Hypaque Parenteral (Diatrizoate)

HYPAQUE® PARENTERAL

Nycomed Imaging A.S.

Diatrizoate Sodium – Diatrizoate Meglumine

Contrast Media

Action And Clinical Pharmacology: When injected into the chambers of the heart or into blood vessels, diatrizoate sodium and diatrizoate meglumine opacify their lumina, then they are rapidly carried via the bloodstream to the kidneys, where they are excreted unchanged mainly by glomerular filtration, permitting radiographic visualization of opacified heart chambers, blood vessels and the urinary tract. Administration into the urinary bladder, ureter, uterus, biliary system or joint cavities opacifies these structures.

When diatrizoate sodium and/or diatrizoate meglumine are employed for contrast enhancement of computed tomography, the degree of enhancement is reported to be directly related to the amount of iodine administered. In adults the amount of iodine usually required for contrast enhancement ranges from 28 to 42 g.

Peak iodine blood levels occur immediately following rapid injection of the dose and fall rapidly within 5 to 10 minutes. With respect to tumors, 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 and vascularity of the tumor. The radiographic enhancement of intracranial lesions other than tumors, e.g., aneurysms and arteriovenous malformations is probably dependent on the iodine content of the circulating blood pool.

Indications And Clinical Uses: Hypaque-M 18%: I.V. drip infusion pyelography, retrograde cystography and voiding urethrocystography and retrograde pyelography.

Hypaque-M 30%: I.V. drip infusion pyelography, retrograde cystography and voiding urethrocystography, retrograde pyelography and i.v. contrast enhancement in computerized tomography.

Hypaque Sodium 50%: Excretory urography, i.v. drip infusion pyelography, retrograde pyelography, operative and postoperative cholangiography, intraosseous venography, hysterosalpingography and i.v. contrast enhancement in computerized tomography.

Hypaque-M 60%: Excretory urography, i.v. drip infusion pyelography, retrograde pyelography, retrograde cystography and voiding urethrocystography, hysterosalpingography, aortography, angiography (peripheral arteriography and venography), cerebral arteriography, operative and postoperative cholangiography, arthrography and i.v. contrast enhancement in computerized tomography.

Hypaque-M 76%: Excretory urography, aortography, peripheral arteriography, angiocardiography, selective coronary arteriography, combined coronary arteriography and left ventriculography, i.v. contrast enhancement in computerized tomography and i.v. digital subtraction arteriography.

Contra-Indications: General: Patients with a hypersensitivity to salts of diatrizoic acid. A history of sensitivity to iodine or to contrast media of different chemical formulae is not an absolute contraindication to the use of Hypaque. The presence of hypersensitivity does however, call for extreme caution in the administration of these media.

Patients with a significant degree of renal failure. Urography and large dose vascular procedures are contraindicated in dehydrated, azotemic patients.

Do not use these solutions for myelography or for examination of dorsal cysts or sinuses which might communicate with the subarachnoid space. Injection of even a small amount into the subarachnoid space may produce convulsions and result in fatality. Epidural injection is also contraindicated.

Manufacturers’ Warnings In Clinical States: Serious or fatal reactions have been associated with the administration of radiopaque media. It is important that a course of action be planned in advance for the immediate treatment of serious reactions, and that adequate and appropriate facilities and personnel be readily available in the event that a severe reaction occurs.

Ionic iodinated contrast media inhibit blood coagulation more than nonionic contrast media. Nonetheless, it is necessary to avoid prolonged contact of blood with syringes containing all contrast media. Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with nonionic and also with 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 medications 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 3-way stopcocks, frequent catheter flushing with heparinized saline solutions, and minimizing the length of the procedure. Although ionic contrast media have been used as flush solutions, the safety of this procedure has not been studied systematically. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of clotting.

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 risk, the amount of radiopaque material 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 intraarterially. Fluid restriction is not advised in these patients.

Some clinicians consider multiple myeloma a contraindication to the use of contrast media because of the possibility of producing transient to fatal renal failure. If contrast media are used in the presence of multiple myeloma, dehydration should be avoided since it favors protein precipitation in renal tubules.

Caution is advised in patients with severe cardiovascular disease, hyperthyroidism, concomitant severe renal and hepatic disease and in patients with a history of bronchial asthma or other allergic manifestations, or of sensitivity to iodine.

Pregnancy: Safety for use in pregnancy has not been determined. Before administration of the solution to women of childbearing potential, the benefit to the patient should be carefully weighed against the possible risk to the fetus.

Lactation: Since diatrizoate contrast media are known to be excreted in breast milk, nursing should be stopped and alternate feeding substituted for 24 to 48 hours following administration of this product.

Precautions: 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.

Prior to injection, the patient should be questioned for a history of allergy. Although a history of allergy may imply a greater than usual risk, it does not arbitrarily contraindicate the use of the medium. Premedication to avoid or minimize possible allergic reactions may be considered. Antihistamines should be given by a separate injection because precipitation may occur when mixed in the same syringe with these radiopaque media.

Do not prefill plastic syringes or other delivery systems with diatrizoate media for prolonged periods (i.e., several hours) before use.

The i.v. injection of a test dose of 0.5 to 1 mL of the contrast agent before injection of the full dose has been employed in an attempt to predict severe or fatal adverse reactions. The preponderance of recent scientific literature, however, now demonstrates that this provocative test procedure is not reliably predictive of serious or fatal reactions. Severe reactions and fatalities have occurred with the test dose alone, with the full dose after a nonreactive test dose, and with or without a history of allergy. No conclusive relationship between severe or fatal reactions and antigen-antibody reactions or other manifestations of allergy has been established. A history of allergy may be more useful in predicting reactions, and warrants special attention when administering the drug. Since delayed severe reactions may occur, the patient should be kept under observation for 30 to 60 minutes following injection.

There have been reports in the literature indicating that patients on adrenergic beta-blockers may be more prone to severe adverse effects to contrast media. At the same time, treatment of allergic-anaphylactoid reactions in these patients is more difficult. Epinephrine should be administered with caution since it may not have its usual effects. On the one hand larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart-block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.

Addition of an inotropic agent to contrast agents may produce a paradoxical depressant response which can be deleterious to the ischemic myocardium.

Under some circumstances (pH, temperature, concentrations, time), diatrizoate solutions are incompatible with promethazine hydrochloride, diphenhydramine hydrochloride, brompheniramine maleate or papaverine hydrochloride solutions.

Because of the possibility of inducing temporary oliguria with contrast media, it is wise to allow an interval of at least 48 hours before studies are repeated especially in patients with unilateral or bilateral reduction of normal renal function.

Renal toxicity has been reported in patients with liver dysfunction who have been given an oral cholecystographic agent prior to the injection of diatrizoates. In such patients the administration of Hypaque should be postponed.

Preparatory dehydration is not necessary and may be dangerous in infants, young children, the elderly, presence of multiple myeloma and azotemic patients (especially those with polyuria, oliguria, diabetes, advanced vascular disease or pre-existing dehydration). The undesirable dehydration in these patients may be accentuated by the osmotic diuretic action of the medium.

When high doses are used, caution should be exercised in patients with congestive heart failure because of the transitory increase in circulatory osmotic load, and such patients should be observed for several hours to detect delayed hemodynamic disturbances.

In angiographic procedures, dehydration of the patient is unnecessary and undesirable, especially if large doses of the medium are to be used.

Special precaution is advised in patients with cerebral thrombosis or embolism, primary or metastatic cerebral lesions, subarachnoid hemorrhage, increased intracranial pressure, arterial spasm, transient ischemic attacks and in any condition when the blood-brain barrier is breached or the transit time of the contrast material through the cerebral vasculature is prolonged, since clinical deterioration, convulsions and serious temporary or permanent neurological complications (including aphasia, cortical blindness, etc.) may occur following i.v. or intraarterial injection of relatively large doses of contrast media. Such patients, and patients in clinically unstable or critical condition should undergo examinations with intravascular contrast media only if in the opinion of the physician the expected benefits outweigh the potential risks and the dose should be kept to the absolute minimum.

When a contrast medium is used with a urea washout procedure, the patient should be observed for a few hours to detect signs of undue dehydration caused by increased diuresis induced by both the medium and the urea. Ingestion of water may be required for rehydration.

The results of PBI and RAI uptake studies, which depend on iodine estimation, will not reflect thyroid function for at least 16 days following administration of iodinated urographic media. However, function tests not depending on iodine estimations, e.g., T3 resin uptake or direct thyroxine assays are not affected (for Specific Precautions, see Dosage).

Adverse Reactions: Reactions accompanying the use of contrast media may vary directly with the concentration of the substance, the amount used, the technique used, and the underlying pathology.

Mild and transient adverse effects occur frequently during or shortly after injection. These include nausea, vomiting, flushing, feeling of warmth, metallic taste, tingling of lips, tongue, mouth or extremities, faintness, sweating, headache, dizziness, tremor, chills, fever.

Minor allergic reactions such as sneezing, rhinitis, nasal stuffiness, coughing, lacrimation, urticaria with or without pruritus, other skin eruptions, mucocutaneous edema and allergic glossitis have occurred.

Severe, life-threatening adverse reactions, requiring immediate emergency measures occur in approximately 1 of 2 000 examinations. These include: laryngospasm, bronchospasm, wheezing and dyspnea, status asthmaticus, angioneurotic edema, subglottic edema with signs of airway obstruction, anaphylactic shock; cardiovascular collapse with peripheral vasodilation, hypotension, tachycardia, dyspnea, cyanosis, sweating, pallor, ventricular fibrillation, cardiac arrest; CNS stimulation or depression with agitation, convulsions, coma, death.

The reported fatality rate is approximately 1 of 40 000 urographic examinations.

Rarely, immediate or delayed rigors can occur, sometimes accompanied by hyperpyrexia. Infrequently, “iodism” (salivary gland swelling) from organic iodinated compounds appears two days after exposure and subsides by the 6th day.

Occasionally, transient proteinuria, and rarely, oliguria or anuria may occur. Serious neurological complications such as hemiplegia, aphasia and cortical blindness have occurred.

S.C. extravasation, chiefly because of hypertonicity of the medium, causes transitory stinging. If the volume is small, ill effects are very unlikely. However, if s.c. extravasation is extensive, especially in poorly vascularized areas (i.e., dorsum of the foot or hand) and in the presence of vascular disease, skin slough may occur. Injection of sterile water to dilute or addition of spreading agents to speed absorption have not been successful and may aggravate the condition.

Diffuse petechiae have been described and, in several instances, were traced to contamination of syringes, gloves with talc, or fine lint.

Rarely, disseminated intravascular coagulation has occurred.

Treatment of Adverse Reactions to Contrast Media: Contrast media should be injected 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.

The following are guidelines for the treatment of adverse reactions. This outline is not intended to be a complete manual on the treatment of adverse reactions to contrast media or on cardiopulmonary resuscitation. The physician should refer to the appropriate texts on the subject. Techniques may vary between institutions and individual practitioners.

Minor allergic reactions: diphenhydramine 25 to 50 mg (or other antihistamine) i.v. or i.m. This is contraindicated in epileptics. Outpatients must not drive or go home unaccompanied due to the resulting drowsiness.

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 cardiorespiratory arrest may ensue.

The following measures should be considered:

1. Start emergency therapy immediately and carefully monitor vital signs. 2. Have emergency resuscitation team summoned. Do not leave patient unattended. 3. Ensure patent airway, guard against aspiration. 4. Commence artificial respiration if patient is not breathing. 5. Administer oxygen if necessary. 6. Start external cardiac massage in the event of cardiac arrest. 7. Establish route for i.v. medication by starting infusion of appropriate solution (5% dextrose in water). 8. 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: soluble hydrocortisone 500 to 1 000 mg i.v. for all acute allergic-anaphylactic reactions; 0.2 to 0.4 mL s.c. epinephrine 1:1 000 for severe allergic reactions. In extreme emergency epinephrine 0.1 mL/minute, appropriately diluted, may be given i.v. until desired effect is obtained. Do not exceed 0.4 mL; in case of cardiac arrest epinephrine 0.1 to 0.2 mL, appropriately diluted, may be given intracardially. In the presence of anoxia, epinephrine may cause ventricular fibrillation. Caution is advised in patients on adrenergic b-blockers (see Precautions). In hypotension (carefully monitoring blood pressure): phenylephrine HCl 0.1 to 0.5 mg appropriately diluted slowly i.v. or by slow infusion or levarterenol bitartrate 4 mL of 0.2% solution in 1 000 mL of 5% dextrose by slow drip infusion. Sodium bicarbonate 5%, 50 mL i.v. every 10 minutes as needed to combat post-arrest acidosis. Atropine 0.4 to 0.6 mg i.v. to increase heart rate in sinus bradycardia. May reverse 2nd or 3rd degree block. To control convulsions: diazepam 5 to 10 mg slowly i.v., titrating the dose to the response of the patient, or phenobarbital sodium may be injected i.v. or i.m. at a rate not in excess of 30 to 60 mg/minute. Depending on the patients response, a total dose of 200 to 300 mg may be required. The dose may be repeated in 6 hours if necessary. 9. Defibrillation, administration of antiarrhythmics and additional emergency measures and drugs may be required. 10. Transfer patient to intensive care unit when feasible for further monitoring and treatment.

Dosage And Administration: uf43 Angiocardiography: Specific Precautions: Due to tonicity, viscosity and the volume administered, it has been shown in vivo and in vitro that Hypaque-M 76% may cause a number of transitory hemodynamic changes, especially in right-sided injections. When the medium is ejected from the left ventricle or introduced at the root of the ascending aorta, a brief (3 seconds) hypertensive response is usually induced, followed immediately by a decrease in aortic and peripheral blood pressures below normal levels, lasting for at least 2 minutes. This hypotensive phase may be followed by a 15 to 20 minute period of fluctuating blood pressure. With large volumes, a drop in peripheral arterial and systemic pressures and cardiac output, a rise in pulmonary arterial and right-heart pressures, bradycardia and cardiac arrhythmia result. The effects of these changes on peripheral arterial and pulmonary arterial pressures are thought to be due to mechanical blockage of the pulmonary vascular bed and clumping of red cells.

Clinical doses (up to 1 mL/kg) injected into the vena cava or right-heart outflow tract usually cause an irregular rise in right ventricular blood pressure, a slight increase in pulmonary artery blood pressure, and delayed signs of peripheral hypotension. Special care should be observed in patients with right ventricular failure, pulmonary hypertension, or obliterated pulmonary vascular beds.

Other changes reported clinically include an increase in cardiac output and atrial pressure, a decrease in myocardial contractile force, and at the peak of post injection hypotension, a marked rise in aortic and carotid blood flow, and elevation of central venous pressure. At dosage levels used in angiocardiography, the hematocrit and hemoglobin level may fall about 10 to 15% and serum osmolality may rise 10 to 12%. Blood carbon dioxide, pH and BUN levels may fall. These changes commence immediately after injection, reach a maximum in 2 to 5 minutes, and return to normal values in 10 to 15 minutes. However, after the initial rise, plasma volume may decrease and continue to fall below control levels, even beyond 30 minutes, probably due to diuresis. If repeat injections are made in rapid succession, these changes are likely to be more pronounced.

During administration of large doses of Hypaque-M 76%, continuous monitoring of vital signs is desirable. Caution is advised in the administration of large doses to patients with incipient heart failure because of the possibility of aggravation of the pre-existing condition. Hypotension should be corrected promptly since it may induce serious arrhythmias.

Precaution in Infants: Apnea, bradycardia and other arrhythmias, cerebral effects (lethargy and depression), and a tendency to acidosis are more likely to occur in cyanotic infants. It is desirable that vital signs be monitored on an intensive care basis afterwards to detect delayed adverse effects (arrhythmias, electrolyte and hemodynamic disturbances). Infants are more likely than adults to respond with convulsions, particularly after repeated injections. The amount of the total dosage in young infants is of particular importance.

Dose: Angiocardiography: The individual dose is influenced by the size of the structure to be visualized, the anticipated degree of hemodilution, and valvular competence. Weight is a minor consideration in adults. The size of each individual dose is more important than the total dosage used. When large individual doses are administered, as for contrast in the cardiac chambers and aorta, it has been suggested that 20 minutes be permitted to elapse between each injection to allow for subsidence of hemodynamic disturbances.

Catheter Angiocardiography: Adults: (Media: Hypaque-M 76%): 35 to 50 mL into the right or left chamber, or vena cava. Children: (Media: Hypaque-M 76%) 0.5 to 1 mL/kg for a subject with heart of normal size and intact valves and septum. For patients with stenotic lesions, 0.5 mL/kg is recommended. Doses up to 1.5 mL/kg may be required in cardiomegaly, large volume shunts or where right cardiac injection is also intended to opacify left chambers. Young infants: The individual dose is similar to that described under Children’s dosage. It has been suggested, however, that the total dosage administered should be maintained below 2 mL/kg in infants under 2 months old in any one procedure.

I.V. Angiocardiography: Adults: 70 to 100 mL.

Aortography: Specific Precautions: 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.

The presence of a vigorous, pulsatile flow should be established before using a catheter or pressure injection technique. A small “pilot” dose (about 2 mL) should be administered to locate the exact site of needle or catheter tip to help prevent injection of the main dose into a branch of the aorta or intramurally. In the translumbar technique, severe pain during injection may indicate intramural placement and abdominal or back pain afterwards may indicate hemorrhage from the injection site. Following catheter procedures, gentle pressure hemostasis for 5 to 10 minutes is advised, followed by observation and immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture.

Under conditions of slowed aortic circulation there is an increased likelihood of aortography causing muscle spasm. Occasional serious neurologic complications, including paraplegia, have also been reported in patients with aorto-iliac or even femoral artery bed obstruction, abdominal compression, hypotension, hypertension, spinal anesthesia, injection of vasopressors to increase contrast, and low injection sites (L 2-3). In these patients the concentration, dose, and number of repeat injections of the medium should be maintained at a minimum with appropriate intervals between injections. The position of the patient and catheter tip should be carefully evaluated.

Aortic branches: Great care is necessary to avoid entry of a large concentrated bolus into an aortic branch. Mesenteric necrosis, acute pancreatitis, renal shut down, persistent cortical blindness, aphasia, serious neurologic complications including spinal cord damage and hemiplegia or quadriplegia have been reported following inadvertent injection of a large part of the aortic dose into an aortic branch or arterial trunks providing spinal or cerebral artery branches.

A “pilot” dose should be utilized to establish correct positioning of the catheter tip. Pain or muscle spasm during the injection may require reevaluation of the procedure.

Entry of the large aortic dose into the renal artery can cause, even in the absence of symptoms, albuminuria, cylindruria, hematuria, elevated BUN, acute tubular necrosis and infarction. Also reported are coronary occlusion, hemorrhage from puncture site, retroperitoneal hemorrhage, arterial perforation by catheter or needle, thrombosis, embolism and subintimal injection with aortic dissection by the medium.

Dose: Translumbar or Retrograde (Catheter) Aortography: Adults: (Media: Hypaque-M 60% or Hypaque-M 76%): Single dose of 15 to 35 mL. Note that sufficient time should elapse between each injection to allow for subsidence of hemodynamic disturbances. Children: (Media: Hypaque-M 60%) The single dose is proportionately less according to age and weight, generally not exceeding 0.5 mL/kg.

Arteriography: Cerebral Arteriography: Patients should be selected with care. There is increased risk in patients who have experienced recent cerebral embolism or thrombosis. The diagnostic value of the procedure must be considered in light of the added risk to the patient.

Reactions may vary directly with the concentration of the substance, the amount used, the speed and frequency of injections, and the interval between injections. In subarachnoid hemorrhage, angiography is expected to be hazardous. In migraine, the procedure can be hazardous because of ischemic complications, particularly if performed during or soon after an attack.

Specific Adverse Reactions: With any contrast medium introduced into the cerebral vasculature, neurologic complications, including neuromuscular disorders, seizures, loss of consciousness, hemiplegia, unilateral dysesthesias, visual field defects, language disorders (aphasia), amnesia and respiratory difficulties may occur. Such untoward reactions are, for the most part, temporary, although permanent defects have been reported.

Amaurosis can occur following carotid or especially selective vertebral arteriography. It is almost always transitory (4 to 48 hours) but may be permanent.

Some investigators who are experienced in angiographic procedure emphasize the fact that reactions tend to occur after repeated injections or higher doses of the contrast medium. Other clinicians find that they occur most frequently in elderly patients. It is noteworthy that the procedure itself is attended by technical difficulties regardless of the risk the patient presents.

Dose: Adults: (Media: Hypaque-M 60%): For carotid and vertebral angiography, depending upon the method used, most clinicians employ doses of 5 to 10 mL of Hypaque-M, 60% injected at a rate not exceeding the normal flow in the carotid artery (about 5 mL/second). The dose may be repeated as indicated, however, an increased risk attends each repeat injection. In the retrograde (brachial) method, a single injection of 35 to 50 mL is generally used. Depending upon the vessel injected and the method employed, other dosages may be used as indicated. Children: Use a smaller dose in proportion to weight. Light anesthesia may be required in these procedures.

Selective Renal Arteriography: Be aware that a transitory increase in the resistance of the renal vascular bed may occur with disturbance of renal function and renal damage.

Dose: Adults and children over 14 years of age: (Media: Hypaque-M 60% or Hypaque-M 76%): A single dose of 5 to 8 mL is recommended. The dose may be repeated if indicated. Children under 14 years of age: (Media: Hypaque-M 60%) The dose is proportionate to age.

Selective Coronary Arteriography: Specific Precautions: Coronary arteriography should only be used in carefully selected patients when the value of the anticipated information outweighs the risk involved. Coronary arteriography should be deferred for 4 weeks in patients with acute myocardial infarction. Continuous ECG monitoring for early detection of arrhythmias and adequate facilities for resuscitation and cardioversion are mandatory.

The injection of large volumes of hypertonic solutions into the heart chambers can cause significant hemodynamic disturbances (see also Specific Precautions in Angiocardiography).

Specific Adverse Reactions: Most patients will have transient ECG changes during the procedure. Serious cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and cardiac arrest have occurred. Other adverse effects include hypotension, shock, minor and life-threatening arrhythmias, anginal pain, myocardial infarction and death. These may result from the manipulation of the catheter or from administration of the medium. Dissection of coronary arteries, dislodgment of arteriosclerotic plaques, perforation, hemorrhage, and thrombosis have been reported.

Dose: Adults: (Media: Hypaque-M 76%): 4 to 10 mL injected into a coronary artery. This dose, repeated if necessary, may be administered into each coronary artery. For combined coronary arteriography with left ventriculography, the intraventricular adult dose is 35 to 50 mL injected into the left ventricle, repeated if necessary.

Peripheral Arteriography and Venography: Specific Precautions: Pulsation must be present in the artery to be injected. Extreme caution is advised in considering peripheral angiography in patients suspected of having thromboangiitis obliterans (Buerger’s disease) since any procedure (even insertion of a needle or catheter) may induce a severe arterial or venous spasm. Caution is also advisable in patients with severe ischemia associated with ascending infection. Special care is required when venography is performed in patients with suspected thrombosis, phlebitis, ischemic disease, local infection or a significantly obstructed venous system. In the presence of venous stasis, vein irrigation with normal saline should be considered following the procedure.

Specific Adverse Reactions: Adverse reactions observed during peripheral arteriography may sometimes be due to arterial trauma during the procedure (i.e., insertion of a needle or catheter, subintimal injection, perforation, etc.), as well as to the hypertonic effect of the medium. Reported adverse reactions include soreness in extremities, transient arterial spasm, extravasation, hemorrhage, hematoma formation with tamponade, injury to nerves in close proximity to artery, thrombosis, dissecting aneurysm, arteriovenous fistula (e.g., with accidental perforation of femoral artery and vein during the needling), and transient leg pain from contraction of calf muscles in femoral arteriography. Transient hypotension has been reported after intraarterial (especially brachial) injection of the medium. Also, brachial plexus injury has been reported with axillary artery injections.

Following venography especially in the presence of venous stasis, inflammatory changes, thrombosis and gangrene may occur. Thrombosis is rare if the vein is irrigated following the injection.

Dose: Peripheral Arteriography: Adults: (Media: Hypaque-M 60% or Hypaque-M 76%): For visualization of an entire extremity, diagnostic arteriograms may be obtained with 25 to 35 mL of Hypaque-M 60% introduced into the larger peripheral arteries by percutaneous needle or catheter methods. For visualization of upper or lower half of extremity only, 10 to 20 mL may be used.

Sometimes Hypaque-M 76% is preferred over less concentrated media in selected cases of femoral and brachio-axillary arteriography. The usual dose of these more concentrated media is 10 to 25 mL, which may be repeated.

Peripheral Venography: Adults: (Media: Hypaque-M 60%): For visualization of an upper extremity 10 to 20 mL is suggested. For visualization of a lower extremity 20 to 40 mL is usually sufficient.

For visualization of the great saphenous vein, the upper femoral or the iliac veins, the medium is generally injected into the great saphenous vein in the lower leg at a rate of 1 mL/second. When demonstration of the small saphenous vein, the popliteal vein, or the lower femoral vein is necessary, injection is performed in a superficial vein of the outer aspect of the foot. The axillary and subclavian veins are best delineated by introducing the medium into the median basilic vein at the rate of 1 mL/second and exposing films during the process of injection.

Intraosseous Venography: Adults: (Media: Hypaque sodium 50% is recommended for injection directly into the bone marrow in the study of venous circulation of the bone and extraosseous tissue in the immediate drainage area). After aspiration of 4 mL of marrow, 10 to 20 mL of the medium are injected.

A general anesthetic is sometimes necessary since the method is painful. Occasionally, extravasation of the contrast medium from the needle into the soft tissue may occur.

Arthrography: Specific Precautions: A strict, aseptic technique is required to avoid introducing infection. Arthrography should not be performed when there is infection in or near the joint.

Specific Adverse Reactions: Injection of Hypaque-M 60% into the joint usually causes immediate but transient discomfort. However, delayed, severe or persistent pain may occur occasionally. Severe pain often results from undue use of pressure or the injection of large volumes. Joint swelling after injection is rare. Effusion, occasionally requiring aspiration, can occur especially in patients with rheumatoid arthritis.

Dose: Adults: (Media: Hypaque-M 60%): The procedure is usually performed with analgesic premedication and under local anesthesia. The amount of medium injected depends on the capacity of the joint.

The following approximate volumes have been used in normal adult joints: knee, shoulder, hip: 5 to 15 mL; temporomandibular: 0.5 mL; other: 1 to 4 mL.

The damaged joint may require doses exceeding those for normal joints. As much fluid as possible should first be aspirated from the joint; then, the medium should be injected gently to avoid overdistention of the joint capsule. Passive manipulation is sometimes used to disperse the medium in the joint. Sometimes a 1 or 2 mL test dose is injected; immediate pain may indicate extravasation or extracapsular injection. A single injection is usually adequate for multiple exposures. Contrast is good during the first 10 minutes after injection, adequate at 10 to 15 minutes, and begins to fade at 15 to 25 minutes.

Double contrast arthrography, using a mixture of the medium and air, has been employed.

Operative, Postoperative (T tube) Cholangiography: Specific Precautions: Injection should be made slowly to prevent extravasation of the medium into the peritoneal cavity, and to minimize reflux flow into the pancreatic duct which may result in pancreatic irritation.

Specific Adverse Reactions: Adverse reactions may often be attributed to injection pressure or excessive volume of the medium, resulting in overdistention. Such pressure may produce a sensation of epigastric fullness, followed by moderate pain in the back or right upper abdominal quadrant, which will subside when injection is stopped.

Some of the medium may enter the pancreatic duct and cause pancreatic irritation with a transient serum amylase elevation 6 to 18 hours later. Occasionally, nausea, vomiting, fever, and tachycardia have been observed. Pancholangitis resulting in liver abscess or septicemia has been reported.

Dose: Adults: (Media: Hypaque sodium 50% or Hypaque-M 60%):

Operative Cholangiography: As soon as the gallbladder and ducts have been exposed surgically, if no resistance is encountered, 10 to 15 mL of a 25 to 50 or 60% solution is injected into the cystic duct or common bile duct, as indicated, or the medium may be injected directly into the gallbladder after aspiration of its contents. Before closure of the abdomen, postexploratory or completion T tube cholangiography may also be performed after exploration of the common bile duct. The usual adult dose is 10 to 15 mL.

Postoperative (T tube) Cholangiography: Delayed cholangiograms are usually made from the fifth to the tenth postoperative day prior to removal of the T tube. Ten to 15 mL of either Hypaque sodium 50% or Hypaque-M 60% is injected into the T tube, preferably under fluoroscopic control.

In the case of a dilated ductal tract, a larger volume of radiopaque medium may be required for complete filling and visualization.

Hysterosalpingography: Specific Precautions: In patients with carcinoma or in those in whom the condition is suspected, caution should be exercised to avoid possible spread of the lesion by the procedure.

The procedure should not be performed during the menstrual period or when menstrual flow is imminent, nor should it be performed when infection is present in any portion of the genital tract, including the external genitalia. The procedure must not be performed in pregnant women or in those in whom pregnancy is suspected. Its use is not advised for 6 months after termination of pregnancy or 30 days after cervical conization or endometrial curettage.

Specific Adverse Reactions: Cramping may occur during the injection and sometimes mild lower abdominal pain may be present for an hour or two afterwards. Even when the medium gains entrance into venous or lymphatic channels, systemic effects are rare. Generalized urticaria or slight transient hyperpyrexia, however, have been reported.

Dose: Adults: (Media: Hypaque sodium 50% or Hypaque-M 60%) Approximately 4 mL of either media will fill the uterine cavity and an additional 3 to 4 mL will fill the oviducts in normal subjects. A larger volume may be required in some disease states. Slow injection through a cannula is advisable, preferably under fluoroscopic control.

It is preferable to perform the procedure approximately 10 days after the patient’s menstrual period. The patient should empty the bladder before the examination. An enema and vaginal douche are not essential but may be given 1 hour before the study.

Urography: Excretory Urography: (Media: Hypaque sodium 50%, Hypaque-M 60% or Hypaque-M 76%):

Specific Precautions for Excretory Urography and Nephrotomography: Some clinicians consider multiple myeloma a contraindication to the use of contrast media because of the great possibility of producing transient to fatal renal failure. Others believe that the risk of causing anuria is definite but small. If contrast media are used in the presence of multiple myeloma, dehydration should be avoided since it favors protein precipitation in renal tubules.

Due to the transitory increase in circulatory osmotic load, use with caution in patients with congestive heart failure. Such patients should be observed for several hours to detect delayed hemodynamic disturbances.

Although moderate azotemia is not considered a contraindication, care is required in patients with significant renal failure. Preparatory dehydration may be dangerous, and urinary output should be observed for 1 to 2 days in these patients.

Preparatory dehydration is not necessary and may be dangerous in infants, young children, the elderly and azotemic patients (especially those with polyuria, oliguria, diabetes, advanced vascular disease, or pre-existing dehydration). The undesirable dehydration in these patients may be accentuated by the osmotic diuretic action of the medium. Dehydration will not improve contrast quality in patients with substantial renal insufficiencies and will increase risk of contrast induced renal damage; dehydration is therefore, contraindicated.

When either of these media is used with a urea washout procedure, the patient should also be observed for a few hours to detect signs of undue dehydration caused by increased diuresis induced by both the medium and the urea. Fluid replacement may be required for rehydration.

Dose: Adults: (Media: Hypaque sodium 50% or Hypaque-M 60%): 30 to 60 mL injected i.v. in 1 to 3 minutes. Children: 0 to 6 months, 5 mL; 6 to 12 months, 6 to 8 mL; 1 to 2 years, 8 to 10 mL; 2 to 5 years, 10 to 12 mL; 5 to 7 years, 12 to 15 mL; 7 to 11 years, 15 to 18 mL; and 11 to 15 years, 18 to 20 mL given i.v. over 1 to 3 minutes.

Adults: (Media: Hypaque-M 76%): 25 to 50 mL injected via the antecubital vein in 1 to 3 minutes. Children and Infants: under 6 months, 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.

Although diagnostic urograms are often seen in patients who have had no preliminary preparation for urography, a laxative may be taken at bedtime to eliminate gas from the intestine, unless contraindicated.

Early minute sequence films may be taken if desired as, for example, in investigating hypertension. Additionally, the urea washout technique may be employed preferably after the 30-minute film.

Nephrotomography: When the prime purpose of the examination is to intensify and prolong the nephrographic effect of the renal parenchyma, especially with tomography, the contrast medium should be injected rapidly i.v.

Drip Infusion Pyelography: (Media: Hypaque-M 18%, Hypaque-M 30%, Hypaque sodium 50% and Hypaque-M 60%):

Specific Precautions: In older patients or those with cardiac disease the rate of infusion should be slower. The drip infusion technique is useful in carefully selected patients but is not considered appropriate for routine pyelography. This technique should not be used in patients with frank or incipient congestive heart failure, or in oliguric or anuric patients.

Dose: Adults: (Media: Hypaque-M 18%): 3 to 7 mL/kg not to exceed 300 mL. (Media: Hypaque-M 30%): 2 to 4 mL/kg not to exceed 300 mL. (Media: Hypaque sodium 50%, Hypaque-M 60%): 1 to 2 mL/kg not exceeding 150 mL mixed with an equal volume of 5% dextrose in water. Children: reduce according to weight and age.

Administer by rapid i.v. drip through an 18 gauge needle. Infusion usually takes 6 to 10 minutes, for optimal pyelogram at 20 and 30 minutes, and for optimal cystogram at 30 to 40 minutes.

When employing drip infusion pyelography, good quality voiding cystograms and urethrograms can also be obtained. To achieve the hydration, diuresis and complete filling of the urinary tract, the reasons for the technique’s advantages, large volumes of contrast medium and fluid are required. The technique is especially useful in the presence of slight to moderate azotemia where ordinary techniques often prove inadequate. Preparatory dehydration is not recommended; diuresis is better if the patient is not dehydrated.

Retrograde Cystography and Voiding Urethrocystography: Dose: Adults: (Media: Hypaque-M 18%, Hypaque-M 30% and Hypaque-M 60%): The usual concentration used for these procedures is 30%, however, some physicians may wish to use less concentrated solutions such as Hypaque-M 18%. Should the 60% solution be used it is necessary to dilute the media with appropriate volumes of sterile water or saline before use.

After the bladder is emptied the medium is gently instilled without force, preferably under fluoroscopic control often beyond the first desire to micturate, but not beyond the point of urgency or mild discomfort. The volume required to fill the bladder to slightly less than capacity may vary from patient to patient. The volume required in adults may vary from 250 to 500 mL with an average capacity of 300 mL. Bladder capacity at birth is 20 to 50 mL. In children 3 to 5 years old, bladder capacity is 150 to 180 mL. In children older than 8 years, it is in the low adult range.

In disease, bladder capacity in adults may vary from 50 mL in a hypertonic reflex bladder to over 1 000 mL in an atonic or sensory paralytic bladder or chronic lower urinary tract obstruction.

Administration of the solution through a catheter may be by gravity flow or by syringe at the discretion of the physician. For gravity flow infusion, it should be noted that the specially designed Hypaque-M 18% and Hypaque-M 30% flask closures may be removed to allow a screw type adaptor to be used to connect the infusion set.

Retrograde Pyelography: (Media: Hypaque-M 18%, Hypaque-M 30%, Hypaque sodium 50% or Hypaque-M 60%):

Specific Precautions: Retrograde pyelography should not be performed in patients with a known active infection process or obstruction of the urinary tract.

Because of the possibility of inducing temporary suppression of urine, it is wise to avoid repetition of retrograde pyelography within 48 hours in patients with reduced renal function.

A physical incompatibility (white precipitate) following the concomitant use of a surgical lubricant containing sodium alginate, has been reported. The use of a surgical lubricant of this type, in retrograde pyelography, is therefore considered to be undesirable.

Costovertebral angle tenderness, elevated temperature and flank pain have been reported in a few patients following use of diatrizoate sodium and diatrizoate meglumine for retrograde pyelography, as have nausea, sweating and flushing. Irritation of the urinary tract mucosa attributable to the contrast agent itself may occur. The technique of retrograde pyelography may be painful, and may initiate pelvic, caliceal or ureteral spasms with consequent renal colic. A few cases of reflex anuria have been reported following retrograde pyelography.

Dose: 30% solution of Hypaque meglumine has been found to be well tolerated when used for retrograde pyelography. Alternatively Hypaque-M 18% or Hypaque-M 60% diluted to a 20 to 30% solution with sterile distilled water, or Hypaque sodium 50% likewise diluted to a 20% solution may be used. The dosage is variable according to renal pelvic capacity. In general, the following volumes may apply for unilateral study.

Adults: 6 to 10 mL. Children over 5 years: 4.0 to 5.0 mL. Children under 5 years: 1.5 to 3.0 mL. Administration by gravity from an elevated buret is preferable. Otherwise injection should be made slowly, without force, and should be stopped at the first sign of discomfort.

I.V. Contrast Enhancement in Computerized Tomography: The entire range of Hypaque media may be useful in the image enhancement of certain intracranial lesions of various etiologies, such as some tumors, vascular lesions, and sites of active infection.

Some cerebral infarctions of recent onset may be better visualized with contrast enhancement, while others are obscured if contrast media are used (see Precautions).

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

The use of contrast enhancement in whole body CT scanning for the demonstration of various organs has been reported. This procedure is still in its early stages of development and requires considerable, careful individualization of technique and familiarity with all factors involved.

Specific Precautions: With the higher doses used for CT in patients with brain metastases and various other cerebral or cerebrovascular lesions, the incidence of seizures and serious neurological complications can be high (1 to 10%). In these patients, the risk/benefit ratio has to be carefully evaluated and prophylactic use of a small (parenteral) dose of diazepam should be considered immediately before injection of the contrast material.

It should also be kept in mind that diabetics with existing renal impairment may develop acute renal failure when administered a large intravenous dose of radiopaque media required for contrast enhancement in computerized tomographic scanning.

Since contrast media may obscure low density lesions, producing false negative results, it is generally recommended that a non-enhanced scan be obtained prior to the contrast enhanced scan, and it should be ensured that the patient has received no injection of contrast media at least 24 hours prior to the plain CT scan.

Dose: Adults: (Media: Hypaque-M 30%, Hypaque sodium 50%, Hypaque-M 60% or Hypaque-M 76%):

For contrast scanning enhancement in computerized tomography the suggested dose of Hypaque-M 30% is 1 to 4 mL/kg but not exceeding 300 mL, by i.v. drip over a period of 10 minutes or longer. Scanning may be performed during administration and/or immediately afterwards.

The suggested i.v. dose range for either Hypaque sodium 50% or Hypaque-M 60% is 50 to 150 mL and, for Hypaque-M 76% 50 to 110 mL. Scanning may be performed immediately after completion of administration. Children: should be proportionately less depending on age and weight.

I.V. Digital Subtraction Arteriography: Arteriograms of diagnostic quality can be obtained following the i.v. administration of Hypaque-M, 76% employing digital subtraction and computer imaging enhancement equipment. The i.v. route of administration using these techniques has the advantage of being less invasive than the corresponding intraarterial catheter placement of the medium. The dose is administered into a peripheral vein or by using an i.v. catheter threaded proximally into larger tributaries, the femoral vein or vena cava usually by mechanical injection although sometimes by rapid manual injection. The technique has been used to visualize the aorta and most of its larger branches including carotid, cerebral, vertebral, renal, celiac, mesenterics, and the major peripheral vessels of the limbs.

Specific Precautions: The risks associated with i.v. DSA include intramural injections, rupture or dissection of venous structures with extravasation into the tissues of extremities or the mediastinum. 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 this potential. With high pressure injection; however, the catheter tip, initially placed in a large venous structure, may still recoil into a small tributary causing rupture of a small vein with extravasation into neighboring tissues.

Dose: (Medium: Hypaque-M 76%): The usual dose of Hypaque-M 76% per injection by the i.v. digital technique is 30 to 60 mL with a range of 0.5 to 1 mL/kg administered as a bolus at a rate of 7.5 to 12.0 mL/second and up to 30 mL/second (if injection is made into a large vein e.g., vena cava) using a pressure injector. The dose and rate of injection will depend primarily on the type of equipment and technique used, with first exposures made on calculated circulation time.

Availability And Storage: Hypaque-M 18%: Each mL of injectable solution contains: diatrizoate meglumine 18% in water for injection (85 mg/mL bound iodine). Flasks of 500 mL, boxes of 6.

Hypaque-M 30%: Each mL of injectable solution contains: diatrizoate meglumine 30% in water for injection (141 mg/mL bound iodine). Vials of 15 mL, boxes of 10; bottles of 300 mL, boxes of 6.

Hypaque Sodium 50%: Each mL of injectable solution contains: diatrizoate sodium 50% in water for injection (300 mg/mL bound iodine). Nonmedicinal ingredients: sodium carbonate, sodium hydroxide or hydrochloric acid. Vials of 50 mL, boxes of 25.

Hypaque-M 60%: Each mL of injectable solution contains: diatrizoate meglumine 60% in water for injection (283 mg/mL bound iodine. Vials of 15 mL, boxes of 10; vials of 30 and 50 mL, boxes of 25; vials of 100 mL, boxes of 10; 150 mL fill in a 300 mL flask, boxes of 6.

Hypaque-M 76%: Each mL of injectable solution contains: diatrizoate meglumine 66% and diatrizoate sodium 10% in water for injection (370 mg/mL bound iodine). Nonmedicinal ingredients: sodium carbonate, sodium hydroxide or hydrochloric acid. Vials of 100 and 200 mL, boxes of 10.

These solutions are stabilized with edetate calcium disodium. Protect from light. Unused portions must be discarded.

HYPAQUE® PARENTERAL Nycomed Imaging A.S. Diatrizoate Sodium – Diatrizoate Meglumine Contrast Media

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