IOPAMIDOL: 2,145 Adverse Event Reports & Safety Profile

1.3 Oral Procedures † ISOVUE is indicated for: CT of the abdomen and pelvis to delineate the gastrointestinal tract in adults and pediatric patients † Specific concentrations of ISOVUE are recommended for each type of imaging procedure [see Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 )].

11 DESCRIPTION ISOVUE (iopamidol) injection is a radiographic contrast agent for intra-arterial or intravenous use. Iopamidol is designated chemically as (S)-N,N’-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo-5- lactamidoisophthalamide with a molecular weight of 777.09, an empirical formula of C17H22I3N3O8, and the following structural formula: ISOVUE is a sterile, clear, colorless to pale yellow solution available in four concentrations of iodine: ISOVUE 200 mg iodine/mL: Each mL contains 408 mg iopamidol (providing 200 mg organically bound iodine) and the following inactive ingredients: 0.26 mg edetate calcium disodium (providing 0.029 mg (0.001 mEq) sodium) and 1 mg tromethamine. ISOVUE 250 mg iodine/mL: Each mL contains 510 mg iopamidol (providing 250 mg organically bound iodine) and the following inactive ingredients: 0.33 mg edetate calcium disodium (providing 0.036 mg (0.002 mEq) sodium) and 1 mg tromethamine. ISOVUE 300 mg iodine/mL: Each mL contains 612 mg iopamidol (providing 300 mg organically bound iodine) and the following inactive ingredients: 0.39 mg edetate calcium disodium (providing 0.043 mg (0.002 mEq) sodium) and 1 mg tromethamine. ISOVUE 370 mg iodine/mL: Each mL contains 755 mg iopamidol (providing 370 mg organically bound iodine) and the following inactive ingredients: 0.48 mg edetate calcium disodium (providing 0.053 mg (0.002 mEq) sodium) and 1 mg tromethamine. The pH of ISOVUE has been adjusted to 6.5 to 7.5 with hydrochloric acid and/or sodium hydroxide. Physicochemical characteristics are shown in Table 5. ISOVUE is hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively).

Table

7: Physicochemical Characteristics of ISOVUE Concentration (mg Iodine/mL) 200 250 300 370 Osmolality @ 37°C (mOsm/kg water) 413 524 616 796 Viscosity (cP) @ 37°C 2.0 3.0 4.7

9.4 Viscosity (cP) @ 20°C 3.3 5.1 8.8

20.9 Specific Gravity @ 37°C 1.227 1.281 1.339 1.405 iopamidol-structure

INDICATIONS AND USAGE ISOVUE (Iopamidol Injection) is indicated for angiography throughout the cardiovascular system in adults, including cerebral and peripheral arteriography, coronary arteriography and ventriculography, selective visceral arteriography and aortography, peripheral venography (phlebography), and in pediatric patients for angiocardiography; or for intravenous use in adult and pediatric for computed tomographic (CT) imaging of the head and body (see below). CT Head Imaging ISOVUE may be used to refine diagnostic precision in areas of the brain which may not otherwise have been satisfactorily visualized. Tumors ISOVUE 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, craniopharyngiomas, germinomas, and metastatic lesions. The usefulness of contrast enhancement for the investigation of the retrobulbar space and in cases of low grade or infiltrative glioma has not been demonstrated. In 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 ISOVUE 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 media are used. The use of iodinated contrast media results in contrast 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 media 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 any 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 Body Imaging ISOVUE (Iopamidol Injection) may be used for enhancement of computed tomographic images for detection and evaluation of lesions in the liver, pancreas, kidneys, aorta, mediastinum, abdominal cavity, pelvis and retroperitoneal space. Enhancement of computed tomography with ISOVUE may be of benefit in establishing diagnoses of certain lesions in these sites with greater assurance than is possible with CT alone, and in supplying additional features of the lesions (e.g., hepatic abscess delineation prior to percutaneous drainage). In other cases, the contrast agent may allow visualization of lesions not seen with CT alone (e.g. tumor extension), or may help to define suspicious lesions seen with unenhanced CT (e.g., pancreatic cyst). Contrast enhancement appears to be greatest within 60 to 90 seconds after bolus administration of contrast agent. Therefore, utilization of a continuous scanning technique (“dynamic CT scanning”) may improve enhancement and diagnostic assessment of tumor and other lesions such as an abscess, occasionally revealing unsuspected or more extensive disease. For example, a cyst may be distinguished from a vascularized solid lesion when precontrast and enhanced scans are compared; the nonperfused mass shows unchanged x-ray absorption (CT number). A vascularized lesion is characterized by an increase in CT number in the few minutes after a bolus of intravascular contrast agent; it may be malignant, benign, or normal tissue, but would probably not be a cyst, hematoma, or other nonvascular lesion. Because unenhanced scanning may provide adequate diagnostic information in the individual patient, the decision to employ contrast enhancement, which may be associated with risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and unenhanced CT findings.

DOSAGE AND ADMINISTRATION In adults a solution that is approximately isotonic (Iopamidol Injection, 41%) is recommended for examination of the lumbar region. For movement of the contrast medium to distant target areas the more concentrated Iopamidol Injection, 61% preparation should be used to compensate for dilution of Iopamidol Injection with cerebrospinal fluid. The usual recommended adult dose range for iopamidol is 2000-3000 mg iodine. Iopamidol formulated to contain more than 300 mgI/mL should not be used intrathecally in adults. The minimum dose needed to perform a procedure should always be used. In pediatric patients , a solution that is approximately isotonic (Iopamidol Injection, 41%) is recommended for all intrathecal procedures. In children, loss of contrast due to mixing on movement of the medium is less apt to occur because of their shorter spinal cord. The usual recommended pediatric dose range for iopamidol is 1400-2400 mg iodine. Iopamidol formulated to contain more than 200 mgI/mL should not be used intrathecally in children. The minimum dose needed to perform a procedure should always be used. See pediatric dosage table for recommended dosage . Anesthesia is not necessary. However, young children may require general anesthesia for technical reasons. Premedication with sedatives or tranquillizers is usually not needed. In patients with a history of seizure activity who are not on anticonvulsant therapy, premedication with barbiturates or phenytoin should be considered. Lumbar puncture is usually made between L3 and L4; if pathology is suspected at this level, the interspace immediately above or below may be selected. A lateral cervical puncture may also be used. Rate of Injection: To avoid excessive mixing with cerebrospinal fluid and consequent loss of contrast as well as premature cephalad dispersion, injection must be made slowly over one to two minutes; the needle may then be removed. An interval of at least 48 hours should be allowed before repeat examination; however, whenever possible five to seven days is recommended. As with all radiopaque contrast agents, only the lowest dose of Iopamidol Injection necessary to obtain adequate visualization should be used. A lower dose reduces the possibility of an adverse reaction. Most procedures do not require use of either a maximum dose or the highest available concentration of Iopamidol Injection; the combination of dose and Iopamidol Injection concentration to be used should be carefully individualized, and factors such as age, body size, anticipated pathology and 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. Following are the usual recommended pediatric and adult doses of Iopamidol Injection. The pediatric doses listed below, intended as a guideline, are based on age rather than weight because the brain and CSF capacity is independent of weight. Variations will depend on such factors as height, suspected pathology, the patient’s condition, technique used, etc. (e.g. CT or standard radiology or movement of the contrast media directed distal to the site of injection).

Pediatric Dosage Table Iopamidol

Injection, 41% (200 mgI/mL)

Procedure Age Years Usual Recommended

Dose (mL) Lumbar, thoracic myelogram 2-7 7-9 8-12 8-11 13-18 10-12 Adult Dosage Table Concentration of Solution (mgI/mL)

Usual Recommended

Dose (mL) Lumbar myelogram 200 10 to 15 Thoracic myelogram 200 10 to 15 Cervical myelogram 200 10 to 15 (via lumbar injection) 300 10 Cervical myelogram (via lateral cervical injection) 200 10 Total columnar myelography 300 10 CT cisternography (via lumbar injection) 200 4 to 6 Following subarachnoid injection, conventional radiography will continue to provide good diagnostic contrast for at least 30 minutes. At about one hour, diagnostic degree of contrast will not usually be available. However, sufficient contrast for CT myelography will be available for several hours. CT myelography following conventional myelography should be deferred for at least four hours to reduce the degree of contrast. Aspiration of iopamidol is unnecessary following intrathecal administration (see CLINICAL PHARMACOLOGY ). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Iopamidol solutions should be used only if clear and within the normal colorless to pale yellow range. Discard any product which shows signs of crystallization or damage to the container-closure system, which includes the glass container, stopper and/or crimp. It is desirable that solutions of radiopaque diagnostic agents for intrathecal use be at body temperature when injected. 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. Patients should be well hydrated prior to and following Iopamidol Injection administration. Suggestions for Usual Patient Management Preprocedure See WARNINGS regarding discontinuation of neuroleptic agents. Maintain normal diet up to 2 hours before procedure. Ensure hydration-fluids up to time of procedure.

During Procedure

Use minimum dose and concentration required for satisfactory contrast. Inject slowly over 1 to 2 minutes to avoid excessive mixing. Abrupt or active patient movement causes excessive mixing with CSF. Instruct patient to remain passive . Move patient slowly and only as necessary. To maintain as a bolus, move medium to distal area very slowly under fluoroscopic control. 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 thoraco-cervical procedures. In patients with excessive lordosis, consider lateral position for injection and movement of the medium cephalad. Avoid intracranial entry of a bolus. Avoid early and high cephalad dispersion of the medium. At completion of direct cervical or lumbo-cervical procedures, raise head of table steeply (45°) for about 2 minutes to restore medium to lower levels.

Postprocedure

Raise head of stretcher to at least 30° before moving patient onto it. Movement onto stretcher, and off the stretcher to bed, should be done slowly with patient completely passive, maintaining head up position. Before moving patient onto bed, raise head of bed 30° to 45° and maintain the patient in this position under close observation for 12 to 24 hours. Advise patient to remain still in bed, in head up position for the first 24 hours. Obtain visitors cooperation in keeping the patient quiet and in head up position, especially in first few hours. Encourage oral fluids and diet as tolerated. Antinauseants of the phenothiazine class should not be administered to treat postprocedural nausea or vomiting (see WARNINGS ). Since persistent nausea and vomiting may result in dehydration, prompt consideration of volume replacement by intravenous fluids is recommended.

Drug Incompatibilities

Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs; therefore, no other pharmaceuticals should be admixed with contrast agents.

CONTRAINDICATIONS Intrathecal administration of corticosteroids with iopamidol is contraindicated. Because of overdosage considerations, immediate repeat myelography in the event of technical failure is contraindicated (see interval recommendation under DOSAGE AND ADMINISTRATION ). Myelography should not be performed in the presence of significant local or systemic infection where bacteremia is likely.

ADVERSE REACTIONS The most frequently reported adverse reactions following intrathecal administration of iopamidol are headache, nausea, vomiting, and musculoskeletal pain. These reactions usually occur 1 to 10 hours after injection, almost all occurring 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. Backache, neck stiffness, numbness and paresthesias, leg or sciatic-type pain occurred less frequently, often in the form of a transient exacerbation of pre-existing symptomatology. Transient alterations in vital signs may occur and their significance must be assessed on an individual basis. The following table of incidence of reactions is based on clinical studies with Iopamidol Injection in about 686 patients.

Adverse Reactions Estimated Overall Incidence

System > 1% ≤ 1% Body as a Whole headache (16.4%) pyrexia muscle weakness hot flashes malaise fatigue weakness Digestive nausea (7.3%) diarrhea vomiting (3.6%) heartburn Musculoskeletal back pain (2.2%) leg cramps leg pain (1.4%) sciatica neck pain (1.1%) cervicobrachial irritation meningeal irritation radicular irritation lumbosacral other musculoskeletal pain involuntary movement burning sensation Cardiovascular hypotension (1.1%) tachycardia hypertension chest pain Nervous none emotional stress dizziness paresthesia confusion hallucinations lightheadedness syncope numbness cold extremities ataxia irritability Urogenital none urinary retention Respiratory none dyspnea Skin and Appendages none rash Miscellaneous none injection site pain Other adverse effects reported in clinical literature for iopamidol include facial neuralgia, tinnitus, and sweating. Major motor seizures have been reported in the clinical literature and since market introduction in the United States. Early onset of seizures (less than two hours) is indicative of early substantial intracranial entry. Transitory EEG changes occur and usually take the form of slow wave activity. While not observed in controlled clinical studies with Iopamidol Injection, the following adverse reactions may occur because they have been reported with Iopamidol Injection and other nonionic water soluble contrast agents: cardiovascular (arrhythmias); pulmonary (apnea); bacterial meningitis, and aseptic meningitis syndrome; allergy or idiosyncrasy (chills, pruritus, nasal congestion, Guillain-Barre syndrome); CNS irritation (psycho-organic syndrome: mild and transitory perceptual aberrations such as depersonalization, anxiety, depression, hyperesthesia, disturbances in speech, sight, or hearing, and disorientation; in addition, hyperreflexia or areflexia, hypertonia or flaccidity, restlessness, tremor, echoacousia, echolalia, asterixis or dysphasia have occurred). Profound mental disturbances have rarely been reported (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 to the point of stupor or coma. In a few cases, these have been accompanied by transitory hearing loss or other auditory symptoms and visual disturbances (believed subjective or delusional). Persistent cortical loss of vision in association with convulsions, and ventricular block have been reported. 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, or sixth nerve palsy, or cauda equina syndrome. Muscle cramps, fasciculation or myoclonia, spinal convulsion, paralysis, or spasticity are unusual.

General Adverse Reactions To Contrast

Media Reactions known to occur with parenteral administration of iodinated ionic contrast agents (see the listing below) are possible with any nonionic agent.

Approximately

95 percent of adverse reactions accompanying the use of other water-soluble intravascularly administered contrast agents are mild to moderate in degree. However, life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Reported incidences of death from the administration of other iodinated contrast media range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (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 medium, the dose, and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category. During intrathecal use, there is a lower incidence of electroencephalographic changes as well as neurotoxicity by virtue of the intrinsic properties of the iopamidol molecule. 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 drug injected, the speed of injection, the mode 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 for 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 intravascular contrast agents appear within one to three minutes after the start of injection, but delayed reactions may occur (see PRECAUTIONS : General ). Because measurable plasma levels are attained following the intrathecal administration of iopamidol, adverse reactions reported with the use of intravascular contrast agents are theoretically possible. These include: Cardiovascular: vasodilation (feeling of warmth), cerebral hematomas, hemodynamic disturbances, sinus bradycardia, transient electrocardiographic abnormalities, ventricular fibrillation, petechiae. Digestive: nausea, vomiting, severe unilateral or bilateral swelling of the parotid and submaxillary glands. Nervous: paresthesia, dizziness, convulsions, paralysis, coma. Respiratory: increased cough, asthma, dyspnea, laryngeal edema, pulmonary edema, bronchospasm, rhinitis. Urogenital: osmotic nephrosis of proximal tubular cells, renal failure, pain.

Special

Senses: perversion of taste; bilateral ocular irritation; lacrimation; itching; conjunctival chemosis, infection, and conjunctivitis. Endocrine: 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 (e.g. rash, erythema, pruritus, urticaria and skin discoloration) to severe: [e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS)]. Injection site pain usually due to extravasation and/or erythematous swelling, skin necrosis, urticaria. The following reactions may also occur: neutropenia, thrombophlebitis, flushing, pallor, weakness, severe retching and choking, wheezing, cramps, tremors, and sneezing.

AND PRECAUTIONS Hypersensitivity Reactions: Life-threatening or fatal reactions can occur. Always have emergency resuscitation equipment and trained personnel available. ( 5.2 )

Acute Kidney

Injury: Acute injury including renal failure can occur. Use the lowest dose and maintain adequate hydration to minimize risk. ( 5.3 )

Cardiovascular Adverse

Reactions: Hemodynamic disturbances including shock and cardiac arrest may occur during or after iopamidol injection administration. ( 5.4 )

Thyroid

Dysfunction in Pediatric Patients 0 Years to 3 Years of Age: Individualize thyroid function monitoring based on risk factors such as prematurity. ( 5.8 )

5.1 Risks Associated with Intrathecal Administration Intrathecal administration, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Iopamidol injection is for intra-arterial or intravenous use only and must not be administered intrathecally <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span>.

5.2 Hypersensitivity Reactions Iopamidol injection can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Most severe reactions develop shortly after the start of injection (e.g., within 1 to 3 minutes), but delayed reactions can also occur. There is increased risk of hypersensitivity reactions in patients with a history of previous reactions to contrast agents, and allergic disorders (i.e., bronchial asthma, allergic rhinitis, and food allergies) or other hypersensitivities. Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions does not prevent serious life-threatening reactions but may reduce both their incidence and severity. Obtain a history of allergy, hypersensitivity, or hypersensitivity reactions to iodinated contrast agents and always have emergency resuscitation equipment and trained personnel available prior to iopamidol injection administration. Monitor all patients for hypersensitivity reactions.

5.3 Acute Kidney Injury Acute kidney injury, including renal failure, may occur after iopamidol injection administration. Risk factors include: pre-existing renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, advanced vascular disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma or other paraproteinemias, and repetitive or large doses of iopamidol injection. Use the lowest necessary dose of iopamidol injection in patients with renal impairment. Adequately hydrate patients prior to and following iopamidol injection administration. Do not use laxatives, diuretics, or preparatory dehydration prior to iopamidol injection administration.

5.4 Cardiovascular Adverse Reactions Iopamidol injection increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in patients with congestive heart failure, severely impaired renal function, combined renal and hepatic disease, and combined renal and cardiac disease, particularly when repetitive or large doses are administered. Fatal cardiovascular reactions have occurred mostly within 10 minutes of iopamidol injection; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Hypotensive collapse and shock have occurred. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography. The administration of iopamidol injection may cause pulmonary edema in patients with heart failure. Based upon published reports, deaths associated with the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Use the lowest necessary dose of iopamidol injection in patients with congestive heart failure and always have emergency resuscitation equipment and trained personnel available. Monitor all patients for severe cardiovascular reactions.

5.5 Thromboembolic Events Serious, in some cases fatal, thromboembolic events, including myocardial infarction and stroke, can occur during angiographic procedures. During these procedures, increased thrombosis and activation of the complement system occurs. Risk factors for developing thromboembolic events include: length of procedure, catheter and syringe material, underlying disease state, and concomitant medications. To minimize thromboembolic events, use meticulous angiographic techniques and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing iodinated contrast agents, which increases risk of clotting. Avoid angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism.

5.6 Extravasation and Injection Site Reactions Extravasation can occur with iopamidol injection administration, particularly in patients with severe arterial or venous disease. Inflammation, blistering, skin necrosis, and compartment syndrome have been reported following extravasation. In addition, injection site reactions such as pain and swelling at the injection site can also occur <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms.

5.7 Thyroid Storm in Patients with Hyperthyroidism Thyroid storm has occurred after the intravascular use of iodinated agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of iopamidol injection

5.8 Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast agents in pediatric patients 0 years to 3 years of age. Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after iodinated contrast agent exposure. Pediatric patients with congenital cardiac conditions may be at greatest risk given that they often require high doses of contrast during invasive cardiac procedures. An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to iodinated contrast agents, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates.

5.9 Hypertensive Crisis in Patients with Pheochromocytoma Hypertensive crisis in patients with pheochromocytoma has occurred with iodinated contrast agents. Closely monitor patients when administering iopamidol injection if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of iopamidol injection necessary and have measures for treatment of hypertensive crisis readily available.

5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease Iodinated contrast agents can promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following iopamidol injection administration and use only if the necessary imaging information cannot be obtained with alternative imaging modalities.

5.11 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 a contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering iopamidol injection to patients with a history of a severe cutaneous adverse reaction to iopamidol injection.

5.12 Interference with Laboratory Tests Iopamidol injection can interfere with protein-bound iodine test <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

PRECAUTIONS General Diagnostic procedures which involve the use of any radiopaque agent 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 reaction 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 may occur. Caution should be exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, such as congestive heart failure. 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). Patients should be well hydrated prior to and following iopamidol administration. The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered (see ADVERSE REACTIONS ). Patients at increased risk include those with a history of a previous reaction to a contrast medium, 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 medium, 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. 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. Pre-existing conditions, such as pacemakers or cardiac medications, specifically beta-blockers, may mask or alter the signs or symptoms of an anaphylactoid reaction, as well as masking or altering the response to particular medications used for treatment. For example, beta-blockers inhibit a tachycardiac response, and can lead to the incorrect diagnosis of a vasovagal rather than an anaphylactoid reaction. Special attention to this possibility is particularly critical in patients suffering from serious, life-threatening reactions. General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions has been reported with radiopaque media in anesthetized patients, which 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. Even though the osmolality of iopamidol is low compared to diatrizoate or iothalamate based 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. Injection site pain and swelling may occur. In the majority of cases it is due to extravasation of contrast medium. Reactions are usually transient and recover without sequelae. However, inflammation and even skin necrosis have been seen on very rare occasions. In angiographic procedures, the possibility of dislodging plaques or damaging or perforating the vessel wall, or inducing vasospasm, and or subsequent ischemic events, should be borne in mind during catheter manipulations and contrast medium injection. Test injections to ensure proper catheter placement are suggested. Selective coronary arteriography should be performed only in selected patients and those in whom the expected benefits outweigh the procedural risk. The inherent risks of angiocardiography in patients with chronic pulmonary emphysema must be weighed against the necessity for performing this procedure. Angiography should be avoided whenever possible in patients with homocystinuria, because of the risk of inducing thrombosis and embolism. See also Pediatric Use . In addition to the general precautions previously described, special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection or a totally obstructed venous system. Extreme caution during injection of contrast media is necessary to avoid extravasation and fluoroscopy is recommended. This is especially important in patients with severe arterial or venous disease. Information for Patients Patients receiving injectable radiopaque diagnostic agents should be instructed to: Inform your physician if you are pregnant. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder (see WARNINGS ). Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous injections of substances used for x-ray procedures (see PRECAUTIONS-General ). Inform your physician about any other medications you are currently taking, including nonprescription drugs, before you have this procedure. Advise patients to inform their physician if they develop a rash after receiving Isovue. Advise parents/caregivers about the risk of developing thyroid dysfunction after ISOVUE administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function (see WARNINGS ).

Drug Interactions

Renal toxicity has been reported in a few patients with liver dysfunction who were given oral cholecystographic agents followed by intravascular contrast agents. Administration of intravascular agents should therefore be postponed in any patient with a known or suspected hepatic or biliary disorder who has recently received a cholecystographic contrast agent. Other drugs should not be admixed with iopamidol.

Drug/Laboratory

Test Interactions The results of PBI and radioactive iodine uptake studies, which depend on iodine estimations, will not accurately reflect thyroid function for up to 16 days following administration of iodinated contrast media. However, thyroid function tests not depending on iodine estimations, e.g., T3 resin uptake and total or free thyroxine (T4) assays are not affected. Any test which might be affected by contrast media should be performed prior to administration of the contrast medium.

Laboratory Test

Findings In vitro studies with animal blood showed that many radiopaque contrast agents, including iopamidol, produced a slight depression of plasma coagulation factors including prothrombin time, partial thromboplastin time, and fibrinogen, as well as a slight tendency to cause platelet and/or red blood cell aggregation (see PRECAUTIONS-General ). Transitory changes may occur in red cell and leucocyte counts, serum calcium, serum creatinine, serum glutamic oxaloacetic transaminase (SGOT), and uric acid in urine; transient albuminuria may occur. These findings have not been associated with clinical manifestations. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. No evidence of genetic toxicity was obtained in in vitro tests. Pregnancy: Teratogenic Effects Reproduction studies have been performed in rats and rabbits at doses up to 2.7 and 1.4 times the maximum recommended human dose (1.48 gI/kg in a 50 kg individual), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to iopamidol. There are, however, no adequate and well-controlled 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 whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when iopamidol is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children has been established in pediatric angiocardiography and computed tomography (head and body). 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, cyanotic heart disease, congestive heart failure, a serum creatinine greater than 1.5 mg/dL or those less than 12 months of age. Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates; some patients were treated for hypothyroidism. After exposure to iodinated contrast media, individualize thyroid function monitoring in pediatric patients 0 to 3 years of age based on underlying risk factors, especially in term and preterm neonates (see WARNINGS and ADVERSE REACTIONS ).

INTERACTIONS

7.1 Drug-Drug Interactions Metformin In patients with renal impairment, metformin can cause lactic acidosis. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. Stop metformin at the time of, or prior to, iopamidol injection administration in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast agents. Re-evaluate eGFR 48 hours after the imaging procedure and reinstitute metformin use only after renal function is stable.

Radioactive Iodine

Administration of iopamidol injection may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post iopamidol injection

7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Iodinated contrast agents, including iopamidol injection, will temporarily increase protein-bound iodine in blood. Avoid protein-bound iodine test for at least 16 days following administration of iopamidol injection . However, thyroid function tests that do not depend on iodine estimations, e.g., triiodothyronine (T 3 ) resin uptake and total or free thyroxine (T 4 ) assays, are not affected.