An Expert Report on Iodixanol (Visipaque®): Pharmacology, Clinical Use, and Comparative Safety

Executive Summary

Iodixanol is a third-generation, non-ionic, dimeric, hexa-iodinated radiographic contrast agent representing a significant development in medical imaging.[1] Marketed principally under the brand name Visipaque®, its defining physicochemical characteristic is its iso-osmolality. At all clinically relevant concentrations, it is isotonic to human blood, with an osmolality of approximately 290 mOsm/kg H₂O, a feature unique among intravascular contrast media.[3] This property was engineered to improve the safety and tolerability profile of iodinated contrast agents, particularly in high-risk patient populations.[5]

Clinically, Iodixanol is utilized for a broad spectrum of intra-arterial and intravenous radiographic procedures. Its applications include angiography, venography, excretory urography, and contrast-enhanced computed tomography (CECT) of the head and body.[6] Notably, it is the only contrast agent with a specific U.S. Food and Drug Administration (FDA) approved indication for Coronary Computed Tomography Angiography (CCTA), positioning it as a key tool in the non-invasive diagnostic evaluation of coronary artery disease.[8]

The pharmacological profile of Iodixanol is characterized by a trade-off inherent to its molecular structure. Its large, dimeric form enables iso-osmolality, which contributes to a favorable tolerability profile with reduced patient discomfort, such as sensations of pain and warmth, compared to hyperosmolar agents.[9] However, this same dimeric structure results in a higher viscosity than that of monomeric low-osmolar contrast media (LOCM), a property that requires clinical management, such as pre-warming the agent before injection.[9] A central theme in the evaluation of Iodixanol is its renal safety. Evidence from numerous clinical trials and meta-analyses indicates a nuanced profile; it demonstrates a significant advantage in reducing the risk of contrast-induced acute kidney injury (CI-AKI) when compared specifically to the LOCM iohexol, particularly in high-risk patients with pre-existing renal dysfunction and/or diabetes mellitus.[12] However, this benefit is less pronounced when compared to the broader class of all LOCMs, where the reduction in risk is often borderline or not statistically significant.[14]

The safety profile of Iodixanol is well-documented and requires stringent risk management. It carries a boxed warning absolutely contraindicating its use for intrathecal administration, as inadvertent injection into the cerebrospinal fluid can be fatal.[16] Other major warnings include the potential for life-threatening hypersensitivity reactions, cardiovascular events, thyroid dysfunction in pediatric patients aged 0-3 years, and severe cutaneous adverse reactions.[6] A clinically critical drug interaction exists with metformin; guidelines mandate its temporary discontinuation in at-risk patients to prevent metformin-induced lactic acidosis in the event of transient renal impairment.[18] This report provides an exhaustive analysis of Iodixanol, synthesizing data on its physicochemical properties, pharmacology, clinical applications, comprehensive safety profile, and its comparative place among other iodinated contrast agents to serve as a definitive reference for medical professionals.

Physicochemical and Pharmaceutical Profile

The clinical performance and safety of Iodixanol are directly rooted in its unique molecular structure and resulting physicochemical properties. A comprehensive understanding of its chemical identity, physical characteristics, and formulation is essential for its appropriate and safe use in diagnostic imaging.

Chemical Identity and Structure

Iodixanol is classified as a small molecule, organoiodine compound, belonging to the class of non-ionic, water-soluble, radiographic contrast media.[3] Its structure is uniquely dimeric, meaning it consists of two covalently linked tri-iodinated benzene rings. This hexa-iodinated structure is fundamental to its properties.[1]

• Chemical Formula: The empirical formula for Iodixanol is C35​H44​I6​N6​O15​.[21]
• Molecular Weight: The average molecular weight is approximately 1550.2 g/mol.[22] The substantial mass is due to the six heavy iodine atoms, which account for 49.1% of the molecule's weight and are the basis of its radiopacity.[1]
• IUPAC Name and Synonyms: The formal International Union of Pure and Applied Chemistry (IUPAC) name is 5,5'-[(2-hydroxypropane-1,3-diyl)bis(acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide].[20] In scientific and clinical literature, it is referred to by several synonyms, including Iodixanolum, Indixanol, and its primary brand names, Visipaque® (for clinical use) and OptiPrep™ (for research applications).[3]

Physical and Chemical Properties

Iodixanol is formulated as an injectable solution with specific physical properties tailored for intravascular administration.

• Appearance: The commercial product is a sterile, pyrogen-free, clear, colorless to pale yellow aqueous solution.[1]
• Solubility: It is a hydrophilic, water-soluble compound.[3] Its solubility in various solvents has been characterized as 30 mg/mL in dimethylformamide (DMF), 15 mg/mL in dimethyl sulfoxide (DMSO), and 10 mg/mL in phosphate-buffered saline (PBS) at pH 7.2. It is notably insoluble in ethanol.[24]
• Melting Point: The melting point is reported in the range of 240–250 °C, with other sources indicating decomposition occurs between 262–267 °C.[1]
• pH: To ensure physiological compatibility and stability, the pH of the final formulation is carefully adjusted with hydrochloric acid and/or sodium hydroxide to a range between 6.8 and 7.7, with a target of 7.4.[2]

Osmolality and Viscosity: The Defining Characteristics

The innovation of Iodixanol lies in a fundamental physicochemical trade-off, where its dimeric structure is simultaneously the source of its greatest clinical advantage and a notable practical challenge.

• Iso-osmolality: Iodixanol is the only iodinated contrast agent that is iso-osmolar, meaning it has the same osmolality as human blood and plasma (approximately 290 mOsm/kg H₂O) at all available concentrations.[3] This is achieved through its dimeric structure, which packs six iodine atoms into a single non-ionic molecule. This high iodine-to-particle ratio minimizes the number of solute particles needed to achieve a high iodine concentration, thereby keeping osmolality low. The final formulation is then made perfectly isotonic through the addition of balanced electrolytes.[2] This property is directly responsible for its improved patient tolerability, as it minimizes the osmotic fluid shifts across vascular endothelial and red blood cell membranes that cause sensations of pain, warmth, and discomfort associated with hyperosmolar agents.[9]
• Viscosity: The same large, dimeric molecular structure that enables iso-osmolality also makes the solution inherently more viscous than smaller, monomeric LOCMs.[9] The viscosity of the 320 mgI/mL solution at 37 °C is approximately 11.4 mPa·s, while the 270 mgI/mL solution has a viscosity of 5.8 mPa·s.[27] For comparison, the viscosity of iopamidol-370 is lower at 9.4 mPa·s at 37 °C.[30] This higher viscosity presents a practical challenge for clinicians, as it can increase the resistance to injection. To mitigate this, it is recommended that Iodixanol be warmed to body temperature (37 °C) before administration, which significantly reduces its viscosity and facilitates a smoother injection.[9] This inherent trade-off—gaining superior patient comfort from iso-osmolality at the cost of managing higher viscosity—is central to understanding the clinical selection and comparative performance of Iodixanol.

Commercial Formulations and Excipients

Iodixanol is available in several formulations for both clinical and research use.

• Brand Names and Manufacturers: The originator brand is Visipaque®, manufactured by GE Healthcare.[1] Following patent expiry, generic versions have become available from companies including Fresenius Kabi and Hengrui Pharma.[16] For laboratory and research applications, it is marketed as OptiPrep™.[4]
• Concentrations: The two primary clinical strengths are defined by their iodine content: 270 mg of organically bound iodine per mL (which corresponds to 550 mg of iodixanol per mL) and 320 mgI/mL (corresponding to 652 mg of iodixanol per mL).[2]
• Excipients: The injectable solutions are preservative-free. In addition to iodixanol and water for injection, the formulations contain several key excipients to ensure stability and physiological compatibility. These include tromethamine as a buffer to maintain pH, edetate calcium disodium as a chelating agent to bind trace metal ions, and a specific ratio of sodium chloride and calcium chloride dihydrate. This electrolyte balance is designed to make the solution not only iso-osmolar but also isotonic, mimicking the electrolyte composition of blood to minimize effects on cardiac contractility.[2]

Clinical Pharmacology

The clinical effects of Iodixanol are governed by its pharmacodynamic and pharmacokinetic properties. Its ability to attenuate X-rays provides the basis for its diagnostic utility, while its absorption, distribution, metabolism, and excretion (ADME) profile determines its duration of action and safety, particularly in specific patient populations.

Mechanism of Action (Pharmacodynamics)

The fundamental mechanism of action for Iodixanol, like all iodinated contrast media, is its ability to increase the density of tissues and fluids to X-rays.

• Radiopacity: The six organically bound iodine atoms within each Iodixanol molecule have a high atomic number and density, allowing them to effectively absorb photons from an X-ray beam.[3] When administered intravascularly, Iodixanol mixes with the blood, making the blood and, consequently, the vessels through which it flows, opaque to X-rays. This opacification allows for the radiographic visualization of internal vascular structures until the agent is diluted by body fluids and eliminated.[2]
• Contrast Enhancement Dynamics: The degree of radiographic enhancement is directly proportional to the concentration of iodine present in the tissue or vessel being imaged.[2] Following a rapid bolus injection, peak iodine plasma concentrations are achieved almost immediately, leading to maximum vascular enhancement within 15 to 120 seconds.[2] Subsequently, the agent diffuses from the intravascular compartment into the extravascular interstitial space. This diffusion allows for the enhancement of highly perfused organ parenchyma. The differential rate of diffusion and accumulation between adjacent tissues, which is related to blood flow and vascular permeability, creates the contrast that allows for the delineation of anatomical structures and pathological lesions.[2] For instance, in the kidneys, visualization of the parenchyma occurs within 30-60 seconds, with opacification of the calyces and pelves becoming apparent within 1-3 minutes in patients with normal renal function.[2]
• Blood-Brain Barrier (BBB) Interaction: The behavior of Iodixanol in the central nervous system depends on the integrity of the blood-brain barrier. In a normal brain with an intact BBB, the hydrophilic Iodixanol molecule is confined to the intravascular space, allowing for the visualization of blood vessels such as in angiography of arteriovenous malformations or aneurysms.[2] In tissues where the BBB is disrupted, such as in certain tumors, infections, or areas of recent infarction, the contrast agent can leak into the interstitial space of the brain. This accumulation within the lesion leads to enhancement, making the pathology visible on imaging.[2] It is important to note that in patients with co-existing renal failure, iodinated contrast agents themselves have been associated with BBB disruption and an accumulation of contrast in the brain, a potential source of neurotoxicity.[2]

Pharmacokinetics (ADME Profile)

The pharmacokinetic profile of Iodixanol is characterized by its simple and direct pathway through the body, which is a key determinant of its safety profile. Its lack of metabolism is a significant safety feature, but its complete reliance on renal excretion is its primary vulnerability, dictating the specific patient populations that require the most careful clinical management.

• Absorption: As Iodixanol is administered directly into the bloodstream via intra-arterial or intravenous injection, absorption is immediate and bioavailability is 100%.[2]
• Distribution: Following administration, Iodixanol distributes rapidly throughout the body. It exhibits negligible binding to plasma proteins, meaning it circulates freely in the blood.[2] The volume of distribution is approximately 0.26 L/kg, which is consistent with its distribution being confined to the extracellular fluid compartment.[2]
• Metabolism: Iodixanol is not metabolized in the body. It is a biologically inert compound, and no metabolites have been identified following its administration.[2]
• Excretion: The elimination of Iodixanol is almost exclusively via the kidneys through glomerular filtration. Approximately 97% of an injected dose is excreted unchanged in the urine within 24 hours. A very small fraction, less than 2%, is eliminated in the feces over a period of five days.[2]
• Elimination Half-Life: The rate at which Iodixanol is cleared from the body is highly dependent on renal function and patient age.
• Adults with Normal Renal Function: In healthy adults, the elimination half-life is consistently reported to be 2.1 hours.[2]
• Pediatric Patients: Renal function matures with age, and this is reflected in the elimination half-life of Iodixanol. In neonates (newborn to <2 months), the half-life is significantly longer at 4.1 hours. It decreases to 2.8 hours in infants aged 2 to <6 months and approaches the adult value at approximately 2.3 hours in children over one year of age.[2] This prolonged exposure in the youngest patients is the pharmacokinetic basis for the specific warnings regarding potential thyroid dysfunction in this age group, as the thyroid gland has a longer period to interact with the iodinated compound.
• Patients with Renal Insufficiency: The direct dependence on renal clearance makes patients with pre-existing renal impairment a major high-risk group. In individuals with significantly impaired renal function, the elimination half-life is dramatically prolonged, extending to as long as 23 hours.[2] In this population, the contrast agent can remain detectable in the plasma for up to five days after a single dose.[37] This prolonged systemic and renal exposure is the likely mechanism underlying the increased risk of CI-AKI in these patients.
• Dialyzability: Iodixanol can be removed from the blood by hemodialysis. In vitro studies have shown that a four-hour dialysis session can remove approximately 36% of the agent using a cellulose membrane and up to 49% using a more modern polysulfone membrane.[2] This provides a potential clearance mechanism for patients with severe renal failure or in cases of overdose.

The entire risk management strategy for Iodixanol revolves around this pharmacokinetic profile. Key clinical precautions, such as ensuring adequate hydration to support renal flow, using the lowest possible diagnostic dose, and avoiding concomitant nephrotoxic medications, are all designed to either facilitate renal clearance or minimize the total renal burden.

Approved Clinical Indications and Dosing Guidelines

Iodixanol is a versatile contrast agent approved for a wide array of diagnostic imaging procedures in both adult and pediatric populations. Its use is governed by specific indications approved by regulatory bodies like the U.S. FDA, with detailed guidelines for dosage and administration tailored to each procedure.

Overview of Approved Uses

Iodixanol injection serves as an iodinated contrast agent to enhance the visualization of anatomical structures and pathologies during radiographic examinations. It is used to diagnose problems in the brain, heart, head, blood vessels (both arteries and veins), and the urinary system (kidneys and bladder), among other parts of the body.[6] Its administration is restricted to intravascular routes (intra-arterial and intravenous) and must be performed by or under the direct supervision of a physician in a hospital or clinic setting.[7]

FDA-Approved Indications

The approved indications for Iodixanol are specific to the route of administration, the concentration of the agent, and the age of the patient. A key distinction is its unique FDA approval for Coronary Computed Tomography Angiography (CCTA), which positions it as a specialized agent for non-invasive cardiac imaging.[8] This approval, granted in 2017, was a strategic development that leveraged the drug's iso-osmolar profile for use in a patient population often presenting with multiple comorbidities.[10] By securing this indication, the manufacturer established a protected niche for Visipaque®, differentiating it from other generic LOCMs and reinforcing its identity as a premium, safety-focused agent for a growing and critical diagnostic modality.

The FDA-approved indications are as follows [8]:

Intra-Arterial Procedures:

• Adults and Pediatric Patients (12 years of age and over):
• Intra-arterial digital subtraction angiography (IA-DSA) [using 270 mgI/mL and 320 mgI/mL concentrations].
• Angiocardiography (including left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography [using the 320 mgI/mL concentration].
• Pediatric Patients (less than 12 years of age):
• Angiocardiography, cerebral arteriography, and visceral arteriography [using the 320 mgI/mL concentration].

Intravenous Procedures:

• Adults and Pediatric Patients (12 years of age and over):
• Contrast-Enhanced Computed Tomography (CECT) of the head and body [using 270 mgI/mL and 320 mgI/mL concentrations].
• Excretory urography [using 270 mgI/mL and 320 mgI/mL concentrations].
• Peripheral venography [using the 270 mgI/mL concentration].
• Coronary Computed Tomography Angiography (CCTA) to assist in the diagnostic evaluation of patients with suspected coronary artery disease [using the 320 mgI/mL concentration].
• Pediatric Patients (less than 12 years of age):
• CECT of the head and body [using the 270 mgI/mL concentration].
• Excretory urography [using the 270 mgI/mL concentration].

Dosage and Administration Guidelines

Adherence to proper dosage and administration guidelines is critical for ensuring both diagnostic efficacy and patient safety.

General Principles:

• Individualization of Dose: The specific volume and concentration of Iodixanol must be carefully individualized for each patient. Clinicians should consider factors such as age, body weight, size of the vessel, rate of blood flow, the specific procedure, and the anticipated pathology.[32]
• Lowest Necessary Dose: The guiding principle is to use the lowest dose necessary to obtain adequate visualization for a diagnostic-quality examination.[6]
• Hydration: It is imperative that all patients are adequately hydrated before and after the intravascular administration of Iodixanol to minimize the risk of CI-AKI.[42]
• Maximum Dose: For adult patients, the maximum recommended total dose of iodine from Iodixanol in a single examination period is 80 grams.[38]

The following table synthesizes the detailed dosage guidelines for common diagnostic procedures, providing a practical reference for clinical use.

Table 1: Iodixanol Dosage and Administration Guidelines for Diagnostic Procedures

Procedure	Patient Population	Concentration (mgI/mL)	Recommended Volume / Dose	Maximum Dose / Comments
Intra-Arterial Administration
Cerebral Arteriography	Adult & Ped. >12y	320	Carotid Arteries: 10-14 mL Vertebral Arteries: 10-12 mL	Max Total Dose: 175 mL
	Ped. 1-12y	320	1-2 mL/kg	Total dose not to exceed 4 mL/kg
Coronary Arteriography & Left Ventriculography	Adult & Ped. >12y	320	Right Coronary: 3-8 mL Left Coronary: 3-10 mL Left Ventricle: 20-45 mL	Max Total Dose: 200 mL
	Ped. 1-12y	320	1-2 mL/kg	Total dose not to exceed 4 mL/kg
Peripheral Arteriography	Adult & Ped. >12y	320	15-30 mL per injection	Max Total Dose: 250 mL
Visceral / Renal Arteriography	Adult & Ped. >12y	320	Renal Arteries: 8-18 mL Major Aortic Branches: 10-70 mL	Max Total Dose: 250 mL
	Ped. 1-12y	320	1-2 mL/kg	Total dose not to exceed 4 mL/kg
Aortography	Adult & Ped. >12y	320	30-70 mL	Max Total Dose: 250 mL
	Ped. 1-12y	320	1-2 mL/kg	Total dose not to exceed 4 mL/kg
IA-Digital Subtraction Angiography (IA-DSA)	Adult & Ped. >12y	270 or 320	Renal Arteries: 10-25 mL (270) Aortography: 10-50 mL (320) Peripheral Arteries: 3-15 mL (320)	Max Total Dose: 250 mL
Intravenous Administration
CECT of Head	Adult & Ped. >12y	270 or 320	75-150 mL	Max Total Volume: 150 mL
	Ped. 1-12y	270	1-2 mL/kg	Total dose not to exceed 2 mL/kg
CECT of Body	Adult & Ped. >12y	270 or 320	100-150 mL	Max Total Volume: 150 mL
	Ped. 1-12y	270	1-2 mL/kg	Total dose not to exceed 2 mL/kg
Excretory Urography	Adult & Ped. >12y	270 or 320	1 mL/kg	Max Total Volume: 100 mL
	Ped. 1-12y	270	1-2 mL/kg	Total dose not to exceed 2 mL/kg
Peripheral Venography	Adult & Ped. >12y	270	50-150 mL per lower extremity	Max Total Volume: 250 mL
Coronary CT Angiography (CCTA)	Adult & Ped. >12y	320	50-150 mL (70-80 mL typical) at 4-7 mL/s, followed by saline flush	Max Total Volume: 150 mL

Data compiled from sources.[8]

Comprehensive Safety Profile and Risk Management

While Iodixanol was developed to improve the safety profile of contrast media, its administration is associated with a range of potential adverse reactions, from mild and transient to severe and life-threatening. A thorough understanding of its safety profile, contraindications, and warnings is essential for proactive risk management. Many of the most severe risks are not entirely idiosyncratic but are predictable consequences of the agent's interaction with a patient's underlying pathophysiology or arise from procedural errors. This understanding shifts the focus of safety from purely reactive management to proactive prevention through careful patient screening and meticulous technique.

Overview of Adverse Reactions

The majority of patients who receive Iodixanol experience no adverse effects or only mild, transient reactions.[43] The most frequently reported adverse events in clinical trials, occurring with an incidence greater than 0.5%, are sensations of discomfort, warmth, or pain at the injection site. Other common effects include taste perversion (dysgeusia), nausea, headache, and vomiting.[6] In a comparative study of iodinated contrast media, adverse events of any kind were observed in 28.8% of patients, with the vast majority being mild, acute reactions (25.5% of the total patient cohort).[45]

Boxed Warning and Absolute Contraindications

The most critical safety information for Iodixanol is highlighted in a boxed warning and its absolute contraindications.

• BOXED WARNING: NOT FOR INTRATHECAL USE: Iodixanol is strictly for intravascular use and is absolutely contraindicated for intrathecal administration. Inadvertent injection into the subarachnoid space can lead to a catastrophic cascade of neurotoxic events, including death, intractable convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema.[16] This warning underscores the critical importance of verifying the correct route of administration before injection.
• Other Contraindications:
• Hypersensitivity: Administration is contraindicated in patients with a known history of a serious hypersensitivity reaction to Iodixanol or any of its components.[32]
• Pediatric Preparation: In children, prolonged fasting and the use of laxatives prior to Iodixanol administration are contraindicated, as this can exacerbate dehydration and increase the risk of renal complications.[48]

Major Warnings and Precautions

A number of significant risks require careful consideration and management before, during, and after Iodixanol administration.

• Hypersensitivity Reactions: Life-threatening or fatal anaphylactic and anaphylactoid reactions can occur. While most severe reactions develop within minutes of injection, delayed reactions can occur hours later.[6] Patients with a history of bronchial asthma, food or drug allergies, or a previous reaction to a contrast agent are at an increased risk. Although premedication with corticosteroids or antihistamines may reduce the incidence and severity of reactions, it does not prevent them entirely. Therefore, emergency resuscitation equipment and appropriately trained personnel must be immediately available whenever Iodixanol is administered.[6]
• Contrast-Induced Acute Kidney Injury (CI-AKI): Acute kidney injury, including renal failure, is a primary concern. The risk is significantly elevated in patients with pre-existing renal impairment (e.g., elevated serum creatinine), diabetes mellitus, dehydration, congestive heart failure, advanced vascular disease, multiple myeloma, and in elderly patients.[6] The risk is a direct consequence of the drug's complete reliance on renal excretion; in a compromised kidney, prolonged exposure to the agent can lead to direct tubular toxicity and medullary hypoxia. Key preventive strategies include ensuring adequate patient hydration before and after the procedure and using the lowest possible diagnostic dose.[18]
• Cardiovascular Adverse Reactions: Life-threatening cardiovascular events, including profound hypotension, shock, and cardiac arrest, have been reported. These events most often occur during or within 5-10 minutes of injection, and pre-existing cardiovascular disease is a major aggravating factor.[6] The hemodynamic stress of a rapid contrast bolus can decompensate a failing heart. The lowest necessary dose should be used in patients with congestive heart failure.[6]
• Thromboembolic Events: During angiographic procedures, serious and rarely fatal thromboembolic events, such as myocardial infarction and stroke, can occur. The contrast agent itself can interact with the coagulation cascade. Meticulous procedural technique is required to minimize this risk. This includes minimizing the duration of the procedure and, critically, avoiding prolonged contact of blood with the contrast agent within syringes, which can promote clotting.[6] Angiography should be avoided in patients with homocystinuria, a genetic disorder that predisposes them to thrombosis and embolism.[6]
• Thyroid Dysfunction in Pediatric Patients (0-3 Years): Iodixanol administration can cause hypothyroidism or transient thyroid suppression in young children. The incidence is reported to be between 1% and 15%.[6] The risk is highest in neonates (especially premature and low birth weight infants) and in children with underlying cardiac conditions who may require higher contrast doses. An underactive thyroid during this critical period of development can be harmful to motor, hearing, and cognitive functions. It is recommended that thyroid function be evaluated in all pediatric patients in this age group within 3 weeks following exposure to Iodixanol.[40]
• Severe Cutaneous Adverse Reactions (SCARs): Rare but severe skin reactions can develop from one hour to several weeks after administration. These include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Acute Generalized Exanthematous Pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).[6] Iodixanol should be avoided in patients with a history of a SCAR to any iodinated contrast agent.[17]
• Extravasation: Leakage of the contrast agent from the vein into surrounding soft tissues during injection can cause significant local injury, including tissue necrosis and compartment syndrome. This risk is elevated in patients with severe arterial or venous disease. Careful monitoring of the injection site is essential.[18]
• Special Patient Populations:
• Hyperthyroidism: In patients with hyperthyroidism or autonomously functioning thyroid nodules, the iodine load from the contrast agent can precipitate a thyroid storm, a life-threatening medical emergency.[18]
• Pheochromocytoma: In patients with this catecholamine-secreting tumor, contrast administration can trigger a massive release of hormones, leading to a severe hypertensive crisis.[16]
• Sickle Cell Disease: In individuals who are homozygous for sickle cell disease, iodinated contrast agents may promote red blood cell sickling, potentially inducing a vaso-occlusive crisis.[16]

Comprehensive List of Adverse Effects by System

The following is a comprehensive list of adverse effects associated with Iodixanol, organized by organ system and compiled from clinical trial data and post-marketing experience.[6]

• General and Administration Site:
• Common: Sensation of warmth, pain, or discomfort at injection site.
• Uncommon: Fatigue, feeling ill (malaise), back pain, fever (pyrexia), chills.
• Post-marketing: Administration site reactions including extravasation.
• Cardiovascular:
• Common: Angina pectoris.
• Uncommon: Hypotension, cardiac failure, conduction abnormalities, arrhythmia, myocardial infarction, flushing, peripheral ischemia.
• Post-marketing: Cardiac arrest, palpitations, spasms of coronary arteries, hypertension.
• Neurological:
• Common: Headache, dizziness (vertigo).
• Uncommon: Migraine, fainting (syncope), abnormal skin sensation (paresthesia), sensory disturbance, convulsions, stupor, confusion, diminished skin sensation (hypoesthesia), cerebral vascular disorder.
• Post-marketing: Tremor, disturbance in consciousness, coma. Transient contrast-induced encephalopathy (due to extravasation) with symptoms such as hallucination, amnesia, paralysis, and speech disorders (aphasia, dysarthria).
• Gastrointestinal:
• Common: Nausea, taste perversion (dysgeusia).
• Uncommon: Vomiting, diarrhea, indigestion (dyspepsia).
• Post-marketing: Abdominal pain, inflammation of the pancreas (pancreatitis), salivary gland enlargement.
• Dermatologic and Hypersensitivity:
• Common: Rash, hives (urticaria), itching (pruritus).
• Uncommon: Increased sweating, hematoma, swelling of the throat (pharyngeal edema).
• Post-marketing: Life-threatening anaphylaxis/anaphylactic shock. Severe cutaneous adverse reactions (SJS, TEN, AGEP, DRESS), skin discoloration.
• Respiratory:
• Uncommon: Shortness of breath (dyspnea), asthma, nasal inflammation (rhinitis), bronchial inflammation (bronchitis), fluid in the lungs (pulmonary edema).
• Post-marketing: Cough, sneezing, throat irritation or tightness, voice box swelling (laryngeal edema), bronchospasm.
• Renal and Genitourinary:
• Uncommon: Abnormal kidney function, blood in urine (hematuria).
• Post-marketing: Acute kidney injury/failure.
• Endocrine:
• Post-marketing: Overactive thyroid (hyperthyroidism), underactive thyroid (hypothyroidism).
• Special Senses:
• Common: Blind spot in the visual field (scotoma), distortion of the sense of smell (parosmia).
• Uncommon: Abnormal vision.
• Post-marketing: Transient visual impairment including cortical blindness, double vision (diplopia), blurred vision.
• Psychiatric:
• Uncommon: Insomnia, nervousness, agitation, anxiety.

Significant Drug and Laboratory Interactions

The interaction profile of Iodixanol is dominated by a single, indirect mechanism: its potential to transiently impair renal function. This primary effect can cascade into clinically significant interactions with other renally-cleared drugs. Therefore, the clinical management of Iodixanol's drug interactions is fundamentally a process of risk stratification. The key task is to identify patients at risk for CI-AKI, as in these individuals, a review of all co-medications that rely on renal clearance is warranted. The stringent guideline for metformin is the most critical and formalized example of this principle.

Interaction with Metformin

The interaction between iodinated contrast media and metformin is of major clinical significance due to the risk of a rare but life-threatening complication.

• Mechanism: The underlying mechanism is not a direct drug-drug interaction. Instead, it is an indirect, pharmacokinetically driven event. If Iodixanol administration leads to CI-AKI, the resulting decline in renal function can impair the excretion of metformin. This leads to the accumulation of metformin in the blood, which can precipitate metformin-associated lactic acidosis, a metabolic emergency with high mortality.[18]
• Clinical Guidelines for Management: To mitigate this risk, specific guidelines for the temporary discontinuation of metformin are in place. Metformin therapy should be stopped at the time of, or prior to, the administration of Iodixanol in patients identified as being at risk.[18] These at-risk patient groups include:
• Patients with moderate renal impairment, defined as an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m².
• Patients with a history of hepatic impairment, alcoholism, or heart failure, as these conditions are also risk factors for lactic acidosis.
• Any patient who will be receiving an intra-arterial administration of Iodixanol, as this route may carry a higher risk of renal effects.
• Resumption of Metformin: Metformin should not be resumed until at least 48 hours after the imaging procedure. Before restarting the medication, the patient's renal function must be re-evaluated and confirmed to be stable and back to baseline.[18]

Other Clinically Relevant Drug Interactions

While the metformin interaction is the most critical, several other drug classes warrant consideration.

• Beta-Adrenergic Blocking Agents (Beta-Blockers): Patients taking beta-blockers present a dual challenge. First, the use of these agents may lower the threshold for developing a hypersensitivity reaction to contrast media and may increase the severity of such a reaction. Second, should an anaphylactic reaction occur, the presence of beta-blockade can render the patient less responsive to standard treatment with epinephrine (adrenaline).[18] Caution is therefore advised when administering Iodixanol to patients on beta-blocker therapy.
• Aldesleukin (Interleukin-2): There is an increased risk of hypersensitivity reactions to Iodixanol in patients who have recently received treatment with aldesleukin, a biologic agent used in cancer therapy.[3] Patients treated with aldesleukin within the preceding two weeks are particularly at risk for delayed reactions, which can manifest as flu-like symptoms or skin reactions.[52]
• Oral Cholecystographic Contrast Agents: There have been reports of renal toxicity in patients with pre-existing liver dysfunction who were given an oral cholecystographic agent (for gallbladder imaging) followed by an intravascular iodinated contrast agent. In such cases, administration of the intravascular agent should be postponed.[18]
• General Excretion-Based Interactions: Due to its potential to affect renal function, Iodixanol can theoretically decrease the excretion rate of any co-administered drug that is cleared by the kidneys. This could lead to higher serum levels and an increased risk of toxicity from the co-administered drug. Drug interaction databases list a vast number of such potential interactions, including with medications like abacavir, acetaminophen, acyclovir, allopurinol, various antibiotics, and NSAIDs.[3] This is not a list of absolute contraindications but serves as a general cautionary principle, reinforcing the need for a thorough medication review in patients at risk for CI-AKI.

Interference with Laboratory and Diagnostic Tests

The high iodine content of Iodixanol can interfere with certain diagnostic tests, particularly those involving the thyroid gland.

• Thyroid Function Tests: The administration of any iodinated contrast medium can interfere with the function of the thyroid gland. The iodine load from Iodixanol can saturate the gland's iodine uptake mechanism, significantly reducing the uptake of radioactive iodine isotopes (I-131 and I-123). This interference can decrease the efficacy of both diagnostic thyroid scans and therapeutic radioactive iodine treatments for thyroid cancer. This effect can persist for a considerable period, lasting up to 6 to 8 weeks after the administration of the contrast agent.[18]
• General Laboratory Tests: Patients should be advised to inform all healthcare providers that they have recently received Iodixanol, as it may affect the results of certain other medical tests for up to 16 days post-administration.[53]

Comparative Analysis with Other Contrast Agents

The clinical positioning of Iodixanol is best understood through its comparison with other available iodinated contrast agents, primarily the class of low-osmolar contrast media (LOCM). The central debate in this field revolves around the relative importance of two key physicochemical properties: osmolality and viscosity. Iodixanol, as an iso-osmolar contrast medium (IOCM), possesses the lowest possible osmolality (290 mOsm/kg), which is theoretically ideal for physiological compatibility. However, due to its dimeric structure, it has a higher viscosity than the monomeric LOCMs (e.g., iohexol, iopamidol), which have a higher osmolality (600-900 mOsm/kg) but lower viscosity.[9] The extensive body of clinical research comparing these agents seeks to determine which of these properties, or combination thereof, most significantly influences patient safety (especially renal outcomes), patient comfort, and diagnostic image quality.

Iodixanol vs. LOCM (General Class) for Contrast-Induced Nephropathy (CIN)

When Iodixanol is compared against the entire, heterogeneous class of LOCMs, the evidence for a superior renal safety profile is present but nuanced.

• Systematic Reviews and Meta-Analyses: Large-scale analyses pooling data from numerous randomized controlled trials (RCTs) have yielded mixed results. A comprehensive 2015 systematic review found a slight reduction in the risk of CIN with Iodixanol compared to a diverse group of LOCMs, with a pooled relative risk of 0.80. However, this result was only borderline statistically significant (p=0.045) and did not meet the pre-specified criterion for being clinically important.[14] Another large meta-analysis of 36 trials found that the overall reduction in CIN incidence with Iodixanol was suggestive but did not reach statistical significance (p=0.11).[13]
• Influence of Administration Route: The comparative risk of CIN between IOCM and the general LOCM class does not appear to differ significantly based on whether the agent is administered via the intra-arterial or intravenous route.[14]
• The "CIN Paradox": The interpretation of all CIN data has been complicated by recent research. Studies that include a control group of patients undergoing unenhanced CT scans have revealed a surprisingly high background incidence of acute kidney injury (AKI) in hospitalized patients, independent of contrast administration. This suggests that the true attributable risk of AKI caused directly by modern contrast media (CI-AKI) may be overstated, and that much of the renal dysfunction observed coincidentally after contrast administration (contrast-associated AKI) may be due to the patient's underlying diseases and other treatments.[58]

Head-to-Head Comparison: Iodixanol vs. Iohexol

The comparison between Iodixanol and the specific LOCM iohexol (Omnipaque®) reveals the most pronounced and clinically significant differences, forming the cornerstone of the evidence for Iodixanol's superior renal safety in certain populations.

• Renal Safety: This specific head-to-head comparison consistently demonstrates a significant benefit for Iodixanol. Multiple meta-analyses have found that Iodixanol is associated with a significantly lower risk of CIN compared to iohexol, particularly in high-risk patients—defined as those with pre-existing chronic kidney disease (CKD) and/or diabetes mellitus.[12] One landmark pooled analysis showed that in patients with CKD, the incidence of CIN was 2.8% with Iodixanol versus 8.4% with LOCM (primarily iohexol). In the highest-risk group of patients with both CKD and diabetes, the difference was even more stark: 3.5% with Iodixanol versus 15.5% with LOCM.[12] This finding is critical, as it suggests that the narrative of Iodixanol's superior renal safety is not a simple "IOCM is better than LOCM" story, but rather a more specific "Iodixanol is better than Iohexol" conclusion.
• Patient Comfort: The iso-osmolality of Iodixanol translates into a clear advantage in patient comfort. Clinical studies consistently show that patients receiving Iodixanol report a significantly lower incidence and severity of injection-related discomfort, such as sensations of pain and warmth, compared to those receiving the hyperosmolar iohexol.[9]
• Image Quality: Despite having a lower iodine concentration in its most common formulation (320 mgI/mL for Iodixanol vs. 350 mgI/mL for iohexol), Iodixanol has been shown to provide similar levels of vascular and myocardial enhancement in cardiac CT. This is attributed to its iso-osmolality, which prevents the osmotic dilution of the contrast bolus that occurs as water is drawn into the vessel by the hyperosmolar iohexol.[63]

Head-to-Head Comparison: Iodixanol vs. Iopamidol

When Iodixanol is compared to other non-iohexol LOCMs, such as iopamidol (Isovue®), the differences are less distinct.

• Renal Safety: In contrast to the iohexol data, trials directly comparing Iodixanol and iopamidol have not shown a significant difference in renal safety. In a study of patients with chronic kidney disease undergoing CT, the rate of CIN was found to be similarly low and not statistically different between iopamidol-370 and iodixanol-320.[64] This reinforces the idea that Iodixanol's renal safety benefit is highly context-dependent and may not extend to all LOCMs.
• Patient Comfort: The results regarding patient comfort are mixed. One CCTA study found no overall difference in moderate-to-severe symptoms between Iodixanol and iopamidol, although a subgroup analysis of patients older than 55 years did report fewer symptoms with Iodixanol.[62] Another study found that Iodixanol 270 had the lowest incidence of flushing when compared to both iopamidol and iohexol.[9]
• Image Quality and Cardiac Effects: The higher iodine concentration of iopamidol-370 has been shown to provide greater vascular contrast enhancement and better depiction of small coronary artery branches compared to iodixanol-320. The same study also observed a statistically significant, albeit small, decrease in heart rate during the administration of iodixanol-320, whereas iopamidol had no significant impact on heart rate.[30] This may be a consideration in cardiac imaging where heart rate stability is crucial.

The following table provides a summary of these key comparative points.

Table 2: Comparative Profile of Iodixanol vs. Key LOCMs

Parameter	Iodixanol (Visipaque®)	Iohexol (Omnipaque®)	Iopamidol (Isovue®)
Class	Iso-Osmolar Contrast Medium (IOCM), Dimer	Low-Osmolar Contrast Medium (LOCM), Monomer	Low-Osmolar Contrast Medium (LOCM), Monomer
Osmolality (mOsm/kg H₂O)	290 (Iso-osmolar)	~844 (Low-osmolar)	~796 (Low-osmolar)
Viscosity @ 37°C (mPa·s)	11.4 (for 320 mgI/mL)	Lower than Iodixanol	9.4 (for 370 mgI/mL)
CIN Risk vs. Iohexol (High-Risk Pts)	N/A	Higher than Iodixanol	N/A (Data suggests similarity to Iodixanol)
Patient Discomfort (Pain/Warmth)	Lowest	Higher than Iodixanol	Higher than Iodixanol, but may be less than Iohexol
Vascular Enhancement	Similar to Iohexol 350; Lower than Iopamidol 370	Similar to Iodixanol 320	Higher than Iodixanol 320
Effect on Heart Rate	Minor decrease observed	Not a prominent reported effect	No significant effect observed

Data compiled from sources.[9]

For clinicians and hospital formulary committees, this comparative data suggests that the choice of contrast agent is not straightforward. If the institutional standard is iohexol, there is strong evidence to support switching to Iodixanol for high-risk patients to reduce the risk of CIN. However, if the alternative is a different LOCM like iopamidol, the decision may be driven more by factors such as cost, contractual agreements, desired image contrast, and patient comfort, as a significant renal safety benefit for Iodixanol has not been clearly demonstrated in this context.

Regulatory, Commercial, and Specialized Applications

Beyond its core clinical use, Iodixanol has a distinct regulatory history, a dynamic commercial landscape, and a unique set of specialized applications that highlight the versatility of its physicochemical properties. The dual identity of Iodixanol as both a high-volume clinical diagnostic agent (Visipaque®) and a high-value precision research tool (OptiPrep™) demonstrates a successful translation of a single molecule's properties across vastly different markets. The properties that make it a superior in-vivo diagnostic agent—iso-osmolality and lack of toxicity, designed to protect human organs—are the very same ones that make it an ideal in-vitro separation medium, preserving the integrity of delicate biological particles.

Regulatory Status and History

Iodixanol has been approved for medical use for several decades and is regulated by health authorities worldwide.

• U.S. Food and Drug Administration (FDA): Visipaque® first received FDA approval on March 22, 1996.[34] A significant update to its label occurred on May 9, 2017, with the approval of a new indication for its use in Coronary Computed Tomography Angiography (CCTA) in adults and pediatric patients aged 12 and older.[10] This made it the first and only contrast agent with this specific FDA-approved indication.[9]
• Generic Availability: The market for Iodixanol expanded with the introduction of generic versions. In response to a nationwide shortage of contrast media, the FDA approved the first generic Iodixanol Injection, USP, from Hengrui Pharma on May 19, 2022, followed by a launch from Fresenius Kabi on July 18, 2022. These generics are considered bioequivalent and fully substitutable for the brand-name Visipaque®.[33]
• International Status: Iodixanol is authorized for use in numerous other countries. In Europe, marketing authorization is typically managed through national procedures in individual member states rather than through a centralized European Public Assessment Report (EPAR) from the European Medicines Agency (EMA).[66] The Summary of Product Characteristics (SmPC) is the key regulatory document outlining its approved use in the EU.[31] It is also approved by other major regulatory bodies, including Australia's Therapeutic Goods Administration (TGA) and Health Canada.[26]

Commercial Landscape

The commercial market for Iodixanol includes both brand-name and generic products for clinical use, as well as specialized formulations for research.

• Manufacturers: The originator product, Visipaque®, is manufactured and marketed globally by GE Healthcare.[1] The entry of generic manufacturers, such as Fresenius Kabi and Hengrui Pharma, has introduced competition into the market.[33]
• Research-Grade Formulations: For laboratory applications, a sterile, endotoxin-tested 60% (w/v) solution of Iodixanol is sold under the trade name OptiPrep™. This high-purity product is supplied by companies like Progen and Sigma-Aldrich (under license) for use in density gradient centrifugation.[4] The rigorous safety and quality control testing required for the human-injectable drug provides an immediate stamp of quality and reliability for the research-grade product, allowing researchers to trust its purity and lack of toxicity.

Specialized and Non-Diagnostic Applications

The unique properties of Iodixanol have led to its adoption in several specialized fields outside of routine diagnostic imaging.

• Density Gradient Centrifugation (OptiPrep™): The properties that make Iodixanol safe for in-vivo use—being non-toxic, metabolically inert, and iso-osmotic—also make it an ideal medium for separating biological particles in vitro without causing damage. OptiPrep™ is widely used in research and biomanufacturing for:
• Virus Purification: It is considered a superior medium for purifying viruses, such as Adeno-Associated Virus (AAV), a key vector in gene therapy. It yields higher recovery rates and greater infectivity compared to traditional cesium chloride (CsCl) gradients.[35]
• AAV Capsid Separation: It is used to separate full (gene-containing) AAV capsids from empty ones, a critical quality control step in the manufacturing of gene therapy products to ensure safety and efficacy.[35]
• Cell and Organelle Isolation: It is used to isolate a wide range of biological materials, including mammalian and non-mammalian cells, subcellular organelles (like mitochondria), plasma membranes, proteins, and plasmid DNA.[24]
• Veterinary Medicine: In equine reproduction, Iodixanol is an active ingredient in specialized 'cushion' products used during the centrifugation of stallion semen. It helps protect the sperm from damage at high g-forces, resulting in improved recovery rates and viability.[22]
• Research in Tissue Engineering: Iodixanol has been explored as a radiopaque additive for biodegradable polymer scaffolds. By incorporating Iodixanol into materials like polycaprolactone (PCL), researchers can create medical implants that are visible on X-ray and micro-CT scans. This allows for non-invasive, real-time monitoring of the implant's position, integration, and degradation kinetics in vivo, offering a powerful tool for developing and evaluating new tissue engineering strategies.[4]

Conclusion and Expert Recommendations

Iodixanol (Visipaque®) stands as a distinct and important agent within the armamentarium of iodinated contrast media. Its development as a non-ionic, dimeric molecule successfully achieved the goal of creating a contrast agent that is iso-osmolar to human blood. This fundamental property defines its clinical profile, which is characterized by a significant trade-off between the benefits of iso-osmolality and the practical challenges of higher viscosity. The primary clinical advantages derived from its iso-osmolality are improved patient comfort and a demonstrated potential for enhanced renal safety in specific, well-defined contexts. Its clinical utility is broad, spanning a wide range of intravenous and intra-arterial procedures, and is distinguished by a unique FDA approval for Coronary Computed Tomography Angiography (CCTA).

The extensive body of evidence from clinical trials and meta-analyses reveals a nuanced safety profile. While the overall risk of contrast-induced acute kidney injury (CI-AKI) compared to the entire class of low-osmolar contrast media (LOCM) is only modestly reduced, there is a clear and statistically significant advantage for Iodixanol when compared directly against the specific LOCM iohexol. This benefit is most pronounced in high-risk patient populations, namely those with pre-existing chronic kidney disease and/or diabetes mellitus. However, this renal safety advantage is not consistently demonstrated when Iodixanol is compared to other non-iohexol LOCMs, such as iopamidol. Therefore, the selection of Iodixanol over other agents requires a careful, evidence-based consideration of the specific alternative agent, the patient's individual risk profile, and other factors such as cost and desired imaging characteristics.

Based on this comprehensive analysis, the following expert recommendations are provided for clinical practice:

Expert Recommendations for Clinical Practice

• Patient Selection and Agent Choice:
• Iodixanol should be strongly considered as the contrast agent of choice for high-risk patients (defined as those with an eGFR <60 mL/min/1.73 m², particularly with co-morbid diabetes) who are scheduled for procedures where the institutional alternative is iohexol. In this specific scenario, the evidence for a reduced risk of CI-AKI is robust.
• When the alternative LOCM is an agent other than iohexol (e.g., iopamidol), the decision to use Iodixanol may be guided by factors other than renal safety, such as institutional contracts, cost, a desire to minimize patient discomfort (pain/warmth), or specific imaging protocol requirements, as a significant renal safety benefit has not been clearly established in these comparisons.
• Proactive Risk Mitigation is Paramount:
• Regardless of the contrast agent selected, a proactive and systematic approach to risk mitigation is the most critical factor in preventing adverse events. This must include:
• Thorough Patient Screening: A comprehensive history should be obtained to identify risk factors, including pre-existing renal dysfunction, diabetes, cardiovascular disease, multiple myeloma, history of allergy to contrast media, asthma, and relevant medication use.
• Adequate Hydration: Ensuring patients are well-hydrated before and after the procedure is a cornerstone of CI-AKI prevention.
• Medication Management: Strict adherence to protocols for managing interacting medications is essential. This is most critical for the temporary discontinuation of metformin in all at-risk patients to prevent lactic acidosis.
• Dose Minimization: Clinicians must adhere to the principle of using the lowest effective dose of contrast agent required to obtain diagnostic-quality images.
• Procedural and Monitoring Considerations:
• Technique: Meticulous intravascular technique is crucial to prevent complications such as extravasation, which can lead to severe tissue injury, and to minimize the risk of thromboembolic events during angiographic procedures.
• Viscosity Management: The higher viscosity of Iodixanol should be managed by warming the agent to body temperature (37 °C) prior to injection to ensure a smooth and controlled administration.
• Pediatric Monitoring: Clinicians must maintain a high index of suspicion for thyroid dysfunction in patients aged 0-3 years following exposure to Iodixanol. Adherence to guidelines for post-procedure thyroid function monitoring in this vulnerable population is mandatory to prevent potential long-term developmental harm.

Future Directions

The evolving understanding of post-contrast acute kidney injury suggests that the true, attributable risk from modern contrast agents may be lower than historically believed. Future research should prioritize large-scale, prospective, randomized trials that include contemporary control groups (i.e., patients not receiving contrast) to more accurately define the true incidence of CI-AKI versus coincidental, contrast-associated AKI. Furthermore, additional large, well-designed head-to-head trials comparing different non-iohexol LOCMs would be valuable to further clarify the relative safety profiles within that class and to better contextualize the performance of Iodixanol.

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