001552 Iocetamic Acid

DESCRIPTION

Iocetamic Acid is a diagnostic cholecystographic radiopaque agent intended for oral administration for the radiographic visualization of the gallbladder and biliary tract. Iocetamic acid is N-acetyl-N-(3-amino-2,4,6-triiodophenyl)-2-methyl-B-alanine and has the following empirical formulae and molecular weight.

Empirical Formula: C12H13I3N2O3 M.W. = 613.96. (CAS-16034-77-8)

It is an off-white, odorless solid which contains 62 percent organically bound iodine. Iocetamic acid is a mixture of two racemates which differ slightly in physical properties. These racemic mixtures are essentially water insoluble.

Each bisected, off-white tablet contains iocetamic acid, 750 mg.

CLINICAL PHARMACOLOGY

The most important characteristic of contrast media is the iodine content. The high atomic weight of iodine contributes sufficient x-radiation attenuation to impart radiographic contrast with surrounding tissue.

Diagnostic enteral radiopaque agents have few known pharmacological effects. Iocetamic acid (Iocetamic Acid) is moderately uricosuric and may have iodine-mediated thyrotropic effects (See PRECAUTIONS.)

Pharmacokinetics

Iocetamic Acid is rapidly absorbed from the gastrointestinal tract by passive diffusion across the gastrointestinal mucosa. The ingestion of food in and of itself will not effect the absorption and subsequent diagnostic quality of cholecystographic examinations with Iocetamic Acid; however, the fat content of food ingested within 12-15 hours of the examination can have an effect. Optimum contrast density and highest diagnostic yield are achieved when low or fat-free diets are prescribed for the meal preceding the ingestion of Iocetamic Acid.

Once absorbed, Iocetamic Acid enters the portal venous system; is transported to the liver and bound to plasma albumin. In the liver, Iocetamic Acid is conjugated with glucuronic acid and actively excreted into the bile as radiopaque glucuronide which is concentrated in the functioning gallbladder. The time of peak opacification of the gallbladder is approximately 10-15 hours following ingestion.

Iocetamic Acid is eliminated from the body by two pathways: excretion into the duodenum via the common bile duct and renal excretion. The ratio of renal to biliary elimination is approximately 60:40; however, this is variable and dependent upon the extent of gastrointestinal absorption and pre-existing renal and/or hepatic disease. The majority of the administered dose is eliminated from the body within 48 hours. However, effect on thyroid function may persist for longer periods.

Oral cholecystographic agents are excreted in breast milk (See PRECAUTIONS, Nursing Mothers.)

Oral cholecystographic agents may produce changes in certain thyroid tests, i.e., PBI, attributable to changes in circulating iodine. Therefore, these tests may not accurately reflect thyroid status following cholecystography. However, thyroid function as measured by in vitro radiometric T3 and T4 uptake is not influenced by oral cholecystography with Iocetamic Acid and may be used to accurately assess thyroid status in the immediate post- cholecystography period.

Oral cholecystographic agents tend to elevate BSP (sulfobromophthalein) determinations. (See PRECAUTIONS, Drug/Laboratory Test Interactions.

INDICATIONS AND USAGE

Iocetamic Acid is indicated for use in oral cholecystography.

CONTRAINDICATIONS

The administration of Iocetamic Acid is contraindicated in patients with advanced hepatorenal disease, severe renal impairment, malabsorptive gastrointestinal disorders and in patients known to be allergic to iocetamic acid.

PRECAUTIONS

General

Severe, advanced liver disease may interfere with the metabolism of oral cholecystographic agents; therefore, a greater amount of unchanged drug will be diverted for renal excretion, increasing the load on the kidneys. Acute renal insufficiency has followed the use of oral cholecystographic agents. Most reported cases were attributed to the use of large doses or multiple agents, to pre- existing dehydration, or hepatic disease.

Renal function, especially in patients with liver disease, should be assessed before cholecystography; urinary output, serum BUN and creatinine, and hepatic function should be observed for a few days after the procedure. Patients with pre-existing renal disease should not receive large doses of cholecystographic agents. All patients, especially those with pre-existing renal or hepatic diseases should be adequately hydrated prior to oral cholecystography. Liberal fluid intake should be encouraged after ingesting the diagnostic agents.

Because oral cholecystographic agents are moderately uricosuric, patients with hyperuricemia may be susceptible to the development of uric acid stones and decreased renal function. Therefore, patients with hyperuricemia receiving oral cholecystographic agents should be well hydrated to maintain adequate urinary output and the possibility of uric acid crystal formation should be kept in mind.

Various factors may result in non-visualization of the hepatic and biliary ducts and the gallbladder. These include gastrointestinal disorders which interfere with absorption, liver disorders which interfere with glucuronide conjugation and excretion, and obstruction of the hepatic or cystic duct which blocks the flow of the contrast medium to the gallbladder.

Cases of hyperthyroidism have been reported with the use of oral contrast media. Some of these patients reportedly had multinodular goiters which may have been responsible for the increased hormone synthesis in response to excess iodine. Administration of an intravascular iodinated radiopaque diagnostic agent to a hyperthyroid patient precipitated thyroid storm. A similar situation could follow administration of oral preparations of iodides.

Therefore, caution should be exercised when administering cholecystographic agents to hyperthyroid and euthyroid goiterous patients.

Information for the Patient

Patients receiving oral cholecystographic agents should be given the following information and instructions:

1) This drug has been prescribed to perform an x-ray study of the gallbladder. All the medication must be taken with water following a fat-free dinner the evening prior to the test. Thereafter, nothing except water should be taken until the test has been completed.

2) Patients should be questioned regarding medicines, including non-prescription drugs, currently being used. Allergies to iodine, any foods or x-ray dyes should also be disclosed.

3) Patients should inform the physician of any liver or kidney disease or pregnancy before taking this drug.

4) Patients should consult the physician if, at some future date, any thyroid tests are planned. The iodine in this agent may interfere with later thyroid tests.

5) This drug may cause abdominal cramping, nausea, vomiting, diarrhea, skin rashes, itching, heartburn, dizziness or headache in some patients, but most reactions are mild and pass quickly.

Drug/Laboratory Test Interactions

Thyroid Function Tests:

Thyroid function tests, if indicated, generally should be performed prior to the administration of any iodinated agent. However, thyroid function can be evaluated after use of these agents by using T3 resin uptake or T4 free thyroxine assay.

Liver Function Tests:

Urine Tests:

Oral cholecystography may lower blood levels and raise urinary excretion of uric acid for a few days.

Pregnancy Category B

Teratology studies with iocetamic acid have been performed in rats and rabbits, and there was no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, these agents should be used during pregnancy only if clearly needed.

Nursing Mothers

Iopanoic acid is excreted in breast milk. Oral administration of 1.98-3.96 g of iodine as iopanoic acid resulted in total iodine excretion of 6.72-29.23 mg in breast milk. Presumably, all of the oral cholecystographic agents act in the same way.

Caution should be exercised when diagnostic enteral radiopaque agents are administered to a nursing mother.

Pediatric Use

The safety and effectiveness of the oral cholecystographic agents in children under 12 years have not been established.

DRUG INTERACTIONS

1) The administration of both oral cholecystographic agents and intravenous iodipamide meglumine within 24 hours is not recommended. The prior administration of an oral cholecystographic agent seems to block the hepatic excretion of the intravenously administered iodipamide meglumine.

2) Renal toxicity has been reported in a few patients with liver dysfunction who were given oral cholecystographic agents followed by intravascular angiourographic radiopaque agents should therefore be postponed in any patient with a known or suspected hepatic or biliary disorder who has recently taken a cholecystographic contrast agent.

ADVERSE REACTIONS

Most adverse reactions observed following the administration of Cholebrine were mild and transient. The following adverse reactions were observed during clinical trials of 677 patients and are grouped by oral system and are listed in order of decreasing frequency.

Disturbances in hepatic, renal or cardiovascular function have been reported with cholecystographic media, usually in patients with pre-existing disease. See PRECAUTIONS, General.

OVERDOSAGE

A few cases of large overdoses of iopanoic acid have been reported, involving ingestion of 30, 36 and 75 g of the drug. Mild, transient renal dysfunction was reported. All patients experienced extreme nausea, diarrhea and vomiting, but survived without permanent adverse effects.

Based upon the clinical pharmacology of iopanoic acid, the following treatment measures are recommended. While specific recommendations for Cholebrine are unavailable, the following measures may be beneficial.

1) Lavage the stomach and administer enemas to remove remaining potentially absorbable contrast media.

2) Force fluids to avoid concentration and possible precipitation or crystallization of the contrast material or uric acid in the kidneys.

3) Alkalinize the urine to increase the solubility of the drug-glucuronide complex and of uric acid.

4) Administer cholestyramine to chelate and reduce absorption of the drug.

5) Monitor blood pressure.

The oral LD50 for Cholebrine in mice is 5.5 g/kg and in rats is 8.2 g/kg.

DOSAGE AND ADMINISTRATION

A single oral dose of 3.0 g (4 tablets) or 4.5 g (6 tablets) administered 10-15 hours prior to cholecystography is recommended for adults. The selection of the proper dosage within this range is largely dependent on the patient's condition and the desired density of the radiographs. In patients with normal liver function and an absence of gastrointestinal symptoms which might prevent or delay the absorption of the entire dose, 3.0 g will provide adequate radiographic visualization. In the more difficult patient (and in order to reduce the incidence of repeat examination), doses of 4.5 g should be employed.

Cholestasis is a common cause of non-visualization. In patients who have been on fat-free diets, it is recommended that they eat a diet containing some fat for a day or so preceding oral cholecystographic examination. However, the evening meal immediately preceding the ingestion of Cholebrine should be fat- free. Following this meal, but not later than 9:00 p.m., the patient should swallow 4 to 6 tablets (3.0 or 4.5 g) individually with water. The patient should have nothing further by mouth except water in moderate amounts until after the cholecystographic examination. In the event the patient requires a repeat examination, maintenance of the fat-free diet is recommended.

If non-visualization occurs or other factors preclude the presentation of a diagnostic study following the initial dose of Cholebrine, a repeat examination utilizing the same 3.0 or 4.5 g dose may be performed on the following day. Larger doses in repeat studies are unnecessary and NOT RECOMMENDED.

NOTE: The use of laxatives in the preparation of the bowel for other radiographic examinations should be carefully considered since they may seriously influence the absorption of the oral cholecystographic medium.

Cholecystagogues may be administered following a successful initial or repeat study to determine the contractibility of the gallbladder. Additional exposures should be made approximately 15 minutes following the administration of the cholecystagogue.

Non-Visualization

Non-visualization following routine oral cholecystography with Cholebrine implies a loss of gallbladder function providing there was proper absorption, a normally functioning liver, an absence of severe gastrointestinal symptoms (i.e., diarrhea, vomiting) and no biliary duct obstruction which might inhibit absorption or excretion. When adequate visualization does not occur following the initial dose, a repeat study may be performed at the recommended dose. Doses larger than those recommended should not be employed. Gallbladder disease may be inferred if non-visualization occurs following repeat examination.

Storage: