Gadovist® 1.0 mmol/ml solution for injection and Gadovist® 1.0 mmol/ml solution for injection pre-filled syringe/cartridge

1 ml of solution for injection contains 604.72 mg of gadobutrol (equivalent to 1.0 mmol gadobutrol containing 157.25 mg gadolinium).

1 vial with 7.5 ml contains 4535.4 mg gadobutrol,

1 vial with 15 ml contains 9070.8 mg gadobutrol,

1 vial with 30 ml contains 18141.6 mg gadobutrol,

1 bottle with 65 ml contains 39306.8 mg gadobutrol.

1 prefilled syringe with 5.0 ml contains 3023.6 mg gadobutrol,

1 prefilled syringe with 7.5 ml contains 4535.4 mg gadobutrol,

1 prefilled syringe with 10 ml contains 6047.2 mg gadobutrol,

1 prefilled syringe with 15 ml contains 9070.8 mg gadobutrol,

1 prefilled syringe with 20 ml contains 12094.4 mg gadobutrol.

1 cartridge with 15 ml contains 9070.8 mg gadobutrol,

1 cartridge with 20 ml contains 12094.4 mg gadobutrol,

1 cartridge with 30 ml contains 18141.6 mg gadobutrol.

1 ml contains 0.00056 mmol (equivalent to 0.013 mg) of sodium (see section 4.4).

For a full list of excipients, see section 6.1.

Solution for injection and solution for injection in pre-filled syringe/cartridge.

Clear, colourless to pale yellow liquid.

Physico-chemical properties:

Osmolality at 37°C: 1603 mOsm/kg H₂O

Viscosity at 37°C: 4.96 mPa^.s

This medicinal product is for diagnostic use only. Gadovist is indicated in adults, adolescents and children aged 2 years and older for:

• Contrast enhancement in cranial and spinal magnetic resonance imaging (MRI).

• Contrast enhanced MRI of liver or kidneys in patients with high suspicion or evidence of having focal lesions to classify these lesions as benign or malignant.

• Contrast enhancement in magnetic resonance angiography (CE-MRA).

Gadovist should only be administered by healthcare professionals experienced in the field of clinical MRI practice.

Method of administration

This medicinal product is for intravenous administration only.

The dose required is administered intravenously as a bolus injection. Contrast-enhanced MRI can commence immediately afterwards (shortly after the injection depending on the pulse sequences used and the protocol for the examination).

Optimal signal enhancement is observed during arterial first pass for CE-MRA and within a period of about 15 minutes after injection of Gadovist for CNS indications (time depending on type of lesion/tissue).

T₁ -weighted scanning sequences are particularly suitable for contrast-enhanced examinations.

Intravascular administration of contrast media should, if possible, be done with the patient lying down. After the administration, the patient should be kept under observation for at least half an hour, since experience shows that the majority of undesirable effects occur within this time.

Instructions for use:

This product is intended for single use only.

This medicinal product should be visually inspected before use.

Gadovist should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container. Contrast medium not used in one examination must be discarded.

Vials

Gadovist should not be drawn up into the syringe from the vial until immediately before use.

The rubber stopper should never be pierced more than once.

If this medicinal product is intended to be used with an automatic application system, its suitability for the intended use has to be demonstrated by the manufacturer of the medicinal device. Any additional instructions from the respective equipment manufacturer must also be strictly adhered to.

Pre-filled syringes

The prefilled syringe must be taken from the pack and prepared for the injection immediately before the administration.

The tip cap should be removed from the prefilled syringe immediately before use.

Cartridges

Administration of contrast media should be performed by qualified personnel with the appropriate procedures and equipment.

Sterile technique must be used in all injections involving contrast media.

The contrast medium must be administered by means of a MEDRAD Spectris® type injector. Instructions of the device manufacturer must be followed.

• Dosage

• Adults

CNS indications:

The recommended dose for adults is 0.1 mmol per kilogram body weight (mmol/kg BW). This is equivalent to 0.1 ml/kg BW of the 1.0 M solution.

If a strong clinical suspicion of a lesion persists despite an unremarkable MRI or when more accurate information might influence therapy of the patient, a further injection of up to 0.2 ml/kg BW within 30 minutes of the first injection may be performed.

CE-MRI of liver and kidneys:

The recommended dose for adults is 0.1 mmol per kilogram body weight (mmol/kg BW). This is equivalent to 0.1 ml/kg BW of the 1.0M solution.

CE-MRA:

Imaging of 1 field of view (FOV): 7.5 ml for body weight below 75 kg; 10 ml for body weight of 75 kg and higher (corresponding to 0.1-0.15 mmol/kg BW).

Imaging of >1 field of view (FOV): 15 ml for body weight below 75 kg; 20 ml for body weight of 75 kg and higher (corresponding to 0.2-0.3 mmol/kg BW).

Special Populations

Impaired renal function

Gadovist should only be used in patients with severe renal impairment (GFR < 30 ml/min/1.73m²) and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4). If it is necessary to use Gadovist, the dose should not exceed 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Gadovist injections should not be repeated unless the interval between injections is at least 7 days.

Paediatric population

For children aged 2 years and older and for adolescents the recommended dose is 0.1 mmol Gadovist per kg body weight (equivalent to 0.1 ml Gadovist per kg body weight) for all indications (see section 4.1).

Gadovist is not recommended for use in children below age 2 years due to a lack of data on efficacy and safety.

Elderly (aged 65 years and above)

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

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

While injecting Gadovist into veins with a small lumen there is the possibility of adverse effects such as reddening and swelling.

The usual safety requirements for magnetic resonance imaging, especially the exclusion of ferromagnetic materials, also apply when using Gadovist.

• Hypersensitivity reactions

Hypersensitivity reactions, including anaphylactoid reactions ranging to shock, have been observed after administration of Gadovist. To be able to react immediately to an emergency, medicinal products and equipment (e.g. endotracheal tube and respirator) should be within hand-reach.

Hypersensitivity reactions are not predictable, however in patients with an allergic disposition hypersensitivity may occur more often than in patients without such a disposition. In rare cases delayed anaphylactoid reactions (after hours to days) have been observed.

• Impaired renal function

Prior to administration of Gadovist, 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 <30ml/min/1.73m²). Patients undergoing liver transplantation period 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 Gadovist, it should therefore only be used in these patients with severe renal impairment and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI).

Haemodialysis shortly after Gadovist administration may be useful at removing Gadovist from the body. There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis.

• Elderly

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

• Seizure disorders

Like with other gadolinium containing contrast agents special precaution is necessary in patients with a low threshold for seizures.

• Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose (based on the average amount given to a 70 kg person), i.e. essentially 'sodium-free'.

No interaction studies have been performed.

Pregnancy

There are no data from the use of gadobutrol in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3).

Gadovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadobutrol.

Lactation

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 or discontinuing of breast feeding for a period of 24 hours after administration of Gadovist, should be at the discretion of the doctor and lactating mother.

Not relevant.

The overall safety profile of Gadovist is based on data from more than 4,500 patients in clinical trials, and from post-marketing surveillance.

The most frequently observed adverse drug reactions ( 0.5%) in patients receiving Gadovist are headache, nausea, injection site reactions, dysgeusia and feeling hot.

The most serious adverse drug reactions in patients receiving Gadovist are cardiac arrest, respiratory arrest and anaphylactoid shock.

Delayed anaphylactoid reactions (hours later up to several days) have been rarely observed (see section 4.4).

Most of the undesirable effects were of mild to moderate intensity.

The adverse drug reactions observed with Gadovist are represented in the table below. They are classified according to System Organ Class (MedDRA). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions from clinical trials are classified according to their frequencies.

Frequency groupings are defined according to the following convention: common: 1/100 to < 1/10; uncommon: 1/1,000 to < 1/100; rare: 1/10,000 to <1/1,000. The adverse drug reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under 'not known'.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions reported in clinical trials or during post-marketing surveillance in patients treated with Gadovist.

^§ Hypersensitivity / anaphylactoid reactions identified only during post-marketing surveillance (frequency not known)

* life-threatening and/or fatal cases have been reported

° Injection site reactions (various kinds) comprise the following terms: Injection site extravasation, injection site burning, injection site coldness, injection site warmth, injection site erythema or rash, injection site pain, injection site hematoma

Patients with an allergic disposition suffer more frequently than others from hypersensitivity reactions.

Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with Gadovist (see section 4.4).

The maximum daily single dose tested in humans is 1.5 mmol gadobutrol/kg body weight.

No signs of intoxication from an overdose have so far been reported during clinical use.

In case of inadvertent overdosage, cardiovascular monitoring (including ECG) and control of renal function is recommended as a measure of precaution.

In case of an overdose in patients with renal insufficiency, Gadovist can be removed by haemodialysis. After 3 haemodialysis sessions approx. 98% of the agent are removed from the body. However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

Pharmacotherapeutic group: Paramagnetic contrast media

ATC - Code: V08C A09

The contrast-enhancing effect is mediated by gadobutrol, the nonionic complex consisting of gadolinium(III) and the macrocyclic ligand dihydroxy- hydroxymethylpropyl- tetraazacyclododecane-triacetic acid (butrol).

In clinical doses, gadobutrol leads to shortening of the relaxation times of protons in tissue water. At 0.47 T (20 MHz), pH 7 and 40°C the paramagnetic effect (relaxivity), as determined from the effect on spin-lattice relaxation time (T₁) measured in plasma - is about 5.6 l mmol^-1 sec^-1 and the spin-spin relaxation time (T₂) is about 6.5 l mmol^-1 sec^-1. Within the range 0.47 to 2.0 Tesla, the relaxivity displays only slight dependency on the strength of the magnetic field.

Gadobutrol does not cross an intact blood-brain barrier and therefore does not accumulate in healthy brain tissue or in lesions featuring an intact blood-brain barrier. With high local tissue concentrations of gadobutrol the T₂ effect results in a lessening of signal intensity.

In a pivotal phase III liver study average sensitivity in combined pre and post-contrast MRI for Gadovist-treated patients was 79% and specificity was 81% for lesion detection and classification of suspected malignant liver lesions (patient-based analysis).

In a pivotal phase III kidney study average sensitivity was 91% (patient-based analysis) and 85% (lesion-based analysis) for classification of malignant and benign renal lesions. Average specificity in a patient-based analysis was 52% and in a lesion based analysis 82%.

The increase of sensitivity from pre-contrast to combined pre and post-contrast MRI for Gadovist-treated patients was 33% in the liver study (patient-based analysis) and 18% in the kidney study (patient based analysis as well as lesion-based analysis). The increase in specificity from pre-contrast to combined pre and post-contrast MRI was 9% in the liver study (patient based analysis) while there was no increase in specificity in the kidney study (patient-based analysis as well as lesion-based analysis).

All results are average results obtained in blinded reader studies.

A single dose phase I/III study in 140 pediatric patients (aged 2 to 17 years) scheduled for CE-MRI of CNS, liver and kidneys or CE-MRA has been performed. Diagnostic efficacy and an increase in diagnostic confidence was demonstrated for all parameters evaluated in the study and there was no difference among the age groups. Gadovist was well tolerated in this study with the same safety profile of gadobutrol as in adults.

After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. Plasma protein binding is negligible.

The pharmacokinetics of gadobutrol in humans are dose proportional. After doses up to 0.4 mmol gadobutrol/kg body weight, the plasma level declines after an early distribution phase with a mean terminal half-life of 1.8 hours (1.3 to 2.1 hours), corresponding to the renal elimination rate. At a dose of 0.1 mmol gadobutrol/kg BW, an average of 0.59 mmol gadobutrol/l plasma was measured 2 minutes after the injection and 0.3 mmol gadobutrol/l plasma 60 minutes post injection. Within two hours more than 50 % and within 12 hours more than 90% of the given dose is eliminated via the urine. At a dose of 0.1 mmol gadobutrol/kg BW, an average of 100.3 ± 2.6 % of the dose was excreted within 72 h after administration. In healthy persons renal clearance of gadobutrol is 1.1 to 1.7 ml min^-1 kg^-1 and thus comparable to the renal clearance of inulin, pointing to the fact that gadobutrol is eliminated primarily by glomerular filtration. Less than 0.1 % of the dose is eliminated via the faeces. No metabolites are detected in plasma or urine.

Characteristics in special patient populations

• Paediatric population

A single dose phase I/III study in 140 pediatric patients (aged 2 to 17 years) scheduled for CE-MRI of CNS, liver and kidneys or CE-MRA has been performed.

It was shown that the overall pharmacokinetic (PK) profile of gadobutrol in children over 2 is similar to that in adults.

PK parameters such as total clearance (CLtot), area under the curve (AUC) and volume of distribution (V) increased with increasing body weight. Neither age nor gender was found to have an additional independent effect on PK. The amount of gadobutrol excreted into urine within 6 hours p.i. was 98.7% (median) of the administered dose, confirming fast renal excretion of gadobutrol also in the paediatric population.

• Elderly population (aged 65 years and above)

Due to physiological changes in renal function with age, in elderly healthy volunteers (aged 65 years and above) systemic exposure was increased by approximately 33% (men) and 54% (women) and terminal half-life by approximately 33% (men) and 58% (women). The plasma clearance is reduced by approximately 25% (men) and 35% (women), respectively. The recovery of the administered dose in urine was complete after 24 h in all volunteers and there was no difference between elderly and non-elderly healthy volunteers.

• Renal impairment

In patients with impaired renal function, the serum half-life of gadobutrol is prolonged due to reduced glomerular filtration. The mean terminal half-life was prolonged to 5.8 hours in moderately impaired patients (80>CL_CR>30 ml/min) and further prolonged to 17.6 hours in severely impaired patients not on dialysis (CL_CR<30 ml/min). The mean serum clearance was reduced to 0.49 ml/min/kg in mild to moderately impaired patients (80>CL_CR>30 ml/min) and to 0.16 ml/min/kg in severely impaired patients not on dialysis (CL_CR<30 ml/min). Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within 5 days (see also sections 4.2 and 4.4).

In patients requiring dialysis, gadobutrol was almost completely removed from serum after the third dialysis.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Repeated intravenous treatment in reproductive toxicology studies caused a retardation of embryonal development in rats and rabbits and an increase in embryolethality in rats, rabbits and monkeys at dose levels being 8 to 16 times (based on body surface area) or 25 to 50 times (based on body weight) above the diagnostic dose in humans. It is not known whether these effects can also be induced by a single administration.

Radioactively labelled gadobutrol administered intravenously to lactating rats was transferred to the neonates via milk at less than 0.1% of the administered dose.

In rats, absorption after oral administration was found to be very small and amounted to about 5% based on the fraction of the dose excreted in urine.

In preclinical cardiovascular safety pharmacology studies, depending on the dose administered, transient increases in blood pressure and myocardial contractility were observed. These effects have not been observed in humans.

Calcobutrol sodium

Trometamol

Hydrochloric acid 1N

Water for injections

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

Shelf life of the medicinal product as packaged for sale:

3 years (vials)

3 years (prefilled syringe)

3 years (cartridge)

Shelf life after first opening of the container:

Any solution for injection not used in one examination must be discarded. Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. 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 and would normally not be longer than 24 hours at 2 to 8 °C, unless opening has taken place in controlled and validated aseptic conditions.

For vials only:

The following applies to the use of the infusion bottle containing 65 ml:

After opening of the infusion bottle under aseptic conditions Gadovist remains stable for at least 8 hours at 25°C.

This medicinal product does not require any special storage conditions.

For storage conditions after first opening, see section 6.3.

Vials

1 vial (type I glass) with a stopper (chlorobutyl elastomer) and a pure aluminium with internal and external lacquer flanged cap containing 7.5 ml, 15 ml or 30 ml solution for injection.

1 infusion bottle (type II glass) with a stopper (chlorobutyl elastomer) and a pure aluminium with internal and external lacquer flanged cap containing 65 ml solution for injection.

Pack sizes of:

1 and 10 vials

1 and 10 bottles

Not all pack sizes may be marketed.

Pre-filled syringes

One 10 ml pre-filled syringe (type I glass) with a plunger stopper (chlorobutyl elastomer) and a tip cap (chlorobutyl elastomer) contains 5 ml, 7.5 ml and 10 ml solution for injection.

One 17 ml pre-filled syringe (type I glass) with a plunger stopper (chlorobutyl elastomer) and a tip cap (chlorobutyl elastomer) contains 15 ml solution for injection.

One 20 ml pre-filled syringe (type I glass) with a plunger stopper (chlorobutyl elastomer) and a tip cap (chlorobutyl elastomer) contains 20 ml solution for injection.

One 65 ml cartridge (cyclo-olefine-polymer) with a plunger stopper (polyisoprene, type I, siliconised with silicone oil), a tip cap (chlorobutyl rubber), a hard core (polycarbonate), a safety cap (polypropylene) and a swivelnut (polycarbonate) contains 15, 20 or 30ml solution for injection.

Pack sizes of:

1 and 5 pre-filled syringes

1 and 5 cartridges

Not all pack sizes may be marketed.

Any contrast medium not used in one examination must be discarded.

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

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

United Kingdom

Date of first authorisation:

Solution for injection (vials): 01 May 2008

Solution for injection (pre-filled syringes/cartridges): 01 May 2008

Date of last renewal:

Solution for injection (vials): 14 October 2010

Solution for injection (pre-filled syringes/cartridges): 14 October 2010

Solution for injection (vials): 19 March 2012

Solution for injection (pre-filled syringes/cartridges): 19 March 2012

POM