EXHIBIT 9-EXCERPT RE SIDE EFFECTS FROM PROPOSED BROCHURE SUBMITTED WITH FLEXILON NEW DRUG APPLICATION SIDE EFFECTS, TOXICITY, AND PRECAUTIONS Flexin has produced no irreversible toxic reactions when administered to patients daily for periods of over 6 months. Individuals receiving Flexin for prolonged periods have been carefully checked with blood counts, urinalyses, and liver function tests. Anemia, leukopenia, or agranulocytosis, has not been reported in any patient receiving Flexin. One report of a transient nephritis thought to be due to Flexin has been published (7). During the 3 years that Flexin has been in use clinically there have been occasional reports of patients who have developed jaundice while receiving Flexin. After careful inquiry into these cases it has usually been concluded that the possibility of a viral hepatitis as the cause, rather than a drug-induced hepatitis, could not be excluded. The possibility exists that Flexin in rare cases may produce hepatitis and jaundice. The most frequent side effects produced by Flexin are gastrointestinal in nature. These include nausea, vomiting, abdominal discomfort, and diarrhea. These side effects can be minimized by always administering the drug with food or during meals, or by use of the enteric coated tablet. Flexin may produce central nervous system effects such as dizziness or lightheadedness and occasional patients may note some drowsiness. These side effects may often be relieved by dosage adjustment. Allergic reactions usually manifest as skin eruptions can occur in patients receiving Flexin. The drug should be discontinued if there is any itching or redness of the skin. In patients with gout the hazard of precipitating urate calculi and renal colic exists unless the precautions of maintaining an adequate urine output and alkalinization of the urine are observed when Flexin is first administered. Most of the side effects produced by Flexin are more annoying than serious. Flexin should be discontinued if gastrointestinal symptoms, dizziness, or lightheadedness cannot be reduced to a tolerable level by dosage adjustment. As with any drug, Flexin should be discontinued if a skin rash suggestive of drug sensitivity develops. As with any potent drug metabolized by the liver and excreted in the urine, caution should be observed in the use of Flexin for patients with significant degrees of renal or hepatic dysfunction. The submission did not show that instead of 32 cases of reversible liver damage, with 2 deaths probably unrelated to use of the drug, the firm then knew of 39 cases of hepatitis in patients taking Flexin, including 11 fatalities, and that 20 of the cases, including 6 deaths, had been ascribed directly to Flexin by the reporting physicians. Here again the benefit-versus-risk decision was that of a single medical officer instead of an institutional decision. During 1959 our New Drug Division was staffed by 4 full-time and 4 part-time medical officers, and in the fiscal year 1959 this force received 369 new drug applications, made 230 such applications effective, and made 690 supplemental new drug applications conditionally or fully effective. As during 1958 this force was faced with 60- and 180-day time limits on their considerations. If they did not act, the applications became effective by law. On January 8, 1960, and again on March 21, 1960, McNeil Laboratories made submissions to FDA in connection with Triurate, another Flexin-containing drug, in which it was stated that: In isolated instances, hypersensitivity reactions thought to be due to Flexin have been reported, such as transient reversible renal irritation or hepatitis. (b) Index card: Draft of index card which will be available to physicians on request. Exhibit 10 is the complete page dealing with the quotation which I have just read. It is on the second page under "Side Effects." Mr. FOUNTAIN. I understand this has also been examined by members of the staff. Exhibit 10 will also become a part of the record of the hearings. (Exhibit 10 follows:) EXHIBIT 10-DRAFT OF PROPOSED PHYSICIANS INDEX CARD FROM TRIURATE NEW DRUG APPLICATION Triurate provides comprehensive therapy in the management of chronic gout and gouty arthritis. Two specific anti-gout agents are present-Flexin, a potent uricosuric compound, which markedly increases urine uric acid excretion and thereby reduces serum uric acid levels (1-5); and colchicine, in a dose found most useful for preventing flareups of acute gout (6, 7). Tylenol supplies effective analgesia (8) for the chronic aching and discomfort present in many patients with gout. Indications Triurate is indicated in chronic gout and gouty arthritis for the reduction of serum uric acid levels and for the prevention of flareups of acute gout. It is particularly useful when aches, pains, and general discomfort accompany chronic gout or gouty arthritis. Advantages Triurate combines the following in one convenient dose : (1) A most potent uricosuric agent, Flexin, for removal of excess amounts of uric acid from the body, resulting in disappearance of tophi, decreased frequency of acute attacks of gout and marked reduction in chronic joint pains between acute attacks. (2) The time-tested agent, colchicine, specific for the control of gout. (3) An effective nonirritating analgesic, Tylenol, for relief of the aching discomfort which commonly accompanies chronic gout and gouty arthritis. Unlike the salicylates, Tylenol does not interfere with the action of uricosuric compounds (9, 10). Triurate thus provides the best overall management of chronic gout and gouty arthritis. Dosage and method of administration Average dose: One tablet three times a day after meals. Care should be taken to maintain an adequate urine output to prevent the precipitation of urate calculi. The patient should be instructed to ingest two full glasses of liquids with each meal and two full glasses of liquids between meals. If possible, serum uric acid should be measured at regular intervals. When the level has stabilized at the lowest attainable in the individual patient (in approximately 2 months), dosage may be reduced to two tablets a day. This dose may be maintained so long as serum uric acid levels remain low. Relation to acute gout: While in the average patient with chronic gout the colchicine in Triurate should prevent a flareup of acute gout, in patients with a history of very frequent or severe attacks, colchicine alone should be given prophylactically for a few days before starting Triurate to avoid such an exacerbation, possible when any potent uricosuric drug is first administered. As with other uricosuric agents, Triurate is not recommended for treatment of acute gout. Colchicine alone or other agents in appropriate doses are required to control this stage of the disease. When the acute inflammation subsides, Triurate should be started to maintain lowered serum uric acid levels and prevent subsequent attacks. Side effects Triurate seldom produces side effects of any significance. Occasional patients may note nausea, dizziness, drowsiness, urticaria, or other allergic-type skin eruptions. In the rare patient, hypersensitive to colchicine, the amount present in Triurate may produce diarrhea. In isolated instances, hypersensitivity reactions thought to be due to Flexin have been reported, such as transient reversible renal irritation (11, 12) or hepatitis (13). If acute abdominal or flank pain, skin rash, or jaundice should develop, Triurate should be discontinued. The onset of acute flank pain may indicate development of urate calculi rather than renal irritation per se. How supplied Triurate is supplied as beige, scored tablets imprinted "McNeil" in bottles of 50. Mr. FOUNTAIN. You refer in that exhibit to the paragraph dealing with side effects? Mr. LARRICK. Correct. Exhibit 11, Mr. Chairman, is the cover letter and the final printed index card for Triurate, submitted to FDA on March 21, 1960. This contains the same statement as the one previously referred to. Mr. FOUNTAIN. If there is no objection, exhibit 11 will become a part of the record of the hearings. (Exhibit 11 follows:) EXHIBIT 11-MEMORANDUM FROM ROBERT L. MCNEIL, JR., CHAIRMAN OF THE BOARD, MCNEIL LABORATORIES, INC., TO FOOD AND DRUG ADMINISTRATION, MARCH 21, 1960, AND FINAL DRAFT OF TRIURATE INDEX CARD MONEIL LABORATORIES, INC., Re NDA 12-272-Tablets Triurate.1 Department of Health, Education, and Welfare, (Attention of Ralph G. Smith, M.D., Chief, New Drug Branch, Bureau of Medicine.) GENTLEMEN: This will acknowledge Dr. DeFelice's letter of March 8, 1960, advising us that in accord with the provisions of regulation 130.4 (d) the abovenamed application is conditionally effective. The letter further states that this application will be effective when we submit specimens of final printed labeling for the drug identical in content to the draft copy. Five copies of the final printed label and five copies of the labeling (index card) are enclosed. Three finished market packages of the drug were forwarded to you by insured parcel post on March 17. We are most appreciative of your consideration of this application. Very truly yours, 1 Trademark. ROBERT L. MCNEIL, Jr., Chairman of the Board. Side effects CHRONIC GOUT AND GOUTY ARTHRITIS TRIURATE* Triurate seldom produces side effects of any significance. Occasional patients may note nausea, dizziness, drowsiness, urticaria, or other allergic-type skin eruptions. In the rare patient hypersensitive to colchicine, the amount present in Triurate may produce diarrhea. In isolated instances, hypersensitivity reactions thought to be due to Flexin have been reported, such as transient reversible renal irritation " 19 or hepatitis 13. If acute abdominal or flank pain, skin rash, or jaundice should develop, Triurate should be discontinued. The onset of acute flank pain may indicate development of urate calculi rather than renal irritation per se. (See bibliography 11, 12, and 13 which are the footnotes for the above references.) How supplied Triurate is supplied as beige, scored tablets imprinted "McNeil" in bottles of 50. BIBLIOGRAPHY 1. Reed, E. B., Feichtmeir, T. V., and Willett, F. M.: New England J. Med. 258: 894-896 (May 1) 1958. 2. Burns, J. J., Yü, T. F., Berger, L., and Gutman, A. B.: Am. J. Med. 25: 401408 (Sept.) 1958. 3. Connor, T. B., Carey, T. N., Davis, T., and Lovice, H.: Clin. Res. 7: 29-30 (Jan.) 1959. 4. Reed, E. B., Feichtmeir, T. V., and Willett, F. M.: Clin. Res. 7: 66 (Jan.) 1959. 5. Kolodny, A. L.: J. Chron. Dis. 11 : 64-68 (Jan.) 1960. 6. Beckman, H.: Pharmacology in Clinical Practice, Philadelphia, W. B. Saunders Co., 1952, pp. 515–516. 7. Talbott, J. H.: J. Bone & Joint Surg. 40-A: 994-1002 (Oct.) 1958. 8. Batterman, R. C., and Grossman, A. J.: J.A.M.A. 159: 1619-1622 (Dec. 24) 1955. 9. Connor, T. B., Carey, T. N., Davis, T., and Lovice, H.: J. Clin. Invest. 38: 997 (June) 1959. 10. Reed, E. B.: Unpublished data. 11. Cohen, T.: New England J. Med. 256: 1193-1194 (June 20) 1957. 12. Streitz, J. M.: New England J. Med. 260: 1278–1279 (June 18) 1959. 13. Hoffbauer, F. W., and Nelson, O. L. N.: Gastroenterology 34: 1048 (June) 1958. Mr. LARRICK. During this period the firm had continued to receive reports that Flexin was directly implicated in deaths and severe permanent injuries caused by hepatitis. On July 13, 1961, a meeting was held at the firm's request between members of the FDA and the firm. At this time the firm's representatives informed FDA that the firm had received a total of 54 reports of hepatitis in patients also receiving Flexin and that they believed the labeling for Flexin should carry a "stronger warning about the possibility that the drug could cause this reaction." FDA demanded and obtained from McNeil Laboratories reports concerning all cases of liver damage associated with use of Flexin. FDA then contacted outstanding experts in the treatment of gout from various medical institutions to determine if in their opinion the value of Flexin in this disease warranted the risks attendant upon its use. The firm sought to convince FDA that Flexin should remain on the market with suitable labeling warnings, and submitted a warning Trademark. letter which they proposed to send to physicians, and proposed revised labeling. Exhibit 12 is a draft of the warning letter to physicians and exhibit 13 is a draft of the proposed revised labeling. Mr. FOUNTAIN. If there is no objection, exhibits 12 and 13 will become a part of the record. (Exhibits 12 and 13 follow :) EXHIBIT 12-DRAFT OF PROPOSED WARNING LETTER TO PHYSICIANS TO ACCOMPANY MAILING OF REVISED LABELING FOR FLEXIN, FLEXILON, FLEXILON-HC, AND TRIURATE DEAR DOCTOR: It has been reported to McNeil Laboratories, and in the medical literature (1-5), that Flexin' zoxazolamine may be associated with the development of hepatitis. It is difficult to assess the role that this drug may have in the production of liver damage. If it is assumed that in all reported cases the hepatitis was due to Flexin the incidence is approximately 2 cases per 100,000 patients treated. During the time that Flexin has been in use the incidence of infectious (viral) hepatitis in the general population has ranged from a low of about 7 cases per 100,000 in 1957 to an expected high in 1961 that may exceed 30 cases per 100,000. Despite the problems involved in determining with certainty if, or how often, Flexin may be the cause of hepatitis, you should be aware that this possibility exists. Enclosed are copies of revised product information on Flexin and Flexincontaining products. Under "Side Effects and Toxicity" and "Precautions and Contraindications" you will find important cautions that should be observed with the use of these drugs. Cordially yours, References: MCNEIL LABORATORIES, INC., Medical Director. 1. Hoffbauer, F.W. et al.: Gastroenterology 34: 1048 (June) 1958. 2. Bartels, E. C.: Med. Clin. N. Amer. 44: 453-463 (March) 1960. 3. Jasper, H.: Amer. J. Gastroent. 34: 419-421 (Oct.) 1960. 4. Carr, H. J., and Knauer, Q. F.: New Engl. J. Med. 264: 977-980 (May 11) 1961. 5. Eisenstadt, H. B., and Elster, B. B.: JAMA 176: 874-876 (June 10) 1961. 1 EXHIBIT 13-REVISED LABELING PROPOSED FOR FLEXIN 1 FLEXIN ZOXAZOLAMINE URICOSURIO AGENT-SKELETAL MUSCLE RELAXANT Side effects and toxicity In the low dosage required for effective uricosuric action, flexin seldom produces side effects of any significance. In the larger doses required for a muscle relaxant effect, flexin may produce dizziness, drowsiness, or gastrointestinal disturbances which can often be prevented by dosage reduction or administration of the drug with food. Flexin may occasionally produce allergic-type skin reactions, and the drug should be discontinued if a skin rash is noted. Flexin may rarely be associated with hepatitis (10-14) or a transient, reversible renal irritation (15-17) apparently as the result of an idiosyncrasy or hypersensitivity reaction. ( (See precautions and contraindications.) Precautions and contraindications Patients treated with Flexin for prolonged periods should be observed at frequent intervals (every 2 to 4 weeks) and should be instructed to report the occurrence of nausea, anorexia, vomiting, epigastric pain, dark urine, or jaundice. 1 Trademark. |