that the final printed labeling was submitted. For some reason, neither form of this statement was included in the final printed version of the labeling. I have a copy of the memo transmitting this statement in two forms to a vice-president of the company, which I will submit for the record, and I would like to show it to you first and then ask you if you feel that this might have had any effect on the actions which you took with respect to that drug from 1956 on? Mr. LARRICK. Mr. Gray, did we ever see this, do you know! Mr. GRAY. You never saw this. It was drafted for inclusion in the physician's index card in October 1956, during the time when the company was going from the draft labeling approved by FDA to the final printed version. What was submitted to you was the version you inserted in the record yesterday as exhibit 3-B, which simply contained some different language, deleting jaundice from the list of side effects which had not been reported. Mr. LARRICK. Do you want Dr. Smith to give an opinion on this now, or would you prefer he give it later after studying it? Mr. GRAY. I think if he reads the memo and the two statements on hepatitis, which are very short, on pages 3 and 3a, he will be able to answer at this point, Mr. Larrick. I think it might be helpful if you read those two statements into the record, Dr. Smith, pages 3 and 3a, if you have had time to read them. Dr. SMITH. I don't see any page 3a here. Mr. GRAY. I am sorry, I believe I gave you the wrong paper. Mr. FOUNTAIN. While he is looking, I think the record should show that none of the questions being propounded by the Chair and other members of the committee and by the staff are designed or intended or should be construed as an expression of opinion by the members of the committee or the staff concerning whether a drug ought to be withdrawn from the market or whether it ought to continue. We are simply trying to develop the facts as to just what has transpired, what the present picture is, and what is anticipated in the future. Mr. Larrick, it appears that the document Mr. Gray wanted to bring to your attention, and upon which his question was asked, has been misplaced. I also have some related questions based upon other documents. So we will submit these documents to you, along with the questions which I wanted to ask concerning them and let you give us your replies for the record. Mr. LARRICK. That we will be very glad to do, Mr. Chairman. (The questions and answers and other relevant documents follow:) In examining the company's files, the subcommittee staff found that drafts of a positive warning statement concerning the possibility that Flexin might cause hepatitis were drawn up by one of the company's consultants and by its medical director for inclusion in the revised labeling for this supplemental application, but for some reason neither form of this statement was included in the final printed version of the labeling. A copy of the proposed labeling and covering memo from the medical director to the president of the company will be inserted in the record at this point. EXHIBIT 27—Memorandum FROM JAMES M. SHAFFER, M.D., DIRECTOR, DIVISION OF CLINICAL INVESTIGATION, MCNEIL LABORATORIES, INC., TO R. L. MCNEIL, JB, OCTOBER 18, 1956, RE REVISED LABELING FOR FLEXIN DIVISION OF CLINICAL INVESTIGATION, Te: Mr. R. L. McNeil, Jr. Subject: Revised Flexin* Index Card Copy. As indicated in our telephone conversation today, a new problem must be considered in relation to this index card revision. On page 3, the last paragraph is the statement concerning liver damage as suggested by Doctor Dripps. On page 3a is an alternate statement pertaining to the same subject. Other changes are of a minor nature and involve primarily the advantages as listed on page 2. JAMES M. SHAFFER, M.D., Director. Attached: Index Card Copy. FLEXIN INDEX CARD REVISED 10/18/56 FLEXIN* (ZOXAZOLAMINE, MCNEIL) Skeletal Muscle Relaxant (Lissive Agent) DESCRIPTION Flexin is an entirely new, orally effective, centrally acting skeletal muscle relaxant. Flexin is not a mephenesin derivative or a meprobamate and it is not related to curare. Flexin is 2-amino-5-chlorobenzoxazole and has the following chemical structure. ACTION The major action of Flexin is a selective inhibition of polysynaptic pathways in the central nervous system (1, 2, 3). This action may be described as “lissive”—a term indicating relief of skeletal muscle spasm without marked interference with normal muscle function. The site of action is central-in the spinal cord and subcortical centers-in contrast to the peripheral site of action of curare. The onset of action with Flexin is usually within 30 to 60 minutes after a dose and the effect persists for about six hours. The clinical effect is a reduction of skeletal muscle spasm or spasticity without paralysis or significant weakness. (NOTE-With Engestic® Coated Tablets Flexin the onset of action is delayed for about four hours.) INDICATIONS Flexin is useful in any disorder where Skeletal Muscle Spasm or Spasticity is an important symptom. Flexin has proved useful in the following conditions: Musculoskeletal Disorders (4,8): Low back disorders. Strains, sprains, and contusions. Rheumatism, myositis, and fibrositis. Spondylitis. Arthritis (chronic, non-inflammatory type). Torticollis, cervical root syndrome, bursitis. Neurological Diseases (5, 6, 7, 8,) : Cerebral palsy. Multiple sclerosis. Spinal spasticity disorders. Cerebrovascular accidents. Parkinson's disease (as an adjunct to other therapy). The more severe types of neurological spasticity states do not respond as well to Flexin as do patients with muscoloskeletal disorders such as low back pain, fibrositis, sprains, strains, and contusions, where a high percentage may be expected to benefit by relief of muscle spasm discomfort (8). Trademark. 1. More effective than any other orally administered skeletal muscle relaxant. 2. Useful duration of action of about six hours. 3. The incidence of side effects is low. The majority of these side effects are of a minor nature. DOSAGE AND ADMINISTRATION Adults: Start with 1 tablet (250 mg.) three or four times a day during meals or always with food. When necessary, the dosage may be gradually increased to 2 or 3 tablets (500 mg. to 750 mg.) three or four times a day. Dosage must be individualized to achieve maximum benefit. Children: Start with 1 table (250 mg.) two to four times a day. For administration to infants and young children, uncoated Flexin tablets should be crushed and mixed with food or a suitable vehicle such as honey or molasses. Flexin tablets should not be chewed as this will produce a burning sensation in the mouth and throat. NOTES.-Engestic Coated Tablets Flexin, 250 mg., are available for patients who exhibit symptoms of gastric upset with the regular, uncoated Flexin tablets. Flexin B C tablets have a four hour delay in onset of action. Flexin EC tablets therefore are also useful for administration at bedtime to patients with pain and discomfort due to skeletal muscle spasm during the night. SIDE EFFECTS Such minor side effects as gastric upset, light-headedness, or dizziness can usually be avoided by administration of Flexin during meals or with food. Engestic Coated Tablets Flexin are available for patients who exhibit gastric symptoms with the regular uncoated tablet. As with any potent drug, idiosynocrasies or hypersensitivity reactions have been reported. The administration of Flexin should be stopped if a skin rash is noted or if severe gastric intolerance develops. Liver damage, with or without jaundice, has been suggested (reported ?) in approximately 15 patients. Data are inconclusive on a cause-effect relationship. The incidence of hepatic involvement appears low; i.e., 12 cases from a patient population of approximately 500.000. Nevertheless this possibility must be kept in mind by the physician prescribing Flexin. (Substitute for last paragraph on page 3): "Liver damage, possibly related to administration of Flexin, has been reported in approximately 15 patients during nine months of general clinical use of this new drug. In most of these patients a definite cause and effect relationship is difficult to establish. The incidence of hepatic involvement appears to be low (probably less than .05 of one per cent). Nevertheless, this possibility should be kept in mind by the physician prescribing Flexin." Unlike many potent drugs, Flexin does not appear to have an undesirable effect on bone marrow. Agranulocytosis, anemia or leukopenia has not been associated with the administration of Flexin. CONTRAINDICATIONS There are no specific contraindications to the use of Flexin. As with any potent drug, Flexin should be used with caution in patients known to have kidney or liver disease. HOW SUPPLIED Tablets, 250 mg. (scored, colored yellow, imprinted "McNeil")-bottles of 50. Tablets, Engestic Coated, 250 mg. (colored pink, imprinted "McNeil")-bottles of 36. BIBLIOGRAPHY 1. Kamijo, K. and Koelle, G. B.: Proc. Soc. Exper. Biol. & Med. 88:565-568 (April) 1955. 2. Funderburk, W. H. and Woodcock, R. T.: Federation Proc. 14:341 (March) 1955. 3. Marsh, D. F.: Federation Proc. 14:366–367 (March) 1955. 4. Smith, R. T., Kron. K. M., Peak, W. P. and Hermann, I. F.: J.A.M.A. 160: 745-748 (March 3) 1956. 5. Abrahamsen, E. H. and Baird, H. W. III: J.A.M.A. 160:749-751 (March 3) 1956. 37-272-64-pt. 2-20 6. Amols, W.: J.A.M.A. 160:742-745 (March 3) 1956. 7. Rodriquez-Gomez, M., Valdes-Rodriguez, A. and Drew, A. L: JAMA. 160: 752-754 (March 3) 1956. 8. Council on Pharmacy and Chemistry, American Medical Association: New and Nonofficial Remedies, J.A.M.A. 162:206-207 (September 15) 1956. Question 1. Was this language ever included in the labeling submitted to FDA in connection with this supplemental application? Do you think it might have had any effect on your subsequent actions with respect to this product if these statements had been submitted to you in 1956? Answer. In the draft copy of the Flexin Index Card (revised October 18, 1956) referred to by the subcommittee staff there are statements referable to liver damage as the last paragraph on page 3 and on page 3a. An examination of the NDA shows that this language was never included in the labeling submitted to FDA in connection with the handling of the supplement for tablets Flexin, engestic coated. If these statements had been submitted to us in 1956, they would have highlighted the problem and may well have had an effect on our subsequent actions with respect to Flexin. Question 2. Included in the material submitted by the company in response to FDA's request on August 23, 1961, for all information relating to hepatitis associated with Flexin, was an unpublished manuscript prepared in 1956 by Dr. William Amols, one of the company's original clinical investigators of Flexin, and two associates. In this article, entitled "Hepatotoxicity During Zoxazolamine (Flexin) Therapy: Report of Four Cases." Dr. Amols and his associates concluded that Flexin was a possible causative agent in all four cases although the evidence was stronger in some cases than in others. I should like to submit for the record a copy of this manuscript along with an excerpt from a summary of a telephone conversation of December 14, 1956, between Dr. Amols and McNeil's medical director indicating that the article would not be published. If this article had been submitted and published, do you think it might have altered the subsequent actions of the agency with respect to this product, and, if so, how? Answer. If the article "Hepatotoxicity During Zoxazolamine (Flexin) Therapy: Report of Four Cases" had been submitted or published, I think it might well have altered subsequent actions of the agency with respect to Flexin. Although these cases do not definitely incriminate the drug, there is good evidence that it was the causative agent in at least one case. The addendum to the paper should also have caused us some concern. At that time the drug had been on the market less than a year. Such reports associated with the use of a drug within this period of time are rare and they would have been highly suggestive of significance. I believe the paper would have put us on guard at an early date to keep in close touch with the firm and other sources of information to learn of any further reports of this nature. We would undoubtedly have required notice of possible liver toxicity in the labeling and might not have approved applications for subsequent dosage forms until the significance and seriousness of these initial observations had been resolved. Action might also have been influenced by the findings in the 5 additional cases mentioned in the addendum or in the total of 15 cases mentioned in the 1 proposed draft of labeling for the file card. RALPH G. SMITH, M.D. EXHIBIT 28A-SUMMARY OF TELEPHONE CONVERSATION BETWEEN JAMES M. SHAF- DIVISION OF CLINICAL INVESTIGATION, Subject: Telephone conversation with Dr. William Amols, Neurological Dr. Amols informed us that the paper describing the patients who developed abnormalities of liver function while receiving Flexin will not be submitted for publication. This paper was reviewed by Dr. Merritt, Neurological In stitute, Dr. Loeb, Professor of Medicine, Columbia, and Dr. Hanger. It was the opinion of all three that the evidence was inconclusive and that the material would probably not be accepted by the editor of any journal. JAMES M. SHAFFER, M.D., Director. EXHIBIT 28B-HEPATOTOXICITY DURING Zoxazolamine (FLEXIN) THERAPY: REPORT OF FOUR CASES, BY ALBERT DAMON, M.D., Ph.D., WILLIAM AMOLS, M.D., AND DONALD HOLUB, M.D., NEW YORK From the Departments of Medicine and Neurology, Columbia University College of Physicians and Surgeons, and the Presbyterian Hospital and Neurological Institute, New York, N.Y. Dr. Damon is a Fellow of the American Heart Association and formerly assistant resident in medicine, Presbyterian Hospital. Dr. Holub is assistant resident in medicine, Presbyterian Hospital. HEPATOTOXICITY DURING ZOXAZOLAMINE (FLEXIN) THERAPY: REPORT OF FOUR CASES Zoxazolamine (Flexin), 2-amino-5-chlorobenzoxazole, is a newly-developed skeletal-muscle relaxant with the structural formula: -NH CH It has been reported to be effective orally in neurological disorders involving spasticity and muscle spasm, such as cerebral palsy, multiple sclerosis, and other spinal cord disorders, and in various rheumatic diseases characterized by stiffness and aching. Side effects in over 385 patients treated for periods up to 6 months were minor, though considered annoying enough in 13 of 100 patients in one study to warrant stopping the drug. These effects consisted chiefly of malaise, nausea and vomiting, anorexia, diarrhea, drowsiness, and light-headedness, with an occasional rash. No instance of liver damage had been published, to our knowledge, as of October 1, 1956. Since the drug is already in wide use, it appears worth while to report several such cases occurring during zoxazolamine therapy. We wish to acknowledge the cooperation of the staff of the Department of Experimental Psychiatry, N.Y. State Psychiatric Institute, for first calling our attention to Case 1 and allowing access to their clinical material on this patient. CASE 1 A 32-year-old Jewish typist was admitted on Sept. 20, 1955, because of anxiety and depression. In 1953 and 1954, she was twice hospitalized elsewhere with the diagnosis of schizophrenia and received 9 electroconvulsive and 87 insulin shock treatments, 34 of the latter being deep comas. Persistence of symptoms led to her voluntary admission for drug treatment. Previous medical history was not contributory, and system review other than psychiatric was negative. There had been no fatty food intolerance nor other gastrointestinal symptom or disease and no known exposure to recent infection, toxic substance, or injection. She had never had a transfusion, and her most recent dental procedure was in January, 1955. Her alcoholic intake was negligible. Physical and neurological examinations, urinalysis, and electrocardiogram in 1953 had been normal. On admission, she was found to be an obese young woman, 67 inches tall and weighing 190 pounds. Physical and neurological examinations were normal. Hemoglobin was 13.5 gm. per 100 cc., red blood cells 4.4 million and white blood cells 10,400 per cubic millimeter, with 65 percent neutrophils, 30 percent lymphocytes, 1 percent monocytes, and 4 percent eosinophils. Urinalysis, chest and skull roentgenograms, and serological test for syphilis were all negative. Hospital course.-On Sept. 30, she received 100 gamma of synthetic Lysergic acid and experienced no abnormal sensory impressions except a few vague color |