Bracco UK Limited

5 ml of solution for injection contain: gadobenic acid 1670 mg (2.5 mmol) as dimeglumine salt. [gadobenate dimeglumine 2645 mg = gadobenic acid 1670 mg + meglumine 975 mg]

10 ml of solution for injection contain: gadobenic acid 3340 mg (5 mmol) as dimeglumine salt. [gadobenate dimeglumine 5290 mg = gadobenic acid 3340 mg + meglumine 1950 mg]

15 ml of solution for injection contain: gadobenic acid 5010 mg (7.5 mmol) as dimeglumine salt. [gadobenate dimeglumine 7935= gadobenic acid 5010 mg + meglumine 2925 mg]

20 ml of solution for injection contain: gadobenic acid 6680 mg (10 mmol) as dimeglumine salt. [gadobenate dimeglumine 10580 mg = gadobenic acid 6680 mg + meglumine 3900 mg]


Section 4.2 - additional text

'and in paediatric patients greater than 2 years of age'

Paediatric population

No dosage adjustment is considered necessary.

Use for MRI of the brain and spine is not recommended in children less than 2 years of age.

Use for MRI of the liver and MRA is not recommended in children less than 18 years of age.

Section 4.2 - text removed

'Multihance should not be used'

The safety and efficacy of MultiHance have not been established in patients under 18 years old. Therefore, use of MultiHance in this patient group cannot be recommended.

Section 4.8 - additional text

Paediatric

In paediatric patients enrolled in clinical trials the most commonly reported adverse reactions included vomiting (1.4%), pyrexia (0.9%) and hyperhydrosis (0.9%). The frequency and nature of adverse reactions was similar to that in adults.

Section 5.1- additional text

'conducted in adults for'


Section 5.2 - additional text

Population pharmacokinetic analysis was performed on systemic drug concentration-time data from 80 subjects (40 adult healthy volunteers and 40 paediatric patients) aged 2 to 47 years following intravenous administration of gadobenate dimeglumine.  The kinetics of gadolinium down to the age of 2 years could be described by a two compartment model with standard allometric coefficients and a covariate effect of creatinine clearance (reflecting glomerular filtration rate) on gadolinium clearance. The pharmacokinetic parameter values (referenced to adult body weight) were consistent with previously reported values for MultiHance and consistent with the physiology presumed to underlie MultiHance distribution and elimination: distribution into extracellular fluid (approximately 15 L in an adult, or 0.21 L/kg) and elimination by glomerular filtration (approximately 130 mL plasma per minute in an adult, or 7.8 L/h and 0.11 L/h/kg). Clearance and volume of distribution decreased progressively for younger subjects due to their smaller body size. This effect could largely be accounted for by normalising pharmacokinetic parameters for body weight. Based on this analysis, weight based dosing for MultiHance in paediatric patients gives similar systemic exposure (AUC) and maximum concentration (Cmax) to those reported for adults, and confirms that no dose adjustment is necessary for the paediatric population over the proposed age range (2 years and above).

Section 6.5 - additional text
'single dose'

Section 10 - date of revision

In two studies designed as intra-individual, crossover comparisons of 0.1 mmol/kg body weight MultiHance vs 0.1 mmol/kg body weight of two active comparators (gadopentetate dimeglumine or gadodiamide), conducted in patients with known or suspected brain or spine disease undergoing MRI of the central nervous system (CNS), MultiHance provided significantly (p<0.001) higher increase in lesion signal intensity, contrast-to-noise ratio, and lesion-to-brain ratio, as well as significantly  (p<0.001) better visualisation of CNS lesions in images obtained with 1.5 Tesla scanners as tabulated below.

In the trials MH-109 and MH-130, the impact of improved visualization of CNS lesions with MultiHance versus gadodiamide or gadopentetate dimeglumine on diagnostic thinking and patient management was not studied.

In section 4.2 (Posology and method of administration) additional text has been added:

Special Populations

Impaired renal function

Use of MultiHance should be avoided in patients with severe renal impairment (GFR < 30 ml/min/1.73m²) and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4). If use of MultiHance cannot be avoided, the dose should not exceed 0.1 mmol/kg body weight when used for MR of the brain and spine or MR-angiography and should not exceed 0.05 mmol/kg body weight when used for MR of the liver. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, MultiHance injections should not be repeated unless the interval between injections is at least 7 days.

Elderly (aged 65 years and above)
No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4)



In section 4.4 (Special warnings and special precaution for use) additional text has been added:

Impaired renal function

Prior to administration of MultiHance, 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 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 MultiHance, 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 MultiHance administration may be useful at removing MultiHance 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 gadobenate dimeglumine may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.


In section 4.6 (Pregnancy and lactation) additional text has been added:

Pregnancy

There are no data from the use of gadobenate dimeglumine in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3).MultiHance should not be used during pregnancy unless the clinical condition of the woman requires use of gadobenate dimeglumine.

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 into milk and poor absorption from the gut. Continuing or discontinuing breast feeding for a period of 24 hours after administration of MultiHance should be at the discretion of the doctor and lactating mother.

In section 4.9 (Overdose) - additional text has been added:

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


In section 6.6 (Special prcautions for disposal and other handlings) additional text has been added:

The peel-off tracking label on the vials should be stuck onto the patient records to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded.

Impaired renal function

There have been reports of Nephrogenic Systemic Fibrosis (NSF) associated with use of some gadolinium-containing contrast agents in patients with severe renal impairment (GFR<30ml/min/1.73m²). As there is a possibility that NSF may occur with MultiHance, it should be avoided in patients with acute or chronic severe renal impairment (GFR<30ml/min/1.73m²) and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period unless the diagnostic information is essential and cannot be obtained through other means.

The risk for the development of NSF in patients with moderate renal impairment is unknown, therefore MultiHance should be used with caution in patients with moderate renal impairment (GFR 30-59ml/min/1.73m²).

All patients should be screened, in particular patients over the age of 65, for renal dysfunction by obtaining a history and/or laboratory tests.

Haemodialysis shortly after MultiHance administration may be useful at removing MultiHance 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.