTICAL PARTICULARS

List of excipients

Versetamide Calcium hydroxide Calcium chloride dihydrate Sodium hydroxide and/or hydrochloric acid for pH adjustment Water for injections

Incompatibilities

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

Shelf-life

3 years. Chemical and physical in-use stability has been demonstrated for 24 hours at up to 25degC. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Special precautions for storage

Keep the syringe 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.

Nature and contents of container

Optimark is filled in pre-filled syringes made of polypropylene. Syringe tip cap and piston are made of bromobutyl rubber. Pack sizes: 1 x 10 ml 10 x 10 ml 1 x 15 ml 10 x 15 ml 1 x 20 ml 10 x 20 ml 1 x 30 ml 10 x 30 ml Not all pack-sizes may be marketed.

Special precautions for disposal and other handling

Optimark is intended for single use only; any unused portions should be discarded. Do not use the solution if it is discoloured or particulate matter is present. If non-disposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

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 1/2 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.

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

1 x 10 ml: EU/1/07/398/007 10 x 10 ml: EU/1/07/398/008 1 x 15 ml: EU/1/07/398/009 10 x 15 ml: EU/1/07/398/010 1 x 20 ml: EU/1/07/398/011 10 x 20 ml: EU/1/07/398/012 1 x 30 ml: EU/1/07/398/013 10 x 30 ml EU/1/07/398/014

DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

13/03/2013 Detailed information on this medicinal 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