A Comprehensive Monograph on Iohexol

Executive Summary

Iohexol is a second-generation, non-ionic, low-osmolality, water-soluble iodinated radiographic contrast agent that stands as a cornerstone of modern diagnostic imaging. Marketed under brand names such as Omnipaque and Oraltag, its development represented a significant advancement in patient safety compared to older, first-generation high-osmolality ionic agents. Its chemical structure, featuring a tri-iodinated benzene ring with hydrophilic, non-ionizing side chains, allows for high concentrations of iodine necessary for X-ray attenuation while maintaining an osmolality closer to that of physiological fluids, thereby reducing systemic toxicity and improving patient tolerance.[1]

The clinical utility of Iohexol is exceptionally broad, encompassing a vast array of procedures across nearly all medical specialties. Its primary applications involve enhancing visualization during X-ray and Computed Tomography (CT) examinations. It is administered via multiple routes—intravascularly, intrathecally, orally, rectally, and into body cavities—to opacify vascular structures, the central nervous system (brain and spinal cord), the urinary tract, joints, and the gastrointestinal (GI) tract.[1] This versatility has secured its place on the World Health Organization's List of Essential Medicines.[1]

Despite its improved safety profile, Iohexol is associated with significant risks that demand rigorous clinical management. A prominent FDA Boxed Warning highlights the potential for catastrophic outcomes, including death and paralysis, from the inadvertent intrathecal administration of specific high-concentration formulations intended only for intravascular use.[6] Other major safety concerns include the risk of hypersensitivity reactions, ranging from mild skin rashes to life-threatening anaphylaxis, and the potential for Contrast-Induced Acute Kidney Injury (CI-AKI), particularly in patients with pre-existing renal disease, diabetes, or dehydration.[8] Clinically significant drug interactions, notably with metformin and medications that lower the seizure threshold, require careful medication reconciliation and management.[4]

In conclusion, Iohexol remains an indispensable tool in diagnostic radiology, enabling precise and detailed anatomical and pathological assessment. Its established efficacy and favorable safety profile relative to older agents are clear. However, its safe and effective application is fundamentally contingent on a comprehensive understanding of its complex pharmacology, strict adherence to procedure-specific dosing and administration protocols, and vigilant risk mitigation strategies tailored to individual patient risk factors.

Section I: Identification and Physicochemical Properties

This section establishes the fundamental chemical and physical identity of Iohexol. The unique molecular structure of Iohexol is directly responsible for its advantageous physicochemical properties, which in turn define its clinical utility and superior safety profile compared to first-generation contrast media.

1.1 Nomenclature and Database Identifiers

Iohexol is identified by a variety of names and codes across chemical, pharmacological, and regulatory databases, which is essential for accurate cross-referencing in research and clinical practice. Its generic name is Iohexol, and it is most widely known by the trade name Omnipaque.[1] Other brand names include Oraltag, Iodaque, and Hexopaque.[1] For non-clinical applications, such as its use as a density gradient medium in laboratory settings, it is sold under names like Accudenz, Histodenz, and Nycodenz.[1]

The systematic chemical name, which describes its structure in full, is 1-N,3-N-Bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl)acetamido]-2,4,6-triiodobenzene-1,3-dicarboxamide.[1] A comprehensive list of its identifiers is provided in Table 1. This consolidation of identifiers is critical for researchers and clinicians to unambiguously locate and integrate information from diverse sources such as chemical registries, pharmacological databases, and clinical trial repositories.

Table 1: Iohexol Identifiers

Identifier Type	Value	Source(s)
DrugBank ID	DB01362	1
CAS Number	66108-95-0	1
PubChem CID	3730	1
UNII	4419T9MX03	1
KEGG ID	D01817	1
ChEBI ID	CHEBI:31709	1
ChEMBL ID	CHEMBL1200455	1
ChemSpider ID	3599	1
EPA CompTox Dashboard	DTXSID6023157	1
European Community (EC) No.	266-164-2	2
HMDB ID	HMDB0015449	2
NCI Thesaurus Code	C65939	2
RxNorm CUI (RXCUI)	5956	2
Harmonized System (HS) Code	292429	14

1.2 Chemical Structure and Formula

The molecular formula of Iohexol is C19​H26​I3​N3​O9​.[1] Its molecular weight is approximately 821.14 g/mol.[1] The chemical structure of Iohexol is a testament to rational drug design, engineered to maximize X-ray opacity while minimizing physiological disruption.

The core of the molecule is a benzene ring that is substituted at three positions (2, 4, and 6) with iodine atoms. It is these heavy iodine atoms that are responsible for the compound's ability to attenuate X-rays, thereby creating contrast in radiographic images.[2]

The remaining positions on the benzene ring are substituted with complex, hydrophilic side chains. Specifically, it is a benzenedicarboxamide with N-(2,3-dihydroxypropyl)carbamoyl groups at the 1- and 3-positions, and an N-(2,3-dihydroxypropyl)acetamido group at the 5-position.[2] These side chains are rich in hydroxyl (-OH) groups, which confer high water solubility. Crucially, these side chains do not carry an electrical charge and do not dissociate into ions when dissolved in water. This "non-ionic" characteristic is the key feature that distinguishes Iohexol and other second-generation agents from older, ionic contrast media.[1]

2D Chemical Structure of Iohexol:

!(https://www.medchemexpress.com/images/products/iohexol/Iohexol\-structure\-HY\-B0594\.png)

Source: Derived from SMILES/InChI data 1

Computed Descriptors:

• IUPAC Name: 5-[acetyl(2,3-dihydroxypropyl)amino]-1-N,3-N-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide [2]
• InChI: InChI=1S/C19H26I3N3O9/c1-8(29)25(4-11(32)7-28)17-15(21)12(18(33)23-2-9(30)5-26)14(20)13(16(17)22)19(34)24-3-10(31)6-27/h9-11,26-28,30-32H,2-7H2,1H3,(H,23,33)(H,24,34) [2]
• InChIKey: NTHXOOBQLCIOLC-UHFFFAOYSA-N [2]
• SMILES: CC(=O)N(CC(CO)O)C1=C(C(=C(C(=C1I)C(=O)NCC(CO)O)I)C(=O)NCC(CO)O)I [1]

1.3 Physical and Chemical Properties

In its solid state, Iohexol is a white to almost white crystalline powder.[19] It has a melting point in the range of 174 to 180 °C and exhibits good stability, with a shelf life of at least 4 years when stored appropriately.[1]

For clinical use, Iohexol is provided as a sterile, pyrogen-free, colorless to pale-yellow aqueous solution.[4] These solutions are sensitive to light and should be protected from exposure.[4] The properties of these solutions, particularly their osmolality and viscosity, are of paramount clinical importance as they directly influence patient tolerance and the risk of adverse effects.

Solubility:

Iohexol is characterized as a water-soluble compound.2 More specific solubility data indicates it is soluble in phosphate-buffered saline (PBS, pH 7.2) at approximately 10 mg/mL.18 It is also soluble in several organic solvents, including dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) at approximately 10 mg/mL, and in ethanol at a lower concentration of about 2 mg/mL.18 More rigorous academic studies have determined its mole fraction solubility in various solvents, finding it is highest in ethanol and lowest in cyclohexane, highlighting the importance of hydrogen bonding in its dissolution process.22 For formulation purposes, it can be dissolved in water, DMSO, and ethanol at concentrations up to 100 mg/mL.23

Osmolality and Viscosity:

The key advantage of Iohexol over first-generation ionic contrast media is its significantly lower osmolality. Ionic agents dissociate into at least two particles (a cation and an anion) in solution for every molecule of contrast, which dramatically increases the osmolality. Because Iohexol is non-ionic, each molecule contributes only one particle to the solution's osmotic pressure.3 This allows for a much lower osmolality at an equivalent iodine concentration, making it a "low-osmolar contrast medium" (LOCM).

The osmolality of Iohexol solutions ranges from approximately 322 mOsm/kg H2O, which is only 1.1 times that of blood plasma, to 844 mOsm/kg H2O for the highest concentrations, which is nearly three times that of blood.[1] While still hypertonic to blood, this is a marked improvement over older agents like diatrizoate, which can have an osmolality more than twice as high as Iohexol.[1] The viscosity of the solution, which affects the force required for injection and the rate of mixing with blood, also increases with concentration.[24] Table 2 details these critical properties for commercially available formulations.

Table 2: Physicochemical Properties of Commercial Iohexol Formulations

Concentration (mg Iodine/mL)	Iohexol Content (mg/mL)	Osmolality (mOsm/kg H2O @ 37°C)	Viscosity (mPa·s @ 37°C)	Ratio to Plasma Osmolality (~290 mOsm/kg)
140	302	322	1.5	~1.1
180	388	~408*	-	~1.4
240	518	510	3.3	~1.8
300	647	640-690	6.1	~2.2-2.4
350	755	780-844	10.6	~2.7-2.9
Sources:.1 Note: Osmolality for 180 mgI/mL is interpolated. Values may vary slightly between manufacturers.

1.4 Implications of Physicochemical Properties

The relationship between Iohexol's chemical structure and its physical properties is a direct illustration of successful pharmaceutical design. The central problem with first-generation ionic contrast media was their high osmolality, a direct consequence of their dissociation into charged particles in solution. This hypertonicity was responsible for a host of adverse effects, including pain on injection, endothelial damage, hemodynamic shifts from fluid redistribution, and a higher risk of renal toxicity.[3]

The molecular design of Iohexol solves this problem. The covalent attachment of three iodine atoms to a single benzene ring provides the necessary radiodensity.[2] The innovation lies in the hydrophilic, polyhydroxylated side chains. These chains serve two purposes: they ensure high water solubility, and, most importantly, they are non-ionizing.[1] Because the Iohexol molecule does not dissociate, a given iodine concentration can be achieved with roughly half the number of solute particles compared to an ionic agent.

This resulting lower osmolality is the direct cause of Iohexol's improved clinical profile. The lower osmotic pressure reduces the fluid shifts and cellular dehydration that cause pain and hemodynamic instability. Studies have shown that Iohexol induces a smaller decrease in cardiac contractile force compared to the high-osmolarity agent metrizoate and exhibits minimal neurotoxicity, effects directly attributable to its lower osmolality and chemotoxicity.[2] Therefore, the journey from its chemical blueprint to its physical behavior in solution and finally to its improved safety in patients is a clear and direct path. The ability to deliver a high payload of iodine with a reduced osmotic penalty is the fundamental reason for Iohexol's enduring role as an essential diagnostic agent.

Section II: Clinical Pharmacology

This section details the interaction of Iohexol with the human body, encompassing its mechanism of action (pharmacodynamics) and its absorption, distribution, metabolism, and excretion (pharmacokinetics). A thorough understanding of these principles is essential for its safe and effective clinical use.

2.1 Mechanism of Action (Pharmacodynamics)

The pharmacodynamic effect of Iohexol is based on its X-Ray Contrast Activity.[2] The mechanism is physical rather than biological. Organic iodine compounds, such as Iohexol, are radiopaque because the iodine atoms within their structure have a high atomic number (Z=53) and electron density. This property allows them to absorb X-ray photons much more effectively than the surrounding soft tissues, which are composed primarily of lighter elements like hydrogen, carbon, and oxygen.[3]

When Iohexol is introduced into a specific body compartment, it blocks the passage of X-rays through that area. On a resulting radiographic image (like an X-ray or CT scan), the regions containing Iohexol appear white or bright (radiopaque), while the surrounding tissues that the X-rays pass through more easily appear dark (radiolucent). The degree of opacity, or contrast, is directly proportional to the concentration of iodine in the path of the X-ray beam.[10] This differential absorption creates a clear delineation of the anatomical structures or fluid-filled spaces containing the contrast agent, allowing for detailed visualization of their morphology and any pathological changes.[5]

The specific action depends on the route of administration:

• Intravascular Administration: When injected into an artery or vein, Iohexol opacifies the blood vessels in its path of flow. This allows for the visualization of the vascular lumen, enabling the diagnosis of conditions like stenosis (narrowing), occlusion (blockage), aneurysms, and other abnormalities. The effect persists until the agent is diluted by blood flow and cleared from the circulation.[10]
• Intrathecal Administration: When injected into the subarachnoid space surrounding the spinal cord and brain, Iohexol mixes with and diffuses throughout the cerebrospinal fluid (CSF). This outlines the contours of the spinal canal, nerve roots, and cisterns of the brain, making it invaluable for myelography and cisternography.[4]
• Oral/Body Cavity Administration: When taken orally or administered rectally, the poorly absorbed Iohexol coats the mucosal lining of the gastrointestinal tract, providing contrast for GI studies. Similarly, when instilled into a joint (arthrography) or the uterus (hysterosalpingography), it fills the space and outlines its internal structures.[1]

2.2 Pharmacokinetics

The pharmacokinetic profile of Iohexol is characterized by its simple disposition: it is distributed in the extracellular fluid, is not metabolized, and is rapidly excreted by the kidneys. However, the specific parameters vary significantly depending on the route of administration, as detailed in Table 3.

Absorption:

The absorption of Iohexol is highly dependent on the administration site. Following intravascular injection, it is immediately and 100% bioavailable to the systemic circulation.27 After intrathecal administration, it is absorbed from the CSF into the bloodstream over several hours.4 In contrast, absorption from an intact gastrointestinal tract is very poor, which is a desirable characteristic for GI imaging as it keeps the agent within the lumen.29 Minimal absorption occurs after intravesical (bladder) instillation. However, if retained within the uterine or peritoneal cavity following hysterosalpingography, systemic absorption can occur within about 60 minutes.10

Distribution:

Once in the systemic circulation, Iohexol distributes primarily throughout the extracellular fluid compartment. Its hydrophilic, water-soluble nature prevents it from significantly crossing intact cell membranes or the blood-brain barrier.3 The apparent volume of distribution (

Vd​) after intravenous injection in healthy volunteers is approximately 0.27 L/kg, consistent with distribution in extracellular water.[21] Following intrathecal administration, the

Vd​ is larger, reported at a mean of 557 mL/kg (or 0.56 L/kg), which reflects its initial distribution within the entire CSF volume before systemic absorption.[4] Protein binding is clinically insignificant, reported to be very low at approximately 1.5%.[4] This lack of binding ensures it is freely available for glomerular filtration.

Metabolism:

Iohexol is not subject to any significant metabolism. It undergoes no biotransformation, deiodination, or conjugation in the body and is excreted from the body chemically unchanged.4 This metabolic inertness is a key feature of an ideal filtration marker.

Elimination:

The primary route of elimination for systemically absorbed Iohexol is renal excretion. In individuals with normal renal function, it is rapidly and completely cleared from the body by glomerular filtration, with little to no tubular secretion or reabsorption.21 Studies show that over 90%, and up to 100%, of an intravenously administered dose is recovered unchanged in the urine within 24 hours.27

The elimination half-life (t1/2​) reflects the speed of this renal clearance. After intravascular administration, the half-life is approximately 2 hours (121 minutes) in patients with normal renal function.[10] The half-life after intrathecal administration is longer, with a mean of 3.4 to 4.0 hours, because the overall elimination rate is limited by the slower process of absorption from the CSF into the blood.[10] The systemic clearance after intrathecal injection is high, around 109 mL/min, which is comparable to glomerular filtration rate (GFR).[4]

Table 3: Pharmacokinetic Parameters by Administration Route

Parameter	Intravascular Route	Intrathecal Route	Oral/Body Cavity Route
Absorption	100% immediate bioavailability	Slow absorption from CSF into bloodstream over hours	Poor to negligible from intact GI tract; some systemic absorption from uterine cavity
Volume of Distribution (Vd​)	~0.27 L/kg (extracellular fluid)	~0.56 L/kg (reflects CSF distribution)	Not applicable (minimal systemic exposure)
Protein Binding	~1.5% (negligible)	~1.5% (negligible)	Not applicable
Metabolism	None; excreted unchanged	None; excreted unchanged	None
Elimination Route	>90% renal excretion via glomerular filtration	Absorption into blood, then >88% renal excretion	Primarily fecal elimination for oral route; local discharge
Half-Life (t1/2​)	~2 hours	~3.4 - 4.0 hours	Not applicable (systemic half-life is irrelevant)
Sources: 4

2.3 Implications of Pharmacological Profile

The clinical pharmacology of Iohexol gives rise to two critical implications that extend beyond its primary function as an imaging agent.

First, its pharmacokinetic profile makes it an exceptionally useful tool for measuring kidney function. An ideal exogenous marker for determining GFR must be physiologically inert, not bind to plasma proteins, be freely filtered at the glomerulus, and not be secreted or reabsorbed by the renal tubules. Iohexol fulfills these criteria almost perfectly.[30] Its complete and unchanged renal excretion via glomerular filtration means that its clearance rate from the plasma is a direct and accurate measure of GFR. This has been validated in studies comparing Iohexol clearance to that of the gold-standard GFR marker, 51Cr-EDTA, where the clearance rates were found to be nearly identical.[21] This property has led to a crucial secondary application for Iohexol: it is widely used in clinical research and specialized nephrology settings as a precise method for GFR determination. Its use as a diagnostic endpoint in clinical trials for conditions like diabetic nephropathy, glomerulonephritis, and obesity-related kidney disease confirms this vital role.[30] Thus, Iohexol possesses the unique dual capability to both visualize the anatomy of the urinary tract and quantify its physiological function.

Second, the pharmacokinetics of Iohexol are a primary determinant of its safety and risk profile. The fact that the drug is almost exclusively eliminated by the kidneys means that patient renal function is the single most important factor governing its safety for systemic administration. In patients with impaired renal function, the elimination of Iohexol is delayed and its plasma half-life is prolonged.[4] This extended exposure increases the duration of contact between the contrast agent and the renal tubules, amplifying its inherent cytotoxic effects and raising the risk of causing or worsening kidney damage—a dangerous feedback loop known as CI-AKI.[10] Similarly, the pharmacokinetic differences between administration routes directly explain their distinct adverse effect profiles. The longer half-life following intrathecal administration, due to slow absorption from the CSF, accounts for the prolonged nature of CNS side effects like post-myelography headache and dictates the need for a significant delay (at least 48 hours, preferably longer) before a repeat procedure can be safely performed.[4] In contrast, its poor oral absorption is precisely why it is safe for GI studies, as systemic exposure is minimal. Therefore, a deep understanding of Iohexol's pharmacokinetic journey is not merely academic; it is fundamental to predicting, managing, and mitigating its clinical risks.

Section III: Clinical Indications and Efficacy

The clinical applications of Iohexol are remarkably broad, reflecting its status as a versatile and essential tool in diagnostic medicine. Its efficacy has been established across a wide range of imaging procedures involving nearly every organ system and administration route.

3.1 Approved Diagnostic Applications

Iohexol is approved by regulatory bodies, including the U.S. Food and Drug Administration (FDA), for an extensive list of diagnostic indications. These are typically specified by the concentration of the Iohexol solution and are categorized by the route of administration.[4]

Intravascular Administration:

This is the most common mode of use, where Iohexol is injected into arteries or veins to visualize the cardiovascular system and other organs.

• Angiocardiography: Used for visualizing the chambers of the heart (ventriculography), the coronary arteries (selective coronary arteriography), the pulmonary arteries, and associated veins, in both adults and children.[4]
• Aortography and Arteriography: Employed for imaging the aorta and its major branches. This includes cerebral arteriography (visualizing blood vessels in the brain), peripheral arteriography (extremities), and visceral arteriography (e.g., renal and celiac arteries).[4]
• Digital Subtraction Angiography (DSA): A specialized technique for which Iohexol is indicated, used for high-resolution imaging of blood vessels. It can be performed via either intravenous (IV-DSA) or intra-arterial (IA-DSA) injection.[11]
• Excretory Urography: Following intravenous injection, Iohexol is concentrated and excreted by the kidneys, providing detailed opacification of the renal pelves, ureters, and bladder.[4]
• Contrast Enhancement for Computed Tomography (CECT): Iohexol is a standard agent for CECT of the head and body. It enhances the contrast between different soft tissues and highlights vascular structures, improving the detection and characterization of tumors, infections, and vascular abnormalities.[1]
• Venography (Phlebography): Used to visualize the venous system, typically in the extremities, to diagnose conditions like deep vein thrombosis.[4]

Intrathecal Administration:

Specific concentrations of Iohexol are approved for injection into the subarachnoid space to visualize the central nervous system.

• Myelography: Used to image the spinal canal, including the lumbar, thoracic, and cervical regions, to diagnose conditions like herniated discs, spinal stenosis, and tumors.[4]
• CT Enhancement: Used in conjunction with CT for enhanced visualization following myelography (CT myelography), or for imaging the basal cisterns (CT cisternography) and ventricles (CT ventriculography) of the brain.[1]

Oral/Rectal Administration:

Iohexol solutions can be administered orally or rectally to opacify the gastrointestinal (GI) tract.

• GI Tract Examination: Used for oral pass-thru studies to visualize the esophagus, stomach, and small bowel. It is often preferred over barium sulfate in certain situations, such as when a perforation is suspected.[11]
• CECT of the Abdomen and Pelvis: Diluted oral Iohexol is used to opacify the bowel loops, which helps distinguish them from adjacent organs, masses, and lymph nodes during abdominal and pelvic CT scans.[11]

Body Cavity Administration:

Iohexol is instilled directly into various body cavities for specific diagnostic purposes.

• Arthrography: Injected into joints (e.g., knee, shoulder) to visualize the joint capsule, cartilage, and ligaments.[1]
• Hysterosalpingography (HSG): Instilled into the uterus and fallopian tubes to assess uterine abnormalities and tubal patency in infertility evaluations.[4]
• Endoscopic Retrograde Cholangiopancreatography (ERCP): Injected into the biliary and pancreatic ducts during an endoscopic procedure to diagnose blockages, stones, and tumors.[4]
• Other uses: Include herniography (visualizing hernias) and sialography (visualizing salivary ducts).[4]

3.2 Investigational and Off-Label Uses

Beyond its approved indications, Iohexol's unique pharmacokinetic properties have led to its prominent use in clinical research as a diagnostic marker.

• Glomerular Filtration Rate (GFR) Measurement: As discussed in the pharmacology section, Iohexol's plasma clearance serves as a highly accurate measure of GFR.[30] It is widely employed in clinical trials and nephrology research to assess renal function and the progression of kidney disease. Active and completed trials show its use in studying diabetic nephropathy, glomerulonephritis, Type 1 and Type 2 diabetes, and the renal effects of conditions like pediatric obesity.[23]
• Contrast-Enhanced Mammography (CEM): In Europe, Iohexol is used for CEM, an emerging imaging technique. Following intravenous injection, it helps to evaluate and detect breast lesions, serving as an adjunct to standard mammography or an alternative to magnetic resonance imaging (MRI) in certain clinical scenarios.[25]

3.3 European Public Assessment Report (EPAR) Summary

While a single, consolidated EPAR for the original Omnipaque product is not available in the provided materials, a clear picture of its European regulatory status can be pieced together from various documents from the European Medicines Agency (EMA) and national health authorities.

Iohexol is a well-established and widely authorized substance in the European Union. Its long history of use means that the focus of regulatory activity is often on post-marketing safety surveillance and the approval of generic products.

• Generic Approval: Generic versions of Iohexol, such as "Iohexol ICG farma," have been authorized through a decentralized procedure (DC). The approval is based on demonstrating that the generic product has a comparable quality profile (e.g., impurity profile, pH, osmolality) and is "essentially similar" to the reference medicine, Omnipaque. This process relies on the extensive clinical data already established for the reference product, obviating the need for new large-scale clinical trials.[39]
• Ongoing Safety Monitoring: The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) and the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) continuously monitor the safety of Iohexol. This is done through Periodic Safety Update Reports (PSURs). These assessments can lead to a "variation" of the marketing authorization, which typically involves updating the Summary of Product Characteristics (SmPC) and Patient Leaflet (PL) to include new information on risks or adverse reactions.[40]
• Reimbursement and Health Technology Assessment: National bodies conduct their own assessments to determine clinical value and reimbursement status. A 2024 opinion from the French National Authority for Health (HAS) regarding the use of Iohexol for contrast-enhanced mammography provides a salient example. The HAS deemed the clinical benefit "substantial" but only in specific, niche situations: for patients with contraindications to MRI or for assessing tumor size where a perfect match with mammography is needed. For other situations, the benefit was judged "insufficient" to justify reimbursement, and the technology was determined to provide no clinical added value over the existing care pathway.[38]

3.4 Implications of Clinical Profile

The vast scope of Iohexol's approved indications solidifies its role not merely as a single drug, but as a fundamental platform technology in the field of diagnostic imaging. Its ability to be safely administered via nearly every possible route—into vessels, the spine, the GI tract, and other body cavities—makes it an extraordinarily versatile agent. A single hospital radiology department can use this one compound to support procedures for cardiology, neurology, urology, gastroenterology, gynecology, and orthopedics. This simplifies inventory management, streamlines staff training on handling and safety protocols, and provides a consistent pharmacological profile across a multitude of examinations. This unparalleled versatility is a primary reason for its inclusion on the WHO List of Essential Medicines and its decades-long status as a standard of care.[1]

Furthermore, the European assessment of Iohexol for contrast-enhanced mammography offers a valuable lesson in modern health technology assessment. It demonstrates that for an established product to gain endorsement for a new indication, simply proving it is effective is not enough. The new application must demonstrate a clear clinical added value and a favorable position within the existing, and often complex, diagnostic algorithm. The HAS opinion shows that new uses are critically evaluated against established standards of care, such as MRI.[38] Reimbursement and full clinical integration are often granted only for specific subpopulations where the new technique fills an unmet need or offers a distinct advantage (e.g., for patients who cannot undergo an MRI). This illustrates the high bar that even proven, effective drugs must clear to expand their clinical role in an evidence-based and cost-conscious healthcare environment.

Section IV: Dosage and Administration Guidelines

The administration of Iohexol is a complex medical procedure that requires meticulous attention to detail. The dosage and administration guidelines are highly specific to the procedure being performed, the concentration of the agent, and the patient population. Adherence to these guidelines is critical for achieving optimal diagnostic quality while minimizing the risk of adverse events.

4.1 General Principles of Use

Several overarching principles apply to all uses of Iohexol, particularly for parenteral administration:

• Patient Hydration: Adequate hydration is crucial. Preparatory dehydration is considered dangerous and must be avoided, as it significantly increases the risk of contrast-induced acute kidney injury (CI-AKI). Patients should be well-hydrated before and after the procedure to promote rapid renal clearance of the agent.[4]
• Lowest Effective Dose: The principle of using the lowest dose and concentration of contrast necessary to obtain adequate diagnostic visualization should always be followed. This helps to minimize the patient's exposure and potential for dose-related side effects.[4]
• Individualization of Dose: The specific volume, concentration, and rate of administration must be individualized for each patient. This decision should take into account the patient's age, body weight, clinical condition (e.g., cardiac and renal status), the size of the vessel or structure to be imaged, and the specific imaging equipment and technique being employed.[4]
• Solution Temperature: Iohexol solutions may be warmed to body temperature (37°C) prior to injection. This can reduce the viscosity of the solution, making injection easier, and may improve patient comfort by reducing the sensation of cold upon injection. The solution should never be heated above 37°C.[4]
• Visual Inspection: As with all parenteral drugs, Iohexol solutions must be visually inspected for particulate matter and discoloration before use. The solution should be clear and colorless to pale yellow. If it is discolored or contains particulates, it must be discarded.[4]
• Sterile Technique: Strict sterile technique is mandatory for all procedures involving the withdrawal of Iohexol from its container and for any parenteral injection to prevent infection.[4]

4.2 Intravascular Dosing (Adult and Pediatric)

Intravascular dosing is highly variable and procedure-dependent. Table 4 provides a summary of recommended doses for major intravascular applications. Total doses for multiple procedures should not exceed established limits, typically around 250 mL for higher concentrations.[11]

Table 4: Detailed Dosing for Intravascular Procedures

Procedure	Patient Population	Recommended Concentration(s) (mgI/mL)	Typical Volume/Dose	Administration Notes
Selective Coronary Arteriography	Adult	350	3-14 mL per injection	Total volume not to exceed 250 mL
Ventriculography	Adult	350	30-60 mL	-
Ventriculography	Pediatric	300 or 350	1.25-1.75 mL/kg	Max total dose 5-6 mL/kg
Aortography	Adult	300 or 350	50-80 mL	-
Cerebral Arteriography	Adult	300	6-12 mL per vessel	-
CECT of Head	Adult	300 or 350	70-150 mL	Rapid injection or infusion
CECT of Body	Adult	300 or 350	50-200 mL	Rapid injection
CECT of Head	Pediatric	240 or 300	1.0-2.0 mL/kg	Max iodine dose 28-35 gI
IV Digital Subtraction Angio. (DSA)	Adult	350	30-50 mL	Bolus injection at 7.5-30 mL/sec
IA Digital Subtraction Angio. (DSA)	Adult	140	4-45 mL depending on vessel	Rate 2-20 mL/sec
Excretory Urography	Adult	300 or 350	40-80 mL (dose based on weight)	-
Excretory Urography	Pediatric	300	1.0-1.5 mL/kg (range 0.5-3.0 mL/kg)	Max total dose 3 mL/kg
Peripheral Venography	Adult	240 or 300	20-150 mL per leg	-
Sources: 4

4.3 Intrathecal Dosing (Adult and Pediatric)

Intrathecal administration requires the utmost care due to the direct exposure of the central nervous system to the contrast agent. Specific concentrations (180, 240, and 300 mgI/mL) are approved for this route; OMNIPAQUE 140 and 350 are strictly contraindicated for intrathecal use.[4] The injection should be performed slowly over 1 to 2 minutes to prevent excessive mixing and dilution with CSF.[4] Patient management, such as keeping the head elevated, is critical to prevent the inadvertent rapid flow of a concentrated bolus to intracranial levels.[4]

Table 5: Detailed Dosing for Intrathecal Procedures

Procedure Type	Patient Population	Recommended Concentration (mgI/mL)	Volume Range (mL)	Total Iodine Dose Limit
Lumbar/Thoracic/Cervical Myelography	Adult	180, 240, or 300	6 - 17 mL	Do not exceed 3060 mg Iodine
Myelography (All levels)	Pediatric (0 to <3 mos)	180	2 - 4 mL	Do not exceed 2700 mg Iodine
Myelography (All levels)	Pediatric (3 mos to <3 yrs)	180	4 - 8 mL	Do not exceed 2700 mg Iodine
Myelography (All levels)	Pediatric (3 to <7 yrs)	180	5 - 10 mL	Do not exceed 2700 mg Iodine
Myelography (All levels)	Pediatric (7 to <13 yrs)	180	5 - 12 mL	Do not exceed 2700 mg Iodine
Myelography (All levels)	Pediatric (13 to 18 yrs)	180	6 - 15 mL	Do not exceed 2700 mg Iodine
Sources: 4

An interval of at least 48 hours, and preferably 5 to 7 days, should be allowed before a repeat intrathecal examination.[29]

4.4 Oral and Body Cavity Dosing

For opacification of the GI tract or other body cavities, doses vary by age and procedure.

• Oral Pass-Thru (Adults): 50-100 mL of OMNIPAQUE 350.[4]
• Oral Pass-Thru (Pediatrics): Volumes range from 5 mL to 100 mL depending on age, using OMNIPAQUE 180, 240, or 300.[4]
• CECT of Abdomen (Adults): A combination of oral and IV contrast is used. The oral dose is typically 500-1000 mL of a diluted solution (6-9 mgI/mL), administered 20-40 minutes before an IV dose of 100-150 mL of OMNIPAQUE 300.[4]
• CECT of Abdomen (Pediatrics): A similar combination approach is used, with an oral dose of diluted Iohexol (9-21 mgI/mL) followed 30-60 minutes later by an IV dose of 2 mL/kg.[11]
• Arthrography (Adults): 5-15 mL of OMNIPAQUE 240, 300, or 350, depending on the joint.[4]
• Hysterosalpingography (Adults): 15-20 mL of OMNIPAQUE 240 or 300.[4]

4.5 Preparation and Dilution of Solutions

For certain applications, particularly oral administration for abdominal CT and pediatric voiding cystourethrography (VCU), the commercially available concentrated solutions must be diluted. These dilutions should be prepared just prior to use, and any unused portion must be discarded.[4] For example, to prepare a solution for abdominal CT, OMNIPAQUE 300 can be mixed with water, carbonated beverages, milk, or juice to achieve the target concentration of 6-9 mgI/mL.[43] For VCU, concentrations of 50-100 mgI/mL are used. Detailed dilution tables are provided in the product's prescribing information to guide these preparations accurately.[4]

4.6 Implications of Dosing Complexity

The extensive and highly detailed nature of the dosage and administration guidelines for Iohexol is a direct consequence of its wide-ranging utility and its inherent risks. The existence of dozens of specific protocols for different procedures, age groups, and concentrations underscores that the use of Iohexol is far from a simple medication administration. It is a complex procedural intervention that demands a high level of expertise, precision, and situational awareness from the entire clinical team, including radiologists, technologists, nurses, and pharmacists.

This complexity highlights a crucial point: the safety and efficacy of Iohexol are inextricably linked to the correct execution of these protocols. Deviations from recommended injection rates, volumes, concentrations, or patient management techniques can lead to suboptimal imaging, or more seriously, to an increased risk of adverse events. For instance, injecting too rapidly or using too high a volume intrathecally can cause severe neurological complications, while failing to hydrate a patient with renal risk factors before a large IV dose can precipitate acute kidney failure. Therefore, the "Dosage and Administration" section of the prescribing information should be viewed not as a mere list of numbers, but as a set of critical safety and operational protocols that form the foundation of responsible clinical practice with this powerful diagnostic agent.

Section V: Safety Profile and Risk Management

The safety profile of Iohexol, while favorable compared to older agents, is complex and requires vigilant risk management. A comprehensive understanding of its contraindications, warnings, adverse reactions, and drug interactions is essential for any clinician involved in its use.

5.1 Boxed Warning and Contraindications

FDA Boxed Warning:

The U.S. Food and Drug Administration has issued a boxed warning for specific formulations of Iohexol, which is the most serious type of warning assigned to a drug. It states:

WARNING: RISKS WITH INADVERTENT INTRATHECAL ADMINISTRATION

OMNIPAQUE injection, 140 and 350 mg iodine/mL

FOR INTRAVENOUS USE ONLY.

Inadvertent intrathecal administration may cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema. 6

This warning underscores the catastrophic potential of a specific type of medication error: administering the high-concentration formulations (140 and 350 mgI/mL), intended only for intravascular or body cavity use, into the spinal canal.

Contraindications:

Iohexol is contraindicated in the following situations:

• General: In patients with a known history of serious hypersensitivity to Iohexol.[4]
• Intrathecal Use: Myelography should not be performed in patients with significant local or systemic infection where bacteremia is a risk. The concurrent intrathecal administration of corticosteroids with Iohexol is contraindicated. An immediate repeat myelography following a technical failure is also contraindicated due to the risk of overdose.[4]
• Hysterosalpingography (HSG): The procedure is contraindicated during pregnancy or suspected pregnancy, during or immediately before the menstrual period, in the presence of any genital tract infection, or within 6 months of pregnancy termination or 30 days of uterine conization or curettage.[4]
• Renal Failure: While not an absolute contraindication for all uses, Iohexol is generally not recommended for use in patients who are anuric (not producing urine).[4]

5.2 Warnings and Precautions

A number of serious warnings and precautions are associated with Iohexol use:

• Hypersensitivity Reactions: Life-threatening or fatal anaphylactic/anaphylactoid reactions can occur, sometimes with no prior history of allergy. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. The risk is higher in patients with a history of a previous reaction to any contrast agent, or with a history of bronchial asthma, food, or drug allergies. Emergency resuscitation equipment and trained personnel must be immediately available whenever Iohexol is administered.[6]
• Contrast-Induced Acute Kidney Injury (CI-AKI): This is one of the most significant risks of intravascular contrast administration. Iohexol is cytotoxic to renal cells, and its administration can lead to acute kidney injury, including renal failure. Key risk factors include: pre-existing renal impairment, diabetes mellitus, dehydration, congestive heart failure, advanced vascular disease, older age, multiple myeloma, and the concomitant use of other nephrotoxic drugs (e.g., NSAIDs, aminoglycosides). Risk mitigation involves using the lowest possible dose, avoiding repeat doses within a short period, and ensuring adequate patient hydration before and after the procedure.[6]
• Cardiovascular Adverse Reactions: Serious hemodynamic disturbances can occur, including shock, cardiac arrest, arrhythmias (e.g., PVCs, PACs), angina, and myocardial infarction. These events can happen during or after administration and require careful patient monitoring.[5]
• Thromboembolic Events: Non-ionic contrast media like Iohexol inhibit blood coagulation less than ionic media, and clotting can occur in vitro when blood remains in contact with syringes. Serious and rarely fatal thromboembolic events, such as stroke and myocardial infarction, have been reported during angiographic procedures. Meticulous intravascular administration technique, including frequent flushing of catheters, is necessary to minimize this risk.[4]
• Neurological Reactions (Intrathecal): In addition to the risks of inadvertent overdose, standard intrathecal use can cause adverse neurological events, including severe headache, aseptic meningitis, and seizures. Extreme caution is advised in patients with a history of epilepsy, chronic alcoholism, or multiple sclerosis. Drugs that lower the seizure threshold should be avoided.[4]
• Thyroid Dysfunction: Due to its iodine content, Iohexol can induce thyroid dysfunction. Thyroid storm, a life-threatening condition, has been reported in patients with pre-existing hyperthyroidism or autonomously functioning thyroid nodules. Conversely, transient hypothyroidism has been observed in pediatric patients, particularly those under 3 years of age, and may require monitoring as it can affect development.[1]
• Extravasation and Injection Site Reactions: If the IV cannula is dislodged, Iohexol can leak into the surrounding subcutaneous tissue (extravasation). This can cause pain, swelling, and in severe cases, compartment syndrome or tissue necrosis.[6]
• Severe Cutaneous Adverse Reactions (SCARs): Delayed, severe, and potentially fatal skin reactions can occur 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). Patients should be counseled on these risks.[4]
• Other Specific Conditions: Caution is required in patients with pheochromocytoma (risk of hypertensive crisis) and sickle cell disease (risk of promoting a sickling crisis).[9]

5.3 Adverse Reactions

The adverse reactions to Iohexol vary significantly depending on the route of administration, the dose, and patient-specific factors. Table 6 provides a consolidated summary of reported adverse events, categorized by frequency and system organ class.

Table 6: Summary of Adverse Reactions by Frequency and System Organ Class

System Organ Class	Frequency	Adverse Reaction	Associated Route(s)
Nervous System	Very Common (>10%)	Headache (can be severe and prolonged)	Intrathecal
	Common (1-10%)	Dizziness, Pain (backache, neckache, neuralgia)	Intrathecal
	Common (1-10%)	Headache, Taste perversion (dysgeusia)	Intravascular, Oral
	Uncommon (0.1-1%)	Aseptic meningitis, Syncope, Transient Ischemic Attack	Intrathecal
	Rare/Very Rare (<0.1%)	Seizures, Transient contrast-induced encephalopathy (amnesia, coma), Paresthesia, Tremor	Intrathecal, Intravascular
Cardiovascular	Common (1-10%)	Arrhythmias (PVCs, PACs), Angina/Chest Pain	Intravascular
	Uncommon (0.1-1%)	Hypotension, Hypertension, Tachycardia, Bradycardia	Intravascular
	Rare/Very Rare (<0.1%)	Myocardial infarction, Cardiac arrest, Shock	Intravascular
Gastrointestinal	Common (1-10%)	Nausea, Vomiting	All routes
	Common (1-10%)	Diarrhea, Abdominal pain, Flatulence	Oral
	Rare/Very Rare (<0.1%)	Pancreatitis (or aggravation of), Salivary gland enlargement ("iodide mumps")	Intravascular, Oral
Renal and Urinary	Common (1-10%)	Increased serum creatinine	Intravascular
	Frequency not reported	Contrast-Induced Acute Kidney Injury (CI-AKI), Oliguria, Anuria, Proteinuria	Intravascular
Skin & Subcutaneous	Common (1-10%)	Skin flushing, Sensation of warmth	Intravascular
	Uncommon (0.1-1%)	Rash, Urticaria (hives), Pruritus (itching)	All routes
	Rare/Very Rare (<0.1%)	Severe Cutaneous Adverse Reactions (SJS, TEN, AGEP, DRESS), Angioedema	All routes
Ocular	Common (1-10%)	Vision abnormalities (blurred vision, photomas)	Intravascular
	Rare/Very Rare (<0.1%)	Transient cortical blindness, Lacrimation, Periorbital edema	Intravascular
General/Body Cavity	Common (1-10%)	Pain at injection/instillation site, Sensation of heat/swelling	Intravascular, Body Cavity
	Common (1-10%)	Fever	Intrathecal, Hysterosalpingography
Sources: 1

5.4 Drug and Food Interactions

Iohexol has several clinically significant interactions that require careful management.

Drug Interactions:

• Metformin: This is a critical interaction. In patients taking metformin, the development of CI-AKI can impair metformin excretion, leading to its accumulation and potentially causing life-threatening lactic acidosis. The American College of Radiology recommends temporarily discontinuing metformin at the time of or prior to the procedure in patients with an eGFR <30 mL/min/1.73 m², those with a history of liver disease, alcoholism, or heart failure, or those receiving intra-arterial contrast. Metformin should be withheld for 48 hours post-procedure and restarted only after renal function is confirmed to be normal.[10]
• Drugs that Lower the Seizure Threshold: This is particularly important for intrathecal administration. Medications such as phenothiazine derivatives (e.g., prochlorperazine), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and other CNS stimulants or antipsychotics can increase the risk of seizures when combined with intrathecal Iohexol. It is recommended that these agents be discontinued at least 48 hours before myelography and not resumed for at least 24 hours after the procedure.[4]
• Aldesleukin (Interleukin-2): Patients who have received treatment with aldesleukin have an increased risk of delayed hypersensitivity reactions to iodinated contrast media.[10]
• Nephrotoxic Drugs: Concomitant use of other drugs known to be harmful to the kidneys (e.g., aminoglycoside antibiotics, cisplatin, NSAIDs) can have an additive effect, increasing the risk of CI-AKI.[17]
• Radioactive Iodine: The stable iodine in Iohexol competes with radioactive iodine isotopes (I-123, I-131) for uptake by the thyroid gland. This can interfere with thyroid uptake scans and the efficacy of radioactive iodine therapy for thyroid cancer for several weeks following contrast administration.[5]

Food Interaction - Caffeine:

While most sources state no food interactions, a specific and significant interaction exists between caffeine and intrathecal Iohexol. High intake of caffeine (from coffee, tea, colas, etc.) can lower the seizure threshold. For patients undergoing myelography, caffeine and caffeine-containing products should be discontinued at least 48 hours before the procedure and withheld for at least 24 hours afterward to minimize the risk of seizures.46

Table 7: Clinically Significant Drug Interactions

Interacting Drug/Class	Effect of Interaction	Proposed Mechanism	Clinical Recommendation/Management
Metformin	Increased risk of lactic acidosis	Iohexol-induced AKI impairs metformin clearance	Withhold metformin for 48h post-procedure in at-risk patients; restart only after confirming normal renal function.
Drugs Lowering Seizure Threshold (Phenothiazines, TCAs, MAOIs)	Increased risk of seizures	Additive effect on lowering seizure threshold	Discontinue agent 48h before and for 24h after intrathecal administration.
Aldesleukin (IL-2)	Increased risk of hypersensitivity reaction	Immunological mechanism	Use with caution; be prepared for delayed reactions.
Nephrotoxic Drugs (NSAIDs, Aminoglycosides)	Increased risk of CI-AKI	Additive renal toxicity	Avoid concomitant use if possible; ensure robust hydration and monitor renal function.
Radioactive Iodine (I-123, I-131)	Decreased thyroid uptake of radioiodine	Competitive inhibition by stable iodine	Postpone thyroid scans or radioiodine therapy for at least 6-8 weeks after Iohexol administration.
Sources: 4

5.5 Use in Specific Populations

• Pregnancy: Iohexol should be used during pregnancy only if clearly needed. Use in the later part of pregnancy may cause transient hypothyroidism in the newborn. It is contraindicated for hysterosalpingography.[1]
• Lactation: Iohexol is excreted in human milk in very small quantities. The risk to the breastfed infant is considered low, and guidelines often suggest that breastfeeding need not be interrupted.[2]
• Pediatrics: Pediatric patients, especially infants and neonates, are at higher risk for certain adverse events. They are particularly susceptible to the effects of dehydration and have a recognized risk of developing transient hypothyroidism following exposure, especially if under 3 years of age. Dosing must be carefully calculated based on age and weight.[5]
• Geriatrics: Elderly patients often have a higher frequency of co-morbidities, such as decreased renal function and cardiovascular disease, placing them at greater risk for adverse events like CI-AKI. Cautious dose selection, typically starting at the low end of the range, is recommended.[4]
• Renal Impairment: This is the highest-risk population for CI-AKI. Iohexol elimination is significantly prolonged. The agent should only be used if the diagnostic benefit is deemed to outweigh the substantial risk. Meticulous hydration is mandatory.[4]

5.6 Overdosage and Management

Overdosage with Iohexol is a serious and potentially life-threatening event, with consequences that depend on the route of administration. There is no specific antidote; management is entirely supportive.[4]

• Intrathecal Overdose: The primary concern is severe CNS toxicity. This can result from an absolute overdose or from the inadvertent intracranial entry of a large bolus. Symptoms include seizures, coma, paralysis, and cerebral edema. Management involves supporting vital functions and may include prophylactic anticonvulsant therapy (e.g., with barbiturates).[4]
• Intravascular Overdose: Massive intravascular overdose primarily affects the cardiovascular and pulmonary systems, and can lead to cardiac arrest, pulmonary hemorrhage, cyanosis, and acidosis. Treatment is directed at supporting all vital functions and promptly initiating symptomatic therapy.[4]
• General Management: In all cases of overdose, maintaining a patent airway and supporting ventilation and circulation are paramount. Fluid and electrolyte balance must be monitored and corrected. Since Iohexol is cleared by the kidneys, maintaining adequate hydration and promoting diuresis can aid elimination. In cases of massive overdose, particularly with co-existing renal failure, Iohexol is dialyzable and hemodialysis may be considered to remove the agent from the body.[47]

5.7 Implications for Risk Management

The safety profile of Iohexol reveals that its risks are significant but largely predictable and manageable through diligent clinical practice. The FDA Boxed Warning, however, points to a risk that transcends individual patient pharmacology and enters the realm of health systems and human factors. The availability of multiple Iohexol concentrations in similar packaging, with some being lethal if given by the wrong route, creates an inherent, system-level vulnerability to catastrophic medication error.

This is not merely a theoretical risk; the issuance of a boxed warning indicates that such errors have occurred and have led to severe patient harm or death. Therefore, an expert analysis of Iohexol's safety must conclude that pharmacological knowledge alone is insufficient. Robust institutional risk mitigation strategies are required. These should include:

1. Physical Segregation of Stock: In hospital pharmacies and radiology suites, Iohexol formulations intended for intrathecal use must be stored physically separate from those intended for intravascular use to prevent mix-ups.
2. Enhanced Labeling: Use of "tall man" lettering (e.g., OMNIPAQUE-350 vs. omnipaque-180) on storage bins and in electronic systems can help differentiate products.
3. Technological Safeguards: Implementation of barcode scanning at the point of administration can provide a final safety check, ensuring the correct concentration is being used for the intended route.
4. Procedural Protocols: Mandatory pre-administration "time-outs" or double-checks by two qualified healthcare professionals should be standard practice for all intrathecal injections.

By addressing the risk at a systems level, healthcare institutions can build layers of defense to prevent these high-severity, low-frequency errors, ensuring that this essential diagnostic tool can be used safely.

Section VI: Regulatory and Commercial Status

Iohexol has a long-standing and well-established presence in the global pharmaceutical market, underscored by its widespread regulatory approval and its inclusion on the WHO's List of Essential Medicines.

6.1 Global Regulatory Approvals and History

Iohexol was first approved for medical use in 1985.[1] In the United States, the initial FDA approval for Omnipaque (NDA N-018956) was granted on December 26, 1985, to GE Healthcare.[48] Over the years, additional formulations and indications have been approved, solidifying its role in clinical practice.

It is widely authorized for use in major markets, including the United States, Canada, and the European Union.[10] Its status as an essential medicine, as designated by the World Health Organization (WHO), highlights its importance for a basic health system, recognizing its critical role in diagnostic procedures and its favorable safety profile compared to older alternatives.[1] In Europe, its ongoing safety is monitored by the EMA through periodic safety update assessments (PSUSA), which can lead to updates in its product information across member states.[40]

6.2 Brand Names and Manufacturers

The most prominent and original brand name for Iohexol is Omnipaque, which is manufactured and marketed globally by GE Healthcare.[1] An oral formulation is also marketed under the brand name

Oraltag by Interpharma Praha.[10] Other trade names mentioned in the literature include Iodaque and Hexopaque.[1]

Given its long time on the market, the patent for Iohexol has expired, and generic versions are now available. For example, Beijing Beilu Pharmaceutical Co., Ltd. has received Marketing Authorization in the European Union for its Iohexol injection, demonstrating that its product meets EU standards for quality, safety, and efficacy.[50] Other companies, such as

LGM Pharma, act as distributors of the active pharmaceutical ingredient (API) to various manufacturers.[51] In Canada, formulations were historically marketed by Sanofi S.R.L. before GE Healthcare became the primary labeller.[10] This competitive landscape, with both a major brand-name manufacturer and several generic producers, helps ensure its continued availability and accessibility for clinical use worldwide.

Section VII: Expert Analysis and Clinical Recommendations

This final section synthesizes the comprehensive data presented in this monograph to provide an expert perspective on Iohexol's role in medicine and to offer clear, actionable recommendations for its safe and effective clinical use.

7.1 Synthesis of Efficacy and Safety: A Balancing Act

Iohexol represents a significant achievement in pharmaceutical development, offering immense diagnostic value across a vast spectrum of clinical applications. Its efficacy as a contrast agent is undisputed, providing the clear anatomical delineation essential for modern radiology. This utility is paired with a safety profile that was a dramatic improvement over the first-generation ionic agents it replaced. Its non-ionic, low-osmolality nature directly translates to better patient tolerance and a lower incidence of many adverse effects.

However, this favorable profile does not imply that Iohexol is a benign substance. As detailed extensively, it carries significant and potentially life-threatening risks. The potential for CI-AKI, severe hypersensitivity reactions, neurological toxicity, and catastrophic medication errors is real. The key takeaway from this monograph is that Iohexol presents a highly favorable risk-benefit ratio, but only when it is used correctly, in the appropriate patient, and with a full understanding of its potential hazards. Its safety is not an inherent property of the molecule alone; it is an outcome of diligent and knowledgeable clinical practice. The responsibility for this balancing act lies with the entire healthcare team.

7.2 Iohexol's Position in Modern Radiologic Practice

Decades after its introduction, Iohexol remains a "workhorse" contrast agent in hospitals worldwide. Its position is secured by its versatility, extensive track record of efficacy, and well-understood safety profile. When compared to older high-osmolality agents like diatrizoate, Iohexol's advantages in terms of lower osmotoxicity are clear and established.[1] Within the class of low-osmolality non-ionic agents, it is a peer to other commonly used molecules like iopamidol and ioversol, with studies generally showing comparable rates of acute adverse events.[36] Its selection over these other agents often comes down to institutional preference, contractual agreements, and historical familiarity.

The emergence of iso-osmolar agents (e.g., iodixanol) has provided an alternative, particularly for high-risk patients, as these agents have an osmolality identical to that of blood, theoretically offering a further reduction in osmotic stress. However, Iohexol's lower cost and vast body of supporting clinical evidence ensure its continued and widespread use as a standard of care for the majority of patients and procedures.

7.3 Key Recommendations for Clinical Practice to Mitigate Risk

Based on the comprehensive analysis of Iohexol's pharmacology, indications, and safety profile, the following evidence-based recommendations are provided to guide clinicians in mitigating its risks and optimizing its use:

1. Mandate Rigorous Patient Screening: Before any administration of Iohexol, a thorough patient history must be obtained. This screening must explicitly focus on identifying key risk factors for the most severe adverse events.

• For CI-AKI: Screen for pre-existing renal disease (obtain a recent eGFR), diabetes mellitus, dehydration, congestive heart failure, and use of concomitant nephrotoxic drugs.[9]
• For Hypersensitivity: Screen for a history of any prior reaction to contrast media, as well as a history of significant allergies, particularly bronchial asthma, and food or drug allergies.[4]

2. Implement a Standardized Hydration Protocol: For all at-risk patients scheduled to receive intravascular Iohexol, a formal, written hydration protocol should be implemented. This is the single most effective measure for preventing CI-AKI. While protocols vary, a common regimen involves intravenous administration of isotonic saline for several hours before and after the procedure.[42] Preparatory dehydration must be strictly avoided.[4]
3. Prioritize Medication Reconciliation and Management: A formal medication reconciliation process is critical.

• Metformin: Identify all patients taking metformin. In accordance with established guidelines, develop a clear institutional policy for temporarily withholding the drug in at-risk patients undergoing contrast procedures.[11]
• Seizure-Lowering Drugs: For patients scheduled for myelography, explicitly identify and manage medications that lower the seizure threshold (e.g., phenothiazines, TCAs). Ensure these are discontinued at least 48 hours prior to the procedure and for 24 hours after.[4]
• Caffeine: Counsel patients undergoing myelography to discontinue all caffeine-containing products for 48 hours before and 24 hours after the procedure to minimize seizure risk.[46]

4. Enforce the "Right Concentration, Right Route" Mandate: The FDA Boxed Warning must be treated with the utmost seriousness. To prevent catastrophic errors with intrathecal administration, institutions must move beyond simple reliance on individual vigilance and implement robust systems-based safeguards.

• Segregate Stock: Physically separate intrathecal-use concentrations of Iohexol from intravascular-use concentrations in all storage areas (pharmacy, radiology suites).[7]
• Utilize Technology: Employ barcode scanning at the point of care and enhanced visual cues (e.g., "tall man" lettering) in electronic systems to provide redundant safety checks.
• Standardize Workflows: Mandate a pre-procedure "time-out" and a formal double-check by two qualified clinicians before any intrathecal injection of a contrast agent.

5. Ensure Comprehensive Post-Procedure Monitoring and Patient Counseling:

• Acute Monitoring: Observe all patients for at least 30 to 60 minutes after parenteral administration to monitor for and manage acute hypersensitivity reactions.[4]
• Patient Education: Counsel patients on the signs and symptoms of delayed adverse reactions, including severe skin reactions (e.g., new rash with fever) and signs of kidney injury (e.g., decreased urination, swelling). Provide clear instructions on when to seek medical attention.[35]
• Follow-up Labs: In high-risk patients (e.g., those with borderline renal function), schedule a follow-up assessment of renal function (e.g., serum creatinine) 48-72 hours after the procedure to screen for CI-AKI.

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