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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, 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. In addition, gadolinium deposits may remain in patients' bodies for months to years after gadolinium-based contrast agent (GBCA) receipt. Bone has been identified as the main reservoir, retaining the highest concentration of gadolinium (nanomoles per gram of tissue) for the longest duration of time. Other organs which retain lesser amounts of gadolinium include the brain, skin, kidney, liver, and spleen. The consequences of gadolinium retention in the brain have not been established; however, retention in the skin and kidney has been associated with pathologic clinical consequences in patients with impaired renal function. There are rare reports of pathologic skin changes in patients with normal renal function. Other patients who may be at higher risk for gadolinium retention include patients requiring multiple lifetime doses, pregnant women, pediatric patients, and patients with inflammatory conditions. Limit repeated GBCA imaging studies, particularly closely spaced MRI studies, but do not defer or avoid necessary GBCA MRI scans. When choosing a GBCA, consider the retention characteristics of each agent. In general, linear GBCAs result in more retention and retention for longer periods of time than do macrocyclic GBCAs. More specifically, at equivalent doses, use of gadodiamide or gadoversetamide results in higher gadolinium concentrations remaining in the body than gadoxetate disodium, gadopentetate dimeglumine, or gadobenate dimeglumine. Gadolinium concentrations in the body are lowest after administration of gadoterate meglumine, gadobutrol, and gadoteridol. Instruct patients to inform their health care professional about all medical conditions, including if pregnant or thinking about becoming pregnant, dates and numbers of any previous gadolinium-enhanced MRIs, and history of kidney problems.

    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

    Use gadopentetate dimeglumine 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, retarded fetal development was observed following intravenous administration of gadopentetate dimeglumine 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. 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 dimeglumine is excreted in human milk. An analysis of 18 lactating women receiving 0.1 mmol/kg found less than 0.04% of the administered gadolinium was excreted into breast milk within 24-hours; for a 70-kg woman, this correlates to less than 3 micromoles of gadolinium. The overall duration of excretion of gadolinium into breast milk, the extent of oral absorption of gadolinium by the breast-fed infant, and its potential effect on the infant remains unknown. 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.

    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 / 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

    Use gadopentetate dimeglumine 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, retarded fetal development was observed following intravenous administration of gadopentetate dimeglumine 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. 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 dimeglumine is excreted in human milk. An analysis of 18 lactating women receiving 0.1 mmol/kg found less than 0.04% of the administered gadolinium was excreted into breast milk within 24-hours; for a 70-kg woman, this correlates to less than 3 micromoles of gadolinium. The overall duration of excretion of gadolinium into breast milk, the extent of oral absorption of gadolinium by the breast-fed infant, and its potential effect on the infant remains unknown. 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.

    MECHANISM OF ACTION

    Gadopentetate dimeglumine, a paramagnetic agent, is used to enhance lesion detection and characterization during magnetic resonance imaging (MRI). In magnetic resonance, 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). Gadopentetate dimeglumine 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 subacute infarcts.

    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.