Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Bayer plc, 400 South Oak Way, Reading, RG2 6AD
Pharmacotherapeutic group: Paramagnetic contrast media,
ATC code: V08CA09
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.
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.
In a study designed as an intra-individual, crossover comparison, Gadovist was compared to gadoterate meglumine (both at 0.1 mmol/kg) in the visualization of cerebral neoplastic enhancing lesions in 132 patients.
The primary efficacy endpoint was the overall preference for either Gadovist or gadoterate meglumine by the median blinded reader. Superiority of Gadovist was demonstrated by a p-value of 0.0004. In detail, a preference of Gadovist was given for 42 patients (32%) compared to an overall preference for gadoterate meglumine for 16 patients (12 %). For 74 patients (56 %) no preference for one or the other contrast agent was given.
For the secondary variables lesion-to-brain ratio was found to be statistically significantly higher for Gadovist (p <0.0003). Percent of enhancement was higher with Gadovist compared to gadoterate meglumine, with a statistical significant difference for the blinded reader (p <0.0003).
Contrast-to-noise ratio, showed a higher mean value following Gadovist (129) compared to gadoterate meglumine (98). The difference was not statistically significant.
Two single dose phase I/III studies in 138 paediatric subjects scheduled for CE-MRI of CNS, liver and kidneys or CE-MRA and in 44 subjects aged 0 - <2 years (including term neonates) scheduled to undergo routine CE-MRI of any body region have been performed. Diagnostic efficacy and an increase in diagnostic confidence was demonstrated for all parameters evaluated in the studies and there was no difference among the paediatric age groups and when compared to adults. Gadovist was well tolerated in these studies 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 in a biphasic manner. At a dose of 0.1 mmol gadobutrol/kg BW, an average of 0.59 mmol gadobutrol/l plasma was measured 20 minutes after the injection and 0.3 mmol gadobutrol/l plasma 60 minutes post injection.
No metabolites are detected in plasma or urine.
Within two hours more than 50% and within 12 hours more than 90% of the given dose is eliminated via urine with a mean terminal half-life of 1.8 hours (1.3-2.1 hours), corresponding to the renal elimination rate. 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 faeces.
Pharmacokinetics of gadobutrol in paediatric population aged <18 years and in adults are similar (see section 4.2).
Two single dose phase I/III studies inpaediatric patients <18 years have been performed. The pharmacokinetics were evaluated in 130 paediatric patients aged 2 - <18 years and in 43 paediatric patients <2 years of age (including term neonates).
It was shown that the pharmacokinetic (PK) profile of gadobutrol in children of all ages is similar to that in adults resulting in similar values for area under the curve (AUC), body weight normalized plasma clearance (CLtot) and volume of distribution (Vss), as well as elimination half-life and excretion rate.
Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to <18 year old age group).
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.
In patients with impaired renal function, the serum half-life of gadobutrol is prolonged due to the reduced glomerular filtration. The mean terminal half-life was prolonged to 5.8 hours in moderately impaired patients (80 >CLCR >30 ml/min) and further prolonged to 17.6 hours in severely impaired patients not on dialysis (CLCR <30 ml/min). The mean serum clearance was reduced to 0.49 ml/min/kg in mild to moderately impaired patients (80 >CLCR >30 ml/min) and to 0.16 ml/min/kg in severely impaired patients not on dialysis (CLCR <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.
Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in children of all ages including term neonates and infants.
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.
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