IOPAMIDOL

Iopamidol Injection, USP is a radiographic contrast agent for intra-arterial or intravenous use. Iopamidol is designated chemically as (S)-N,N’-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo-5-lactamidoisophthalamide with a molecular weight of 777.09, an empirical formula of C 17 H 22 I 3 N 3 O 8 , and the following structural formula: Iopamidol Injection, USP is a sterile, clear, colorless to pale yellow solution available in four concentrations of iodine: Iopamidol Injection, USP, 200 mg iodine/mL: Each mL contains 408 mg iopamidol (providing 200 mg organically bound iodine) and the following inactive ingredients: 0.26 mg edetate calcium disodium (providing 0.029 mg (0.001 mEq) sodium) and 1 mg tromethamine. Iopamidol Injection, USP, 250 mg iodine/mL: Each mL contains 510 mg iopamidol (providing 250 mg organically bound iodine) and the following inactive ingredients: 0.33 mg edetate calcium disodium (providing 0.036 mg (0.002 mEq) sodium) and 1 mg tromethamine. Iopamidol Injection, USP, 300 mg iodine/mL: Each mL contains 612 mg iopamidol (providing 300 mg organically bound iodine) and the following inactive ingredients: 0.39 mg edetate calcium disodium (providing 0.043 mg (0.002 mEq) sodium) and 1 mg tromethamine. Iopamidol Injection, USP, 370 mg iodine/mL: Each mL contains 755 mg iopamidol (providing 370 mg organically bound iodine) and the following inactive ingredients: 0.48 mg edetate calcium disodium (providing 0.053 mg (0.002 mEq) sodium) and 1 mg tromethamine. The pH of Iopamidol Injection, USP has been adjusted to 6.5 to 7.5 with hydrochloric acid and/or sodium hydroxide. Physicochemical characteristics are shown in Table 5. Iopamidol Injection, USP is hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively). Table 5: Physicochemical Characteristics of Iopamidol Injection, USP Concentration (mg Iodine/mL) 200 250 300 370 Osmolality @ 37°C (mOsm/kg water) 413 524 616 796 Viscosity (cP) @ 37°C 2.0 3.0 4.7 9.4 Viscosity (cP) @ 20°C 3.3 5.1 8.8 20.9 Specific Gravity @ 37°C 1.227 1.281 1.339 1.405 image-01.jpg

Iopamidol Injection, USP 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 * Specific concentrations are recommended for each type of imaging procedure. ( 2.2 , 2.3 , 2.4 ) 1.1 Intra-arterial Procedures* 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* Excretory urography in adults and pediatric patients Computed tomography (CT) of head and body in adults and pediatric patients Peripheral venography in adults * Specific concentrations of Iopamidol Injection, USP are recommended for each type of imaging procedure [see Dosage and Administration ( 2.2 , 2.3 , 2.4 )].

Individualize the volume and concentration according to the specific dosing tables accounting for factors such as age, body weight, size of the vessel, and the rate of blood flow within the vessel. ( 2.2 , 2.3 , 2.4 ) See full prescribing information for important dosage and administration information. ( 2.1 ) 2.1 Important Dosing and Administration Information Iopamidol Injection, USP is for intra-arterial or intravenous use only and must not be administered intrathecally [see Warnings and Precautions ( 5.1 )] . Specific concentrations of Iopamidol Injection, USP are recommended for each type of imaging procedure [see Dosage and Administration ( 2.2 , 2.3 , 2.4 )] . Individualize the volume, concentration, and injection rate of iopamidol injection according to the specific dosing tables [see Dosage and Administration ( 2.2 , 2.3 , 2.4 )] . Consider factors such as: age, body weight, blood vessel size and blood flow rate, anticipated pathology and degree and extent of opacification required, structures or area to be examined, concomitant medical conditions, imaging equipment, and technique to be employed. Hydrate patients before and after Iopamidol Injection, USP administration [see Warnings and Precautions ( 5.3 )] . Use aseptic technique for all handling and administration of Iopamidol Injection, USP. Iopamidol Injection, USP may be administered at either body temperature (37°C, 98.6°F) or room temperature (20°C to 25°C, 68°F to 77°F). Visually inspect Iopamidol Injection, USP for particulate matter or discoloration before administration. Do not administer Iopamidol Injection, USP if particulate matter or discolorations are observed. Do not mix Iopamidol Injection, USP with other drugs or inject in intravenous lines containing other drugs or total nutritional admixtures. Iopamidol Injection, USP single-dose containers are intended for one procedure only. Discard any unused portion. 2.2 Recommended Dosage for Intra-arterial Procedures in Adults The recommended doses for intra-arterial procedures in adults are shown in Table 1. Table 1: Recommended Concentrations and Volumes of Iopamidol Injection, USP for Intra-arterial Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume to Administer per Single Injection for Selected Injection Sites Maximum Cumulative Total Dose Cerebral Arteriography 300 8 mL to 12 mL by carotid puncture or transfemoral catheterization 90 mL Peripheral Arteriography 300 • 5 mL to 40 mL into the femoral artery or subclavian artery • 25 mL to 50 mL into the aorta for a distal runoff 250 mL Selective Visceral Arteriography and Aortography 370 • Up to 10 mL for the renal arteries • Up to 50 mL into the larger vessels such as the aorta or celiac artery 225 mL Coronary Arteriography and Cardiac Ventriculography 370 • 2 mL to 10 mL for selective coronary artery injection • 25 mL to 50 mL for cardiac ventriculography or for nonselective opacification of multiple coronary arteries following injection at the aortic root 200 mL 2.3 Recommended Dosage for Intravenous Procedures in Adults The recommended doses for intra-arterial procedures in adults are shown in Table 2. Table 2: Recommended Concentrations and Volumes of Iopamidol Injection, USP for Intravenous Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume to Administer Excretory Urography 250 300 370 50 mL to 100 mL by rapid injection 50 mL by rapid injection 40 mL by rapid injection CT of the Head 250 300 130 mL to 240 mL 100 mL to 200 mL CT of Body 250 300 370 130 mL to 240 mL by rapid infusion or bolus injection 100 mL to 200 mL by rapid infusion or bolus injection 80 mL to 160 mL by rapid infusion or bolus injection Peripheral Venography 200 25 mL to 150 mL per lower extremity; the maximum total dose is 350 mL 2.4 Recommended Dosage in Pediatric Patients The recommended doses in pediatric patients are shown in Table 3. Table 3: Recommended Concentrations and Volumes per Body Weight of Iopamidol Injection, USP for Intra-arterial and Intravenous Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume per Body Weight to Administer Maximum Dose Intra-arterial Procedures Angiocardiography 370 0.5 mL/kg to 2 mL/kg per single injection Maximum Cumulative Dose by Weight • Neonates: 5 mL/kg • Aged 4 weeks and older: 8 mL/kg • Do not exceed maximum cumulative doses by age below. Maximum Cumulative Dose by Age • <2 years 40 mL • 2 years to 4 years 50 mL • 5 years to 9 years 100 mL • 10 years to 18 years 125 mL Intravenous Procedures Excretory Urography 250 1.2 mL/kg to 3.6 mL/kg 120 mL 300 1 mL/kg to 3 mL/kg 100 mL CT of the Head and Body 250 1.2 mL/kg to 3.6 mL/kg 120 mL 300 1 mL/kg to 3 mL/kg 100 mL

None. None ( 4 )

The following adverse reactions are described in greater detail in other sections: 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%) are pain, hot flashes, burning sensation, nausea, and warmth. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, Inc. at 1-888-341-9214 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 Adults The safety of iopamidol injection was evaluated in 2,246 adult patients receiving iopamidol injection by intra-arterial or intravenous route in clinical studies. Table 4 shows the common adverse reactions (>1%). Table 4: Adverse Reactions Reported in >1% of Patients Receiving Intra-arterial or Intravenous Injection of Iopamidol in Clinical Studies Adverse Reaction Iopamidol Injection (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 iopamidol injection: 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 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of iopamidol injection. 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 Gastrointestinal disorders : retching, abdominal pain, salivary hypersecretion, salivary gland enlargement 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, face edema

7.1 Drug-Drug Interactions Metformin In patients with renal impairment, metformin can cause lactic acidosis. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. Stop metformin at the time of, or prior to, iopamidol injection administration in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast agents. Re-evaluate eGFR 48 hours after the imaging procedure and reinstitute metformin use only after renal function is stable. Radioactive Iodine Administration of iopamidol injection may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post iopamidol injection 7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Iodinated contrast agents, including iopamidol injection, will temporarily increase protein-bound iodine in blood. Avoid protein-bound iodine test for at least 16 days following administration of iopamidol injection . However, thyroid function tests that do not depend on iodine estimations, e.g., triiodothyronine (T 3 ) resin uptake and total or free thyroxine (T 4 ) assays, are not affected.