Iopamidol

ISOVUE is a radiographic contrast agent indicated for: Intra-arterial Procedures † ( 1.1 ) Cerebral arteriography in adults Peripheral arteriography in adults Selective visceral arteriography and aortography in adults Coronary arteriography and cardiac ventriculography in adults Angiocardiography in pediatric patients Intravenous Procedures † ( 1.2 ) Excretory urography in adults and pediatric patients Computed tomography (CT) of head and body in adults and pediatric patients Peripheral venography in adults Oral Procedures † ( 1.3 ) CT of the abdomen and pelvis to delineate the gastrointestinal tract in adults and pediatric patients † Specific concentrations are recommended for each type of imaging procedure. ( 2.2 , 2.3 , 2.4 , 2.5 )

1.1 Intra-arterial Procedures † ISOVUE is indicated for: Cerebral arteriography in adults Peripheral arteriography in adults Selective visceral arteriography and aortography in adults Coronary arteriography and cardiac ventriculography in adults Angiocardiography in pediatric patients

1.2 Intravenous Procedures † ISOVUE is indicated for: Excretory urography in adults and pediatric patients Computerized tomography (CT) of the head and body in adults and pediatric patients Peripheral venography in adults

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 )].

Injection: Clear, colorless to pale yellow solution available in the following concentrations of iodine: Concentration (mg Iodine/mL) Package Size Package Type 200 200 mL Single-Dose Bottle 250 100 mL Single-Dose Bottle 300 30 mL and 50 mL Single-Dose Vial 100 mL and 150 mL Single-Dose Bottle 370 50 mL Single-Dose Vial 100 mL, 125 mL, and 150 mL Single-Dose Bottle Injection: 200 mg Iodine/mL, 250 mg Iodine/mL, 300 mg Iodine/mL, and 370 mg Iodine/mL in single-dose vials or bottles ( 3 )

None. None ( 4 )

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 ISOVUE 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 of ISOVUE, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. ISOVUE is for intra-arterial, intravenous, or oral use only [see Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 )].

5.2 Hypersensitivity Reactions ISOVUE can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock [see Adverse Reactions ( 6.2 )] . Most severe reactions develop shortly after the start of administration (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 ISOVUE administration. Monitor all patients for hypersensitivity reactions.

5.3 Acute Kidney Injury Acute kidney injury, including renal failure, may occur after intavascular administration of ISOVUE. 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 ISOVUE. Use the lowest necessary dose of ISOVUE in patients with renal impairment. Adequately hydrate patients prior to and following ISOVUE administration. Do not use laxatives, diuretics, or preparatory dehydration prior to ISOVUE administration.

5.4 Cardiovascular Adverse Reactions Intravascular administration of ISOVUE 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 ISOVUE 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 ISOVUE 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 ISOVUE 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 intravascular ISOVUE 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 [see Adverse Reactions ( 6.2 )] . 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 contrast agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of ISOVUE.

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 ISOVUE, 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 ISOVUE intravascularly if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of ISOVUE necessary and have measures for treatment of hypertensive crisis readily available.

5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease ISOVUE administered intravascularly can promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following ISOVUE 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 ISOVUE 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). […]

The following adverse reactions are described in greater detail elsewhere in the labeling: Risks Associated with Intrathecal Administration [see Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Acute Kidney Injury [see Warnings and Precautions ( 5.3 )] Cardiovascular Adverse Reactions [see Warnings and Precautions ( 5.4 )] Thromboembolic Events [see Warnings and Precautions ( 5.5 )] Extravasation and Injection Site Reactions [see Warnings and Precautions ( 5.6 )] Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age [see Warnings and Precautions ( 5.8 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (incidence >1%) from intra-arterial or intravenous use are pain, hot flashes, burning sensation, nausea, and warmth. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions from Intra-arterial or Intravenous Use in Adults The safety of ISOVUE was evaluated in 2,246 adult patients receiving ISOVUE by intra-arterial or intravenous route in clinical studies. Table 6 shows the common adverse reactions (>1%). Table 6: Adverse Reactions Reported in >1% of Patients Receiving Intra-arterial or Intravenous Injection of ISOVUE in Clinical Studies Adverse Reaction ISOVUE (N=2,246) % Pain

2.8 Hot flashes

1.5 Burning sensation

1.4 Nausea

1.2 Warmth

1.1 The following adverse reactions occurred in ≤ 1% of patients receiving intra-arterial or intravenous injection of ISOVUE: Cardiovascular disorders: tachycardia, hypotension, hypertension, myocardial ischemia, circulatory collapse, S-T segment depression, bigeminy, extrasystoles, ventricular fibrillation, angina pectoris, bradycardia, transient ischemic attack, thrombophlebitis Gastrointestinal disorders: vomiting, anorexia General disorders: headache, fever, chills, excessive sweating, back spasm Nervous system disorders: vasovagal reaction, tingling in arms, grimace, faintness Renal and urinary disorders: urinary retention Respiratory: throat constriction, dyspnea, pulmonary edema Skin and subcutaneous tissues: rash, urticaria, pruritus, flushing Special senses: taste alterations, nasal congestion, visual disturbances Adverse Reactions from Intra-arterial Use in Pediatric Patients In a clinical trial with 76 pediatric patients undergoing angiocardiography, two adverse reactions (2.6%) were reported: worsening cyanosis and worsening peripheral perfusion. Adverse Reactions from Oral Use in Adult and Pediatric Patients There were no new adverse reactions from oral use of ISOVUE in adult and pediatric patients [see Clinical Studies ( 14 )].

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ISOVUE or other iopamidol-containing products by intra-arterial, intravenous, or oral administration. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytopenia Cardiovascular disorders: cardiopulmonary arrest, cardiac decompensation, arrhythmias, myocardial infarction, shock, electrocardiographic changes (e.g., increased QTc, increased R-R, increased T-wave amplitude), decreased systolic pressure, deep vein thrombosis, arterial spasms, vasodilation, chest pain, pallor Endocrine disorders: hyperthyroidism, hypothyroidism Eye disorders: lacrimation increased, conjunctivitis, eye pruritus, transient blindness, visual disturbance, photophobia, eyelid edema Gastrointestinal disorders: nausea, vomiting, diarrhea, retching, esophageal pain, abdominal pain, salivary hypersecretion, salivary gland enlargement, oral paresthesia, lip swelling General disorders and administration site conditions: injection site pain, malaise Immune system disorders: anaphylaxis characterized by cardiovascular, respiratory, and cutaneous manifestations (e.g., chest tightness, laryngeal edema, periorbital edema, facial edema); delayed hypersensitivity reactions including generalized maculopapular rash, erythema, pruritus, localized blistering, skin peeling Musculoskeletal disorders: compartment syndrome following extravasation, muscle spasm, musculoskeletal pain, muscular weakness Nervous system disorders: coma, seizure, tremors, syncope, depressed level of consciousness or loss of consciousness, encephalopathy Psychiatric disorders: confusional state Respiratory system disorders: respiratory arrest, respiratory failure, acute respiratory distress syndrome, respiratory distress, apnea, asthma, sneezing, choking, laryngeal edema, bronchospasm, rhinitis Skin and subcutaneous tissue disorders : Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme and drug reaction with eosinophilia and systemic symptoms (DRESS), skin necrosis, urticaria, face edema

Lactation: A lactating woman may pump and discard breast milk for 10 hours after ISOVUE administration. ( 8.2)

8.1 Pregnancy Risk Summary Available data from published literature and postmarketing cases from decades of use with iopamidol during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Iopamidol crosses the placenta and reaches fetal tissues in small amounts ( see Data ). In animal reproduction studies, no adverse developmental outcomes were observed with intravenous administration of iopamidol to pregnant rats and rabbits during organogenesis at doses up to 2.7 and 1.4 times, respectively, the maximum recommended human dose ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Literature reports show that intravenously administered iopamidol crosses the placenta and is visualized in the digestive tract of exposed infants after birth. Animal Data Iopamidol did not affect fetal development and did not induce teratogenic changes in the offspring in either rats or rabbits at the following dose levels tested: 600 mg, 1,500 mg, or 4,000 mg iodine/kg in rats, administered intravenously once a day during days 6 through 15 of pregnancy; 300 mg, 800 mg, or 2,000 mg iodine/kg in rabbits, administered intravenously once a day during days 6 through 18 of pregnancy.

8.2 Lactation Risk Summary There are no data on the presence of iopamidol in human milk, the effects on the breastfed infant, or the effects on milk production. Iodinated contrast agents are present unchanged in human milk in very low amounts, with poor absorption from the gastrointestinal tract of a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ISOVUE and any potential adverse effects on the breastfed infant from ISOVUE or from the underlying maternal condition. Clinical Considerations Interruption of breastfeeding after exposure to iodinated contrast agents is not necessary because the potential exposure of the breastfed infant to iodine is small. However, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 10 hours (approximately 5 half- lives) after ISOVUE administration in order to minimize drug exposure to a breastfed infant.

8.4 Pediatric Use The safety and effectiveness of ISOVUE have been established in pediatric patients for intra-arterial administration for angiocardiography and for intravenous administration for excretory urography and contrast computed tomography (head and body). The safety and effectiveness of ISOVUE have been established in pediatric patients for oral administration for CT of the abdomen and pelvis to delineate the gastrointestinal tract. Use of ISOVUE for this indication is supported by evidence from an adequate and well-controlled clinical study in adults (n=152) and pediatric patients 3 to 16 years of age (n=66) who underwent CT of the abdomen and pelvis with oral administration of ISOVUE and from additional safety data from post-approval use of enteral iopamidol in adult and pediatric patients [see Adverse Reactions ( 6.2 )] and Clinical Studies ( 14 )] . Pediatric patients at higher risk of experiencing adverse reactions during and after ISOVUE administration may include those having asthma, sensitivity to medication or allergens, cyanotic heart disease, congestive heart failure, or 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 reported following iodinated contrast agent administration in pediatric patients, including term and preterm neonates; some patients were treated for hypothyroidism. After exposure to ISOVUE, individualize thyroid function monitoring in pediatric patients 0 years to 3 years of age based on underlying risk factors, especially in term and preterm neonates [see Warning and Precautions ( 5.8 ) and Adverse Reactions ( 6.2 )] . The safety and effectiveness of ISOVUE for cerebral, peripheral, and selective visceral arteriography, aortography, coronary arteriography, cardiac ventriculography, and peripheral venography have not been established in pediatric patients.

8.5 Geriatric Use Iopamidol is excreted by the kidney, and the risk of adverse reactions to ISOVUE may be greater in patients with renal impairment. Because patients 65 years of age and older are more likely to have renal impairment, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations [ 8.6 ]) .

8.6 Renal Impairment The clearance of iopamidol decreases with increasing degree of renal impairment and results in delayed opacification of the urinary system. In addition, preexisting renal impairment increases the risk for acute kidney injury [see Warnings and Precautions ( 5.3 )] . Iopamidol can be removed by dialysis.