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Gadoteridol (Systemic)


VA CLASSIFICATION
Primary: DX900

Commonly used brand name(s): ProHance.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Diagnostic aid, paramagnetic (brain disorders; spine disorders)—
Note: Gadoteridol is a nonionic paramagnetic agent. {03} {05}



Indications

Accepted

Brain imaging, magnetic resonance—Gadoteridol is indicated to provide contrast enhancement during magnetic resonance imaging (MRI) and facilitate visualization of intracranial lesions with abnormal vascularity or those suspected of causing an abnormality in the blood-brain barrier. {01} {03} {06} {08} {10} {15}

Spinal lesions imaging, magnetic resonance—Gadoteridol is indicated to provide contrast enhancement during MRI and facilitate visualization of lesions in the spine and associated tissues. {01} {06} {08} {10}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    558.7 {01}


Osmolality
    630 mOsmol per kg of water {01}


pH
    6.5 to 8.0 {01}

Mechanism of action/Effect:

Based on the behavior of protons when placed in a strong magnetic field, which is interpreted and transformed into images by magnetic resonance (MR) instruments. Paramagnetic agents have unpaired electrons that generate a magnetic field about 700 times larger than the proton's field, thus disturbing the proton's local magnetic field. When the local magnetic field around a proton is disturbed its relaxation process is altered. MR images are based on proton density and proton relaxation dynamics. MR instruments can record two different relaxation processes, the T1 (spin-lattice or longitudinal relaxation time) and T2 (spin-spin or transverse relaxation time). In MRI, visualization of normal and pathological brain tissue depends in part on variations in the radiofrequency signal intensity that occur with changes in proton density, alteration of the T1, and variation in T2. When placed in a magnetic field, gadoteridol shortens the T1 relaxation time in tissues where it accumulates. Gadoteridol does not cross the intact blood-brain barrier; therefore, it does not accumulate in normal brain tissue or in central nervous system (CNS) lesions that have not caused an abnormal blood-brain barrier (e.g., cysts, mature post-operative scars). Abnormal vascularity or disruption of the blood-brain barrier allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. {01} {06} {15}

Half-life:

Distribution—0.20±0.04 hours (mean). {01} {05}

Elimination—1.57±0.08 hours (mean). {01} {05}

Elimination:
    Renal (approximately 94% of dose excreted within 24 hours). {01} {05}


Precautions to Consider

Carcinogenicity

Animal studies to evaluate the carcinogenic potential of gadoteridol have not been performed. {01}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Also, although there is no evidence that the magnetic and electric fields associated with MRI have an effect on human development, in vitro studies and theoretical predictions raise concern regarding the risk of exposure of the developing embryo and fetus to MR. More studies are needed to establish the safety of MRI in pregnant patients. {16}

Studies in rats showed that gadoteridol at doses 33 times the maximum recommended human dose for 12 days during gestation doubled the incidence of postimplantation loss. Also, when rats were administered gadoteridol at doses 20 to 33 times the maximum human dose for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. {01} {12}

FDA Pregnancy Category C. {01}

Breast-feeding

It is not known whether gadoteridol is distributed into breast milk. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of gadoteridol have not been performed in the pediatric population. However, clinical trials conducted to date in a limited number of pediatric patients have not demonstrated pediatrics-specific problems that would limit the usefulness of gadoteridol in children. {01} {02} {04} {17}


Geriatrics


Appropriate studies on the relationship of age to the effects of gadoteridol have not been performed in the geriatric population. However, clinical trials conducted to date, which included older patients, have not demonstrated geriatrics-specific problems that would limit the usefulness of this agent in the elderly. {06} {10}

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Allergies or asthma, history of    (increased risk of idiosyncratic response {01})


Anemia, hemolytic    (although this effect has not been specifically reported for gadoteridol, the use of gadopentetate dimeglumine, another paramagnetic contrast agent, has been associated with an increased risk of hemolysis; until more conclusive evidence is available, caution is recommended {01} {06} {12})


» Renal function impairment, severe    (excretion of gadoteridol may be impaired {01})


» Sensitivity to gadoteridol
Sickle cell disease    (in in vitro studies deoxygenated sickle erythrocytes have been shown to align perpendicular to a magnetic field, which may result in vascular occlusion in vivo ; however, more studies are needed to establish extent of risk {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
{01}    
Cardiovascular effects (low blood pressure; fast or irregular heartbeat)
    
pseudo-allergic reaction {01}{05}{06}{11}(itching, watery eyes; skin rash or hives; swelling of face; thickening of tongue; wheezing, tightness in chest, or troubled breathing)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Changes in taste
    
nausea or vomiting{01}{03}{06}{11}

Incidence less frequent or rare
    
CNS effects (anxiety; confusion; dizziness)
    
diarrhea
    
headache
    
pain at injection site
    
vasodilation {01}{03}{06}{11}(unusual warmth and flushing of skin)





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, MRI Contrast Agents (Diagnostic)

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use
Action in the body: Accumulates in brain and spinal lesions creating a local magnetic field; visualization of lesions possible with MR instruments

Before having this test
»   Conditions affecting use, especially:
Sensitivity to gadoteridol
Other medical problems, especially allergies or asthma (history of) or severe renal function impairment

Preparation for this test
Special preparatory instructions may apply; patient should inquire in advance


Side/adverse effects
Signs of possible side effects, especially cardiovascular effects and pseudo-allergic reaction


General Dosing Information
The manufacturer's package insert or other appropriate literature should be consulted for specific techniques and procedures for the administration of gadoteridol.

During and for at least 30 to 60 minutes after injection of gadoteridol, the patient should be observed for possible severe reactions; competent personnel and emergency facilities should be available during this period. {01}

Imaging procedures should be completed within 1 hour of injection of gadoteridol. {01}


Parenteral Dosage Forms

GADOTERIDOL INJECTION

Usual adult and adolescent dose
Brain and spinal lesions imaging, magnetic resonance
Intravenous, as rapid infusion or direct injection (bolus, >60 mL per minute), 0.2 mL (0.1 mmol) per kg of body weight. {01} {06} {11} {13}


Note: To insure complete injection of gadoteridol, a 5-mL flush using 0.9% sodium chloride injection should be administered following injection of gadoteridol. {01}
A second dose of 0.4 mL (0.2 mmol) per kg of body weight may be administered up to 30 minutes after the first dose in patients suspected of having cerebral metastases or other poorly enhancing lesions, or in the presence of negative or equivocal scans. {01} {07} {09} {14}


Usual pediatric dose
Brain and spinal lesions imaging, magnetic resonance
Dosage must be individualized by physician.


Note: In clinical trials, 0.2 mL (0.1 mmol) of gadoteridol per kg of body weight was used in pediatric patients. {02} {04} {17}


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


279.3 mg (0.5 mmol) per mL of gadoteridol (Rx) [ProHance (0.23 mg of calteridol calcium) ( 1.21 mg tromethamine, per mL)]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a light-resistant container, unless otherwise specified by manufacturer. Protect from freezing. {01}



Revised: 08/30/1994



References
  1. ProHance package insert (Squibb—US), Rev 11/92.
  1. Ball WS Jr, Parker JR, Davis PC, et al. Efficacy of gadoteridol for contrast-enhanced magnetic resonance imaging in children. Invest Radiol (suppl) 1992; 1: 445S-52S.
  1. Carvlin MJ, De Simone DN, Meeks MJ. Phase II clinical trial of gadoteridol injection, a low-osmolal magnetic resonance imaging contrast agent. Invest Radiol (suppl) 1992; 1: 16S-21S.
  1. Debatin JF, Nadel SN, Gray L, et al. Phase III clinical evaluation of gadoteridol injection: experience in pediatric neuro-oncologic MR imaging. Pediatr Radiol 1992; 22(2): 93-8.
  1. McLachlan SJ, Eaton S, De Simone DN. Pharmacokinetic behavior of gadoteridol injection. Invest Radiol (suppl) 1992; 1: 12S-15S.
  1. Runge VM, Bradley WG, Brant-Zawadzki MN, et al. Clinical safety and efficacy of gadoteridol: a study in 411 patients with suspected intracranial and spinal disease. Radiology 1991; 181(3): 701-9.
  1. Runge VM, Kirsch JE, Thomas GS. High-dose applications of gadolinium chelates in magnetic resonance imaging. Magn Reson Med 1991; 22(2): 358-63.
  1. Runge VM, Dean B, Lee C, et al. Phase III clinical evaluation of Gd-HP-DO3A in head and spine disease. J Magn Reson Imaging 1991; 1(1): 47-56.
  1. Runge VM, Kirsch JE, Burke VJ, et al. High-dose gadoteridol in MR imaging of intracranial neoplasms. J Magn Reson Imaging 1992; 2(1): 9-18.
  1. Runge VM, Bronen RA, Davis KR. Efficacy of gadoteridol for magnetic resonance imaging of the brain and spine. Invest Radiol (suppl) 1992; 1: 22S-32S.
  1. Seiderer M. Phase III clinical studies with gadoteridol for the evaluation of neurologic pathology. A European perspective. Invest Radiol (suppl) 1992; 1: 33S-8S.
  1. Soltys RA. Summary of preclinical safety evaluation of gadoteridol injection. Invest Radiol (suppl) 1992; 1: 7S-11S.
  1. Yuh WT, Fisher DJ, Engelken JD, et al. MR evaluation of CNS tumors: dose comparison study with gadopentetate dimeglumine and gadoteridol. Radiology 1991; 180(2): 485-91.
  1. Yuh WT, Engelken JD, Muhonen MG, et al. Experience with high-dose gadolinium MR imaging in the evaluation of brain metastases. Am J Neuroradiol 1992; 13(1): 335-45.
  1. Wolf GL. Magnetic resonance imaging and the future of cardiac imaging. Am J Cardiol 1989; 64: 60E-3E.
  1. National Institutes of Health Panel Issues Report. Consensus Development Conference: Magnetic resonance imaging 1987; Vol. 6 No. 14.
  1. Reviewers' comments as per monograph revision of 02/17/93.
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