HYPAQUE

HYPAQUE- diatrizoate meglumine and diatrizoate sodium injection, solution
Amersham Health Inc.

Sterile Aqueous Injection

For Excretory Urography
Aortography
Angiocardiography (Ventriculography, Pulmonary
Angiography, Selective Coronary Arteriography)
Peripheral Angiography (Peripheral Arteriography
and Peripheral Venography)
Intravenous Digital Arteriography
Contrast Enhancement of Computed
Tomographic Head Imaging
Contrast Enhancement of Computed
Tomographic Body Imaging
Selective Renal Arteriography
Selective Visceral Arteriography
Central Venography
Renal Venography

NOT FOR INTRATHECAL USE

DESCRIPTION

HYPAQUE-76, brand of diatrizoate meglumine and diatrizoate sodium, is a water-soluble, radiopaque diagnostic medium. It is supplied as a 76 percent sterile aqueous solution providing 66 percent (w/v) diatrizoate meglumine and 10 percent (w/v) diatrizoate sodium. It is a triiodinated benzoic acid derivative containing 37 percent (w/v) organically bound iodine. Each mL contains 370 mg iodine and 3.68 mg (0.16 mEq) sodium. It is constituted as a radiopaque iodinated anion, diatrizoate, and the radiolucent cations meglumine and sodium. It is the organically bound iodine of the anion which opacifies internal structures for x-ray visualization and fluoroscopy.

The solution is hypertonic to blood with an osmolality of 2016 mosm/kg (determined by VPO). The viscosity is 9 cp at 37° C. The pH is adjusted between 6.0 and 7.7 using Na₂ CO₃ with HCl or NaOH. The pKa is 3.4 for diatrizoic acid. Edetate calcium disodium 0.01 percent has been added as a sequestering stabilizing agent. The solution is clear, colorless to pale yellow.

Diatrizoate meglumine is 1-deoxy-1-(methylamino)-D-glucitol 3, 5-diacetamido-2,4,6-triiodobenzoate (salt) and has the following structural formula:

Diatrizoate sodium is monosodium, 3, 5-diacetamido-2,4,6-triiodobenzoate and has the following structural formula:

CLINICAL PHARMACOLOGY

Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures of the human body until significant hemodilution occurs.

At physiologic pH, the water-soluble contrast media are completely dissociated into a radiopaque anion and a solubilizing cation. While circulating in tissue fluids, the compound remains ionized. However, it is not metabolized but excreted unchanged in the urine, each diatrizoate molecule remaining “obligated” to its sodium or meglumine moiety.

Following intravenous injection, the radiopaque diagnostic agents are immediately diluted in the circulating plasma. Equilibrium is reached with the extracellular compartment at about 10 minutes. Hence, the plasma concentration at 10 minutes is closely related to the dose corrected to body size.

The pharmacokinetics of the intravenously administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slow beta phase for drug elimination. In patients with normal renal function, the alpha and beta half-lives were respectively 30 minutes and 120 minutes for diatrizoate. But in patients with renal functional impairment, the elimination half-life for the beta phase can be prolonged up to several days.

Injectable radiopaque diagnostic agents are excreted either through the liver or through the kidneys. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be governed by the affinity of the contrast medium for serum albumin. From 0% to 10% of diatrizoate sodium is bound to serum protein.

Diatrizoate salts are excreted unchanged predominantly through the kidneys by glomerular filtration. The amount excreted by the kidney during any period of time is determined by the filtered load; i.e., the product of plasma contrast media concentration and glomerular filtration rate. The plasma concentration is dependent upon the dose administered and the body size. The glomerular filtration rate varies with the body size, sex, age, circulatory dynamics, diuretic effect of the drug, and renal function. In patients with normal renal function the maximum urinary concentration of diatrizoate meglumine and diatrizoate sodium occurs within 10 minutes with 12 percent of the administered dose being excreted. The mean values of cumulative urinary excretion for diatrizoate meglumine and diatrizoate sodium expressed as percentage of administered dose are 38 percent at 60 minutes, 45 percent at 3 hours, and 94 to 100 percent at 24 hours.

Urinary excretion of contrast media is delayed in infants younger than 1 month and in patients with urinary tract obstruction. The urinary iodine concentration is higher with the sodium salt of diatrizoic acid than with the meglumine salt.

The liver and small intestine provide the major alternate route of excretion for diatrizoate. In patients free of severe renal disease, the fecal recovery is less than 2 percent of the administered dose. In patients with severe renal impairment the excretion of these contrast media through the gallbladder and into the small intestine sharply increases; up to 20 percent of the administered dose has been recovered in the feces in 48 hours.

Saliva is a minor secretory pathway for injectable radiopaque diagnostic agents. In patients with normal renal function, minimal amounts of contrast media are secreted unchanged. However, in uremic patients small amounts of free iodides resulting from deiodination prior to administration or in vivo, have been detected in the saliva.

Diatrizoate salts cross the placental barrier in humans by simple diffusion and appear to enter fetal tissue passively. No apparent harm to the fetus was observed when diatrizoate sodium and diatrizoate meglumine were injected intravenously 24 hours prior to delivery. However, abnormal neonatal opacification of the small intestine and colon were detected 4 to 6 days after delivery. Procedures including radiation involve a certain risk related to the exposure of the fetus. (See PRECAUTIONS—General, Pregnancy Category C.)

Injectable radiopaque diagnostic agents are excreted unchanged in human milk. (See PRECAUTIONS—General, Nursing Mothers.)

Computed Tomography

HYPAQUE-76 enhances computed tomographic brain scanning through augmentation of radiographic efficiency. The degree of enhancement of visualization of tissue density is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid injection of the dose. These levels fall rapidly within 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 in 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 radiographic contrast enhancement is at least in part dependent on the accumulation of iodine within the lesion and outside the blood pool, although the mechanism by which this occurs is not clear. The radiographic enhancement of nontumoral lesions, such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of the circulating blood pool.

In brain scanning, HYPAQUE-76, brand of diatrizoate meglumine and diatrizoate sodium injection, does not accumulate in normal brain tissue due to the presence of the blood-brain barrier. The increase in x-ray absorption in normal brain is due to the presence of contrast agent within the blood pool. A break in the blood-brain barrier such as occurs in malignant tumors of the brain allows the accumulation of the contrast medium within the interstitial tumor tissue. Adjacent normal brain tissue does not contain the contrast medium.

In nonneural tissues (during computed tomography of the body), diatrizoate diffuses rapidly from the vascular into the extravascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium, and extraction of the contrast medium by interstitial tumor tissue since no barrier exists. Contrast enhancement is thus due to the relative differences in extravascular diffusion between normal and abnormal tissue, quite different from that in the brain.

The pharmacokinetics of diatrizoate in both normal and abnormal tissue have been shown to be variable. Contrast enhancement appears to be greatest soon after administration of the contrast medium, and following intra-arterial rather than intravenous administration. The greatest enhancement can be detected by a series of consecutive two- to three-second scans performed just after injection (within 30 to 90 seconds), i.e., dynamic computed tomographic scanning.