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MD-76
Mallinckrodt
Diatrizoate Meglumine -
Diatrizoate Sodium
Radiopaque Medium
 
Action And Clinical Pharmacology: Following intravascular injection, MD-76 is rapidly transported through the bloodstream to the kidneys and is excreted unchanged in the urine by glomerular filtration. When urinary tract obstruction is severe enough to block glomerular filtration, the agent appears to be excreted by the tubular epithelium.

Renal accumulation is sufficiently rapid that the period of maximal opacification of the renal passages may begin as early as 5 minutes after injection. In infants and small children excretion takes place somewhat more promptly than in adults, so that maximal opacification occurs more rapidly and is less sustained. The normal kidney eliminates the contrast medium almost immediately. In nephropathic conditions, particularly when excretory capacity has been altered, the rate of excretion varies unpredictably, and opacification may be delayed for 30 minutes or more after injection; with severe impairment opacification may not occur. Generally, however, the medium is concentrated in sufficient amounts and promptly enough to permit a thorough evaluation of the anatomy and physiology of the urinary tract.

Intravascular injection also opacifies those vessels in the path of flow of the medium, permitting visualization until the circulating blood dilutes the concentration of the medium. Thus selective angiography may be performed following injection directly into veins or arteries.

Injectable iodinated contrast agents are excreted either through the kidneys or through the liver. These 2 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. Diatrizoate 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.

Diatrizoate salts cross the placental barrier in humans and are excreted unchanged in human milk.

Computerized Tomography of the Head: 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 5 to 10 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 10 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 5 to 40 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, although the mechanism by which this occurs is not clear.

In brain scanning, the contrast medium (MD-76) 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.

The image enhancement of non-tumoral lesions, such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of the circulation blood pool.

Computerized Tomography of the Body: In non-neural tissues (during CT of the body), MD-76 diffuses rapidly from the vascular to 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 tissue since no barrier exists; contrast enhancement is thus due to the relative differences in extravascular diffusion between normal and abnormal tissue, quite different than that in the brain.

Enhancement of CT with MD-76 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 MD-76 in normal and abnormal tissue has been shown to be variable. Contrast enhancement appears to be greatest within 30 to 90 seconds after bolus administration, thus greatest enhancement can be detected by a series of consecutive 2 to 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.

Indications And Clinical Uses: In excretory urography, aortography, pediatric angiocardiography, peripheral arteriography, selective renal arteriography, selective visceral arteriography, selective coronary arteriography with or without left ventriculography, i.v. contrast enhancement of computed tomography and for i.v. digital subtraction angiography.

Contra-Indications: Known hypersensitivity to diatrizoic acid; anuria or severe oliguria. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Serious or fatal reactions have been associated with the administration of iodine containing radiopaque media. It is of utmost importance to be completely prepared to treat any contrast medium reaction.

Serious neurologic sequelae, including permanent paralysis, have been reported following injections of concentrated contrast media into arteries supplying the spinal cord. The injection of a contrast medium should never be made following the administration of vasopressors since they strongly potentiate neurologic effects (see Precautions pertaining to Aortography).

A previous reaction to a contrast medium or a history of iodine sensitivity is not an absolute contraindication to the use of MD-76. However, extreme caution should be exercised in injecting these patients and prophylactic therapy should be considered (see Precautions, General).

In patients with subarachnoid hemorrhage, a rare association between contrast administration and clinical deterioration, including convulsions and death, has been reported. Therefore, administration of intravascular iodinated ionic contrast media in these patients should be undertaken with extreme caution and only if in the opinion of the physician the expected benefits outweigh the potential risks.

A definite risk exists in the use of intravascular contrast agents in patients who are known to have multiple myeloma. In such instances there has been anuria resulting in progressive uremia, renal failure and eventually death. Although neither the contrast agent nor dehydration has separately proved to be the cause of anuria in myeloma, it has been speculated that the combination of both may be the causative factor. The risk in myelomatous patients is not a contraindication to the procedures; however, partial dehydration in the preparation of these patients for the examination is not recommended since this may predispose to the precipitation of myeloma protein in the renal tubules. No form of therapy, including dialysis, has been successful in reversing this effect. Myeloma, which occurs most commonly in persons over age 40, should be considered before intravascular administration of a contrast agent.

Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure and measures for treatment of a hypertensive crisis should be available.

Contrast media have been shown to promote the phenomenon of sickling in individuals who are homozygous for sickle cell disease when the material is injected i.v. or intra-arterially.

Avoid accidental introduction of this preparation into the subarachnoid space since even small amounts may produce convulsions and possible fatal reactions.

Convulsions have occurred in patients with primary or metastatic cerebral lesions following the administration of contrast media for contrast enhancement of CT brain images.

In computed tomography, it has been reported that in low density lesions, false negative results may be produced following contrast media administration, i.e., contrast media may obscure low-density lesions. Steps should be taken to insure that patients undergoing computed tomography have received no injections of water-soluble contrast media at least 24 hours prior to examination. The necessity to obtain a non-enhanced CT scan prior to the administration of MD-76 has to be assessed by the physician.

Precautions: General: Diagnostic procedures which involve the use of radiopaque contrast agents should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed (see Adverse Effects).

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, diabetic patients and those with multiple myeloma.

Severe, life-threatening reactions suggest hypersensitivity to the radiopaque agent, which has prompted the use of several pre-testing methods, none of which can be relied upon to predict severe reactions. Many authorities question the value of any pre-test. A history of bronchial asthma or allergy, a family history of allergy, or a previous reaction to a contrast agent warrant special attention. Such a history, by suggesting histamine sensitivity and a consequent proneness to reactions, may be more accurate than pre-testing in predicting the likelihood of a reaction, although not necessarily the severity or type of reaction in the individual case.

Prophylactic therapy including corticosteroids and antihistamines should be considered for patients who present 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 2 to 3 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 may be administered if considered necessary by the physician. When used, antihistamines should be administered within 30 minutes of the contrast media injection.

The sensitivity test most often performed is the slow injection of 0.5 to 1.0 mL of the radiopaque medium, administered i.v., prior to injection of the full dose. It should be noted that the absence of a reaction to the test dose does not preclude the possibility of a reaction to the full dose. If the test dose (or subsequent diagnostic injection) causes an untoward response, the examination should be terminated and appropriate measures taken to combat the adverse reaction. In rare instances, reactions to the test dose itself may be extremely severe; therefore, close observation of the patient, and facilities for emergency treatment, are indicated.

Renal toxicity has been reported in a few patients with liver dysfunction who were given oral cholecystographic agents followed by intravascular iodinated radiopaque agents, and also in patients with occult renal disease, notably diabetics and hypertensives. Administration of MD-76 should be postponed in patients with hepatic or biliary disorder who have recently taken a cholecystographic agent. In infants, young children, in diabetics, in patients with multiple myeloma and in cases of impaired renal function, there should be no fluid restriction and every attempt made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most important factor influencing further renal impairment. The possibility of thrombosis should be borne in mind when percutaneous techniques are employed.

Injection of MD-76 should be undertaken with extreme caution in patients with severe concomitant hepatic and renal disease. Consideration must be given to the functional ability of the kidneys before injecting this preparation.

Caution should be exercised in performing contrast medium studies in patients with endotoxemia and/or those with elevated body temperatures.

General anesthesia may be indicated in the performance of some procedures in young and 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.

Recent reports of thyroid storm occurring following 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 such patients before use of this drug. Iodine containing contrast agents may alter the results of thyroid function tests which depend on iodine estimation, e.g., PBI and radioactive iodine uptake studies. Such tests, if indicated, should be performed prior to the administration of this preparation.

Contrast agents may interfere with some chemical determinations made on urine specimens; therefore, urine should be collected before administration of the contrast medium or 2 or more days afterwards.

Pregnancy: Category B: Diatrizoate sodium and diatrizoate meglumine administered i.v. cross the placenta and are evenly distributed in fetal tissues. No teratogenic effects attributable to diatrizoate sodium or diatrizoate meglumine have been observed in teratology studies performed in animals. There are, however, no adequate and well-controlled studies in pregnant women. Because animal teratology studies are not always predictive of human response, this agent should be used during pregnancy only if clearly needed.

Lactation: Diatrizoate salts are excreted unchanged in human milk. Because of the potential for adverse effects in nursing infants, bottle feedings should be substituted for breast feedings for at least 24 hours following the administration of this drug. Therefore, a decision should be made whether to discontinue nursing or not to administer the drug, taking into account the importance of the drug to the mother.

(Precautions for specific procedures receive comment under that procedure.)

Adverse Reactions: General: Adverse reactions accompanying the use of iodine-containing intravascular contrast agents are usually mild and transient, although severe and life-threatening reactions, including fatalities, have occurred. Because of the possibility of severe reactions to the procedure and/or the radiopaque medium, appropriate emergency facilities and well-trained personnel should be available to treat both conditions. Emergency facilities and personnel should remain available for 30 to 60 minutes following the procedure since severe delayed reactions have been known to occur.

Nausea, vomiting, flushing, or a generalized feeling of warmth are the reactions seen most frequently with intravascular injection. Symptoms which may occur include chills, fever, sweating, headache, dizziness, pallor, weakness, severe retching and choking, wheezing, a rise or fall in blood pressure, facial or conjunctival petechiae, urticaria, pruritus, rash and other eruptions, edema, cramps, tremors, itching, sneezing and lacrimation. Antihistaminic agents may be of benefit; rarely such reactions may be severe enough to require discontinuation of dosage.

Although local tissue tolerance is usually good, there have been a few reports of a burning or stinging sensation or numbness and of venospasm or venous pain, and partial collapse of the injected vein. Neutropenia or thrombophlebitis may occur. Tissue necrosis has occurred with extravasation. Severe reactions which may require emergency measures may take the form of a cardiovascular reaction characterized by peripheral vasodilatation with resultant hypotension and reflex trachycardia, dyspnea, agitation, confusion, convulsions, and cyanosis progressing to unconsciousness. Or, the histamine-liberating effect of these compounds may induce an allergic-like reaction which may range in severity from rhinitis or angioneurotic edema to laryngeal or bronchial spasm or anaphylactoid shock.

Extremely rare cases of disseminated intravascular coagulation resulting in death have been reported. Renal shutdown or other nephropathy may occur.

In addition to the adverse reactions described above, adverse reactions may sometimes occur as a consequence of the procedure for which the contrast agent is used. Adverse reactions in excretion urography have included cardiac arrest, ventricular fibrillation, anaphylaxis with severe asthmatic reaction, and flushing due to generalized vasodilation. In aortography, the risks of procedures include injury to the aorta and neighboring organs, pleural puncture, renal damage including infarction and acute tubular necrosis with oliguria and anuria, accidental selective filling of the right renal artery during the translumbar approach, spinal cord injury and pathology associated with the syndrome of transverse myelitis, generalized petechiae, and death following hypotension, arrhythmia, and anaphylactoid reactions. Adverse reactions in pediatric angiocardiography have included arrhythmia and death. During peripheral arteriography, complications have occurred including hemorrhage from the puncture site, thrombosis of the vessel, and brachial plexus palsy following axillary artery injections. During selective coronary arteriography with or without left ventriculography most patients will have transient ECG changes. Ventricular tachycardia, ventricular fibrillation, other arrhythmias and cardiac arrest may result from manipulation of the catheter during the procedure or administration of the medium. Other reactions may include hypotension, chest pain, and myocardial infarction. Transient elevation of creatinine phosphokinase has occurred in approximately 30% of patients tested. Fatalities have been reported. Complications due to the procedure include hemorrhage, thrombosis, pseudoaneurysms at the puncture site, and dislodgement of arteriosclerotic placques. Dissection of the coronary vessels and transient sinus arrest have occurred rarely.

Adverse reactions in selective renal arteriography include nausea, vomiting, hypotension and hypertension.

Post-arteriographic changes in laboratory studies include transient elevations in BUN, serum creatinine, glucose and serum enzymes.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 specific therapy.

Diatrizoate salts are dialyzable.

Treatment of Adverse Effects: Contrast media should be administered only by physicians thoroughly familiar with the emergency treatment of all adverse reactions to contrast media. The assistance of other trained personnel such as cardiologists, internists and anesthetists is required in the management of severe reactions.

A guideline for the treatment of adverse reactions is presented below. This outline is not intended to be a complete manual on the treatment of adverse reactions to contrast media or on cardio-pulmonary resuscitation. The physician should refer to the appropriate texts on the subject.

It is also realized that institutions or individual practitioners will already have appropriate systems in effect and that circumstances may dictate the use of additional or different measures.

Minor Allergic Reactions (if considered necessary): The i.v. or i.m. administration of an antihistamine such as diphenhydramine; 25 to 50 mg is generally sufficient (contraindicated in epileptics). The resulting drowsiness makes it imperative to ensure that out-patients do not drive or go home unaccompanied.

Major or Life-threatening Reactions: A major reaction may be manifested by signs and symptoms of cardiovascular collapse, severe respiratory difficulty and nervous system dysfunction. Convulsions, coma and cardio-respiratory arrest may ensue.

The following measures should be considered: Start emergency therapy immediately, carefully monitoring vital signs. Have emergency resuscitation team summoned: do not leave patient unattended. Ensure patent airway: guard against aspiration. Commence artificial respiration if patient is not breathing. Administer oxygen, if necessary. Start external cardiac massage in the event of cardiac arrest. Establish route for i.v. medication by starting infusion of appropriate solution (5% dextrose in water). Judiciously administer specific drug therapy as indicated by the type and severity of the reaction. Careful monitoring is mandatory to detect adverse reactions of all drugs administered: a) soluble hydrocortisone 500 to 1 000 mg i.v. for all acute allergic-anaphylactic reactions. b) epinephrine 1:1 000 solution (in the presence of anoxia it may cause ventricular fibrillation). i) 0.2 to 0.4 mL s.c. for severe allergic reactions. ii) in extreme emergency 0.1 mL/minute, appropriately diluted, may be given i.v. until desired effect is obtained. Do not exceed 0.4 mL. iii) in case of cardiac arrest 0.1 to 0.2 mL, appropriately diluted, may be given intracardially. c) In hypotension (carefully monitoring blood pressure): i) phenylephrine HCl 0.1 to 0.5 mg appropriately diluted slowly i.v. or by slow infusion or ii) levarterenol bitartrate 4 mL of 0.2% solution in 1 000 mL of 5% dextrose by slow drip infusion. d) Sodium bicarbonate 5%; 50 mL i.v. every 10 minutes as needed to combat post-arrest acidosis. e) Atropine 0.4 to 0.6 mg i.v. to increase heart rate in sinus bradycardia. May reverse 2nd or 3rd degree block. f) To control convulsions: i) pentobarbital sodium 50 mg in fractional doses slowly i.v. (contraindicated if cyanosis is present) or ii) diazepam 5 to 10 mg slowly i.v. titrating the dose to the response of the patient. Defibrillation, administration of antiarrhythmics and additional emergency measures and drugs may be required. Transfer patient to intensive care unit when feasible for further monitoring and treatment.

Dosage And Administration: MD-76 should be at body temperature when injected, and may need to be warmed before use. If kept in a syringe before injection, it should be protected from exposure to strong light. Discard unused portion.

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.

Excretory Urography: Patient Preparation: Appropriate preparation of the patient is desirable for optimal results. In adults and older children, a low residue diet is recommended for the day preceding the examination and a laxative is given the evening before the examination, unless contraindicated.

Precautions: In addition to the general precautions previously described, infants and young children should not have fluid restrictions prior to excretory urography. Injection of MD-76 represents 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).

Maintenance of adequate fluid intake is particularly desirable in uremic patients and patients with impaired renal function, multiple myeloma or diabetes. Adequate visualization may be difficult or impossible to attain in uremic patients or others with severely impaired renal function (see Precautions, General).

Usual Dosage: The dose range for adults is 20 to 40 mL; the usual dose is 20 mL; children require proportionately less. Suggested dosages are as follows: under 6 months of age: 4 mL; 6 to 12 months: 6 mL; 1 to 2 years: 8 mL; 2 to 5 years: 10 mL; 5 to 7 years: 12 mL; 8 to 10 years: 14 mL; 11 to 15 years: 16 mL. In adults, when the smaller dose has provided inadequate visualization, or when poor visualization is anticipated, the 40 mL dose may be given.

The preparation is given by i.v. injection. If flushing or nausea occur during administration, injection should be slowed or briefly interrupted until the side effects have disappeared.

In patients with renal dysfunction, optimal visualization may be delayed until 30 minutes or more after injection.

Aortography: MD-76 may be administered by accepted techniques to visualize the aorta and its major branches. Normal hydration should be maintained.

Manufacturers' Warnings In Clinical States: In addition to the warnings previously described, during aortography by the translumbar technique, extreme care is advised to avoid inadvertent intrathecal injection since the injection of even small amounts of the contrast medium may cause convulsions, permanent sequelae, or fatality. Should the accident occur, the patient should be placed upright to confine the hyperbaric solution to a low level, anesthesia may be required to control convulsions, and if there is evidence of a large dose having been administered, a careful cerebrospinal fluid exchange-washout should be considered.

Precautions: 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.

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 to 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 an excessive dose being 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 reevaluation of the placement of the catheter tip or needle.

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

Usual Dosage: For adults and children over 16 years of age, the usual dose is 15 to 40 mL as a single injection, repeated if indicated. Children require less in proportion to weight.

Since the medium is given by rapid injection in this procedure, patients should be watched for untoward reactions during the injection. Unless general anesthesia is employed, patients should be warned that they may feel some transient pain or burning during the injection followed by a feeling of warmth immediately afterwards.

Pediatric Angiocardiography: Angiocardiography with MD-76 may be performed by injection into the large peripheral vein or by direct catheterization of the heart.

Patient Preparation: Normal patient hydration should be maintained. Appropriate preanesthetic medication should be given.

Manufacturers' Warnings In Clinical States: In addition to the general warnings previously described, the inherent risks of angiocardiography in cyanotic infants and patients with chronic pulmonary emphysema must be weighed against the necessity for performing this procedure. In pediatric angiocardiography, a dose of 10 to 20 mL may be particularly hazardous in infants weighing less than 7 kg. This risk is probably significantly increased if these infants have pre-existing right heart strain, right heart failure, and effectively decreased or obliterated pulmonary vascular beds.

Adverse Reactions: In addition to the adverse reactions previously described, clinical studies in man, and related animal experiments, have suggested that the hypertonicity of diatrizoate contrast agents produces significant hemodynamic effects, especially in right-sided injections. Large volumes of such agents cause a drop in peripheral arterial and systemic pressures and cardiac output, a rise in pulmonary arterial and right-heart pressures, bradycardia, and regular ectopic beats. Resulting effects on peripheral arterial and pulmonary arterial pressures are postulated to be due to mechanical blockage of the pulmonary vascular bed and clumping of red cells.

Hypertonic solutions cause a decrease in hematocrit in vitro and in vivo, and shrinkage of red blood cells.

It is suggested that hemodynamic changes be monitored and that pressures considered abnormal under roentgenographic conditions be allowed to return to a pre-angiographic level before continuation of radiopaque injection; this usually takes 15 minutes.

Usual Dosage: The suggested single dose for children under 5 years of age is 10 to 20 mL, depending on the size of the child. For children 5 to 10 years of age, single doses of 20 to 30 mL are recommended. The dose may be repeated if required.

Peripheral Arteriography: MD-76 may be injected into the peripheral arterial circulation. Injection is made into the femoral or subclavian artery by the percutaneous or operative method.

Patient Preparation: The procedure is normally performed with local or general anesthesia (see Precautions, General). Premedication may be employed as indicated.

Precautions: In addition to the general precautions previously described, hypotension or moderate decreases in blood pressure seem to occur frequently with intra-arterial (brachial) injections; therefore, the blood pressure should be monitored during the immediate 10 minutes after injection; this blood pressure change is transient and usually requires no treatment. Extreme caution during injection of the contrast agent is necessary to avoid extravasation and fluoroscopy is recommended. This is particularly important in patients with severe arterial disease.

Adverse Reactions: In addition to the adverse reactions previously described, since the contrast agent is given by rapid injection, pain and flushing of the skin may occur. Patients not under general anesthesia may experience nausea and vomiting or a transient feeling of warmth. Vascular spasm occurs rarely as does thrombosis of the vessel and brachial plexus palsy following axillary artery injection.

Usual Adult Dosage: For visualization of an entire extremity, a single dose of 20 to 40 mL is suggested; for the upper or lower half of the extremity only, 10 to 20 mL is usually sufficient. The dose for children is reduced in proportion to body weight.

Selective Renal Arteriography: Usual Adult Dosage: The usual dose is 5 to 10 mL injected into either or both renal arteries via femoral artery catheterization. This dose may be repeated as necessary; cumulative total doses up to 60 mL have been given.

Selective Visceral Arteriography: Usual Adult Dosage: The usual dose for injections into the superior mesenteric artery is 40 mL with a range of 30 to 50 mL; inferior mesenteric artery, usual dose of 15 mL with a range of 10 to 25 mL; celiac artery, usual dose of 40 mL with a range of 30 to 50 mL; hepatic artery, usual dose of 25 mL with a range of 15 to 35 mL; splenic artery, usual dose of 35 mL with a range of 30 to 40 mL. These doses may be repeated as necessary.

Selective Coronary Arteriography with or without Left Ventriculography: Precautions: In addition to the general precautions previously described, it is recommended that this procedure should not be performed for approximately 4 weeks following the diagnosis of myocardial infarction. Mandatory prerequisites to the procedure are experienced personnel, ECG monitoring apparatus, and adequate facilities for resuscitation and cardioversion.

Patients should be monitored continuously by ECG throughout the procedure.

Usual Adult Dosage: 4 to 10 mL injected into either coronary artery and repeated as necessary. For left ventriculography the usual dose is 35 to 50 mL injected into the left ventricles and repeated as necessary. The total dose for combined selective coronary arteriography and left ventriculography should not exceed 200 mL.

I.V. Contrast Enhancement in Computed Tomography (CT): Computed Tomography of the Brain: Tumors: MD-76 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.

Non-Neoplastic Conditions: The use of MD-76 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 1 week to 4 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 content of the circulating blood pool.

Hematomas and intraparenchymal bleeders seldom demonstrate any contrast enhancement. However, in cases of intraparenchymal clot, for which there is no obvious clinical explanation, contrast medium administration may be helpful in ruling out the possibility of associated arteriovenous malformation.

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

Body Computed Tomography: MD-76 may be administered when necessary to visualize vessels and organs in patients undergoing CT of the chest, abdomen and pelvis.

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

Continuous or multiple scans separated by intervals of 1 to 3 seconds during the first 30 to 90 seconds post-injection of the contrast medium (dynamic CT scanning) 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 are usually 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.

Manufacturers' Warnings In Clinical States: Patients with diabetes mellitus and impaired renal function are considered to be at greater risk to develop acute renal failure following the injection of large doses of contrast media required for contrast enhancement in CT scanning.

Convulsions have occurred in patients with primary or metastatic cerebral lesions following the administration of iodine-containing radiopaque media for enhancement of CT brain images.

Patient Preparation: No special patient preparation is required for contrast enhancement in computerized tomography. However, it is advisable to insure that patients are well hydrated prior to examination. In patients undergoing abdominal or pelvic examination, opacification of the bowel may be valuable in scan interpretation.

Precautions: 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 effect 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.

Usual Dosage: Computerized Tomography of the Brain: 1.3 mL/kg not to exceed 120 mL in adults and a proportionally smaller amount in children depending on age and weight. 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.

Usual Adult Dosage: Body Computed Tomography: MD-76 may be administered by i.v. bolus injection, by rapid infusion, or by a combination of both.

For vascular opacification, a bolus injection of 25 to 50 mL may be used, repeated as necessary. When prolonged arterial or venous phase enhancement is required and for the enhancement of specific lesions, a rapid infusion of 100 mL may be used.

I.V. Digital Subtraction Angiography (I.V. DSA): I.V. DSA is a radiographic modality which allows dynamic imaging of the arterial system following i.v. injection of iodinated x-ray contrast media through the use of image intensification, enhancement of the iodine signal and digital processing of the image data. Temporal subtraction of the images obtained during the first arterial pass of the injected contrast medium from images obtained before and after contrast medium injection yield images which are devoid of bone and soft tissue.

Areas that have been examined by i.v. DSA are the heart, including coronary by-pass grafts; the pulmonary arteries; the arteries of the brachiocephalic circulation; the aortic arch; the abdominal aorta and its major branches including the celiac, mesenterics and renal arteries; the iliac arteries; and the arteries of the extremities.

Patient Preparation: No special patient preparation is required for DSA. However, it is advisable to insure that patients are well hydrated prior to examination.

Precautions: In addition to the general precautions previously described, the risks associated with DSA are those usually attendant with catheter procedures and include intramural injections, vessel dissection or rupture and tissue extravasation. Small test injections of contrast medium made under fluoroscopic observation to insure the catheter tip is properly positioned, and in the case of peripheral placement that the vein is of adequate size, will reduce the potential for intramural injections, vessel dissection or tissue extravasation occurring.

Patient motion, including respiration and swallowing, can result in marked image degradation yielding non-diagnostic studies. Therefore, patient cooperation is essential.

Adverse Reactions: See Adverse Effects, General.

Usual Adult Dosage: MD-76 may be injected either centrally, into the superior or inferior vena cava, or peripherally into an appropriate arm vein. For central injections, catheters may be introduced at the antecubital fossa into either the basilic or cephalic vein or at the leg into the femoral vein and advanced to the distal segment of the corresponding vena cava. For peripheral injections, the catheter is introduced at the antecubital fossa into an appropriate size arm vein. In order to reduce the potential for extravasation during peripheral injection, a catheter of approximately 20 cm in length should be employed.

Depending on the area to be imaged, the usual dose range is 20 to 60 mL. Injections may be repeated as necessary.

Central catheter injections are usually made with a power injection with an injection rate of between 10 and 30 mL/second. When making peripheral injections, rates of 12 to 20 mL/second should be used, depending on the size of the vein. Also, since contrast medium may remain in the arm vein for an extended period following injection, it may be advisable to flush the vein, immediately following injection with an appropriate volume (20 to 25 mL) of 5% dextrose in water or normal saline.

Availability And Storage: Each mL of sterile aqueous solution contains: diatrizoate meglumine 660 mg (iodine 37%), diatrizoate sodium 100 mg, edetate calcium disodium 0.110 mg as a sequestering agent and monobasic sodium phosphate 0.125 mg as a buffer. Sodium: <1 mmol (3.66 mg)/mL. Vials of 50 mL, boxes of 12; bottles of 100 mL fill/150 mL, boxes of 12; bottles of 150 mL, boxes of 12; bottles of 200 mL fill/250 mL, boxes of 12. Pharmacy Bulk Vial: Multiple dispensing bottles of 500 mL, boxes of 12.

Store between 15 to 30C. Protect from light. Protect from freezing. Discard unused portion.