We will be most happy to answer any questions or comments that you may have on Torecan or any other of our drugs. Sincerely, CRAIG D. BURRELL, M.D., Director Medical Services. GEIGY PHARMACEUTICALS, Yonkers, N.Y., November 27, 1962. DEAR DOCTOR: The November 17, 1962 issue of the British Medical Journal carried a letter to the editor concerning a woman who had taken Preludin®, brand of phenmetrazine hydrochloride and who had been delivered of two children with severe congential defects of the left diaphragm. Although this internal defect bears no relation to phocomelia, the authors reviewed the patient's history of drug therapy during early pregnancy, and reported that she had taken Preludin between the fourth and twelfth weeks of pregnancy. We enclose a reproduction of the full publication. Apparently, the history of drug ingestion "on the advice of a friend" was obtained in retrospect years after the event. There is also no information concerning the nature of two earlier miscarriages in the same patient. The recurrence of congential defects in repeated pregnancies of the same woman is well recognized. Butler and Claireaux (Lancet, March 31, 1962, pp. 659– 663, "Congential Diaphragmatic Hernia as a Cause of Perinatal Mortality") described this phenomenon and cite inherited factors and several common complications of pregnancy as possibly etiologic. Their description of pathologic findings closely parallels that reported in the British Medical Journal, and includes an instance of two infants with diaphragmatic hernia born to the same mother eight years apart. It is estimated that there have been over ten million patient months of therapy with Preludin in the United States. Approximately 85% of these patients were females, and about 5 to 10% of them had obtained their prescriptions from obstetricians. We estimate that about 500,000 pregnant women received Preludin in the United States. There has been no evidence of a change in incidence of fatal diaphragmatic hernia as compared to the pre-Preludin era and we know of no other reports suggesting any type of congential problems in relation to Preludin. Accordingly, we believe that the position of Preludin in the treatment of obesity has not been altered by the recent publication in England. In general, we can understand the view expressed in some medical circles that no drug should be employed during early pregnancy unless the physician feels there is a clear need for it. However, we see no reason why Preludin differs from literally hundreds of other commonly used drugs in this respect. Only the physician can evaluate the dangers of obesity to the health of each individual patient, and match this with the therapeutic measures he deems advisable. Sincerely yours, HART E. VAN RIPER, M.D., Medical Director. G. D. SEARLE & CO., Chicago, Ill., August 7, 1962. IMPORTANT-DRUG CAUTION DEAR DOCTOR: We are addressing this letter to you in keeping with our policy of bringing to you all of the pertinent facts concerning our products and as a response to recent publicity dealing with the occurrence of thrombo-embolic phenomena coincident with women receiving Enovid. Since its introduction there have been reported to us as of this date 28 cases of thrombo-embolic disease in the more than one million users of Enovid in the United States. Among these were 10 cases of pulmonary embolism, 5 of which were fatal. In addition, there are press reports of 4 cases, including 1 death from the United Kingdom. In some of these one or more of the usually accepted inciting causes of thrombophlebitis were evident; in some they were not. Reports to the manufacturer do not reflect the accurate incidence of reactions and the available statistics are not adequate to determine whether or not there is a causal relationship, but caution requires consideration of this possibility. It must be remembered that pulmonary embolism can occur without discernible inciting cause and without preceding peripheral thrombophlebitis. Nevertheless, careful studies by investigators experienced in the measurement of the extremely complex factors involved in the clotting mechanism are continuing, including an evaluation of the role of fluid accumulation sometimes seen after Enovid administration. This will be reported in a technical bulletin at an early date. At the present time the available laboratory data neither prove nor disprove a causal relationship between Enovid administration and the occurrence of thrombophlebitis. The cases of thromphlebitis reported to us have usually occurred early in the course of Enovid administration and at the lower dosage level. Experience based on patients taking Enovid at higher doses has not demonstrated any dose response relationship. Physicians should be as alert to the possible occurrence of thrombophlebitis in patients to whom Enovid is prescribed as they are in patients taking other medication. The above facts should be given particular attention if Enovid is considered for administration to patients with thrombotic disease or a history of thromphlebitis. We request that any thrombo-embolic occurrence in women receiving Envoid be reported to us and to the Food and Drug Administration. Sincerely yours, IRWIN C. WINTER, Ph. D., M.D., Vice President, Medical Affairs. THE WM. S. MERRELL CO., Cincinnati, Ohio, April 17, 1962. DEAR DOCTOR: This letter is to inform you of the Merrell decision to withdraw MER/29 (triparanol) from the market. We are today, with the cooperation of the Federal Food & Drug Administration, asking all hospital and retail pharmacies, as well as other possible outlets, to return immediately their total stock of this drug. This decision is based on additional reports of side effects of the kind reported to you in our letter of December 1, 1961, some of which have occurred at the usual dosage. It is recommended that you have your patients discontinue use of MER/29. As you probably know, Merrell has had and will continue to have an extensive research program in cardiovascular disease. MER/29 has been one important phase of this effort. The work on this compound by us and many others has made contributions to basic knowledge in this field. We would appreciate any data you may be able to furnish us concerning your own past experience with this drug. Such data are most useful when supplied in case history form. Sincerely yours, FRANK N. GETMAN. PFIZER LABORATORIES, DEAR DOCTOR: Enclosed you will find a copy of the new Product Brochure for our multi-spectrum antibiotic, Signemycin. In October 1961, we informed you that studies were in progress to investigate reports of changes in tests of liver function in some patients treated with triacetyloleandomycin. Confirmatory studies have been concluded and the results have led to revisions which have been incorporated in the new Product Brochure. DEAR DOCTOR: In spite of extensive pre-marketing clinical and animal studies which indicated a wide margin of safety, an occasional patient has developed agranulocytosis in association with the administration of Monase. Because of this unforeseen and nonpredictable occurrence, The Upjohn Company in cooperation with the Federal Food and Drug Administration is withdrawing Monase from the market. It has not been possible to establish definitely that Monase was the sole causative agent in every case since other drugs were sometimes administered concurrently. However, in each instance, Monase was the common factor. We request that you instruct your patients to discontinue Monase. Refund for returned tablets will be arranged through the dispensing pharmacist. Very sincerely yours, EARL L. BURBIDGE, M.D. THE WM. S. MERRELL Co., Cincinnati, Ohio, February 21, 1962. DEAR DOCTOR: On December 5th, 1961 we advised you of the possible relationship of congenital malformations observed abroad in offsprings of certain patients who had taken thalidomide (Kevadon in Canada) early in pregnancy. This letter is to summarize the current status. There still is no positive proof of a causal relationship between the use of thalidomide during pregnancy and malformations in the newborn. Reports are now appearing in the medical literature indicating only that thalidomide was employed in certain cases where malformation developed. The research necessary to determine whether or not such malformation may indeed be related to the drug is continuing and because of the complexity of the problem will require considerable time. It is encouraging to note that studies in pregnant rats have not shown a single malformation in more than 1,100 offsprings of thalidomide-treated animals. Additional surveys are under way to determine if there has been an increase in the incidence of malformations both in countries where thalidomide has been extensively employed as a sedative/hypnotic and in certain other countries where it is not marketed. In view of the complexity of the problem and the time required to delineate the facts, the contraindication stated in our December 5th letter is still necessary. A new and fully descriptive brochure containing the contraindication to the use of Kevadon in women of child-bearing age will reach you shortly. Sincerely yours, JOHN N. PREMI, M.D., Medical Director. WYETH LABORATORIES, Philadelphia, Pa., January 23, 1962. NEW INFORMATION-TRIACETYLOLEANDOMYCIN DEAR DOCTOR: In October 1961, I informed you of the occurrence of jaundice and hepatic biochemical abnormalities resulting from the administration of triacetyloleandomycin administered in doses of one gram (1 Gm.) per day for periods of two weeks and longer. These observations have been confirmed by further studies and appropriate changes have now been incorporated in our directions for use of triacetyloleandomycin, Wyeth, Cyclamycin®. A copy of the revised directions for use is enclosed for your study and reference. Additional studies of triacetyloleandomycin, Cyclamycin, administered in doses of one gram (1 Gm.) per day for one week reveal no significant hepatic abnormality and that the drug is safe for use by the recommended dosage schedule. The effectiveness of triacetyloleandomycin, Cyclamycin, is such that prolonged therapy is seldom required in the treatment of most common susceptible infections for which it is recommended. Sincerely yours, GEORGE E. FARRAR, Jr., M.D., Medical Director. J. B. ROERIG & CO., New York, N. Y., January 1962. DEAR DOCTOR: We are pleased to report to you in the enclosed new prescription information the current status of our antibiotic products TAO, and TAOMID. These revised brochures are based on extensive, carefully controlled clinical studies and provide you with complete prescription information for your guidance in the use of our TAO products in your practice As you may recall, in October 1961, we advised the medical profession of two preliminary studies in which abnormal changes in liver function tests had been observed following the administration of TAO for 14 days or longer. These observations have been confirmed by further studies and appropriate changes have now been incorporated in our directions for use of our TAO product. The effectiveness of TAO is such that prolonged therapy is seldom required in the treatment of most common susceptible infections for which it is recommended. It is therefore concluded that you may continue to employ TAO in your practice with full confidence in the treatment of acute bacterial infection including cases due to staphylococci resistant to other antibiotics, in accordance with the enclosed prescription information. Sincerely yours, JOHN L. WATTERS, M.D., Medical Director. THE WM. S. MERRELL Co., Cincinnati, Ohio, December 5, 1961. DRUG WARNING-KEVADON DEAR DOCTOR: We have received information from abroad on the occurrence of congenital malformations in the offspring of a few mothers who had taken thalidomide (marketed in Canada as Kevadon) early in their pregnancies It is impossible at this time to determine whether, in fact, there is any causal relationship. However, until definitive information is available to us, as a precaution we are adding the following contraindication to the use of Kevadon : Kevadon should not be administered to pregnant women nor to premenopausal women who may become pregnant. We are actively following this matter and you will be advised when it is finally determined whether or not this precautionary step was necessary Sincerely yours, JOHN N. PREMI, M.D., THE WM. S. MERRELL Co., Cincinnati, Ohio, December 1, 1961. DRUG WARNING-MER/29 (TRIPARANOL) DEAR DOCTOR: In cooperation with the United States Food and Drug Administration, we are writing to inform and caution you concerning adverse effects, including some unpublished reports, associated with the use of MER/29 (triparanol). Although comparatively few serious clinical injuries have been reported to date, their possible significance is emphasized by findings from animal studies. Cataracts. Four cases of cataracts in humans are reported in patients who have received MER/29. One of these cases occurred in a patient receiving the recommended dosage of 250 mg. of MER/29 daily. Cataracts and corneal opacities have also been produced with MER/29 in animals. Slit lamp examinations are necessary for early detection of developing cataracts. For this reason such examinations are indicated prior to and periodically during therapy. Before this problem came to our attention, approximately one thousand persons being treated with MER/29 were patients of ophthalmologists. Most of them have had careful eye examinations, including use of the slit lamp, before and during drug therapy. Results on these patients will be reported to you as soon as they are available. Hair Changes. There have been many cases of hair loss, either baldness or thinning of hair, changes in hair color and texture, and loss of body hair. Such hair changes may be related to the skin change discussed below as well as to the eye changes discussed above. It is recommended that MER/29 therapy be discontinued promptly at the first evidence of hair or skin changes to minimize progressive effects possible including eye injury. Ichthyosis and other skin changes. There are reports of skin reactions ranging from dryness, itching, and scaling to severe exfoliation, and ichthyosis. Some of these changes were also associated with hair loss and cataracts. It is recommended that MER/29 therapy be stopped immediately if such skin changes occur. Depression of Adrenocortical Function. Adrenocortical function depression as shown by reduced output of adrenal steroids has been produced by MER/29 in animals, and in man at high dosage levels. This effect has not been ruled out in humans at recommended dosage levels. Appropriate precautions should be observed if MER/29 is employed in patients with suspected borderline adrenocortical function or in patients who are subjected to stress. Other Adverse Effects. Other adverse clinical effects reported include 4 possible cases of leukopenia and scattered cases of abnormal liver function tests, impotence, diminished libido, veginal smear alterations, nausea, vomiting and urine test changes simulating proteinuria. At a level of 25 mg/kg per day of MER/29 deaths have occurred in some dogs within 35 days, with liver damage in some animals. It has caused abortion and prevented conception in rodents, diminished spermatogenesis in dogs, stopped egg laying in chickens, and was assumed to cause acute intravascular hemolytic episodes in some dogs in one study. The side effects of all types reported to us to date total substantially less than one percent of the patients treated. This includes a number of patients who have been treated with MER/29 in clinical research studies for continuous periods of more than a year, including a few in excess of three years. In view of all reports concerning adverse effects, it is recommended that MER/29 be used only in patients who can be maintained under very close supervision and frequent observation. Dosage should never exceed 250 mg. per day. Further studies are under way to assess more fully the incidence and seriousness of adverse effects, with a view to a re-evaluation of the conditions and indications for use of MER/29. We will appreciate any information you may contribute from your clinical experience with MER/29. Sincerely, CARL A. BUNDE, PH. D., M.D., (Whereupon, at 4:20 p.m. the subcommittee was adjourned to reconvene at 10 a.m., Tuesday, November 28, 1967.) |