Ultravist (Iopromide)

ULTRAVIST®

Berlex Canada

Iopromide

Nonionic Iodinated Radiographic Contrast Medium

Action And Clinical Pharmacology: Iopromide is a nonionic iodinated radiographic contrast medium which is available in 3 stable, ready-to-use solutions of different concentrations. Following intravascular injection, iopromide provides radiographic opacification of the vasculature and extracellular space allowing diagnostic assessment of the limbs and internal organs. For example, after i.v. injection, opacification of the renal parenchyma begins within 1 minute. Excretion of the contrast agent becomes apparent in 1 to 3 minutes with optimal contrast in the calyces and collecting system occurring between 5 and 15 minutes. In nephropathic conditions, particularly when excretory capacity has been altered, the excretion rate varies unpredictably and opacification may be delayed for several hours after injection.

Pharmacokinetics: The pharmacokinetics of iopromide are similar to those of other ionic and nonionic contrast media. Immediately following intravascular injection, iopromide reaches peak plasma concentrations and is then rapidly distributed throughout the extracellular fluid compartment. It is excreted unchanged by the kidneys mainly by glomerular filtration. About 90% of the injected dose is excreted unchanged by the kidneys during the first 24 hours with peak urine concentrations occurring in the first hour. In healthy volunteers, elimination half-life is approximately 2 hours and renal clearance is 93±14 mL/min.

Iopromide does not cross the intact blood-brain barrier. It displays little tendency to bind to serum or plasma proteins, and there is no evidence of metabolism, deiodination or biotransformation in rats and humans.

In double blind clinical trials iopromide has shown diagnostic efficacy comparable to other nonionic and ionic radiographic contrast agents when studied in excretory urography (vs iopamidol, ioxithalamate, and ioxaglate); renal arteriography (vs amidotrizoate); cerebral arteriography (vs iopamidol); peripheral arteriography of the leg (vs ioxaglate); phlebography of the pelvis and leg (vs ioglicinate); coronary arteriography and ventriculography (vs iohexol and diatrizoate and amidotrizoate); and in computed tomography (vs ioglicinate). In these studies, iopromide has demonstrated properties comparable to other nonionic compounds with respect to neuroangiographic and cardiovascular tolerance and has demonstrated superiority over ionic agents particularly in causing less pain and warmth following injection.

The influence of iopromide on clotting, fibrinolysis, complement activation and erythrocyte morphology has been minimal (see Warnings).

Indications And Clinical Uses: For intravascular use to provide diagnostic information in a number of radiographic contrast procedures. It is also indicated for the visualization of various body cavities, e.g., arthrography and hysterosalpingography.

Ultravist 240: computed tomography (CT), peripheral arteriography (bifemoral pelvis/leg), phlebography of the extremities, cerebral arteriography, arthrography and hysterosalpingography.

Ultravist 300: computed tomography (CT), excretory urography, pediatric excretory urography, renal arteriography, peripheral arteriography (bifemoral pelvis/leg), cerebral arteriography, phlebography of the extremities and arthrography.

Ultravist 370: computed tomography (CT), excretory urography, coronary arteriography (including PTCA), with or without left ventriculography, pediatric angiocardiography and arthrography.

Contra-Indications: Iopromide is not indicated for use in myelography, cerebral ventriculography and cisternography.

Iopromide should not be administered to patients with known hypersensitivity to the drug, anuria or severe oliguria, clinically significant impairment of both renal and hepatic function or with manifest hyperthyroidism.

Hysterosalpingography must not be performed during pregnancy or in the presence of acute inflammatory process in the pelvic cavity.

Manufacturers’ Warnings In Clinical States: Nonionic iodinated contrast media inhibit blood coagulation less than ionic contrast media. Clotting has been reported in vivo and in vitro when blood remains in contact with syringes, catheters or tubes containing nonionic contrast media.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both nonionic and ionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, number of injections, catheter and syringe material, underlying disease state, and concomitant medication may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended including close attention to keeping guidewires, catheters and all angiographic equipment free of blood; use of manifold systems and/or 3-way stopcocks; frequent catheter flushing with heparinized saline solution; and minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting. Nonionic contrast media are not suitable flush solutions.

Iopromide is related chemically to other tri-iodinated benzoic acid derivatives which have been associated with serious and fatal reactions. Therefore, clear indication and evaluation of the benefit/risk ratio for every patient should precede each examination with contrast media. Also, it is of utmost importance that adequate facilities and appropriate personnel be readily available and a course of action be planned in advance for the immediate treatment of any serious untoward reaction. Diagnostic procedures utilizing a radiopaque contrast agent should be conducted only by a physician with the requisite training and a thorough knowledge of the particular procedure to be performed. The physician must also be thoroughly familiar with the emergency treatment of all adverse effects.

Precautions: Before any contrast medium is injected, the patient should be questioned for a history of allergy (i.e., shellfish), sensitivity to iodine or to radiographic media and bronchial asthma, as the reported incidence of adverse reactions to contrast media are higher in patients with these conditions. Most adverse reactions to contrast agents appear within 30 minutes after the start of their injection, but a delayed reaction may occur. Premedication with corticoids may be considered in order to avoid or minimize possible allergic adverse reactions. However, antihistamines or corticosteroids should not be mixed in the same syringe with any contrast medium because of potential chemical incompatibility.

Caution is advised in patients with cardiac and circulatory insufficiency, hypertension, pheochromocytoma, cerebral arteriosclerosis, latent hyperthyroidism, severe impairment of hepatic or renal function, pulmonary emphysema, very poor general condition, diabetes with renal dysfunction requiring treatment, cerebral arterial spasm, bland nodular goiter and multiple myeloma, homocystinuria and other paraproteinemias and renal transplant.

An i.v. test dose of 0.5 to 1 mL of the contrast agent before injection of the full dose has been employed to predict severe or fatal reactions. These provocative tests may themselves cause severe, even fatal, reactions and are unreliable in predicting patients at special risk.

Renal function should be assessed before injecting iopromide since the drug is excreted largely by the kidney and may accumulate in the absence of normal renal function.

In patients with myeloma, diabetes mellitus, polyuria, oliguria or gout and in newborns, small children and in patients in poor general health, fluid intake should not be restricted even before the use of low-osmolar contrast media.

Assessment of thyroid function may be obscured for several weeks following the administration of iopromide.

Reports of thyroid storm after the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule suggest that this additional risk be evaluated in appropriate patients prior to the use of iopromide.

Administration of iopromide should be postponed in patients who have to undergo oral cholecystography.

Premedication with an blocker is recommended in patients having a pheochromocytoma because of the risk of hypertensive crises.

In patients with decreased renal function, 48 hours should elapse between 2 examinations. Special attention should be paid to patients with increased intracranial pressure, disrupted blood-brain barrier (tumor, meta supra-arachnoid hemorrhage, transient ischemic attack, cerebral thrombosis, ischemia) or any condition whereby the presence of contrast material in the vessels is prolonged. Serious neurological sequelae (stroke, aphasia, cortical blindness, convulsions) may occur following intra-arterial or intravascular infusion of contrast media. The benefit/risk ratio of the procedure has to be evaluated and the amount of contrast medium necessary to obtain a diagnostic picture kept to a minimum.

Iopromide should be administered intravascularly with caution to patients with known convulsive disorders.

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

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

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

Intravascular Use: Iopromide produces less circulatory osmotic load than ionic contrast agents; however, it can produce significant hemodynamic disturbances especially in patients with reduced cardiac reserve. The volume of injection should be minimized and the patient’s vital signs should be continuously monitored for several hours following the procedure to detect delayed hemodynamic disturbances. Hypotension should be corrected promptly as it can lead to serious arrhythmias. Special care regarding dosage should be observed in patients with right ventricular failure, pulmonary emphysema, pulmonary hypertension or a stenotic pulmonary vascular bed because serious hemodynamic changes may occur in these individuals.

Mesenteric necrosis, acute pancreatitis, renal shutdown and serious neurologic complications including spinal cord damage and hemiplegia have been reported following inadvertent injection of a large part of the aortic dose of an ionic contrast medium directly into an aortic branch or arterial trunk.

There are inherent dangers associated with catheter manipulation, contrast medium injection and angiographic procedures. Dislodging plaques or damaging, dissecting or perforating a vessel wall or causing injury to neighboring organs can lead to embolization. The possibility of these occurrences should be borne in mind during the procedure. Therefore, fluoroscope guidance is to be used to place the catheter.

Pulsation must be present in the artery to be injected. Extreme caution is therefore advised for the patients considered for angiography, particularly those suspected of having thromboangiitis obliterans (Buerger’s disease), since vascular procedures may induce severe arterial spasm.

In intra-arterial administration, caution is advisable in patients with suspected thrombosis, ischemic disease, local infection, a totally obstructed vascular system or severe ischemia associated with ascending infection or advanced arteriosclerosis. With the use of conventional ionic contrast media, occasional serious neurologic complications, including paraplegia, have been reported in patients with aorto-iliac or femoral artery obstruction, abdominal compression, hypotension or hypertension and following the injection of vasopressors.

When large individual doses are administered, an appropriate time interval should elapse between injections to allow any hemodynamic disturbances to subside. Hemodynamic changes are likely to be more pronounced following repeated injections given in rapid succession.

Following arterial catheterization and injection, pressure hemostasis is advisable with immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture.

Drug Interactions: Diabetic nephropathy may predispose to renal impairment following intravascular contrast media administration. Since biguanides may precipitate lactic acidosis in patients with renal impairment, they should be discontinued 48 hours prior to the contrast medium examination and reinstated only after adequate renal function has been regained.

The prevalence of delayed reactions (e.g., fever, rash, flu-like symptoms, joint pain and pruritus) to contrast media is higher in patients who received interleukins.

Treatment with b-blockers or general anesthesia increases the incidence of adverse reactions, particularly in people with asthma.

Adverse Reactions: Adverse reactions reported with iopromide have generally been less frequent than with some commonly used iodinated compounds. However, all side effects and toxicity associated with this class of compound are possible during the use of iopromide.

Careful patient observation for adverse reactions is recommended in the use of all contrast media. Reactions accompanying use may vary with the dosage, the technique of administration, the procedure and the underlying condition of the patient. Adverse reactions generally occur within 30 minutes after injection but some may be delayed or of long-lasting nature. These reactions include: laryngospasm, bronchospasm, wheezing, dyspnea, and status asthmaticus; angioedema, subglottic edema and signs of airway obstruction; anaphylactic shock; cardiovascular collapse with peripheral vasodilation, hypotension, tachycardia, dyspnea, cyanosis, sweating, pallor, ventricular fibrillation and cardiac arrest; CNS stimulation or depression with agitation, convulsions, coma and death. Severe life-threatening reactions to iodinated contrast media require appropriate emergency measures.

Many life-threatening reactions begin with only mild symptoms such as nasal congestion, sneezing, watery eyes, skin erythema, or a vague sense of discomfort. It is therefore extremely important that all patients be watched closely until their symptoms have abated. The symptoms, which occur regardless of the amount of contrast medium administered and the mode of administration, can indicate incipient shock. Administration of the contrast medium must then be interrupted immediately and, if necessary, specific therapy initiated i.v. In the case of i.v. administration use of a flexible indwelling catheter is therefore recommended.

The most common adverse event following i.v. injection of iopromide is a sensation of warmth and/or pain especially in peripheral arteriography. This is generally less severe with iopromide than with ionic contrast media.

Cardiovascular: hypotension (0.4%); tachycardia (0.3%); unconsciousness/collapse (0.3%); hypertension (0.1%); bradycardia (0.1%); extrasystoles (0.1%); left bundle branch heart block (0.1%); anginal symptoms (0.1%); arrhythmia (0.1%).

CNS: restlessness/anxiety (0.3%); paresthesia (0.2%): arm or face; vertigo (0.1%); blurred vision (0.1%).

Others: taste sensation (0.4%); headache (0.3%); knee swelling/pain (0.1%); shoulder pain (0.1%); venous pressure (0.1%); numbness (0.1%); shivers (0.1%); popliteal region tension (0.1%); pressure over eyes (0.1%); vegetative dystonia (0.1%); sore throat (0.1%); septicemia (0.1%); dizziness (0.1%).

The following additional adverse reactions have been reported postmarketing: allergic reactions, agitation, amnesia, anaphylactic and anaphylactoid reactions, blood pressure disturbances, cardiac arrest, cardiac rhythm or function disturbances, chills, confusion, conjunctivitis, convulsion, heart rate disturbances, cyanosis, dyspnea, fever, hearing disturbances, hypertonia, increased sweating, laryngeal spasm or edema, malaise, paralysis, paresis, photophobia, pruritus, renal impairment or failure, respiratory arrest, respiratory distress, rhinitis, shock, speech disturbances, Stevens-Johnson syndrome, thrombophlebitis, transient local pain and edema or local inflammation sometimes leading to tissue necrosis in the case of inadvertent paravascular administration, transient disturbances in respiratory rate, tremor, vasodilatation, venous thrombosis, vision disturbances.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: An overdose of iopromide should be treated by support of vital functions and prompt institution of symptomatic therapy.

Dosage And Administration: General: Solutions of iopromide, like those of other radiopaque contrast agents, should be at or close to body temperature when injected. As with other sterile parenteral products, iopromide should not be withdrawn from the vial except immediately prior to use (see Warnings). Iopromide should not be mixed with other drugs. Any unused portion should be discarded.

Vials containing contrast medium solutions are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once. The use of a cannula or needle with a long tip and a maximum diameter of 18 G is recommended for piercing the stopper and drawing up the contrast medium.

Patients should be in a fasted state (when this can be safely achieved) and adequately hydrated on the day of the examination. Disturbances of water and electrolyte balance must be corrected prior to the administration of iopromide.

In the case of abdominal angiography and urography, the diagnostic yield is increased if the bowels are empty of fecal matter and gas. It may be necessary to administer an enema or laxative in the evening prior to examination, provided purging of the bowels is not contraindicated.

However, in infants and young children, prolonged fasting, restriction of fluids and the administration of a laxative before the examination are contraindicated.

Experience shows that pronounced states of excitement, anxiety and pain can be the cause of side effects or intensified contrast medium-related reactions. They can be counteracted by calm management of the patients and the use of suitable drugs.

Intravascular administration of contrast media should, if possible, be done with the patient lying down. After the administration, the patient should be kept under observation for at least 30 minutes, since experience shows that the majority of all severe incidents occur within this time.

The recommended dosages of iopromide should not be exceeded. The volume of each individual injection is a more important consideration than the total dose used. When large individual volumes are administered, as in cardiac ventriculography, sufficient time should be permitted to elapse between injections to allow any hemodynamic disturbances to subside.

Excretory Urography: Adults: Recommended doses: Ultravist 300: 40 to 70 mL. Ultravist 370: 30 to 55 mL.

The dose may be adjusted in special indications (e.g., obese patients, impaired renal function), if necessary.

Children: The physiologically poor concentrating ability of the immature nephron necessitates the administration of relatively high doses of contrast medium in children.

The dose of Ultravist 300 should not exceed: Neonates: 4 mL/kg of body weight equivalent to 1.2 g I/kg. Infants: 3 mL/kg of body weight equivalent to about 1 g I/kg. Small Children: 1.5 mL/kg of body weight equivalent to about 0.5 g I/kg.

Computerized Tomography (CT): Cranial CT: The following doses are recommended and should not be exceeded: Ultravist 240: 105 to 175 mL. Ultravist 300: 70 to 140 mL. Ultravist 370: 70 to 105 mL.

Whole-body CT: In whole-body computerized tomography, the necessary doses of iopromide and the rates of administration depend on the organs under investigation, the diagnostic problem and, in particular, the different scan and image reconstruction times of the scanner. An infusion is preferred for slow scanners and a bolus injection, for fast scanners.

Recommended doses: Ultravist 240: 125 to 180 mL. Ultravist 300: 100 to 150 mL. Ultravist 370: 80 to 120 mL.

Angiography: The dosage depends on the age, weight, cardiac output and general condition of the patient, the clinical problem, examination technique, and the nature and volume of the vascular region to be investigated.

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

Hysterosalpingography: Hysterosalpingographic contrast media should be instilled into the uterine cavity under controlled pressure with fluoroscopic monitoring of the dose to avoid excessive injection pressures and doses.

Usual recommended single dose of Ultravist 240 is 10 to 25 mL.

Availability And Storage: Ultravist 240 (iopromide 49.9%): Each mL of sterile, colorless to pale yellow aqueous solution contains: iopromide 499 mg equivalent to 240 mg of organically bound iodine. Nonmedicinal ingredients: calcium disodium edetate (EDTA), hydrochloric acid and tromethamine. Preservative-free. pH has been adjusted to 6.5 to 8 with hydrochloric acid. Vials of 50 and 200 mL.

Ultravist 300 (iopromide 62.3%): Each mL of sterile, colorless to pale yellow aqueous solution contains: iopromide 623 mg equivalent to 300 mg of organically bound iodine. Nonmedicinal ingredients: calcium disodium edetate (EDTA), hydrochloric acid and tromethamine. Preservative-free. pH has been adjusted to 6.5 to 8 with hydrochloric acid. Vials of 50, 100 and 150 mL.

Ultravist 370 (iopromide 76.9%): Each mL of sterile, colorless to pale yellow aqueous solution contains: iopromide 769 mg equivalent to 370 mg of organically bound iodine. Nonmedicinal ingredients: calcium disodium edetate (EDTA), hydrochloric acid and tromethamine. Preservative-free. pH has been adjusted to 6.5 to 8 with hydrochloric acid. Vials of 50, 100 and 200 mL.

Store between 15 and 30°C and protect from light. It should be visually inspected and used only if clear and within the normal colorless to pale yellow range. Discard unused portions.

ULTRAVIST® Berlex Canada Iopromide Nonionic Iodinated Radiographic Contrast Medium

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