Tomohexol

SECTION I - INTRATHECAL

Tomohexol 180, Tomohexol 240, and Tomohexol 300 are indicated for intrathecal administration in adults including myelography (lumbar, thoracic, cervical, total columnar) and in contrast enhancement for computerized tomography (myelography, cisternography, ventriculography). Tomohexol 180 is indicated for intrathecal administration in children including myelography (lumbar, thoracic, cervical, total columnar) and in contrast enhancement for computerized tomography (myelography, cisternography).

SECTION II - INTRAVASCULAR

General

Tomohexol 350 is indicated in adults for angiocardiography (ventriculography, selective coronary arteriography), aortography including studies of the aortic root, aortic arch, ascending aorta, abdominal aorta and its branches, contrast enhancement for computed tomographic head and body imaging, intravenous digital subtraction angiography of the head, neck, abdominal, renal and peripheral vessels, peripheral arteriography, and excretory urography.

Tomohexol 350 is indicated in children for angiocardiography (ventriculography, pulmonary arteriography, and venography; studies of the collateral arteries and aortography, including the aortic root, aortic arch, ascending and descending aorta).

Tomohexol 300 is indicated in adults for aortography including studies of the aortic arch, abdominal aorta and its branches, contrast enhancement for computed tomographic head and body imaging, cerebral arteriography, peripheral venography (phlebography), and excretory urography.

Tomohexol 300 is indicated in children for angiocardiography (ventriculography), excretory urography, and contrast enhancement for computed tomographic head imaging. Tomohexol 240 is indicated in adults for contrast enhancement for computed tomographic head imaging and peripheral venography (phlebography).

Tomohexol 140 is indicated in adults for intra-arterial digital subtraction angiography of the head, neck, abdominal, renal and peripheral vessels.

Tomohexol 240 is indicated in children for contrast enhancement for computed tomographic head imaging.

SECTION III - ORAL/BODY CAVITY USE

General

Tomohexol 240, Tomohexol 300, and Tomohexol 350 have osmolalities from approximately 1.8 to 3.0 times that of plasma (285 mOsm/kg water) and are hypertonic under conditions of use.

Adults: Tomohexol 350 is indicated in adults for arthrography and oral pass-thru examination of the gastrointestinal tract.

Tomohexol 300 is indicated in adults for arthrography and hysterosalpingography. Tomohexol 240 is indicated in adults for arthrography, endoscopic retrograde pancreatography and cholangiopancreatography, herniography, and hysterosalpingography. Tomohexol diluted to concentrations from 6 mgI/mL to 9 mgI/mL administered orally in conjunction with Tomohexol 300 at a concentration of 300 mgI/mL administered intravenously is indicated in adults for contrast enhanced computed tomography of the abdomen.

Children: Tomohexol 300 is indicated in children for examination of the gastrointestinal tract.

Tomohexol 240 is indicated in children for examination of the gastrointestinal tract.

Tomohexol 180 is indicated in children for examination of the gastrointestinal tract.

Tomohexol diluted to concentrations from 50 mgI/mL to 100 mgI/mL is indicated in children for voiding cystourethrography.

Tomohexol diluted to concentrations from 9 mgI/mL to 21 mgI/mL administered orally in conjunction with Tomohexol 240 at a concentration of 240 mgI/mL or Tomohexol 300 at a concentration of 300 mgI/mL administered intravenously is indicated in children for use in contrast enhanced computed tomography of the abdomen.

SECTION I - INTRATHECAL

The volume and concentration of Tomohexol 180, Tomohexol 240, or Tomohexol 300 to be administered will depend on the degree and extent of contrast required in the area(s) under examination and on the equipment and technique employed.

Tomohexol 180 at a concentration of 180 mgI/mL, Tomohexol 240 at a concentration of 240 mgI/mL, or Tomohexol 300 at a concentration of 300 mgI/mL is recommended for the examination of the lumbar, thoracic, and cervical regions in adults by lumbar or direct cervical injection and is slightly hypertonic to CSF.

Tomohexol 180 at a concentration of 180 mgI/mL is recommended for the examination of the lumbar, thoracic, and cervical regions in children by lumbar injection and is slightly hypertonic to CSF.

A total dose of 3060 mg iodine or a concentration of 300 mgI/mL should not be exceeded in adults and a total dose of 2700 mg iodine or a concentration of 180 mgI/mL should not be exceeded in children in a single myelographic examination. This is based on clinical trial evaluation to date. As in all diagnostic procedures, the minimum volume and dose to produce adequate visualization should be used. Most procedures do not require either maximum dose or concentration.

Anesthesia is not necessary. Premedication sedatives or tranquilizers are usually not needed (see PRECAUTIONS). Patients should be well hydrated prior to and following contrast administration. Seizure-prone patients should be maintained on anticonvulsant medication. Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs; therefore, concurrent drugs should not be physically admixed with contrast agents.

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 contrast medium which may be required for the procedure a small amount of CSF may be removed to minimize distention of the subarachnoid spaces.

The lumbar or cervical puncture needle may be removed immediately following injection since it is not necessary to remove Tomohexol after injection into the subarachnoid space.

Adults

The usual recommended total doses for use in lumbar, thoracic, cervical, and total columnar myelography in adults are 1.2 gI to 3.06 gI as follows:

Pediatrics

The usual recommended total doses for lumbar, thoracic, cervical, and/or total columnar myelography by lumbar puncture in children are 0.36 gI to 2.7 gI (see table below). Actual volumes administered depend largely on patient age and the following guidelines are recommended.

Withdrawal of contrast agents from their containers should be accomplished under aseptic conditions with sterile syringes. Spinal puncture must always be performed under sterile conditions.

Parenteral products should be inspected visually for particulate matter or discoloration prior to administration. If particulate matter or discoloration is present, do not use. Repeat Procedures: If in the clinical judgment of the physician sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. An interval of at least 48 hours should be allowed before repeat examination; however, whenever possible, 5 to 7 days is recommended.

SECTION II - INTRAVASCULAR

General

As with all radiopaque contrast agents, the lowest dose of Tomohexol necessary to obtain adequate visualization should be used. A lower dose may reduce the possibility of an adverse reaction. Most procedures do not require use of either the maximum volume or the highest concentration of Tomohexol. The combination of volume and concentration of Tomohexol to be used should be carefully individualized accounting for factors such as age, body weight, size of the vessel and the rate of blood flow within the vessel. Other factors such as anticipated pathology, degree and extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed should be considered.

Sterile technique must be used in all vascular injections involving contrast media. Withdrawal of contrast agents from their containers should be accomplished under aseptic conditions with sterile equipment. Sterile techniques must be used with any invasive procedure. If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

It may be desirable that solutions of radiopaque diagnostic agents be used at body temperature when injected.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions of Tomohexol should be used only if clear and within the normal colorless to pale yellow range. If particulate matter or discoloration is present, do not use.

Individual Indications And Usage

Angiocardiography

Pharmacology - Hemodynamic Changes

Tomohexol 350 at a concentration of 350 mgI/mL is indicated in adults for angiocardiography (ventriculography, aortic root injections, and selective coronary arteriography).

Tomohexol 350 at a concentration of 350 mgI/mL is indicated in children for angiocardiography (ventriculography, pulmonary arteriography, and venography, and studies of the collateral arteries).

Tomohexol 300 at a concentration of 300 mgI/mL is indicated in children for angiocardiography (ventriculography).

After both ventricular and coronary injection, decreases in systolic pressure were less pronounced and returned to baseline values earlier with Tomohexol 350 than with diatrizoate meglumine and diatrizoate sodium injection.

Tomohexol 350 produced less Q-T interval prolongation than seen with diatrizoate meglumine and diatrizoate sodium injection.

In children, after injection of all sites, but particularly following ventricular and pulmonary artery injections, decreases in both systolic and diastolic intravascular pressure were significantly less pronounced with Tomohexol 350 than with diatrizoate meglumine and diatrizoate sodium injection.

In children, Tomohexol 350 produced significantly less shortening of the R-R interval than seen with diatrizoate meglumine and diatrizoate sodium injection. If repeat injections are made in rapid succession, all these changes are likely to be more pronounced. (See DOSAGE AND ADMINISTRATION.)

Precautions

During administration of large doses of Tomohexol 350, continuous monitoring of vital signs is desirable. 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 after injection into the right heart outflow tract. (See PRECAUTIONS - General.)

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 greater than 1.5 mg/dL or those less than 12 months of age.

Adverse Reactions

Cardiovascular system reactions in angiocardiography included angina (8%), hypotension (2.5%), bradycardia (1.0%), and tachycardia (1.0%). (See ADVERSE REACTIONS: Intravascular - General.)

Dosage And Administration

The individual dose or volume is determined by the size of the structure to be visualized, the anticipated degree of hemodilution, and valvular competence. Weight is a minor consideration in adults, but must be considered in infants and young children. The volume of each individual injection is a more important consideration than the total dosage used. When large individual volumes are administered, as in ventriculography and aortography, it has been suggested that several minutes be permitted to elapse between each injection to allow for subsidence of possible hemodynamic disturbances. The recommended single injection volume of Tomohexol 350 for angiocardiographic procedures in adults and the recommended single injection volumes of Tomohexol 350 and Tomohexol 300 for angiographic procedures in children are as follows:

Ventriculography

Adults:

The usual adult volume for a single injection is 40 mL with a range of 30 mL to 60 mL. This may be repeated as necessary. When combined with selective coronary arteriography, the total administered volume should not exceed 250 mL (87.5 gI).

Pediatrics:

The usual single injection dose of Tomohexol 350 is 1.25 mL/kg of body weight with a range of 1.0 mL/kg to 1.5 mL/kg. For Tomohexol 300 the usual single injection dose is 1.75 mL/kg with a range of 1.5 mL/kg to 2.0 mL/kg. When multiple injections are given, the total administered dose should not exceed 5 mL/kg up to a total volume of 250 mL of Tomohexol 350 or up to a total volume of 291 mL of Tomohexol 300.

Selective Coronary Arteriography

The usual adult volume for right or left coronary arteriography is 5 mL (range 3 mL to 14 mL) per injection.

Aortic Root And Arch Study When Used Alone

The usual adult single injection volume is 50 mL, with a range of 20 mL to 75 mL.

Pulmonary Angiography

Pediatrics: The usual single injection dose is 1.0 mL/kg of Tomohexol 350.

Combined Angiocardiographic Procedures

Multiple Procedures

Adults: The visualization of multiple vascular systems and target organs is possible during a single radiographic examination of the patient.

Large doses of Tomohexol 350 were well tolerated in angiographic procedures requiring multiple injections.

The maximum total volume for multiple procedures should not exceed 250 mL of 350 mgI/mL(87.5 gI).

Pediatrics: Visualization of multiple vascular systems and target organs is possible during a single radiographic examination of the patient.

The maximum total dose for multiple injection procedures should not exceed 5.0 mL/kg up to a total volume of 250 mL of Tomohexol 350 or 6.0 mL/kg up to a total volume of 291 mL of Tomohexol 300.

Aortogarphy And Selective Visceral Arteriography

Tomohexol 300 at a concentration of 300 mgI/mL and Tomohexol 350 at a concentration of 350 mgI/mL are indicated in adults for use in aortography and selective visceral arteriography including studies of the aortic arch, ascending aorta, and abdominal aorta and its branches (celiac, mesenteric, renal, hepatic and splenic arteries).

Tomohexol 350 at a concentration of 350 mgI/mL is indicated in children for use in aortography including studies of the aortic root, aortic arch, ascending and descending aorta.

Precautions

Under conditions of slowed aortic circulation there is an increased likelihood for aortography to cause muscle spasm. Occasional serious neurologic complications, including paraplegia, have also been reported in patients with aortoiliac obstruction, femoral artery obstruction, abdominal compression, hypotension, hypertension, spinal anesthesia, and injection of vasopressors to increase contrast. 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, and an elevated creatinine and urea nitrogen. Rapid and complete return of function usually follows. (See PRECAUTIONS - General.)

Adverse Reactions

See ADVERSE REACTIONS: Intravascular - General, and ADVERSE REACTIONS - ANGIOCARDIOGRAPHY.

Dosage And Administration

Adults: The usual adult volume as a single injection is 50 mL to 80 mL for the aorta, 30 mL to 60 mL for major branches including celiac and mesenteric arteries, and 5 mL to 15 mL for renal arteries. Repeated injections may be performed if indicated, but the total volume should not exceed 291 mL of Tomohexol 300 or 250 mL of Tomohexol 350 (87.5 gI).

Pediatrics: The usual single injection dose is 1.0 mL/kg of Tomohexol 350 and should not exceed 5.0 mL/kg up to a total volume of 250 mL of Tomohexol 350.

Cerebral Arteriography

Tomohexol 300 at a concentration of 300 mgI/mL is indicated in adults for use in cerebral arteriography.

The degree of pain and flushing as the result of the use of Tomohexol 300 in cerebral arteriography is less than that seen with comparable injections of many contrast media.

In cerebral arteriography, patients should be appropriately prepared consistent with existing or suspected disease states.

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, and cardiac decompensation. Since the contrast medium is given by rapid injection, the patient should be monitored for possible untoward reactions. (See PRECAUTIONS - General.)

Adverse Reactions

Cerebral arteriography with water-soluble contrast media has been associated with temporary neurologic complications including seizures, drowsiness, transient paresis, and mild disturbances in vision such as photomas of 1-second or less duration.

Central nervous system reactions in cerebral arteriography included photomas (15%), headache (5.5%), and pain (4.5%). (See ADVERSE REACTIONS: Intravascular - General.)

Dosage And Administration

Tomohexol 300 is recommended for cerebral arteriography at the following volumes: common carotid artery (6 mL to 12 mL), internal carotid artery (8 mL to 10 mL), external carotid artery (6 mL to 9 mL), and vertebral artery (6 mL to 10 mL).

Contrast Enhanced Computed Tomography

Tomohexol 240 at a concentration of 240 mgI/mL, Tomohexol 300 at a concentration of 300 mgI/mL, and Tomohexol 350 at a concentration of 350 mgI/mL are indicated in adults for use in intravenous contrast enhanced computed tomographic head and body imaging by rapid injection or infusion technique.

Tomohexol 240 at a concentration of 240 mgI/mL and Tomohexol 300 at a concentration of 300 mgI/mL are indicated in children for use in intravenous contrast enhanced computed tomographic head imaging by rapid bolus injection.

CT Scanning Of The Head

Tomohexol may be used to redefine diagnostic precision in areas of the brain which may not otherwise have been satisfactorily visualized.

Tumors

Tomohexol may be useful to investigate the presence and extent of certain malignancies such as: gliomas including malignant gliomas, glioblastomas, astrocytomas, oligodendrogliomas and gangliomas, ependymomas, medulloblastomas, meningiomas, neuromas, pinealomas, pituitary adenomas, carniopharyngiomas, germinomas, and metastatic lesions. The usefulness of contrast enhancement for the investigation of the retrobulbar space and in cases of low grade or infiltrative glioma has not been demonstrated. In calcified lesions, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement. The opacification of the inferior vermis following contrast media administration has resulted in false-positive diagnosis in a number of otherwise normal studies.

Nonneoplastic Conditions

Tomohexol may be beneficial in the image enhancement of nonneoplastic lesions. Cerebral infarctions of recent onset may be better visualized with contrast enhancement, while some infarctions are obscured if contrast medium is used. The use of iodinated contrast media results in enhancement in about 60 percent of cerebral infarctions studied from one to four weeks from the onset of symptoms.

Sites of active infection may also be enhanced following contrast medium administration. Arteriovenous malformations and aneurysms will show contrast enhancement. For these vascular lesions the enhancement is probably dependent on the iodine content of the circulating blood pool. Hematomas and intraparenchymal bleeders seldom demonstrate contrast enhancement. However, in cases of intraparenchymal clot, for which there is no obvious clinical explanation, contrast media administration may be helpful in ruling out the possibility of associated arteriovenous malformation.

CT Scanning Of The Body

Tomohexol 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.

Enhancement of computed tomography with Tomohexol may be of benefit in establishing diagnoses of certain lesions in these sites with greater assurance than is possible with CT alone. In other cases, the contrast agent may allow visualization of lesions not seen with CT alone (ie, tumor extension) or may help to define suspicious lesions seen with unenhanced CT (ie, pancreatic cyst).

For information regarding the use of dilute oral plus intravenous Tomohexol in CT of the abdomen, see Individual Indications And Usage - Oral Use.

Precautions

See PRECAUTIONS - General.

Adverse Reactions

Immediately following intravascular injection of contrast medium, a transient sensation of mild warmth is not unusual. Warmth is less frequent with Tomohexol than with ionic media. (See ADVERSE REACTIONS: Intravascular - General.)

Dosage And Administration

The concentration and volume required will depend on the equipment and imaging technique used.

Tomohexol (iohexol) Injection

The dosage recommended for use in adults for contrast enhanced computed tomography is as follows:

The dosage recommended for use in children for contrast enhanced computed tomographic head imaging is 1.0 mL/kg to 2.0 mL/kg for Tomohexol 240 or Tomohexol 300. It should not be necessary to exceed a maximum dose of 28 gI with Tomohexol 240 or 35 gI with Tomohexol 300.

Digital Subtraction Angiography

Intravenous Administration

Tomohexol 350 at a concentration of 350 mgI/mL is indicated in adults for use in intravenous digital subtraction angiography (I.V.DSA) of the vessels of the head, neck, and abdominal, renal and peripheral vessels.

Arteriograms of diagnostic quality can be obtained following the intravenous administration of contrast media employing digital subtraction and computer imaging enhancement techniques. The intravenous 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, the superior vena cava or right atrium, usually by mechanical injection although sometimes by rapid manual injection. The technique has been used to visualize the ventricles, aorta and most of its larger branches, including the carotids, cerebrals, vertebrals, renal, celiac, mesenterics, and the major peripheral vessels of the limbs. Radiographic visualization of these structures is possible until significant hemodilution occurs.

Tomohexol 350 can be injected intravenously as a rapid bolus to provide arterial visualization using digital subtraction radiography. Preprocedural medications are not considered necessary.

Tomohexol 350 has provided diagnostic arterial radiographs in about 95% of patients. In some cases, poor arterial visualization has been attributed to patient movement. Tomohexol 350 is very well tolerated in the vascular system. Patient discomfort (general sensation of heat and/or pain) following injection is less than with various other contrast media.

Precautions

Since the contrast medium is usually administered mechanically under high pressure, rupture of smaller peripheral veins can occur. It has been suggested that this can be avoided by using an intravenous catheter threaded proximally beyond larger tributaries or, in the case of the antecubital vein, into the superior vena cava. Sometimes the femoral vein is used. (See PRECAUTIONS - General.)

Adverse Reactions

Cardiovascular system reactions in digital arteriography included transient PVCs (16%) and PACs (6.5%). (See ADVERSE REACTIONS: Intravascular - General.)

Dosage And Administration

The usual injection volume of Tomohexol 350 for the intravenous digital technique is 30 mL to 50 mL of a 350 mgI/mL solution. This is administered as a bolus at 7.5 to 30 mL/second using a pressure injector. The volume and rate of injection will depend primarily on the type of equipment and technique used. Frequently three or more injections may be required, up to a total volume not to exceed 250 mL (87.5 gI).

Intra-Arterial Administration

Tomohexol 140 at a concentration of 140 mgI/mL is indicated for use in intra-arterial digital subtraction angiography of head, neck, abdominal, renal and peripheral vessels. The intra-arterial route of administration has the advantages of allowing a lower total dose of contrast agent since there is less hemodilution than with the intravenous route of administration. Patients with poor cardiac output would be expected to have better contrast enhancement following intra-arterial administration as compared with intravenous administration. A higher concentration of contrast agent may be needed to facilitate catheter placement under fluoroscopic control.

Precautions

High pressure intra-arterial injections may cause the rupture of smaller peripheral arteries. (See PRECAUTIONS - General.)

Adverse Reactions

Central nervous system reactions in intra-arterial digital angiography include transient ischemia attacks (1.6%) and cerebral infarctions (1.6%). These occurred in high risk patients having a cerebral examination and the relationship to the contrast medium was uncertain. (See ADVERSE REACTIONS - General.) Headache occurred in 6.3% of the patients, all of whom were having cerebral examinations.

Dosage And Administration

Mechanical or hand injection can be used to administer one or more bolus intra-arterial injections of Tomohexol 140. The volume and rate of injection will depend on the type of equipment, technique used, and the vascular area to be visualized. The following volumes and rates of injection have been used with Tomohexol 140.

Peripheral Angiography

Tomohexol 300 at a concentration of 300 mgI/mL or Tomohexol 350 at a concentration of 350 mgI/mL is indicated in adults for use in peripheral arteriography. Tomohexol 240 at a concentration of 240 mgI/mL or Tomohexol 300 at a concentration of 300 mgI/mL is indicated in adults for use in peripheral venography.

Sedative medication may be employed prior to use. Anesthesia is not considered necessary. Patient discomfort during and immediately following injection is substantially less than that following injection of various other contrast media. Moderate to severe discomfort is very unusual.

Precautions

Pulsation should be present in the artery to be injected. In thromboangiitis obliterans, or ascending infection associated with severe ischemia, angiography should be performed with extreme caution, if at all. (See PRECAUTIONS - General.)

Adverse Reactions

A transient sensation of mild warmth is usual, immediately following injection. This has not interfered with the procedure.

In phlebography the incidence of leg pain was 21%. This usually was mild and lasted a short time after injection. (See ADVERSE REACTIONS: Intravascular - General.)

Dosage And Administration

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 imaging technique used. The dosage recommended for use in peripheral angiography is as follows:

Excretory Urography

Tomohexol 300 at a concentration of 300 mgI/mL or Tomohexol 350 at a concentration of 350 mgI/mL is indicated for use in adults in excretory urography to provide diagnostic contrast of the urinary tract.

Tomohexol 300 at a concentration of 300 mgI/mL is indicated in children for excretory urography. (See Section III for information on voiding cystourethrography.)

For pharmacokinetics of excretion in adults, see CLINICAL PHARMACOLOGY - Intravascular.

Precautions

Preparatory dehydration is not recommended 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 greater than 1.5 mg/dL or those less than 12 months of age.

Since there is a possibility of temporary suppression of urine formation, it is recommended that a suitable interval elapse before excretory urography is repeated, especially in patients with unilateral or bilateral reduction in renal function. (See PRECAUTIONS - General.)

Adverse Reactions

See ADVERSE REACTIONS: Intravascular - General.

Dosage And Administration

Adults: Tomohexol 300 and Tomohexol 350 at dosages from 200 mgI/kg body weight to 350 mgI/kg body weight have produced diagnostic opacification of the excretory system in patients with normal renal function.

Pediatrics

Excretory Urography

Tomohexol 300 at doses of 0.5 mL/kg to 3.0 mL/kg of body weight has produced diagnostic opacification of the excretory tract. The usual dose for children is 1.0 mL/kg to 1.5 mL/kg. Dosage for infants and children should be administered in proportion to age and body weight. The total administered dose should not exceed 3 mL/kg.

SECTION III - ORAL/BODY CAVITY USE

General

See SECTION II, DOSAGE AND ADMINISTRATION; General.

Individual Indications And Usage

Oral Use

Adults: Tomohexol 350 at a concentration of 350 mgI/mL is indicated in adults for use in oral pass-thru examination of the gastrointestinal tract. Tomohexol diluted to concentr

SECTION I - INTRATHECAL

Tomohexol should not be administered to patients with a known hypersensitivity to iohexol.

Myelography should not be performed in the presence of significant local or systemic infection where bacteremia is likely.

Intrathecal administration of corticosteroids with Tomohexol is contraindicated.

Because of the possibility of overdosage, immediate repeat myelography in the event of technical failure is contraindicated (see DOSAGE AND ADMINISTRATION).

SECTION II - INTRAVASCULAR

Tomohexol should not be administered to patients with a known hypersensitivity to iohexol.

SECTION III - ORAL/BODY CAVITY USE

Tomohexol should not be administered to patients with a known hypersensitivity to iohexol.

WARNINGS

SECTION I - INTRATHECAL

General

Severe Adverse Event - Inadvertent Intrathecal Adminisatration

Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that Tomohexol 140 and 350 are not administered intrathecally. (All other concentrations of Tomohexol are approved for intrathecal administration.)

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

Caution is advised in patients with a history of epilepsy, severe cardiovascular disease, chronic alcoholism, or multiple sclerosis.

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 paid to dose and concentration of the medium, hydration, and technique used.

Patients who are receiving anticonvulsants should be maintained on this therapy. Should a seizure occur, intravenous diazepam or phenobarbital sodium is recommended. In patients with a history of seizure activity who are not on anticonvulsant therapy, premedication with barbiturates should be considered.

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

Drugs which lower the seizure threshold, especially phenothiazine derivatives, including those used for their antihistamine properties, are not recommended for use with Tomohexol. Others include MAO inhibitors, tricyclic antidepressants, CNS stimulants, and psychoactive drugs described as analeptics, major tranquilizers, or antipsychotic drugs. While the contributory role of these medications has not been established, the use of such drugs should be based on physician evaluation of potential benefits and potential risks. Physicians have discontinued these agents at least 48 hours before and for at least 24 hours postprocedure.

Care is required in patient management to prevent inadvertent intracranial entry of a large dose or concentrated bolus of the medium. Also, effort should be directed to avoid rapid dispersion of the medium causing inadvertent rise to intracranial levels (eg, by active patient movement). Direct intracisternal or ventricular administration for standard radiography (not CT) is not recommended.

In most reported cases of major motor seizures with nonionic myelographic media, one or more of the following factors were present. Therefore avoid:

• Deviations from recommended procedure or in myelographic management.
• Use in patients with a history of epilepsy.
• 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 the procedure, on the stretcher, or in bed.
• Excessive and particularly active patient movement or straining.

SECTION II - INTRAVASCULAR

General

Nonionic iodinated contrast media inhibit blood coagulation, in vitro, less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing nonionic contrast media.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, 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 guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions 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.

Tomohexol should be used with extreme care in patients with severe functional disturbances of the liver and kidneys, severe thyrotoxicosis, or myelomatosis. Diabetics 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. Tomohexol is not recommended for use in patients with anuria.

Radiopaque contrast agents are potentially hazardous in patients with multiple myeloma or other paraproteinemia, particularly in those with therapeutically resistant anuria. Although neither the contrast agent nor dehydration has separately proven to be the cause of anuria in myeloma, it has been speculated that the combination of both may be causative factors. The risk in myelomatous patients is not a contraindication; however, special precautions are necessary. Partial dehydration in the preparation of these patients prior to injection is not recommended since this may predispose the patient to precipitation of the myeloma protein in the renal tubules. No form of therapy, including dialysis, has been successful in reversing the effect. Myeloma, which occurs most commonly in persons over age 40, should be considered before instituting intravascular administration of contrast agents.

Ionic contrast media, when injected intravenously or intra-arterially, may promote sickling in individuals who are homozygous for sickle cell disease.

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

Reports of thyroid storm following the use of iodinated, ionic radiopaque contrast media in patients with hyperthyroidism or with an autonomously functioning thyroid nodule suggest that this additional risk be evaluated in such patients before use of any contrast medium.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions(SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering Tomohexol to patients with a history of a severe cutaneous adverse reaction to Tomohexol. Urography should be performed with caution in patients with severely impaired renal function and patients with combined renal and hepatic disease.

SECTION III - ORAL/BODY CAVITY USE

General

See SECTION II, General.

PRECAUTIONS

SECTION I - INTRATHECAL

General

Diagnostic procedures which involve the use of radiopaque diagnostic agents should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reactions to the contrast agent itself. After parenteral administration of a radiopaque agent, competent personnel and emergency facilities should be available for at least 30 to 60 minutes since severe delayed reactions have occurred. (See ADVERSE REACTIONS.)

Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with preexisting renal disease). Dehydration in these patients seems to be enhanced by the osmotic diuretic action of contrast agents. Patients should be well hydrated prior to and following administration of any contrast medium, including iohexol.

The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid, cardiovascular or central nervous system reactions, should always be considered (see ADVERSE REACTIONS). Therefore, it is of utmost importance that a course of action be carefully planned in advance for the immediate treatment of serious reactions, and that adequate and appropriate facilities and personnel be readily available in case of any reaction.

The possibility of an idiosyncratic reaction in susceptible patients should always be considered (see ADVERSE REACTIONS). The susceptible population includes, but is not limited to, patients with a history of a previous reaction to contrast media, patients with a known sensitivity to iodine per se, and patients with a known clinical hypersensitivity: bronchial asthma, hay fever, and food allergies.

The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to the injection of any contrast media, may be more accurate than pretesting in predicting potential adverse reactions.

A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution should be exercised (see ADVERSE REACTIONS). Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered. Recent reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.

In patients with severe renal insufficiency or failure, compensatory biliary excretion of the drug is anticipated to occur, with a slow clearance into the bile. Patients with hepatorenal insufficiency should not be examined unless the possibility of benefit clearly outweighs the additional risk. Administration of contrast media should be performed by qualified personnel familiar with the procedure and appropriate patient management (see PATIENT INFORMATION). Sterile technique must be used with any spinal puncture. When Tomohexol is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately. If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is present, do not use. Repeat Procedures: If in the clinical judgment of the physician sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY).

Information For Patients (Or If Applicable, Children)

Patients receiving injectable radiopaque diagnostic agents should be instructed to:

1. Inform your physician if you are pregnant (seeCLINICAL PHARMACOLOGY).
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or known thyroid disorder (see WARNINGS).
3. Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous injections of dyes used for x-ray procedures (see PRECAUTIONS - General).
4. Inform your physician about any other medications you are currently taking, including nonprescription drugs, before you are administered this drug.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term animal studies have been performed to evaluate carcinogenic potential, mutagenesis, or whether Tomohexol can affect fertility in men or women.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits with up to 100 times the recommended human dose. No evidence of impaired fertility or harm to the fetus has been demonstrated due to Tomohexol. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known to what extent iohexol is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast media are administered to nursing women. Bottle feedings may be substituted for breast feedings for 24 hours following administration of Tomohexol.

Pediatric Use

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 greater than 1.5 mg/dL or those less than 12 months of age.

SECTION II - INTRAVASCULAR

General

Diagnostic procedures which involve the use of radiopaque diagnostic agents should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reactions to the contrast agent itself. After parenteral administration of a radiopaque agent, competent personnel and emergency facilities should be available for at least 30 to 60 minutes since severe delayed reactions have occurred (see ADVERSE REACTIONS: Intravascular - General).

Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with preexisting renal disease), infants and small children. Dehydration in these patients seems to be enhanced by the osmotic diuretic action of urographic agents. It is believed that overnight fluid restriction prior to excretory urography generally does not provide better visualization in normal patients. Patients should be well hydrated prior to and following administration of any contrast medium, including iohexol.

Acute renal failure has been reported in diabetic patients with diabetic nephropathy and in susceptible non-diabetic patients (often elderly with preexisting renal disease) following excretory urography. Therefore, careful consideration of the potential risks should be given before performing this radiographic procedure in these patients.

Immediately following surgery, excretory urography should be used with caution in renal transplant recipients.

The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered (see ADVERSE REACTIONS: Intravascular - General). It is of utmost importance that a course of action be carefully planned in advance for immediate treatment of serious reactions, and that adequate and appropriate personnel be readily available in case of any reaction.

The possibility of an idiosyncratic reaction in susceptible patients should always be considered (see ADVERSE REACTIONS: Intravascular - General). The susceptible population includes, but is not limited to, patients with a history of a previous reaction to contrast media, patients with a known sensitivity to iodine per se, and patients with a known clinical hypersensitivity: bronchial asthma, hay fever, and food allergies.

The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to the injection of any contrast media, may be more accurate than pretesting in predicting potential adverse reactions.

A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution should be exercised (see ADVERSE REACTIONS: Intravascular - General). Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered and administered using separate syringes. Recent reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.

Even though the osmolality of Tomohexol is low compared to diatrizoate-or iothalamatebased ionic agents of comparable iodine concentration, the potential transitory increase in the circulatory osmotic load in patients with congestive heart failure requires caution during injection. These patients should be observed for several hours following the procedure to detect delayed hemodynamic disturbances.

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

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

In angiographic procedures, the possibility of dislodging plaques or damaging or perforating the vessel wall should be borne in mind during the catheter manipulations and contrast medium injection. Test injections to ensure proper catheter placement are recommended. Selective coronary arteriography should be performed only in those patients in whom the expected benefits outweigh the potential risk. The inherent risks of angiocardiography in patients with chronic pulmonary emphysema must be weighed against the necessity for performing this procedure.

When Tomohexol is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately.

If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is present, do not use.

Information for Patients

Patients receiving injectable radiopaque diagnostic agents should be instructed to:

1. Inform your physician if you are pregnant (see CLINICAL PHARMACOLOGY - Intravascular).
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder (see WARNINGS).
3. Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous injections of dyes used for x-ray procedures (see PRECAUTIONS - General).
4. Inform your physician about any other medications you are currently taking, including nonprescription drugs, before you are administered this drug.
5. Advise patients to inform their physician if they develop a rash after receiving Tomohexol.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term animal studies have been performed to evaluate carcinogenic potential, mutagenesis, or whether Tomohexol can affect fertility in men or women.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits with up to 100 times the recommended human dose. No evidence of impaired fertility or harm to the fetus has been demonstrated due to Tomohexol. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known to what extent iohexol is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast media are administered to nursing women. Bottle feedings may be substituted for breast feedings for 24 hours following administration of Tomohexol.

Pediatric Use

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 greater than 1.5 mg/dL or those less than 12 months of age.

SECTION III - ORAL/BODY CAVITY USE

General

See SECTION II, PRECAUTIONS, General.

Orally administered hypertonic contrast media draw fluid into the intestines which, if severe enough, could result in hypovolemia. Likewise, in infants and young children, the occurrence of diarrhea may result in hypovolemia. Plasma fluid loss may be sufficient to cause a shock-like state which, if untreated, could be dangerous. This is especially pertinent to the elderly, cachectic patients of any age as well as infants and small children.

SECTION I - INTRATHECAL

The most frequently reported adverse reactions with Tomohexol 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 and their significance must be assessed on an individual basis. Those reactions reported in clinical studies with Tomohexol are listed below in decreasing order of occurrence, based on clinical studies of 1531 patients.

Headaches:The most frequently occurring adverse reaction following myelography has been headache, with an incidence of approximately 18%. Headache may be caused by either a direct effect of the contrast medium or by CSF leakage at the dural puncture site. However, in managing the patient, it is considered more important to minimize intracranial entry of contrast medium by postural management than attempting to control possible CSF leakage (see PATIENT INFORMATION).

Pain:Mild to moderate pain including backache, neckache and stiffness, and neuralgia occurred following injection with an incidence of about 8%.

Nausea and Vomiting:Nausea was reported with an incidence of about 6%, and vomiting about 3% (see PATIENT INFORMATION). Maintaining normal hydration is very important. The use of phenothiazine antinauseants is not recommended. (See WARNINGS - General.) Reassurance to the patient that the nausea will clear usually is all that is required.

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

Other Reactions: Other reactions occurring with an individual incidence of less than 0.1% included: feeling of heaviness, hypotension, hypertonia, sensation of heat, sweating, vertigo, loss of appetite, drowsiness, hypertension, photophobia, tinnitus, neuralgia, paresthesia, difficulty in micturition, and neurological changes. All were transient and mild with no clinical sequelae.

Pediatrics

In controlled clinical trials involving 152 patients for pediatric myelography by lumbar puncture, adverse events following the use of Tomohexol 180 were generally less frequent than with adults.

Headache:9%

Vomiting:6%

Backache:1.3%

Other Reactions: Other reactions occurring with an individual incidence of less than 0.7% included: fever, hives, stomachache, visual hallucination, and neurological changes. All were transient and mild with no clinical sequelae.

General Adverse Reactions To Contrast Media

Physicians should remain alert for the occurrence of adverse effects in addition to those discussed above, particularly the following reactions which have been reported in the literature for other nonionic, water-soluble myelographic media, and rarely with iohexol. These have included, but are not limited to, convulsion, aseptic and bacterial meningitis, and CNS and other neurological disturbances.

An aseptic meningitis syndrome has been reported rarely (less than 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 started to clear spontaneously about 10 hours after onset, with complete recovery over 2 to 3 days.

Allergy or Idiosyncrasy: Chills, fever, profuse diaphoresis, pruritus, urticaria, nasal congestion, dyspnea, and a case of Guillain-Barré syndrome.

CNS Irritation: Mild and transitory perceptual aberrations such as hallucinations, depersonalization, amnesia, hostility, amblyopia, diplopia, photophobia, psychosis, insomnia, anxiety, depression, hyperesthesia, visual or auditory or speech disturbances, confusion and disorientation. In addition, malaise, weakness, convulsion, EEG changes, meningismus, hyperreflexia or areflexia, hypertonia or flaccidity, hemiplegia, paralysis, quadriplegia, restlessness, tremor, echoacousia, echolalia, asterixis, cerebral hemorrhage, and dysphasia have occurred.

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, without aftereffects. 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 (believed subjective or delusional), 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 for the reaction event.

Rarely, persistent though transitory weakness in the leg or ocular muscles has been reported. Peripheral neuropathies have been rare and transitory. They include sensory and/or motor or nerve root disturbances, myelitis, persistent leg muscle pain or weakness, 6th nerve palsy, or cauda equina syndrome. Muscle cramps, fasciculation or myoclonia, spinal convulsion, or spasticity is unusual and has responded promptly to a small intravenous dose of diazepam. In general, the reactions which are known to occur upon parenteral administration of iodinated contrast agents are possible with any nonionic agent. Approximately 95 percent of adverse reactions accompanying the use of water-soluble contrast agents are mild to moderate in degree. However, severe, life-threatening, anaphylactoid and fatal reactions, mostly of cardiovascular origin and central nervous system origin, have occurred.

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

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

Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the amount of dose injected, the speed of injection, and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory. 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. Most adverse reactions to injectable contrast media appear within 1 to 3 minutes after the start of injection, but delayed reactions may occur.

SECTION II - INTRAVASCULAR

General

Adverse reactions following the use of Tomohexol 140, Tomohexol 240, Tomohexol 300, and Tomohexol 350 are usually of mild to moderate severity. However, serious, life-threatening and fatal reactions, mostly of cardiovascular origin, have been associated with the administration of iodine-containing contrast media, including Tomohexol. The injection of contrast media is frequently associated with the sensation of warmth and pain, especially in peripheral angiography; pain and warmth are less frequent and less severe with Tomohexol than with many contrast media.

Cardiovascular System:Arrhythmias including PVCs and PACs (2%), angina/chest pain (1%), and hypotension (0.7%). Others including cardiac failure, asystole, bradycardia, tachycardia, and vasovagal reaction were reported with an individual incidence of 0.3% or less. In controlled clinical trials involving 1485 patients, one fatality occurred. A cause and effect relationship between this death and iohexol has not been established.

Nervous System:Vertigo (including dizziness and lightheadedness) (0.5%), pain (3%), vision abnormalities (including blurred vision and photomas) (2%), headache (2%), and taste perversion (1%). Others including anxiety, fever, motor and speech dysfunction, convulsion, paresthesia, somnolence, stiff neck, hemiparesis, syncope, shivering, transient ischemic attack, cerebral infarction, and nystagmus were reported, with an individual incidence of 0.3% or less.

Respiratory System: Dyspnea, rhinitis, coughing, and laryngitis, with an individual incidence of 0.2% or less.

Gastrointestinal System: Nausea (2%) and vomiting (0.7%). Others including diarrhea, dyspepsia, cramp, and dry mouth were reported, with an individual incidence of less than 0.1%.

Skin and Appendages: Urticaria (0.3%), purpura (0.1%), abscess (0.1%), and pruritus (0.1%). Individual adverse reactions which occurred to a significantly greater extent for a specific procedure are listed under that indication.

Pediatrics

In controlled clinical trials involving 391 patients for pediatric angiocardiography, urography, and contrast enhanced computed tomographic head imaging, adverse reactions following the use of Tomohexol 240, Tomohexol 300, and Tomohexol 350 were generally less frequent than with adults.

Cardiovascular System: Ventricular tachycardia (0.5%), 2:1 heart block (0.5%), hypertension (0.3%), and anemia (0.3%).

Nervous System: Pain (0.8%), fever (0.5%), taste abnormality (0.5%), and convulsion (0.3%).

Respiratory System: Congestion (0.3%) and apnea (0.3%).

Gastrointestinal System: Nausea (1%), hypoglycemia (0.3%), and vomiting (2%).

Skin and Appendages: Rash (0.3%).

General Adverse Reactions To Contrast Media

Physicians should remain alert for the occurrence of adverse effects in addition to those discussed above.

The following reactions have been reported after administration of other intravascular iodinated contrast media, and rarely with iohexol. Reactions due to technique: hematomas and ecchymoses. Hemodynamic reactions: vein cramp and thrombophlebitis following intravenous injection. Cardiovascular reactions: rare cases of cardiac arrhythmias, reflex tachycardia, chest pain, cyanosis, hypertension, hypotension, peripheral vasodilatation, shock, and cardiac arrest. Endocrine reactions: Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration to adult and pediatric patients, including infants. Some patients were treated for hypothyroidism. Skin and Subcutaneous Tissue Disorders: Reactions range from mild (rash, erythema, pruritus, urticaria, skin discoloration) to severe: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Renal reactions: occasionally, transient proteinuria, and rarely, oliguria or anuria. Allergic reactions: asthmatic attacks, nasal and conjunctival symptoms, dermal reactions such as urticaria with or without pruritus, as well as pleomorphic rashes, sneezing and lacrimation and, rarely, anaphylactic reactions. Rare fatalities have occurred, due to this or unknown causes. Signs and symptoms related to the respiratory system: pulmonary or laryngeal edema, bronchospasm, dyspnea; or to the nervous system: restlessness, tremors, convulsions. Other reactions: flushing, pain, warmth, metallic taste, nausea, vomiting, anxiety, headache, confusion, pallor, weakness, sweating, localized areas of edema, especially facial cramps, neutropenia, and dizziness. Rarely, immediate or delayed rigors can occur, sometimes accompanied by hyperpyrexia. Infrequently, “iodism” (salivary gland swelling) from organic iodinated compounds appears two days after exposure and subsides by the sixth day.

In general, the reactions which are known to occur upon parenteral administration of iodinated contrast agents are possible with any nonionic agent. Approximately 95 percent of adverse reactions accompanying the use of water-soluble intravascularly administered contrast agents are mild to moderate in degree. However, severe, life-threatening anaphylactoid reactions, mostly of cardiovascular origin, have occurred. Reported incidences of death range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 (0.01 percent). Most deaths occur during injection or 5 to 10 minutes later; the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. The incidence of shock is estimated to be 1 out of 20,000 (0.005 percent) patients.

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

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

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

Most adverse reactions to injectable contrast media appear within 1 to 3 minutes after the start of injection, but delayed reactions may occur.

Regardless of the contrast agent employed, the overall estimated incidence of serious adverse reactions is higher with angiocardiography than with other procedures. Cardiac decompensation, serious arrhythmias, angina pectoris, or myocardial ischemia or infarction may occur during angiocardiography and left ventriculography. Electrocardiographic and hemodynamic abnormalities occur less frequently with Tomohexol than with diatrizoate meglumine and diatrizoate sodium injection.

SECTION III - ORAL/BODY CAVITY USE

General

Body Cavities

In controlled clinical trials involving 285 adult patients for various body cavity examinations using Tomohexol 240, 300, and 350, the following adverse reactions were reported.

Cardiovascular System

Incidence > 1%: None

Incidence ≤ 1%: Hypertension

Nervous System

Incidence > 1%: Pain (26%)

Incidence ≤ 1%: Headache, somnolence, fever, muscle weakness, burning, unwell feeling, tremors, lightheadedness, syncope

Respiratory System

None

Gastrointestinal System

Incidence > 1%: None Incidence ≤ 1%: Flatulence, diarrhea, nausea, vomiting, abdominal pressure

Skin and Appendages

Incidence > 1%: Swelling (22%), heat (7%)

Incidence ≤ 1%: Hematoma at injection site

The most frequent reactions, pain and swelling, were almost exclusively reported after arthrography and were generally related to the procedure rather than the contrast medium. Gastrointestinal reactions were almost exclusively reported after oral pass-thru examinations. For additional information on adverse reactions that may be expected with specific procedures, see Individual Indications And Usage. For information on general adverse reactions to contrast media, see SECTION II, ADVERSE REACTIONS: Intravascular - General. No adverse reactions associated with the use of Tomohexol for VCU procedures were reported in 51 pediatric patients studied.

Oral Use

See Individual Indications And Usage, Oral Use - Adverse Reactions.

SECTION I - INTRATHECAL

Clinical consequences of overdosage with Tomohexol have not been reported. However, based on experience with other nonionic myelographic media, physicians should be alert to a potential increase in frequency and severity of CNS-mediated reactions. Even use of a recommended dose can produce effects tantamount to overdosage, if incorrect management of the patient during or immediately following the procedure permits inadvertent early intracranial entry of a large portion of the medium.

The intracisternal LD₅₀ value of Tomohexol (in grams of iodine per kilogram body weight) is greater than 2.0 in mice.

SECTION II - INTRAVASCULAR

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

The intravenous LD₅₀ values of Tomohexol (in grams of iodine per kilogram body weight) are 24.2 in mice and 15.0 in rats.

SECTION III - ORAL/BODY CAVITY USE

See also SECTION II.

The recommended dose of Tomohexol 350 at a concentration of 350 mgI/mL for adult oral pass-thru examination of the gastrointestinal tract is 50 mL to 100 mL. In a Phase I study, 150 mL of Tomohexol 350 was administered orally to 11 healthy male subjects. The incidence of diarrhea was 91% (10 of 11) and abdominal cramping was 27% (3 of 11). Despite all of these events being mild and transient the occurrences were more than double that seen at the recommended doses. It is apparent from this finding that larger volumes of hypertonic contrast media, like Tomohexol, increase the osmotic load in the bowel, which may result in greater fluid shifts.