ISOVUE 300

ISOVUE (Iopamidol Injection) is a stable, aqueous, sterile, and nonpyrogenic solution for intravascular administration. Each bottle is to be used as an Imaging Bulk Package for dispensing multiple single doses of iopamidol injection for multiple patients, using an automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this contrast agent in this Imaging Bulk Package. Each mL of ISOVUE-300 (Iopamidol Injection 61%) provides 612 mg iopamidol with 1 mg tromethamine and 0.39 mg edetate calcium disodium. The solution contains approximately 0.043 mg (0.002 mEq) sodium and 300 mg organically bound iodine per mL. Each mL of ISOVUE-370 (Iopamidol Injection 76%) provides 755 mg iopamidol with 1 mg tromethamine and 0.48 mg edetate calcium disodium. The solution contains approximately 0.053 mg (0.002 mEq) sodium and 370 mg organically bound iodine per mL. The pH of ISOVUE contrast media has been adjusted to 6.5-7.5 with hydrochloric acid and/or sodium hydroxide. Pertinent physicochemical data are noted below. ISOVUE (Iopamidol Injection) is hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively). Iopamidol Parameter 61% 76% Concentration (mg iodine/mL) 300 370 Osmolality @ 37° C (mOsm/kg water) 616 796 Viscosity (cP) @ 37° C 4.7 9.4 @ 20° C 8.8 20.9 Specific Gravity @ 37° C 1.339 1.405 Iopamidol is designated chemically as (S)-N,N’-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo-5-lactamidoisophthalamide. Structural formula: MW 777.09 C 17 H 22 I 3 N 3 O 8 CAS-60166-93-0 Organically Bound Iodine: 49% Isovue structure

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.

General 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 intravascular use be at body temperature when injected. Sterile techniques must be used with any intravascular injection. The transferring of ISOVUE from the ISOVUE Imaging Bulk Package container should be performed utilizing aseptic technique. The Imaging Bulk Package closure may be penetrated only one time, with a suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this Imaging Bulk Package. Patients should be well hydrated prior to and following ISOVUE (Iopamidol Injection) administration. As with all radiopaque contrast agents, only the lowest dose of ISOVUE 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 ISOVUE; the combination of dose and ISOVUE concentration to be used should be carefully individualized, and factors such as age, body size, size of the vessel and its blood flow rate, 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. Cerebral Arteriography ISOVUE-300 (Iopamidol Injection, 300 mg iodine/mL) should be used. The usual individual injection by carotid puncture or transfemoral catheterization is 8 to 12 mL, with total multiple doses up to 90 mL. Peripheral Arteriography ISOVUE-300 usually provides adequate visualization. For injection into the femoral artery or subclavian artery, 5 to 40 mL may be used; for injection into the aorta for a distal runoff, 25 to 50 mL may be used. Doses up to a total of 250 mL of ISOVUE-300 have been administered during peripheral arteriography. Peripheral Venography (Phlebography) ISOVUE-300 should be used. The usual dose is 15 mL to 100 mL per lower extremity. The combined total dose for multiple injections should not exceed 230 mL. Selective Visceral Arteriography and Aortography ISOVUE-370 (Iopamidol Injection, 370 mg iodine/mL) should be used. Doses up to 50 mL may be required for injection into the larger vessels such as the aorta or celiac artery; doses up to 10 mL may be required for injection into the renal arteries. Often lower doses will be sufficient. The combined total dose for multiple injections has not exceeded 225 mL. Pediatric Angiocardiography ISOVUE-370 should be used. Pediatric angiocardiography may be performed by injection into a large peripheral vein or be direct characterization of the heart. The usual dose range for single injections is provided in the following table: Single Injection Usual Dose Range Age mL <2 years 10–15 2–9 years 15–30 10–18 years 20–50 The usual recommended dose for cumulative injections is provided in the following table. Cumulative Injection Usual Recommended Dose Age mL <2 years 40 2–4 years 50 5–9 years 100 10–18 years 125 Coronary Arteriography and Ventriculography ISOVUE-370 should be used. The usual dose for selective coronary artery injections is 2 to 10 mL. The usual dose for ventriculography, or for nonselective opacification of multiple coronary arteries following injection at the aortic root is 25 to 50 mL. The total dose for combined procedures has not exceeded 200 mL. EKG monitoring is essential. Computed Tomography CT OF THE HEAD: The suggested dose for ISOVUE-300 is 100 to 200 mL by intravenous administration. Imaging may be performed immediately after completion of administration. CT OF THE BODY: The usual adult dose range for ISOVUE-300 is 100-to 200 mL administered by rapid intravenous infusion or bolus injection. Equivalent doses of ISOVUE-370 based on organically bound iodine content may also be used. The total dose for either CT procedure should not exceed 60 grams of iodine. Pediatric Computed Tomography The dosage recommended for use in children for contrast enhanced computed tomography is 1.0 mL/kg to 3.0 mL/kg for ISOVUE-300. It should not be necessary to exceed a total dose of 30 grams of iodine. 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.

None.

Adverse reactions following the use of iopamidol are usually mild to moderate, self-limited, and transient. In angiocardiography (597 patients), the adverse reactions with an estimated incidence of one percent or higher are: hot flashes 3.4%; angina pectoris 3.0%; flushing 1.8%; bradycardia 1.3%; hypotension 1.0%; hives 1.0%. In a clinical trial with 76 pediatric patients undergoing angiocardiography, 2 adverse reactions (2.6%) both remotely attributed to the contrast media were reported. Both patients were less than 2 years of age, both had cyanotic heart disease with underlying right ventricular abnormalities and abnormal pulmonary circulation. In one patient pre-existing cyanosis was transiently intensified following contrast media administration. In the second patient pre-existing decreased peripheral perfusion was intensified for 24 hours following the examination. (See “ PRECAUTIONS ” Section for information on high risk nature of these patients.) Intravascular injection of contrast media is frequently associated with the sensation of warmth and pain especially in peripheral arteriography and venography; pain and warmth are less frequent and less severe with ISOVUE (Iopamidol Injection) than with diatrizoate meglumine and diatrizoate sodium injection. The following table of incidence of reactions is based on clinical studies with ISOVUE in about 2246 patients. Adverse Reactions Estimated Overall Incidence System > 1% ≤ 1% Cardiovascular none tachycardia hypotension hypertension myocardial ischemia circulatory collapse S-T segment depression bigeminy extrasystoles ventricular fibrillation angina pectoris bradycardia transient ischemic attack thrombophlebitis Nervous pain (2.8%) burning sensation (1.4%) vasovagal reaction tingling in arms grimace faintness Digestive nausea (1.2%) vomiting anorexia Respiratory none throat constriction dyspnea pulmonary edema Skin and Appendages none rash urticaria pruritus flushing Body as a Whole hot flashes (1.5%) headache fever chills excessive sweating back spasm Special Senses warmth (1.1%) taste alterations nasal congestion visual disturbances Urogenital none urinary retention Regardless of the contrast agent employed, the overall estimated incidence of serious adverse reactions is higher with coronary arteriography than with other procedures. Cardiac decompensation, serious arrhythmias, or myocardial ischemia or infarction have been reported with ISOVUE and may occur during coronary arteriography and left ventriculography . Following coronary and ventricular injections, certain electrocardiographic changes (increased QTc, increased R-R, T-wave amplitude) and certain hemodynamic changes (decreased systolic pressure) occurred less frequently with ISOVUE (Iopamidol Injection) than with diatrizoate meglumine and diatrizoate sodium injection; increased LVEDP occurred less frequently after ventricular iopamidol injections. In aortography , the risks of procedures also include injury to the aorta and neighboring organs, pleural puncture, renal damage including infarction and acute tabular necrosis with oliguria and anuria, accidental selective filling of the right renal artery during the translumbar procedure in the presence of pre-existing renal disease, retroperitoneal hemorrhage from the translumbar approach, and spinal cord injury and pathology associated with the syndrome of transverse myelitis. The following adverse reactions have been reported for Iopamidol: Cardiovascular : arrhythmia, arterial spasms, flushing, vasodilation, chest pain, cardiopulmonary arrest; Nervous System : confusion, paresthesia, dizziness, temporary cortical blindness, temporary amnesia, convulsions, paralysis, coma; Respiratory : increased cough, sneezing, asthma, apnea, laryngeal edema, chest tightness, rhinitis; Skin and Appendages : injection site pain usually due to extravasation and/or erythematous swelling, pallor, periorbital edema, facial edema; Urogenital : pain, hematuria; Special Senses : watery itchy eyes, lacrimation, conjunctivitis; Musculoskeletal : muscle spasm, involuntary leg movement; Body as a whole : tremors, malaise, anaphylactoid reaction (characterized by cardiovascular, respiratory and cutaneous symptoms), pain; Digestive : severe retching and choking, abdominal cramps. Some of these may occur as a consequence of the procedure. Other reactions may also occur with the use of any contrast agent as a consequence of the procedural hazard; these include hemorrhage or pseudoaneurysms at the puncture site, brachial plexus palsy following axillary artery injections, chest pain, myocardial infarction, and transient changes in hepatorenal chemistry tests. Arterial thrombosis, displacement of arterial plaques, venous thrombosis, dissection of the coronary vessels and transient sinus arrest are rare complications. 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. 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. Delayed reactions, usually involving the skin, may uncommonly occur within 2-3 days (range 1-7 days) after the administration of contrast (see PRECAUTIONS-General ). Delayed allergic reactions are more frequent in patients treated with immunostimulants, such as interleukin-2. In addition to the adverse drug reactions reported for iopamidol, the following additional adverse reactions have been reported with the use of other intravascular contrast agents and are possible with the use of any water-soluble iodinated contrast agent: Cardiovascular : cerebral hematomas, petechiae; Hematologic : neutropenia; Urogenital : osmotic nephrosis of proximal tubular cells, renal failure; Special Senses : conjunctival chemosis with infection. Endocrine : hyperthyroidism, hypothyroidism; Skin and Subcutaneous Tissue Disorders : Skin necrosis; Reactions range from mild (e.g. rash, erythema, pruritus, uticaria and skin discoloration) to severe: [e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), cute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS)].

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 HANDLING 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. Directions for Proper Use of the ISOVUE Imaging Bulk Package The ISOVUE Imaging Bulk Package is used for dispensing multiple single doses of iopamidol injection for multiple patients, using an automated contrast injection system contrast management system, or contrast media transfer set approved or cleared for use with this contrast agent in this Imaging Bulk Package. Preparations of 0.9% Sodium Chloride Injection USP, with a sterile port for an intravenous administration set, are to be used with the ISOVUE Imaging Bulk Package and automated contrast injection systems or contrast management systems approved for use with the ISOVUE Imaging Bulk Package. Please see drug and device labeling for information on devices indicated for use with this Imaging Bulk Package and techniques to help assure safe use. The ISOVUE Imaging Bulk Package is to be used only in a room designated for radiological procedures that involve intravascular administration of a contrast agent. The transferring of ISOVUE from the Imaging Bulk Package should be performed utilizing aseptic technique. Prior to penetrating the container closure, swab the face of the container stopper with 70% isopropyl alcohol. The container closure may be penetrated only one time with a suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this Imaging Bulk Package. Once the Imaging Bulk Package is punctured, it should not be removed from the work area during the entire period of use, and the bottle should be maintained in an inverted position such that container contents are in continuous contact with the dispensing set. A maximum use time of 10 hours from initial closure entry is permitted to complete fluid transfer. Any unused ISOVUE injection must be discarded 10 hours after initial puncture of the Imaging Bulk Package. After the container closure is punctured, if the integrity of the Imaging Bulk Package and the delivery system cannot be assured though direct continuous supervision, the Imaging Bulk Package and all associated disposables for the automated contrast injection system, contrast management system, or contrast media transfer set should be discarded. Storage temperature of the ISOVUE Imaging Bulk Package container after the closure has been entered should not exceed 25° C (77° F); however, it is desirable that the contents be warmed to body temperature prior to injection. If 0.9% Sodium Chloride Injection USP is used, prepare the intravenous port in accordance with the DOSAGE AND ADMINISTRATION section of the approved prescribing information of the product. Multiple-dose use of 0.9% Sodium Chloride Injection USP: 0.9% Sodium Chloride Injection USP should only be used to deliver multiple doses to multiple patients when used with an automated contrast injection system or contrast management system approved or cleared for multiple-dose use of 0.9% Sodium Chloride Injection. The intravenous administration port of the sodium chloride container may be penetrated only one time with a suitable sterile component of the contrast management system approved for use with the ISOVUE Imaging Bulk Package, using aseptic technique. A maximum use time of 10 hours from initial closure entry is permitted to complete the fluid transfer. Any unused sodium chloride must be discarded 10 hours after initial puncture of the 0.9% Sodium Chloride Injection USP container. The container of 0.9% Sodium Chloride Injection USP is to be used only in an area designated for radiological procedures that involve intravascular administration of contrast. All above instructions in c. through e. for the ISOVUE Imaging Bulk Package should be followed for the 0.9% Sodium Chloride Injection USP container. Strap the saline tag provided with the ISOVUE Imaging Bulk Package on the 0.9% Sodium Chloride Injection USP container. Single-dose use of 0.9% Sodium Chloride Injection USP: Use in accordance with the manufacturers Prescribing Information.