PRODUCT MONOGRAPH

ULTRAVIST(r)

(iopromide injection)

ULTRAVIST(r) 240

(iopromide injection 240 mg I/mL)

ULTRAVIST(r) 300

(iopromide injection 300 mg I/mL)

ULTRAVIST(r) 370

(iopromide injection 370 mg I/mL)

Non-ionic Iodinated Radiographic Contrast Medium Bayer Inc. Date of Preparation: 77 Belfield Road April 11, 2007 Toronto, Ontario M9W 1G6 Canada http://www.bayer.ca Submission Control No. : 113332 (c) 2007, Bayer Inc.

PRODUCT MONOGRAPH

ULTRAVIST(r)

(iopromide injection)

ULTRAVIST(r) 240

(iopromide injection 240 mg I/mL)

ULTRAVIST(r) 300

(iopromide injection 300 mg I/mL)

ULTRAVIST(r) 370

(iopromide injection 370 mg I/mL)

Non-ionic Iodinated Radiographic Contrast Medium

ACTION AND CLINICAL PHARMACOLOGY

ULTRAVIST (iopromide) is a non-ionic iodinated radiographic contrast medium which is available in three stable, ready-to-use solutions of different concentrations. Following intravascular injection, iopromide provides radiographic opacification of the vasculature and extracellular space allowing diagnostic assessment of the limbs and internal organs. For example, after intravenous injection, opacification of the renal parenchyma begins within 1 minute. Excretion of the contrast agent becomes apparent in 1 to 3 minutes with optimal contrast in the calyces and collecting system occurring between 5 and 15 minutes. In nephropathic conditions, particularly when excretory capacity has been altered, the excretion rate varies unpredictably and opacification may be delayed for several hours after injection. The pharmacokinetics of iopromide are similar to those of other ionic and non-ionic contrast media. Immediately following intravascular injection, iopromide reaches peak plasma concentrations and is then rapidly distributed throughout the extracellular fluid compartment. It is excreted unchanged by the kidneys mainly by glomerular filtration. About 90% of the injected dose is excreted unchanged by the kidneys during the first 24 hours with peak urine concentrations occurring in the first hour. In healthy volunteers, elimination half-life is approximately 2 hours and renal clearance is 93 +- 14 mL/min. Iopromide does not cross the intact blood-brain barrier. It displays little tendency to bind to serum or plasma proteins and there is no evidence of metabolism, deiodination or biotransformation in rats and humans. In double-blind clinical trials ULTRAVIST has shown diagnostic efficacy comparable to other non-ionic and ionic radiographic contrast agents when studied in excretory urography (vs. iopamidol, ioxithalamate, and ioxaglate); renal arteriography (vs. amidotrizoate) cerebral arteriography (vs. iopamidol); peripheral arteriography of the leg (vs. ioxaglate); phlebography of the pelvis and leg (vs. ioglicinate); coronary arteriography and ventriculography (vs. iohexol and diatrizoate and amidotrizoate); and in computed tomography (vs. ioglicinate). In these studies ULTRAVIST has demonstrated properties comparable to other non-ionic compounds with respect to neuroangiographic and cardiovascular tolerance and has demonstrated superiority over ionic agents particularly in causing less pain and warmth following injection. The influence of iopromide on clotting, fibrinolysis, complement activation and erythrocyte morphology has been minimal (see WARNINGS).

CONTRAINDICATIONS

ULTRAVIST (iopromide) is not indicated for use in myelography, cerebral ventriculography, and cisternography.

ULTRAVIST should not be administered to patients with known hypersensitivity to the drug, anuria or severe oliguria, clinically significant impairment of both renal and hepatic function, or with manifest hyperthyroidism. Hysterosalpingography must not be performed during pregnancy or in the presence of acute inflammatory process in the pelvic cavity.

WARNINGS

The use of renally excreted intravascular X-ray contrast media can lead to transient impairment of kidney function. This may result in lactic acidosis in patients who are taking biguanides. As a precaution, biguanides should be discontinued 48 hours prior to the contrast medium examination until at least 48 hours after the administration of contrast medium and reinstated only after adequate renal function has been regained. Non-ionic iodinated contrast media inhibit blood coagulation less than ionic contrast media. Clotting has been reported in vivo and in vitro when blood remains in contact with syringes, catheters or tubes containing non-ionic contrast media. Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both non-ionic and ionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, number of injections, catheter and syringe material, underlying disease state, and concomitant medication may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended including close attention to keeping guidewires, catheters and all angiographic equipment free of blood; use of manifold systems and/or three way stopcocks; frequent catheter flushing with heparinized saline solution; and minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting. Non-ionic contrast media are not suitable flush solutions. ULTRAVIST (iopromide) is related chemically to other tri-iodinated benzoic acid derivatives which have been associated with serious and fatal reactions. Therefore, clear indication and evaluation of the benefit/risk ratio for every patient should precede each examination with contrast media. Also, it is of utmost importance that adequate facilities and appropriate personnel be readily available and a course of action be planned in advance for the immediate treatment of any serious untoward reaction. Diagnostic procedures utilizing a radiopaque contrast agent should be conducted only by a physician with the requisite training and a thorough knowledge of the particular procedure to be performed. The physician must also be thoroughly familiar with the emergency treatment of all adverse effects.

PRECAUTIONS

Before any contrast medium is injected, the patient should be questioned for a history of allergy (e.g. shellfish), sensitivity to iodine or to radiographic media and bronchial asthma, as the reported incidence of adverse reactions to contrast media are higher in patients with these conditions. Most adverse reactions to contrast agents appear within 30 minutes after the start of their injection, but a delayed reaction may occur. Premedication with corticoids may be considered in order to avoid or minimize possible allergic adverse reactions. However, antihistamines or corticosteroids should not be mixed in the same syringe with any contrast medium because of potential chemical incompatibility. Caution is advised in patients with cardiac and circulatory insufficiency, hypertension, pheochromocytoma, cerebral arteriosclerosis, latent hyperthyroidism, severe impairment of hepatic or renal function, pulmonary emphysema, very poor general condition, diabetes with renal dysfunction requiring treatment, cerebral arterial spasm, bland nodular goiter and multiple myeloma, homocystinuria and other paraproteinemias, and renal transplant. An intravenous test dose of 0.5 - 1.0 mL of the contrast agent before injection of the full dose has been employed to predict severe or fatal reactions. These provocative tests may themselves cause severe, even fatal, reactions and are unreliable in predicting patients at special risk. Renal function should be assessed before injecting ULTRAVIST (iopromide) since the drug is excreted largely by the kidney and may accumulate in the absence of normal renal function. In patients with myeloma, diabetes mellitus, polyuria, oliguria or gout, in newborns, small children, and in patients in poor general health, fluid intake should not be restricted even before the use of low-osmolar contrast media. Assessment of thyroid function may be obscured for several weeks following the administration of ULTRAVIST. Reports of thyroid storm after the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule suggest that this additional risk be evaluated in appropriate patients prior to the use of ULTRAVIST. Administration of ULTRAVIST should be postponed in patients who have to undergo oral cholecystography. Premedication with an alpha-blocker is recommended in patients having a pheochromocytoma because of the risk of hypertensive crises. In patients with decreased renal function, 48 hours should elapse between 2 examinations. Special attention should be paid to patients with increased intracranial pressure, disrupted blood-brain barrier (tumour, subarachnoid hemorrhage, transient ischemic attack, cerebral thrombosis, ischemia) or any condition whereby the presence of contrast material in the vessels is prolonged. Serious neurological sequelae (stroke, aphasia, cortical blindness, convulsions) may occur following intraarterial or intravascular infusion of contrast media. The benefit/risk ratio of the procedure has to be evaluated and the amount of contrast medium necessary to obtain a diagnostic picture kept to a minimum. ULTRAVIST should be administered intravascularly with caution to patients with known convulsive disorders. The administration of iodinated contrast media may aggravate the symptoms of myasthenia gravis.

Use in Pregnancy

The safe use of ULTRAVIST during pregnancy has not been established. Therefore, it should not be used unless the benefits outweigh the risks.

Use in Lactation

If the use of ULTRAVIST is considered necessary in a nursing mother, it is suggested to discontinue breast feeding for 48 hours.

Use in the Elderly

Elderly patients may present a special risk in the use of radiographic contrast media. These patients may have compromised renal and cardiac function and may be taking medication (e.g. beta-blockers) which may make them more susceptible to the potentially harmful effects of procedures involving the use of contrast agents.

Intravascular Use

ULTRAVIST produces less circulatory osmotic load than ionic contrast agents; however, it can produce significant hemodynamic disturbances especially in patients with reduced cardiac reserve. The volume of injection should be minimized and the patient's vital signs should be continuously monitored for several hours following the procedure to detect delayed hemodynamic disturbances. Hypotension should be corrected promptly as it can lead to serious arrhythmias. Special care regarding dosage should be observed in patients with right ventricular failure, pulmonary emphysema, pulmonary hypertension or a stenotic pulmonary vascular bed because serious hemodynamic changes may occur in these individuals. Mesenteric necrosis, acute pancreatitis, renal shutdown and serious neurologic complications including spinal cord damage and hemiplegia have been reported following inadvertent injection of a large part of the aortic dose of an ionic contrast medium directly into an aortic branch or arterial trunk. There are inherent dangers associated with catheter manipulation, contrast medium injection and angiographic procedures. Dislodging plaques or damaging, dissecting or perforating a vessel wall or causing injury to neighbouring organs can lead to embolization. The possibility of these occurrences should be borne in mind during the procedure. Fluoroscope guidance is to be used to place the catheter. Pulsation must be present in the artery to be injected. Extreme caution is therefore advised for patients considered for angiography, particularly those suspected of having thromboangiitis obliterans (Buerger's disease), since vascular procedures may induce severe arterial spasm. In intraarterial administration, caution is advisable in patients with suspected thrombosis, ischemic disease, local infection, a totally obstructed vascular system, or severe ischemia associated with ascending infection or advanced arteriosclerosis. With the use of conventional ionic contrast media, occasional serious neurologic complications, including paraplegia, have been reported in patients with aorto-iliac or femoral artery obstruction, abdominal compression, hypotension or hypertension, and following the injection of vasopressors. When large individual doses are administered, an appropriate time interval should elapse between injections to allow any hemodynamic disturbances to subside. Hemodynamic changes are likely to be more pronounced following repeated injections given in rapid succession. Following arterial catheterization and injection, pressure hemostasis is advisable with immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture.

Drug Interactions

The prevalence of delayed reactions (eg. fever, rash, flu-like symptoms, joint pain and pruritis) to contrast media is higher in patients who received interleukins. Treatment with beta-blockers or general anesthesia increases the incidence and may aggravate adverse reactions, particularly in people with asthma.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

An overdose of ULTRAVIST (iopromide) should be treated by support of vital functions and prompt institution of symptomatic therapy.

DOSAGE AND ADMINISTRATION

General Information

Solutions of ULTRAVIST (iopromide), like those of other radiopaque contrast agents, should be at or close to body temperature when injected. As with other sterile parenteral products, ULTRAVIST should not be withdrawn from the vial except immediately prior to use (see WARNINGS). ULTRAVIST should not be mixed with other drugs. Any unused portion should be discarded. Vials containing contrast medium solutions are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once. The use of a cannula or needle with a long tip and a maximum diameter of 18 G is recommended for piercing the stopper and drawing up the contrast medium. Patients should be in a fasted state (when this can be safely achieved) and adequately hydrated on the day of the examination. Disturbances of water and electrolyte balance must be corrected prior to the administration of ULTRAVIST. In the case of abdominal angiography and urography, the diagnostic yield is increased if the bowels are empty of fecal matter and gas. It may be necessary to administer an enema or laxative in the evening prior to examination, provided purging of the bowels is not contraindicated. However, in infants and young children, prolonged fasting, restriction of fluids and the administration of a laxative before the examination are contraindicated. Experience shows that pronounced states of excitement, anxiety and pain can be the cause of side effects or intensified contrast medium-related reactions. They can be counteracted by calm management of the patients and the use of suitable drugs. Intravascular administration of contrast media should, if possible, be done with the patient lying down. After the administration, the patient should be kept under observation for at least 30 minutes, since experience shows that the majority of all severe incidents occur within this time.

The recommended dosages of ULTRAVIST should not be exceeded.

The volume of each individual injection is a more important consideration than the total dose used. When large individual volumes are administered, as in cardiac ventriculography,

sufficient time should be permitted to elapse between injections to allow any hemodynamic disturbances to subside.

EXCRETORY UROGRAPHY

Adults

Recommended doses for each concentration of ULTRAVIST: ULTRAVIST 300: 40 - 70 mL ULTRAVIST 370: 30 - 55 mL The dose may be adjusted in special indications (e.g. obese patients, impaired renal function), if necessary.

Children

The physiologically poor concentrating ability of the immature nephron necessitates the administration of relatively high doses of contrast medium in children. The doses of ULTRAVIST 300 should not exceed: Neonates: 4 mL/kg of body weight equivalent to 1.2 g I/kg. Infants: 3 mL/kg of body weight equivalent to about 1.0 g I/kg. Small Children: 1.5 mL/kg of body weight equivalent to about 0.5 g I/kg.

COMPUTERIZED TOMOGRAPHY ( CT )

Cranial CT

The following doses are recommended and should not be exceeded: ULTRAVIST 240: 105 - 175 mL ULTRAVIST 300: 70 - 140 mL ULTRAVIST 370: 70 - 105 mL

Whole-body CT

In whole-body computerized tomography, the necessary doses of ULTRAVIST and the rates of administration depend on the organs under investigation, the diagnostic problem and, in particular, the different scan and image reconstruction times of the scanner. An infusion is preferred for slow scanners, and a bolus injection for fast scanners. Recommended doses for each concentration of ULTRAVIST: ULTRAVIST 240: 125 - 180 mL ULTRAVIST 300: 100 - 150 mL ULTRAVIST 370: 80 - 120 mL

ANGIOGRAPHY

The dosage of ULTRAVIST depends on the age, weight, cardiac output and general condition of the patient, the clinical problem, examination technique, and the nature and volume of the vascular region to be investigated. The following dosages may serve as a guide:

ARTHROGRAPHY

Intraarticular injections of contrast media should be monitored by fluoroscopy to ensure adequate injection technique and opacification while preventing over distention of the joint space. Excessive dilution of the contrast medium should be avoided.

Hysterosalpingography contrast media should be instilled into the uterine cavity under controlled pressure with fluoroscopic monitoring of the dose, to avoid excessive injection pressures and doses. 240 10 - 25

PHARMACEUTICAL INFORMATION DRUG SUBSTANCE

Structural Formula:

Molecular Formula: C18H24I3N3O8

Molecular Weight:

791.12

Chemical Name

: 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid[(2,3-dihydroxy-N-methylpropyl)-(2,3- dihydroxypropyl)] diamide

Non-medicinal Ingredients:

calcium disodium edetate (EDTA), hydrochloric acid

and tromethamine. Preservative-free. pH has been adjusted to between 6.5 and 8.0 with hydrochloric acid.

Physical Properties:

STABILITY AND STORAGE RECOMMENDATIONS

ULTRAVIST (iopromide) should be stored between 15degC and 30degC and protected from light. It should be visually inspected and used only if clear and within the normal colourless to pale yellow range. Discard unused portions.

AVAILABILITY OF DOSAGE FORMS

ULTRAVIST (iopromide) is a sterile colourless to pale yellow solution of iopromide in water and contains no preservative. Solutions do contain tromethamine (0.24%) as a buffer and calcium disodium edetate (EDTA) 0.1 mg/mL as a sequestering agent. The pH has been adjusted to between 6.5 and 8.0 with hydrochloric acid. ULTRAVIST 240 (iopromide 49.9%) provides 499 mg of iopromide per mL equivalent to 240 mg of organically bound iodine per ml. It is supplied in 50 and 200 mL vials. ULTRAVIST 300 (iopromide 62.3%) provides 623 mg of iopromide per mL equivalent to 300 mg of organically bound iodine per mL. It is supplied in 50, 100, and 150 mL vials. ULTRAVIST 370 (iopromide 76.9%) provides 769 mg of iopromide per mL equivalent to 370 mg of organically bound iodine per mL. It is supplied in 50, 100, and 200 mL vials.

PHARMACOLOGY PHARMACODYNAMICS

Hemodynamics

In isolated perfused rabbit hearts, iopromide (370 : 1480 mg I) produced initial vasodilatation with increased coronary flow and a positive inotropic effect; ventricular fibrillation subsequently complicated these observations. Anesthetized rats given a single intravenous administration of iopromide (1110 mg I/kg) showed increases in mean arterial pressure, maximum rate of increase in left ventricular pressure (dp/dt), cardiac minute volume, end diastolic pressure and myocardial oxygen consumption during the first 2-3 minutes post-injection. Heart rate was transiently lowered immediately post-injection and vascular resistance was reduced significantly. Extrasystoles occurred during the first 56 seconds post-injection. Cardiovascular effects in anesthetized cats given a single intravenous injection of iopromide 1110 mg I/kg included increases in blood pressure, end diastolic pressure, central venous pressure, pulmonary artery pressure, cardiac minute volume, and contractility; peripheral resistance was decreased and heart rate was lowered transiently. Dogs injected with iopromide (3 g I) into the coronary arteries following cardiac catheterization demonstrated a positive inotropic effect and slightly decreased coronary sinus blood flow.

Lungs

Tests of lung and cardiovascular function in the guinea pig after intravenous iopromide administration (1-2 g I/kg) revealed an increased negativity of the expiratory intrapleural pressure, increased respiratory rate, decreased blood pressure, decreased compliance and increased airways resistance.

Arterial Tolerance

The ED50 of iopromide for femoral artery pain in the rat was greater than 3.0 g I/kg. The rat showed only slight behavioural anomalies after up to 3 g I/kg were administered by the carotid artery; little pain response was seen with femoral artery administration of up to 4 g I/kg. Iopromide concentrations greater than 320 mg I/ml were less painful than iohexol or iopamidol in the femoral artery.

Central Nervous System

Intracerebral administration of iopromide in the rat revealed an ED50 of 86 mg I/kg and an LD50 of 588 mg I/kg. Intracisternal administration in the rat resulted in an ED50 of 53 mg I/kg and an LD50 of 222 mg I/kg. Intraarterial administration into the common carotid artery of the rat resulted in an ED50 of 2.3 g I/kg. Iopromide was better tolerated than iopamidol and meglumine ioglicinate. Vertebral angiography in the rabbit was associated with greater brachycardia after iopromide administration (3.5 g I/animal) than after iopamidol or metrizamide at equivalent doses.

Renal

Radiography of the renal parenchyma in the dog following a single intravenous administration of iopromide 300-600 mg I/kg provided good to moderate visualization of the renal parenchyma. Plasma iodine concentrations after 300 mg I/kg i.v. were 2.6 to 3.0 mg I/ml and decreased to 0.8 to 0.9 mg I/mL 20 minutes post-administration. After 600 mg I/kg i.v. plasma iodine concentrations were 5.2 to 6.2 mg I/mL and dropped to 1.5 - 2.0 mg I/mL within 20 minutes post administration. A decrease in hematocrit was also observed. After renal arteriography in the rat, greater albuminuria was noted after administration of iopromide (400 mg I/kg) than in the controls; however, no statistically significant differences were noted between iopromide, iohexol and iopamidol in this respect. In rabbits, the potential of iopromide to cause renal damage was determined after a single intravenous administration of 1 - 10.5 g I/kg. Findings included increased protein excretion, increased GGT, increased serum urea-N, increased serum creatinine and changes in SGOT, SGPT, and alkaline phosphatase levels. Kidney changes (tubular necrosis, pallor, dilated tubules) and increased kidney weight were also apparent. In white rabbits a single intravenous dose of iopromide (5 g I/kg) had a greater effect than iopamidol on serum creatinine, serum urea-N, urine protein and flow as well as on the occurrence of histological findings. An investigation of renal function in rhesus monkeys after a single intravenous injection of iopromide (5 g I/kg) revealed no abnormalities.

Other

In vitro and in vivo investigations with iopromide revealed very little plasma protein binding (0.9%) and demonstrated only a slight influence on erythrocyte morphology in comparison with iosimide, metrizamide and ioglicinate. A low rate of lysozyme inhibition (ID50=142 mg I/mL), hemolysis inhibition (ID50=15.2 mg I/mL) and complement activation (ED50=176 mg I/mL) similar to that of other non-ionic contrast media was also determined. In one investigation, to determine histamine release from rat mast cells, contamination of the test substance (150 mg I/mL) caused an extremely high histamine release (82%); this investigation was non-reproducible. Histamine release in another investigation with rat mast cells was much lower (7%) and compared favourably with metrizamide and iopamidol.

PHARMACOKINETICS

Following a single intravenous injection of 125I-iopromide 1 and 10 g I/kg in rats, 56% and 26% of the dose, respectively, was excreted in the urine within 30 minutes. Ninety per cent of either dose was excreted in the urine, and 10% in the stool, by the seventh day after administration. The pre-injection isomeric ratio was unchanged and no metabolites were observed in urine or bile. Accumulation of iodine in the thyroid gland was noted in the rat after the radio-labelled drug was administered. In another experiment, the disappearance of 3H-iopromide from the thyroid was similar to that for other organs, indicating that the accumulation of iodine in the thyroid was not due to an accumulation of iopromide. The plasma half-life in the conscious rat was short at about 15 minutes. In the dog the plasma half-life was 45 minutes and total plasma clearance was about 3 mL/min/kg, indicating primary elimination by glomerular filtration in the kidney. The apparent volume of distribution of iopromide corresponded to the extracellular compartment. No metabolites were apparent. The ratio of stereoisomers for the drug was unchanged in the urine. In the rat 125I-iopromide appeared not to cross the placental barrier appreciably, although in rabbits, radioactivity which approximated 5-10% of the maternal plasma level was measured in the fetus.

TOXICOLOGY ACUTE TOXICITY

Iopromide, by single intracisternal injection, was less well tolerated in the rat than was metrizamide. The LD50 for iopromide was 222 mg I/kg and for metrizamide it was 325 mg I/kg (p <= 0.05). Toxic effects included various motor disturbances seen in all animals with survivors recovering within 48 hours. In two studies in rats, the LD50 of iopromide was found to be 14.5 g I/kg and > 14.8 g I/kg, following a single intravenous injection. In weanling rats the LD50 of iopromide was 15.5 g I/kg following a single intravenous injection. Signs of toxicity included apathy, prone posture, spastic gait, ruffled fur and necrosis/discolouration at the injection site. Surviving rats were free of neurologic symptoms within 48 hours. Rats which died showed renal pallor, pulmonary edema and hydrothorax. The intravenous LD50 of iopromide in mice was greater than 18.5 g I/kg. Signs of toxicity were similar to those seen in the rat. Additionally, paleness of the liver occurred in mice that died. The LD50 following a single injection into the right carotid artery of rats was about 50% of the intravenous LD50. Seizures occurred in all animals after 10.0 g I/kg. Injections of iopromide, metrizamide or iopamidol (3.5 g I/animal) into the vertebral artery of rabbits were equally well tolerated with little evidence of arterial (intracranial) spasm following any of these agents. In the beagle dog the intravenous LD50 was greater than 10 g I/kg. Toxic effects included apathy, diuresis, blood-stained feces, cutaneous erythema, auricular vesiculation and swollen lips and eyelids. However, no dogs died and no abnormalities were seen at autopsy.

SUBACUTE TOXICITY

Iopromide was administered to rats and beagle dogs of both sexes for 4-5 weeks. No animals died and no severe adverse effects were recorded. Mild to moderate vacuolization of the hepatocytes in rats, and slight to moderate vacuolization of the proximal tubular epithelial cells in dogs were observed after 3.7 g I/kg

LOCAL TOLERANCE

Local tolerance studies in rabbits after a single intravenous or intraarterial application into the ear vessels did not give any evidence for unequivocal local changes at the administration site. After a single intramuscular injection, the same animal species showed slight local reactions, which were only slightly more marked than those observed after 0.9% (w/v) NaCl solution.

REPRODUCTION AND TERATOLOGY

Pregnant female rats, after daily intravenous administration (days 6 to 15 of gestation) with doses of 0.37, 1.11 and 3.7 g I/kg/day showed adverse local reactions from 1.11 g I/kg/day and a slight decline in body weight gain after 3.7 g I/kg/day. Fetal examinations revealed an increased incidence of minor skeletal anomalies at all doses and additional 14th ribs in the high dose group. A similar investigation in the rabbit was invalid owing to an unacceptably high content of free amines in the test substance. Findings in the doe included convulsions and increased mortality. In the fetus findings included slight retardational effects in surviving animals, increased embryomortality, increased frequency of supernumerary 13th ribs and increased incidence of postural limb anomalies. Female rabbits received doses of 0.37, 1.11 and 3.7 g I/kg/day on days 6-18 of gestation. Fetal observations included increased minor external anomalies, increased rate of retarded ossification of sternebrae at 1.11 g I/kg/day and above, as well as, decreased mean fetal weight and increased rate of minor visceral anomalies or variations at the highest dose. There was an increased mortality rate in does after 3.7 g I/kg/day. Rabbits, administered dosages of 0.4, 1.2, 3.6 g I/kg/day, during days 6 to 18 of gestation, showed no change in general condition, mortality rate, or incidence of abortions. No effect was observed on the number, size, weight and sex of the fetuses or on pre-and post-implantational loss or incidence of fetal anomalies. Determination of gamma-glutamyl transferase in 24 h urine, urea nitrogen, and serum creatinine revealed no compound-related effects. There was no change in the kidney in respect to absolute or relative organ weight, or histology.

MUTAGENICITY

No positive mutagenic responses were observed for iopromide in the mouse during the micronucleus and dominant lethal tests. No evidence of mutagenicity was observed in the Ames test with Salmonella typhimurium. Similarly, there was no indication of clastogenic potential in the human lymphocyte test.

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