Conray^® 400
[IOTHALAMATE SODIUM 66.8% INJECTION U.S.P.]

January 1998

Mallinckrodt Inc.

NOT FOR INTRATHECAL USE

CONRAY 400 is a sterile aqueous solution intended for intravascular administration as a diagnostic radiopaque medium. CONRAY 400 contains 66.8% w/v of iothalamate sodium which is monosodium 5-acetamido-2,4,6-triiodo-N-methylisophthalamate and has the following structural formula:

Each milliliter contains 668 mg of iothalamate sodium, 0.110 mg edetate calcium disodium as a stabilizer and 0.125 mg of monobasic sodium phosphate as a buffer. The solution contains approximately 24.2 mg (1.05 mEq) sodium in each milliliter of solution and provides 40% (400 mg/mL) organically bound iodine. CONRAY 400 has an osmolarity of approximately 1700 mOsmol per liter, an osmolality of approximately 2300 mOsmol per kilogram and is, therefore, hypertonic under conditions of use. The viscosity (cps) is approximately 7 at 25°C and 4.5 at 37°C. The pH is 6.5-7.7. CONRAY 400 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.

Following intravascular injection, CONRAY 400 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 400 were approximately 10 and 90 minutes.

Angiography may be performed following intravascular injection which will permit visualization until significant hemodilution occurs.

Renal accumulation is sufficiently rapid that maximum radiographic density in the calyces and pelves occurs in most instances about 3-8 minutes after injection. 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.

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 400) 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 span of the circulating blood pool.

In non-neural tissues (during CT of the body), CONRAY 400 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 400 in normal and abnormal tissues has been shown to be variable.

Enhancement of CT with CONRAY 400 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 30-90 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 2-3 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 CTfindings.

CONRAY 400 is indicated for use in excretory urography, angiocardiography, aortography and for contrast enhancement of computed tomographic brain images.

CONRAY 400 may 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. Enhancement of computed tomography with CONRAY 400 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). Continuous or multiple scans separated by intervals of 1-3 seconds during the first 30-90 seconds post-injection of the contrast medium (dynamic CT scanning) may provide enhancement of diagnostic significance. 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 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.

Refer to PRECAUTIONS, General, concerning hypersensitivity. CONRAY 400 should not be used for myelography. This product should not be used for cerebral angiography by direct injection into the carotid or vertebral arteries due to the high concentration of the solution. (See WARNINGS.)

Diagnostic procedures which involve the use of iodinated intra-vascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. All procedures utilizing contrast media carry a definite risk of producing adverse reactions. While most reactions may be minor, life threatening and fatal reactions may occur without warning. The risk-benefit factor should always be carefully evaluated before such a procedure is undertaken. At all times a fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all severity, or situations which may arise as a result of the procedure, should be immediately available. If a serious reaction should occur, immediately discontinue administration. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes after administration. (See ADVERSE REACTIONS.)

Preparatory dehydration is dangerous and may contribute to acute renal failure in infants, young children, the elderly, patients with pre-existing renal insufficiency, patients with advanced vascular disease and diabetic patients.

Severe reactions to contrast media often resemble allergic responses. This has prompted the use of several provocative pretesting methods, none of which can be relied on to predict severe reactions. No conclusive relationship between severe reactions and antigen-antibody reactions or other manifestations of allergy has been established. The possibility of an idiosyncratic reaction in patients who have previously received a contrast medium without ill effect should always be considered. Prior to the injection of any contrast medium, the patient should be questioned to obtain a medical history with emphasis on allergy and hypersensitivity. A positive history of bronchial asthma or allergy, including food, a family history of allergy, or a previous reaction or hypersensitivity to a contrast agent may imply a greater than usual risk. Such a history, by suggesting histamine sensitivity and consequently proneness to reactions, may be more accurate than pre-testing in predicting the potential for reaction, although not necessarily the severity or type of reaction in the individual case. A positive history of this type does not arbitrarily contraindicate the use of a contrast agent, when a diagnostic procedure is thought essential, but does call for caution. (See ADVERSE REACTIONS.)

Prophylactic therapy including corticosteroids and antihistamines should be considered for patients who present with a strong allergic history, a previous reaction to a contrast medium, or a positive pre-test since in these patients the incidence of reaction is two to three times that of the general population. Adequate doses of corticosteroids should be started early enough prior to contrast medium injection to be effective and should continue through the time of injection and for 24 hours after injection. Antihistamines should be administered within 30 minutes of the contrast medium injection. Recent reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity A separate syringe should be used for these injections.

General anesthesia may be indicated in the performance of some procedures in young or uncooperative children and in selected adult patients; however, a higher incidence of adverse reactions has been reported in these patients, and may be attributable to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anesthesia which can prolong the circulation time and increase the duration of contact of the contrast agent.

Angiography should be avoided whenever possible in patients with hemocystinuria because of the risk of inducing thrombosis and embolism.

Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions.

Chemotoxic reactions result from the physio-chemical properties of the contrast media, the dose and speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category.

Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the amount of dose injected, the speed of injection, the mode of injection and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory.

Fatalities have been reported following the administration of iodine-containing contrast agents. Based upon clinical literature, the incidence of death is reported to range from one in 10,000 (0.01 percent) to less than one in 100,000 (0.001 percent).

The following adverse reactions have been observed in conjunction with the use of iodine-containing contrast agents.

The most frequent adverse reactions are nausea, vomiting, facial flush and a feeling of body warmth. These are usually of brief duration. Other reactions include the following:

Hypersensitivity reactions: Dermal manifestations of urticaria with or without pruritus, erythema and maculopapular rash. Dry mouth. Sweating. Conjunctival symptoms. Facial, peripheral and angioneurotic edema. Symptoms related to the respiratory system include sneezing, nasal stuffiness, coughing, choking, dyspnea, chest tightness and wheezing, which may be initial manifestations of more severe and infrequent reactions including asthmatic attack, laryngospasm and bronchospasm with or without edema, pulmonary edema, apnea and cyanosis. Rarely, these allergic-type reactions can progress into anaphylaxis with loss of consciousness and coma and severe cardiovascular disturbances.

Cardiovascular reactions: Generalized vasodilation, flushing and venospasm. Occasionally, thrombosis or rarely, thrombophlebitis. Red blood cell clumping and agglutination, crenation and interference in clot formation. Extremely rare cases of disseminated intravascular coagulation resulting in death have been reported. Severe cardiovascular responses include rare cases of hypotensive shock, coronary insufficiency, cardiac arrhythmia, fibrillation and arrest. These severe reactions are usually reversible with prompt and appropriate management; however, fatalities have occurred.

Technique reactions: Extravasation with burning pain, hematomas, ecchymosis and tissue necrosis, paresthesia or numbness, vascular constriction due to injection rate, thrombosis and thrombophlebitis.

Neurological reactions: Spasm, convulsions, aphasia, syncope, paresis, paralysis resulting from spinal cord injury and pathology associated with syndrome of transverse myelitis, visual field losses which are usually transient but may be permanent, coma and death.

Other reactions: Headache, trembling shaking, chills without fever and lightheadedness. Temporary renal shutdown or other nephropathy.

(Adverse reactions to specific procedures receive comment under that procedure.)

Overdosage may occur. The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular system. The symptoms may include cyanosis, bradycardia, acidosis, pulmonary hemorrhage, convulsions, coma and cardiac arrest. Treatment of an overdose is directed toward the support of all vital functions and prompt institution of symptomatic therapy.

Iothalamate salts are dialyzable.

The intravenous LD₅₀ value of various concentrations of Iothalamate Sodium (in grams of iodine/kilogram body weight) varied from 6.4 to 13.5 g/kg in mice, 6.9 to 9.5 g/kg in rats and 8.3 to 11.1 g/kg in rabbits. The LD₅₀ values decrease as the rate of injection increases.

It is advisable that CONRAY 400 be at or close to body temperature when injected.

The patient should be instructed to omit the meal that precedes the examination. Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination.

A preliminary film is recommended to check the position of the patient and the x-ray exposure factors.

If during administration a minor reaction occurs the injection should be slowed or stopped until the reaction has subsided. If a major reaction occurs the injection should be discontinued immediately.

Under no circumstances should either corticosteroids or antihistamines be mixed in the same syringe with the contrast medium because of a potential for chemical incompatibility.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Following intravenous injection, CONRAY 400 is rapidly excreted by the kidneys. CONRAY 400 may be visualized in the renal parenchyma 30 seconds following bolus injection. Maximum radiographic density in the calyces and pelves occurs in most instances within 3-8 minutes after injection. In patients with severe renal impairment contrast visualization may be substantially delayed.

Appropriate preparation of the patient is important for optimal visualization. A low residue diet is recommended for the day preceding the examination and a laxative is given the evening before the examination, unless contraindicated.

Infants and small children should not have any fluid restrictions prior to excretory urography. Injections of CONRAY 400 represent an osmotic load which, if superimposed on increased serum osmolality due to partial dehydration, may magnify hypertonic dehydration. (See WARNINGS and PRECAUTIONS, General concerning preparatory dehydration.)

See section on general Adverse Reactions.

Adults – The usual dose is 25-50 mL. Children 14 years of age and over, of average weight, may receive the adult dose. The total dose is normally injected within 30-90 seconds. Higher dosage may be indicated to achieve optimum results in instances where poor visualization may be anticipated (e.g., elderly patients or patients with impaired renal function). When nephrograms and/or sequential urograms are desired, the total dose should be rapidly injected, normally within 15-30 seconds. The dosage for children is reduced in proportion to age and body weight. The following approximate schedule is recommended for infants and children based on a dosage of about 0.5 mL/kg of body weight.

•  Under 6 months of age     5 mL
•  6-12 months              8 mL
•  1-2 years                10 mL
•  2-5 years                12 mL
•  5-8 years                15 mL
•  8-12 years               18 mL
•  12-14 years          20-30 mL

CONRAY 400 may be administered by injection into an appropriate peripheral vein, or by means of a catheter, directed to the chambers of the heart or associated large blood vessels to be visualized. Injection through a catheter usually provides adequate opacity with a lower dosage because less dilution of the medium takes place. Regardless of the mode of administration, rapid injection is essential. Satisfactory results usually require injection of the total dosage in 1-2 seconds. In most cases, this may be accomplished by manual injection. If indicated, shorter injection times may be obtained with a mechanical injector.

In addition to the general precautions previously described, continuous monitoring of ECG and vital signs is recommended during the procedure. When large individual doses are administered, a minimum of 15 minutes between injections is recommended to permit subsidence of any hemodynamic disturbances.

In addition to the adverse reactions previously uled, this procedure has been complicated by intramural injection with marked adverse effects on cardiac function. Hemodynamic changes which occur on injection into the heart chambers can aggravate incipient heart failure and serious arrhythmias, and cardiac arrest may be precipitated.

The volume of individual doses should be determined by the size of the structure to be visualized, and in adults, the weight of the patient is only a minor consideration. The anticipated degree of hemodilution at the site of injection and valvular competence should also be taken into consideration.

To visualize the aorta and its major branches, CONRAY 400 may be administered by the arterial or intravenous methods. Renal arteriograms may be obtained by any accepted technique which provides for delivery of the medium above the level of the renal arteries. Nephrograms or nephrotomograms may also be obtained by these methods of administration.

In addition to the general precautions previously described, the hazards of aortography include those associated with the particular technique employed, the contrast medium and the underlying pathology which warrants the procedure. There is, therefore, a definite risk.

In order to prevent the inadvertent injection of a large dose into a branch of the aorta or intramurally the position of the catheter tip or needle should be carefully evaluated. A small dose of 1-2 mL should be administered to locate the exact site of the needle or catheter tip. Inadvertent direct injection of contrast medium into brachiocephalic vessels may result in significant slowing of heart rate, peripheral hypotension and severe CNS reactions, including convulsions. Toxic effects may also be produced if large quantities of contrast medium are injected directly into aortic branches such as the renal artery, and repetitive injection of the recommended clinical dosage may be hazardous.

Occasional serious neurologic complications, including paraplegia and quadriplegia have been reported and may be attributable to excess doses injected into arterial trunks supplying the spinal arteries or to prolonged contact time of the concentrated contrast medium on the CNS tissue. Conditions which can contribute to prolonged contact time include decreased circulation, aortic occlusions distal to the site of injection, abdominal compression, hypotension, general anesthesia or the administration of vasopressors. When these conditions exist or occur, the necessity of performing or continuing the procedure should be carefully evaluated and the dose and number of repeat injections should be maintained at a minimum with appropriate intervals between injections.

Severe pain, paresthesia, or peripheral muscle spasm during injection may require discontinuance of the procedure and a re-evaluation of the placement of the catheter tip or needle. When employing the translumbar technique, extreme caution is advised to avoid inadvertent intrathecal injection.

Following catheter procedures, gentle pressure hemostasis is advised, followed by observation and immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture.

In addition to the general adverse reactions previously uled, adverse reactions following aortography include injury to the aorta and to neighboring organs, renal damage including infarction and acute tubular necrosis, spinal cord damage resembling transverse myelitis, retroperitoneal hemorrhage, arterial thrombosis, intestinal necrosis and diffuse cutaneous petechiae.

CONRAY 400 may be useful to enhance the demonstration of the presence and extent of certain malignancies such as: gliomas including malignant gliomas, glioblastomas, astrocytomas, oligodendrogliomas and gangliomas; ependymomas; medulloblastomas; meningiomas; neuromas; pinealomas; pituitary adenomas; craniopharyngiomas; germinomas; and metastatic lesions.

The usefulness of contrast enhancement for the investigation of the retrobulbar space and in cases of low grade or infiltrative glioma has not been demonstrated.

In cases where lesions have calcified, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement.

The use of CONRAY 400 may be beneficial in the image enhancement of non-neoplastic lesions. Cerebral infarctions of recent onset may be better visualized with the contrast enhancement, while some infarctions are obscured if contrast media are used. The use of iodinated contrast media results in contrast enhancement in about 60% of cerebral infarctions studied from one to four weeks from the onset of symptoms.

Sites of active infection may also be enhanced following contrast medium administration.

Arteriovenous malformations and aneurysms will show contrast enhancement. In the case of these vascular lesions, the enhancement is probably dependent on the iodine span of the circulating blood pool.

The opacification of the inferior vermis following contrast medium administration has resulted in false positive diagnoses in a number of normal studies.

No special patient preparation is required for contrast enhancement of CT brain scanning. However, it is advisable to insure that patients are well hydrated prior to examination.

The usual dose in adults and children is 1.5 mL/kg (0.7 mL/lb) by rapid intravenous administration not to exceed a total dose of 100 mL. In most cases, scanning may be performed immediately after completion of administration however, when fast scanning equipment (less than 1 minute) is used consideration should be given to waiting approximately 5 minutes to allow for maximum contrast enhancement.

CONRAY 400 may be administered when necessary to visualize vessels and organs in patients undergoing CT of the chest, abdomen and pelvis.

No special patient preparation is required for contrast enhancement in body CT. In patients undergoing abdominal or pelvic examination, opacification of the bowel may be valuable in scan interpretation.

In addition to the general precautions previously described, it is advisable to insure that patients are adequately hydrated prior to examination. Patient motion, including respiration, can markedly affect image quality, therefore, patient cooperation is essential. The use of an intravascular contrast medium can obscure tumors in patients undergoing CT evaluation of the liver resulting in a false negative diagnosis. Dynamic CT scanning is the procedure of choice for malignant tumor enhancement. (See Clinical Pharmacology.)

The usual adult dose is 25 to 60 mL administered by rapid intravenous bolus injection. Scanning is performed immediately or within 30 to 90 seconds after injection.

¹ Young, S. W., Turner, R. J., Castellino, R. A.: “A strategy for the contrast enhancement of malignant tumors using dynamic computed tomography and intravascular pharmacokinetics,” Radiology, 137:137-147, October 1980.

Mallinckrodt

Mallinckrodt Inc.
St. Louis, MO 63042 USA

MKR 0954198
Rev 1/98
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