Food and Drug Administration, HHS § 201.304

§ 201.302 Notice to manufacturers, when taken in substantially larger packers, and distributors of drugs amounts. Actually, it is quite toxic for internal use which contain min- when taken in quantities of a teaspoon- eral oil. ful or more. Wintergreen oil and prep- (a) In the past few years research arations containing it have caused a studies have altered medical opinion as number of deaths through accidental to the usefulness and harmfulness of misuse by both adults and children. mineral oil in the human body. These Children are particularly attracted by studies have indicated that when min- the odor and are likely to swallow eral oil is used orally near mealtime it these products when left within reach. interferes with absorption from the di- (b) To safeguard against fatalities gestive tract of provitamin A and the from this cause, the Department of fat-soluble vitamins A, D, and K, and Health and Human Services will regard consequently interferes with the utili- as misbranded under the provisions of zation of calcium and phosphorus, with the Federal Food, Drug, and Cosmetic the result that the user is left liable to Act any drug containing more than 5 deficiency diseases. When so used in percent methyl salicylate (wintergreen pregnancy it predisposes to hemor- oil), the labeling of which fails to warn rhagic disease of the newborn. that use otherwise than as directed (b) There is accumulated evidence therein may be dangerous and that the that the indiscriminate administration article should be kept out of reach of of mineral oil to infants may be fol- children to prevent accidental poi- lowed by aspiration of the mineral oil soning. and subsequent ‘‘lipoid pneumonia.’’ (c) This statement of interpretation (c) In view of these facts, the Depart- in no way exempts methyl salicylate ment of Health and Human Services (wintergreen oil) or its preparations will regard as misbranded under the from complying in all other respects provisions of the Federal Food, Drug, with the requirements of the Federal and Cosmetic Act a drug for oral ad- Food, Drug, and Cosmetic Act. ministration consisting in whole or in part of mineral oil, the labeling of § 201.304 Tannic acid and barium which encourages its use in pregnancy enema preparations. or indicates or implies that such drug (a) It has become a widespread prac- is for administration to infants. tice for tannic acid to be added to bar- (d) It is also this Department’s view ium enemas to improve X-ray pictures. that the act requires the labelings of Tannic acid is capable of causing di- such drugs to bear a warning against minished liver function and severe consumption other than at bedtime liver necrosis when absorbed in suffi- and against administration to infants. cient amounts. The medical literature The following form of warning is sug- reports a number of deaths associated gested: ‘‘Caution: To be taken only at with the addition of tannic acid to bar- bedtime. Do not use at any other time ium enemas. There is a lack of sci- or administer to infants, except upon entific evidence to establish the condi- the advice of a physician.’’ tions, if any, under which tannic acid (e) This statement of interpretation is safe and effective for use in enemas. does not in any way exempt mineral oil Tannic acid for rectal use to enhance or preparations containing mineral oil X-ray visualization is regarded as a from complying in all other respects new drug within the meaning of section with the requirements of the Federal 201(p) of the Federal Food, Drug, and Food, Drug, and Cosmetic Act. Cosmetic Act. (b) In view of the hazards involved § 201.303 Labeling of drug prepara- when tannic acid is used in barium en- tions containing significant propor- emas, any shipments of tannic acid la- tions of wintergreen oil. beled to come within the exemptions (a) Because methyl salicylate (win- under 502(f) of the Act containing such tergreen oil) manifests no toxicity in phrases as: ‘‘Caution: For manufac- the minute amounts in which it is used turing, processing, or repackaging,’’ as a flavoring, it is mistakenly re- ‘‘For prescription compounding,’’ or garded by the public as harmless even ‘‘Diagnostic reagent—For professional

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use only’’ will be regarded by the Com- isoproterenol inhalation preparations. The missioner of Food and Drugs as mis- cause of this refractory state is unknown. It branded within the meaning of section is advisable that in such instances the use of 502(f) of the Federal Food, Drug, and this preparation be discontinued imme- diately and alternative therapy instituted, Cosmetic Act unless the label and the since in the reported cases the patients did labeling bear conspicuously a warning not respond to other forms of therapy until to the effect: ‘‘Warning— Not for use in the drug was withdrawn. enemas.’’ Deaths have been reported following exces- (c) Any tannic acid intended for use sive use of isoproterenol inhalation prepara- by man and found within the jurisdic- tions and the exact cause is unknown. Car- tion of the Federal Food, Drug, and diac arrest was noted in several instances. Cosmetic Act labeled contrary to this (c)(1) The Commissioner also con- section after 60 days from the date of cludes that in view of the manner in its publication in the FEDERAL REG- which these preparations are self-ad- ISTER may be made the subject of regu- ministered for relief of attacks of bron- latory proceedings. chial asthma and other chronic bron- § 201.305 Isoproterenol inhalation chopulmonary disorders, it is necessary preparations (pressurized aerosols, for the protection of users that warn- nebulizers, powders) for human ing information to patients be included use; warnings. as a part of the label and as part of any (a) Accumulating reports have been instructions to patients included in the received by the Food and Drug Admin- package dispensed to the patient as fol- istration and have appeared in the lows: medical literature of severe paradox- Warning: Do not exceed the dose prescribed ical bronchoconstriction associated by your physician. If difficulty in breathing with repeated, excessive use of persists, contact your physician imme- isoproterenol inhalation preparations diately. in the treatment of bronchial asthma (2) The warning on the label may be and other chronic bronchopulmonary accomplished (i) by including it on the disorders. The cause of this paradoxical immediate container label with a reaction is unknown; it has been ob- statement directed to pharmacists not served, however, that patients have not to remove the label or (ii) by including responded completely to other forms of therapy until use of the isoproterenol in the package a printed warning with inhalation preparation was discon- instructions to pharmacists to place tinued. In addition, sudden unexpected the warning on the container prior to deaths have been associated with the dispensing. excessive use of isoproterenol inhala- (d) The marketing of isoproterenol tion preparations. The mechanism of inhalation preparations may be contin- these deaths and their relationship, if ued if all the following conditions are any, to the cases of severe paradoxical met: bronchospasm are not clear. Cardiac (1) Within 30 days following the date arrest was noted in several of these of publication of this section in the cases of sudden death. FEDERAL REGISTER: (b) On the basis of the above informa- (i) The label and labeling of such tion and after discussion with and con- preparations shipped within the juris- currence of the Respiratory and Anes- diction of the act are in accordance thetic Drugs Advisory Committee for with paragraphs (b) and (c) of this sec- Food and Drug Administration, the tion. Commissioner of Food and Drugs con- (ii) The holder of an approved new- cludes that in order for the labeling of drug application for such preparation such drugs to bear adequate informa- submits a supplement to his new-drug tion for their safe use, as required by application to provide for appropriate § 201.100, such labeling must include the labeling changes as described in para- following: graphs (b) and (c) of this section. Warning: Occasional patients have been re- (2) Within 90 days following the date ported to develop severe paradoxical airway of publication of this section in the resistance with repeated, excessive use of FEDERAL REGISTER, the manufacturer,

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