INDICATIONS FOR CHOLECYSTOGRAPHY WITH ORABILEX Orabilex is the preferred medium in every instance where cholecystography or oral cholangiography is indicated. It may be used advantageously in cases with vague or nonspecific abdominal symptoms, such as bowel disorders, pain, epigastric distress, vomiting, food intolerance, weight loss, flatulence, and cardiospasm. It is often essential for the differential diagnosis of precordial pain, renal colic, peptic ulcer, cholecystitis and cholelithiasis. It is an effective agent for study of gallbladder physiology and in preoperative workup. When indicated in a particular patient, Orabilex has been used without untoward effects in the presence of jaundice or fever. DOSAGE AND ADMINISTRATION The recommended dose of Orabilex is uniform for the average adult patient, regardless of weight or age. The patient is instructed to take the full dose of 6 capsules approximately 12 to 14 hours before the examination. If less dense contrast is desired, particularly in the slight patient, 3 grams (four capsules) will probably suffice. Should non visualization occur, one additional 4.5 gram dose of Orabilex may be given the patient for reexamination the following day. Should nonvisualization persist, additional dosage is without value since the high absorption index of Orabilex will have provided sufficient iodine blood level to grant adequate visualization. Capsules should not be removed from the envelope until use. The 6 capsules 0.75 grams each should be swallowed one at a time with liberal amounts of water at intervals of 2 to 5 minutes (there is evidence that distilled water may promote a rapid passage into the duodenum). Only water may be swallowed thereafter. There is no variation from the usual manner of patient preparation; on the day prior to examination, some physicians prefer a lunch high in fat content to empty the gallbladder and thus facilitate its later filling with the bile containing Orabilex. A careful history of the patient's medications should be obtained to preclude an extraneous effect on biliary physiology. INDICATIONS FOR CHOLECYSTOGRAPHY WITH ORABILEX Orabilex is the preferred medium in every instance where cholecystography or oral cholangiography is indicated. It may be used advantageously in cases with vague or nonspecific abdominal symptoms, such as bowel disorders, pain, epigastric distress, vomiting, food intolerance, weight loss, flatulence, and cardiospasm. It is often essential for the differential diagnosis of precordial pain, renal colic, peptic ulcer, cholecystitis, and cholelithiasis. It is an effective agent for study of gallbladder physiology and in preoperative workup. DOSAGE AND ADMINISTRATION The recommended dose of Orabilex is uniform for the average adult patient, regardless of weight or age. The patient is instructed to take the full dose of 6 capsules approximately 12 to 14 hours before the examination. In the slight patient (up to 120 pounds) or if less dense contrast is desired, 3 grams (four capsules) will suffice. Should nonvisualization occur, only one additional 4.5 gram dose (six capsules) or 3 gram dose (four capsules) of Orabilex may be given the patient for reexamination the following day. Should nonvisualization persist, further repeat doses are without value and may be dangerous (see precaution statement on p. 9). However, should the physician believe that if further attempts to obtain gallbladder visualization are indicated utilizing other cholescystographic agents, such procedures should be deferred for 1 week to permit complete excretion of the Orabilex initially employed. In the presence of an impaired hepato-biliary clearance the normal excretion ratios hepato-biliary vs. renal-will no longer prevail and virtually all media employed will be excreted by the renal system. Overloading may be dangerous and even fatal. Capsules should not be removed from the envelope until use. The 6 capsules 0.75 grams each should be swallowed one at a time with liberal amounts of water at intervals of 2 to 5 minutes (there is evidence that distilled water may promote a rapid passage into the duodenum). Only water may be swallowed thereafter. There is no variation from the usual manner of patient preparation; on the day prior to ex Orabilex is not recommended for use in the jaundiced patient exhibiting a serum bilirubin of more than 5 mg. percent or a B.S.P. retention greater than 35 percent, signifying advanced parenchymal liver disease or biliary obstruction. In these situations biliary tract visualization cannot be anticipated. Similarly, gastrointestinal disorders which would prevent absorption renders worthless an oral procedure. In the presence of iodine sensitivity, either allergic or acquired, the employment of Orabilex or other iodine bearing contrast media should be approached with caution. Assessment should be made of the information to be gained in relation to the possible hazard. Although occurring somewhat less frequently than with other oral cholecystographic agents, urticariausually mild, but occasionally severe has been reported following the administration of Orabilex. PRECAUTIONS Although a direct cause and effect relationship has not been established, it has been reported that excessive dosage of Orabilex and other cholecystographic media may have been associated with the development of renal insufficiency. Following excessive dosage transient oliguria and elevated B.U.N. values have been observed, as well as more severe acute renal failure (tubular necrosis) resulting in death. The symptomatogy of these patients was marked by dehydration, electrolyte imbalance; e.g., hypopotassemia and advanced parenchymal hepatic derangement. Marked hyperbilirubinemia was frequently present. The mechanism by which oral ingestion of cholecystographic media may contribute to renal embarrassment is not known. Extensive experiments in laboratory animals have failed to produce either functional or histologic evidence of nephrotoxicity following feedings or Orabilex up to 60 times the human dose level. Renal tubular necrosis resulting from dehydration often associated with electrolyte imbalance; e.g., hypopotassemia, is a recognized clinical entity. Concomitant renal failure in connection with severe liver disease is well known to the pathologist who has frequently observed the duality of renal and hepatic abnormality in the post mortem study of the oliguric or anuric jaundiced patient. While substantial clinical evidence is lacking, the possibility of a subclinical hypotensive episode induced by multiple dosage must be considered. Recently the blood pressure lowering effect of idopate calcium, another chemically related cholecystographic medium, was reported. Against a background of dehydration, electrolyte imbalance, and severe liver disease, a marked, though transient, drop in blood pressure might produce a crucial reduction in renal blood flow resulting in ischemic tubular necrosis. Orabilex is not recommended for use in the jaundiced patient exhibiting a serum bilirubin of more than 5 mg. percent or a B.S.P. retention greater than 35 percent, signifying advanced parenchymal liver disease or biliary obstruction. In these situations biliary tract visualization cannot be anticipated. Similarly, gastrointestinal disorders which would prevent absorption renders worthless an oral procedure. In the presence of iodine sensitivity, either allergic or acquired, the employ ment of Orabilex or other iodine bearing contrast media should be approached with caution. Assessment should be made of the information to be gained in relation to the possible hazard. Although occurring somewhat less frequently than with other oral cholecystographic agents, urticariausually mild, but occasionally severehas been reported following the administration of Orabilex. ADDITIONS TO BIBLIOGRAPHY 54. Rene, R. M. and Mellinkoff, S. M.: Renal Insufficiency after Oral Administration of a Double Dose of a Cholecystographic Medium. New Eng. J. Med., 261, 289-91 (1959). 55. Blythe, W. B. and Woods, J. W.: Acute Renal Insufficiency after Ingestion of a Gallbladder Dye. New Eng. J. Med., 264, 1045-46 (1962). 56. Gottlieb, A., Spiera, H. and Gordis, E. Fatal Renal Insufficiency After Oral Cholecystography. New Eng. J. Med., 267 (8), 389-92 (1962). EXHIBIT 40-NOTICE OF HEARING IN THE MATTER OF ORABILEX CAPSULES UNITED STATES OF AMERICA DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE FDC-D-72 IN THE MATTER OF "ORABILEX CAPSULES," E. FOUGERA & Co., INC., HICKSVILLE, N.Y. NOTICE OF HEARING Notice is hereby given to the applicant E. Fougera & Co., Inc., Hicksville, N.Y., that the Commissioner of Food and Drugs proposes to issue an order withdrawing approval of New Drug Application No. 11-584 and all amendments and effective supplements thereto held by E. Fougera & Co., Inc. for the drug "Orabilex Capsules," and refusing to approve the supplement thereto filed on January 4, 1963, on the grounds that clinical experience shows that such drug is unsafe for use under the conditions of use upon the basis of which the application was approved; and that new evidence of clinical experience not contained in such application or not available until after such application was approved, evaluated together with the evidence available when the application was approved, shows that the drug is not shown to be safe for use under the conditions for use upon the basis for which the application was approved in that: (1) Clinical experience shows that the use of the drug, and particularly the administration of a second dose, has been associated with the development of oliguriarenal tubular necrosis, and death. The labeling for the drug fails to disclose these facts and specifically recommends a repeat dose in the event of non-visualization. (2) Clinical experience shows that the drug is contraindicated in patients with a history of renal disease or in the presence of any symptoms or signs suggestive of renal disease and dysfunction. The labeling for the drug fails to reveal these contraindications. (3) Clinical experience shows that renal function tests prior to the use of the drug are necessary for the safety of patients. The labeling fails to disclose this fact. In accordance with the provisions of Section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) and the regulations appearing in Title 21, Code of Federal Regulations, Part 130, the Commissioner will give the applicant an opportunity for a hearing commencing at 10 a.m., March 11, 1963, in Room 5131, North Building, Department of Health, Education, and Welfare, 3rd & Independence Avenue, SW., Washington 25, D.C., at which time the applicant may produce evidence and arguments to show why approval of New Drug Application No. 11-584 should not be withdrawn. The applicant is required to make a written appearance on or before the fifteenth day after receipt of this notice by filing with the Hearing Clerk of the Department of Health, Education, and Welfare, Office of the General Counsel, Food and Drug Division, Room 5440, North Building of the Department of Health, Education, and Welfare, 3rd and Independence Avenue, SW., Washington, D.C., a statement electing whether: (1) To avail itself of the opportunity for a hearing at the time and place specified herein; or (2) Not to avail itself of the opportunity for a hearing. If the applicant elects not to avail itself of the opportunity for a hearing, the Commissioner, without further notice, will enter a final order withdrawing the approval of the New Drug Application. Failure of the applicant to file such a written appearance of election, on or before the fifteenth day after receipt of this Notice of Hearing, will be construed as an election by the applicant not to avail itself of the opportunity for a hearing. The hearing contemplated by this Notice of Hearing will not be a public hearing unless the applicant requesting the hearing specifies in its written appearance that it desires a public hearing, in which event the hearing will be public. If the applicant elects to avail itself of the opportunity for a hearing and files a timely written appearance, it may present such evidence and argument at the hearing as are relevant and material to the above specified ground on which it is proposed to withdraw the approval of the application. The Food and Drug Administration of the Department of Health, Education, and Welfare will also be permitted to produce evidence and argument relevant and material to such grounds. Done at Washington, D.C., this 28th day of January, 1963. GEO. P. LARRICK, Commissioner of Food and Drugs. Mr. RANKIN. The firm then agreed to issue a warning letter to all general practitioners, internists, gastroenterologists, surgeons, radiologists, and pediatricians in the United States, including Puerto Rico, and to make the labeling changes as proposed by FDA on December 26, 1962. Mailing of the warning letter to 136,266 physicians was completed by March 29, 1963, and the revised labeling was also in use by then. I submit for the record a copy of the drug warning letter dated March 1963 and a copy of the revised labeling which was adopted that same month. (The documents referred to follow as exhibits 41 and 42:) EXHIBIT 41-Warning Letter FROM E. FOUGERA & Co., INC., to Doctors, March 1963, RE DOSAGE PRECAUTIONS AND CONTRAINDICATIONS IN CHOLECYSTOGRAPHY WITH ORABILEX Recent reports have described the occurrence of certain severe side effects following the administration of more than 4.5 grams of Orabilex (bunamiodyl sodium). Dosage recommendations and precautions have been revised as follows: 1. Repeat doses (that is, more than 4.5 grams) of Orabilex may be as sociated with the development of oliguria, renal tubular necrosis, and death. Use of other cholecystographic agents within 1 week after Orabilex ingestion may be dangerous and even fatal. 2. Orabilex is contraindicated in patients with a history of renal disease, or in the presence of any symptoms or signs suggestive of renal disease or dysfunction. Evaluation of renal function should be performed preparatory to the use of Orabilex. A revised package brochure is enclosed for your review. The mechanism by which multiple doses of cholecystographic media may contribute to renal embarrassment is not known. Continuing clinical and laboratory investigations bearing on this problem are in progress. We would appreciate the submission of reports of side effects or adverse reactions following the use of Orabilex or other cholecystographic media at your earliest convenience. Sincerely yours, F. J. SANEN, M.D., Medical Director. |