PRODUCT MONOGRAPH Proprietary name: Hexabrix® 200 Proper name: Ioxaglate Meglumine 24.6% and Ioxaglate Sodium 12.3% Proprietary name: Hexabrix® 320 Proper name: Ioxaglate Meglumine 39.3% and Ioxaglate Sodium 19.6% Pharmacology classification: Ionic, low osmolality, water soluble radiopaque contrast medium for intravascular use. GUERBET BP 57400 95943 Roissy CdG Cedex FRANCE Control No. 162948 Revised: April 4, 2013 1 PRODUCT MONOGRAPH NAME OF DRUG HEXABRIX® 200 (Ioxaglate Meglumine 24.6% and Ioxaglate Sodium 12.3%) HEXABRIX® 320 (Ioxaglate Meglumine 39.3% and Ioxaglate Sodium 19.6%) Therapeutic or Pharmacological Classification Ionic, Low Osmolality, Water Soluble, Radiopaque Contrast Medium for Intravascular Use 2 ACTIONS AND CLINICAL PHARMACOLOGY Following intravascular injection, Hexabrix is rapidly transported through the circulatory system to the kidneys and is excreted unchanged in the urine. 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 Hexabrix 320 were 12 and 92 minutes, respectively. Following the intravenous administration of 50 mL of Hexabrix 320 in normal volunteers, the mean peak plasma concentration occurred at two minutes, reaching a concentration of 2.13 mg/mL. Fifty percent of the intravenously administered dose was recovered in the urine at 2 hours, and approximately 90% was recovered at 24 hours. 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. Ioxaglate 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. Hexabrix appears to be excreted primarily by glomerular filtration but some tubular re-absorption may occur. In the rat, biliary excretion plays a major role (up to 30%). As with iothalamate, in patients, especially with renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases. Occasional visualization of the gallbladder following administration of Hexabrix is suggestive of such a mechanism. Heterogenic excretion to a lesser extent occurs via the saliva, sweat and colon. Studies in the pregnant mouse have shown that ioxaglate and diatrizoate are capable of crossing the placental barrier and invading fetal tissue. Angiography Hexabrix opacifies vessels along the path of injection until such time as hemodilution renders them no longer visible. The digital subtraction technique allows arterial visualization following intravenous injection of Hexabrix 320, or following intraarterial injection of the lower concentration contrast media, Hexabrix 200. The joint spaces, as well as the uterus and fallopian tubes, may be visualized by direct injection of the contrast medium into those structures. Computerized Tomography of the Head 3 When Hexabrix is used for contrast enhancement in computed tomographic brain scanning, the degree of enhancement is related to the amount of iodine administered. Rapid infusion of the entire dose amount yields peak blood iodine concentrations immediately following the infusion, 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. Equilibrium with the extracellular compartments is reached by about ten minutes; thereafter, the fall becomes exponential. With respect to tumors, maximum contrast enhancement frequently occurs at a time following peak blood iodine concentration. This delay in maximum contrast enhancement can range from five to forty minutes, depending on the peak iodine levels achieved and the cell type and vascularity of the tumor. This lag suggests that the contrast enhancement of the image is at least in part dependent on the passage of iodine through the defective blood-brain barrier and on its accumulation within the lesion and outside the blood pool. The image enhancement of non-tumoral lesions, such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of the circulating blood pool. Studies indicate that equilibriated blood iodine levels of 100 mg% are required in most cases to achieve adequate contrast enhancement. This can be accomplished by the rapid infusion of approximately 30 to 40 grams of iodine. In brain scanning, the contrast medium 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 the contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium. Computerized Tomography of the Body In non-neural tissues (during CT of the body), Hexabrix 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 from that in the brain. Enhancement of CT with Hexabrix 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. The pharmacokinetics of Hexabrix in normal and abnormal tissue has been shown to be variable. Contrast enhancement appears to be greatest within 30 - 90 seconds after bolus administration, thus greatest enhancement can be detected by a series of consecutive 2 - 3 second scans ("Dynamic CT Scanning") during this time period. Dynamic 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. 4 5 Due to the low osmolality of Hexabrix, the increase in circulating blood volume is less than that caused by traditional iodinated contrast agents. This was demonstrated by hematocrit determinations in animals and is consistent with mean values for cardiac output observed in controlled clinical studies. In some double blind clinical trials, Hexabrix produced statistically significant reductions in some hemodynamic changes and discomfort (pain) when compared to contrast agents with higher osmolalities and different iodine content and concentration. Hexabrix produced significant but transient reductions in respiratory rate, increase or decrease in pulse rate, significant post-injection increases or decreases in systolic and diastolic blood pressure, LVSP, RVSP, LVEDP, RVEDP, and pulmonary artery pressure. Statistically significant laboratory parameter changes have occurred, such as decreased HB, RBC, HCT, relative lymphopenia, increased SGPT, CPK, LDH, bilirubin and decreased serum Na, Cl, K and Ca. With respect to ECG changes, arrhythmias and S-T wave changes, these showed a similar incidence with Hexabrix 320 and Na meglumine diatrizoate 37% I. Two studies of the action of Hexabrix 320 on the EEG have been carried out. In one, changes were seen in only 1 patient out of 16, who had shown Stage 1 coma and evidence of intracranial hypertension prior to the examination. In the other transient low voltage delta waves were noted 5 times in 38 injections. Effects of Hexabrix on thyroid function consisted of significant but slight rises in hormonal iodine and T3 and minor decreases in rT3. There were no changes in TSH. Both Hexabrix and diatrizoic acid activated both the classical and alternative complement pathways in vitro. Hexabrix 320 has a viscosity of 8.9 at 37°C, as compared to iothalamate meglumine 52% and iothalamate sodium 26% (40%I) which is approximately 9.0,iothalamate meglumine 60% (28.2%I) which is approximately 4.0, and diatrizoate meglumine 66% and diatrizoate sodium 10% (37%I) which has a viscosity of approximately 7.6 at 37°C. 6 INDICATIONS AND CLINICAL USAGE Hexabrix 320 is indicated for use in cerebral angiography, peripheral arteriography, selective coronary arteriography with or without left ventriculography, pediatric angiocardiography, intravenous digital subtraction angiography and intravenous contrast enhancement of computed tomography of the brain and body. It is also indicated in phlebography, arthrography, excretory urography and hysterosalpingography. Hexabrix 200 is indicated for use in phlebography, intra-arterial