optiray 350 (Ioversol)  injection 
optiray 320 (Ioversol)  injection 
optiray 300 (Ioversol)  injection 
optiray 240 (Ioversol)  injection 
optiray 160 (Ioversol)  injection 
[Mallinckrodt Inc.]

March 2008
tyco Healthcare/Mallinckrodt

Rx only

DESCRIPTION

OPTIRAY (ioversol injection) formulations are sterile, nonpyrogenic, aqueous solutions intended for intravascular administration as diagnostic radiopaque media. Ioversol is designated chemically as N,N'-Bis (2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl) -glycolamido] -2,4,6-triiodoisophthalamide and has the following structural formula:

The molecular weight of ioversol is 807.11 and the organically bound iodine content is 47.2%. Ioversol is nonionic and does not dissociate in solution.

Each milliliter of OPTIRAY 350 (ioversol injection 74%) contains 741 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. OPTIRAY 350 provides 35% (350 mg/mL) organically bound iodine.

Each milliliter of OPTIRAY 320 (ioversol injection 68%) contains 678 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. OPTIRAY 320 provides 32% (320 mg/mL) organically bound iodine.

Each milliliter of OPTIRAY 300 (ioversol injection 64%) contains 636 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. OPTIRAY 300 provides 30% (300 mg/mL) organically bound iodine.

Each milliliter of OPTIRAY 240 (ioversol injection 51%) contains 509 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. OPTIRAY 240 provides 24% (240 mg/mL) organically bound iodine.

Each milliliter of OPTIRAY 160 (ioversol injection 34%) contains 339 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. OPTIRAY 160 provides 16% (160 mg/mL) organically bound iodine.

The pH of the OPTIRAY formulations has been adjusted to 6.0 to 7.4 with hydrochloric acid or sodium hydroxide. All solutions are sterilized by autoclaving and contain no preservatives. Unused portions should be discarded. OPTIRAY solutions are sensitive to light and therefore should be protected from exposure.

Some physical and chemical properties of these formulations are listed below:

The OPTIRAY formulations are clear, colorless to pale yellow solutions containing no undissolved solids. Crystallization does not occur at room temperature. The products are supplied in containers from which the air has been displaced by nitrogen. OPTIRAY solutions have osmolalities 1.2 to 2.8 times that of plasma (285 mOsm/kg water) as shown in the above table and are hypertonic under conditions of use.

CLINICAL PHARMACOLOGY

The pharmacokinetics of ioversol intravascularly administered in normal subjects conform to an open two compartment model with first order elimination (a rapid alpha phase for drug distribution and a slower beta phase for drug elimination). Based on the blood clearance curves for 12 healthy volunteers (6 receiving 50 mL and 6 receiving 150 mL of OPTIRAY 320), the biological half-life was 1.5 hours for both dose levels and there was no evidence of any dose related difference in the rate of elimination.

Ioversol is excreted mainly through the kidneys following intravascular administration. In patients with impaired renal function, the elimination half-life is prolonged. In the absence of renal dysfunction, the mean half-life for urinary excretion following a 50 mL dose was 118 minutes (105 to 156) and following a 150 mL dose was 105 minutes (74 to 141). Greater than 95% of the administered dose was excreted within the first 24 hours, with the peak urine concentration occurring in the first 2 hours after administration. Fecal elimination was negligible. Ioversol does not bind to serum or plasma proteins to any extent and no significant metabolism, deiodination or biotransformation occurs.

OPTIRAY probably crosses the placental barrier in humans by simple diffusion. It is not known to what extent ioversol is excreted in human milk.

Intravascular injection of ioversol opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures until significant hemodilution occurs.

Ioversol may be visualized in the renal parenchyma within 30 to 60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1 to 3 minutes, with optimum contrast occurring within 5 to 15 minutes.

Animal studies indicate that ioversol does not cross the blood-brain barrier or cause endothelial damage to any significant extent.

OPTIRAY enhances computed tomographic imaging through augmentation of radiographic efficiency. The degree of density enhancement is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid intravenous injection. Blood levels fall rapidly within 5 to 10 minutes and the vascular compartment half-life is approximately 20 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached in about 10 minutes; thereafter, the fall becomes exponential.

The pharmacokinetics of ioversol in both normal and abnormal tissue have been shown to be variable. Contrast enhancement appears to be greatest immediately after bolus administration (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (i.e., dynamic computed tomographic imaging). Utilization of a continuous scanning technique (i.e., dynamic CT scanning) may improve enhancement and diagnostic assessment of tumor and other lesions such as abscess, occasionally revealing unsuspected or more extensive disease. For example, a cyst may be distinguished from a vascularized solid lesion when precontrast and enhanced scans are compared; the nonperfused mass shows unchanged x-ray absorption (CT number). A vascularized lesion is characterized by an increase in CT number in the few minutes after a bolus of intravascular contrast agent; it may be malignant, benign, or normal tissue, but would probably not be a cyst, hematoma, or other nonvascular lesion.

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

CT SCANNING OF THE HEAD

In contrast enhanced computed tomographic head imaging, OPTIRAY does not accumulate in normal brain tissue due to the presence of the normal blood-brain barrier. The increase in x-ray absorption in the 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 for the accumulation of contrast medium within the interstitial tissue of the tumor. Adjacent normal brain tissue does not contain the contrast medium.

Maximum contrast enhancement in tissue frequently occurs after peak blood iodine levels are reached. A delay in maximum contrast enhancement can occur. Diagnostic contrast enhanced images of the brain have been obtained up to 1 hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing medium 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 patients where the blood-brain barrier is known or suspected to be disrupted, the use of any radiographic contrast medium must be assessed on an individual risk to benefit basis. However, compared to ionic media, nonionic media are less toxic to the central nervous system.

CT SCANNING OF THE BODY

In contrast enhanced