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OMNIPAQUE®
Nycomed Imaging A.S.
Iohexol
Nonionic Radiographic Contrast Medium
 
Action And Clinical Pharmacology: Immediately following rapid intravascular injection, iohexol reaches peak plasma concentration and is then rapidly distributed throughout the extracellular fluid compartment. Iohexol does not normally cross the blood-brain barrier to any significant extent. It is excreted unchanged by the kidneys, mainly by glomerular filtration; tubular secretion plays a minor role, and a very small quantity (1 to 2%) is excreted via the bile. About 80 to 90% of the injected dose is excreted in the first 24 hours, with peak urine concentrations occurring in the first hour.

Pharmacokinetic studies of iohexol following i.v. injection in healthy male volunteers showed, using a 3 compartment open model, that its distribution half-life (alpha phase) is 22 minutes, excretion half-life (beta phase) 2.1 hours, and first-order terminal elimination half-life (gamma phase) 12.6 hours. The volume of distribution of the central compartment is 165-270 mL/kg, the mean renal clearance 120 mL/minute, and the mean total body clearance is 131 mL/minute.

In the presence of impaired renal function, the excretion of iohexol by the kidneys will be delayed and the amount excreted in the bile increases.

Iohexol is not known to be appreciably metabolized in humans. No metabolites have been found in urine. The presence or absence of metabolites in human bile has not been ascertained. (Small quantities of two metabolites were detected in rabbit bile and urine.)

Following its injection into the subarachnoid space, iohexol mixes readily with the cerebrospinal fluid (CSF) and diffuses into root sleeves and upward in the spinal and intracranial subarachnoid spaces. The time it takes iohexol to reach the cervical and intracranial subarachnoid spaces will depend to a large degree on the patient's position and movements. As it diffuses upward, its concentration decreases. Iohexol is eliminated into the systemic circulation via the subarachnoid granulations in the spine and the skull, and is subsequently excreted by the kidneys. Peak plasma concentration following subarachnoid injection of iohexol is reached in 2 to 6 hours. When fitted to a one compartment open model with first order absorption, the mean plasma elimination half-life (beta phase) is 3.4 hours (2.2 to 7.9 hours) and the mean apparent terminal elimination half-life (gamma phase) is 4.5 hours. The mean volume of distribution is 559 mL/kg, the mean renal clearance 111 mL/minute and the total body clearance 119 mL/minute. Within the first 24 hours, about 84% of the injected dose is recovered from the urine.

Subarachnoid: Iohexol, when injected into the lumbar subarachnoid space, will opacify the lumbar subarachnoid spaces and their associated root sleeves to provide contrast for these structures.

Following lumbar subarachnoid injection in conventional radiography, iohexol will continue to provide good diagnostic contrast for at least 30 minutes. After approximately 1 hour, contrast of diagnostic quality will not be available for conventional myelography, due to diffusion throughout the cerebrospinal fluid as well as transfer into the general circulation. If computerized tomography is to follow, it should be deferred for 2 to 6 hours to allow the degree of contrast to decrease. For computerized tomography without conventional radiography, a smaller dose or lower concentration of iohexol would be required.

Computerized tomography shows cerebrospinal fluid contrast enhancement in the thoracic region in about one hour, in the cervical region in about 2 hours, in the basal cisterns in 3 to 4 hours, and in the ventricles and sulci in 5 to 6 hours. Between 8 and 12 hours after lumbar injection, CT scans of the brain may demonstrate contrast medium enhancement of brain tissue in contact with the subarachnoid spaces indicating permeation of the cerebral cortex by the contrast medium; this "blush" effect will normally disappear in 24 hours.

In lumbar myelography studies, iohexol was injected into the lumbar subarachnoid space of 576 adult patients while an additional 208 adult patients received metrizamide under similar dosages and conditions.

Clinically significant, transient individual changes in vital signs, serum chemistry, hematology and neurological tests, when observed, were similar in magnitude and frequency with the two contrast agents used. The electroencephalogram was recorded in 182 patients who received iohexol. EEG changes (mostly theta and delta waves) were recorded in approximately 4% of patients who received iohexol, compared to 35% who received metrizamide. No significant changes in cerebrospinal fluid chemistry obtained by repuncture at either 6 or 24 hours after injection of Omnipaque were evident. Although a few minor increases in cerebrospinal fluid protein, WBC and other laboratory parameters were reported, no effect on IgG, creatinine kinase (CK) or CK-BB band isoenzyme was observed.

Intravascular: Following intravascular injection, iohexol will opacify those vessels in the path of flow of the contrast medium, permitting radiographic visualization of the vasculature of the internal structures and extremities until significant dilution occurs.

After i.v. injection opacification of the renal parenchyma may begin within one minute. Excretion of the contrast material becomes apparent in about 1 to 3 minutes, with optimal contrast in the calyces and collecting system occurring between 5 to 15 minutes. In nephropathic conditions, particularly when excretory capacity has been altered, the rate of excretion varies unpredictably, and opacification may be delayed for up to several hours after injection. Severe renal impairment may result in a lack of diagnostic opacification of the urinary tract, and depending on the degree of renal impairment, prolonged plasma iohexol levels may be anticipated in these patients as well as in infants with immature kidneys.

In comparative clinical trials of the vascular procedures of angiocardiography, cerebral arteriography, peripheral arteriography, urography, peripheral venography and intravenous digital subtraction angiography a total of 885 consenting adult patients received iohexol (523 by arterial injection and 362 by i.v. route) while 724 patients received conventional ionic media (444 intra-arterially and 280 i.v.) for their radiographic examinations.

Statistically significant reductions in patient discomfort, during or shortly after injection, were generally observed with iohexol compared to conventional ionic contrast media. Injection of iohexol was also associated with statistically significant reduction of changes in mean values of some physiological parameters (heart rate, QT interval, ST segment, and systemic pressures), compared to those associated with the use of conventional ionic media in some procedures, especially in angiocardiography. Clinically significant, transient individual changes noted in vital signs and laboratory parameters (increased serum creatinine CK, LDH, AST, ALT, K, decreased creatinine clearance; increased urinary protein, WBC and RBC; and variations in hematology parameters) after administration of Omnipaque were similar in scope to those caused by conventional ionic contrast agents.

In vitro studies done on human basophils from nonallergic, nonatopic, nonreactor subjects showed that iohexol caused a lesser degree of histamine release than diatrizoate, an ionic contrast agent.

As with any iodinated contrast agent, administration of iohexol may lead to changes in thyroid function in some patients, and elevation of thyroxine and/or TSH may be observed.

Since iohexol does not ionize in solution, there is less dilution through hyperosmolar fluid shifts within the renal tubules and hence less osmotic diuresis, compared to conventional ionized contrast media, and a higher iodine concentration in the tubular urine is obtained. Several studies have shown that conventional ionic contrast media caused significantly greater increases in proteinuria, urinary b-hexosaminidase and serum creatinine than did nonionic media at comparable doses. One study, on the other hand, involving 20 pediatric patients, showed that the significant increase in urinary excretion of other renal enzymes (NAG, GGT, MU) following the intravascular administration of iohexol was approximately the same as that caused by conventional ionic contrast media. The clinical relevance of these findings is unclear at the present time.

The lower osmolality of iohexol compared to conventional ionic media of similar iodine concentration can be expected to cause fewer and less severe osmolality-related disturbances. At 350 mg I/mL, the highest concentration used clinically, iohexol has less than half the osmolality of monomeric ionic media of equi-iodine concentration (i.e., approximately 844 m0sm/kg H20 vs 1 800 m0sm/kg H20).

CT Scanning of the Head: In i.v. contrast enhanced computed tomographic head imaging, iohexol does not accumulate in normal brain tissue due to the presence of the normal blood-brain barrier. The increase in x-ray absorption in normal brain is due to the presence of contrast agent within the blood pool. A break in the blood-brain barrier, such as occurs in malignant tumors of the brain, abscesses, vascular accidents, etc. allows for the accumulation of contrast medium within the interstitial tissue of the tumor, and some other lesions. Adjacent normal brain tissue does not contain the contrast medium. The degree of density enhancement is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid i.v. injection. Blood levels fall rapidly within 5 to 10 minutes and the vascular compartment half-life is approximately 20 minutes. Maximum contrast enhancement in tissue frequently occurs after peak blood iodine levels are reached. Diagnostic contrast enhancement images of the brain have been obtained up to 1 hour after i.v. bolus administration.

CT Scanning of the Body: In i.v. contrast enhanced computed tomographic body imaging (nonneural tissue), iohexol diffuses rapidly from the vascular into 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 of tumors since no barrier exists. Contrast enhancement is thus due to the relative differences in vascularity and extravascular diffusion between normal and abnormal tissue, quite different from that in the brain.

Contrast enhancement appears to be greatest immediately after bolus administration (15 to 120 seconds).

Utilization of a continuous scanning technique (i.e., dynamic CT scanning) may improve enhancement and diagnostic assessment of tumor and other lesions such as abscess, occasionally revealing unsuspected or more extensive disease.

Iohexol may be useful for enhancement of computed tomographic images for detection and evaluation of lesions in the liver, pancreas, kidneys, aorta, mediastinum, pelvis, abdominal cavity and retroperitoneal space.

Indications And Clinical Uses: Subarachnoid: Omnipaque 180, Omnipaque 240 and Omnipaque 300: For lumbar, thoracic, cervical and total columnar myelography in adults. Omnipaque 180 is indicated for subarachnoid administration in children, by lumbar injection, for lumbar, thoracic, cervical and total columnar myelography and for contrast enhancement in computerized tomography (myelography, cisternography and ventriculography). Delayed CT scans of spinal subarachnoid space and of the intracranial CSF spaces may be obtained at appropriate times following myelography, taking advantage of delayed opacification by the physiological cephalad circulation of the opacified CSF.

Intravascular: Omnipaque 350: In adults for left ventriculography, coronary arteriography, i.v. contrast enhancement for computed tomographic head and body imaging, peripheral arteriography, excretory urography and i.v. digital subtraction arteriography. Omnipaque 350 is indicated in children for angiocardiography.

Omnipaque 300: In adults for cerebral arteriography, peripheral arteriography, i.v. contrast enhancement for computed tomographic head and body imaging, peripheral venography and excretory urography. Omnipaque 300 is indicated in children for excretory urography and may be used in infants for angiocardiography.

Omnipaque 240: In adults for i.v. contrast enhancement in computed tomographic head imaging, and for peripheral venography.

Arthrography: Omnipaque 300 or Omnipaque 240 is recommended in adults for arthrography of the knee joint. Omnipaque 300 is recommended for arthrography of the shoulder joint in adults.

Contra-Indications: Iohexol should not be administered to patients with known or suspected hypersensitivity to iohexol or in cases of clinically significant impairment of both hepatic and renal function. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Use the recommended concentration for the particular procedure to be undertaken.

General: Serious or fatal reactions have been associated with the administration of water-soluble contrast media. It is of utmost importance that a course of action be carefully planned in advance for immediate treatment of serious reactions, and that adequate facilities and appropriate personnel be readily available in case a severe reaction should occur.

Diagnostic procedures which involve the use of radiopaque contrast agents should be carried out only by physicians with the prerequisite training and with a thorough knowledge of the particular procedure to be performed and who are thoroughly familiar with the emergency treatment of all adverse reactions to contrast media.

In addition to the following information, generally accepted contraindications, warnings, precautions and adverse reactions commonly related to the use of radiopaque contrast media should be kept in mind during its administration.

Administration of radiopaque media 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 a minimum. The blood pressure should be assessed throughout the procedure and measures for treatment of a hypertensive crisis should be available.

Ionic 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 a decision to use iohexol is made, the patient should be well hydrated beforehand, since dehydration favors protein precipitation in the renal tubules. A minimal diagnostic dose should be used and renal function and extent of urinary precipitation of the myeloma protein checked for a few days afterwards.

Caution is advised in patients with severe cardiovascular disease, hyperthyroidism, and in patients with a history of bronchial asthma or other allergic manifestations or of sensitivity to iodine. Patients with significant hepatorenal disease should not be examined unless the possibility of benefit clearly outweighs the additional risk. As with other iodinated contrast media, the use of iohexol is not recommended in patients with anuria or severe oliguria.

Elderly patients may present a greater risk (see Precautions, General). Special attention must be paid to dose and concentration of the medium, hydration and technique used.

Subarachnoid: Myelography should not be performed when lumbar puncture is contraindicated as in the presence of local or systemic infection where bacteremia is likely.

Myelography should be performed only in hospitalized patients under close medical observation, which is to be continued for 24 hours following the procedure.

Patients receiving anticonvulsants should be maintained on this therapy. Should a seizure occur, i.v. diazepam or phenobarbital is recommended. In patients with a history of seizure activity who are not on anticonvulsant therapy, premedication with barbiturates should be considered. Iohexol should be used in epileptics only if a water-soluble contrast medium is considered essential.

Prophylactic anticonvulsant treatment with barbiturates should be considered in patients with evidence of inadvertent intracranial entry of a large bolus of contrast medium, since there may be increased risk of seizure in such cases.

Gravitational displacement of a concentrated bolus of iohexol above the level of C1, especially into the intracranial subarachnoid spaces is not recommended.

Vascular: Nonionic iodinated contrast media inhibit blood coagulation less than ionic contrast media. Clotting has been reported 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 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. Nonionic iodinated contrast media are not recommended as flush solutions. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of clotting.

Patients with a serum creatinine level above 3 mg/dL should not be examined unless the possible benefits of the examination clearly outweigh the additional risk.

Extreme caution is advised should the injection of a contrast medium be indicated following the administration of vasopressors since they may strongly potentiate neurologic effects.

General anesthesia may be indicated in some procedures; however, one should be aware of possible increased incidence of adverse reactions in such circumstances.

See Dosage for special warnings and precautions.

Precautions: General: Before any contrast medium is injected, the patient should be questioned for a history of allergy or bronchial asthma. Although a history of allergy may imply a greater than usual risk, it does not arbitrarily contraindicate the use of the medium, but does warrant special precaution. A previous reaction to a contrast medium or a history of iodine sensitivity is not an absolute contraindication to the use of iohexol, however, extreme caution should be exercised in injecting these patients and prophylactic therapy should be considered. Additionally, the possibility of an idiosyncratic reaction in patients who have previously received a contrast medium without ill effect should always be considered.

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 full dose after a non-reactive 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 close observation following injection (see also Patient Management under Subarachnoid Administration).

It is expected that the results of thyroid function tests will not reflect true function for several weeks following radiopaque examination. Such tests, if indicated, should be performed prior to the administration of this preparation. Tests which directly determine thyroxine levels are less likely to be affected.

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 prior to the use of iohexol.

Preparatory dehydration is unnecessary and usually contraindicated with the use of iohexol for all indications.

Administration of water-soluble contrast media should be deferred for 48 hours in patients with hepatic or biliary disorders who have recently been administered cholecystographic agents, as renal toxicity has been reported in the literature in such patients who received conventional contrast agents.

Caution should be exercised in performing contrast medium examination in patients with endotoxemia and in those with elevated body temperature.

There have been reports in the literature indicating that patients on adrenergic beta-blockers may be more prone to severe adverse reaction 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.

Special precaution is advised in patients with increased intracranial pressure, cerebral thrombosis or embolism, primary or metastatic cerebral lesions, subarachnoid hemorrhage, 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 stroke, 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.

Caution should be exercised in the administration of contrast media to severely debilitated patients, particularly those with severe hypertension and impaired renal function. Acute renal failure has been reported in patients with diabetic nephropathy and in susceptible nondiabetic patients (often elderly with pre-existing renal disease) following administration of iodinated contrast agents. Careful consideration of the potential risks should be given before performing radiographic procedures in these patients.

Pregnancy: There are no studies on the use of iohexol in pregnant women. Reproduction studies have been performed in rats and rabbits with up to 100 times the recommended human dose. No evidence of impaired fertility or definite harm to the fetus has been demonstrated due to iohexol. Animal reproduction studies are not always predictive of human response; therefore, iohexol should be used during pregnancy only if the benefit to the mother clearly outweighs the risk to the fetus.

Lactation: It is not known to what extent iohexol is excreted in human milk. If use of iohexol is considered necessary, it is suggested to discontinue breast feeding for at least 48 hours after administration.

Children: (Indicated for Angiocardiography and Urography) Pediatric patients at higher risk of experiencing adverse events during contrast medium administration may include those having asthma, a sensitivity to medication and/or allergens, congestive heart failure, a serum creatinine >1.5 mg/dL or those less than 12 months of age.

Subarachnoid: Elderly patients may present a greater risk following myelography. The need for the procedure in these patients should be evaluated carefully. Special attention must be given not to exceed the recommended dose of the contrast medium, to see that the patient is sufficiently hydrated and to ensure proper and sterile radiographic technique.

If grossly bloody CSF is encountered, the possible benefits of a myelographic procedure should be considered in terms of the risk to the patient.

Any intrathecally administered medication including non-ionic contrast media such as iohexol can enter the brain substance which may increase the risk of adverse effects associated with the procedure. Such adverse reactions may be delayed and, in extremely rare cases, may be life-threatening (see Adverse Effects). Careful patient and dose selection and proper patient management before, during and after the procedure are therefore imperative.

Care is required in patient management to prevent inadvertent intracranial entry of a large bolus of contrast medium. Also, effort should be made to avoid rapid dispersion of the medium (i.e., by active patient movement).

Previous experience with the use of water-soluble contrast media in myelography indicates that in most cases of major motor seizure one or more of the following factors were present, and should therefore, be avoided: deviations from recommended procedure on myelographic management; use in patients with a history of epilepsy; inadvertent overdosage; intracranial entry of a bolus or premature diffusion of a high concentration of the medium; medication with neuroleptic drugs or phenothiazine antinauseants; failure to maintain elevation of the head during and after the procedure; active patient movement or straining.

Repeat procedures: If in the clinical judgment of the physician a repeat examination is required, an interval of 5 days between procedures is recommended.

Drug Interactions: Drugs which lower seizure threshold, especially phenothiazine derivatives including those used for their antihistaminic or antinauseant properties, should not be used with iohexol. Others include MAO inhibitors, tricyclic antidepressants, CNS stimulants, psychoactive drugs described as analeptics, major tranquilizers, or antipsychotic drugs. Such medications should be discontinued at least 48 hours before myelography; should not be used for the control of nausea or vomiting during or after myelography; and should not be resumed for at least 24 hours postprocedure. In nonelective procedures in patients on these drugs, consider prophylactic use of anticonvulsants.

Intravascular: Preparatory dehydration may be dangerous in infants, young children, the elderly, in the presence of multiple myeloma and azotemic patients (especially those with polyuria, oliguria, diabetes, advanced vascular disease or preexisting dehydration). The undesirable dehydration in these patients may be accentuated by the osmotic diuretic action of the medium.

When high doses of contrast media 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.

When considering aortic injection 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.

Avoid entry of a large concentrated bolus into an aortic branch. Mesenteric necrosis, acute pancreatitis, renal shut-down, 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 of contrast media into an aortic branch or arterial trunks providing spinal or cerebral artery branches.

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 in patients with suspected thrombosis, ischemic disease, local infection or a significantly obstructed vascular system. Occasional serious neurologic complications, including paraplegia have been reported in patients with aorto-iliac or femoral artery bed obstruction, abdominal compression, hypotension, hypertension and following injection of vasopressors.

When large individual doses are administered an appropriate time interval should be permitted to elapse between injections to allow for subsidence of hemodynamic disturbances.

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

Special precautions, to be observed when performing specific diagnostic procedures, are listed in the Dosage section, under individual paragraphs pertaining to specific procedures.

Adverse Reactions: General: Since the reactions which are known to occur upon parenteral administration of iodinated contrast agents are possible with any nonionic agent, the same degree of careful patient observation for adverse reactions, as with the use of conventional contrast media, should be strictly followed. Adequate equipment and appropriate personnel should be readily available in case a severe reaction should occur.

Adverse reactions following the use of iohexol are usually of mild to moderate severity. However, serious, lifethreatening and fatal adverse reactions have been associated with both the intravascular and subarachnoid use of iodinated contrast media, including iohexol.

It should be kept in mind that, although most adverse reactions occur soon after the administration of the contrast medium, some adverse reactions may be delayed and may be of long-lasting nature.

The reported incidence of adverse reactions to contrast media in patients with a history of allergy is twice that of the general population. Patients with a history of previous reactions to a contrast medium are three times more susceptible than other patients. However, sensitivity to contrast media does not appear to increase with repeated examinations.

Reactions Related to Technique: Adverse reactions to specific procedures are dealt with under Dosage. General reactions attributed to technique and/or procedure may include extravasation with burning pain, hematomas, ecchymosis and tissue necrosis, vascular spasm thrombosis, thrombophlebitis, bleeding, perforation, rupture and dissection of blood vessels, dislodgment of atheromatous plaques or thrombi with embolization, subintimal injection, injury to nerves and other structures and general trauma during the procedure.

Subarachnoid: Following subarachnoid administration of iohexol, as with other currently used non-ionic contrast media, the most important adverse reactions involve the CNS and the incidence of such adverse reactions increases when the more cephalad segments of the spinal cord are exposed to the contrast material. The amount and concentration of the contrast material also appear to have a direct relationship to the frequency and severity of such adverse effects.

Adverse reactions known to occur with the subarachnoid use of other nonionic iodinated contrast media may also follow the use of iohexol. Most adverse reactions occur several hours following the procedure necessitating close and prolonged observation.

The most frequently reported adverse reactions are headache, mild to moderate pain including backache, neckache and stiffness, nausea and vomiting. These reactions usually occur 1 to 10 hours after injection, and almost all occur within 24 hours. They are usually mild to moderate in degree, lasting for a few hours, and usually disappearing within 24 hours. Rarely, headaches may be severe or persist for days. Headache is often accompanied by nausea and vomiting and tends to be more frequent and persistent in patients not optimally hydrated.

Transient alterations in vital signs may occur.

Those reactions reported in clinical studies are listed below in decreasing order of occurrence, based on clinical studies of 1 531 patients.

Headache: The most frequently occurring adverse reaction following myelography with iohexol has been headache, with an incidence of approximately 18%. Rarely, headache may be severe, lasting in some cases for several days. In managing the patient, it is considered very important to prevent intracranial entry of contrast medium by postural management (see Patient Management).

Pain: Pain in the back, leg, neck, stiffness and neuralgia occurred following injection with a total incidence of about 8%.

Nausea and vomiting: Mild to severe nausea and vomiting was reported with an incidence of approximately 6% and 3% respectively (see Patient Management). Maintaining normal hydration is very important. The use of phenothiazine antinauseants is not recommended.

Dizziness: Transient dizziness was reported in about 2% of the patients.

The following serious adverse reactions involving the CNS, have been reported with the myelographic use of iohexol (in approximately<0.1%): convulsions, aseptic meningitis syndrome (see below), toxic encephalopathy, myelitis with transient or persistent sensory and motor disturbances of the central and peripheral nervous system; transient or persistent cortical blindness, unilateral or bilateral loss of vision, amblyopia, diplopia, oculomotor weakness, 6th nerve palsy, photophobia, nystagmus, hearing loss, dysphasia, dysarthria, quadriplegia, hemiplegia, spastic paraparesis, paralysis, areflexia, flaccidity, muscle weakness, hyperreflexia, hypertonia, myoclonus, fasciculation, general spasm, muscle spasm, spinal convulsion, cauda equina syndrome, urinary retention, nerve root disturbances, sensory loss, meningismus, neck stiffness, fever, fainting, cerebral edema, cerebral hemorrhage, hydrocephalus, somnolence, stupor, coma, confusion, disorientation, hallucination, decreased concentration, memory dysfunction, amnesia, depersonalization, psychosis, anxiety, agitation, depression, nightmares, elevated WBC and protein in spinal fluid, EEG changes.

An aseptic meningitis syndrome has been reported rarely (<0.01%). It was usually preceded by pronounced headaches, nausea and vomiting. Onset usually occurred about 12 to 18 hours postprocedure.

Prominent features were meningismus, fever, sometimes with oculomotor signs and mental confusion. Lumbar puncture revealed a high white cell count, high protein content often with a low glucose level and with absence of organisms. The condition usually clears spontaneously within a few days.

Profound mental disturbances have also rarely been reported. They have usually consisted of various forms and degrees of aphasia, mental confusion or disorientation. The onset is usually at 8 to 10 hours and lasts for about 24 hours or more. However, occasionally they have been manifest as apprehension, agitation, or progressive withdrawal in several instances to the point of somnolence, stupor and coma. In a few cases these have been accompanied by transitory hearing loss or other auditory symptoms and visual disturbances, including unilateral or bilateral loss of vision which may last for hours. In one case, persistent cortical loss of vision has been reported in association with convulsions. Ventricular block has been reported; amnesia of varying degrees may be present.

Although not previously reported with Omnipaque, as with the injection of any foreign substance into the subarachnoid space, the possibility of the potential of iohexol to produce adhesive arachnoiditis cannot be excluded.

Other reactions occurring with an individual incidence of less than 0.1% include: feelings of heaviness, severe hypotension, vasovagal reactions, bradycardia, cardiorespiratory arrest, sensation of heat, sweating and loss of appetite. Also chills, fever, profuse diaphoresis, pruritus, rash, erythema, periorbital edema, nasal congestion, dyspnea and a case of Guillain-Barré Syndrome.

Children: In controlled clinical trials involving 152 patients for pediatric myelography by lumbar puncture, adverse events following the use of Omnipaque 180 and Omnipaque 210 were as follows: headache 9%, vomiting 6%, backache 1.3%.

Other Reactions: Other reactions occurring with an individual incidence of less than 0.7% (single occurrence in 152 patients) included: fever, hives, stomach ache and visual hallucination.

Intravascular: Adverse reactions following the intravascular use of iohexol are usually of mild to moderate severity. However, as with other iodine-containing contrast media, serious, lifethreatening and fatal reactions have been associated with the intravascular administration of iohexol.

The injection of contrast media is frequently associated with the sensation of warmth and pain, burning sensation, flushing, nausea, vomiting and taste alterations. These relatively minor adverse effects are generally less frequent and less severe with Omnipaque than with conventional ionic contrast media.

Adverse reactions following the intravascular use of iohexol include: Cardiovascular: arrhythmias including PVCs and PACs (2%), angina/chest pain (1%), and severe hypotension (0.8%). Others including cardiac failure, asystole, bradycardia, tachycardia, atrial and ventricular fibrillation, premature beats, bundle branch block, vasovagal reaction, chest pain, coronary thrombosis, dyspnea, pulmonary edema, cyanosis, severe hypertension, hypertensive crisis, hypotension, peripheral vasodilation, acute vascular insufficiency, circulatory collapse, hypotensive and cardiogenic shock, cardiac arrest, and cardiorespiratory arrest were reported with an individual incidence of less than 0.4%.

CNS: vertigo (including dizziness and lightheadedness) (0.7%), pain (3%), photomas (2%), headache (2%) and taste perversion (1%). Others including anxiety, blurred vision, transient or persistent blindness, impairment of memory and coordination, tinnitus, fever, motor and speech dysfunction, convulsion, paresthesia, somnolence, confusion, dizziness, loss of consciousness, coma, apnea, psychotic reaction, stroke, stiff neck, hemiparesis, hemiplegia, nystagmus, restlessness and tremors were reported with an individual incidence of<0.4%.

Renal: occasionally transient proteinuria, hematuria and rarely oliguria, anuria and renal failure.

Allergic anaphylactoid: urticaria (0.3%) and purpura (0.1%). Occasionally asthmatic attacks, nasal and conjunctival symptoms (such as nasal congestion, sneezing, rhinitis, conjunctivitis, lacrimation), dermal reactions (such as urticaria with or without pruritus, erythematous, bullous and pleomorphic rashes), laryngospasm, bronchospasm, wheezing, laryngeal edema, angioneurotic edema, edema of glottis with signs of airway obstruction and rarely, anaphylactic shock leading to cardiorespiratory failure and death.

Other Reactions: Nausea (2%) and vomiting (0.7%), diarrhea, dyspepsia, and dry mouth were reported with an individual incidence of<0.1%, pallor, weakness, sweating, localized areas of edema, especially facial, vein cramps and thrombophlebitis following i.v. injection, rare cases of disseminated intravascular coagulation, neutropenia. Rarely, immediate or delayed rigors can occur, sometimes accompanied by hyperpyrexia. Infrequently, iodism (salivary gland swelling) from organic iodinated compounds appears 2 days after exposure and subsides by the 6th day.

Transient changes in some laboratory parameters are not uncommon.

The occurrence of thyroid storm in patients with hyperthyroidism or with autonomously functioning thyroid nodule have been reported following the use of iodinated contrast media.

Individual adverse reactions which occurred to a significantly greater extent for a specific procedure are also listed under Dosage for that procedure.

Treatment of Adverse Effects: 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.

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 cardiopulmonary 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.

For minor allergic reactions: (If considered necessary) The i.v. or i.m. administration of an antihistaminic such as diphenhydramine HCl 25-50 mg is generally sufficient (contraindicated in epileptics). The resulting drowsiness makes it imperative to ensure that outpatients do not drive or go home unaccompanied.

Major or lifethreatening 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 to all drugs administered: soluble hydrocortisone 500 to 1 000 mg, i.v. for all acute allergic-anaphylactic reactions; epinephrine 1:1 000 solution (in the presence of anoxia it may cause ventricular fibrillation - caution in patients on adrenergic b-blockers - see Precautions): 0.2 to 0.4 mL s.c. for severe allergic reactions. 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. In case of cardiac arrest 0.1 to 0.2 mL appropriately diluted, may be given intracardially. In hypotension (carefully monitoring blood pressure): phenylephrine HCl 0.1 to 0.5 mg appropriately diluted slowly i.v., or by slow infusion, or norepinephrine 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 postarrest 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 patient's response a total dose of 200 to 300 mg may be required. The dose may be repeated in 6 hours if necessary.

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: Before use, the vials should be inspected visually for particulate matter and/or discoloration. If either is present, the vials should be discarded. Iohexol should be injected at or close to body temperature and should be used immediately once the vial seal has been punctured. It should not be transferred from the vial to other delivery systems except immediately prior to use; nor should it be mixed with other drugs. Any unused portion should be discarded. The vials should be protected from exposure to light. Syringes, needles and catheter tips must be kept free of aspirated blood to prevent clotting from prolonged contact.

Subarachnoid: Omnipaque 180, Omnipaque 240 or Omnipaque 300 is recommended for the examination of lumbar, thoracic and cervical regions in adults by lumbar or direct cervical injection. Omnipaque 180 is recommended for the examination of the lumbar, thoracic and cervical regions in children by lumbar injection. Myelography should not be performed in the presence of significant local or systemic infection where bacteremia is likely, or when lumbar or cervical puncture is contraindicated. The volume and concentration of Omnipaque 180, 240 or 300 to be administered will depend on the degree and extent of contrast required within the recommended dose range in the area under examination, and on the equipment and technique employed. Omnipaque solutions are slightly hypertonic to CSF.

Adults: A total dose of 3 060 mg iodine or a concentration of 300 mg I/mL should not be exceeded in adults in a single myelographic examination.

Children: A total dose of 2 700 mg iodine or a concentration of 180 mg I/mL should not be exceeded in children in a single myelographic examination. As in all diagnostic procedures, the minimum volume and dose to produce adequate visualization should be used. Most procedures do not require maximum dose.

Anesthesia is not necessary. Patients should be well hydrated. Seizure-prone patients should be maintained on anticonvulsant medication.

Rate of injection: To avoid excessive mixing with CSF and consequent dilution of contrast, injection should be made slowly, over 1 to 2 minutes.

Depending on the estimated volume of iohexol which may be required for the procedure, a small amount of CSF may be removed to minimize distention of the subarachnoid spaces, unless contraindicated.

The spinal puncture needle may be removed immediately following injection since, usually it is not necessary to remove iohexol after injection into the subarachnoid space.

If, in the clinical judgment of the physician, a repeat examination is required, an interval of 5 days between procedures is recommended.

Adults: The usual recommended total dosages of Omnipaque 180, 240 or 300 for use in lumbar, thoracic, cervical and total columnar myelography are in Table I (not to exceed maximum total dose of 3 060 mg iodine).

If computerized tomography is to follow, it should be deferred for 2 to 6 hours to allow the degree of contrast to decrease. Computerized tomography shows CSF contrast enhancement in the thoracic region in about 1 hour, in the cervical region in about 2 hours, in the basal cisterns in 3 to 4 hours and in the ventricles and sulci in 5 to 6 hours.

Children: The usual recommended total doses for lumbar, thoracic, cervical and/or total columnar myelography by lumbar puncture in children range from 0.36 to 2.70 g I. Actual volumes administered depend largely on patient age and the following guidelines are recommended (see Table II).

Patient management following subarachnoid administration: Good patient management should be exercised at all times to minimize the potential for complications.

Preprocedure: Discontinue neuroleptic drugs (including phenothiazines, e.g., chlorpromazine, prochlorperazine, and promethazine) at least 48 hours beforehand. Maintain normal diet up to 2 hours before procedure. Ensure hydration with fluids up to procedure. Premedication is not usually considered necessary. Should myelography be necessary in patients with a history of seizures, such patients should be maintained on their anticonvulsant medication.

During procedure: Use minimum dose required for satisfactory contrast (see Dosage). In all positioning techniques keep the patient's head elevated above highest level of spine. Do not lower head of table more than 15° during examination. In patients with excessive lordosis consider lateral position for injection. Inject slowly (over 1 to 2 minutes) to avoid excessive mixing. Move medium within spinal subarachnoid space under fluoroscopic monitoring. Avoid intracranial entry of a bolus. Avoid early and high cephalad dispersion of the medium. Avoid abrupt or active patient movement to minimize excessive mixing with CSF. Instruct patient to remain passive. Move patient slowly and only as necessary.

Post-procedure: Following myelography move contrast medium to low lumbosacral area by upright positioning of the patient, for a few minutes. Raise head of stretcher to at least 30° before moving patient onto it. Movement onto and off the stretcher should be done slowly with patient completely passive, maintaining head up position. Before moving patient onto bed, raise head of bed 30° to 45°. Some clinicians advise patients to remain still in bed, in head up position or in the semi-sitting position, especially in the first few hours. Others have encouraged their patients to be fully ambulatory and have noted a reduction in the incidence of headache, nausea and vomiting. Maintain close observation and head up position for at least 24 hours after myelogram. Obtain visitors' cooperation in keeping the patient quiet and in head up position, especially in first few hours. Encourage oral fluids. Diet as tolerated. If nausea or vomiting occur, do not use phenothiazine antinauseants. Persistent nausea and vomiting will result in dehydration. Therefore prompt consideration of replacement by i.v. fluids is recommended.

Intravascular: (see Intravascular Dosage tables for recommended indications and dosage for intravascular administration).

Adult Left Ventriculography, Coronary Arteriography and Pediatric Angiocardiography: Omnipaque 350 is recommended in adults for left ventriculography, selective coronary arteriography and aortic root injections.

Omnipaque 350 is recommended in children for angiocardiography. Omnipaque 300 may be used in infants for angiocardiography.

Specific Precautions: During administration of Omnipaque 300 and Omnipaque 350, continuous monitoring of vital signs is desirable and adequate facilities for immediate resuscitation and cardioversion are mandatory. Caution is advised in the administration of large volumes to patients with incipient heart failure because of the possibility of aggravating the preexisting condition. Hypotension should be corrected promptly since it may induce serious arrhythmias.

Special care regarding dosage should be observed in patients with right ventricular failure, pulmonary hypertension or stenotic pulmonary vascular beds because of the hemodynamic changes which may occur.

Injection of contrast media into the cardiac chambers or great vessels causes significant hemodynamic disturbances, especially in right sided injections. Depending on the injection site and the time of recording, significant changes include a drop in cardiac output, elevation or decrease in ventricular pressures (RVSP, LVSP, LVEDP, RVEDP), systemic pressure, peripheral hypotension, brady or tachycardia, ectopic beats and other arrhythmias.

The hemodynamic changes which occur during and after ventricular and coronary injections are, in general, less pronounced with the low-osmolality Omnipaque than those seen with similar concentrations of conventional ionic contrast media, but, serious and life threatening hemodynamic disturbances can occur with the administration of all iodinated contrast media, including iohexol.

If repeat injections are made in rapid succession, all these changes are likely to be more pronounced.

After an initial rise, plasma volume may decrease and continue to fall below control levels, even beyond 30 minutes, probably due to diuresis.

The volume of each individual injection is a more important consideration than the total dose used. When large individual volumes are administered, as in ventriculography, sufficient time should be permitted to elapse between each injection to allow for subsidence of hemodynamic disturbances.

Due to increased risk of adverse reactions following recent acute myocardial infarction, careful patient selection is necessary, and the timing and performance of the examination should be carried out with extreme caution, if invasive radiographic procedures are considered necessary.

Pediatric patients at higher risk of experiencing adverse events during contrast medium administration include those having asthma, a sensitivity to medication and/or allergens, congestive heart failure, preexistent right heart strain, narrowed pulmonary vascular bed, a serum creatinine >1.5 mg/dL or those less than 12 months of age.

Specific Adverse Effects: Transient ECG changes occur frequently during the procedure. The following adverse effects have also occurred following administration of iohexol for this procedure: cardiac arrhythmias (bradycardia, ventricular tachycardia, atrial and ventricular fibrillation, heart block), anginal pain, coronary thrombosis, cardiac arrest, hypotensive shock and death. Apnea, arrhythmias, cerebral effects, convulsions, electrolyte and hemodynamic disturbances are more likely to occur in cyanotic infants.

Procedural complications include dissection of coronary arteries, dislodgment of atheromatous plaques, perforation of heart chambers or coronary arteries, hemorrhage and thrombosis.

Dosage And Administration: Adults: Left ventriculography: The usual adult volume of Omnipaque 350 for a single injection is 40 mL with a range of 30 to 60 mL. These doses may be repeated if necessary, but the total procedural dose should be limited to the minimum volume required to achieve a diagnostic examination.

Selective coronary arteriography: The usual adult volume for right or left coronary arteriography is 5 mL (range 3 to 10 mL)/ injection.

Aortic root injection when used alone: The usual adult single injection volume is 35 mL, with a range of 20 to 50 mL.

Children: Weight, a minor consideration in adults, must be considered in infants and young children during the administration of radiographic contrast media.

The usual recommended single injection volume of Omnipaque 350 and Omnipaque 300 for angiographic procedures in children are as follows: Angiocardiography: The usual single injection dose range is 0.5 to 1.5 mL/kg for Omnipaque 300 and 0.5 to 1.2 mL/kg for Omnipaque 350. When multiple injections are given, the total administered dose should not exceed 4 mL/kg or 100 mL, whichever is less.

The inherent risk of angiocardiography in cyanotic infants must be weighed against the necessity for performing this procedure. 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 preexisting right heart strain, heart failure and effectively decreased or obliterated pulmonary vascular beds.

Apnea, bradycardia and other arrhythmias, cerebral effects, electrolyte and hemodynamic disturbances are more likely to occur in cyanotic infants. Infants are more likely than adults to respond with convulsions, particularly after repeated injections.

Cerebral Arteriography: Omnipaque 300 is recommended in adults for use in cerebral arteriography.

In cerebral arteriography, appropriate patient preparation is indicated. This may include suitable premedication.

Specific Precautions: Cerebral arteriography should be undertaken with extreme care, with special caution in elderly patients, patients in poor clinical condition, advanced arteriosclerosis, severe arterial hypertension, recent cerebral embolism or thrombosis, cardiac decompensation, subarachnoid hemorrhage and following a recent attack of migraine, if the examination is considered to be essential for the welfare of the patient and the patient should be watched for possible untoward reactions.

Specific Adverse Effects: Repeated injections of contrast material, administration of doses in excess of those recommended, the presence of occlusive atherosclerotic vascular disease and the technique and method of injection appear to contribute to the majority of adverse effects attributable to cerebral arteriography.

Normally, adverse effects are mild and transient such as a frequent feeling of warmth in the face and neck and infrequently a more severe burning discomfort is experienced.

Although the degree of pain, flushing and patient movement as the result of the use of iohexol in cerebral arteriography is generally less than that seen with comparable injections of monomeric ionic contrast media, cerebral arteriography has been associated with neurologic complications such as seizures, drowsiness, paresthesia, TIA, cerebral infarct, transient or persistent hemiparesis, and disturbances in speech and vision (slurred speech, blurred vision, nystagmus, photomas). Other adverse effects include hypotension, bradycardia, arrhythmia, vertigo, syncope and ECG and EEG changes. Permanent defects are possible (see Adverse Effects, Intravascular).

Usual Adult Dose: The recommended single dose of Omnipaque 300 for cerebral arteriography is as follows: common carotid artery 6 to 12 mL; internal carotid artery 5 to 10 mL; external carotid artery 4 to 8 mL and vertebral artery 6 to 10 mL. It is advisable to inject at rates approximately equal to the flow rate of the vessel being injected.

Contrast Enhanced Computed Tomography: Omnipaque 240 (iohexol 240 mgI/mL) may be used for i.v. contrast enhanced computed tomography of the head; Omnipaque 300 and Omnipaque 350 are indicated in adults for use in i.v. contrast enhanced computed tomographic head and body imaging by rapid injection or infusion technique.

Specific Warnings: In patients where the blood-brain barrier is known or suspected to be disrupted, the use of any radiographic contrast medium must be assessed on an individual risk to benefit basis, since neurological complications are more likely to occur. Caution is advised in patients with impaired renal function and with congestive heart failure.

Specific Precautions: The decision to employ contrast enhancement should be based upon a careful evaluation of clinical, other radiological and unenhanced CT findings, because unenhanced scanning may provide adequate diagnostic information in the individual patient, and because contrast enhancement may be associated with risk, may obscure certain lesions and increases radiation exposure.

I.V. CT scans of the head performed within 24 hours following myelography may yield false results due to the permeation of the brain by the contrast medium from adjacent CSF spaces. Therefore, if indicated, i.v. CT scan of the brain should be performed either before, or after a period of at least 24 hours following myelography.

Specific Adverse Effects: Following intravascular injection of large doses, transient or persistent neurological changes have been reported.

Usual Adult Dose: The concentration and volume required is influenced by the equipment and imaging technique used. The total procedural dose should be limited to the minimum volume required to achieve a diagnostic examination. The usual adult dose range is: Omnipaque 240: 85 to 150 mL; Omnipaque 300: 60 to 120 mL; Omnipaque 350: 50 to 80 mL.

Peripheral Arteriography: Omnipaque 350 or Omnipaque 300 is recommended in adults for use in peripheral arteriography by aortic (bifurcation) or by femoral artery injection. Sedative premedication may be employed prior to the use of Omnipaque. General anesthesia is not considered necessary.

Specific Precautions: Peripheral arteriography (by aortic injection): Under conditions of slowed aortic circulation there is an increased likelihood for aortic injection to cause muscle spasm. Occasional serious neurologic complications, including paraplegia, have also been reported in patients with aorto-iliac obstruction, femoral artery obstruction, abdominal compression, hypotension, hypertension, spinal anesthesia, injection of vasopressors to increase contrast, and low injection sites (L2-3). Especially in these patients the concentration, volume, 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 monitored.

Entry of a large aortic dose into the renal artery may cause, even in the absence of symptoms, albuminuria, hematuria, elevated creatinine and urea nitrogen and possible renal damage.

Specific Precautions: Peripheral arteriography (by femoral injection): Patient discomfort during and immediately following injection is generally less than that following injection of conventional ionic media. The incidence of discomfort for the second and subsequent injection may be somewhat higher than with the first injection.

Pulsation must be present in the artery to be injected. In thromboangiitis obliterans, severe ischemia with or without ascending infection, severe atherosclerosis or obstruction, arteriography should be performed with extreme caution, if at all.

Specific Adverse Effects: Adverse reactions observed during peripheral arteriography may sometimes be due to trauma during the procedure. Adverse reactions reported with the use of iodinated contrast media include hypotension, soreness in extremities, transient arterial spasm, gangrene, perforation of vessels, extravasation, hemorrhage, hematoma formation with tamponade, injury to nerves and other structures in close proximity to the artery, thrombosis, dissecting aneurysm, arteriovenous fistula, dislodgment of atheromatous plaques, subintimal injection and transient leg pain from contraction of calf muscles in femoral arteriography.

Usual Adult Dose: The volume required will depend on the size, flow rate and disease state of the injected vessel and on the size and condition of the patient, as well as the technique used. Omnipaque dosage recommendations for use in peripheral arteriography are in Table III.

I.V. Digital Subtraction Arteriography: Omnipaque 350 is recommended in adults for use in i.v. digital subtraction arteriography.

It has been demonstrated that arteriograms of diagnostic quality can be obtained following the i.v. administration of contrast media employing digital subtraction and computer imaging enhancement techniques. The i.v. route of administration using these techniques has the advantage of being less invasive than the corresponding selective catheter placement of medium.

The dose is administered into a peripheral vein or the superior vena cava usually by mechanical injection although sometimes by rapid manual injection. Iohexol with this technique has been used to visualize the vessels of the head and neck. Radiographic visualization of these structures is dependent on timing (synchronizing with circulation time).

The solution can be injected i.v. as a rapid bolus to provide arterial visualization using digital subtraction radiography. Preprocedural medications are not considered necessary. Iohexol has provided diagnostic carotid arterial radiographs by i.v. injection in about 92% of patients. In some cases poor arterial visualization has been attributed to patient movement. There is generally less subjective or objective evidence of patient discomfort (general sensation of heat or pain) following injection compared with monomeric ionic media. In about 65% of patients discomfort is either absent or is mild, and is severe in about 2% of patients.

Specific Precautions related to the procedure: Since the dose is usually administered mechanically under high pressure, rupture of venous structures has occurred with extravasation of the contrast medium into the tissues of extremities or the mediastinum. It has been suggested that this is less likely to occur if an i.v. catheter is threaded proximally beyond larger tributaries in the case of the antecubital vein, into the superior vena cava or if the femoral vein is used. However with high pressure injection the catheter tip initially placed in larger venous structures may still recoil into a small tributary resulting in rupture of a small vein with extravasation into the neighboring tissues. In case of mediastinal extravasation severe pain and hypotensive shock have been reported.

Usual Adult Dose: The usual injection volume of Omnipaque 350 for the i.v. digital technique is 30 to 50 mL. This is administered as a bolus at 10 to 30 mL/second either by hand or using a pressure injector. The volume and rate of injection will depend primarily on the type of equipment and technique used, with first exposure made on calculated circulation time.

A dextrose solution may be layered over the contrast medium in the injector with the purpose of delivering the remnant of the bolus forward into the main circulation, and to flush the vein.

The patient is urged not to move or swallow during or immediately after the injection.

Peripheral Venography: Omnipaque 300 or Omnipaque 240 is recommended in adults for peripheral venography.

Specific Precautions: Special care is required when venography is performed in patients with suspected thrombosis, phlebitis, ischemic disease, local infection or significantly obstructed venous system. In the presence of venous stasis, vein irrigation with normal saline should be considered following the procedure.

Specific Adverse Effects: Following venography with iodinated contrast media, 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.

Usual Adult Dose: The recommended single dose for use in peripheral lower extremity venography is: 20 to 100 mL Omnipaque 240, or 20 to 100 mL Omnipaque 300.

Excretory Urography: Omnipaque 350 or Omnipaque 300 is recommended in adults for excretory urography. Omnipaque 300 is recommended in children for excretory urography.

For pharmacodynamics of excretion in adults see Pharmacology, Intravascular. For adverse effects see Adverse Effects, General and Intravascular.

Patient preparation: Appropriate preparation of the patient is desirable for optimal results. A laxative the night before the examination, unless contraindicated and a low residue diet the day before the examination are recommended.

Specific Precautions: Preparatory dehydration is not recommended, especially in the elderly, infants, young children, diabetic or azotemic patients, or in patients with suspected myelomatosis.

Pediatric patients at higher risk of experiencing adverse events during contrast medium administration may include those having asthma, a sensitivity to medication and/or allergens, congestive heart failure, a serum creatinine >1.5 mg/dL or those less than 12 months of age.

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 a decision to use iohexol is made, the patient should be well hydrated beforehand, since dehydration favors protein precipitation in the renal tubules, a minimal diagnostic dose used, and renal function and extent of urinary precipitation of the myeloma protein checked for a few days afterwards.

Caution is advised in patients with congestive heart failure and in cases of impaired renal function. In these patients the patient's clinical status and renal function should be carefully monitored.

Since there is a possibility of temporary suppression of urine formation, it is recommended that an interval of at least 48 hours elapse before excretory urography is repeated in patients with unilateral or bilateral reduction in renal function.

Usual Adult Dose: The usual recommended adult dose range for use in excretory urography is 25 to 50 mL i.v. of Omnipaque 350 or Omnipaque 300.

Children: Excretory Urography: The usual dose of Omnipaque 300 for children is 0.7 to 1.5 mL/kg. Dosage for infants and children should be administered in proportion to age and body weight. The total administered dose in infants should not exceed 3 mL/kg. In older children the maximum dose should not exceed 1.5 mL/kg or 50 mL, whichever is less.

Arthrography: Omnipaque 300 or Omnipaque 240 is recommended in adults for arthrography of the knee joint. Omnipaque 300 is recommended for arthrography of the shoulder joint in adults.

Specific Precautions: Strict aseptic technique is required to prevent infection. Fluoroscopic control should be used to ensure proper needle placement, prevent extracapsular injection and prevent dilution of contrast medium. Undue pressure should not be exerted during injection.

Specific Adverse Effects: Injection of Omnipaque into the joint is associated with transient discomfort, i.e., pain, swelling. However, delayed severe or persistent discomfort may occur occasionally. Severe pain may often result from undue use of pressure or the injection of large volumes. Joint swelling and effusion may occur. These adverse effects are partly procedurally dependent and of greater frequency when double-contrast technique is employed.

Adverse effects during arthrography included pain (36%), swelling sensation (58%), heat sensation (8%), muscle weakness (0.4%) and hematoma at the injection site (1%). Occasionally, muscle twitching, rash, itching, fatigue, and dry lips, were also observed during clinical studies involving 429 patients who had received iohexol by injection to the knee or shoulder joints. A single case of allergic synovitis associated with the use of Omnipaque has been reported in the literature.

Usual Adult Dose: Arthrography is usually performed under local anesthesia. As much fluid as possible should be aspirated from the joint. Passive or active manipulation is used to disperse the medium throughout the joint space. The amount of Omnipaque injected is largely dependent on the size of the joint to be examined and the technique employed. Contrast is good during the first 5 to 10 minutes following injection and begins to fade at 15 to 20 minutes.

The following concentrations and volumes are recommended for normal adult knee and shoulder joints but should only serve as guidelines since joints may require more or less contrast medium for optimal visualization.

Knee: 5 to 15 mL Omnipaque 300 or Omnipaque 240.

Shoulder: 5 to 10 mL Omnipaque 300.

Lower volumes of contrast medium are usually injected when performing double-contrast examinations of the knee.

Availability And Storage: Omnipaque is provided as a sterile, pyrogen-free colorless to pale yellow solution, in the following iodine concentrations: 180, 240, 300 and 350 mg I/mL. Each mL iohexol solution contains: tromethamine 1.21 mg and of edetate calcium disodium 0.1 mg in water for injection. pH adjusted between 6.8 and 7.7 with hydrochloric acid or sodium hydroxide. All solutions are sterilized by autoclaving and contain no preservatives. Solutions must be protected from light. Unused portions must be discarded.

Directions for Dispensing from Pharmacy Bulk Vial: The use of Pharmacy Bulk vials is restricted to hospitals with a recognized i.v. admixture program. The Pharmacy Bulk Vial is intended for single puncture, multiple dispensing.

Iohexol at recommended concentrations is hypertonic to CSF and blood (300 mOsm/kg).

Normal range for the specific gravity of CSF is 1.005 to 1.009 and for blood, 1.050 to 1.064.

Omnipaque 180: Vials of 10 mL, 180 mg I/mL, boxes of 10. Vials of 15 mL, 180 mg I/mL, boxes of 10.

Omnipaque 240: Vials of 10 mL, 240 mg I/mL, boxes of 10. Vials of 20 mL (with 15 mL fill), 240 mg I/mL, boxes of 10. Vials of 50 mL, 240 mg I/mL, boxes of 10. Bottles of 100 mL, 240 mg I/mL, boxes of 10. Bottles of 200 mL, 240 mg I/mL, boxes of 10. Flexible containers of 100 mL, 240 mg I/mL, boxes of 10. Flexible containers of 200 mL, 240 mg I/mL, boxes of 10.

Omnipaque 300: Vials of 10 mL, 300 mg I/mL, boxes of 10. Vials of 20 mL, 300 mg I/mL, boxes of 10. Vials of 50 mL, 300 mg I/mL, boxes of 10. Bottles of 50 mL, 300 mg I/mL, boxes of 10. Bottles of 100 mL, 300 mg I/mL, boxes of 10. Bottles of 200 mL (with 150 mL fill), 300 mg I/mL, boxes of 10. Bottles of 200 mL, 300 mg I/mL, boxes of 10. Bottles of 500 mL, 300 mg I/mL, boxes of 6. Flexible containers of 100 mL, 300 mg I/mL, boxes of 10. Flexible containers of 150 mL, 300 mg I/mL, boxes of 10.

Omnipaque 350: Vials of 50 mL, 350 mg I/mL, boxes of 10. Bottles of 50 mL, 350 mg I/mL, boxes of 10. Bottles of 100 mL, 350 mg I/mL, boxes of 10. Bottles of 200 mL (with 150 mL fill), 350 mg I/mL, boxes of 10. Bottles of 200 mL, 350 mg I/mL, boxes of 10. Bottles of 500 mL, 350 mg I/mL, boxes of 6. Flexible containers of 100 mL, 350 mg I/mL, boxes of 10. Flexible containers of 150 mL, 350 mg I/mL, boxes of 10. Flexible containers of 200 mL, 350 mg I/mL, boxes of 10.