Dotarem

MRI Agents

 
NOTE: Hypersensitivity reactions may occur. Before administration, assess all patients for previous reactions to contrast media. Trained personnel and therapies used to treat hypersensitivity reactions (epinephrine, antihistamines, and corticosteroids) should be readily available. During and after administration, observe patient for signs and symptoms of hypersensitivity reactions.[53854]

Visually inspect for particulate matter and discoloration prior to administration. The solution is clear and colorless to yellow. Do not use if particulate matter is present or if container appears damaged.
Do not mix with other drugs.
Perform the magnetic resonance imaging (MRI) immediately after the bolus injection.[53854] [62368]

Glass Vials
Aseptically draw up the contrast medium into a disposable syringe and use immediately.[53854]
 
Prefilled Glass or Plastic Syringe
Holding the syringe barrel firmly, screw the threaded tip of the plunger rod clockwise into the cartridge plunger.
For the glass prefilled syringe: Push forward a few millimeters to break any friction between the cartridge plunger and the syringe barrel.
For the plastic prefilled syringe: After screwing the push rod into the syringe cartridge plunger, turn the push rod clockwise an additional half turn, so the cartridge plunger rotates freely.
Holding the syringe vertically, aseptically remove the rubber cap from the tip of the syringe and attach either a sterile disposable needle or compatible needless luer lock tubing set. If using a needle, hold the syringe vertically and push the plunger forward until all air is evacuated and fluid appears at the needle tip. If using a needleless luer lock tubing set, check the connection between the syringe and tubing as the fluid flows.
Storage: Product contains no antimicrobial preservatives. Discard any unused product.[53854]
 
Pharmacy Bulk Packaging
Do not use bulk packaging for direct IV administration. Contents must be transferred to empty sterile syringes in an aseptic work area (i.e., laminar flow hood using aseptic technique and suitable transfer device).
Bulk packaging may only be penetrated once. Do not remove from aseptic work area after container closure is punctured.
Use each individual dose promptly after withdrawal from the pharmacy bulk packaging.
Storage: Use the contents of the bulk packaging within 24 hours after the initial puncture.[62368]
 
Bolus Injection
Ensure catheter and venous patency before the injection. Extravasation may result in tissue irritation.
Administer as a single IV bolus injection at a rate of 2 mL/second for adults and 1 to 2 mL/second for pediatric patients.
Follow the bolus injection with a normal saline flush to ensure administration of the total dose.[53854] [62368]

renal failure (unspecified) / Delayed / 0-0.2
nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) / Delayed / Incidence not known
cyanosis / Early / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
laryngospasm / Rapid / Incidence not known
cardiac arrest / Early / Incidence not known
respiratory arrest / Rapid / Incidence not known
coma / Early / Incidence not known
seizures / Delayed / Incidence not known
bradycardia / Rapid / Incidence not known
arrhythmia exacerbation / Early / Incidence not known

palpitations / Early / 0-0.2
hypertension / Early / 0-0.2
hypotension / Rapid / 0-0.2
blepharitis / Early / Incidence not known
conjunctivitis / Delayed / Incidence not known
sinus tachycardia / Rapid / Incidence not known

headache / Early / 0.4-1.1
nausea / Early / 0.6-0.6
pruritus / Rapid / 0-0.4
injection site reaction / Rapid / 0-0.4
rash / Early / 0-0.2
asthenia / Delayed / 0-0.2
drowsiness / Early / 0-0.2
fatigue / Early / 0-0.2
paresthesias / Delayed / 0-0.2
dizziness / Early / 0-0.2
anxiety / Delayed / 0-0.2
dysgeusia / Early / 0-0.2
vomiting / Early / 0-0.2
urticaria / Rapid / Incidence not known
hyperhidrosis / Delayed / Incidence not known
lacrimation / Early / Incidence not known
parosmia / Delayed / Incidence not known
tremor / Early / Incidence not known
syncope / Early / Incidence not known
hypersalivation / Early / Incidence not known
diarrhea / Early / Incidence not known
weakness / Early / Incidence not known
fever / Early / Incidence not known
malaise / Early / Incidence not known

Serious adverse reactions, including nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD), have been reported in patients with renal impairment after receiving gadolinium-based contrast agents (GBCAs), such as gadoterate meglumine. NSF may result in fatal or debilitating systemic fibrosis affecting the internal organs, muscle, and skin. Patients at highest risk for NSF are those with chronic, severe renal disease or renal failure (glomerular filtration rate [GFR] less than 30 mL/minute/1.73 m2) and patients with acute renal injury. Avoid use of GBCAs in patients with impaired drug elimination unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. Use of higher than recommended doses or repeated administration may increase the risk for NSF; therefore, administer the lowest dose necessary for adequate imaging and, if needed, only repeat the dose after a sufficient period of time has passed for elimination of the agent from the body. Gadoterate meglumine is removed by hemodialysis. For patients receiving hemodialysis, it may be prudent to dialyze patients after receiving the contrast agents, although a relationship between dialysis and prevention of NSF has not been determined. Of note, hemodialysis is the preferred method of dialysis as continuous ambulatory peritoneal dialysis does not appear to be as effective in eliminating GBCAs. All patients should be screened for evidence of renal dysfunction by obtaining a medical history or laboratory results prior to the administration of GBCAs. Acute renal injury occurs commonly after surgery, severe infection, injury, or drug-induced renal toxicity. In patients with acute renal injury, serum creatinine concentrations and estimated GFR may not reliably assess renal function; therefore, obtaining a medical history in these patients is of utmost importance. For patients at risk of chronic renal disease (e.g., patients with hypertension, diabetes mellitus, or geriatric patients [60 years of age or older]), estimate the GFR through laboratory testing. Counsel patients on the signs and symptoms of NSF/NFD. Report possible cases of NSF to the FDA through the FDA MedWatch program at 800-FDA-1088 and to the manufacturer at 877-729-6679. In contrast, guidelines suggest kidney function screening is optional for American College of Radiology (ACR) group II GBCAs, which includes gadoterate meglumine, given risk of NSF is very low comparatively; the risk of NSF is very low for a standard dose (0.1 mmol/kg) of group II GBCA, even in patients with eGFR less than 30 mL/minute/1.73 m2. Do not withhold or delay group II GBCA in patients with kidney disease if harm would result from not proceeding with an indicated contrast-enhanced MRI. If multiple urgent group II GBCA doses are indicated, do not delay subsequent dose(s) for NSF concerns. If not urgent, delaying the subsequent dose(s) for more than 24 hours or performing intercurrent dialysis can promote GBCA clearance. In general, do not initiate or alter dialysis based on group II GBCA administration. These recommendations are not altered by patients receiving concomitant nephrotoxic medications, chemotherapy, or contrast-enhanced CT.

Dotarem

Rx

Paramagnetic gadolinium-based contrast agent
Used to enhance MRI of the brain, spine, and associated tissues with abnormal vascularity
Nephrogenic systemic fibrosis (NSF) may occur in those with renal insufficiency; screening of renal function prior to administration is recommended

0.2 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection at a rate of 2 mL/second. Data for repeat injections are not available; however, if in the clinical judgment of the physician, sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. Cumulative doses up to 0.3 mmol/kg have been administered to patients and healthy volunteers without increased adverse events. The FDA-approved product labeling provides weight-adjusted dose volumes as follows: 30 kg: 6 mL; 40 kg: 8 mL; 50 kg: 10 mL; 60 kg: 12 mL; 70 kg: 14 mL; 80 kg: 16 mL; 90 kg: 18 mL; 100 kg: 20 mL; 110 kg: 22 mL; 120 kg: 24 mL; 130 kg: 26 mL; 140 kg: 28 mL; 150 kg: 30 mL.

0.2 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection at a rate of 1 to 2 mL/second. Data for repeat injections are not available; however, if in the clinical judgment of the physician, sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. Cumulative doses up to 0.3 mmol/kg have been administered to patients and healthy volunteers without increased adverse events. The FDA-approved product labeling provides weight-adjusted dose volumes as follows: 2.5 kg: 0.5 mL; 5 kg: 1 mL; 10 kg: 2 mL; 20 kg: 4 mL; 30 kg: 6 mL; 40 kg: 8 mL; 50 kg: 10 mL; 60 kg: 12 mL; 70 kg: 14 mL; 80 kg: 16 mL; 90 kg: 18 mL; 100 kg: 20 mL; 110 kg: 22 mL; 120 kg: 24 mL; 130 kg: 26 mL; 140 kg: 28 mL; 150 kg: 30 mL.

0.2 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection at a rate of 1 to 2 mL/second. Data for repeat injections are not available; however, if in the clinical judgment of the physician, sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. Cumulative doses up to 0.3 mmol/kg have been administered to patients and healthy volunteers without increased adverse events. The FDA-approved product labeling provides weight-adjusted dose volumes as follows: 2.5 kg: 0.5 mL; 5 kg: 1 mL.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

No dosage adjustments are recommended; do not exceed recommended dose and allow sufficient time for elimination prior to any repeat administration. The manufacturer recommends caution in patients with chronic, severe renal disease (GFR < 30 mL/min/1.73 m2) and in patients with acute kidney injury; these patients are at highest risk for renal side effects of contrast use. Avoid use in these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities.
 
Intermittent hemodialysis
Gadoterate meglumine is removed from the body by hemodialysis. For patients receiving hemodialysis, consider initiating a hemodialysis session after drug administration in order to enhance clearance of the contrast agent.

There are no drug interactions associated with Gadoterate meglumine products.

Dotarem/Gadoterate meglumine Intravenous Inj Sol: 0.5mMole, 1mL

0.2 mL/kg (0.1 mmol/kg) IV single dose.

0.2 mL/kg (0.1 mmol/kg) IV single dose.

0.2 mL/kg (0.1 mmol/kg) IV single dose.

0.2 mL/kg (0.1 mmol/kg) IV single dose.

0.2 mL/kg (0.1 mmol/kg) IV single dose.

Term Neonates: 0.2 mL/kg (0.1 mmol/kg) IV single dose.
Premature Neonates: Safety and efficacy have not been established.

Gadoterate meglumine, a paramagnetic agent, is used to enhance lesion detection and characterization during magnetic resonance imaging (MRI). In MRI, the visualization of normal or pathological tissue depends on changes in the radiofrequency signal intensity that occur with: differences in proton density; differences of the spin-lattice or longitudinal relaxation time (T1); and differences in the spin-spin or transverse relaxation time (T2). Gadoterate meglumine causes increased signal intensity by developing a magnetic moment when placed in a magnetic field. This magnetic moment enhances the relaxation rates of water protons, thereby shortening T1 and T2 in target tissues. When administered at recommended doses, the effects are primarily observed in the T1 relaxation time. Disruption of the blood-brain barrier or abnormal vascularity allows accumulation of the diagnostic agent in lesions such as neoplasms, abscesses, and infarcts.

Gadoterate meglumine is administered intravenously. At steady state, the volume of distribution is approximately equivalent to extracellular water at 179 +/- 25 mL/kg in females and 211 +/- 35 mL/kg in males. No protein binding has been observed in vitro, and gadoterate meglumine is not known to be metabolized. The mean elimination half-life is approximately 1.5 hours in females and 2 to 2.5 hours in males. Elimination occurs primarily via the kidneys, with 72.9 +/- 17% and 85.4 +/- 9.7% of a single 0.1 mmol/kg dose excreted in the urine within 48 hours, in females and males, respectively. Within the studied dosage ranges (0.1 to 0.3 mmol/kg), the kinetics of the contrast agents appear to be linear.
 
Affected cytochrome P450 isoenzymes: None

After intravenous administration in normal subjects, the pharmacokinetics of gadoterate meglumine conform to a one-compartment open-model.

Use gadoterate meglumine during pregnancy only if imaging is essential and cannot be delayed. Gadolinium-based contrast agents (GBCAs) cross the placenta and result in fetal exposure and gadolinium retention. Pregnant women may be at greater risk for gadolinium retention. Data on the association between GBCAs and adverse fetal outcomes in human pregnancy are limited and inconclusive. In animal studies, no adverse effects on embryo fetal development were observed after intravenous administration of gadoterate meglumine to pregnant rats at 3-, 7-, and 16-times the recommended human dose (based on body surface) or when administered to pregnant rabbits at 3- and 10-times the recommended human dose. The American College of Radiology (ACR) manual on contrast media acknowledges that a standard gadolinium-based contrast agent (GBCA) crosses the primate placenta; however, the risk to the human fetus is unknown. Therefore, the ACR advises against its routine use in pregnant women; the drug should only be administered during pregnancy if absolutely necessary and only after informed consent is obtained. The Guidelines for Computed Tomography and Magnetic Resonance Imaging in Pregnancy and Lactation states that because of the potential for fetal toxicity, the drug should only be used during pregnancy if deemed absolutely essential.

There are no data on the presence of gadoterate meglumine in human milk, the effects on the breast-fed infant, or the effects on milk production. Limited data demonstrates that breast-feeding after administration of another gadolinium-based contrast agent (GBCA) to the mother would result in the infant receiving an oral dose of 0.01% to 0.04% of the maternal dose. Gastrointestinal absorption of a GBCA is limited. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for gadoterate meglumine and any potential adverse effects on the breast-fed infant from gadoterate meglumine or the underlying maternal condition. Previous American Academy of Pediatrics (AAP) recommendations considered GBCAs compatible with breast-feeding. Additionally, the Guidelines for Computed Tomography and Magnetic Resonance Imaging Use During Pregnancy and Lactation and the American College of Radiology (ACR) manual on contrast media state that lactating women receiving GBCAs can continue to breast-feed without interruption. The reasoning for this recommendation is based on estimates of limited systemic exposure in the breast-fed infant and reviews that conclude maternally administered drug poses no risk to the nursing infant.