KV_Gadovist_PowerofContrast_max(1)
  • Gadovist®

Gadovist®

High relaxivity2 and safety profile6,7 due to macrocyclic structure5

Clear Direction. A good feeling to be sure*. In moments like this it’s good to know that you can rely on Gadovist® for an accurate diagnosis.3,4 Additionally, its macrocyclic structure contributes to a very good safety profile.5 – 7

Gadovist®

What is Gadovist®?

Gadovist®, as a macrocyclic agent, belongs to the class with high kinetic stability and therefore, low, almost negligible, release of Gd.5 Gadovist® 1.0 has higher gadolinium concentration (1.0 mol/L) than all the other marketed extracellular gadolinium based contrast agents (0.5M).
 

How does Gadovist® work?

The active ingredient in Gadovist® is gadobutrol. Gadobutrol contains gadolinium (Gd3+) which is firmly bound in a macrocyclic complex. Gadolinium is a rare earth element, which causes contrast enhancement in MRI scans. The mode of action is the same as with all currently marketed extracellular Gd-containing products. High concentration and high relaxivity result in highest T1 shortening per mL, thus resulting in excellent image quality.2
 

Application

Gadovist® is offered as a ready-to-use solution in 2, 7.5, 10, 15, 30, 60 mL vial/bottles and 5, 7.5, 10 mL prefilled syringes. In some countries, prefilled cartridges are available.
 

How is Gadovist® administered?

Gadovist® is injected intravenously as a bolus, in some indications preferably via an MR power injector.
 

Indications

Approved Gadovist® indications are MRI brain and spine, MRA, liver and kidneys, and imaging of the whole body in adults and children of all ages including term neonates.7

011_Image-Highlight_Gadovist

1 Rohrer M, Bauer H, Mintorovitch J, et al. Invest Radiol. 2005;40(11):715–24.
2 Frenzel T, Lengsfeld P, Schirmer H et al. Invest Radiol. 2008;43(12):817–28.
3 Michaely HJ, Aschauer M, Deutschmann H, et al. Invest Radiol. 2017;52(1):55–60.
4 Endrikat J, Vogtlaender K, Dohanish S, et al. Invest Radiol. 2016;51(9):537–43.
5 Glutig K, Bhargava R, Hahn G, et al. Pediatr Radiol. 2016;46(9):1317–23.
6 Prince MR, Lee HG, Lee CH, et al. Eur Radiol. 2017;27(1):286–95.
7 Gadovist®SmPC July 2016´

Characteristics

Gadovist® is registered at dosages up to 0.3 mmol/kg body weight (b.w.) in adults and at 0.1 mmol/kg b.w. for pediatric use. The standard dose of Gadovist® with 0.1 mmol/kg body weight is suitable from 0 years onwards. The required dose is administered intravenously as a bolus injection.
 

Pharmacokinetics

The pharmacokinetic distribution and renal clearance of Gadovist® 1.0 is comparable in adults and children, with no dose adjustment from the standard adult dose based on bodyweight (0.1 mmol/kg) necessary in pediatric patients aged 0 to 17 years.1,2 After more than 16 years and over 25 million applications* of routine clinical use, the favorable safety profile demonstrated in clinical studies of Gadovist® 1.0 remains unchanged. No relevant differences have been observed for patients with hepatic or renal impairment, allergic dispositions or hemoglobinopathies, or in children or elderly patients.1,2
 

Safety

Gadovist® has been investigated at doses of up to 0.5 mmol/kg b.w. in clinical trials. The safety of Gadovist® 1.0 has been demonstrated in clinical studies involving a wide variety of patients, including those with renal insufficiency.3,4

Adverse drug reactions occurring in ≥ 0.1% of the patients following the administration of Gadobutrol

 

Adverse Drug Reaction Incidence (%)**

Headache

1.5

Nausea

1.2

Injection site reaction (various kinds)

0.6

Dysgeusia

0.5

Feeling hot

0.5

Dizziness

0.4

Vomiting

0.4

Rash (includes generalzed, macular, papular, pruritic rash)

0.3

Pruritus (includes generalized pruritus)

0.2

Erythema

0.2

Dyspnea

0.2

Paresthesia

0.1+

 

Source: Voth M et al. Invest Radiol 2011;46:663-71.

* Bayer data on file PSUR 2015
** Adverse reactions that occurred with a frequency of 0.1% include hypersensitivity/ anaphylactoid reaction, loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise, and feeling cold.
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.
1 Hahn G, et al. Invest Radiol 2009;44:776-83.
2 Hahn G et al. RSNA 2014; Abstract SSM20-04.
3 Tombach B, et al. Eur Radiol 2008;18:2610-9.
4 Balzer JO, et al. Eur Radiol 2003;13:2067-74


Gadovist® 1.0 mmol / mL solution for injection.

Composition: 1 mL solution for injection contains 604.72 mg gadobutrol (equiv. 1.0 mmol gadobutrol containing 157.25 mg gadolinium) as active ingredient. Excipient with known effect: 1 mL contains 0.00056 mmol (equivalent to 0.013 mg) of sodium.

Indications: For diagnostic use only. Gadovist® 1.0 is indicated in adults and children of all ages (including term neonates) for: 1.) Contrast enhancement in cranial and spinal magnetic resonance imaging (MRI); 2.) 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; 3.) Contrast enhancement in MR angiography; 4.) MR Imaging of pathologies of the whole body. Gadovist® 1.0 facilitates visualisation of abnormal structures or lesions and helps in the differentiation between healthy and pathological tissue. Gadovist® 1.0 should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI).

Posology: Gadovist® 1.0 should only be administered by healthcare professionals experienced in the field of clinical MRI practice. The lowest dose that provides sufficient enhancement for diagnostic purposes should be used. The dose should be calculated based on the patient’s body weight, and should not exceed the recommended dose per kilogram of body weight detailed in this section. Gadovist® 1.0 is for intravenous administration only.

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

Special warnings and precautions for use:

While injecting Gadovist® 1.0 into veins with a small lumen there is the possibility of adverse effects such as reddening and swelling. The usual safety requirements for MRI, especially the exclusion of ferromagnetic materials, also apply when using Gadovist® 1.0.

Hypersensitivity reactions: As with other intravenous contrast agents, Gadovist® 1.0 can be associated with anaphylactoid / hypersensitivity or other idiosyncratic reactions, characterized by cardiovascular, respiratory or cutaneous manifestations, and ranging to severe reactions including shock. In general, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes of severe hypersensitivity reactions. The risk of hypersensitivity reactions may be higher in case of:

  1. previous reaction to contrast media;
  2. history of bronchial asthma;
  3. history of allergic disorders.

In patients with an allergic disposition the decision to use Gadovist® 1.0 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.

Impaired renal function: Prior to administration of Gadovist® 1.0 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 < 30 mL / min / 1.73 m2). 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 Gadovist® 1.0, it should therefore only be used in 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 MRI. Haemodialysis shortly after Gadovist® 1.0 administration may be useful at removing Gadovist® 1.0 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.

Neonates and infants: Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Gadovist® 1.0 should only be used in these patients after careful consideration.

Elderly: As the renal clearance of Gadovist® 1.0 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.

Pregnancy and lactation: There are no data from the use of Gadovist® 1.0 in pregnant women. Gadovis® 1.0 should not be used during pregnancy unless the clinical condition of the woman requires use of Gadovist® 1.0. Continuing or discontinuing of breast feeding for a period of 24 hours after administration of Gadovist® 1.0, should be at the discretion of the doctor and lactating mother.

Undesirable effects: The overall safety profile of Gadovist® 1.0 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 Gadovist® 1.0 are headache, nausea and dizziness. The most serious adverse drug reactions in patients receiving Gadovist® 1.0 are cardiac arrest and severe anaphylactoid reactions (including respiratory arrest and anaphylactic shock). Delayed anaphylactoid reactions (hours later up to several days) have been rarely observed. Most of the undesirable effects were of mild to moderate intensity. Following adverse reactions have been observed: 1.) Common (≥ 1 / 100 to < 1 / 10) headache, nausea; 2.) Uncommon (≥ 1 / 1,000 to < 1 / 100) hypersensitivity/anaphylactoid reaction, dizziness, dysgeusia, paresthesia, dyspnea, vomiting, erythema, pruritus, rash, injection site reaction, feeling hot; 3.) Rare (≥ 1 / 10,000 to < 1 / 1,000) loss of consciousness, convulsion, parosmia, tachycardia, palpitations, dry mouth, malaise, feeling cold; 4.) Not known: cardiac arrest, NSF. Patients with an allergic disposition suffer more frequently than others from hypersensitivity reactions. Isolated cases of NSF have been reported with Gadovist® 1.0.

Paediatric population: Frequency, type and severity of adverse reactions in children of all ages (including term neonates) are consistent with the adverse drug reaction profile known in adults.

Overdose: 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 overdose in patients with renal insufficiency, Gadovist® 1.0 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 NSF.

Reporting of suspected adverse reactions: Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system or to DrugSafety.
GPV.US@bayer.com.

Date of revision of text: December 2017.

Please note: For current prescribing information refer to the package insert and / or contact your local Bayer AG.

Case Reports

Adults

History: A 69-year-old female, 57 kg, presenting with confusion, expressive aphasia, dysarthria, left upper motor neuron facial weakness, left arm and leg weakness. She does not have any other preexisting medical conditions. She has a skin lesion in the right temple.

Highlight_Adults-Case1

1 T1 Flash
2 T1 Flash + Gadovist
3 rCBV + Gadovist
4 Ktrans + Gadovist
5 CBV + Gadovist

(Courtesy of Thanh Binh Nguyen, The Ottawa Hospital, Ottawa, Canada)

MRI: An initially suspected hemorrhagic lesion was detected as neoplasm. Structural (B) and dynamic contrast enhanced MRI (D and E) revealed an underlying enhancing mass in the right frontal lobe, suspicious for metastasis or glioblastoma multiforme (GBM). Dynamic Gadovist®. 1.0-enhanced MR perfusion (D and E) is more useful than DSC-MR perfusion (C) in the presence of hemorrhage as it is not limited by susceptibility artifacts.

Final Diagnosis: Metastatic melanoma in the right frontal lobe

Patient Outcome: MRI prompted the patient to undergo a full metastatic workup and surgical resection.

History: 49-year-old asymptomatic female without pathological findings in X-ray mammography (A). Concomitant ultrasound showed a suspicious nodule in the left breast (B).

Highlight_Adults-Case2

1 MLO Mammography
2 Ultrasound
3 Early Substraction Imaging
4 Early 1.00 M contrast-enhanced T1w

(Courtesy of B.-K. Han; Samsung Medical Center/Department of Radiology, Seoul, South Korea.)

MRI: Early dynamic THRIVE subtraction MRI (C) and early dynamic THRIVE MRI (D) show a 0.9-cm, spiculated, enhancing mass in the upper outer quadrant of the left breast, characterized by fast post-initial washout.
Gadovist®-MRI improves the sensitivity of breast lesion detection, aiding the diagnosis of invasive ductal carcinoma, even in dense breast tissue.

Pediatrics

History: A 3-day-old male infant weighing 3.7 kg with no preexisting conditions presented with paraplegia of the legs. Gadovist® 1.0 contrast-enhanced MRI was ordered to assess the neurological deficit.

Highlight_Padiatrics-Case1

(Courtesy of Dr. Gabriele Hahn, Pediatrician and Pediatric Radiologist, Carl Gustav Carus University Hospital Dresden, Germany)

Findings: Large retroperitoneal mass directly extending into the spinal canal through the neural foramina with resultant spinal cord compression.


Diagnosis: “Dumbbell” neuroblastoma forming an hourglass shaped mass with strong contrast enhancement.
Patient Management and Outcome: The tumor was biopsied and pathology was proven. Chemotherapy was administered to reduce the tumor. Surgery was performed to remove the residual tumor.


Take-Home Messages

  • Imaging of neuroblastoma with transforaminal extension requires contrast administration.
  • The large tumor with strong contrast enhancement was clearly visible retroperitoneally and intraspinally.
  • Gadovist® 1.0 was well tolerated in this neonate without symptoms or side effects.

History: A 2-month-old male patient with left frontal lobe tumor (Desmoplastic infantile ganglioglioma; DIG).

Highlight_Padiatrics-Case2

(Courtesy of Bhargava R and Noga M, Magnetic Resonance Insights 2013; 6:1–12)

MRI: Pre-contrast, transverse T2-weighted (A), T1-weighted (B) and post-gadobutrol T1-weighted MR images show a lobulated left cerebral hemisphere mass. Post-contrast gadobutrol (Gadovist® 1.0) image (C) shows a homogeneous enhancement of the tumor with notable enhancing extension of the tumor to the dura laterally, a distinguishing feature of DIG.

Studies

Five Star Data for Gadovist®

An extensive analysis on safety and efficacy of the extracellular contrast agent Gadovist®...

Gadovist® goes along well with apparent diffusion coefficients

The gadolinium-based contrast agent Gadovist® does not disturb the signals....

Gadobutrol shows good safety profile in elderly patients

A meta-analysis of internationally relevant clinical studies, pharmacovigilance...

 

Gadobutrol has a good safety profile for children

A prospective international study on the macrocyclic contrast agent gadobutrol...

Relaxivity

How to Investigate the Clinical Effect of Relaxivity?

Direct comparison studies have been conducted to investigate the effect of the high relaxivity of Gadovist® vs. the other macrocyclic GBCAs gadoteridol and gadoterate meglumine.

Injected dose and imaging parameters need to be kept identical in intra-individual trials when investigating possible effects of relaxivity differences between two GBCAs.

 

Relaxivity Matters

 

What Is Relaxivity?

Relaxivity is a marker for the ability of a GBCA to enhance signal intensity.

Why is Relaxivity Important?

Image quality depends on relaxivity: High relaxivity improves image quality.

Macrocyclic GBCAs differ in their relaxivity

While the absolute relaxivity values differ, the order of relaxivity values is consistent. Gadovis shows consistently high relaxivity values.

Molecular Structure & Relaxivity

Molecular properties of Gadovist® are designed to produce high relaxivity.

CNS: Gadovist® vs. Gadoteridol

Gadovist® shows significantly higher sensitivity and accuracy in detecting malignant lesions.

Radiosurgery Planning: Benefits of Gadovist®

Gadovist® could be effectively used for radiosurgery planning of malignant CNS lesions.

Brain Tumors: Gadovist® vs. Gadoteridol

Gadovist® demonstrated significant superiority in lesion-to-brain contrast.

CNS: Gadovist® vs. Gadoterate Meglumine

Gadovist® provided better visualization of enhancing brain lesions.

CNS MRA: Gadovist® vs. Gadoterate Meglumine

Gadovist® improved the vascular assessment in patients with chronic vascular disease (CVD).

Supra-Aortic Vessels MRA: Gadovist® vs. Gadoterate Meglumine

Gadovist® showed higher image quality with equimolar dose.

MS: Gadovist® vs. Gadoterate Meglumine

Increased Enhancement in Multiple Sclerosis (MS) lesions with Gadovist®.

Disclaimer

Effective November 23, 2017, the European Commission (EC) issued a final decision in the Article 31 referral procedure evaluating the presence of gadolinium (Gd) in the body and gadolinium-based contrast agents (GBCAs) to the EU Member States and countries in the European Economic Area (EEA). In general, the EC has adopted the opinion of the European Medicine’s Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP). The EC decision is two-fold:

  • Suspension of all multipurpose linear GBCAs, including Bayer’s Magnevist® i.v.
  • Updates to the labels / prescribing information of all GBCAs remaining on the market, including Bayer’s Gadovist® 1.0 and its specialty linear GBCAs Primovist® and Magnevist® 2 mmol / L intra-articular formulation.

Importantly, EMA’s CHMP in their final opinion confirms that “there is currently no evidence that gadolinium deposition in the brain has caused any harm to patients; however EMA has recommended restrictions for some intravenous linear agents in order to prevent any risk that could potentially be associated with gadolinium brain deposition.”

Magnevist® is not available in all countries.

 

References

* Gadovist® 1.0 provides diagnostic confidence and is well tolerated
1 Gadovist®SmPC July 2016
2 Rohrer M, Bauer H, Mintorovitch J, et al. Invest Radiol. 2005;40(11):715–24.
3 Sardanelli F, Newstead GM, Putz B, et al. Invest Radiol. 2016;51(7):454–61.
4 Gutierrez JE, Rosenberg M, Seemann J, et al. Magn Reson Insights. 2015;8:1–10. Frenzel T, Lengsfeld P, Schirmer H, et al. Invest Radiol. 2008;43(12):817–28.
5 Endrikat J, Vogtlaender K, Dohanish S, et al. Invest Radiol. 2016;51(9):537–43.
6 Prince MR, Lee HG, Lee CH, et al. Eur Radiol. 2017;27(1):286–95.

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