Ioversol

OPTIRAY is indicated for: OPTIRAY is a radiographic contrast agent indicated for the following: Intra-arterial Procedures ( 1.1 ) Adults: Cerebral Arteriography (320 mg iodine/mL) Peripheral Arteriography (320, 350 mg iodine/mL ) Visceral and Renal Arteriography, Aortography (320 mg iodine/mL) Coronary Arteriography and Left Ventriculography (320, 350 mg iodine/mL) Pediatric Patients: Angiocardiography (320, 350 mg iodine/mL) Intravenous Procedures ( 1.2 ) Adults: Computed tomography (CT) Imaging of Head and Body (320, 350 mg iodine/mL) Venography (320, 350 mg iodine/mL) Intravenous Excretory Urography (320, 350 mg iodine/mL) Intravenous Digital Subtraction Angiography (350 mg iodine/mL) Pediatric Patients: CT Imaging of the Head and Body, and Intravenous Excretory Urography (320mg iodine/mL).

1.1 Intra-arterial In adults OPTIRAY 320: cerebral arteriography, peripheral arteriography, visceral and renal arteriography, aortography, coronary arteriography, and left ventriculography. OPTIRAY 350: peripheral arteriography, coronary arteriography, and left ventriculography. In pediatric patients OPTIRAY 320 and OPTIRAY 350: angiocardiography.

1.2 Intra-venous In adults OPTIRAY 320: CT imaging of the head and body, venography, and intravenous excretory urography. OPTIRAY 350: CT imaging of the head and body, venography, intravenous excretory urography, and intravenous digital subtraction angiography (IV-DSA). In pediatric patients OPTIRAY 320: CT imaging of the head and body, and intravenous excretory urography.

Injection: clear, colorless to pale yellow solutions containing no undissolved solids, available in the following strengths and multiple-dose containers: Imaging Product mg of ioversol per mL mg of organically bound iodine per mL Pharmacy Bulk Pack Presentation OPTIRAY 320 (Ioversol 68%) 678 320 Yes OPTIRAY 350 (Ioversol 74%) 741 350 Yes OPTIRAY Pharmacy Bulk Package is available in two strengths: Injection: 320 mg iodine/mL (ioversol 68%), 350 mg iodine/mL (ioversol 74%) in pharmacy bulk package bottles. ( 3 )

Symptomatic hyperthyroidism. Symptomatic Hyperthyroidism ( 4 )

Hypersensitivity Reactions: life-threatening or fatal reactions can occur. Always have emergency equipment and trained personnel available. ( 5.2 ) Contrast Induced 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 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 OPTIRAY is indicated for intravascular use only [see Dosage and Administration ( 2.1 )] . Inadvertent intrathecal administration can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.

5.2 Hypersensitivity Reactions OPTIRAY can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis and anaphylactic shock. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Most severe reactions develop shortly after the start of the injection (e.g. within 1 to 3 minutes), but delayed reactions may occur. There is an increased risk in patients with a history of a previous reaction to contrast agent, and known allergies (i.e., bronchial asthma, drug, or food allergies), and 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 prior hypersensitivity reactions to iodinated contrast agents. Always have emergency resuscitation equipment and trained personnel available and monitor all patients for hypersensitivity reactions.

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

5.4 Cardiovascular Adverse Reactions OPTIRAY 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, combined renal and cardiac disease, particularly when repetitive or large doses are administered. Life-threatening or fatal cardiovascular reactions have occurred with the use of OPTIRAY, including cardiac arrest, hypotensive collapse, and shock. 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 OPTIRAY 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 Angiocardiography Serious, fatal, thromboembolic events causing myocardial infarction and stroke can occur during angiographic procedures with OPTIRAY. During these procedures, increased thrombosis and activation of the complement system occurs. Risk factors for thromboembolic events include: length of procedure, catheter and syringe material, underlying disease state, and concomitant medications. To minimize thromboembolic events use meticulous angiographic technique. Avoid blood remaining in contact with syringes containing OPTIRAY, which increases the risk of clotting. Avoid angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism [see Clinical Pharmacology ( 12.2 )] .

5.6 Extravasation and Injection Site Reactions Extravasation can occur with OPTIRAY administration, particularly in patients with severe arterial or venous disease and can be associated with pain, hemorrhage and necrosis. 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 OPTIRAY is contraindicated in patients with symptomatic hyperthyroidism [see Contraindications ( 4 )] . Thyroid storm has occurred following the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of OPTIRAY.

5.8 Thyroid Dysfunction in Pediatric Patients 0 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 media (ICM) in pediatric patients 0 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 ICM exposure. Pediatric patients with congenital cardiac conditions may be at the 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 ICM, 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 radiopaque contrast agents in patient with pheochromocytoma. Closely monitor patients when administering OPTIRAY if pheochromocytoma or catecholamine-secreting paraganglioma is suspected. Inject the minimum amount of OPTIRAY 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 may promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following OPTIRAY administration, use OPTIRAY only if the necessary imaging information cannot be obtained with alternative imaging modalities, and inject the minimum amount necessary.

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 OPTIRAY to patients with a history of a severe cutaneous adverse reaction to OPTIRAY.

The following clinically significant adverse reactions are described elsewhere in the labeling: Risks Associated with Inadvertent Intrathecal Administration [see Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Contrast Induced 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 )] 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 ( 5.10 ) The most common reaction is nausea, occurring at a rate of greater than 1 percent. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact LIEBEL-FLARSHEIM COMPANY LLC at 855-266-5037 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience Adult Patients 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. The following table shows reactions based upon clinical trials with OPTIRAY (ioversol) in 4,187 patients. Adverse reactions are listed by organ system according to clinical importance. More severe reactions are listed before others in a system regardless of incidence. The most common reaction is nausea, occurring at a rate of 1 percent. Cardiac disorders Cardiac arrest, myocardial infarction, arrhythmia, atrioventricular block complete, atrioventricular block, nodal rhythm, bradycardia, angina pectoris, palpitations Ear and labyrinth disorders Vertigo, tinnitus Eye disorders Vision blurred, periorbital edema, conjunctivitis Gastrointestinal disorders Vomiting, abdominal pain, dysphagia, dry mouth General disorders and administration site conditions Chest pain, pain, injection site pain, injection site hematoma, extravasation, pyrexia, swelling, asthenia, malaise, fatigue, chills Infections and infestations Rhinitis Injury, poisoning, and procedural complications Heart injury, vascular pseudoaneurysm Investigations Electrocardiogram ST segment depression, blood pressure decreased Metabolism and nutrition disorders Acidosis Musculoskeletal and connective tissue disorders Muscular weakness, muscle spasms, back pain Nervous system disorders Cerebral infarction, aphasia, tremor, dizziness, presyncope, headache, paraesthesia, dysgeusia Psychiatric disorders Hallucination, visual hallucination, disorientation, anxiety Renal and urinary disorders Urinary retention, renal pain, polyuria Respiratory, thoracic, and mediastinal disorders Laryngeal edema, hypoxia, pulmonary edema, dyspnea, hyperventilation, cough, sneezing, nasal congestion Skin and subcutaneous tissue disorders Urticaria, rash, pruritus, swelling face, hyperhidrosis, erythema Vascular disorders Hypertension, hypotension, arterial spasm, vasospasm, vasodilation, flushing Pediatric Patients In clinical trials involving 311 patients for pediatric angiocardiography, contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography; 6% of patients reported an adverse reactions, with the most common adverse reactions being nausea and fever. Adverse reactions reported were similar in quality and frequency to the adverse events reported by adults.

6.2 Postmarketing Experience The following adverse drug reactions have been reported during post-approval use of OPTIRAY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a casual relationship to drug exposure. Cardiac disorders: coronary artery spasm, cyanosis, arrhythmia (ventricular fibrillation, tachycardia, extrasystole), ECG abnormal. Endocrine disorders: Hyperthyroidism, hypothyroidism. Eye disorders: temporary blindness, conjunctivitis (including eye irritation, ocular hyperemia, watery eyes). Gastrointestinal disorders: tongue edema, salivary hypersecretion. General disorders and administration site conditions: injection site reactions including pain, hemorrhage, and necrosis especially after extravasation [see Warnings and Precautions ( 5.6 )] , face edema, feeling hot. Immune system disorders: hypersensitivity reactions including fatal anaphylactic shock. Nervous system disorders: seizure, loss of consciousness, somnolence, hypoesthesia, dyskinesia, amnesia. Respiratory disorders: respiratory arrest, asthma, bronchospasm, laryngeal spasm and obstruction, throat irritation, dysphonia. 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). Vascular Disorders: phlebitis, thrombosis.

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, OPTIRAY administration in patients with an eGFR between 30 and 60 mL/min/1.73 m2; 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 only after renal function is stable. Radioactive Iodine Administration of iodinated contrast agents may interfere with thyroid uptake of radioactive iodine (I 131) and decrease therapeutic efficacy in patients with carcinoma of the thyroid. The decrease in efficacy lasts for 6-8 weeks. Oral Cholecystographic Contrast Agents Renal toxicity has been reported in patients with liver impairment who were given oral cholecystographic agents followed by intravascular contrast agents. Administration of OPTIRAY should be postponed in patients who have recently received a cholecystographic contrast agent.

7.2 Drug/Laboratory Test Interactions Protein-Bound Iodine, Radioactive Iodine Determinations The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for up to 16 days following administration of iodinated contrast agent. However, thyroid function tests that do not depend on iodine estimations, e.g., T3 resin uptake and total or free thyroxine (T4) assays are not affected.

Lactation: A lactating woman may pump and discard breast milk for 8 hours after OPTIRAY administration. ( 8.2 )

8.1 Pregnancy Risk Summary Postmarketing data with OPTIRAY use in pregnant women are insufficient to determine if there is a risk of drug-associated adverse developmental outcomes. Ioversol crosses the placenta and reaches fetal tissues in small amounts [see Data]. In animal reproduction studies, no adverse developmental effects were observed following daily intravenous administrations of ioversol to pregnant rats (from Gestation Day 7 to 17) and rabbits (Gestation Day 6 to 18) at doses 0.35 and 0.71 times, respectively, the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Literature reports show that ioversol crosses the placenta and is visualized in the digestive tract of exposed infants after birth. Animal Data Developmental toxicity studies were conducted with ioversol given intravenously at doses of 0, 0.2, 0.8, and 3.2 g iodine/kg/day from Gestation Day7 to 17 and 6 to 18, in rats and rabbits, respectively. No adverse effects on embryo-fetal development were observed in either species at the maximum dose tested (3.2 g iodine/kg/day). Maternal toxicity was observed in rabbits at 0.8 and 3.2 g iodine/kg/day.

8.2 Lactation Risk Summary There is no information about the presence of ioversol in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, iodinated contrast agents are excreted unchanged in human milk in very low amounts with poor absorption from the gastrointestinal tract of the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OPTIRAY and any potential adverse effects on the breastfed infant from OPTIRAY 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 8 hours (approximately 5 elimination half-lives) after OPTIRAY administration in order to minimize drug exposure to a breast fed infant.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have been established for the use of OPTIRAY 350 and OPTIRAY 320 in angiocardiography; and for OPTIRAY 320 in contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography. Use of OPTIRAY 350 and OPTIRAY 320 in these age groups is based on controlled clinical trials involving 159 patients for pediatric angiocardiography; contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography. In general, the types of adverse reactions reported are similar to those of adults [see Adverse Reactions ( 6.1 )] . Safety and effectiveness of OPTIRAY 350 and OPTIRAY 320 have not been established in pediatric patients less than 1 month of age. Pediatric patients at higher risk of experiencing adverse reactions to OPTIRAY include patients with: asthma, sensitivity to medication and/or allergens, congestive heart failure, serum creatinine greater than 1.5 mg/dL, or age less than 12 months. Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration in pediatric patients, including infants. Some patients were treated for hypothyroidism [See Adverse Reactions ( 6.2 )] . 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 Precautions ( 5.8 ) and Adverse Reactions ( 6.2 )].

8.5 Geriatric Use OPTIRAY is substantially excreted by the kidney, and the risk of adverse reactions to OPTIRAY may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, dose selection should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment In patients with impaired renal function, the elimination half-life is prolonged. Ioversol can be removed by dialysis.

Intravascular injection of ioversol opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures until significant hemodilution occurs. Ioversol may be visualized in the renal parenchyma within 30 to 60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1 to 3 minutes, with optimum contrast occurring within 5 to 15 minutes. OPTIRAY enhances computed tomographic imaging through augmentation of radiographic efficiency. The degree of density enhancement is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid intravenous injection. Blood levels fall rapidly within 5 to 10 minutes and the vascular compartment half-life is approximately 20 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached in about 10 minutes; thereafter, the fall becomes exponential.