Ioversol Injection

Optiray (ioversol injection) formulations are sterile, nonpyrogenic, aqueous solutions intended for intravascular administration as diagnostic radiopaque media. Ioversol is designated chemically as N,N'-Bis (2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl) glycolamido] -2,4,6-triiodoisophthalamide and has the following structural formula:

The molecular weight of ioversol is 807.11 and the organically bound iodine content is 47.2%. Ioversol is nonionic and does not dissociate in solution.

Each milliliter of Optiray 350 (ioversol injection 74%) contains 741 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. Optiray 350 provides 35% (350 mg/mL) organically bound iodine.

Each milliliter of Optiray 320 (ioversol injection 68%) contains 678 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. Optiray 320 provides 32% (320 mg/mL) organically bound iodine.

Each milliliter of Optiray 300 (ioversol injection 64%) contains 636 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. Optiray 300 provides 30% (300 mg/mL) organically bound iodine.

Each milliliter of Optiray 240 (ioversol injection 51%) contains 509 mg of ioversol with 3.6 mg of tromethamine as a buffer and 0.2 mg of edetate calcium disodium as a stabilizer. Optiray 240 provides 24% (240 mg/mL) organically bound iodine.

The pH of the Optiray formulations has been adjusted to 6.0 to 7.4 with hydrochloric acid or sodium hydroxide. All solutions are sterilized by autoclaving and contain no preservatives. Unused portions should be discarded. Optiray solutions are sensitive to light and therefore should be protected from exposure.

Some physical and chemical properties of these formulations are listed below:

The Optiray formulations are clear, colorless to pale yellow solutions containing no undissolved solids. Crystallization does not occur at room temperature. The products are supplied in containers from which the air has been displaced by nitrogen. Optiray solutions have osmolalities 1.8 to 2.8 times that of plasma (285 mOsm/kg water) as shown in the above table and are hypertonic under conditions of use.

The pharmacokinetics of ioversol intravascularly administered in normal subjects conform to an open two compartment model with first order elimination (a rapid alpha phase for drug distribution and a slower beta phase for drug elimination). Based on the blood clearance curves for 12 healthy volunteers (6 receiving 50 mL and 6 receiving 150 mL of Optiray 320), the biological half-life was 1.5 hours for both dose levels and there was no evidence of any dose related difference in the rate of elimination.

Ioversol is excreted mainly through the kidneys following intravascular administration. In patients with impaired renal function, the elimination half-life is prolonged. In the absence of renal dysfunction, the mean half-life for urinary excretion following a 50 mL dose was 118 minutes (105 to 156) and following a 150 mL dose was 105 minutes (74 to 141). Greater than 95% of the administered dose was excreted within the first 24 hours, with the peak urine concentration occurring in the first 2 hours after administration. Fecal elimination was negligible.

Ioversol does not bind to serum or plasma proteins to any extent and no significant metabolism, deiodination or biotransformation occurs.

Optiray probably crosses the placental barrier in humans by simple diffusion. It is not known to what extent ioversol is excreted in human milk.

Intravascular injection of ioversol opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures until significant hemodilution occurs.

Ioversol may be visualized in the renal parenchyma within 30 to 60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1 to 3 minutes, with optimum contrast occurring within 5 to 15 minutes.

Animal studies indicate that ioversol does not cross the blood-brain barrier or cause endothelial damage to any significant extent.

Optiray enhances computed tomographic imaging through augmentation of radiographic efficiency. The degree of density enhancement is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid intravenous injection. Blood levels fall rapidly within 5 to 10 minutes and the vascular compartment half-life is approximately 20 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached in about 10 minutes; thereafter, the fall becomes exponential.

The pharmacokinetics of ioversol in both normal and abnormal tissue have been shown to be variable. Contrast enhancement appears to be greatest immediately after bolus administration (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (i.e., dynamic computed tomographic imaging). Utilization of a continuous scanning technique (i.e., dynamic CT scanning) may improve enhancement and diagnostic assessment of tumor and other lesions such as abscess, occasionally revealing unsuspected or more extensive disease. For example, a cyst may be distinguished from a vascularized solid lesion when precontrast and enhanced scans are compared; the nonperfused mass shows unchanged x-ray absorption (CT number). A vascularized lesion is characterized by an increase in CT number in the few minutes after a bolus of intravascular contrast agent; it may be malignant, benign, or normal tissue, but would probably not be a cyst, hematoma, or other nonvascular lesion.

Because unenhanced scanning may provide adequate diagnostic information in the individual patient, the decision to employ contrast enhancement, which may be associated with risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and unenhanced CT findings.

CT Scanning Of The Head

In contrast enhanced computed tomographic head imaging, Optiray does not accumulate in normal brain tissue due to the presence of the normal blood-brain barrier. The increase in x-ray absorption in the normal brain is due to the presence of contrast agent within the blood pool. A break in the blood-brain barrier such as occurs in malignant tumors of the brain allows for the accumulation of contrast medium within the interstitial tissue of the tumor. Adjacent normal brain tissue does not contain the contrast medium.

Maximum contrast enhancement in tissue frequently occurs after peak blood iodine levels are reached. A delay in maximum contrast enhancement can occur. Diagnostic contrast enhanced images of the brain have been obtained up to 1 hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing medium within the lesion and outside the blood pool, although the mechanism by which this occurs is not clear. The radiographic enhancement of nontumoral lesions, such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of the circulating blood pool.

In patients where the blood-brain barrier is known or suspected to be disrupted, the use of any radiographic contrast medium must be assessed on an individual risk to benefit basis. However, compared to ionic media, nonionic media are less toxic to the central nervous system.

CT Scanning Of The Body

In contrast enhanced computed tomographic body imaging (nonneural tissue), Optiray diffuses rapidly from the vascular into the extravascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium, and extraction of the contrast medium by interstitial tissue of tumors since no barrier exists. Contrast enhancement is thus due to the relative differences in extravascular diffusion between normal and abnormal tissue, quite different from that in the brain.

You should not receive ioversol if you have any type of active infection.

Tell your doctor if you have asthma, hay fever, or history of food or drug allergies, especially if you have had any type of reaction to another contrast agent.

Drink extra fluids before and after you receive ioversol. This medication can cause you to get dehydrated, which can lead to dangerous effects on your kidneys. Follow your doctor's instructions about the types and amount of fluids you should drink before and after your test.

Tell your doctor if you have ever had any type of reaction to another contrast agent.

You should not receive ioversol if you have any type of active infection.

Before receiving ioversol, tell your doctor if you have:

• a brain tumor or hematoma;
• a recent head or brain injury;
• epilepsy or other seizure disorder;
• a bleeding or blood clotting disorder;
• kidney disease;
• liver disease;
• diabetes;
• heart disease, angina, or congestive heart failure;
• homocysteinuria;
• sickle cell disease;
• a history of stroke, blood clots, or circulation problems;
• asthma, hay fever, or a history of food or drug allergies;
• multiple myeloma (bone cancer);
• pheochromocytoma; or
• a thyroid disorder.

If you have any of these conditions, you may not be able to receive ioversol, or you may need a dosage adjustment or special tests during treatment.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether ioversol passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Older adults may need special care in avoiding dehydration by drinking extra fluids before and after the radiologic test. Your kidney function may also need to be watched closely after you have received ioversol.

Adverse reactions following the use of Optiray formulations are usually mild to moderate, of short duration and resolve spontaneously. However, serious, life-threatening and fatal reactions have been associated with the administration of Optiray.

Optiray has also been shown to cause changes in cardiac function and systemic blood pressure. These changes include cardiac output, left ventricular systolic and end-diastolic pressure, right ventricular systolic and pulmonary artery systolic pressures and decreases in systolic and diastolic blood pressures.

The following table of incidence of reactions is based upon clinical trials with Optiray formulations in 4,187 patients. This listing includes reactions associated with the administration of ioversol. Adverse reactions are listed by organ system according to clinical importance. More severe reactions are listed before others in a system regardless of frequency. The most common reaction is nausea, occurring at a rate of greater than 1 percent. All other reactions in the table occur at less than 1 percent.

Adverse Reactions

Pediatrics

In controlled clinical trials involving 159 patients for pediatric angiocardiography, contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography, adverse reactions reported were as follows: pyrexia (1.3%), nausea (0.6%), muscle spasm (0.6%), LV pressure changes (0.6%).

Postmarketing Experience

The following adverse drug reactions have been reported during post-approval use of Optiray. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency.

Endocrine disorders: transient hypothyroidism neonatal

Eye disorders: transient cortical blindness

General disorders and administrative site conditions: injection site reactions (nerve injury, extravasation, pruritus, induration, bruising, rash, erythema)

Immune system disorders: anaphylactoid shock (with multi-organ failure and cardiorespiratory arrest which may be fatal), anaphylactic shock, anaphylactic/hypersensitivity reaction, urticaria

Renal and urinary disorders: acute kidney injury

Skin and subcutaneous tissue disorders: erythema multiforma, acute generalized exanthematous pustulosis (AGEP)

The following adverse reactions are possible with any parenterally administered iodinated contrast medium. Severe life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Most deaths occur during injection or 5 to 10 minutes later; the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. Based upon clinical literature, reported deaths from the administration of conventional iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent).

The reported incidence of adverse reactions to contrast media in patients with a history of allergy is twice that of the general population. Patients with a history of previous reactions to a contrast medium are three times more susceptible than other patients.

However, sensitivity to contrast media does not appear to increase with repeated examinations.

Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions.

Chemotoxic reactions result from the physiochemical properties of the contrast medium, the dose and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category.

Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the dose injected, the speed of injection, the mode of injection and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory.

In addition to the adverse reactions reported for ioversol, the following additional adverse reactions are possible with any water soluble, iodinated contrast agent.

Nervous: convulsions, aphasia, paralysis, visual field losses which are usually transient but may be permanent, coma and death.

Cardiovascular: angioneurotic edema, peripheral edema, vasodilation, thrombosis and rarely thrombophlebitis, disseminated intravascular coagulation and shock.

Skin: maculopapular rash, erythema, conjunctival symptoms, ecchymosis and tissue necrosis.

Respiratory: choking, dyspnea, wheezing which may be an initial manifestation of more severe and infrequent reactions including asthmatic attack, laryngospasm and bronchospasm, apnea and cyanosis. Rarely these allergic-type reactions can progress into anaphylaxis with loss of consciousness, coma, severe cardiovascular disturbances and death.

Endocrine: Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration to adult and pediatric patients, including infants. Some patients were treated for hypothyroidism.

Miscellaneous: hyperthermia, temporary anuria or other nephropathy.

Other reactions may also occur with the use of any contrast agent as a consequence of the procedural hazard; these include hemorrhage or pseudoaneurysms at the puncture site, brachial plexus palsy following axillary artery injections, chest pain, myocardial infarction, and transient changes in hepatorenal chemistry tests. Arterial thrombosis, displacement of arterial plaques, venous thrombosis, dissection of the coronary vessels and transient sinus arrest are rare complications. (Adverse reactions for specific procedures receive comment in the Indications, Usage and Procedural Information section).

Read the entire FDA prescribing information for Optiray Injection (Ioversol Injection)

It is very important that your doctor check the progress of you or your child closely while you are receiving ioversol. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it.

ioversol may cause heart attack, stroke, and blood clotting problems during angiographic procedures. Tell your doctor right away if you have chest pain that may spread to your arms, jaw, back, or neck, trouble breathing, nausea, unusual sweating, faintness, coughing up blood, numbness or weakness in your arm or leg, or on one side of your body, sudden or severe headache, or problems with vision, speech, or walking after receiving ioversol.

Severe kidney problems may occur after receiving ioversol. This is more likely to occur if you receive too much of ioversol. Tell your doctor right away if you or your child have the following symptoms after receiving the medicine: agitation, confusion, decreased urine output, dizziness, headache, muscle twitching, rapid weight gain, or swelling of the face, ankles, or hands.

ioversol may cause a serious type of allergic reaction called anaphylaxis, which can be life-threatening and requires immediate medical attention. Tell your doctor or nurse right away if you or your child has a skin rash, itching, shortness of breath, sweating, swelling of the face, tongue, and throat, or tightness in the chest after you get the injection.

Serious skin reactions can occur with ioversol. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills while you are receiving ioversol.

Check with your doctor right away if you have a fever, chills, cough, sore throat, swollen, painful, or tender lymph glands in the neck, armpit, or groin, or yellow skin or eyes while using ioversol. These could be symptoms of a serious condition called drug reaction with eosinophilia and systemic symptoms (DRESS).

Tell your doctor right away if you or your child have mild, burning pain, feeling of warmth or coldness, peeling of the skin, redness, or swelling at the injection site.

Make sure your doctor knows if you or your child have had an allergic reaction to any dye or medicine given during a test or procedure.

While using ioversol, you may be exposed to radiation. Talk with your doctor if you have concerns about this.

Make sure any doctor or dentist who treats you knows that you are using ioversol. ioversol may affect the results of certain medical tests.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.