Each mL contains 1.0 mmol gadobutrol (equivalent to 604.72 mg gadobutrol) as active ingredient.
The physico-chemical properties of the 1.0 mmol/mL solution for injection Gadobutrol (Gadovist) listed as follows are: Osmolarity at 37 °C: 1117 mOsm/L solution.
Osmolality at 37°C: 1603 mOsm/kg H2O.
pH of the solution: 6.6-8.0.
Viscosity at 37°C: 4.96 mPa·s.
List of excipients: 1 N hydrochloric acid, Calcobutrol sodium, Trometamol, Water for injection.
Pharmacotherapeutic group: Paramagnetic contrast media. ATC Code: V08C A09.
Pharmacology: Pharmacodynamics: Mechanism of action: Gadobutrol (Gadovist) is a paramagnetic contrast agent for magnetic resonance imaging.
The contrast-enhancing effect is mediated by gadobutrol, a neutral (non-ionic) complex consisting of gadolinium (III) and the macrocyclic ligand dihydroxy-hydroxymethylpropyltetraazacyclododecane- triacetic acid (butrol).
When T1-weighted scanning sequences are used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues. In T2*-weighted sequences, however, the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease.
Pharmacodynamic effects: Gadobutrol leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, a magnetic field strength of 0.47 T and 40°C the relaxivity (r1) - determined from the influence on the spin-lattice relaxation time (T1) of protons in plasma - is about 5.6 L/(mmol·sec) and the relaxivity (r2) - determined from the influence on the spin-spin relaxation time (T2)- is about 6.5 L/(mmol sec). The relaxivity displays only slight dependency on the strength of the magnetic field.
The macrocyclic ligand forms a stable complex with the paramagnetic gadolinium ion with extremely high in-vivo and in-vitro stability (thermodynamic stability constant: log K = 21-22). Gadobutrol is a highly water-soluble, extremely hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006. The substance does not display any inhibitory interaction with enzymes.
Clinical efficacy and safety: In a study designed as an intra-individual, crossover comparison, Gadobutrol (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 Gadobutrol (Gadovist) or gadoterate meglumine by the median blinded reader. Superiority of Gadobutrol (Gadovist) was demonstrated by a p-value of 0.0004. In detail, a preference of Gadobutrol (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 Gadobutrol (Gadovist) (p<0.0003). Percent of enhancement was higher with Gadobutrol (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 Gadobutrol (Gadovist) compared to gadoterate meglumine. The difference was not statistically significant.
Pharmacokinetics: General introduction: Gadobutrol behaves in the organism like other highly hydrophilic biologically inert, renally excreted compounds (e.g. mannitol or inulin).
Absorption and distribution: Gadobutrol is rapidly distributed in the extracellular space. Protein binding is negligible. After a dose of 0.1 mmol gadobutrol/kg body weight, 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 p.i.
Investigations in animals: In rats it has been demonstrated that gadobutrol does not penetrate the intact blood-brain barrier.
In rabbits the placental transfer was insignificant, 0.01 % of the administered dose being detected in the fetuses.
In lactating rats, less than 0.1% of the total administered dose was excreted into the breast milk. 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.
Enterohepatic circulation has not been observed.
Metabolism: Gadobutrol is not metabolized.
Elimination: Gadobutrol is eliminated from plasma with a mean terminal half-life of 1.81 hours (range 1.33-2.13 hours).
Gadobutrol is excreted in an unchanged form via the kidneys. The extrarenal elimination is negligible. Renal clearance of gadobutrol is 1.1 to 1.7 mL/min/kg in healthy subjects and, thus, comparable to the renal clearance of inulin, pointing to the fact that gadobutrol is eliminated by glomerular filtration. More than 50% of the given dose were excreted within two hours after intravenous administration via the urine. Gadobutrol was completely excreted within 24 hours. Less than 0.1% was eliminated via the feces.
Linearity/Non-linearity: The pharmacokinetics of gadobutrol in humans were dose proportional (e.g. Cmax, AUC) and dose independent (e.g. Vss, t1/2), respectively.
Additional information on special populations: Geriatric patients: 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.
Pediatric patients: Pharmacokinetics of gadobutrol in the pediatric population aged <18 years and in adults are similar (see Dosage & Administration).
Two single dose phase I/III studies in pediatric patients <18 years have been performed. The pharmacokinetics were evaluated in 130 pediatric patients aged 2 to <18 years and in 43 pediatric patients <2 years of age (including full-term newborns).
It was shown that the pharmacokinetic profile of gadobutrol in children of all ages is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance and Vss, as well as elimination half-life and excretion rate.
Patients with renal impairment: 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 mildly to 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 mildly 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 Dosage & Administration and Precautions).
Hemodialysis treatment might be considered necessary if renal function is severely restricted. In patients requiring dialysis, gadobutrol was almost completely removed from serum after the third dialysis.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of systemic toxicity, genotoxicity, and contact sensitizing potential.
Systemic tolerance: Experimental systemic tolerance studies in animals following repeated daily intravenous administration produced no findings which oppose a single diagnostic administration of Gadobutrol (Gadovist) to humans. On the basis of the results of the acute toxicity studies, a risk of acute intoxication is highly unlikely with Gadobutrol (Gadovist).
Reproduction toxicity: Repeated intravenous dosing 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.
Gadobutrol (Gadovist) was not embryotoxic when given repeatedly during organogenesis at doses up to 2 times (rats and monkeys) or 5 times (rabbits) the recommended single human dose based on body surface area or up to 6 times (monkeys) or 15 times (rats and rabbits) the recommended single human dose based on body weight.
Gadobutrol (Gadovist) was not teratogenic in rats, rabbits and monkeys even when given repeatedly during organogenesis at maximum dose levels tested being 8 to 32 times (based on body surface area) or 25 to 100 times (based on body weight) above the diagnostic dose in humans.
Studies in neonatal/juvenile animals: 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 full-term newborns and infants.
Genotoxicity: Studies of genotoxic effects (gene-, chromosomal- and genome mutation tests) of Gadobutrol (Gadovist) in vivo and in vitro gave no indication of a mutagenic potential.
A study of the tumorigenicity potential of Gadobutrol (Gadovist) was not performed. This was not considered necessary since Gadobutrol (Gadovist) showed no genotoxic properties and no toxic effect on fast growing tissues.
Local tolerance and contact-sensitizing potential: Experimental local tolerance studies with Gadobutrol (Gadovist) following single as well as repeated intravenous administration and single intraarterial administration did not result in adverse local effects.
Experimental local tolerance studies following a single paravenous, subcutaneous as well as intramuscular application indicated that slight local intolerance reactions could occur at the administration site after inadvertent paravenous administration.
Studies of contact-sensitizing effects gave no indication of a sensitizing potential of Gadobutrol (Gadovist).
Safety pharmacology: 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.
This medicinal product is for diagnostic use only.
Gadobutrol (Gadovist) is indicated in adults and children of all ages including full-term newborns for contrast enhanced whole body magnetic resonance imaging (MRI) including: Contrast enhancement in cranial and spinal MRI: Following the injection of Gadobutrol (Gadovist), improved diagnostic information as compared to the mere native MRI scan can be obtained in areas with a penetrable or missing blood-brain barrier, owing to an altered perfusion or to enlarged extracellular space, e.g. in case of primary and secondary tumors, inflammatory diseases, demyelinating diseases.
Special indications in spinal MRI: Differentiation of intra- and extramedullary tumors, demonstration of solid tumor areas in known syrinx, determination of intramedullary tumor spread.
Gadobutrol (Gadovist) is especially suited for high dose indications: such as cases where the exclusion or demonstration of additional foci may influence the therapy or patient management, for detection of very small lesions and for visualization of lesions that do not readily take up contrast media.
Gadobutrol (Gadovist) is also suitable for perfusion studies: for the diagnosis of stroke, the detection of focal cerebral ischemia, and tumor perfusion.
Contrast enhanced MRI of the head and neck region.
Contrast enhanced MRI of the thoracic space.
Contrast enhanced MRI of the breast.
Contrast enhanced MRI of the abdomen (e.g. pancreas, liver and spleen).
Contrast enhanced MRI of the pelvis (e.g. prostate, bladder and uterus).
Contrast enhanced MRI of the retroperitoneal space (e.g. kidney).
Contrast enhanced MRI of the extremities and musculoskeletal system.
Contrast enhancement in Magnetic Resonance Angiography (CE-MRA).
Contrast enhanced cardiac MRI including assessment of myocardial perfusion under pharmacological stress conditions and viability diagnostics (delayed enhancement).
Dosage regimen: Adults: Dosage depends on indication. A single intravenous injection of 0.1 mmol gadobutrol per kg body weight (equivalent to 0.1 mL Gadobutrol (Gadovist) per kg body weight) is generally sufficient. A total amount of 0.3 mmol gadobutrol per kg body weight (equivalent to 0.3 mL Gadobutrol (Gadovist) per kg body weight) may be administered at maximum.
Whole Body MRI (except MRA): In general, the administration of 0.1 mL Gadobutrol (Gadovist) per kg body weight is sufficient to answer the clinical question.
Additional dosage recommendation for cranial and spinal MRI: If a strong clinical suspicion of a lesion persists despite a normal contrast-enhanced MRI or when more accurate information on the number, size or extent of lesions might influence management or therapy of the patient, a further injection of 0.1 mL Gadobutrol (Gadovist) per kg body weight up to 0.2 ml Gadobutrol (Gadovist) per kg body weight within 30 minutes of the first injection may increase the diagnostic yield of the examination.
For the exclusion of metastases or recurrent tumors the injection of 0.3 mL Gadobutrol (Gadovist) per kg body weight often leads to higher diagnostic confidence. This applies to lesions with poor vascularization and/or small extracellular space or when relatively less heavily T1-weighted scanning sequences are used.
For brain perfusion studies the use of an injector is recommended: 0.1-0.3 mL Gadobutrol (Gadovist) per kg body weight (3-5 mL/sec).
CE-MRA: Imaging of one field of view: 7.5 mL for body weight less than 75 kg: 10 mL for body weight of 75 kg or more (corresponding to 0.1-0.15 mmol per kg body weight).
Imaging of more than one field of view: 15 mL for body weight less than 75 kg: 20 mL for body weight of 75 kg or more (corresponding to 0.2-0.3 mmol per kg body weight).
Special patient populations: Pediatric patients: For children of all ages including full-term newborns the recommended dose is 0.1 mmol gadobutrol per kg body weight (equivalent to 0.1 mL Gadobutrol (Gadovist) per kg body weight) for all indications, see Indications.
Geriatric patients: In clinical studies, no overall differences in safety or effectiveness were observed between elderly (aged 65 years and above) and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment is considered necessary.
Patients with hepatic impairment: Since Gadobutrol is exclusively eliminated in an unchanged form via the kidneys, no dosage adjustment is considered necessary (see also Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: The elimination of gadobutrol is prolonged in patients with renal impairment. However, to ensure diagnostically useful images no dosage adjustment is recommended (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Method of Administration: This medicinal product is for intravenous administration only.
The dose required is administered as a bolus injection.
For brain perfusion studies the use of an injector is recommended.
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 Gadobutrol (Gadovist) for other indications (time depending on type of lesion/tissue).
T1-weighted scanning sequences are particularly suitable for contrast-enhanced examinations.
The usual safety rules for magnetic resonance imaging must be observed, e.g. exclusion of cardiac pacemakers and ferromagnetic implants.
Single doses of gadobutrol as high as 1.5 mmol gadobutrol/kg body weight were tolerated well.
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 are recommended as a measure of precaution.
Gadobutrol (Gadovist) can be removed by hemodialysis (see Precautions).
There are no absolute contraindications to the use of Gadobutrol (Gadovist).
Pronounced states of excitement, anxiety and pain may increase the risk of adverse reactions or intensify contrast medium-related reactions.
Hypersensitivity: Particularly careful risk-benefit assessment is required in patients with known hypersensitivity to Gadobutrol (Gadovist).
As with other intravenous contrast agents, Gadobutrol (Gadovist) can be associated with anaphylactoid/hypersensitivity or other idiosynchratic reactions, characterized by cardiovascular, respiratory or cutaneous manifestations, and ranging to severe reactions including shock.
The risk of hypersensitivity reactions is higher in case of: previous reaction to contrast media; history of bronchial asthma; history of allergic disorders.
In patients with an allergic disposition the decision to use Gadobutrol (Gadovist) must be made after particularly careful evaluation of the risk-benefit ratio.
Most of these reactions occur within half an hour of administration.
Therefore, post-procedure observation of the patient is recommended.
Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary. Delayed reactions (after hours up to several days) have been rarely observed (see Adverse Reactions).
Patients taking beta blockers who experience such reactions may be resistant to treatment with beta agonists.
Impaired renal function: No impairment of renal function has so far been observed.
Prior to administration of Gadobutrol (Gadovist) all patients should be screened for renal dysfunction by obtaining a history and/or laboratory tests.
In patients with severely impaired renal function the benefits must be weighed carefully against the risks, since contrast medium elimination is delayed in such cases.
Because Gadobutrol is renally excreted sufficient period of time for elimination of the contrast agent from the body prior to any re-administration in patients with renal impairment should be ensured. Usually, 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 at least 80% of the administered dose was recovered in the urine within 5 days (see also Pharmacology: Pharmacokinetics under Actions).
Gadobutrol (Gadovist) can be removed from the body by hemodialysis. After 3 dialysis sessions approx. 98 % of the agent are removed from the body. For patients already receiving hemodialysis at the time of Gadobutrol (Gadovist) administration, prompt initiation of hemodialysis following the administration of Gadobutrol (Gadovist) should be considered, in order to enhance the contrast agent's elimination.
There have been reports of nephrogenic systemic fibrosis (NSF) (see Adverse Reactions) associated with the use of gadolinium-containing contrast agents including Gadobutrol (Gadovist) in patients with acute or chronic severe renal impairment (GFR <30 mL/min/1.73m2) or acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.
Therefore, Gadobutrol (Gadovist) should only be used in these patients after careful risk/benefit assessment.
Seizure disorders: As with other gadolinium-chelate-containing contrast media, special precaution is necessary in patients with a low threshold for seizures.
Effects on ability to drive or use machines: Not known.
Pregnancy: For gadobutrol no clinical study data on exposed pregnancies are available.
Animal studies at clinically relevant doses have not shown reproductive toxicity after repeated administration (see section Pharmacology: Toxicology: Preclinical safety data under Actions).
The potential risk for humans is unknown.
Gadobutrol (Gadovist) should not be used during pregnancy unless clearly necessary.
Lactation: It is unknown whether gadobutrol is excreted in human milk.
There is evidence from non-clinical data that gadobutrol is excreted into breast milk in very small amounts (less than 0.1% of the dose intravenously administered) and the absorption via the gastrointestinal tract is poor (about 5% of the dose orally administered were excreted in the urine) (see Pharmacology: Pharmacokinetics under Actions).
At clinical doses, no effects on the infant are anticipated and Gadobutrol (Gadovist) can be used during breastfeeding.
Summary of the safety profile:
The overall safety profile of Gadobutrol (Gadovist) is based on data from more than 6,300 patients in clinical trials, and from post-marketing surveillance.
The most frequently observed adverse drug reactions (≥0.5%) in patients receiving Gadobutrol (Gadovist) are headache, nausea, and dizziness.
The most serious adverse drug reactions in patients receiving Gadobutrol (Gadovist) are cardiac arrest and severe anaphylactoid reactions.
Delayed allergoid reactions (hours later up to several days) have been rarely observed. Most of the undesirable effects were of mild to moderate intensity.
Tabulated list of adverse reactions:
The adverse drug reactions observed with Gadobutrol (Gadovist) are represented in the table below. They are classified according to System Organ Class (MedDRA version 14.1). 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. (See table.)
Click on icon to see table/diagram/image
Additional information on special populations: Pediatric patients: Based on two single dose phase I/III studies in 138 subjects aged 2-17 years and 44 subjects aged 0-<2 years the frequency, type and severity of adverse drug reactions in children of all ages including full-term newborns are consistent with the adverse drug reaction profile known in adults. This has been confirmed in a phase IV study including more than 1,100 pediatric patients and postmarketing surveillance.
No interactions studies with other medicinal products have been conducted.
Visual Inspection: This medicinal product should be visually inspected before use.
Gadobutrol (Gadovist) should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container.
Vials: Gadobutrol (Gadovist) should only be drawn into the syringe immediately before use.
The rubber stopper should never be pierced more than once.
Any contrast medium solution not used in one examination must be discarded.
Prefilled 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.
Any contrast medium solution not used in one examination must be discarded.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Store at temperatures not exceeding 30°C.
Shelf life: After the vial/bottle has been opened or the prefilled syringe or prefilled cartridge has been prepared for use, Gadobutrol (Gadovist) remains stable for 24 hours at 20 to 25°C and must be discarded thereafter.
V08CA09 - gadobutrol ; Belongs to the class of paramagnetic agents used as magnetic resonance imaging contrast media.
Soln for inj (pre-filled syringe) 1 mmol/mL (clear, colorless to pale yellow solution) x 5 mL x 1's, (vial) 15 mL x 1's.