Gadoversetamide

661.8 g/mol

662.15468 g/mol

RLM74T3Z9D

DTXSID10156865

C47545

V08CA06|V - Various

207 Ų

logP (butanol/water) = -1.93

1.160 at 25 °C

Freely soluble in water

Store between 20 and 25 °C (68 to 77 °F). Protect from light and freezing.

Osmolality (37 deg): 1110 mOsmol/kg water

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including gadoversetamide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

IDENTIFICATION AND USE: Gadoversetamide is soluble in water. It is used as a MRI contrast agent in medical applications. HUMAN EXPOSURE AND TOXICITY: Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency, and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure. The possibility of a reaction, including serious, life threatening, fatal, anaphylactoid or cardiovascular reactions or other idiosyncratic reactions should always be considered, especially in those patients with a known clinical hypersensitivity, a history of asthma, or other respiratory disorders. Gadolinium pharmacokinetics were affected by renal impairment: area under the curve, half-life, and steady-state distribution volume significantly increased with declining renal function, while total body clearance decreased. ANIMAL STUDIES: Gadopentetate dimeglumine (Magnevist), gadoteridol (ProHance), gadodiamide (Omniscan), and gadoversetamide were evaluated at standard concentration and compared with a control (physiologic saline) and the conventional ionic radiographic contrast medium meglumine diatrizoate (Renografin 60). Each mouse received a sc injection in the hindlimb of contrast or saline. Of the four MR contrast agents, gadopentetate dimeglumine caused the greatest tissue damage, and gadoteridol and gadodiamide-the two lowest osmolar agents-the least. The difference was statistically significant in terms of both inflammation and necrosis for gadoteridol, and for gadodiamide, when these agents were compared with gadopentetate dimeglumine. In regard to the control experiments, for all three variables (necrosis, edema, and inflammation), there was no statistically significant difference between the results with gadoteridol or gadodiamide and those with saline. Gadoversetamide, which has an osmolality between the ionic agent (gadopentetate dimeglumine) and the other two nonionic agents, caused a reaction that could not be differentiated from that seen with gadopentetate dimeglumine for both necrosis and edema. Only in the scoring of inflammation was the effect less using gadoversetamide compared to gadopentetate dimeglumine with any statistical significance . The risk of tissue damage due to extravasation is not widely appreciated for the gadolinium chelates. Care should be exercised during contrast injection, to avoid inadvertent extravasation and its deleterious consequences, in particular with the two higher osmolar agents (gadopentetate dimeglumine and gadoversetamide). Anesthetized beagles were instrumented to record the electrocardiogram and to measure arterial blood pressure. Each animal was injected with gadoversetamide, gadopentetate dimeglumine, gadodiamide, and gadoteridol. IV administration of gadoversetamide caused transient decreases in both heart rate and blood pressure. The rate of injection did not affect the magnitude of the heart rate or blood pressure changes. Administration of gadoversetamide, gadopentetate dimeglumine, and gadodiamide elicited equivalent changes in cardiovascular function. Injection of gadoteridol caused a similar degree of hypotension, but the changes lasted longer. Fertility, reproductive performance, and postnatal fetal development were not affected in the rat. No teratogenicity was observed in the rat and in the rabbit. Gadoversetamide had a negative impact on male rat fertility, causing reduction and degeneration of spermatocytes, when given intravenously (four times the human dose based on body surface area (BSA) for seven weeks). 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 dose (six times the human dose based on BSA) given for 28 days. 1 to 25 times the human dose based on( BSA) doses did not produce adverse effects on the reproductive system in male rats. Gadoversetamide was not found to be mutagenic in the Salmonella typhimurium ( Ames assay), mouse lymphoma mutagenesis assay, or mammalian micronucleus assay. The in vitro CHO chromosome aberration assay without metabolic activation was positive. Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoversetamide.

LD50 Mouse iv 30.3 mmol/kg

Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Do not administer Optimark to patients with: chronic, severe kidney disease (GFR <30 mL/min/1.73 sq m), or acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. Do not exceed the recommended Optimark dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration.|In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of gadolinium-based contrast agents (GBCAs). The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging.|Severe hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products including Optimark. ... Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders may be at greater risk and should be closely observed during the procedure and for several hours after drug administration.

Gadoversetamide's use as a contrast agent in magnetic resonance imaging (MRI) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: The elements of the lanthanide series typically occur as the +3 ion either in solution or in compounds(1). Based on the Gd3+/Gd reduction potential of -2.28 V(1), gadolinium(III) ions do not undergo oxidation-reduction reactions under normal environmental conditions(SRC). Gadolinium ions are likely to adsorb to soils(SRC). In general, metal cations in solution are attracted to the negatively charged surfaces of soil particles(2). The extent of adsorption of metal ions to soils depends on the pH, the mineral content, and organic content of the soil(2). Gadolinium compounds do not volatilize from dry or moist soil surfaces due to their ionic character(SRC).

Bioconcentration is not expected to be an important fate process due to the ionic nature of gadolinium compounds. (SRC)

Ionic gadolinium compounds will not volatilize from dry or moist soils or from water surfaces. (SRC)

While data specific to gadoversetamide were not located(SRC, 2007), the literature suggests that some contrast agents originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2).

EXPERIMENTAL: (153)Gd-labeled Optimark injection was excreted in the milk of lactating rats receiving a single intravenous dose of 0.1 mmol/kg.|Women should discontinue nursing and discard breast milk up to 72 hours after Optimark injection administration(1).

Occupational exposure to gadolinium compounds may occur through dermal contact with these compounds at workplaces where gadolinium is produced or used. Monitoring data indicate that the general population may be exposed to gadolinium compounds via ingestion of contaminated drinking water. Limited monitoring data indicate that exposure may occur via ingestion of contaminated food and inhalation. Direct exposure to gadolinium compounds among the general population will also be to those administered contrast agents containing gadolinium prior to MRI procedures. (SRC)

Gadoversetamide is an MRI contrast agent used for MRI diagnostic procedures to provide increased enhancement and visualization of lesions of the brain, spine and liver, including tumors.|FDA Label|This medicinal product is for diagnostic use only.Optimark is indicated for use with magnetic resonance imaging (MRI) of the central nervous system (CNS) and liver. It provides contrast enhancement and facilitates visualisation and helps with the characterisation of focal lesions and abnormal structures in the CNS and liver in patients with known or highly suspected pathology.

Contrast Media|Optimark is indicated for use with magnetic resonance imaging (MRI) in patients with abnormal blood-brain barrier or abnormal vascularity of the brain, spine and associated tissues. /Included in US product labeling/|Optimark is indicated for use with MRI to provide contrast enhancement and facilitate visualization of lesions with abnormal vascularity in the liver of patients who are highly suspect for liver structural abnormalities on computed tomography. /Included in US product labeling/

/BOXED WARNING/ WARNING: NEPHROGENIC SYSTEMIC FIBROSIS. Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Do not administer Optimark to patients with: chronic, severe kidney disease (GFR <30 mL/min/1.73 sq m), or acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. Do not exceed the recommended Optimark dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration.|Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73sq m) as well as patients with acute kidney injury. Do not administer Optimark to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73 sq m) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73 sq m). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. ... Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury, or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronic kidney disease (e.g., age >60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. When administering Optimark, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to any re-administration.|Severe hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products including Optimark. Before administering Optimark ensure the availability of resuscitation equipment and personnel trained in resuscitation techniques. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders may be at greater risk and should be closely observed during the procedure and for several hours after drug administration. If a reaction occurs, stop Optimark and immediately begin appropriate therapy including resuscitation.|FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./|For more Drug Warnings (Complete) data for GADOVERSETAMIDE (14 total), please visit the HSDB record page.

Substances used to allow enhanced visualization of tissues. (See all compounds classified as Contrast Media.)

The mean cumulative urinary excretion of gadoversetamide at 72 hours was approximately 93.5% for renal impaired patients and 95.8% for subjects with normal renal function|162 ± 25 mL/kg [normal subjects]|72 +/- 16.3 mL/hr/kg [healthy]|Gadoversetamide (0.1 mmol/kg) is eliminated primarily in the urine with 95.5 + or - 17.4% (mean + or - SD) of the administered dose eliminated by 24 hours. Animal data demonstrated that insignificant levels of 153Gd-labeled gadoversetamide are eliminated via the feces. In experimentally induced anephria in the rat, hepatobiliary excretion did not significantly compensate for the absence of urinary elimination. The renal and plasma clearance rates of gadoversetamide in normal subjects are similar (69 + or - 15.4 and 72 + or - 16.3 mL/hr/kg, respectively) indicating that the drug is cleared through the kidneys via glomerular filtration. Within the studied dose range (0.1 to 0.7 mmol/kg), the kinetics of gadoversetamide appear to be linear.|The volume of distribution at steady state of gadoversetamide in normal subjects is 162 + or - 25 mL/kg, roughly equivalent to that of extracellular water.|Radiolabeled gadoversetamide ((153)Gd) was excreted in the milk of lactating rats receiving a single intravenous dose of 0.1 mmol/kg.|Optimark injection does not cross the intact blood brain barrier, and, therefore, does not accumulate in the normal brain or in lesions that may have a normal blood-brain barrier (eg, cysts, mature post-operative scars, etc.). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of Optimark injection in the extravascular spaces of lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of Optimark injection in various lesions are not known.|For more Absorption, Distribution and Excretion (Complete) data for GADOVERSETAMIDE (6 total), please visit the HSDB record page.

None detected|Gadoversetamide is not metabolized.

Distribution 13.3 ± 6.8 (mean) minutes, elimination 103.6 ± 19.5 (mean) minutes.|The pharmacokinetics of intravenously administered gadoversetamide in normal subjects conforms to a two-compartment open-model with mean distribution and elimination half-lives (reported as mean + or - SD) of about 13.3 + or - 6.8 and 103.6 + or - 19.5 minutes.

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.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Treatment of overdose is directed toward supporting vital functions and prompt institution of symptomatic therapy. Optimark has been shown to be dialyzable.

/SIGNS AND SYMPTOMS/ Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Do not administer Optimark to patients with: chronic, severe kidney disease (GFR <30 mL/min/1.73 sq m), or acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. Do not exceed the recommended Optimark dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration.|/SIGNS AND SYMPTOMS/ Severe hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products including Optimark. ... Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders may be at greater risk and should be closely observed during the procedure and for several hours after drug administration.

gadoversetamide

Optimark (gadoversetamide) injection is a nonionic gadolinium chelate of diethylenetriamine pentaacetic acid bismethoxyethylamide (gadoversetamide), for intravenous injection. Optimark injection is provided as a sterile, preservative-free, nonpyrogenic, clear, and colorless to pale yellow, aqueous solution of gadoversetamide. Each mL of Optimark contains 330.9 mg of gadoversetamide (0.5 millimole), 28.4 mg of calcium versetamide sodium (0.05 millimole), 0.7 mg calcium chloride dihydrate (0.005 millimole), and water for injection. Sodium hydroxide and/or hydrochloric acid may have been added for pH adjustment.

Prepared as 0.5 mmol/mL soln

Analyte: gadoversetamide; matrix: chemical identification; procedure: retention time of the major peak of the liquid chromatogram with comparison to standards|Analyte: gadoversetamide; matrix: chemical purity; procedure: liquid chromatography with detection at 205 nm and comparison to standards|Analyte: gadoversetamide; matrix: pharmaceutical preparation (injection solution); procedure: liquid chromatography with detection at 205 nm and comparison to standards (chemical purity)

Analyte: gadoversetamide; matrix: blood (serum); procedure: inductively coupled plasma-mass spectrometry; limit of quantitation: 0.25 ug Gd/mL|Analyte: gadoversetamide; matrix: blood (serum), urine; procedure: inductively coupled plasma-mass spectrometry; limit of quantitation: 1.0 ug/mL

Human drugs -> Optimark -> EMA Drug Category|Contrast media -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients