has indicated that this drug is well tolerated in doses of 250 milligrams, three or four times a day.

When Flexin is administered as a uricosuric agent, the same precautions should be used that apply to other potent drugs with this action. These precautions include maintenance of an adequate urinary output and alkalinization of the urine at least during the first several days of treatment. precautions are particularly important in any patient with a history of renal colic or passage of urate stones.

These

At this time it appears that acute manifestations of gout may occur during Flexin therapy despite the marked uricosuric action. This same phenomenon has been observed with other uricosuric agents such as probenecid. If patients with gout have been controlled symptomatically with colchicine, it is probably advisable to continue the use of colchicine when administration of Flexin is started. There does not appear to be any contraindication to the use of colchicine and Flexin together in the management of patients with gout.

Preliminary information suggests that salicylates may not block the uricosuric action of Flexin. If this is the case, there is no need to caution against the simultaneous administration of Flexin and salicylates. Other uricosuric agents such as probenecid, phenylbutazone, and phenylbutazone analogs lose their activity if salicylates are administered at the same time.

Mr. LARRICK. The accompanying brochure, however, contained the statement

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 brochure also stated in part that:

Flexin has produced no irreversible toxic reactions when administered to patients daily for periods of over 6 months.

Exhibit 5, which consists of the page from the brochure submitted on June 11, 1958, entitled "Side Effects, Toxicity, and Precautions" contains the quotation that I have just read into the record; in the first line of the first paragraph, and in the second paragraph.

Mr. FOUNTAIN. If there is no objection, exhibit 5 will become a part of the record.

EXHIBIT 5-EXCERPT RE ADVERSE REACTIONS TO FLEXIN FROM PROPOSED BROCHURE SUBMITTED WITH SUPPLEMENTAL NEW DRUG APPLICATION OF JUNE 11, 1958

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 coli 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.

Mr. FOUNTAIN. At this point, Mr. Larrick, I wonder if you would explain just what the term "irreversible toxic reactions" means? Mr. LARRICK. An irreversible toxic reaction is harm brought about to a person that cannot be corrected. If you have damage to an organ, that organ is permanently damaged to the extent that it was involved. If it is reversible, time or treatment cures it and you are restored to your original state of health.

Mr. FOUNTAIN. Thank you very much.

Go right ahead.

Mr. LARRICK. The facts are that, at that time, the firm had received reports of seven deaths from hepatitis of patients who were also taking Flexin. The total number of cases known to the firm of patients who had developed liver damage while taking Flexin was 29. The firm had not conducted a "careful inquiry" into many of the

cases.

A note in the NDA by the reviewing medical officer concerning this submission states in part, "their new brochure just brings up to date the uricosuric properties of the drug."

Exhibit 6 is the handwritten note by the reviewing medical officer of the Food and Drug Administration, and is dated July 23,

1958.

Mr. FOUNTAIN. If there is no objection, exhibit 6 will become a part of the record of the hearings.

(Exhibit 6 follows:)

EXHIBIT 6-INTRA-AGENCY MEMORANDUM RE SUPPLEMENTAL NEW DRUG

APPLICATION FOR FLEXIN, JULY 23, 1958

It has been found that Flexin, in addition to its other actions, is uricosuric, in dose ranges for which there is already an effective NDA as of January 13, 1956. This supplement is for inclusion of gout under indications of use of the drug. The same data regarding safety would apply to this new use. Their data regarding uric acid excretion looks good. Their new brochure just brings up to date the uricosuric properties of the drugs and extends use in gout as well as its precursory uses for which they have an effective NDA.

SIEGEL.

Mr. LARRICK. As we pointed out in our appearance before your committee on March 24, this decision would, under our present practice, be an institutional decision. During June 1958, the Division of New Drugs was staffed by three full-time and four half-time medical officers. During that year, this handful of people received 445 new drug applications; made effective 334 new drug applications; made fully or conditionally effective 1,400 supplemental new drug applications; and in all of their considerations were faced with a statutory time

limit of 60 or 180 days in which each new drug application and supplemental new drug application submitted would become automatically effective by law unless FDA took positive affirmative action to insure against it.

On September 29, 1959, the firm submitted another supplemental NDA to FDA for "Flexilon," a Flexin-containing drug, which stated with respect to Flexin, that

during the past 3 years there have been a total of 32 reports to McNeil Laboratories suggesting that the administration of the drug may have been associated with the development of hepatitis with jaundice. In all such instances, McNeil Laboratories has attempted to obtain complete information in order to arrive at a reasonable conclusion as to the possible role that the drug may have played. It has usually been difficult, if not impossible, to decide whether the individual case was due to a viral hepatitis or to a drug-induced hepatitis.

A report on two of these cases was published in Gastroenterology, "Fatal Liver Necrosis in Two Patients Receiving Zoxazolamine. The authors' conclusions seem to be a fair statement of the situation in regard to Flexin and possibly liver damage.

Exhibit 7 deals with the citations that I have just made and fills in the space where, in my prepared testimony, there are asterisks. Mr. FOUNTAIN. Members of the staff have already examined this exhibit; am I right?

Mr. GRAY. Yes.

Mr. FOUNTAIN. If there is no objection, exhibit 7 will become a part of the record of the hearings.

(Exhibit 7 follows:)

EXHIBIT 7-EXCERPT FROM SUPPLEMENTAL NEW DRUG APPLICATION FOR FLEXILON

Hepatic toxicity

During the past 3 years there have been a total of 32 reports to McNeil Laboratories suggesting that the administration of the drug may have been associated with the development of hepatitis with jaundice. In all such instances McNeil Laboratories has attempted to obtain complete information in order to arrive at a reasonable conclusion as to the possible role that the drug may have played. It has usually been difficult, if not impossible, to decide whether the individual case was due to a vital hepatitis or to a drug-induced hepatitis.

A report on two of these cases was published in Gastroenterology. (American Association for the Study of Liver Diseases-Abstracts of Presentation at the Annual Meeting, Chicago, Ill., Oct. 31, 1957.) (Hoffbauer, F. W. and Nelson, O.L. N.) Fatal Liver Necrosis in Two Patients Receiving Zoxazolamine, Gastroenterology 34: 1046 (June) 1958. The authors' conclusions seem to be a fair statement of the situation in regard to Flexin and possible liver damage (see exhibit (1) (b)−7).

:

The small number of reported cases and the large number (estimated at more than 3 million) of patients who have received the drug would tend to support a conclusion that the development of hepatitis and jaundice may have been coincidental to the administration of the drug since the incidence is approximately 1 to 100,000. However, the possibility exists that Flexin may rarely produce liver damage. This possibility has been recognized and an appropriate caution statement included in the professional literature on this product (see Flexin brochure, p. 4, and index card, exhibit (1) (b)−10).

Renal toxicity

There has been very little clinical evidence to indicate that Flexin produces kidney damage. One case was reported by Cohen (see reprint, exhibit (1) (b)−8) in 1957. Two other cases have recently been reported by Streitz (see reprint, exhibit (1)(b)-9). In all three cases the acute onset of symptoms and subsequent evidence of renal irritation suggest that these episodes were either a form

of hypersensitivity to the drug or a manifestation of its potent uricosuric action with precipitation of urate calculi in the kidneys. In all three cases the evidence of renal involvement was completely reversible and the acute symptomatology subsided rapidly. Laboratory evidence of renal damage subsided within a few days in all cases reported. It should be noted that Streitz does not believe that the precipitation of uric acid in the urinary tract could explain the findings in his cases.

Regardless of the explanation for the rare occurrence of a transient nephritis associated with the use of Flexin, it is proposed to include a suitable statement about this possible undesirable reaction in all professional literature on Flexin or Flexin containing products as follows:

Rarely Flexilon may be associated with a transient renal irritation or with a hepatitis with jaundice. Flexilon may occasionally cause urticaria or other allergic-type skin eruptions. If acute abdominal or navel pain, a skin rash, or jaundice should develop, the drug should be discontinued.

Mr. FOUNTAIN. Again, was the statement which you made, or the quotation which you gave, just prior to the introduction of the exhibit an attempt to convey the substance of what is contained in that exhibit?

Mr. LARRICK. It is our summary of what is in the exhibit.

Mr. GRAY. I beg your pardon, was that not a direct quote from the New Drug Application, Mr. Larrick?

Mr. LARRICK. Yes, sir, it was.

The exhibit referred to was a reprint of a short article which reported two deaths in patients receiving Flexin, and which stated in part:

The following two cases are reported because the sequence of events suggested, though by no means proved, a possible relationship between fatal liver disease and the employment of this agent. The possibility that these patients represented sporadic cases of fulminant viral hepatitis could not be excluded. Pathologists who examined the sections expressed variable opinions as to the possible etiology of the diffuse necrosis on the basis of their interpretation of the histopathology present. Although no positive relationship of drug idiosyncrasy and liver necrosis could be established in the two cases, this possibility must be considered.

Exhibit 8 is a copy of the complete article entitled "Fatal Liver Necrosis in Two Patients Receiving Zoxazolamine." Zoxazolamine is the chemical name or the common name for the drug we are discussing.

Mr. FOUNTAIN. Have members of the staff examined this exhibit? Mr. GRAY. Yes.

Mr. FOUNTAIN. Exhibit 8, if there is no objection, will become a part of the record.

(Exhibit 8 follows:)

EXHIBIT 8-ARTICLE DESCRIBING FATAL LIVER DAMAGE IN TWO PATIENTS

RECEIVING ZOXAZOLAMINE

Hoffbauer, F. W., and Nelson, O. L. N.: Fatal Liver Necrosis in Two Patients Receiving Zoxazolamine, Gastroenterology 34: 1048 (June) 1958.

The drug Flexin (Zoxazolamine, McNeil) is a preparation designed to relieve skeletal muscle spasm. Although the drug has been widely used, the incidence of serious side effects has been extremely low. It is said to have been administered to over a million persons. The following two cases are reported because the sequence of events suggested, though by no means proved, a possible relationship between fatal liver disease and the employment of this agent.

37-272-64-pt. 2--15

Case 1: A 63-year-old woman was admitted to St. Barnabas Hospital, Minneapolis, on September 23, 1956, because of jaundice of 10 days' duration. The patient had a residual hemiparesis following a stroke in 1951. Physiotherapeutic measures were necessary because of the residual deformity and muscle spasm secondary to the hemiparesis. On August 7, 1956, therapy with zoxazolamine was begun. The patient took the tablets until September 13, when anorexia followed by jaundice occurred. No history of recent contact with cases of viral hepatitis was elicited. The patient had not received transfusions of blood or plasma or parenteral injections in the preceding 6 months. The physical examination on September 23 revealed deep jaundice (total serum bilirubin, 23 mg. per 100 ml.). The liver was not enlarged. Despite supportive measures the patient's condition rapidly deteriorated. Cortisone exerted no beneficial effect. She died in coma 10 days after admission. At necropsy the liver weighed 1100 gm.; the capsule was wrinkled. Microscopic examination revealed a diffuse hemorrhagic centrolobular necrosis of the liver. No other significant pathology was observed.

Case 2: A 43-year-old woman was admitted to St. Joseph's Mercy Hospital, Sioux City, Iowa, on December 6, 1956, because of nausea, jaundice, and lethargy of 10 days' duration. Shortly after admission the patient lapsed into coma. This patient developed multiple sclerosis in 1946. Because of increasing muscle spasm, Flexin therapy (250 mg. three times daily) was begun late in September 1956, and continued until the onset of jaundice. No history of recent exposure to cases of viral hepatitis was elicited. No injections other than vitamin B12 had been administered in the recent past. The patient died on the fourth hospital day. At autopsy the liver was reduced in size, one lobe flabby in consistency, and it exhibited the gross characteristics of acute red and yellow atrophy. Microscopic examination revealed an extensive diffuse necrosis of the liver.

The possibility that these patients represented sporadic cases of fulminant viral hepatitis could not be excluded. Pathologists who examined the sections expressed variable opinions as to the possible etiology of the diffuse necrosis on the basis of their interpretation of the histopathology present. Although no positive relationship of drug idiosyncrasy and liver necrosis could be established in the two cases, this possibility must be considered.

Mr. FOUNTAIN. At this point, Mr. Larrick, will you define "etiology” for the record?

Mr. LARRICK. The cause.

cult to understand.

Doctors always use words that are diffi

Mr. FOUNTAIN. Go right ahead.

Mr. LARRICK. The referenced supplemental NDA also contained the statement:

The small number of reported cases and the large number (estimated at more than 3 million) of patients who had received the drug would tend to support a conclusion that the development of hepatitis and jaundice may have been coincidental to the administration of the drug * * *. However, the possibility exists that Flexin may rarely produce liver damage *

This is quoted from exhibit 7 which you have previously received for the record.

The brochure submitted with this supplemental NDA contained the statement:

Flexin has produced no irreversible toxic reactions when administered to patients daily for periods of over 6 months.

Exhibit 9 is the page from the brochure submitted with the supplemental NDA of September 29, 1959.

Mr. FOUNTAIN. If there is no objection, exhibit 9 will become a part of the record.

(Exhibit 9 follows:)