Gadopentetate Dimeglumine - A Comprehensive Review of an MRI Contrast Agent

Overview

Gadopentetate, commonly known as Gadopentetate dimeglumine, is a magnetic resonance imaging (MRI) contrast agent used for enhancing spinal and cranial images in MRIs. This injectable contrast medium was initially approved for clinical use by the US FDA (United States Food and Drug Administration) in 1988. Contrast-enhanced magnetic resonance imaging is primarily indicated for detecting central nervous system (CNS) pathologies. Gadopentetate dimeglumine is injected into the body during specific MRI studies to improve tissue visualization. The drug has documented an effective clinical safety profile with rare incidences of side effects. However, its use in certain clinical conditions like renal dysfunction or liver disease should be cautiously monitored.

Drug Group

Gadopentetate comes under the drug class gadolinium-containing contrast agents. Gadolinium (Gd) is a metal ion (Lanthanide series) that forms gadolinium chelate complexes with salts like meglumine. These gadolinium chelates are highly soluble in water and are effectively distributed in extracellular (outside the cell) spaces. This water-soluble property also helps in its elimination through the kidneys (glomerular filtration by renal tubules).

Image contrast in MRI scans refers to the brightness differentiation of the area of interest from the surrounding tissues. Gadolinium-based contrast agents like Gadopentetate dimeglumine produce larger differences in the image brightness, enabling easy differentiation of tissue types.

These gadolinium-containing contrast agents possess paramagnetic action with positive susceptibility to the applied magnetic field. However, they return to normal when the external magnetic force is removed.

Indications

Gadopentetate dimeglumine injection is indicated for magnetic resonance imaging (MRI) in the following cases:

• CNS Imaging - Its use is indicated for MRI in adult individuals and children who are two years of age and above for visualizing abnormal intracranial (inside the skull) lesions with altered vascularity present in the brain, spinal cord, and related tissues.

• Extracranial and Extraspinal Lesions - Gadopentetate is also used to image abnormal vascularity of extracranial (outside the skull) lesions in the adult population and the pediatric age group (two years and above). These lesions are widely seen in the head and neck regions.

• Whole Body (Excluding Heart) - It is indicated for visualizing lesions with altered or abnormal vascularity anywhere in the body other than the heart.

Contraindications

The use of Gadopentetate dimeglumine is contraindicated in the following clinical conditions:

• Severe forms of chronic kidney disease (CKD) where the GFR (glomerular filtration rate) is below 30 mL/min/1.73m2 (milliliter per minute per meter square).

• In cases of acute kidney injuries.

• History of developing severe hypersensitivity or anaphylactic reactions to Gadopentetate.

• MRI contrast agents are also contraindicated in individuals with cardiac pacemaker implants, cochlear implants (implanted inner ear devices), and indwelling catheters with metallic components.

Dosing Strengths and Available Forms

The Gadopentetate injection is a colorless, slightly yellow, clear solution containing 469.01 mg (milligram) of Gadopentetate dimeglumine per mL (milliliter). It is available in the following dosing strengths:

• Single-Dose Vials - 5 mL (milliters), 10 mL, 15 mL, and 20 mL.

• Pre-filled Disposable Syringes - 10 mL, 15 mL, and 20 mL.

Warnings and Precautions

Gadopentetate dimeglumine contains gadolinium, which is very toxic in ionic form. Gadolinium-based contrast agents (GBCAs) are categorized under the FDA-issued boxed warning indicating the potential risks associated with the use of such drugs.

• Boxed Warning - The use of Gadopentetate dimeglumine carries the potential risk of causing nephrogenic systemic fibrosis (NSF) in individuals with impaired drug elimination. Higher dosing of Gadopentetate dimeglumine more than recommended doses or repeated dosages increase the occurrence of NSF.

• Hypersensitivity - Anaphylactoid or anaphylactic reactions, including respiratory, cardiovascular, and cutaneous manifestations, occur during Gadopentetate usage. Emergency cardiac and respiratory support is needed in such cases to avoid fatal consequences.

• Renal Failure - Acute kidney failure or worsening of renal functioning occurs while using the drug. Immediate dialysis within 48 hours of Gadopentetate injection is required during such cases.

For Patients

What is Magnetic Resonance Imaging?

Magnetic resonance imaging (MRI) is a noninvasive imaging technique used for clinical diagnostic and treatment intervention. This imaging procedure provides detailed images of the internal structures such as organs, muscles, blood vessels, and bones. The scanners in MRI machines use large magnetic waves and radio waves to visualize and create accurate images of internal structures inside the human body. MRI scan is unique because it does not use ionizing radiation usually employed in X-rays or CT (computed tomography) scans, thereby significantly reducing the risk potential of radiation exposure during MRI scans.

Working Principle - The MRI scanner consists of a long sliding table (where the subject is placed) and a huge closed cylinder (which produces magnetic waves) so the table can slide into the cylinder. The machine is operated only by a trained radiographer or MRI scan technologist. The MRI scan works on the following principle:

• The magnetic field created by the cylinder is powerful. These magnetic waves act on the components of water molecules (atoms and protons) present in the soft tissues and cause changes in the alignment. These atomic particles get magnetized under the influence of the magnetic field.

• Subsequent radio waves from the MRI scanner are directed at the magnetized subatomic particles, where they tend to change their original position.

• On stopping the radio waves, the subatomic particles (protons) tend to go back to their resting position and, while doing so, send radio reflections back in the form of echos (reflected radio signals).

• These reflected signals are captured as images by a computerized device and visualized through a monitor.

MRI scans are beneficial in visualizing soft tissue structures such as the liver, brain, or blood vessels because any abnormal tissue or pathology is differentiated from normal soft tissues. Also, multiple cross-sectional images from any angle could be obtained for a particular organ or tissue structure. Thus, MRI scans help better diagnose the medical condition and enhance the planning of treatment interventions.

Why Is a Magnetic Resonance Imaging Contrast Agent Needed?

Contrast agents used in magnetic resonance imaging are primarily pharmaceutical agents that help in studying the diagnostic images in a detailed manner. The benefits of using an MRI contrast agent such as Gadopentetate dimeglumine are as follows:

• It helps to provide detailed information about the scanned images.

• The specificity and sensitivity of the diagnostic images are improved by using gadolinium-containing contrast agents as they alter the intrinsic molecular tissue properties.

• Preferential enhancement of the targeted tissue is obtained since the contrast agent acts locally on the tissue by accumulating in it.

What Is the Dosage and Administration of Gadopentetate?

Gadopentetate dimeglumine is a contrasting agent and not a therapeutic medication. It is administered only for diagnostic purposes by a trained healthcare provider in authorized hospital settings.

• Route of Administration - Intravenous (IV) infusion.

• Recommended Dosage - 0.2 mL/kg (milliliter per kilogram) (0.1 mmol/kg) (millimole per kilogram) of Gadopentetate dimeglumine.

• Injection Rate - The injection is given at a controlled rate, not exceeding 10 mL for each 15 seconds.

• The total volume of the drug to be injected is calculated according to the individual's body weight. For a person with an average weight of 70 Kg (154 lbs), Gadopentetate dimeglumine dose should not exceed 14 mL.

• Dosing of more than 26 mL of Gadopentetate dimeglumine has yet to be clinically studied.

• Five mL of normal saline is flushed after Gadopentetate dimeglumine injection to ensure the drug has been completely injected into the bloodstream.

• The MRI procedure should commence immediately and be completed within one hour from the Gadopentetate dimeglumine injection.

What Are the Side Effects of Gadopentetate Dimeglumine?

Clinical studies have documented that injecting Gadopentetate dimeglumine could result in adverse side effects in some individuals. Some of the reported side effects are listed below:

• Transient headache (mild to moderate in severity).

• Nausea.

• Dizziness.

• Localized coldness (confined to the injection site).

• Injection site reactions like burning sensation, edema, pain, or irritation in and around the area injected.

• Fatigue (tiredness).

• Chest tightness.

• Change in blood pressure (hypotension or hypertension).

• Abdominal pain.

• Vomiting.

• Diarrhea.

• Dental pain.

• Anxiety.

• Excessive sweating.

• Dryness in the mouth.

• Eye irritation.

What Are the Precautions to Be Followed during Gadopentetate Injection?

Gadopentetate dimeglumine is a drug used for diagnostic imaging and not prescribed for therapeutic usage. The precautionary measures to be followed during the procedure are listed below:

• Gadopentetate dimeglumine is given in the form of an injection and is only administered by a trained healthcare provider in hospital settings.

• Before scanning, the individual is clearly explained about the procedure and screened to confirm eligibility. It is often conducted before the MRI scanning procedure.

• The contrast agent interacts with metallic components. Therefore, the individuals are screened for metallic implants, devices like pacemakers, neurostimulation systems, and metallic-tipped catheters. These projects interfere during MRI evaluation and also cause health hazards.

• Before initiating the procedure, the patient should inform the doctor about existing prostheses, plates, or implants.

• Previous history of renal disorders, liver problems, allergic episodes, or any other ailment should be discussed with the healthcare provider during the screening process.

• If the individual is pregnant or suspects pregnancy, the doctor or MRI technologist must be informed about it during the screening process.

• If the individual is breastfeeding or nursing an infant, it should be informed to the radiologist or the doctor. Though no potential infant risks are documented, mothers are often advised to pump and store breast milk before the MRI scanning procedure. They are advised to breastfeed after 24 to 48 hours of Gadopentetate dimeglumine injection.

• Before administering the injection, the healthcare provider has to inspect the solution visually for particulate components or discoloration. If the container is damaged or the solution is contaminated, the vials should be disposed of immediately. Unused or expired solutions should be discarded following prescribed guidelines.

For Doctors

What Are the Pharmacological Aspects of Gadopentetate Dimeglumine?

Pharmacodynamics

MRI usually detects molecular compositions and motions about the nature of surrounding tissue. However, its sensitivity is reduced in sensing molecules related to single imaging. Using contrast agents like Gadopentetate dimeglumine enhances molecular imaging since the drug helps detect molecular changes more accurately.

In conventional MRI, the brain tissue (normal and pathological) is visualized depending on the intensity variations of radiofrequency signaling that occur due to proton density change and relaxation time, T1 and T2 (parameters of spin characteristics in MRI scanning). Since brain tissue or the neural system is compactly packed with numerous interconnected structures, these exaggerated signals do not produce well-defined structural details affecting the diagnostic outcomes.

Gadopentetate dimeglumine accumulates in the targeted tissue and prolongs the relaxation time (T1 and T2) duration under the influence of the magnetic field. A fully intact and functional blood-brain barrier (BBB) prevents the drug from entering the brain tissue. Disruption in the blood-brain barrier due to abnormal vascularity occurs in lesions such as abscesses, subacute infarcts, and neoplasms. Gadopentetate dimeglumine accumulates in such pathological lesions. However, in conditions like cysts or post-operative matured scars (the blood-brain barrier is normal), accumulation of this contrast agent does not occur.

Mechanism of Action

• Gadopentetate dimeglumine contains gadolinium ions and is a potent paramagnetic agent. A magnetic moment is developed when a gadolinium-based drug is placed under the magnetic field.

• Due to the paramagnetic action of Gadopentetate dimeglumine, a larger magnetic moment is produced by a relatively larger localized magnetic field (MRI scanner).

• This magnetic moment sustains relaxation rates produced by water protons and helps enhance the image details.

Pharmacokinetics

Gadopentetate dimeglumine enters the bloodstream directly as it is intravenously administered. It is processed inside the body in the following ways:

• Distribution - Gadopentetate dimeglumine undergoes two-compartment pharmacokinetics, where the drug gets distributed in the plasma (central compartment) and the peripheral tissues (peripheral compartment).

• Half-Life - The mean distribution half-life is approximately 0.13 to 0.33 hours, and its elimination half-life is nearly 1.5 to 1.73 hours.

• Metabolism - Gadopentetate dimeglumine is not metabolized, decomposed, or biotransformed inside the body. The meglumine component gets dissociated completely from the drug complex.

• Elimination - Gadopentetate gets eliminated exclusively through urine, where nearly 80 percent of the given dose is eliminated within six hours and 90 percent within 24 hours.

• Clearance Rate - The renal clearance rate of Gadopentetate is 1.76 mL/min/kg (milliliter per minute per kilogram), and plasma clearance is 1.94 mL/min/kg. The elimination kinetics indicate that the drug is cleared only through the kidneys.

• Distribution Volume - The volume of distribution is approximately 266 mL/kg). There is no evidence of protein binding.

Dosage and Administration

MRI scans are diagnostic procedures that are safe and do not cause any pain or tissue damage. The procedure is only done by trained healthcare personnel like MR technologists who follow MR safety protocols and instruction guidelines. Gadopentetate dimeglumine is administered only in well-equipped healthcare settings in the following steps:

• Preparation - The individual’s consent is recorded before initiating the scanning process. Once consent is given, the individual is given a sterile gown that should be worn during the procedure. Any metallic jewelry or metallic object is removed as per instructions.

• Infusion - A suitable vein is identified from the accessible limb of the individual, and a small IV catheter is placed in it. When the catheter line is placed, Heparin with normal saline is flushed through the catheter into the vein to prevent clotting or clogging of the established intravenous line or vein.

• Dosage - The recommended Gadopentetate dimeglumine dose of 0.2 mL/kg (0.1 mmol/kg) is intravenously administered with an infusion rate not exceeding 10 mL per 15 seconds.

• The dosing of Gadopentetate dimeglumine is calculated according to the individual’s body weight and should not exceed 26 mL (maximum dosage clinically studied).

• Normal saline of five mL is administered as a flush after Gadopentetate dimeglumine administration to ensure a complete drug infusion.

• The imaging process is completed within one hour of Gadopentetate dimeglumine injection.

Toxicity

Gadopentetate dimeglumine is an FDA-approved, well-tolerated contrast agent following all safety protocols during clinical trials. However, some adverse toxicities were reported during post-marketing use. Some of the toxic adverse effects reported during postmarketing experience are listed below:

• Anaphylactic shock.

• Respiratory distress or laryngeal edema.

• Cardiac arrest or cardiogenic shock.

• Nephrogenic fibrosis.

• Urticaria and skin rash.

• Angioedema.

• Acute renal injury or failure.

• Urinary incontinence or urinary urgency.

• Vascular abnormalities like deep vein thrombophlebitis.

• Sensory abnormalities such as hearing impairment and visual disturbances.

• Arthralgia.

• Speech disorder.

• Parosmia (distorted sensation of smell).

What Are the Drug Interactions of Gadopentetate Dimeglumine?

There is no clinical evidence of drug interactions since Gadopentetate dimeglumine is not metabolized or transformed inside the body. The drug shows no interference with serum calcium levels during colorimetric assays.

Use in Specific Populations

• Pregnancy - Gadopentetate dimeglumine comes under Category C for pregnancy use, which indicates that the drug has affected fetal development during a few animal studies (retarded fetal growth). Due to a lack of well-controlled human clinical studies, the use of Gadopentetate dimeglumine in pregnant women is considered to weigh potential risks and benefits.

• Lactation and Breastfeeding - Less than one percent of gadolinium ions are secreted in human milk after Gadopentetate dimeglumine administration in nursing mothers. Also, it shows poor oral absorption, and the likelihood of the drug reaching the infant’s bloodstream is negligible. However, due to a lack of clinical studies, its use during breastfeeding is prescribed with caution.

• Pediatric Use - Clinical studies have established the safety and efficacy of using Gadopentetate dimeglumine in CNS and spinal imaging of children from two to 16 years of age. Its use in children under two years of age has yet to be studied.

• Geriatric Use - There is no documented evidence of the drug’s safety and efficacy in the elderly (above 65 years). The use of Gadopentetate dimeglumine in this age group is determined by the individual's health status and other associated clinical conditions.