UROTROPIN OMITTED FROM N. N. R.

Report of the Council on Pharmacy and Chemistry

Urotropin is a proprietary name applied to the substance which is known in chemical literature as hexa­methylene­tetramin and which is designated hexa­methylen­amine in the U. S. Pharmacopeia. The Council has authorized publication of the following report explaining that Urotropin was omitted from New and Non­official Remedies because Schering & Glatz, Inc. (the firm that markets this brand of hexa­methylen­amin in the United States), refused to place the U. S. Pharmacopeia name Hexa­methylen­amine (hexa­methylen­amina) on the label and in its advertising so as to make clear to physicians the identity of the product, and, furthermore, because it was sold under therapeutic claims which the Council held unwarranted.

W. A. Puckner, Secretary.

Commercial History of Hexamethylenamin

This substance which is generally referred to in chemical literature as hexa­methylene­tetramin, the cyclic condensation product of formaldehyd and ammonia, appears to have been described first in 1860 (Butlerow: Ann. d. Chem. 115:322, 1860). Subsequently, numerous references to the preparation, properties and constitution of the substance appeared in chemical literature.

Hexamethylenetetramin is said to have been first used for therapeutic purposes by G. Bardet, who, in 1894, reported to the Société de Thérapeutique that he believed this substance to be a uric acid solvent. At about the same period, A. Nicolaier, who gave Bardet credit for suggesting the use of hexa­methylene­tetramin as a uric acid solvent, announced the discovery of its antiseptic action (Centralbl. f. d. med. Wissensch. 32:897, 1894; Deutsche med. Wchnschr. 21:541, 1895). Shortly thereafter as a result of Nicolaier’s publication, the Chemische Fabrik auf Aktien vorm. E. Schering, Berlin, Germany, began to offer the product to the medical profession under the trademarked and nondescriptive name “Urotropine.” In the United States, it was marketed by Schering and Glatz, who then were acting as American agents for the Schering works of Germany.

It soon became evident that hexa­methylene­tetramin was a valuable drug. As the substance was introduced at a time when new “synthetic” drugs were rapidly appearing and when unlimited and uncritical confidence was placed in them, and before the medical profession became skeptical of the claims advanced by manufacturers for their respective “discoveries,” it was not long before this new drug was placed on the market by many firms, each applying its own name and often keeping the chemical character of it in the background. Some of the names which were thus applied to hexa­methylen­amin were Cystogen, Aminoform, Formin, Uritone, Urisol, {and} Cystamine.

In 1907 the late Prof. J. O. Schlotterbeck, then a member of the Council, protested against the confusion caused by the marketing of a given drug under different names. He stated that it was not uncommon for a physician to prescribe two or more of these identical substances in the same mixture, expecting to get the combined action of different urinary antiseptics; also, that patients had been treated first with hexa­methylen­amin under one name and later by the same substance under another name (The Journal, Jan. 19, 1907, p. 241).

Hexamethylenetetramin was admitted to the eighth revision of the U. S. Pharmacopeia. In part because of this official recognition and standard­ization and in part because the extravagant reports of its virtues had been largely discounted, physicians have in general prescribed the drug by its pharmacopeial name, with one notable exception: Urotropin. One reason for this is that Urotropin was the first proprietary brand of hexa­methylene­tetramin introduced, a second reason is that through the extensive and persistent advertising of the proprietary name under which the substance was introduced, it has become firmly fixed in the minds of many physicians. The other is that the product was claimed to be of greater purity than the product sold under the pharmacopeial or other name although no evidence confirmatory of this claim has ever been published. On the other hand, Daniel Base, as long ago as 1907, found that hexa­methylen­amin sold under its pharmacopeial name is just as pure as when sold under proprietary names. When, in 1907, urotropin was admitted to New and Non­official Remedies, the published description showed that it was manufactured by the Chemische Fabrik auf Aktien vorm. E. Schering, Berlin, and that Schering and Glatz were the United States agents. In 1919, the description was revised to show that Schering and Glatz were no longer selling the German product.

As it is the general practice to omit articles that are admitted to the U. S. Pharmacopeia for the reason that their quality is guaranteed under the federal Food and Drugs Act and because pharmacopeial nonproprietary articles are rarely advertised with claims that require the Council’s control, yet, in the case of Urotropin, it was retained because it was sold under a name not recognized in the pharmacopeia and because special (proprietary) claims were made for it.

Urotropin Marketed Under Unwarranted Therapeutic Claims

The period for which Urotropin stood “Accepted” expired with the close of 1921. To determine its continued eligibility for New and Non­official Remedies, the Council examined the labels and circular matter sent by Schering and Glatz for the purpose and also a booklet “Urotropin,” subsequently sent by the firm to physicians.

It was found that the pamphlet contained a number of unwarranted statements. Particularly objectionable are the claims made for the use of Urotropin as an antiseptic in body fluids that are alkaline, such as the cerebrospinal fluid, bile, aqueous humor of the eye, saliva, the excretions caused by middle ear infection and other excretions of the nasal, bronchial, laryngeal and mucous membranes. The lack of efficacy of hexa­methylen­amin in alkaline secretions is generally admitted and the clinical references to the use of hexa­methylen­amin in the pamphlet are obsolete. In the introduction to the pamphlet, Schering and Glatz state that they are well acquainted with the scientific research work discrediting the efficiency of hexa­methylen­amin in nonacid mediums, but that they feel that the accumulated evidence for its efficacy in such conditions should not be “brushed aside.” However, the pamphlet is not made up of quotations, but of unqualified statements. With one exception, all references to the antiseptic properties of the drug in alkaline mediums are previous to 1913, that is, before the importance of reaction of the medium was fully appreciated. To quote these earlier articles without regard to the later work, which in most eyes discredited them, constitutes in effect an exploitation of this brand of hexa­methylen­amin under unwarranted therapeutic claims.

Urotropin a Brand of Hexamethylenamine, U. S. P.

In consideration of the confusion which arises from the application of different names to an identical article, the rules of the Council provide that when an article which has been accepted for New and Non­official Remedies is admitted to the U. S. Pharmacopeia under another name, it will be retained, provided the official name is given prominence on the label and in the advertising of such article. Neither the label nor the advertising for Urotropin gives prominence to the pharmacopeial name as a synonym nor indeed does it bring out the fact that Urotropin is a brand of hexa­methylen­amine, U. S. P. Schering and Glatz, Inc., was advised that Urotropin could be retained in New and Non­official Remedies only on condition that the objections to the therapeutic recommendations were removed and on agreement that the U. S. P. name appear on the labels and circular matter. The firm did not offer to make the product eligible for continued recognition; accordingly the Council directed the omission of Urotropin because of conflict with Rule 6 (Unwarranted Therapeutic Claims) and with Rule 8 (Objectionable Names).—(From Reports of Council on Pharmacy and Chemistry, 1921, p 71.)