Gadopentetate Dimeglumine

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).

EXPERIMENTAL: Magnevist is excreted in human milk. Magnevist injection was administered intravenously to 18 lactating women with normal renal function at a dose of 0.1 mmol/kg body weight. In these women, <0.04% of the administered gadolinium was excreted into the breast milk during the 24-hour period following dosing. Breast milk obtained during the 24 hours following dosing revealed the average cumulative amount of gadolinium excreted in breast milk was 0.57 + or - 0.71 umol. The amount transferred from a 70 kg woman (receiving 0.1 mmol/kg body weight) to an infant by breast feeding over a period of 24 hrs translates into <3 umol of gadolinium.

IDENTIFICATION AND USE: Gadopentetate dimeglumine (Gd-DTPA;Magnevist) is injectable contrast medium for magnetic resonance imaging (MRI). HUMAN EXPOSURE AND TOXICITY: 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 Magnevist to patients with: chronic, severe kidney disease, 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 (for example, older than 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. Do not exceed the recommended Magnevist dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration. Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. The intravenous administration of Gd-DTPA is relatively safe and rarely causes systemic toxicity in the course of routine imaging studies. However, the general safety of intrathecal Gd-DTPA has not been established. The literature describes a rare case of an overdose intrathecal Gd-DTPA injection presenting with neurotoxic manifestations, including a decreased level of consciousness, global aphasia, rigidity, and visual disturbance. The other case described a serious adverse reaction following the administration of Gd-DTPA. The patient showed sneezing and hoarseness when Gd-DTPA was administered for the first time. At the second injection, when hydrocortisone was used in advance to prevent allergic reaction, patient lapsed into a pre-shock state and anaphylactic reaction was strongly suggested by the laboratory data. ANIMAL STUDIES: Gadopentetate dimeglumine (Magnevist), gadoteridol (ProHance), gadodiamide (Omniscan), and gadoversetamide (Optimark) were evaluated at standard concentration and compared with a control (physiologic saline) and the conventional ionic radiographic contrast medium meglumine diatrizoate (Renografin 60). Of the four MR contrast agents, Gd-DTPA caused the greatest tissue damage, and gadoteridol and gadodiamide-the two lowest osmolar agents-the least when injected in the hindlimb of mice. The hemodynamic reactions of high doses (0.6 mmol/ kg) of Gd-DTPA were evaluated and compared with the side effects of ionic (diatrizoate: Urografin 76%) and nonionic (iopamidol, Solutrast 370) radiographic contrast media in pigs. Pulmonary artery pressure, cardiac output, and stroke volume increased for several minutes. The vascular resistance declined. Diatrizoate induced stronger and longer-lasting side effects than Gd-DTPA and iopamidol. In other experiments, high doses of Gd-DTPA significantly decreased left ventricular and systemic blood pressure and depressed left ventricular contractility in anesthetized dogs. In conscious rats Gd-DTPA produced signs of acute neurotoxicity over several hours (stereotyped movements and myoclonus), medium-term signs over several days (ataxia and tremor), and neuropathologic changes over 24 hours, with reactive changes persisting for 42 days. In reproductive studies in rats, when administered intraperitoneally to male and female rats daily prior to mating, during mating, and during embryonic development for up to 74 days (males) or 35 days (females), Gd-DTPA caused a decrease in number of corpora lutea at the 0.1 mmol/kg dose level. After daily dosing with 2.5 mmol/kg suppression of food consumption and body weight gain (males and females) and a decrease in the weights of testes and epididymis were also observed. In another experiment in rats, daily injections of Gd-DTPA over 16 days caused spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5 mmol/kg. This atrophy was not reversed within a 16-day observation period following the discontinuation of the drug. A comprehensive battery of in vitro and in vivo studies in bacterial and mammalian systems suggest that Gd-DTPA is not mutagenic or clastogenic and does not induce unscheduled DNA repair in rat hepatocytes or cause cellular transformation of mouse embryo fibroblasts. However, the drug did show some evidence of mutagenic potential in vivo in the mouse dominant lethal assay at doses of 6 mmol/kg, but did not show any such potential in the mouse and dog micronucleus tests at intravenous doses of 9 mmol/kg and 2.5 mmol/kg, respectively.

/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 Magnevist 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 (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. Do not exceed the recommended Magnevist dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration.

/SIGNS AND SYMPTOMS/ Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. The risk of hypersensitivity reactions is higher in patients with a history of reaction to contrast media, bronchial asthma, or allergic disorders. Hypersensitivity reactions can occur with or without prior exposure to gadolinium-based contrast agents (GBCAs). Have appropriately trained personnel administer Magnevist in a facility that has immediate availability of resuscitative equipment. If a hypersensitivity reaction occurs, stop Magnevist injection and immediately begin appropriate therapy. Observe closely patients with a history of drug reactions, allergy, or other hypersensitivity disorders, during and up to several hours after Magnevist injection.

/CASE REPORTS/ The intravenous administration of gadopentetate dimeglumine (GD) is relatively safe and rarely causes systemic toxicity in the course of routine imaging studies. However, the general safety of intrathecal GD has not been established. We report a very rare case of an overdose intrathecal GD injection presenting with neurotoxic manifestations, including a decreased level of consciousness, global aphasia, rigidity, and visual disturbance.

/CASE REPORTS/ ... a case of serious adverse reaction following the administration of Gd-DTPA (gadolinium with diethylenetriamine pentaacetic acid) /is described/. The patient showed sneezing and hoarseness when Gd-DTPA was administered for the first time. At the second injection, when hydrocortisone was used in advance to prevent allergic reaction, she lapsed into a pre-shock state and anaphylactic reaction was strongly suggested by the laboratory data. The possibility that Gd-DTPA may cause the severe side effects must be noted.

/EPIDEMIOLOGY STUDIES/ ... A total of 924 subjects were enrolled in 10 clinical trials in which gadobenate dimeglumine (Gd-BOPTA) was compared with gadopentetate dimeglumine (Gd-DTPA). Of these subjects, 893 were patients with known or suspected disease and 31 were healthy adult volunteers. Of the 893 patients, 174 were pediatric subjects (aged two days to 17 years) referred for MRI of the brain or spine. Safety evaluations included monitoring vital signs, laboratory values, and adverse events (AE) ... The rate of AE in adults was similar between the two agents (Gd-BOPTA: 51/561, 9.1%; Gd-DTPA: 33/472, 7.0%; P = 0.22). In parallel-group studies in which subjects were randomized to either agent, the rate of AE was 10.9% for Gd-BOPTA and 7.9% for Gd-DTPA (P = 0.21). In the subset of subjects receiving both agents in intraindividual crossover trials, the rate of AE was 8.0% for Gd-BOPTA and 8.5% for Gd-DTPA (P = 0.84). Results of other safety assessments (laboratory tests, vital signs) were similar for the two agents ... The safety profile of Gd-BOPTA is similar to Gd-DTPA in patients and volunteers. Both compounds are equally well-tolerated in patients with various disease states undergoing MRI.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Gadopentetate dimeglumine

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DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ ... Gadopentetate dimeglumine (Magnevist), gadoteridol (ProHance), gadodiamide (Omniscan), and gadoversetamide (Optimark) 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 0.3 mL of contrast or saline. There were 6 experimental groups, with 15 animals in each group. ... 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 (P = 0.0008 for gadoteridol, and P = 0.006 for gadodiamide) and necrosis (P = 0.0067 for gadoteridol, and P = 0.031 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. In terms of both edema and inflammation, the effect of gadopentetate dimeglumine, although less, could not be differentiated with any statistical significance from that of meglumine diatrizoate. 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 (P = 0.021). CONCLUSIONS: 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).

/LABORATORY ANIMALS: Acute Exposure/ A nonionic (gadodiamide injection) and an ionic (gadopentetate dimeglumine) contrast medium were compared for their effect on hemodynamics in the anesthetized, open-chest dog. Both agents were administered iv over 15 s at dosages of 1.0 and 1.5 mmol/kg, in randomized order. Both contrast agents resulted in transient but statistically significant decreases in aortic pressure, left ventricular pressure, indices of left ventricular contractility and relaxation, and systemic and pulmonary vascular resistance, and increases in aortic blood flow. At each dosage investigated, the changes associated with the administration of gadodiamide injection were of significantly smaller magnitude than those seen after gadopentetate dimeglumine and returned to preadministration levels sooner. The results from this study confirm that gadodiamide injection produces less severe alterations in hemodynamics than gadopentetate dimeglumine.

/LABORATORY ANIMALS: Acute Exposure/ The hemodynamic reactions of high doses (0.6 mmol/ kg) of gadopentetate dimeglumine (gadolinium [Gd]-DTPA, Magnevist) were evaluated and compared with the side effects of ionic (diatrizoate: Urografin 76%) and nonionic (iopamidol, Solutrast 370) radiographic contrast media. ... In 18 pigs, pressure and flow of the systemic and pulmonary circulation were monitored after intracardiac bolus injections (2-4 seconds) of dose volumes of 1.2 mL/kg of each contrast agent. ... All contrast media decreased the aortic pressure transiently (Gd-DTPA and diatrizoate: -25%, iopamidol: -10%; P < 0.01). Pulmonary artery pressure, cardiac output, and stroke volume increased for several minutes. The vascular resistance declined. Diatrizoate induced stronger and longer-lasting side effects (P < 0.01) than Gd-DTPA and iopamidol...

/LABORATORY ANIMALS: Acute Exposure/ ... Gadodiamide injection or gadopentetate dimeglumine, each at doses of 0.3 or 1.5 mmol/kg of bw, or saline volume control was administered iv in the cephalic vein of anesthetized dogs. Hemodynamic parameters, electrocardiographic parameters, and peripheral flow were measured. ... Neither the low or high dose of gadodiamide injection caused statistically significant (P<0.05) changes in any of the measured cardiovascular parameters. High doses of gadopentetate dimeglumine, however, significantly decreased left ventricular and systemic blood pressure and significantly depressed left ventricular contractility (P<0.05)...

For more Non-Human Toxicity Excerpts (Complete) data for GADOPENTETATE DIMEGLUMINE (12 total), please visit the HSDB record page.

Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. The risk of hypersensitivity reactions is higher in patients with a history of reaction to contrast media, bronchial asthma, or allergic disorders. Hypersensitivity reactions can occur with or without prior exposure to gadolinium-based contrast agents (GBCAs). Have appropriately trained personnel administer Magnevist in a facility that has immediate availability of resuscitative equipment. If a hypersensitivity reaction occurs, stop Magnevist injection and immediately begin appropriate therapy. Observe closely patients with a history of drug reactions, allergy, or other hypersensitivity disorders, during and up to several hours after Magnevist injection.

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 Magnevist 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 (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. Do not exceed the recommended Magnevist dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration.

In patients with renal impairment, acute renal failure (acute kidney injury) requiring dialysis or worsening renal function has occurred, mostly within 48 hours of Magnevist injection. The risk of acute renal failure is higher with increasing dose of contrast. Use the lowest possible dose, evaluate renal function in patients with renal impairment, and allow sufficient time for contrast elimination before re-administration.