Gadopentetate dimeglumine

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have a serious side effect such as:

• urinating less than usual or not at all;
• drowsiness, confusion, mood changes, increased thirst, loss of appetite;
• swelling, weight gain, feeling short of breath; or
• swelling, bruising, redness, itching, burning, or skin changes where the injection was given.

Less serious side effects may include:

• headache, dizziness;
• nausea;
• feeling unusually hot;
• unusual or unpleasant taste in your mouth;
• flushing (warmth, redness, or tingly feeling);
• numbness; or
• cold feeling, warmth, pain, or burning where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Central Nervous System

MAGNEVIST Injection is indicated for use with magnetic resonance imaging (MRI) in adults, and pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. MAGNEVIST Injection has been shown to facilitate visualization of intracranial lesions including but not limited to tumors.

Extracranial/Extraspinal Tissues

MAGNEVIST is indicated for use with MRI in adults and pediatric patients (2 years of age and older) to facilitate the visualization of lesions with abnormal vascularity in the head and neck.

Body

MAGNEVIST Injection is indicated for use in MRI in adults and pediatric patients (2 years of age and older) to facilitate the visualization of lesions with abnormal vascularity in the body (excluding the heart).

Pharmacokinetics

The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal subjects conforms to a two compartment open-model with mean distribution and elimination half-lives (reported as mean ± SD) of about 0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively.

Upon injection, the meglumine salt is completely dissociated from the gadopentetate dimeglumine complex. Gadopentetate is exclusively eliminated in the urine with 83 ± 14% (mean ± SD) of the dose excreted within 6 hours and 91 ± 13% (mean ± SD) by 24 hours, post-injection. There was no detectable biotransformation or decomposition of gadopentetate dimeglumine.

The renal and plasma clearance rates (1.76 ± 0.39 mL/min/kg and 1.94 ± 0.28 mL/min/kg, respectively) of gadopentetate are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (266 ± 43 mL/kg) is equal to that of extracellular water and clearance is similar to that of substances which are subject to glomerular filtration.

In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In vivo protein binding studies have not been done.

Gadopentetate dimeglumine is excreted via the kidneys, even in patients with impaired renal function. In patients with impaired renal function, the serum half-life of gadopentetate dimeglumine is prolonged. Mean serum elimination half-lives of a single intravenous dose of gadopentetate dimeglumine (0.1 mmol/kg) were 2.6 ± 1.2 h, 4.2 ± 2.0 h and 10.8 ± 6.9 h, for mildly (creatinine clearance, CLCR = 60 to < 90 mL/min), moderately (CLCR = 30 to < 60 mL/min) and severely (CLCR = < 30 mL/min) impaired patients, respectively, as compared with 1.6 ± 0.1 h in healthy subjects.

Pharmacodynamics

Gadopentetate dimeglumine is a paramagnetic agent and, as such, it develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.

In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) changes in proton density; 2) alteration of the spin-lattice or longitudinal relaxation time (T1); and 3) variation of the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadopentetate dimeglumine decreases the T1 and T2 relaxation time in tissues where it accumulates. At usual doses the effect is primarily on the T1 relaxation time.

Gadopentetate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadopentetate dimeglumine in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of MAGNEVIST in various lesions are not known.

Clinical Trials

MAGNEVIST Injection was administered to 1272 patients in open label controlled clinical studies. The mean age of these patients was 46.4 years (range 2 to 93 years). Of these patients, 55% (700) were male and 45% (572) were female. Of the 1271 patients who received MAGNEVIST Injection and for whom race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other. Of the 1272 patients, 550 patients were evaluated in blinded reader studies. These evaluated the use of contrast enhancement in magnetic resonance imaging of lesions in the head and neck, brain, spine and associated tissues, and body (excluding the heart). Of the 550 patients, all patients had a reason for an MRI and efficacy assessments were based on pre-and post- MAGNEVIST injection film quality, film contrast, lesion configuration (border, size, and location), and the number of lesions. The protocols did not include systematic verification of specific diseases or histopathologic confirmation of findings.

Of the above 550 patients, 97 patients received 0.1 mmol/kg MAGNEVIST Injection IV in two clinical trials of MAGNEVIST MRI contrast enhancement for body imaging. Of these 97, 68 had MRIs of the internal organs/structures of the abdomen or thorax (excluding the heart); 8 had breast images and 22 had images of appendages. The results of MRIs before and after MAGNEVIST use were compared blindly. Overall additional lesions were identified in 22/97 (23%) of the patients after MAGNEVIST Injection. The mean number of lesions identified before (1.49/patient) and after MAGNEVIST (1.75/patient) were similar. Seven (8%) of the patients had lesions seen before MAGNEVIST that were not seen after MAGNEVIST. Overall, after MAGNEVIST Injection, 41% of the images had a higher contrast score than before injection; and 18% of the images had a higher contrast score before MAGNEVIST Injection than after MAGNEVIST Injection. MAGNEVIST MRI of the 8 patients with breast images were not systematically compared to the results to mammography, breast biopsy or other modalities. In the 22 patients with appendage images (e.g., muscle, bone and intraarticular structures), MAGNEVIST MRI was not systematically evaluated to determine the effects of contrast biodistribution in these different areas.

Of the above 550 patients, 66 patients received MAGNEVIST 0.1 mmol/kg IV in clinical trials of MAGNEVIST MRl contrast enhancement of lesions in the head and neck. A total of 66 MRI images were evaluated blindly by comparing each pair of MRI images, before and after MAGNEVIST Injection. In these paired images, 56/66 (85%) had greater enhancement after MAGNEVIST and 40/66 (61%) had better lesion configuration or border delineation after MAGNEVIST. Overall, there was better contrast after MAGNEVIST in 55% of the images, comparable enhancement in 44 (36%) before and after MAGNEVIST, and better enhancement in 9% without MAGNEVIST.

In the studies of the brain and spinal cord, MAGNEVIST 0.1 mmol/kg IV provided contrast enhancement in lesions with an abnormal blood brain barrier.

In two studies, a total of 108 patients were evaluated to compare the dose response effects of 0.1 mmol/kg and 0.3 mmol/kg of MAGNEVIST in CNS MRI. Both dosing regimens had similar imaging and general safety profiles; however, the 0.3 mmoL/kg dose did not provide additional benefit to the final diagnosis (defined as number of lesions, location and characterization).

Since gadopentetate dimeglumine is used only during your MRI, you will not be on a dosing schedule.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have a serious side effect such as:

• urinating less than usual or not at all;

• drowsiness, confusion, mood changes, increased thirst, loss of appetite;

• swelling, weight gain, feeling short of breath; or

• swelling, bruising, redness, itching, burning, or skin changes where the injection was given.

Less serious side effects may include:

• headache, dizziness;

• nausea;

• feeling unusually hot;

• unusual or unpleasant taste in your mouth;

• flushing (warmth, redness, or tingly feeling);

• numbness; or

• cold feeling, warmth, pain, or burning where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Usual Adult Dose for CNS Magnetic Resonance Imaging:

0.1 mmol/kg (0.2 mL/kg) as a rapid bolus intravenous injection, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 pounds has not been studied. To ensure complete injection of the medium, the injection should be followed by a saline flush of at least 5 mL.

Usual Adult Dose for Vascular Magnetic Resonance Imaging:

0.1 mmol/kg (0.2 mL/kg) as a rapid bolus intravenous injection, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 pounds has not been studied. To ensure complete injection of the medium, the injection should be followed by a saline flush of at least 5 mL.

Usual Pediatric Dose for CNS Magnetic Resonance Imaging:

2 years to 18 years of age: 0.1 mmol/kg (0.2 mL/kg) as a rapid bolus intravenous injection, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 pounds has not been studied. To ensure complete injection of the medium, the injection should be followed by a saline flush of at least 5 mL.

Usual Pediatric Dose for Vascular Magnetic Resonance Imaging:

2 years to 18 years of age: 0.1 mmol/kg (0.2 mL/kg) as a rapid bolus intravenous injection, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 pounds has not been studied. To ensure complete injection of the medium, the injection should be followed by a saline flush of at least 5 mL.

• It is used during an MRI (magnetic resonance imaging) test.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.