Iomeprol

IOMERVU is a radiographic contrast agent indicated for: Intra-arterial Procedures † ( 1.1 ) Cerebral arteriography, includingintra-arterial digital subtraction angiography (IA-DSA), in adults and pediatric patients Visceral and peripheral arteriography and aortography, including IA-DSA, in adults and pediatric patients Coronary arteriography and cardiac ventriculography in adults Radiographic evaluation of cardiac chambers and related arteries in pediatric patients Intravenous Procedures † ( 1.2 ) Computed tomography (CT) of the head and body in adults and pediatric patients CT angiography of intracranial, visceral, and lower extremity arteries in adults and pediatric patients Coronary CT angiography in adults and pediatric patients CT urography 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 † IOMERVU is indicated for: Cerebral arteriography, including intra-arterial digital subtraction angiography (IA-DSA), in adults and pediatric patients Visceral and peripheral arteriography and aortography, including IA-DSA, in adults and pediatric patients Coronary arteriography and cardiac ventriculography in adults Radiographic evaluation of cardiac chambers and related arteries in pediatric patients

1.2 Intravenous Procedures † IOMERVU is indicated for: Computed tomography (CT) of the head and body in adults and pediatric patients CT angiography of intracranial, visceral, and lower extremity arteries in adults and pediatric patients Coronary CT angiography in adults and pediatric patients CT urography in adults and pediatric patients † Specific concentrations of IOMERVU 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 iodine concentrations and configurations: Concentration (mg Iodine/mL) Package Size Package Type 250 100 mL Single-dose bottles 300 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 350 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 400 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles Injection: 250 mg Iodine/mL, 300 mg Iodine/mL, 350 mg Iodine/mL, and 400 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. Minimize 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 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 Inadvertent Intrathecal Administration IOMERVU is for intra-arterial or intravenous use only and must not be administered intrathecally [see Dosage and Administration ( 2.1 )]. 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.

5.2 Hypersensitivity Reactions IOMERVU 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 injection (e.g., within 1 to 3 minutes), but delayed reactions can occur. There is an increased risk in patients with a history of a previous reaction to contrast agents, and known allergic disorders (i.e., bronchial asthma, drug, or food allergies) or other hypersensitivities. Premedication with antihistamines or corticosteroids to minimize possible allergic reactions does not prevent serious life-threatening reactions, but may reduce their incidence and severity. Obtain a history of allergy, hypersensitivity, and hypersensitivity reactions to iodinated contrast agents. Always have emergency resuscitation equipment and trained personnel available before use of IOMERVU. Monitor all patients for hypersensitivity reactions.

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

5.4 Cardiovascular Adverse Reactions IOMERVU increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in patients with heart failure, severely impaired renal function, combined renal and hepatic disease, or combined renal and cardiac disease, particularly when repetitive or large doses are administered. Life-threatening or fatal cardiovascular reactions including hypotension, shock, and cardiac arrest have occurred with the use of IOMERVU. Most deaths occur within 10 minutes of injection, with cardiovascular disease as the main underlying factor. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography. Based upon literature reports, deaths from 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 IOMERVU in patients with 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 with iodinated contrast agents including IOMERVU. During these procedures, increased thrombosis and activation of the complement system can occur. Risk factors for developing thromboembolic events include length of procedure, catheter and syringe material, underlying disease state, and concomitant medications. To reduce risk of thromboembolic events, use meticulous angiographic techniques and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing IOMERVU, which increases the 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 IOMERVU 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 ( 6.1 , 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 IOMERVU.

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 IOMERVU, 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 has occurred after the use of iodinated contrast agents in patients with pheochromocytoma. Closely monitor patients when administering IOMERVU if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of IOMERVU necessary, assess blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.

5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease Iodinated contrast agents when administered intravascularly may promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following IOMERVU administration and use IOMERVU 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). […]

The following clinically significant adverse reactions are described 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 Years 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 ≥0.5%) are feeling hot, headache, nausea, chest pain, back pain, and vomiting. ( 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 in Adult Patients The safety of IOMERVU was evaluated in 4,621 adult patients who received 1,500 mg to 86,000 mg iodine doses of IOMERVU intra-arterially or intravenously in clinical trials. The average age was 60 years (range 18 years to 99 years), and 34% were female. The racial and ethnic distribution was 83% White, 10% Asian, 1% Black, 1% Hispanic, and 5% patients of other or unspecified groups. Table 5 provides a summary of the adverse reactions reported in ≥0.5% of adult patients. Table 5: Adverse Reactions Reported in ≥0.5% of 4,621 Adult Patients Receiving Intra-arterial or Intravenous Administration of IOMERVU in Clinical Trials Adverse Reaction Incidence (%) Feeling hot 2 Headache

1.2 Nausea 1 Chest pain

0.6 Back pain

0.5 Vomiting

0.5 The following adverse reactions were observed in <0.5% of the adult patients receiving IOMERVU: Blood and lymphatic system disorders: activated partial thromboplastin time prolonged, prothrombin time prolonged Cardiovascular disorders: ventricular fibrillation, hypertensive crisis, coronary arteriospasm, congestive cardiac failure, cardiac flutter, atrioventricular block, right bundle branch block, hypotension, arrhythmia, bradycardia, supraventricular extrasystoles, ventricular extrasystoles, increased blood pressure, flushing Ear and labyrinth disorders : vertigo, ear discomfort Eye disorder: vision blurred, periorbital edema, photopsia Gastrointestinal : esophageal varices hemorrhage, abdominal pain, abdominal distension, alanine aminotransferase (ALT) increased, constipation, diarrhea, dry mouth, salivary hypersecretion, oral paresthesia General disorders: pain, injection site reactions (pain, discomfort, or warmth), peripheral edema, chills, asthenia, malaise Musculoskeletal and connective tissue disorders: arthralgia, pain in jaw Nervous system disorders: cerebrovascular disorder, dysarthria, visual field defect, burning sensation, presyncope, dizziness, dysgeusia, paresthesia Psychiatric disorders : delirium, anxiety, insomnia Renal and urinary disorders: acute kidney injury, increased blood creatinine, urinary urgency Respiratory, thoracic, and mediastinal disorders: respiratory arrest, pulmonary edema, bronchospasm, dyspnea, cough, rhinitis, throat irritation or tightness, sneezing Skin and subcutaneous tissue disorders: urticaria, blister, purpura, ecchymosis, rash, pruritus, erythema Adverse Reactions in Pediatric Patients The safety of IOMERVU was evaluated in 184 pediatric patients who received 1,800 mg to 76,000 mg iodine doses of IOMERVU intra-arterially or intravenously in clinical trials. The average age was 6 years (range 11 days to 17 years), and 47% were female. The racial distribution was 98% White, 1% Black, and 1% patients of other or unspecified groups. The overall character, quality, and severity of adverse reactions reported in pediatric patients were similar to those reported in adult patients.

6.2 Post Marketing Experience The following adverse reactions have been identified during post-approval use of IOMERVU outside the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytopenia, leukopenia, leukocytosis Cardiovascular disorders: cardio-respiratory arrest, circulatory collapse or shock, myocardial infarction, atrial fibrillation, cyanosis, pallor Endocrine disorders: hyperthyroidism, hypothyroidism Eye disorders: transient blindness, conjunctivitis, increased lacrimation Gastrointestinal disorders: salivary gland enlargement, increased aspartate aminotransferase (AST), dysphagia General disorders and administration site conditions: injection site swelling (usually due to extravasation) Immune system disorders: hypersensitivity reactions including fatal anaphylaxis Nervous system disorders: coma, loss of consciousness, encephalopathy, transient ischemic attack, paralysis, convulsion, syncope, amnesia, somnolence Psychiatric disorders : confusional state Respiratory, thoracic, and mediastinal disorders: acute respiratory distress syndrome (ARDS), laryngeal edema, pharyngeal edema, dysphonia Skin and subcutaneous tissue disorders : severe reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS)) and mild reactions (rash, erythema, pruritus, urticaria, and skin discoloration)

7.1 Drug-Drug Interactions Metformin Stop metformin at the time of, or prior to, IOMERVU 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 only after renal function is stable. Metformin can cause lactic acidosis in patients with renal impairment. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. Radioactive Iodine Avoid thyroid therapy or testing using radioactive iodine for up to 6 weeks post IOMERVU. Administration of IOMERVU may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy.

7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Do not perform a protein-bound iodine test for at least 16 days following administration of IOMERVU. Iodinated contrast agents, including IOMERVU, will temporarily increase protein-bound iodine in blood. 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.

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

8.1 Pregnancy Risk Summary Available data from literature and postmarketing reports on iomeprol use in pregnant women over decades have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental outcomes were observed with intravenous administration of iomeprol to pregnant rats and rabbits at doses up to 0.45-times the maximum recommended human dose of 86,000 mg iodine. Animal studies show that iomeprol crosses the placenta ( 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 defects, 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 Animal Data Embryo-fetal developmental toxicity studies were performed with intravenous administration of iomeprol in rats at daily doses of 600 mg, 1,500 mg, or 4,000 mg iodine/kg (0.07-, 0.17- or 0.45-fold the human equivalent dose (HED, mg/m 2 ) using the maximum human dose of 86,000 mg iodine per administration) from gestation days (GD) 6 to 15 and in rabbits at daily doses of 300 mg, 800 mg, or 2,000 mg iodine/kg (0.07-, 0.18- or 0.45-fold the HED using the maximum human dose of 86,000 mg iodine per administration) from GD 6 to 18. Iomeprol did not result in fetal harm at the highest doses evaluated, 0.45-times the maximum recommended human dose of 86,000 mg iodine. A biodistribution study with a single intravenous administration of 1,000 mg iodine/kg (0.11-fold the HED using the maximum human dose of 86,000 mg iodine per administration) of radiolabeled iomeprol to pregnant rats showed that iomeprol crosses the placenta. No accumulation of radioactivity in fetal tissues was observed.

8.2 Lactation Risk Summary There are no data on the presence of iomeprol in human milk, the effects on the breastfed infant, or the effects on milk production. Iomeprol is present in animal milk (see Data) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. Iodinated contrast agents are excreted 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 IOMERVU and any potential adverse effects on the breastfed infant from IOMERVU 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 elimination half-lives) after IOMERVU administration to minimize any potential drug exposure to a breastfed infant. Data An animal study with a single intravenous administration of 500 mg iodine/kg (0.06-fold the HED using the maximum human dose of 86,000 mg iodine per administration) of radiolabeled iomeprol to lactating rats showed that iomeprol rapidly distributed into the milk.

8.4 Pediatric Use Intra-arterial Use The safety and effectiveness of IOMERVU have been established in pediatric patients for cerebral, visceral, and peripheral arteriography, aortography including intra-arterial digital subtraction angiography, and radiographic evaluation of cardiac chambers and related arteries. Use of IOMERVU is supported by evidence from adequate and well-controlled studies of IOMERVU in adults, pharmacokinetic data in pediatric patients aged 3 years to 17 years, pharmacokinetic simulation in pediatric patients younger than 3 years of age, and safety data obtained in 44 pediatric patients including 29 who were < 2 years of age, 14 children (2 years to 11 years), and 1 adolescent (12 years to 17 years). In general, adverse reactions reported in pediatric patients were similar to those in adults [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.1 )] . Intravenous Use The safety and effectiveness of IOMERVU have been established in pediatric patients for CT of the head and body, CT angiography of intracranial, visceral, and lower extremity arteries, coronary CT angiography, and CT urography. Use of IOMERVU is supported by evidence from adequate and well-controlled studies of IOMERVU in adults, pharmacokinetic data in pediatric patients aged 3 years to 17 years, pharmacokinetic simulation in pediatric patients younger than 3 years of age, and safety data obtained in 140 pediatric patients including 22 who were < 2 years of age, 92 children (2 years to 11 years), and 26 adolescents (12 years to 17 years). In general, adverse reactions reported in pediatric patients were similar to those in adults [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.2 )] . Intra-arterial and Intravenous Use Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent may include those with asthma, sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, heart failure, or serum creatinine greater than 1.5 mg/dL, or those less than 12 months of age. Pediatric patients with immature renal function or dehydration may be at increased risk for adverse events due to slower elimination of iodinated contrast agents [See Clinical Pharmacology ( 12.3 )]. 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 iodinated contrast agents, 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 Warnings and Precautions (5.8) and Adverse Reactions ( 6.2 )].

8.5 Geriatric Use Of the total number of subjects in clinical studies of IOMERVU, 1,977 (43%) patients were 65 years and older, while 629 (14%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Iomeprol is excreted by the kidneys, and the risk of adverse reactions to IOMERVU is greater in patients with renal impairment. Because elderly patients 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 Preexisting renal impairment increases the risk for acute kidney injury . Renal impairment reduces the rate of elimination of iomeprol . Iomeprol can be removed by dialysis [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )].

Iomeprol is a radiographic iodinated contrast agent that opacifies the vessels and body structures where the contrast agent is present following intravenous or intra-arterial administration, permitting radiographic visualization of the internal structures through attenuation of X-ray photons. In imaging of the body, iodinated contrast agents diffuse from the vessels into the extravascular space. In normal brain with an intact blood-brain barrier, the contrast agent does not diffuse into the extravascular space and contrast enhancement is generally due to the presence of contrast within the vascular space. In patients with a disrupted blood-brain barrier, the contrast agent accumulates in the extravascular space in the region of disruption.