Conray 43

CONRAY 43- iothalamate meglumine injection
Mallinckrodt Inc.

NOT FOR INTRATHECAL USE

DESCRIPTION

Conray 43 is a sterile aqueous solution intended for use as a diagnostic radiopaque medium. Conray 43 contains 43% w/v iothalamate meglumine which is 1-deoxy-1-(methylamino)-D-glucitol 5-acetamido-2,4,6-triiodo-N-methylisophthalamate (salt), and has the following structural formula:

Chemical Structure
(click image for full-size original)

Each milliliter contains 430 mg of iothalamate meglumine, 0.110 mg edetate calcium disodium as a stabilizer and 0.115 mg of monobasic sodium phosphate as a buffer. The solution provides 20.2% (202 mg/mL) organically bound iodine. Conray 43 has an osmolarity of approximately 800 mOsmol per liter, an osmolality of approximately 1000 mOsmol per kilogram and is, therefore, hypertonic under conditions of use. The viscosity (cps) is approximately 3 at 25°C and 2 at 37°C. The pH is 6.6 to 7.6.

Conray 43 is a clear solution containing no undissolved solids. Crystallization does not occur at normal room temperatures. It is supplied in containers from which the air has been displaced by nitrogen.

CLINICAL PHARMACOLOGY

Intravascular Procedures

Following intravascular injection, Conray 43 is rapidly transported through the circulatory system to the kidneys and is excreted unchanged in the urine by glomerular filtration. The pharmacokinetics of intravascularly administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slower beta phase for drug elimination. In patients with normal renal function, the alpha and beta half-lives of Conray 43 were approximately 10 and 90 minutes, respectively.

Arteriography and venography may be performed following injection into an appropriate vessel and will permit visualization until significant hemodilution occurs.

Following infusion of Conray 43, the upper and lower urinary tract is opacified. Renal accumulation is sufficiently rapid that maximum radiographic density in the calyces and pelves occurs by the time the infusion is complete. In patients with impaired renal function, diagnostic opacification frequently is achieved only after prolonged periods.

Injectable iodinated contrast agents are excreted either through the kidneys or through the liver. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be related to the affinity of the contrast medium for serum albumin. Iothalamate salts are poorly bound to serum albumin, and are excreted mainly through the kidneys.

The liver and small intestine provide the major alternate route of excretion. In patients with severe renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases.

Iothalamate salts cross the placental barrier in humans and are excreted unchanged in human milk.

CT Scanning of the Head

When used for contrast enhancement in computed tomographic brain scanning, the degree of enhancement is directly related to the amount of iodine administered. Rapid injection of the entire dose yields peak blood iodine concentrations immediately following the injection, which fall rapidly over the next five to ten minutes. This can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached by about ten minutes; thereafter the fall becomes exponential. Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached. The delay in maximum contrast enhancement can range from five to forty minutes, depending on the peak iodine levels achieved and the cell type of the lesion. This lag suggests that the contrast enhancement of the image is at least in part dependent on the accumulation of iodine within the lesion and outside the blood pool.

In brain scanning, the contrast medium (Conray 43) does not accumulate in normal brain tissue due to the presence of the “blood brain barrier.” The increase in x-ray absorption in the normal brain is due to the presence of the contrast agent within the blood pool. A break in the blood brain barrier, such as occurs in malignant tumors of the brain, allows accumulation of contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium.

The image enhancement of non-tumoral lesions, such as arteriovenous malformations and aneurysms, is dependent on the iodine content of the circulating blood pool.

CT Scanning of the Body

Conray 43 may also be used for enhancement of computed tomographic scans performed for detection and evaluation of lesions in the liver, pancreas, kidneys, abdominal aorta, mediastinum, abdominal cavity and retroperitoneal space.

In non-neural tissues (during computed tomography of the body), Conray 43 diffuses rapidly from the vascular to the extra-vascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium and extraction of the contrast medium by interstitial tissue since no barrier exists; contrast enhancement is thus due to the relative differences in extra-vascular diffusion between normal and abnormal tissue, a situation quite different than that in the brain.

The pharmacokinetics of Conray 43 in normal and abnormal tissues has been shown to be variable.

Enhancement of CT with Conray 43 may be of benefit in establishing diagnoses of certain lesions in some sites with greater assurance than is possible with unenhanced CT and in supplying additional features of the lesions. In other cases, the contrast medium may allow visualization of lesions not seen with CT alone or may help to define suspicious lesions seen with unenhanced CT.

Contrast enhancement appears to be greatest within the 30 to 90 seconds after bolus administration of the contrast agent, and after intra-arterial rather than intravenous administration. Therefore, the use of a continuous scanning technique (a series of two to three second scans beginning at the injection – dynamic CT scanning) may improve enhancement and diagnostic assessment of tumors and other lesions such as an abscess, occasionally revealing more extensive disease.

A cyst or similar non-vascularized lesion may be distinguished from vascularized solid lesions by comparing enhanced and unenhanced scans; the non-vascularized lesions show no change in CT number, the vascularized lesions would show an increase. The latter might be benign, malignant or normal, but it is unlikely that it would be a cyst, hematoma, or other non-vascularized lesion.

Because unenhanced scanning may provide adequate information in the individual patient, the decision to employ contrast enhancement, which is associated with additional risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and unenhanced CT findings.

Retrograde Urographic Procedures

The most important characteristic of contrast media is the iodine content. The relatively high atomic weight of iodine contributes sufficient radiodensity for radiographic contrast.

Following instillation by sterile catheter, Conray 43 provides for visualization of the lower urinary tract. Clinical literature reports indicate that routinely less than 1 percent of a retrograde urographic radiopaque is absorbed systemically; however, as much as 12 percent absorption was observed with pyelorenal back flow and may produce iodine mediated thyrotropic effects described under PRECAUTIONS.

INDICATIONS AND USAGE

Intravascular Indications

Conray 43 is indicated for use in lower extremity venography, intravenous infusion urography, contrast enhancement of computed tomographic brain images and arterial digital subtraction angiography.

Conray 43 may also be used for enhancement of computed tomographic scans performed for detection and evaluation of lesions in the liver, pancreas, kidneys, abdominal aorta, mediastinum, abdominal cavity and retroperitoneal space. Continuous or multiple scans separated by intervals of 1 to 3 seconds during the first 30 to 90 seconds post-injection of the contrast medium (dynamic CT scanning) may provide enhancement of diagnostic significance, and may be of benefit in establishing diagnoses of certain lesions in these sites with greater assurance than is possible with CT alone and in supplying additional features of the lesions. In other cases, the contrast agent may allow visualization of lesions not seen with CT alone, or may help to define suspicious lesions seen with unenhanced CT (see CLINICAL PHARMACOLOGY). Subsets of patients in whom delayed body CT scans might be helpful have not been identified. Inconsistent results have been reported and abnormal and normal tissues may be isodense during the same time frame used for delayed CT scanning. The risks of such indiscriminate use of contrast media are well known and such use is not recommended. At present, consistent results have been documented using dynamic CT techniques only.

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