FLUISEDAL SANS PROMETHAZINE

Conray is a sterile aqueous solution intended for use as a diagnostic radiopaque medium.

Conray contains 60% w/v iothalamate meglumine, which is 1-deoxy-1-(methylamino)-D-glucitol 5-acetamido-2,4,6 triiodo-N-methylisophthalamate (salt), and has the following structural formula: Each milliliter contains 600 mg of iothalamate meglumine, 0.09 mg edetate calcium disodium as a stabilizer and 0.125 mg of monobasic sodium phosphate as a buffer.

The solution provides 28.2% (282 mg/mL) organically bound iodine.

Conray has an osmolarity of approximately 1000 mOsmol per liter, an osmolality of approximately 1400 mOsmol per kilogram and is, therefore, hypertonic under conditions of use.

The viscosity (cps) is approximately at 25°C and at 37°C. The pH is 6.5 to 7.7.

Conray is a clear solution containing no undissolved solids.

Crystallization does not occur at normal room temperatures.

It is supplied in containers from which the air has been displaced by nitrogen.

Supplemental treatment of bronchial secretion disorders.

Productive coughs, which are a fundamental component of the broncho-pulmonary defence, are to be observed.

The combination of bronchial mucomodifiers with antitussives and/or secretion-destying substances (atropinic) is irrational.

Muscolytics can cause bronchial over-crowding in infants because their ability to drain bronchial mucus is limited due to physiological characteristics of their respiratory tree.

Therefore, they should not be used in infants.

Treatment should be reassessed if symptoms or pathology persist or worsen.

This medication contains sucrose.

It is not recommended for use in patients with fructose intolerance, glucose and galactose malabsorption syndrome or sucras/isomaltase deficiency.

Precautions for use

Caution is recommended in patients with gastroduodenal ulcers.

In patients with diabetes or hypoglucides, take into account 1 tablespoon of coffee and 3.6 g sucrose.

Caution should be exercised.

Following intravascular injection, Conray is rapidly transported through the circulatory system to the kidneys and is excreted unchanged in the urine by glomerular filtration.

The pharmacokinetics of intravascularly administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slower beta phase for drug elimination.

In patients with normal renal function, the alpha and beta half-lives of Conray were approximately and 90 minutes, respectively.

Angiography may be performed following intravascular injection which will permit visualization until significant hemodilution occurs.

Renal accumulation is sufficiently rapid that maximum radiographic density in the calyces and pelves occurs, in most instances, about to 8 minutes after injection.

In patients with impaired renal function, diagnostic opacification frequently is achieved only after prolonged periods.

Injectable iodinated contrast agents are excreted either through the kidneys or through the liver.

These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be related to the affinity of the contrast medium for serum albumin.

Iothalamate salts are poorly bound to serum albumin, and are excreted mainly through the kidneys.

The liver and small intestine provide the major alternate route of excretion.

In patients with severe renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases.

Iothalamate salts cross the placental barrier in humans and are excreted unchanged in human milk.

The biliary system, pancreatic duct or joint spaces may be visualized by the direct injection of contrast medium into the region to be studied.

When used for contrast enhancement in computed tomographic brain scanning, the degree of enhancement is directly related to the amount of iodine administered.

Rapid injection of the entire dose yields peak blood iodine concentrations immediately following the injection, which fall rapidly over the next five to ten minutes.

This can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes an initial sharp fall in plasma concentration.

Equilibration with the extracellular compartments is reached by about ten minutes; thereafter, the fall becomes exponential.

Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached.

The delay in maximum contrast enhancement can range from five to forty minutes, depending on the peak iodine levels achieved and the cell type of the lesion.

This lag suggests that the contrast enhancement of the image is at least in part dependent on the accumulation of iodine within the lesion and outside the blood pool.

In brain scanning, the contrast medium (Conray) does not accumulate in normal brain tissue due to the presence of the “blood brain barrier.” The increase in x-ray absorption in the normal brain is due to the presence of the contrast agent within the blood pool.

A break in the blood brain barrier, such as occurs in malignant tumors of the brain, allows accumulation of contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium.

The image enhancement of non-tumoral lesions, such as arteriovenous malformations and aneurysms, is dependent on the iodine content of the circulating blood pool.

When used for cranial computerized angiotomography, rapid bolus injection and/or infusion combined with rapid CT scanning will provide clear delineation of the cerebral vessels.

In non-neural tissues (during CT of the body), Conray diffuses rapidly from the vascular to the extra-vascular 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, since no barrier exists; contrast enhancement is thus due to the relative differences in extra-vascular diffusion between normal and abnormal tissue, a situation quite different than that in the brain.

The pharmacokinetics of

Conray in normal and abnormal tissues has been shown to be variable.

Enhancement of CT with

Conray may be of benefit in establishing diagnoses of certain lesions in some sites with greater assurance than is possible with unenhanced CT and in supplying additional features of the lesions.

In other cases, the contrast medium may allow visualization of lesions not seen with CT alone or may help to define suspicious lesions seen with unenhanced CT.

Contrast enhancement appears to be greatest within the to 90 seconds after bolus administration of the contrast agent, and after intra-arterial, rather than intravenous, administration.

Therefore, the use of a continuous scanning technique (a series of to 3 second scans beginning at the injection - dynamic CT scanning) may improve enhancement and diagnostic assessment of tumors and other lesions, such as an abscess, occasionally revealing more extensive disease.

A cyst, or similar non-vascularized lesion, may be distinguished from vascularized solid lesions by comparing enhanced and unenhanced scans; non-vascularized lesions show no change in CT number, whereas vascularized lesions would show an increase.

The latter might be benign, malignant or normal, but it is unlikely that it would be a cyst, hematoma, or other non-vascularized lesion.

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

respiratory system) .

Risk of bronchial congestion, particularly in infants and in certain patients unable to perform effective sputum.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the drug is important, allowing for continuous monitoring of the benefit/risk ratio of the drug.

Health professionals report any suspected adverse reactions via the national reporting system: National Agency for the Safety of Drugs and Health Products (ANSM) and the Network of Regional Pharmacovigilance Centres.

Overdosage may occur.

The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular system.

The symptoms may include cyanosis, bradycardia, acidosis, pulmonary hemorrhage, convulsions, coma and cardiac arrest.

Treatment of an overdose is directed toward the support of all vital functions and prompt institution of symptomatic therapy.

Iothalamate salts are dialyzable.

The intravenous

LD 50 value of various concentrations of Iothalamate Meglumine (in grams of iodine/kilogram body weight) varied from 5.7 to 8.9 g/kg in mice and 9.8 to 11.2 g/kg in rats.

LD 50 values decrease as the rate of injection increases.

Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use.

These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.

Special attention must be given to ensure that this drug product is not administered intrathecally.

Ionic iodinated contrast media inhibit blood coagulation, in vitro, more than nonionic contrast media.

Nonetheless, it is prudent to avoid prolonged contact of blood with syringes containing ionic contrast media.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media.

Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events.

Numerous factors, including length of procedure, catheter and syringe material, underlying disease state and concomitant medications may contribute to the development of thromboembolic events.

For these reasons, meticulous angiographic techniques are recommended, including close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length of the procedure.

The use of plastic syringes in place of glass syringes has been reported to decrease, but not eliminate, the likelihood of in vitro clotting.

Serious or fatal reactions have been associated with the administration of iodine-containing radiopaque media.

It is of utmost importance to be completely prepared to treat any contrast medium reaction.

Serious neurologic sequelae, including permanent paralysis, have been reported following cerebral arteriography, selective spinal arteriography and arteriography of vessels supplying the spinal cord.

The intravascular injection of a contrast medium should never be made following the administration of vasopressors since they strongly potentiate neurologic effects.

In patients with subarachnoid hemorrhage, a rare association between contrast administration and clinical deterioration, including convulsions and death, has been reported.

Therefore, administration of intravascular iodinated ionic contrast media in these patients should be undertaken with caution.

A definite risk exists in the use of intravascular contrast agents in patients who are known to have multiple myeloma.

In such instances, anuria has developed, resulting in progressive uremia, renal failure and eventually death.

Although neither the contrast agent nor dehydration has separately proved to be the cause of anuria in myeloma, it has been speculated that the combination of both may be causative factors.

The risk in myelomatous patients is not a contraindication to the procedure; however, partial dehydration in the preparation of these patients for the examination is not recommended, since this may predispose to precipitation of myeloma protein in the renal tubules.

No form of therapy, including dialysis, has been successful in reversing the effect.

Myeloma, which occurs most commonly in persons over 40, should be considered before instituting intravascular administration of contrast agents.

Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution.

If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum.

The blood pressure should be assessed throughout the procedure, and measures for treatment of a hypertensive crisis should be available.

Contrast media have been shown to promote the phenomenon of sickling in individuals who are homozygous for sickle cell disease when the material is injected intravenously or intra-arterially.

Convulsions have occurred in patients with primary or metastatic cerebral lesions following the administration of iodine-containing radiopaque media for the contrast enhancement of CT brain images.

In patients with advanced renal disease, iodinated contrast media should be used with caution, and only when the need for the examination dictates, since excretion of the medium may be impaired.

Patients with combined renal and hepatic disease, those with severe hypertension or congestive heart failure, and recent renal transplant recipients may present an additional risk.

Renal failure has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by an intravascular iodinated radiopaque agent, and also in patients with occult renal disease, notably diabetics and hypertensives.

In these classes of patients, there should be no fluid restriction and every attempt made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most important factor influencing further renal impairment.

Acute renal failure has been reported in diabetic patients with diabetic nephropathy and in susceptible non-diabetic patients (often elderly with pre-existing renal disease) following the administration of iodinated contrast agents.

Therefore, careful consideration of the potential risks should be given before performing this radiographic procedure in these patients.

Caution should be exercised in performing contrast medium studies in patients with endotoxemia and/or those with elevated body temperatures.

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

Iodine containing contrast agents may alter the results of thyroid function tests which depend on iodine estimation, e.g. PBI and radioactive iodine uptake studies.

Such tests, if indicated, should be performed prior to the administration of this preparation.

Patients to 3 Years of Age: Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast media (ICM) in pediatric patients to 3 years of age.

Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after ICM exposure.

Pediatric patients with congenital cardiac conditions may be at the greatest risk given that they often require high doses of contrast during invasive cardiac procedures.

An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy.

After exposure to

ICM, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates.

Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration.

These reactions include

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS).

Reaction severity may increase and time to onset may decrease with repeat administration of contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions.

Avoid administering

Conray to patients with a history of a severe cutaneous adverse reaction to Conray.

Refer to

PRECAUTIONS, General, concerning hypersensitivity.

Conray should not be used for myelography.

Arthrography should not be performed if infection is present in or near the joint.

Percutaneous transhepatic cholangiography is contraindicated in patients with coagulation defects and prolonged prothrombin times.

Endoscopic retrograde cholangiopancreatography is contraindicated during an acute attack of pancreatitis or during severe clinically evident cholangitis and in patients in whom endoscopy is prohibited.

It is advisable that

Conray be at or close to body temperature when injected.

The patient should be instructed to omit the meal that precedes the examination.

Appropriate premedication, which may include a barbiturate, tranquilizer or analgesic drug, may be administered prior to the examination.

A preliminary film is recommended to check the position of the patient and the x-ray exposure factors.

If a minor reaction occurs during administration, the injection should be slowed or stopped until the reaction has subsided.

If a major reaction occurs, the injection should be discontinued immediately.

Under no circumstances should either corticosteroids or antihistamines be mixed in the same syringe with the contrast medium because of a potential for chemical incompatibility.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Conray ® Glass Vials/Bottles NDC Number 25x30 mL vials 0019-0953-23 25x50 mL vials 0019-0953-05 12x100 mL bottles 0019-0953-10 12x150 mL bottles 0019-0953-50 Storage Store below 30°C (86°F).

Exposing this product to very cold temperatures may result in crystallization of the salt.

If this occurs, the container should be brought to room temperature.

Shake vigorously to assure complete dissolution of any crystals.

The speed of dissolution may be increased by heating with circulating warm air.

Before use, examine the product to assure that all solids are redissolved, and that the container and closure have not been damaged.

This preparation is sensitive to light and must be protected from strong daylight or direct exposure to the sun.

As with all contrast media, glass containers should be inspected prior to use to ensure that breakage or other damage has not occurred during shipping and handling.

All containers should be inspected for closure integrity.

Damaged containers should not be used.

Reference 1 Young, S. W., Turner, R.J., Castellino, R. A.: “A strategy for the contrast enhancement of malignant tumors using dynamic computed tomography and intravascular pharmacokinetics,” Radiology, 137:137-147, October 1980.

Store below 30°C (86°F).

Exposing this product to very cold temperatures may result in crystallization of the salt.

If this occurs, the container should be brought to room temperature.

Shake vigorously to assure complete dissolution of any crystals.

The speed of dissolution may be increased by heating with circulating warm air.

Before use, examine the product to assure that all solids are redissolved, and that the container and closure have not been damaged.

This preparation is sensitive to light and must be protected from strong daylight or direct exposure to the sun.

As with all contrast media, glass containers should be inspected prior to use to ensure that breakage or other damage has not occurred during shipping and handling.

All containers should be inspected for closure integrity.

Damaged containers should not be used.

Reference 1 Young, S. W., Turner, R.J., Castellino, R. A.: “A strategy for the contrast enhancement of malignant tumors using dynamic computed tomography and intravascular pharmacokinetics,” Radiology, 137:137-147, October 1980.

Reproduction studies have been performed in mice, rats, and rabbits at doses up to 6.6 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Conray.

There are, however, no adequate and well controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Iothalamate salts are excreted unchanged in human milk.

Because of the potential for adverse effects in nursing infants, bottle feedings should be substituted for breast feedings for 24 hours following the administration of this drug. (Precautions for specific procedures receive comment under that procedure).

Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates; some patients were treated for hypothyroidism.

After exposure to iodinated contrast media, individualize thyroid function monitoring in pediatric patients to 3 years of age based on underlying risk factors, especially in term and preterm neonates See WARNINGS and ADVERSE REACTIONS.