The only common factor of possible etiologic significance in these 4 cases of hepatotoxicity was zoxazolamine, administered for a few weeks. Three of the patients received previous or concurrent meprobamate, and the other (Case 2) may have had serum hepatitis rather than drug sensitivity, so that the possible potentiating role of meprobamate must remain unsettled. No instance of liver damage from meprobamate has been reported, to our knowledge or that of the manufacturers, as of Oct. 1, 1956. Even in Case 2, although zoxazolamine may not have been the initial etiologic agents, a hepatotoxic effect was suggested when the patient was "challenged" with the drug. Clinically, all 4 patients had liver cell damage, as manifested in 3 by abnormal cephalin flocculation and thymol turbidity, and in the other (Case 3) by height. ened bromsulfalein retention. Cases 1 and 2 likewise showed a mild obstructive component. The picture of hepatotoxicity here was thus unlike that of "primary intrahepatic cholestasis,"" an obstructive type of jaundice encountered as a variant in viral infections and as a reaction to arsenicals (arsphenamine and carbarsone), chlorpromazine, methyl testosterone, and thiouracil. Although not wholly typical of any single disorder, the hepatotoxicity in our 4 patients more nearly resembled that usually caused by infections, bacterial or viral, and sometimes by certain chemical agents. Para-amino-salicylic acid" and phenylacetylurea (Phenurone) are examples of drugs which have caused hepatocellular damage after weeks to months of ingestion. 13 The mechanism of damage is unknown. The evidence for an allergic reaction is poor, in the absence of eosinophilia and perhaps in the failure of 2 or 3 patients to duplicate the picture when "challenged." Histological evidence here is lacking, but the structure of the zoxazolamine molecule contains a chlorinated hydrocarbon, as do some known hepatotoxins. No experimental animal has developed liver damage from zoxazolamine, nor does the drug accumulate in the liver." Indeed, zoxazolamine is said to disappear rapidly from the blood, in man as well as animals, only 2 percent of an administered dose being detec table as such in the urine. While hepatotoxicity disappeared promptly on withholding zoxazolamine in our 4 cases, it would appear prudent, pending more data, to observe and test patients on zoxazolamine regularly for evidence of liver damage and to use the drug with great caution, if at all, for patients with impaired liver function or in conjunction with potential hepatotoxins like chlorpromazine. SUMMARY Four cases have been presented in which hepatotoxicity of primarily parenchymatous type, without eosinophilia, developed after zoxazolamine (Flexin), a voluntary-muscle relaxant, had been administered for a few weeks. Clinical and laboratory manifestations promptly receded after the drug was withheld and failed to recur, except for transient right-upper-quadrant tenderness, in 2 of 3 patients "challenged" with the drug. In 1 patient (Case 2), abnormal laboratory as well as clinical findings reappeared when zoxazolamine was reinstituted. ADDENDUM Five additional cases of hepatotoxicity during zoxazolamine administration had been reported to the manufacturers by Oct. 1, 1956.* BIBLIOGRAPHY (Footnotes for exhibit 28B) 1. Amols, W., Clinical Experience with a New Muscle Relaxant, Zoxazolamine, A.M.A. 160:742 (March 3) 1956. 2. Smith, R. T.; Kron, K. M.; Peak, W. P.; and Hermann, I. F., Zoxazolamine (Flexin) in Rheumatic Diseases, J.A.M.A. 160:745 (March 3) 1956. 3. Abrahamsen, E. H., and Baird, H. W., III, Use of Zoxazolamine (Flexin) in Children with Cerebral Palsy, J.A.M.A. 160:749 (March 3) 1956. 4. Rodriguez-Gomez, M.; Valdes-Rodrigues, A.; and Drew, A. L, Effect of Zoxazolamine (Flexin) in Treatment of Spasticity, JA.M.A. 160: 752 (March 3) 1956. 5. Personal communication to the authors from Ciba Pharmaceutical Products, Inc., Summit, N.J. 6. Davis, C. A., and Gruener, R. D., Glutethimide, A New Nonbarbiturate Hypnotic, Calif. Med. 84:290, 1956. 7. Malitz, S., Personal communication. 8. Malitz, S., and Hoch, P. H., Preliminary Evaluation of a New Phenothiazine Derivative-NP-207. Psych. Quart., in press. 9. Kinross-Wright, V., Clinical Trial of a New Phenothiazine Compound, NP207. A.P.A. Psychiatric Research Reports 4:89, 1956. 10. Sparine, Wyeth Laboratories, Radnor, Pa., 1956. 11. Johnson, H. C., Jr., and Doenges, J. P., Intrahepatic Obstructive Jaundice (Primary Cholestasis), a Clinico-pathologic Syndrome of Varied Etiology: a Review with Observations of the Use of Corticotropin as a Diagnostic Tool, Ann. Int. Med. 44:589, 1956. 12. Bellamy, W. E.; Mauck, H. P., Jr.; Hennigar, G. R.; and Wigod, M., Jaundice Associated with the Administration of Sodium p-Amino salicylic Acid, Ann. Int. Med. 44:764, 1956. 13. Field, J. B., and Justi, R. A., Fatal Hepatitis after Phenurone Therapy for Epilepsy, N.E.J.M. 251:147, 1954. 14. Flexin, McNeil Laboratories, Philadelphia, Pa., 1956. 15. Personal communication to the authors from Wallace Laboratories, New Brunswick, N.J., and Wyeth Laboratories, Radnor, Pa. 16. Personal communication to the authors from McNeil Laboratories, Philadelphia, Pa. Question 3: I submit for the record a synopsis of reports and inquiries regarding hepatic injury in association with Flexin. This document was prepared by McNeil Laboratories and was obtained by the subcommittee from the company's files. Would you compare this list with the cases reported to FDA by the company and tell us whether all of them were reported to you and which, if any, were omitted? Answer: Reports of all of the adverse reactions numbered 1 through 57 on the list were furnished to FDA personally by Dr. Shaffer of the firm on October 3, 1951. The reports were accompanied by a cover letter dated September 29, 1961. Those adverse reactions on the list numbered 58 through 60 were supplied to FDA inspectors during a visit to McNeil Laboratories of September 26, 1962. During this visit on September 26, 1952, the firm supplied our inspectors copies of correspondence between the firm and various physicians, attorneys, and an individual, concerning 13 reports of adverse reactions to Flexin and 2 to Triurate (a Flexin containing drug). The firm said it had received these reports since September 15, 1961, Before furnishing this material to our inspectors, the firm blocked out the names of all the persons involved. While this correspondence appears to include those cases of adverse reactions numbered from 61 through 69 on the list we cannot be certain of this because our files do not contain the names of those involved. (Exhibit 29 follows:) Date reported EXHIBIT 29-SYNOPSIS OF REPORTS AND INQUIRIES RE HEPATic Injury-FLEXIN 1. Dec. 2, 1955.. 11. Sept. 4, 1956. 18. Dec. 8, 1950.. 19. Jan. 11, 1937..... Dripps, M.D. Hoffebauer, Male.... Pennsylvania. 80 Female.. Maryland.. Yes.... Yes... Final diagnosis and/or comments Pathological examination: Hepatic necrosis, diffuse. Prob- Nonobstructive Jaundice; probably toxic hepatitis. Lab- Nonviral acute hepatitis. Biopsy. Flexin aggravating Obstructive jaundice; death probably due to vascular Yes..... Hepatocellular liver damage; Flexin implicated. Lab- Yes..... Possible homologous serum hepatitis; evidence suggests 1 dose..... No.... Yes.... Yes..... Beveral No.... Yes..... Yes..... No.... Yes..... Yes. Yes..... No...... Yes. months. 8 doses... 4 months.. Yes... Bee footnotes at end of table. Final diagnosis and/or comments EXHIBIT 29-SYNOPSIS OF REPORTS AND INQUIRIES RE HEPATIC INJURY-FLEXIN-Continued McNeil followup Yes.. No...... Questionable case. Liver disease suspected. No autopsy. Report quotes medical doctor. Flexin not necessarily suspect. Questionable case. Report quotes medical doctor that Infectious hepatitis, but clinical symptoms disappeared Questionable. Yellow atrophy of liver (autopsy). Toxic hepatitis. Laboratory evidence. Questionable. Asks for information re Flexin and liver damago. Questionable. Medical doctor asked if information avail- Pathological report: impossible to state if hepatic damage Intrahepatic obstructive Jaundice due to drug sensitivity Nonviral hepatitis. Laboratory evidence. Possibility of Flexin involvement must be considered (hepatitis). Laboratory evidence. Hepatic damage. Flexin not excluded. Laboratory Date reported Reported by Age of patient 8cx Geographical Period ad- Fatal- Follow Response No.... Yes..... No.. Yes... Yes.. Yes. South Africa.. Yes, to No. report Becker, O.D. 78 Female. Yes... .do.. No. Male. flawail. No.... Yes.. Yes. Westdeno .do..... South Africa. No.... Yes, to Rabic, M.D. Hyman, M.D....... Pennsylvania. Yes. No.. DRUG SAFETY LIVER CASES WHICH SHOULD HAVE BEEN INCLUDED IN 8EPTEMBER 1961 REPORT 667 REPORTS OF ADVERSE REACTIONS AFTER SEPT. 16, 1961 Medical doctor quoted as "may have had a case." Toxic hepatitis, laboratory tests indicate bepatocellular type of jaundice. NOTE.-On Oct. 12, 1968, Dr. Damon (Amol's colleague) wrote: Only 2 of 4 above may have been due to Flexin. |