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    MRI Agents

    BOXED WARNING

    Diabetes mellitus, dialysis, geriatric, hypertension, nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), renal disease, renal failure, renal impairment

    Gadopentetate (Magnevist) is contraindicated in patients with renal failure, acute kidney injury, and in patients with chronic, severe renal disease (GFR < 30 mL/min/1.73 m2). Serious adverse reactions, including nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD), have been reported in patients with renal impairment after receiving gadopentetate. Although rare, NSF may result in fatal or debilitating systemic fibrosis affecting the internal organs, muscle, and skin. Patients at highest risk for NSF after receiving gadopentetate are those with impaired elimination of the drug, including those with acute renal insufficiency of any severity due to hepato-renal syndrome or liver transplant in the perioperative period. Avoid use of gadopentetate in patients with impaired drug elimination unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF has not been reported in patients with normal kidney function, but use of higher than recommended doses or repeated administration may increase the risk for NSF. Re-administration should occur only after a sufficient period of time has passed for elimination of the agent from the body. Gadopentetate 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 gadolinium-containing contrast media. All patients should be screened for evidence of renal dysfunction by obtaining a medical history and/or laboratory results prior to the administration of gadolinium-based contrast agents. Acute kidney injury occurs commonly after surgery, severe infection, injury, or drug-induced kidney toxicity. In patients with acute kidney 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]), estimate the GFR through laboratory testing. Tell patients about the signs and symptoms of NSF/NFD. Report possible cases of NSF to the FDA through the FDA Medwatch program.

    DEA CLASS

    Rx

    DESCRIPTION

    Paramagnetic, gadolinium-containing contrast agent used to enhance MRI of intracranial, spinal, head, neck, and body lesions with abnormal vascularity.
    Nephrogenic systemic fibrosis (NSF) may occur in those with renal insufficiency.
    Screening of renal function prior to administration is recommended.

    COMMON BRAND NAMES

    Magnevist

    HOW SUPPLIED

    Magnevist Intravenous Inj Sol: 1mL, 469.01mg

    DOSAGE & INDICATIONS

    For use as contrast enhancement in magnetic resonance imaging (MRI) to visualize lesions with abnormal vascularity within the central nervous system (brain, spine, and associated tissues), head, neck, and body (excluding the heart).
    Intravenous dosage
    Adults, including the Geriatric

    0.2 mL/kg (0.1 mmol/kg) given intravenously at a rate not to exceed 10 mL per 15 seconds. Doses in excess of 26 mL, for patients > 130 kg (or 286 pounds) has not been studied. 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. In studies of CNS MRI, no difference in safety, imaging, or diagnosis was found between 0.1 mmol/kg and 0.3 mmol/kg.

    Adolescents and Children >= 2 years of age

    0.2 mL/kg (0.1 mmol/kg) given intravenously at a rate not to exceed 10 mL per 15 seconds.

    MAXIMUM DOSAGE

    Adults

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

    Geriatric

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

    Adolescents

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

    Children

    >= 2 years: 0.2 mL/kg (0.1 mmol/kg) IV.
    < 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. However, patients are advised to inform their provider of any liver disease prior to receiving gadopentetate.

    Renal Impairment

    GFR >= 30 mL/min/1.73 m2: No dosage adjustments are recommended; do not exceed recommended dose and allow sufficient time for elimination prior to any repeat administration. For patients at higher risk for renal side effects of contrast use.; avoid use unless the diagnostic information is essential and not available with non-contrast MRI or other modalities.
     
    GFR < 30 mL/min/1.73 m2: Contraindicated. Includes patients with chronic severe kidney disease and acute kidney injury.
     
    Intermittent hemodialysis
    Gadopentetate is removed from the body by hemodialysis.

    ADMINISTRATION

     
    NOTE: Hypersensitivity reactions may occur. Epinephrine, antihistamines, and corticosteroids should be on hand for immediate treatment.

    Injectable Administration

    Visually inspect solution for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is present. Do not use if container has been damaged or protective seal broken.

    Intravenous Administration

    The imaging procedure should be completed within 1 hour of injection of gadopentetate dimeglumine.
    Usual safety rules customary for magnetic resonance imaging (e.g., exclusion of cardiac pacemakers and ferromagnetic implants) must be observed.
    Administer as single intravenous injection. The rate of administration should not exceed 10 mL per 15 seconds.
    To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush.
    Data for repeat injections are not available. 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.
    When gadopentetate dimeglumine is to be injected using a plastic disposable syringe, the contrast medium should be drawn into the syringe and used immediately.
    The product contains no antimicrobial preservatives. Discard all unused product. Discard any unused portion in accordance with regulations dealing with the disposal of such materials.
    When using the 100 mL Pharmacy Bulk Package, the contents should be used within 12 hours after the initial puncture. After 12 hours, any unused portion should be discarded.
    If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

    STORAGE

    Magnevist:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Diagnostic procedures that involve the use of contrast agents, such as gadopentetate, should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.

    Magnetic resonance imaging (MRI)

    Diagnostic procedures that involve use of contrast agents, such as gadopentetate dimeglumine, should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. As with any paramagnetic contrast agent, the use of gadopentetate dimeglumine during contrast enhanced magnetic resonance imaging (MRI) may impair visualization of lesions seen on non-contrast MRI. Caution must be used when contrast enhanced imaging is interpreted without a companion non-contrast image. Repeated use (4 MRI scans or more) of gadolinium-based contrast agents (GBCA) has resulted in gadolinium deposits in the brain that remain long after drug receipt. No adverse health effects with gadolinium retention in the brain have been identified. Limit use of GBCA to situations in which the information provided is considered necessary, and assess the necessity of repetitive GBCA MRIs.

    Asthma, atopy, radiopaque contrast media hypersensitivity

    Administration to patients with a history of severe hypersensitivity reactions to gadopentetate dimeglumine is contraindicated. The drug has been associated with serious, and sometimes fatal, anaphylactoid/anaphylactic reactions, with cardiovascular, respiratory, and/or cutaneous manifestations. Patients with a history of iodinated radiopaque contrast media hypersensitivity, atopy (including hay fever, food allergies, and drug allergies), or a history of asthma or other allergic respiratory disorders are at increased risk of these reactions. Standard policies and procedures to prevent allergic-type reactions in patients at risk are not available currently. At minimum, appropriate facilities should be available for coping with the emergency treatment of severe reactions to the contrast agent; patients at risk should be closely observed during the procedure and for several hours following drug administration. One group of authors, however, recommends taking similar precautions to those that are taken in patients who have previously reacted to iodinated radiopaque contrast media that require subsequent doses. First, the necessity of contrast enhancement during MRI should be determined. If it is determined that contrast enhancement outweighs any potential risk, the intensity of a previous reaction (to either iodinated or gadolinium-based contrast media) should guide precautionary measures. If the previous reaction to contrast media was mild or nonallergic, use of a different or low-osmolar (i.e., gadoteridol or gadodiamide) agent is recommended. If the previous reaction to contrast media was moderate or severe, premedication with steroids (e.g., for adults, prednisone 50 mg PO or equivalent 13, 7, and 1 hour prior to the exam ) and antihistamines (e.g., adult dose diphenhydramine 50 mg IM/PO one hour prior to the exam ) along with the use of a different or low-osmolar contrast agent is recommended.

    Diabetes mellitus, dialysis, geriatric, hypertension, nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), renal disease, renal failure, renal impairment

    Gadopentetate (Magnevist) is contraindicated in patients with renal failure, acute kidney injury, and in patients with chronic, severe renal disease (GFR < 30 mL/min/1.73 m2). Serious adverse reactions, including nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD), have been reported in patients with renal impairment after receiving gadopentetate. Although rare, NSF may result in fatal or debilitating systemic fibrosis affecting the internal organs, muscle, and skin. Patients at highest risk for NSF after receiving gadopentetate are those with impaired elimination of the drug, including those with acute renal insufficiency of any severity due to hepato-renal syndrome or liver transplant in the perioperative period. Avoid use of gadopentetate in patients with impaired drug elimination unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF has not been reported in patients with normal kidney function, but use of higher than recommended doses or repeated administration may increase the risk for NSF. Re-administration should occur only after a sufficient period of time has passed for elimination of the agent from the body. Gadopentetate 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 gadolinium-containing contrast media. All patients should be screened for evidence of renal dysfunction by obtaining a medical history and/or laboratory results prior to the administration of gadolinium-based contrast agents. Acute kidney injury occurs commonly after surgery, severe infection, injury, or drug-induced kidney toxicity. In patients with acute kidney 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]), estimate the GFR through laboratory testing. Tell patients about the signs and symptoms of NSF/NFD. Report possible cases of NSF to the FDA through the FDA Medwatch program.

    Extravasation

    Prior to gadopentetate injection, the patency and integrity of the intravenous line should be determined. Furthermore, appropriate surveillance of the dosing limb for the development of local injection site reactions is recommended. Care should be taken to avoid extravasation as significant tissue damage may occur. Skin and soft tissue necrosis, thrombosis, fasciitis, and compartment syndrome requiring surgical intervention (e.g. compartment release or amputation) have occurred very rarely at the site of contrast injection or the dosed limb. Phlebitis and thrombophlebitis may be observed generally within 24 hours after injection and resolve with supportive treatment. In animal models, gadopentetate caused the greatest tissue damage when extravasation occurred compared to other gadolinium-containing contrast media. Such findings were expected as gadopentetate had the highest osmolality of the gadolinium-containing contrast media tested; similar to iodinated radiopaque contrast media, extravasation of high-osmolar contrast media may cause more damage when compared to low-osmolar contrast media. Extravasation of gadopentetate is not greatly appreciated as small doses and slow injection rates are traditionally used. Total volume and rate of injection, extravasation of contrast agent, and patient susceptibility contribute to these reactions.

    Pregnancy

    Gadopentetate is classified as FDA pregnancy risk category C. In animal studies, retarded fetal development was observed following intravenous administration to pregnant rats for 10 days at 2.5-, 7.5-, and 12.5-times the human dose (based on body weight) and when administered to pregnant rabbits for 13 days at 7.5- and 12.5-times the human dose. No congenital anomalies were noted in rats or rabbits. Because there are no adequate and well-controlled studies in pregnant women, the manufacturer recommends use during pregnancy only if the benefit to the mother justifies the potential risk to the fetus. The American College of Radiology (ACR) manual on contrast media states that the drug crosses the human placenta when administered in clinical doses; however, the risk to the 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.

    Breast-feeding

    Gadopentetate is excreted in human milk. An analysis of 18 lactating women receiving 0.1 mmol/kg, found < 0.04% of the administered gadolinium was excreted into breast milk within 24-hours; for a 70-kg woman, this correlates to < 3 micromol of gadolinium. The overall duration of excretion into breast milk, the extent of oral absorption by the breast-fed infant, and the drugs potential effect on the infant remains unknown. The manufacturer recommends caution when administering to a lactating woman; however, the American Academy of Pediatrics (AAP) considers the drug 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 gadopentetate 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 pose no risk to the nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Sickle cell disease

    Deoxygenated sickle erythrocytes have been shown in vitro to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by gadolinium-based contrast agents (GBCAs), such as gadopentetate dimeglumine, may possibly potentiate sickle erythrocyte alignment. Although the use of gadopentetate dimeglumine in patients with sickle cell disease and other hemoglobinopathies has not been studied, the American College of Radiology (ACR) manual on contrast media considers any special risk to sickle cell patients from administration of GBCAs to be extremely low; no restrictions for use of GBCAs are recommended by the ACR.

    Children, infants, neonates, premature neonates

    The use of gadopentetate dimeglumine in children aged 2 years and older has been established; however, safety and efficacy in neonates, infants, and children under the age of 2 years have not been established in adequate and well-controlled clinical trials. Furthermore, gadopentetate dimeglumine has not been studied in children with severe renal dysfunction, clinically unstable or uncontrolled hypertension, or in premature neonates.

    Seizure disorder

    Rarely, seizures have been reported in patients receiving gadopentetate. Evidence indicating that gadopentetate directly precipitates convulsions is lacking; however, the majority of seizures have been reported in patients with a history of seizures. In Canadian product monograph information, the manufacturer recommends close monitoring and having injectable anticonvulsants readily available when gadopentetate is used in patients with a known seizure disorder. Following these recommendations may be prudent.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0-1.0
    thrombosis / Delayed / 0-1.0
    skin necrosis / Early / 0-1.0
    tissue necrosis / Early / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    renal failure (unspecified) / Delayed / Incidence not known
    nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) / Delayed / Incidence not known
    coma / Early / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    laryngospasm / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    cyanosis / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    pulmonary edema / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known

    Moderate

    hypotension / Rapid / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    nystagmus / Delayed / 0-1.0
    urinary incontinence / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    headache / Early / 4.8-4.8
    nausea / Early / 2.7-2.7
    injection site reaction / Rapid / 2.3-2.3
    anxiety / Delayed / 0-1.0
    drowsiness / Early / 0-1.0
    agitation / Early / 0-1.0
    dizziness / Early / 1.0-1.0
    paresthesias / Delayed / 0-1.0
    fever / Early / 0-1.0
    vomiting / Early / 0-1.0
    abdominal pain / Early / 0-1.0
    diarrhea / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    hypersalivation / Early / 0-1.0
    dental pain / Delayed / 0-1.0
    hyperhidrosis / Delayed / 0-1.0
    rash (unspecified) / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    pruritus / Rapid / 0-1.0
    rhinitis / Early / 0-1.0
    throat irritation / Early / 0-1.0
    sneezing / Early / 0-1.0
    diplopia / Early / 0-1.0
    lacrimation / Early / 0-1.0
    otalgia / Early / 0-1.0
    ocular pain / Early / 0-1.0
    xerostomia / Early / 0-1.0
    ocular irritation / Rapid / 0-1.0
    back pain / Delayed / 0-1.0
    fatigue / Early / 0-1.0
    asthenia / Delayed / 0-1.0
    urinary urgency / Early / Incidence not known
    tremor / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    shivering / Rapid / Incidence not known
    chills / Rapid / Incidence not known
    cough / Delayed / Incidence not known
    syncope / Early / Incidence not known
    pallor / Early / Incidence not known
    parosmia / Delayed / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Gadopentetate products.

    PREGNANCY AND LACTATION

    Pregnancy

    Gadopentetate is classified as FDA pregnancy risk category C. In animal studies, retarded fetal development was observed following intravenous administration to pregnant rats for 10 days at 2.5-, 7.5-, and 12.5-times the human dose (based on body weight) and when administered to pregnant rabbits for 13 days at 7.5- and 12.5-times the human dose. No congenital anomalies were noted in rats or rabbits. Because there are no adequate and well-controlled studies in pregnant women, the manufacturer recommends use during pregnancy only if the benefit to the mother justifies the potential risk to the fetus. The American College of Radiology (ACR) manual on contrast media states that the drug crosses the human placenta when administered in clinical doses; however, the risk to the 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.

    Gadopentetate is excreted in human milk. An analysis of 18 lactating women receiving 0.1 mmol/kg, found < 0.04% of the administered gadolinium was excreted into breast milk within 24-hours; for a 70-kg woman, this correlates to < 3 micromol of gadolinium. The overall duration of excretion into breast milk, the extent of oral absorption by the breast-fed infant, and the drugs potential effect on the infant remains unknown. The manufacturer recommends caution when administering to a lactating woman; however, the American Academy of Pediatrics (AAP) considers the drug 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 gadopentetate 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 pose no risk to the nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Gadopentetate dimeglumine, a paramagnetic agent, is used to enhance lesion detection and characterization during magnetic resonance imaging (MRI). When given intravenously, gadopentetate dimeglumine equilibrates rapidly between intra- and extra-cellular spaces of soft tissues. Gadopentetate does not cross an intact blood-brain barrier; however, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadopentetate dimeglumine in lesions such as neoplasms, abscesses, and subacute infarcts. Gadopentetate dimeglumine develops a magnetic moment when placed in a magnetic field. The resultant large, local magnetic field can enhance the relaxation rates of water protons in the tissues, where the paramagnetic agent accumulates. In MRI, the visualization of normal or pathological tissue depends on changes in the radiofrequency signal intensity that occur with: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and the variation of the spin-spin or transverse relaxation time (T2). Gadopentetate dimeglumine, at usual doses, primarily effects the T1 relaxation time.

    PHARMACOKINETICS

    Gadopentetate dimeglumine injection is administered intravenously. The extent of protein binding and blood cell partitioning of gadopentetate dimeglumine is not known; the volume of distribution (266 +/- 43 mL/kg) is equal to that of extracellular water.
     
    Gadopentetate dimeglumine is exclusively eliminated in the urine with (reported as mean +/- SD) 83 +/- 14% of the dose excreted within 6 hours, and 91 +/- 13% excreted within 24 hours post-injection. There was no detectable biotransformation or decomposition of gadopentetate dimeglumine. The mean elimination half-life (reported as mean +/- SD) was 1.6 +/- 0.13 hours. The urinary and plasma clearance rates (1.76 +/- 0.39 mL/min/kg and 1.94 +/- 0.28 mL/min/kg, respectively) of gadopentetate dimeglumine are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney; furthermore, clearance is similar to that of substances which are subject to glomerular filtration.

    Intravenous Route

    Human pharmacokinetic studies show that in normal subjects intravenously administered gadopentetate dimeglumine conforms to a two compartment open model with a mean distribution half-life (reported as mean +/- SD) of about 0.2 +/- 0.13 hours. Upon injection, the meglumine salt is completely dissociated from the gadopentetate dimeglumine complex.