The dosage should be reduced if gastrointestinal symptoms develop. If these symptoms persist or if acute abdominal or flank pain develop, Flexin should be stopped. Mr. LARRICK. This material, in the opinion of our medical staff, minimized, qualified, and cast doubt upon the validity of the reactions attributed to Flexin and did not inform about the high incidence of fatality associated with these reactions. FDA decided that the risks of the use of Flexin outweighed its therapeutic value, and on October 13, 1961, the NDA for Flexin was formally suspended. Exhibit 14 is the governmental document constituting the suspension order for Flexin. Mr. FOUNTAIN. If there is no objection, exhibit 14, entitled "Suspension Order," dated October 13, 1961, will also become a part of the record. (Exhibit 14 follows:) EXHIBIT 14-SUSPENSION ORDER FOR FLEXIN NEW DRUG APPLICATION UNITED STATES OF AMERICA DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE FDC-D-65 In the Matter of Tablets Flexin, Zoxazolamine, 250 mg., Tablets Flexin, Zoxazola. mine, Enteric Coated, 250 mg., McNeil Laboratories, Inc., Camp Hill Road, Fort Washington, Pennsylvania, Applicant SUSPENSION ORDER The Commissioner of Food and Drugs, by virtue of the authority vested in the Secretary by the provisions of the Federal Food, Drug, and Cosmetic Act (Section 505(e); 52 Stat. 1052; 21 U.S.C. 355 (e)), and delegated to the Commissioner by the Secretary (21 F.R. 1996), finds that clinical experience shows that the drugs "Tablets Flexin, Zoxazolamine, 250 mg." and "Tablets Flexin, Zoxazolamine, Enteric Coated, 250 mg." for which New Drug Application No. 10250 is effective, may be unsafe for use under the conditions of use upon the basis of which the application became effective. And, the holder of New Drug Application No. 10250, McNeil Laboratories, Inc., Fort Washington, Pennsylvania, having filed a Written Appearance herein dated October 6, 1961, requesting a voluntary suspension of said New Drug Application, thereby waiving Notice of Hearing as required by Section 505 (e) of the Federal Food, Drug, and Cosmetic Act; it is therefore ORDERED that New Drug Application No. 10250 and all supplements and amendments thereto be suspended as of the date of this order. Dated October 13, 1961, at Washington, D.C. JOHN L. HARVEY, Deputy Commissioner of Food and Drugs. Mr. LARRICK. Before 1957, during the development of Flexin, McNeil Laboratories developed a chemical analog which was named "Paraflex." This was also offered as a muscle relaxant. A new drug application for this drug was submitted to FDA by McNeil Laboratories on November 1, 1957, and FDA permitted it to become effective on December 19, 1957. On August 23, 1961, FDA asked McNeil Laboratories if hepatitis had been reported in association with use of this drug. The firm acknowledged receipt of three such reports. Up to that time labeling for Paraflex and Paraflex-containing drugs contained statements that: Paraflex has had extensive clinical use and has not caused serious toxic reactions or undesirable effects on the blood-forming organs, liver, or kidney; Paraflex has produced no blood dyscrasias, hepatitis, jaundice, or nephritis and Paraflex has produced no serious toxic reactions. Exhibit 15 is the Paraflex brochure cover sheet and the page on the adverse reactions and index card cover sheet and page on adverse reactions. These documents include the partial quotations which I have read into the record from them. Mr. FOUNTAIN. If there is no objection, exhibit 15 will become a part of the record of the hearings. (Exhibit 15 follows:) EXHIBIT 15-EXCERPTS FROM PARAFLEX NEW DRUG APPLICATION Paraflex-Chlorzoxazone: Specific for skeletal muscle spasm. spasm. Parafon with Codeine: Supplemental analgesia when pain is severe. Parafon with Prednisolone: For skeletal muscle spasm with inflammatory involvement. SIDE EFFECTS AND TOXICITY Paraflex chlorzoxazone has produced no serious toxic reactions. Daily administration for as long as one year has produced no evidence of damage to the liver, kidneys, or bone marrow. Paraflex has produced no blood dyscrasias, hepatitis, jaundice or nephritis. In animals, daily administration of high dosage levels for three months produced no detrimental effects as reflected by weight changes, blood counts or tissue pathology. Of Paraflex: As indicated in the published studies, summarized above, side effects seldom occur with the use of Paraflex or Parafon. When side effects do occur, they are rarely severe enough to require discontinuation of the drug. Paraflex may occasionally cause gastrointestinal symptoms which include heartburn, nausea, abdominal discomfort, constipation or diarrhea. Central nervous system effects are infrequent, but occasionally patients may note some dizziness, lightheadedness, drowsiness, over stimulation, headache, lethargy or malaise. Of Parafon components: The components of the Paraflex combinations are equally well established agents of low toxicity which produce few, if any, side effects: Tylenol acetaminophen (N-acetyl-p-aminophenol) is a nonirritating analgesic, particularly effective in pain associated with musculoskeletal disorders. To date there have been no cases reported of alterations in the blood picture including methemoglobinemia, and no undesirable effects on the liver or kidneys. Tylenol produces none of the undesirable side effects such as gastric irritation or hypoprothrombinemia often encountered with acetylsalicylic acid. There have been no reports of acid-base imbalance. 1 U.S. patent No. 2,895,877. Index card: Draft of index card which will be available to physicians on request. TABLETS PARAFLEX-TYLENOL MUSCLE RELAXANT ANALGESIC For relief of pain, stiffness, and limitation of motion associated with skeletal muscle spasm Description Tablets Paraflex-Tylenol: Each compressed tablet contains: Pain, stiffness, and limitation of motion are associated with most disorders involving skeletal muscle spasm. Tablets Paraflex-Tylenol provide optimum symptom relief in these conditions by (a) effective relaxation of muscle spasm, and (b) effective analgesic action. Relaxation of skeletal muscle spasm is accomplished by Paraflex, a new, effective, and well-tolerated centrally acting agent (1). The analgesic effect of Tablets Paraflex Tylenol is produced by Tylenol, a nonirritating analgesic particularly useful in the management of pain associated with musculoskeletal disorders (2, 3). Indications Acute, subacute, and chronic musculoskeletal disorders characterized by pain, stiffness, limitation of motion, and skeletal muscle spasm, such as: Acute and chronic low back disorders-lumbago, acute paravertebral spasm or sacroiliac strain. Tablets Paraflex-Tylenol contain a unique combination of agents which provide distinct advantages: 1. Paraflex, a new and superior skeletal muscle relaxant, provides longlasting relief (approximately 6 hours) with practical dosage (1). Just two tablets three or four times a day is the average effective dose. 2. Tylenol is an effective and nonirritating analgesic (4)—preferred for painful musculoskeletal disorders (2,3). Dosage and administration Acute or subacute conditions involving moderate to severe discomfort: Two Tablets Paraflex-Tylenol t.i.d. or q.i.d. Acute or subacute conditions involving milder degrees of discomfort: One Tablet Paraflex-Tylenol t.i.d. or q.i.d. Side effects and precautions An occa Tablets Paraflex-Tylenol seldom produce undesirable side effects. sional patient may note some mild nausea, drowsiness, or dizziness, but these are seldom severe enough to require discontinuation of the drug. Paraflex has had extensive clinical use and has not caused serious toxic reactions or undesirable effects on the blood-forming organs, liver, or kidneys. Rarely, hypersensitivity reactions with skin rash can occur. The drug should be discontinued if urticaria, redness, or itching of the skin develop. Tylenol is an unusually safe analgesic agent that can be administered without risk of producing blood dyscrasias or other toxic reactions. How supplied Tablets Paraflex-Tylenol are supplied in bottles of 50. BIBLIOGRAPHY 1. Peak, W. P., and Smith, R. T.: To be published. 2. Batterman, R. C., and Grossman, A. J.: "Effectiveness of Salicylamide as an Analgesic and Antirheumatic Agent-Evaluation of the Double Blindfold Technique for Studying Analgesic Drugs, J.A.M.A." 159:1619-1622 (December 24) 1955. 3. Batterman, R. C., and Grossman, A. J.: "Analgesic Effectiveness and Safety of N-Acetyl-para-aminophenol," Federation Proc. 14:316-317 (March) 1955. 4. Roth, J. L. A.: "Management of the Gastric Ulcer Patient," M. Clin. North America 41:1517-1537 (November) 1957. Mr. LARRICK. FDA has considered the status of Paraflex and Paraflex-containing drugs on several occasions in the intervening period. Since cases of liver damage in patients who have received Paraflex have been reversible in nature and few in number, FDA's institutional decision to date has been to permit Paraflex and Paraflex-containing drugs to remain on the market pending an additional evaluation of the effectiveness of the drugs for the purposes claimed in their labeling. McNeil Laboratories was requested on April 6, 1964, to make this evaluation through well-controlled clinical studies and to report the results promptly to FDA. Exhibit 16 is the letter from the Food and Drug Administration to McNeil Laboratories of April 8, 1964, asking for the action to which I have just testified. Mr. FOUNTAIN. I believe exhibit 16, dated April 6, 1964, is one which the committee has not had an opportunity to examine and for that reason, Mr. Larrick, if you will, we would like you to read that. Mr. LARRICK. I would be glad to. This is a letter dated August 6, 1964, addressed to the "McNeil Laboratories, Inc., Attention of Joseph S. Harum, M.D., Camp Hill Road, Fort Washington, Pa." EXHIBIT 16-LETTER FROM ROBERT J. ROBINSON, M.D., MEDICAL OFFICER, NEW DRUG SURVEILLANCE BRANCH, DIVISION OF NEW DRUGS, BUREAU OF MEDICINE, TO MCNEIL LABORATORIES, INC., REGARDING EFFECTIVENESS OF PARAFLEX, AUGUST 6, 1964 GENTLEMEN: We acknowledge the receipt on January 9, 1964, of your communication dated January 6, 1964, with which you submitted the latest printed labeling for "Tablets Paraflex" and "Tablets Parafon with Codeine" to bring up to date the labeling dealing with reports of liver damage. It is noted that since the labeling for these preparations furnishes a statement concerning the specific number of reported cases of liver damage, it will continue to require frequent revision to keep it up to date. We do not insist that the precise number be cited in the labeling. An approximation would be sufficient and would not require frequent changes in the labeling. We are, however, concerned with the reports of jaundice associated with the use of these preparations even though they are as yet few in number and the jaundice has been reversible. Such reports raise a question of the safety of these drugs in the absence of substantial evidence of effectiveness that justifies any risk of injury. In particular, it is noted that we do not now have evidence derived from well-controlled clinical studies establishing the effectiveness of these preparations for the purposes claimed in the labeling. In view of the above, we recommend that at the earliest possible date you undertake such studies and report their results promptly. Further, in order to facilitate estimates of the incidence of the adverse effects reported to be associated with the use of the drug, we are requesting that you submit information concerning the quantity of the drug distributed in a manner and form that facilitates such estimates. In addition to information concerning the number and size of packages distributed by appropriate time intervals, we will appreciate any information you may have concerning the amount of drugs that may still be in channels of distribution and any estimates you may make of the number of patients treated and the number of doses and duration of use per patient. We will appreciate an early acknowledgment of the receipt of this letter and a statement of the steps you may take to comply with our requests. Sincerely yours, ROBERT J. ROBINSON, M.D., Medical Officer, New Drug Surveillance Branch, Mr. LARRICK. A copy went to Dr. Ruskin, Dr. Cohn, and Dr. Ellenhorn. Mr. FOUNTAIN. Thank you very much. You may proceed, Mr. Larrick. Mr. LARRICK. Since August 23, 1961, at FDA's request, McNeil Laboratories has been submitting periodic quarterly statements to FDA on all adverse reaction reports received, and has been making special reports to FDA within 15 days on all new or unusual reports of adverse reactions received. FDA has also required that the kind and approximate number of adverse reactions caused by Paraflex be listed in the labeling and advertising. As a result, these have undergone several revisions. As an example, the 1962 PDR (Physicians Desk Reference) contained the statement with regard to Paraflex side effects that: Paraflex has produced no serious toxic reactions, blood dyscrasias, hepatitis, jaundice, or kidney damage. In the 1963 PDR the statement was changed to: Five patients have been reported in whom the administration of Paraflex or Paraflex-containing products was suspected of causing liver damage. One of these five patients had cancer of the head of the pancreas, another is suspected of having cancer with bony metastasis; in the remaining three patients it is not possible to state that the hepatitis was or was not drug induced. Finally, in the 1964 PDR this was found changed to read: Nine patients have been reported in whom the administration of Paraflex chlorzoxazone or chlorzoxazone-containing products was suspected of causing liver damage. One of these patients had cancer of the pancreas, another is suspected of having cancer with bony metastasis; in the remaining patients it is not possible to state that the hepatitis was or was not drug induced. Exhibit 17 consists of the statements from the Physicians Desk Reference which I have just read. They are exhibits 17, 18, and 19. Mr. FOUNTAIN. Has the staff examined all of these? Mr. GRAY. Yes. Mr. FOUNTAIN. Exhibits 17, 18, and 19, if there is no objection, will become a part of the record of the hearings. (Exhibits 17, 18, and 19 follow :) EXHIBIT 17-DESCRIPTIONS OF PARAFLEX PRODUCTS FROM 1962 PHYSICIAN'S DESK REFERENCE PARAFLEX (R) (par' a flex) CHLORZOXAZONE Composition: Each scored, orange tablet contains Paraflex Chlorzoxazone 250 mg. Action and Uses: Paraflex, an orally effective skeletal muscle relaxant, acts mainly on the spinal cord to inhibit transmission of nerve impulses through multi-synaptic reflex arcs involved in the production of painful skeletal muscle spasm. The clinical effect is a reduction of muscle spasm with relief of pain and increased mobility of the involved muscles. |