tion should be capable of a double or triple dose without any toxic reaction because of the possibility of this happening to the measuring of the dose by the mothers. Dr. Jarvis felt that the information provided by the G. D. Searle Company was wholly inadequate, and his feelings are expressed in the letter which he sent to Dr. Goddard, dated May 19, 1966, which is quoted below:

"The G. D. Searle Company apparently knows little or nothing about their product Lomotil (Diphenoxylate HCA with/Atropine). On February 25 I performed an autopsy on a three-year-old boy who (I believe) died as a direct result of Lomotil overdosage. Enclosed is a copy of a report from the Searle Company which appears to say that the postmortem serum samples submitted to them for assay had a Diphenoxylate level as high as their high standard. However, in personal conversation with Dr. McGovern of their Division of Clinical Research, I gather that they do not know what an overdose is, or how it reacts on the living organism.

"I find this state of affairs somewhat appalling, so I am referring the matter to you. If you wish, I will send a copy of the autopsy."

The sequence of events with respect to this case are as follows:

The patient was examined at a Minneapolis Naval Air Station, Outpatient Clinic on 10/20/65, 1/22/66, 1/29/66, and 1/30/66. (The father was a member of the Navy at this time.) The patient was seen for respiratory problems. (See exhibit #6, which is a copy of "Doctor's Progress Notes" from the Naval Air Station.) The "Doctor's Progress Notes" indicate that in the course of the visit to the facility, Penicillin and an expectorant were prescribed. Note that the entry dated 1/30/66 indicates an Rx of referral to a private M.D. for hospital admission.

On 1/30/66 at 4:05 p.m., the patient was admitted to Bethesda Lutheran Hospital, St. Paul, Minnesota; again, with a diagnosis of respiratory distress. (See exhibit #7 for the complete chart of this hospital admission.) The attending physician was Dr. S. Loken, St. Paul, Minnesota. Again the patient was given Penicillin and also Decadron, Chloromycetin, and on 2/3 and 4, Lomotil was given. (The progress and treatment record dated 2/3/66 indicates a "loose stool," and this was when the Lomotil was first prescribed. The patient was discharged on 2/6/66. On 6/15/66, I talked with Dr. Loken at his office. Dr. Loken stated that the patient was suffering from upper respiratory trouble with difficulty in breathing, and that he was rather acutely ill for what his temperature and other vital things would indicate. He stated that he was rather alarmed and called in Dr. Jack Hilgen, an ear, nose, and throat specialist. (See exhibit #7 for notes of Dr. Loken and Dr. Hilgen and others.) Dr. Loken stated that the patient was listless and had difficulty in breathing over and above what would be expected from his temperature.

On 6/14/66, I talked with the parents of the deceased, Mr. and Mrs. Richard Ehrich at their home at Route 1, Hugo, Minnesota. (The address of 445 Sherburne, St. Paul, Minnesota, on the hospital forms is not correct since the family has recently moved.) According to the mother, the patient was receiving Penicillin for his throat, and on approximately February 19, a prescription for Lomotil was obtained from Dr. Loken for diarrhea. According to the mother, the Lomotil was given at the rate of 1 teaspoon four times each day. On 2/24/66, the child could not be awakened and was again taken to Bethesda Lutheran Hospital, St. Paul, Minnesota. The provisional diagnosis, discharge summary, etc., may be seen on the chart for this second admission to Bethesda Hospital, which is exhibit #8. The child was admitted in a comatose state as indicated. Dr. Martha Strickland, pedatrician at Childrens Hospital at St. Paul, Minnesota, was brought in as a consultant. The child was transferred to Childrens Hospital on the same day. The patient was admitted to Childrens Hospital on 2/24/66 at 6:45 p.m. and expired on 2/25/66 at 10:00 a.m. The sequence of events and the notes on this episode may be seen on the chart for this admission to Childrens Hospital, which is exhibit #9. Many of the entries are by Dr. Strickland and some by Dr. Bloom, who was a pediatric resident at that time. On 6/20/66 I talked with Dr. Strickland at Childrens Hospital, St. Paul, Minnesota. Dr. Strickland stated that she first saw the patient at Bethesda Hospital when he was brought in comatose on 2/24/66. The patient had pinpoint pupils and other indications which caused her to think first of an overdose of some opiate. The patient at his best downhill course did not appear to have the classic encephalitis symptoms. According to Dr. Strickland, the patient had very low blood pressure (impossible to get a blood pressure reading initially) and low renal function, neither condition being

normal in pneumonia, although the patient had aspiration pneumonia on admission. Dr. Strickland stated that similar aspiration pneumonia cases have not been fatal.

When I talked to Dr. Jarvis, he told me of two other cases where Lomotil toxicity was suspected in the death of children of the same approximate age as Terrance Ehrich. Therefore, in connection with this investigation I also obtained information on these two additional cases. The first of these is the case of Lisa Hoffman of Coon Rapids, Minnesota, who expired on 5/16/66 from an overdose of Lomitil. In connection with this case, I talked with Dr. Ronald Bloom at University of Minnesota Hospitals, Minneapolis, Minnesota. According to Dr. Bloom, he is familiar with the case, but the attending physician was Dr. Gregory Culley, who saw the patient on admission and stayed on the case until the patient expired. (Dr. Bloom also worked with Dr. Strickland on the Ehrich case.) Dr. Culley was not available for an interview at this time. The hospital chart for this case contains a sequence of events and notes on the case by Dr. Culley and is exhibit #10. The patient apparently ingested 25 milligram Hydrodiruil and Lomotil tablets. According to Dr. Bloom he was interested in this case because of his association with the Ehrich case. Serum from the Lisa Hoffman case was submitted to G. D. Searle Company, and the letter of reply is exhibit #11. According to Dr. Bloom, the figures given with respect to the blood level are absurd, taking into account the blood volume of a child of this size. Dr. Bloom stated that T. G. Hiebert, Ph. D., M.D., the Director, Division of Medical Intelligence at G. D. Searle Company, visited the hospital but could not provide them with any definitive information with respect to what constitutes a therapeutic or toxic blood level of Lomotil. Also, the Searle people allegedly could not provide any information with respect to Lomotil toxicity. Dr. Bloom also pointed out that after 18 hours (see exhibit #11) a drug is still absorbed. However, no meaning can be attached to the blood level figures since, according to Dr. Bloom, the Searle people could not indicate what these figures meant with respect to Lomotil toxicity. The background information referred to in the exhibit #11 letter is a binder of information entitled "Lomotil Background Information" which was sent to Dr. Bloom by the G. D. Searle Company. Dr. Bloom pointed out that the only study he could find in this where the Lomotil was the only variable is the Study No. 5, which is circled on the contents page. Parts of this background information are in French. An autopsy was performed on the deceased in this case, but the report was not available at this time. The report is being sent to me by the University of Minnesota Hospitals and will be available if desired.

The second of the additional Lomotil intoxication cases is that of James Hesse, St. Paul, Minnesota, who expired on 9/1/63. The attending physician was Dr. Leonard Phillips, St. Paul, Minnesota. This is a case of a two-year-old white male admitted to St. Joseph's Hospital, St. Paul, Minnesota, on 8/29/63 in a comatose state. According to Dr. Leonard Phillips, the child was receiving Lomotil for a chronic diarrhea thought to be caused by teething. The child ingested 10 to 20 tablets of Lomotil, and according to a consulting pediatrician, Dr. Shirley Lanske of the University of Minnesota Hospitals, the patient was unresponsive from the time of admission until the time of death. According to Dr. Lanske, there was a time lapse of 12 to 15 hours between the time of ingestion and the time she saw the patient in the emergency room of St. Joseph's Hospital. The patient was receiving Lomotil tablets at least several days prior to the time of the overdosage. According to Dr. Phillips, this is a litigation case. The chart from St. Joseph's Hospital, St. Paul, Minnesota, on James Hesse is exhibit #13.

A drug reaction report was made out by Dr. Jarvis for the Ehrich case for the G. D. Searle Company. A copy was obtained and is submitted as part of exhibit #1, with the autopsy report. The information not filled in was left out by Dr. Jarvis because it was either available in the autopsy report or in the charts. Drug reaction reports have been filled out for the other two cases as truly as is possible. FRED S. HALVERSON, Inspector.

JUNE 29, 1966.

To: Acting Chief, DSB/DMR.

From: A. L. Kaminsky, M.D., Medical Officer, DSB/MBR.
Subject: Lomotil NDA12-462, 12-699. Toxicity and lethal effects in children.

(G. D. Searle & Co., Chicago, Ill., AF 13-505.)

Hospital records and autopsy protocols received in deaths of Terrence J. Erich 3 years old and James Besse 2 years old. The former due to toxicity to "therapeutic" (?) dose and the latter to overdosage.

Dr. Charles Jarvis, Pathologist to Children's Hospital, St. Paul, Minn., sums up the substance of the death in a letter to Dr. Goddard dated May 19, 1966 quote:

66

I gather they (Searle & Co.) do not know what an overdose is, or how it reacts on the living organism. I find this state of affairs appalling.

Conclusion

It was recommended in a Summary of Supplement of September 16, 1965 dated April 27, 1966 signed Aaron L. Kaminsky, M.D. that:

1. "Dosage Children: Delete entire section"

No studies have been performed using diphenexylate hydrochloride with 0.05 mg. atropine sulfate in children. The uncontrolled studies on children were accomplished using R1135 (diphenoxylate hydrochloride). Adverse reactions, including deaths, have been reported in children using therapeutic doses. Furthermore, fraction of tablets and teaspoons (varying from 4-5 cc.) are really not proper dosage forms for children who are very sensitive to the action of atropine. 2. "Summary: It is recommended that":

1. The drug be discontinued for children under 12 years of age. No valid, well controlled and double blind, studies were performed delineating the safety and efficiency of diphenoxylate hydrochloride with atropiue sulfate (0.025 mg.) for children.

2. A warning label to indicate the dangerous nature of the drug on children e.g. "Warning: Keep Out of Reach of Children, Dangerous Drug."

3. Labeling change are necessary as enumerated to labeling action. The labeling is in dire need of updating, correction, amendment, additions and deletion of dosage for children.

4. Atropine, even in subtherapeutic doses, should be removed from the mixture especially to obviate mortality in children.

It is the considered opinion of the undersigned, agreed to by G. M. Carroll, M.D. (Pediatrician), that Lomotil HC1 with atropine sulfate is not safe for children under 12 years of age. There are no adequate controlled studies for various age groups and for delineation of absorption, degradation, and excretion in children in a time sequence.

SUMMARY OF SUPPLEMENT

NDAS 12-462 (tablet), 12-699 (liquid).

G. D. Searle & Company, Chicago, Illinois AF 13-505.

App. Date: 9/29/60 (NDA 12-462) ; 1/17/61 (NDA 12–699).

Nov. 22, 1961 (Supplement).

Aug. 9, 1965 & Sept. 16, 1965-(Supplement).

Type of Drug.-Antidiarrheal.

Trade Name.-Lomotil.

Generic Name.-Diphenoxylate Hydrochloride and Atropine Sulfate 0.025 mg. (1/2400 gr.).

Dosage Form.-Tablets 2.5 mg. ; Liquid 2.5 mg. per 5 cc.

Date of Supplement.-Nov. 22, 1961, Aug. 9, 1965 and Sept. 16, 1965
Chemist Summary.—see Chemist Summary

Pharmacologist Summary.—No new pharmacology. Vol. I three III, 130.13 report of September 14, 1965.

Clinical Evaluation.-Diphenoxylate Hydrochloride, a congener of meperidine (Demerol) with atropine sulfate 0.025 mg. (Lomotil) is indicated in the treatment of diarrhea secondary to motor disturbance, acute or chronic diseases of the gastrointestinal tract, and systemic disease. It is an adjuvant to specific and general therapy for the various functional, organic and post operative disorders of the gastrointestinal tract manifested by diarrhea.

All studies cited as part of the NDA's were performed with diphenoxylate hydrochloride without atropine sulfate, which is now included in the mixture called Lomotil. The original liquid form was deleted from NDA 12-462 because of stability problems. The company modified the liquid dosage from 2.5 mg. per 4 cc., in NDA 12-699, to 2.5 mg. per 5 cc. to conform with that enumerated, in the approval as an exempt narcotic, in the Federal Register, Tuesday, July 25, 1961. The same studies used for NDA 12-462 were used in the application of NDA 12-699. Labeling remained unchanged. The drug was approved as Lomotil, (diphenoxylate hydrochloride with atropine sulfate), without any clinical, pharmacological, (animal and human) and toxicological data and studies evaluating actions, safety and efficacy of the drug as a mixture.

The company reported on 521 patients evaluated by 31 clinicians in the United States and one (1) in Belgium; 830 cases by 88 investigators in Belgium, France and the Belgium Congo. The studies were poorly controlled to uncontrolled, and testimonial as noted in an "Evaluation and Summary" by John Nestor, M.D., Vol. I (7 pages) dated 5/14/64 and Vol. II (7 pages) dated 7/21/64. G. van Dorstoppen et al, used R1132 (diphenoxylate hydrochloride) in 10 ileostomy patient's and evaluated the drug against a placebo. The drug was effective in 8 patients.

Isbell and Fraser, in a beautiful study, evaluated the abuse potential and addicting dosage for diphenoxylate hydrochloride. They found the drug nonaddicting in therapeutic doses.

The clinical reports indicated that the usefulness of the drug was greatest in the diarrhea associated with the irritable bowel syndrome, (functional bowel), and in the acute diarrhea. It was least effective in the diarrhea associated with moderate to severe regional enteritis, ulcerative colitis and other inflammatory disease of the bowels. The fact of that specific modalities of therapy were used must be noted, e.g. drug, supportive and psychologic. These, in themselves, may modify the diarrhea by either ameliorating and/or curing the underlying disorder. Lomotil is only an adjuvant in the treatment of diarrhea.

The only double blind study available to me was by H. Barowsky and S. A. Schwartz, JAMA 1962. They used Lomotil tablets, placebo and camphorated tincture of opium in 40 patients with varying diarrheal disorders. They concluded that, "at varying levels of daily dosage a 2.5 mg. dose of diphenoxylate hydrochloride (1 tablet) is equivalent in antidiarrhea efficacy to 4 cc. of camphorated tincture of opium." In mild cases, Lomotil tablets gave good results with a decreasing effectiveness with increasing dosage in moderate to severe conditions. The drug was found useful in chronic diarrhea where addiction to an opiate may be undesirable.

Clinical experience, as revealed in the reference section and the letter of Davis, DVM, (FDA) of the toxicology section, indicated safety and efficacy of the drug in tablet or liquid form for adults.

There are no valid or controlled clinical studies using diphenoxylate hydrochloride with atropine sulfate in children, pregnancy or lactation. Adverse reaction of serious import involving atropine toxicity have been reported in children; 13 with recovery, 6 with deaths, overdosage with tablet and liquid forms of the drug were responsible for 14 reactions with 4 deaths. Therapeutic dose regimens accounted for 2 deaths and 4 reactions with recovery; 1 child had permanent brain damage.

Review of Labeling.-Last approval date supplement September 24, 1965 and date of insert 1960 and 1961. The last, insert of 1961 reads as follows:

"References and a more detailed discussion of Lomotil are contained in Searle Physicians Product Brochure No. 81, available from the Medical Service Dept. G. D. Searle & Company, P.O. Box 5110, Chicago 80, Illinois." "September 5, 1961". The 1961 insert is an abbreviated 1960 new Product Brochure #81.

The physicians brochure and the insert are in dire need up updating, correction, amending with additions as noted below:

1. Contraindications.

2. Precautions.

3. Adverse reactions and deaths.

4. Overdose and treatment.

5. Antidotes.

6. Elimination of dosage for children.

A partial review of the Brochure #81 and drug insert dated in 1961 reveals the following deficiencies and need for change:

Page 1, par. 3 line 4:

Substitute: "but such agents have an addiction potential with long term use except in those individuals with a history of addiction or barbituation to narcotics in the past."

Instead of: "but such agents are frequently over constipating and they have a recognized addicting potential.”

A double blind study concluded 2.5 mg. Lomotil was effective as 4 cc. of camphorated tincture of opium (Barowsky and Schwartz). Codeine was preferred by a few patients to Lomotil (Bachrach and Voigtlin). Codeine, tincture of opium and other narcotics are not more constipating than Lomotil, a congener of meperidine (Demerol).

The addiction potential of a narcotic is type, time and dose related. The longer the use of a narcotic the greater the addiction or abuse potential. The only advantage of Lomotil, in therapeutic doses only, over the use of other narcotics for the treatment of a symptom, chronic diarrhea, it is minimal addicting potention on long term use.

Page 2 Clinical Application: line 1 delete "excessive" after "undergone."

Line 2: Substitute: "It, as an adjuvant to specific therapy and a general treatment program" for: "It is the sole treatment or as part of a general treatment program."

Line 12: Add after "regional enteritis" mild. It has been shown that moderate and severe inflammatory disease of the intestinal tract, e.g. regional enteritis, ulcerative colitis, acute ileitis of varying etiologies, etc., react poorly, if at all, to the administration of Lomotil and other narcotics.

A compensated incomplete intestinal obstruction secondary to the intrinsic granulamatous disease process of regional enteritis may be converted to a complete obstruction by the use of this drug; and, an ileus created in ulcerative colitis. (Sleisinger and Almy)

Line 14: Add "mild" after "ulcerative colitis". Poor results were reported in the use of Lomotil in moderate and severe ulcerative colitis. Precaution must be exercised in the use of the drug to obviate ileus with possible complicating toxic megacolon, perforation, etc.

Page 3, par. 2 line 3 beginning "Machella" change "6" to "8".

Line 4: Change "9" to "8".

Line 17: Add, after "seen no undesirable sequelae", the statement: "There were no efficacious results even with high dosage (40 mg. daily) in sprue, regional enteritis and fair to poor results in 5 cases of ulcerative colitis".

Line 18: After "have ever used" add in parenthesis (1 case). The testimonial of one case questions the accompanying quote of "it is the best I have ever used" in the brochure.

Page 5 par. 1 line 8: After "treatment" add 8 patients benefited from treatment. See authors summary and conclusions.

Par. 2 line 6: Add "which is generally a self limiting disease" instead of “effect in acute diarrhea."

Dosage Children: Delete entire section.

No studies have been performed using diphenoxylate hydrochloride with 0.05 mg. atropine sulfate in children. The uncontrolled studies on children were accomplished using R1135 (diphenoxylate hydrochloride). Adverse reactions, including deaths, have been reported in children using therapeutic doses. Furthermore, fraction of tables and teaspoons (varying from 4-5 cc.) are really not proper dosage forms for children who are very sensitive to the action of atropine. Par. 6-Side effects: Add: headache, lightheadedness, toxicosis, angioneurotic edema, giant urticaris, lethargy, anorexia, atropine effects, respiratory difficulty and coma.

NOTE.

The statement that "Side Effects are relatively rare" is not accurate e.g.:
Schwartz, 24 side effects in 53 pts. 24/53.
Bachrach, 2 side effects in 6 pts. 2/6.
Voigtlin, 5 side effects in 11 pts. 5/11.
Klotz, 4 side effects in 24 pts. 4/24.

Texter, 3 side effects in 15 pts. 3/15.
McGlone, 5 side effects in 24 pts. 5/24.

European study, 24/364.

(Severe enough to withdraw drug)

This does not constitute, in any language, statistically or otherwise infrequent reactions. nor can one justify the appellation of "relatively rare" to the number and type of reactions. Nausea, as one (1) symptom, was corrected in many instances by withdrawing the drug or reducing the dose. Can this deserve the statement that most cases of nausea were due to the underlying condition or it is apparent the drug contributed its share to the production of nausea in both adults and children?