HYPAQUE – CYSTO

HYPAQUE — CYSTO- diatrizoate meglumine injection, solution
Amersham Health Inc.

Sterile Aqueous Injection

NOT FOR INTRATHECAL USE

Not For Intravascular Use

For Retrograde Cystourethrography

R_x ONLY

DESCRIPTION

HYPAQUE-CYSTO, brand of diatrizoate meglumine, is a water-soluble radiopaque diagnostic medium. It is a triiodinated benzoic acid derivative. It is constituted as a radiopaque iodinated anion (diatrizoate) and a radiolucent cation (meglumine). It is a colorless, microcrystalline solid which is readily soluble in water.

HYPAQUE-CYSTO is a sterile aqueous solution containing 30 g (w/v) of the meglumine salt of diatrizoic acid per 100 mL aqueous solution. The sterile solution is clear and colorless to pale yellow. The pH is adjusted between 6.5 and 7.7 with hydrochloric acid, or diatrizoic acid, or meglumine. It does not contain an antibacterial preservative. It is relatively thermostable and may be autoclaved. Edetate calcium disodium 1:10,000 has been added as a sequestering stabilizing agent. Each 1 mL contains approximately 141 mg of organically bound iodine.

It has an osmolality of 633 mosm/kg (determined by VPO) and is hypertonic to blood.

The viscosity of the solution is 1.94 cp at 25°C and 1.42 cp at 37°C.

HYPAQUE-CYSTO is a 30 percent solution of 1-Deoxy-l (methylamino)-D-glucitol 3,5-diacetamido-2,4,6-triiodobenzoate (C₁₁ H₉ I₃ N₂ O₄ • C₇ H₁₇ NO₅ ) with a molecular weight of 809.13, and has the following structural formula:

CLINICAL PHARMACOLOGY

Retrograde introduction of HYPAQUE-CYSTO solution provides radiopacity of the contents of the urinary bladder. When used during micturation as a function test, it also opacifies the bladder neck and lower urinary tract. Continuous fluoroscopic and monitoring of urinary bladder contractions will demonstrate cystoureteric reflux and its extent, if present.

HYPAQUE-CYSTO is not absorbed from the urinary tract to any extent (< 2°), therefore, systemic effects are rare. However, pyelorenal intravasation (especially in patients with ureteric reflux) can occur. Therefore, the potential for adverse effects, such as occur with intravascular use, are possible.

At physiologic pH, the water-soluble contrast media are completely dissociated into a radiopaque anion and a solubilizing cation.

EXCRETION

HYPAQUE-CYSTO which gains inadvertent intravascular entry is not metabolized but excreted unchanged in the urine, each diatrizoate molecule remaining “obligated” to its cation moiety.

Diatrizoate solutions may be excreted either through the kidneys or the liver. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be governed by the affinity of the contrast medium for serum albumin. From 0% to 10% of diatrizoate meglumine is bound to serum protein.

Diatrizoate salts are excreted unchanged predominantly through the kidneys by glomerular filtration. The amount excreted during any period of time is determined by the filtered load; ie, the product of plasma contrast media concentration and glomerular filtration rate.

The liver and small intestine provide the major alternate route of excretion for diatrizoate. In patients free of severe renal disease, the fecal recovery is less than 2 percent. In patients with severe renal impairment the excretion of these contrast media through the gallbladder and into the small intestine sharply increases; up to 20 percent in the feces in 48 hours.

Saliva is a minor secretory pathway for injectable radiopaque diagnostic agents. In patients with normal renal function, minimal amounts of contrast media are secreted unchanged.

PREGNANCY AND LACTATION

Diatrizoate meglumine crosses the human placental barrier by simple diffusion and appears to enter fetal tissues passively. No apparent harm to the fetus occurs. Procedures including radiation involve a certain risk related to the exposure of the fetus.

Diatrizoate solutions are excreted unchanged in human milk.

HYPAQUE – CYSTO Indications and Usage

HYPAQUE-CYSTO is indicated for retrograde cystourethrography in adult and pediatric patients.

CONTRAINDICATIONS

HYPAQUE-CYSTO has no absolute contraindication in its recommended use.

WARNINGS

SEVERE ADVERSE EVENTS—INADVERTENT INTRATHECAL USE

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

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 syringe 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 vascular entry of radiopaque media. It is important that a course of action be carefully planned in advance for the treatment of possible serious reactions.

PRECAUTIONS

General

Diagnostic procedures which involve the use of radiopaque diagnostic agents should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for the management of any complication of the procedure, as well as for emergency treatment of severe reactions to the contrast agent itself. Competent personnel and emergency facilities should be available for at least 30 to 60 minutes since severe delayed reactions have occurred (See ADVERSE REACTIONS).

The possibility of a reaction, including serious, life-threatening, fatal, anaphylatic or cardiovascular reactions should always be considered (see ADVERSE REACTIONS). It is of utmost importance that a course of action be carefully planned in advance for immediate treatment of serious reactions, and that adequate and appropriate personnel be readily available in case of any reaction.

ALLERGIC HISTORY

Before injecting a contrast medium, the patient should be questioned for a history of allergy. A positive history does not arbitrarily contraindicate the use of a contrast agent where a diagnostic procedure is considered essential, but caution should be exercised (see ADVERSE REACTIONS).

The possibility of an idiosyncratic reaction in susceptible patients should always be considered (see ADVERSE REACTIONS). The susceptible population includes patients with a history of a previous reaction to a contrast media, patients with a known sensitivity to iodine per se, and patients with known clinical hypersensitivity (ie, bronchial asthma, hay fever, and food allergies).

Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered. Recent reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.

TEST DOSE

The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to the injection of any contrast media, may be more accurate than pretesting in predicting adverse reactions.