Oxilan Description

OXILAN® (Ioxilan Injection) formulations are stable, aqueous, sterile, and non- pyrogenic solutions for intravascular administration as diagnostic radiopaque media. Ioxilan is designated chemically as N-(2,3-dihydroxypropyl)-N’-(2- hydroxyethyl)-5-[N-(2,3-dihydroxypropyl) acetamido]-2,4,6-triiodoisophthal-amide and has the following structural formula:

The molecular weight of ioxilan is 791.12 and the organically bound iodine content is 48.1%. Ioxilan is nonionic and does not dissociate in solution. OXILAN® (Ioxilan Injection) Pharmacy Bulk Package is available in two strengths: OXILAN® (Ioxilan Injection) 300 mgI/mL and OXILAN® (Ioxilan Injection) 350 mgI/mL.

Each mL of OXILAN® (Ioxilan Injection) 300 mgI/mL provides 623 mg ioxilan. Each mL of OXILAN® (Ioxilan Injection) 350 mgI/mL provides 727 mg ioxilan. Each mL of OXILAN® (Ioxilan Injection) 300 mgI/mL Pharmacy Bulk Package provides 623 mg ioxilan.

Each mL of OXILAN® (Ioxilan Injection) 350 mgI/mL Pharmacy Bulk Package provides 727 mg ioxilan.

Each mL of OXILAN® solution contains 0.1 mg edetate calcium disodium (anhydrous basis), 1.0 mg tromethamine, 0.5 mg sodium chloride and a minimum of 0.2 mg (0.01 mEq) sodium. The pH is adjusted to 6.8 (5.5 to 7.5) with hydrochloric acid and sodium hydroxide. The solutions contain no preservative.

Pertinent physicochemical data are below. OXILAN® (Ioxilan Injection) is hypertonic compared to plasma (approximately 285 mOsm/kg water).

The OXILAN® formulations are clear, colorless to pale yellow solutions containing no undissolved solids. Crystallization does not occur at room temperature. OXILAN® solutions have osmolalities of 2.1 and 2.5 times that of plasma (285 mOsm/kg water) and are hypertonic under conditions of use.

Each bottle of OXILAN® Pharmacy Bulk Package is to be used for dispensing multiple single dose preparations utilizing a suitable transfer device.

Oxilan - Clinical Pharmacology

Clinical Studies

OXILAN® Injection was administered to 834 patients in controlled and uncontrolled studies. Of these 679 patients were between 18 and 69 years of age, and 155 patients were 70 years of age or older; the mean age was 56.4 years (range 18-88). Of the 834 patients, 579 (69%) were male and 255 (31%) were female. The racial distribution was: Caucasian 668 (80%), Black 84 (10%), Hispanic 58 (7%), Asian 14 (2%), and other or unknown 10 (1%). The demographic information for patients who received the comparator (iohexol) was similar.

In the controlled studies, 530 patients given OXILAN® Injection and 540 patients given the comparator (iohexol) were evaluated for efficacy. Efficacy assessment was based on the global evaluation of the quality of the radiographs by rating visualization as either excellent, good, poor, or no image, and on the ability to make a diagnosis. Results were compared to those with the active control (iohexol injection) at concentrations which were identical to those of OXILAN® Injection.

Four (4) intraarterial and three (3) intravenous procedures were studied with 1 of 2 concentrations (350 mgI/mL and 300 mgI/mL). These procedures were: aortography/visceral angiography, coronary arteriography and left ventriculography, cerebral arteriography, peripheral arteriography, contrast- enhanced computed tomography (CECT) of head and body, and excretory urography.

Cerebral arteriography was evaluated in 3 randomized, double-blind clinical trials of OXILAN® Injection 300 mgI/mL in patients with conditions such as altered cerebrovascular perfusion and/or permeability occurring in central nervous system diseases due to various CNS disorders. Results were assessed in 78 patients with OXILAN® (Ioxilan Injection) and 83 with iohexol injection 300 mgI/mL. Visualization ratings were good or excellent in 95% of the patients with OXILAN® Injection; a radiologic diagnosis was made in the majority of the patients. The results were similar to those with iohexol injection. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Coronary arteriography/left ventriculography was evaluated in 4 randomized, double-blind clinical trials of OXILAN® Injection 350 mgI/mL in patients with conditions such as altered coronary artery perfusion due to metabolic causes and in patients with conditions such as altered ventricular function. Results were assessed in 139 patients with OXILAN® Injection and 142 with iohexol injection 350 mgI/mL. Visualization ratings were good or excellent in 99% or more of the patients with OXILAN® Injection; a radiologic diagnosis was made in the majority of the patients. The results were similar to those with iohexol injection. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Aortography/visceral angiography was evaluated in 3 randomized, double- blind clinical trials of OXILAN® Injection 350 mgI/mL in patients with conditions such as altered aortic blood flow and/or visceral vascular disorders. The results were assessed in 51 patients with OXILAN® Injection 350 mgI/mL and 47 with iohexol injection 350 mgI/mL. Visualization ratings were good or excellent in the majority of the patients; a radiologic diagnosis was made in 90% of the patients with OXILAN® Injection. The results were similar to those with iohexol injection. Confirmation of radiologic findings by other diagnostic methods was not obtained.

Intravenous excretory urography was evaluated in 2 randomized, double- blind clinical trials of OXILAN® Injection 350 mgI/mL. The results were assessed in 61 patients with OXILAN® Injection 350 mgI/mL and 62 with iohexol injection 350 mgI/mL. Visualization ratings were good or excellent in all of the patients; a radiologic diagnosis was made in 100% of the patients with OXILAN® Injection. The results were similar to those with iohexol injection. Confirmation of radiologic findings by other diagnostic methods was not obtained.

CECT of head and body was evaluated in 5 randomized, double-blind clinical trials in patients with vascular disorders. A total of 146 patients received OXILAN® Injection 300 mgI/mL and 149 received iohexol injection 300 mgI/mL. Visualization ratings were good or excellent in 98% of the patients with OXILAN® Injection; a radiologic diagnosis was made in the majority of the patients. The results were similar to those with iohexol injection.

Indications and Usage for Oxilan

Contraindications

OXILAN® Injection is not indicated for intrathecal use.

Warnings

SEVERE ADVERSE EVENTS-INADVERTENT INTRATHECAL ADMINISTRATION: Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not administered intrathecally.

Nonionic iodinated contrast media inhibit blood coagulation, in vitro, less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing nonionic contrast media. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and concomitant medications may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended including close attention to guidewire and catheter manipulation, use of manifold systems and/or three way stopcocks, frequent catheter flushing with heparinized saline solutions, and minimizing the length of the procedure.

Serious or fatal reactions have been associated with the administration of iodine-containing radiopaque media. It is of utmost importance to be completely prepared to treat any contrast agent reaction.

Caution must be exercised in patients with severely impaired renal function, combined renal and hepatic disease, combined renal and cardiac disease, severe thyrotoxicosis, myelomatosis, or anuria, particularly when large doses are administered. (See PRECAUTIONS.)

Intravascularly administered iodine-containing radiopaque media are potentially hazardous in patients with multiple myeloma or other paraproteinacious diseases, who are prone to disease-induced renal insufficiency and/or failure. Although neither the contrast agent nor dehydration has been proven to be the cause of renal insufficiency (or worsening renal insufficiency) in myelomatous patients, it has been speculated that the combination of both may be causative. Special precautions, including maintenance of normal hydration and close monitoring, are required. Partial dehydration in the preparation of these patients prior to injection is not recommended since this may predispose the patient to precipitation of the myeloma protein.

Reports of thyroid storm following the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of any contrast agent.

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 contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering Oxilan to patients with a history of severe cutaneous adverse reaction to Oxilan.

Administration of radiopaque materials to patients with known or suspected pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure and measures for treatment of a hypertensive crisis should be available. These patients should be monitored very closely during contrast enhanced procedures.

Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when administered intravascularly.

Precautions

General: THE DECISION TO USE CONTRAST ENHANCEMENT IS ASSOCIATED WITH RISK AND INCREASED RADIATION EXPOSURE, AND SHOULD BE BASED UPON A CAREFUL EVALUATION OF CLINICAL, OTHER RADIOLOGIC DATA, AND THE RESULTS OF UNENHANCED CT FINDINGS.

Patients receiving contrast agents, and especially those who are medically unstable, must be closely supervised. Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all types should always be available. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes after administration.

Dehydration, Renal Insufficiency, Congestive Heart Failure: Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, congestive heart disease, diabetic patients, and other patients such as those on medications which alter renal function and the elderly with age related renal impairment. Patients should be adequately hydrated prior to and following the intravascular administration of iodinated contrast agents. Dose adjustments in renal impairment have not been studied.

Iodinated contrast agents may cross the blood-brain barrier. In patients where the blood-brain barrier is known or suspected to be disrupted, or in patients with normal blood-brain barriers and associated renal impairment, CAUTION MUST BE EXERCISED IN CONSIDERING THE USE OF AN IODINATED CONTRAST AGENT. (See Pharmacodynamics.)

Patients with congestive heart failure receiving concurrent diuretic therapy may have relative intravascular volume depletion, which may affect the renal response to the contrast agent osmotic load. Such patients should be observed for several hours following the procedure to detect delayed hemodynamic renal function disturbances.

Immunologic Reactions: The possibility of a reaction, including serious, life- threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered. Increased risk is associated with a history of previous reaction to a contrast agent, a known sensitivity to iodine and known allergies (i.e., bronchial asthma, hay fever and food allergies) other hypersensitivities, and underlying immune disorders, autoimmunity or immunodeficiencies that predispose to specific or non-specific mediator release.

Skin testing cannot be relied upon to predict severe reactions and may itself be hazardous to the patient. A thorough medical history with emphasis on allergy and hypersensitivity, immune, autoimmune and immunodeficiency disorders, and prior receipt of and response to the injection of any contrast agent, may be more accurate than pretesting in predicting potential adverse reactions.

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. Extreme caution should be exercised in considering the use of iodinated contrast agents in patients with these histories or disorders.

Anesthesia: General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions has been reported in these patients. It is not clear if this is due to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia, which can prolong the circulation time and increase the duration of exposure to the contrast agent.

Angiography: In angiographic procedures, the possibility of dislodging plaques or damaging or perforating the vessel wall with resultant pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery etc., should be considered during catheter manipulations and contrast agent injection. Angiography may be associated with local and distal organ damage, ischemia, thrombosis and organ failure (e.g., brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepato-renal function abnormalities, etc.). Test injections to insure proper catheter placement are suggested. Increased thrombosis and activation of the complement system have also occurred. (See WARNINGS.)

Angiography also should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism. (See Pharmacodynamics.)

Selective coronary arteriography should be performed only in selected patients and those in whom the expected benefits outweigh the procedural risk. Also, the inherent risks of angiocardiography in patients with chronic pulmonary emphysema must be weighed against the necessity for performing this procedure.

Venography: The safety of ioxilan in venographic procedures has not been studied.

Extreme caution during injection of a contrast agent is necessary to avoid extravasation. This is especially important in patients with severe arterial or venous disease.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Long-term animal studies have not been performed with ioxilan to evaluate carcinogenic potential or effects on fertility. Ioxilan was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes analysis of chromosomal aberrations, an in vivo mouse micronucleus assay, and in an in vivo mouse dominant lethal assay.

Adverse Reactions/Side Effects

For demographics, see CLINICAL TRIALS section.

The following table of incidence of reactions is based upon controlled clinical studies in which OXILAN® was compared with a nonionic contrast agent (iohexol) in 531 patients. It includes all reported adverse events, regardless of attribution.

Adverse reactions are listed by body system and in decreasing order of occurrence greater than 0.5% in the OXILAN® group.

One or more adverse reactions were reported in 76 of 531 (14.3%) of patients in the clinical trials, coincidental with the administration of OXILAN® or within the study follow-up period of 24 to 72 hours. The incidence and type of adverse reactions were similar to those associated with the nonionic comparator (iohexol) used in the clinical trials. OXILAN®, as do other iodinated contrast agents, often causes warmth and/or pain on injection. The rates are similar to that of the iohexol comparator.

Serious, life threatening and fatal reactions have been associated with the administration of iodine-containing contrast media. In all clinical trials 3/835 (0.3%) patients given OXILAN® and 3/542 (0.6%) given iohexol died 4 days or later after drug administration. In the controlled trials 8/531 (1.5%) patients given OXILAN® and 6/542 (1.1%) given iohexol had serious adverse events.

The following adverse reactions were observed ≤ 0.5% of patients receiving OXILAN® Injection:

BODY: allergic reaction, asthenia, chest and back pain, edema of the neck, facial edema, pain, peripheral edema; CARDIOVASCULAR: atrial fibrillation, syncope, tachycardia, vasodilation, ventricular extrasystole; DIGESTIVE: anorexia, constipation, dyspepsia, dysphagia, GI hemorrhage, ileus, liver failure; NERVOUS: hypotonia, nystagmus, paresthesia, somnolence, vertigo; RESPIRATORY: dyspnea, pharyngitis, rhinitis; SKIN: pruritus, sweating; SPECIAL SENSES: amblyopia, conjunctivitis, taste perversion, vision abnormality; UROGENITAL: anuria, dysuria, hematuria, infection of urinary tract, impairment of urination, kidney failure.

Additional adverse events reported in postmarketing surveillance with the use of OXILAN® Injection include: bronchospasm.

Overdosage

The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.

OXILAN® Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.

How is Oxilan supplied

OXILAN® (Ioxilan Injection) 300 mgI/mL -

Ten 50 mL single dose bottles, NDC 67684-1000-1

Ten 100 mL single dose bottles, NDC 67684-1000-2

Ten 150 mL single dose bottles, NDC 67684-1000-3

OXILAN® (Ioxilan Injection) 350 mgI/mL -

Ten 50 mL single dose bottles, NDC 67684-1001-1

Ten 100 mL single dose bottles, NDC 67684-1001-2

Ten 150 mL single dose bottles, NDC 67684-1001-3

Ten 200 mL single dose bottles, NDC 67684-1001-4

OXILAN® (Ioxilan Injection) 300 mgI/mL Pharmacy Bulk Package - Six 500 mL bottles, NDC 67684-1000-5

OXILAN® (Ioxilan Injection) 350 mgI/mL Pharmacy Bulk Package - Six 500 mL bottles, NDC 67684-1001-5

Storage and Handling

Store at room temperature between 15° and 30°C (59° and 86°F) and protect from light. Do not freeze.

RX only.

U.S. patent numbers 4,954,348; 5,035,877

Guerbet LLC - Princeton, NJ 08540
Distributed by Guerbet LLC
821 Alexander Road, Suite 204, Princeton, NJ 08540

Revised 03/2017

OXILAN® (Ioxilan Injection) 350 mgI/mL, 200 mL bottles

Six 200 mL bottles, NDC 67684-1001-4

OXILAN® (Ioxilan Injection) 350 mgI/mL, 200 mL bulk pharmacy bottles

200 mL bulk pharmacy bottle label