Gadoversetamide (Systemic)


VA CLASSIFICATION
Primary: DX900

Commonly used brand name(s): OptiMARK.

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; liver disorders)—
Note: Gadoversetamide is a nonionic paramagnetic agent.{01}



Indications

Accepted

Brain imaging, magnetic resonance—Gadoversetamide is indicated in adults to provide contrast enhancement during magnetic resonance imaging (MRI) and thus to facilitate visualization of intracranial lesions in patients with an abnormal blood brain barrier or abnormal vascularity of the brain.{01}

Liver lesions imaging, magnetic resonance—Gadoversetamide is indicated in adults to provide contrast enhancement and thus to facilitate visualization during MRI of lesions in the liver with abnormal vascularization in patients who are suspected on computed tomography of having structural abnormalities.{01}

Spine lesions imaging, magnetic resonance—Gadoversetamide is indicated in adults to provide contrast enhancement during MRI of lesions of the spine and associated tissues.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    661.77{01}


Density
    1.160 gm per mL at 25 °C.{01}



Osmolality
    1110 mOsmol per kg of water at 37 °C (approximately 4 times the osmolality of plasma).{01}

Note: Gadoversetamide is hypertonic under conditions of use.




pH
    5.5 to 7.5.{01}



Viscosity
    3.1 cP at 20 °C.{01}
    2.0 cP at 37 °C.{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. MR images are based primarily on proton density and proton relaxation dynamics. MR instruments are sensitive to two different relaxation processes, the T1 (spin-lattice or longitudinal relaxation time) and T2 (spin-spin or transverse relaxation time). Paramagnetic agents contain one or more unpaired electrons that enhance the T1 and T2 relaxation rates of protons in their molecular environment. In MRI, visualization of normal and pathological brain, spinal and hepatic tissue depends in part on variations in the radio frequency signal intensity that occur with changes in proton density, alteration of the T1, and variation in T2. When placed in a magnetic field, gadoversetamide shortens the T1 and T2 relaxation times in tissues where it accumulates. At the recommended dose, the effect is primarily on T1 relaxation time, and produces an increase in signal intensity (brightness). Gadoversetamide does not cross the intact blood-brain barrier; therefore, it does not accumulate in normal brain tissue or in CNS lesions that may have a normal blood-brain barrier (e.g., cysts, mature post-operative scars). Abnormal vascularity or disruption of the blood-brain barrier allows accumulation of gadoversetamide in lesions such as neoplasms, abscesses, and subacute infarcts.{01}

Distribution:

Volume of distribution (Vol D)—approximately 162 ± 25 mL per kg of body weight.{01}

Protein binding:

Gadoversetamide does not undergo protein binding in vitro.{01}

Biotransformation:

Biotransformation or decomposition has not been detected.{01}

Half-life:


Distribution:

13.3 ± 6.8 (mean) minutes.{01}



Elimination:

103.6 ± 19.5 (mean) minutes.{01}


Elimination:
    Renal, by glomerular filtration (approximately 96% of dose excreted within 24 hours). Slightly delayed in patients with renal insufficiency.{01}


Precautions to Consider

Carcinogenicity

Long-term animal studies to evaluate carcinogenic potential of gadoversetamide have not been performed. {01}

Mutagenicity

Gadoversetamide was not found to be mutagenic in the Ames assay, mouse lymphoma mutagenesis assay, or mammalian micronucleus assay. The in vitro CHO chromosome aberration assay without metabolic activation was positive.{01}

Pregnancy/Reproduction
Fertility—
Gadoversetamide had a negative impact on male rat fertility, causing reduction and degeneration of spermatocytes, when given intravenously at doses of 2 mmol per kg (four times the human dose based on body surface area [BSA]) for seven weeks. These effects were not seen at doses of 0.5 mmol per kg (one time the human dose based on BSA). Reduction of male rat reproductive organ weight, testicular germinal epithelium degeneration, germ cell presence in epididymides, and reduced sperm count were all seen at intravenous doses of 3 mmol per kg daily (six times the human dose based on BSA) given for 28 days. These effects were not observed at a dose of 0.6 mmol per kg (one time the human dose based on BSA), nor were these effects observed in studies performed on dogs. One-time 0.5 to 15 mmol per kg (1 to 25 times the human dose based on BSA) doses did not produce adverse effects on the reproductive system in male rats.{01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Offspring of female rats given 4.9 mmol per kg (ten times the human dose based on BSA) daily on days 7 through 17 of gestation exhibited reduced mean fetal weight, abnormal liver lobation, delayed ossification of sternebrae, and delayed behavioral development. Maternal toxicity was also observed at this dose. Doses of 0.7 mmol per kg daily did not produce these effects. Studies in rabbits given 0.4 or 1.6 mmol per kg daily (1 and 4 times the human dose, respectively, based on BSA) revealed fetuses with forelimb flexures and cardiovascular abnormalities, including malformed arteries, septal defects, and abnormal ventricular structure. Doses of 0.1 mmol per kg daily (0.3 times the human dose based on BSA) did not produce these defects. Maternal toxicity was not observed at any dose.{01}

FDA Pregnancy Category C.{01}

Breast-feeding

Studies indicate that gadoversetamide distributes into rat milk, however, it is unknown if this occurs in humans. The manufacturer recommends discontinuing nursing and pumping and discarding breast milk for up to 72 hours after gadoversetamide administration.{01}

Pediatrics

Appropriate studies have not been performed on the relationship of age to the effects of gadoversetamide in the pediatric population. Safety and efficacy have not been established.


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of gadoversetamide in the elderly.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Calcium, serum and
Copper, serum and
Iron, serum and
Zinc, serum    (transient changes have been observed; clinical significance is unknown{01})


Calcium, serum    (gadoversetamide may cause colorimetric interference with calcium determinations, resulting in an apparent decrease in serum calcium concentrations{01})


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).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hypersensitivity to gadolinium or versetamide
Risk-benefit should be considered when the following medical problems exist
Arrhythmia    (gadoversetamide may cause prolongation of the QT interval{01})


Asthma or
Other respiratory disorders    (may be exacerbated by any allergic reaction to gadoversetamide{01})


» Renal insufficiency    (excretion of gadoversetamide may be impaired{01})


Sickle cell anemia or
Other hemoglobinopathies    (sickle erythrocytes may align perpendicular to a magnetic field, resulting in vessel or tissue occlusion{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 rare
    
Arrhythmia (fast or irregular heart beat)—including tachycardia and palpitations
    
blood glucose alterations (dizziness ; increased urination)— blood glucose may increase or decrease
    
blood pressure alterations (dizziness)—blood pressure may increase or decrease; high blood pressure is usually asymptomatic
    
chest pain
    
cough or difficulty breathing
    
dizziness, drowsiness, or fainting
    
hypercalcemia —may be a laboratory artifact
    
hyponatremia ( confusion; seizures [convulsions]; decreased urine output; dizziness)
    
hemoptysis (spitting or coughing up blood)
    
skin rash
    
throat spasm
    
thrombocytopenia (black, tarry stools; unusual bleeding or bruising)
    
thrombophlebitis (hot skin, pain, swelling, tenderness, and/or skin color changes )



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Headache
    
injection site reactions
    
taste perversion ( bad, unusual, or unpleasant taste or aftertaste)
    
vasodilation (unusual warmth and flushing of skin)

Incidence less frequent
    
Abdominal pain
    
asthenia (loss of strength or energy ; muscle pain or weakness; unusual feeling of weakness)
    
back pain
    
diarrhea
    
dyspepsia (stomach discomfort, upset, or pain; heartburn, belching, acid or sour stomach; indigestion)
    
nausea
    
paresthesia (burning, tingling or prickly sensation)
    
rhinitis (stuffy, runny nose or sneezing)

Incidence rare
    
Agitation, anxiety or confusion
    
arthralgias (pain, swelling, or redness in joints )
    
appetite changes —may increase or decrease
    
changes in sense of hearing or smell
    
depersonalization (loss of sense of reality)
    
dry mouth
    
edema, generalized (swelling of face, hands, lower legs or feet )
    
frequent or painful urination or decreased urine volume
    
gas, bloating, flatulence, or constipation
    
hallucinations (seeing, hearing or smelling things that are not there)
    
increased salivation
    
musculoskeletal effects, such as
dystonia (twisting or other unusual body movements), hypertonia ( increased muscle tone), spasm
tremor
weakness
    
nosebleeds
    
pallor (paleness)
    
thirst
    
sore throat or voice changes
    
vision disturbances, such as
amblyopia (blurred vision), diplopia (double vision), or conjunctivitis (redness, pain, or swelling of eye )
    
vomiting





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Treatment of overdose
To enhance elimination—Instituting hemodialysis may be beneficial since gadoversetamide is almost exclusively excreted via the kidney.

Supportive care—Monitoring and support of vital functions is crucial, along with provision of symptomatic treatment as needed.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Magnetic Resonance Imaging 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 gadoversetamide





Breast-feeding—Distributed into breast milk; temporary discontinuation of breast-feeding should be considered
Other medical problems, especially renal insufficiency

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


Side/adverse effects
Signs of possible adverse effects, especially arrhythmias, blood glucose alterations, blood pressure alterations, chest pain, cough, difficulty breathing, dizziness, drowsiness, fainting, hypercalcemia, hyponatremia, hemoptysis, skin rash, throat spasm, thrombocytopenia, thrombophlebitis or anaphylactoid reactions


General Dosing Information
Patients undergoing diagnostic procedures with gadoversetamide should be under supervision of a physician experienced in the use of contrast agents. {01}

The manufacturer's package insert or other appropriate literature should be consulted for specific techniques and procedures for the administration of gadoversetamide.{01}

When plastic disposable syringes are used, gadoversetamide should be drawn into the syringe and used immediately.{01}

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

Images should be interpreted in comparison to unenhanced MRI, since some paramagnetic contrast agents may impair visualization of existing lesions that are visible on an unenhanced, noncontrast MRI.{01}


Parenteral Dosage Forms

GADOVERSETAMIDE INJECTION

Usual adult dose
Brain and spinal lesion imaging, magnetic resonance; liver lesion imaging, magnetic resonance
Intravenous, direct, 0.2 mL per kg of body weight (0.1 mmol per kg) at a rate of 1 to 2 mL per second.{01}

To ensure complete injection of the contrast media, a 5-mL normal saline flush should be administered following injection of gadoversetamide. {01}


Usual pediatric dose
Safety and efficacy have not been established.

Usual geriatric dose
See Usual adult dose

Strength(s) usually available
U.S.—


330.9 mg per mL (0.5 mmol per mL) (Rx) [OptiMARK (calcium versetamide sodium, 28.4 mg [0.05 mmol]) (calcium chloride dihydrate, 0.7 mg [0.005 mmol])]

Packaging and storage:
Store between 20 and 25 °C (68 to 77 °F). Protect from light and freezing.{01}

Incompatibilities:
Gadoversetamide should not be mixed with other contrast agents or with parenteral nutrition due to the possibility of chemical incompatibility.{01}



Developed: 03/20/2000



References
  1. Product Information: OptiMARK, gadoversetamide. Mallinckrodt, Inc, St. Louis, MO (PI revised 12/99) reviewed 2/2000.
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