"Diagnostic reagent-For professional use only" will be regarded by the Commissioner of Food and Drugs as misbranded within the meaning of section 502(f) of the Federal Food, Drug, and Cosmetic Act unless the label and the labeling bear conspicuously a warning to the effect: "Warning-Not for use in enemas."

(c) Any tannic acid intended for use by man and found within the jurisdiction of the Federal Food, Drug, and Cosmetic Act labeled contrary to this section after 60 days from the date of its publication in the FEDERAL REGISTER may be made the subject of regulatory proceedings.

§ 201.305 Isoproterenol inhalation preparations (pressurized aerosols, nebulizers, powders) for human use; warnings.

(a) Accumulating reports have been received by the Food and Drug Administration and have appeared in the medical literature of severe paradoxical bronchoconstriction associated with repeated, excessive use of isoproterenol inhalation preparations in the treatment of bronchial asthma and other chronic bronchopulmonary disorders. The cause of this paradoxical reaction is unknown; it has been observed, however, that patients have not responded completely to other forms of therapy until use of the isoproterenol inhalation preparation was discontinued. In addition, sudden unexpected deaths have been associated with the excessive use of isoproterenol inhalation preparations. The mechanism of these deaths and their relationship, if any, to the cases of severe paradoxical bronchospasm are not clear. Cardiac arrest was noted in several of these cases of sudden death.

(b) On the basis of the above information and after discussion with and concurrence of the Respiratory and Anesthetic Drugs Advisory Committee for Food and Drug Administration, the Commissioner of Food and Drugs concludes that in order for the labeling of such drugs to bear adequate information for their safe use, as required by § 201.100, such labeling must include the following:

Warning: Occasional patients have been reported to develop severe paradoxical

airway resistance with repeated, excessive use of isoproterenol inhalation preparations. The cause of this refractory state is unknown. It is advisable that in such instances the use of this preparation be discontinued immediately and alternative therapy instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn.

Deaths have been reported following excessive use of isoproterenol inhalation preparations and the exact cause is unknown. Cardiac arrest was noted in several instances.

(c)(1) The Commissioner also concludes that in view of the manner in which these preparations are self-administered for relief of attacks of bronchial asthma and other chronic bronchopulmonary disorders, it is necessary for the protection of users that warning information to patients be included as a part of the label and as part of any instructions to patients included in the package dispensed to the patient as follows:

Warning: Do not exceed the dose prescribed by your physician. If difficulty in breathing persists, contact your physician immediately.

(2) The warning on the label may be accomplished (i) by including it on the immediate container label with a statement directed to pharmacists not to remove the label or (ii) by including in the package a printed warning with instructions to pharmacists to place the warning on the container prior to dispensing.

(d) The marketing of isoproterenol inhalation preparations may be continued if all the following conditions are met:

(1) Within 30 days following the date of publication of this section in the FEDERAL REGISTER:

(i) The label and labeling of such preparations shipped within the jurisdiction of the act are in accordance with paragraphs (b) and (c) of this section.

(ii) The holder of an approved newdrug application for such preparation submits a supplement to his new-drug application to provide for appropriate labeling changes as described in paragraphs (b) and (c) of this section.

(2) Within 90 days following the date of publication of this section in

the FEDERAL REGISTER, the manufacturer, packer, or distributor of any drug containing isoproterenol intended for inhalation for which a new-drug approval is not in effect submits a new-drug application containing satisfactory information of the kinds required by § 314.50 of this chapter, including appropriate labeling as described in paragraphs (b) and (c) of this section.

(3) The applicant submits additional information required for the approval of the application as may be specified in a written communication from the Food and Drug Administration.

(e) After 270 days following expiration of said 90 days, regulatory proceedings based on section 505(a) of the Federal Food, Drug, and Cosmetic Act may be initiated with regard to any such drug shipped within the jurisdiction of the act for which an approved new-drug application is not in effect.

[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]

§ 201.306 Potassium salt preparations intended for oral ingestion by man. (a) The Food and Drug Administration will initiate no regulatory action with respect to the continued marketing of coated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet provided all the following conditions are met:

(1) Within 30 days from the date of publication of this statement of policy in the FEDERAL REGISTER:

(i) The labeling of the drug bears the prescription caution statement quoted in section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act;

(ii) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the "full disclosure" labeling requirements of § 201.100 of this chapter, including the following warning statement: "Warning-There have been several reports, published and unpublished, concerning nonspecific small-bowel lesions consisting of stenosis, with or without ulceration, associated with the administration of enteric-coated thiazides with potassium salts. These lesions may occur with en

teric-coated potassium tablets alone or when they are used with nonentericcoated thiazides, or certain other oral diuretics. These small-bowel lesions have caused obstruction, hemorrhage, and perforation. Surgery was frequently required and deaths have occurred. Based on a large survey of physicians and hospitals, both United States and foreign, the incidence of these lesions is low, and a causal relationship in man has not been definitely established. Available information tends to implicate enteric-coated potassium salts, although lesions of this type also occur spontaneously. Therefore, coated potassium-containing formulations should be administered only when indicated, and should be discontinued immediately if abdominal pain, distention, nausea, vomiting, or gastrointestinal bleeding occur. Coated potassium tablets should be used only when adequate dietary supplementation is not practicable."

(Although the warning statement includes references to enteric-coated potassium salt preparations, it applies to any capsule or coated tablet of a potassium salt intended for oral ingestion without prior dilution with an adequate volume of liquid to preclude gastrointestinal injury.)

(iii) Any other labeling or additional advertising for the drug conforms to the labeling described in paragraph (a) (1) (ii) of this section, in accordance with §§ 202.1 and 201.100 of this chapter.

(2) Within 90 days from the date of publication of this statement of policy in the FEDERAL REGISTER, the manufacturer, packer, or distributor of the drug shall submit a new-drug application containing satisfactory information of the kind required by § 314.50 of this chapter, with appropriate labeling as described in this paragraph.

(b) The Food and Drug Administration may initiate regulatory proceedings after 30 days from the date of publication of this section, with respect to the marketing of uncoated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet or with respect to liquid preparations containing potassium

chloride or other potassium salts which supply 20 milligrams or more of potassium per milliliter, labeled or intended for human use, unless all the following conditions are met:

(1) The labeling of the drug bears the prescription caution statement quoted in section 503(b) (4) of the Federal Food, Drug, and Cosmetic Act; and

(2) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the "full disclosure" labeling requirements of § 201.100 of this chapter, including a recommendation that patients be directed to dissolve any such tablets in an appropriate amount of liquid and to dilute any such liquid preparations adequately to assure against gastrointestinal injury associated with the oral ingestion of concentrated potassium salt preparations.

[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]

§ 201.307 Chlorcyclizine, cyclizine, meclizine; warnings; labeling requirements. (a) The Food and Drug Administration, pursuant to its responsibility for the safety and effectiveness of drugs, has conducted active investigations of reports of available animal data which reveal that chlorcyclizine hydrochloride, cyclizine hydrochloride and lactate, and meclizine hydrochloride exert a teratogenic response in animals such as the rat, mouse, rabbit, pig, and dog. While clinical studies to date are inconclusive, scientific experts are of the opinion that these drugs may possess a potential for adverse effects on the human fetus. Investigations have led to the conclusion that there exists sufficient evidence of teratogenicity in animals administered these drugs to justify warnings against their use in pregnancy except on advice of a physician. An Ad Hoc Advisory Committee on the Teratogenic Effect of Certain Drugs, comprised of scientists in various branches of medicine concerned with the problem, has submitted its findings and conclusions to the Commissioner of Food and Drugs and has recommended that all over-the-counter preparations contain

ing chlorcyclizine, cyclizine, or meclizine or their salts bear a warning.

(b) On the basis of studies made by the Food and Drug Administration and on the recommendations of the Advisory Committee, the Commissioner of Food and Drugs has concluded that it is necessary for the protection of users that the label and labeling of all over-the-counter preparations containing chlorcyclizine, cyclizine, or meclizine or their salts bear a statement to the following effect: "Warning— Not for use by women who are pregnant or who may possibly become pregnant, unless directed by a physician, since this drug may have the potentiality of injuring the unborn child."

(c) The marketing of oral and parenteral drugs containing chlorcyclizine, cyclizine, or meclizine or their salts may be continued provided that all the following conditions are met:

(1) Within 30 days from the date of publication of this statement in the FEDERAL REGISTER.

(i) The label and applicable labeling of drugs containing chlorcyclizine, cyclizine, or meclizine or their salts at acceptable levels for over-the-counter distribution, shall prominently and conspicuously display the statement: "Warning-Not for use by women who are pregnant or who may possibly become pregnant, unless directed by a physician, since this drug may have the potentiality of injuring the unborn child."

(ii) The package labeling and other labeling providing professional use information concerning prescription drugs containing chlorcyclizine, cyclizine, or meclizine or their salts and not contraindicated for use in pregnancy because of some other ingredient, shall bear, in accordance with § 201.100* of this chapter, a section under "Adverse Reactions" headed "Use in Pregnancy," as follows:

The following information should be taken into account in determining whether the potential benefits of [chlorcyclizine, cyclizine, meclizine, or their salts] outweigh the risks of their use in women of childbear

*Section 202.1 will require that prescription drug advertising contain this warning.

ing age and particularly during pregnancy. A review of available animal data reveals that this drug exerts a teratogenic response in the [rat, mouse, rabbit, pig, dog]. While available clinical data are inconclusive, scientific experts are of the opinion that this drug may possess a potential for adverse effects on the human fetus. Consequently, consideration should be given to initial use of a nonphenothiazine agent that is not suspected of having a teratogenic potential. In any case, the dosage and duration of treatment should be kept to a minimum.

This statement shall be followed with an appropriate summary of the pertinent animal studies and adverse clinical experiences, with adequate references to the scientific literature. Also, the labeling shall contain, in juxtaposition with any representation for use in the treatment of nausea and vomiting in pregnancy, the following statement:

The effectiveness of for the prevention and treatment of nausea and vomiting of pregnancy has not been established, and the decision to use---should be based on the seriousness of the situation, remembering that while this drug has been used clinically for a decade, there are yet no controlled studies to demonstrate its usefulness in an objective fashion. In most cases, nausea and vomiting of pregnancy may be unpleasant but do not present a serious threat to the health of the patient or to the progress of her pregnancy. In view of the desirability of keeping the administration of all drugs to a minimum during pregnancy, management by physiologic means such as proper nutrition and by psychologic support is preferable to antiemetic therapy.

(2) Within 30 days from the date of publication of this statement of policy in the FEDERAL REGISTER, the applicant under an approved new-drug application for a drug containing chlorcyclizine, cyclizine, or meclizine or their salts shall submit a supplement to his new-drug application, providing for appropriate labeling changes as described in paragraphs (c) (1) (i) or (ii) of this section.

(3) Within 90 days from the date of publication of this statement of policy in the FEDERAL REGISTER, the manufacturer, packer, or distributor of any drug containing chlorcyclizine, cyclizine, or meclizine or their salts for which a new-drug approval is not in effect shall submit a new-drug application containing satisfactory informa

tion of the kinds required in the newdrug application (see § 314.50 of this chapter), including appropriate labeling as described in paragraphs (c) (1) (i) or (ii) of this section.

of

(d) In view of the fact that no substantial evidence has been offered for the effectiveness of chlorcyclizine, cyclizine, and meclizine or their salts in the prevention and treatment nausea and vomiting of pregnancy, but mindful of the fact that some practicing physicians believe that these drugs exert a beneficial effect upon this condition, the Food and Drug Administration will permit a modified claim in indications for this use for a period not exceeding 2 years. However, this modified indication for use of these drugs in the prevention and treatment of nausea and vomiting of pregnancy will be deleted from the labeling unless substantial evidence is offered before the expiration of this period of time. The Food and Drug Administration will also continue to follow the largescale surveys of clinical experience and any reports of adverse reaction that may be due to the use of these drugs under the revised labeling.

[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]

EFFECTIVE DATE NOTE: At 57 FR 58374, Dec. 9, 1992, §201.307 was removed, effective Dec. 9, 1993.

§ 201.308 Ipecac syrup; warnings and directions for use for over-the-counter sale.

(a) It is estimated that each year about 500,000 accidental poisonings occur in the United States and result in approximately 1,500 deaths, of which over 400 are children. In the emergency treatment of these poisonings, ipecac syrup is considered the emetic of choice. The immediate availability of this drug for use in such situations is critical, since rapid treatment may be the difference between life and death. The restriction of this drug to prescription sale limits its availability in emergencies. On the other hand, it is the consensus of informed medical opinion that ipecac syrup should be used only under medical supervision in the emergency treatment of poisonings. In view of these

facts, the question of whether ipecac syrup labeled as an emergency treatment for use in poisonings should be available over the counter has been controversial.

(b) In connection with its study of this problem, the Food and Drug Administration has obtained the views of medical authorities. It is the unanimous recommendation of the American Academy of Pediatrics, the American Association of Poison Control Centers, the American Medical Association, and the Medical Advisory Board of the Food and Drug Administration that ipecac syrup in 1 fluid ounce containers be permitted to be sold without prescription so that it will be readily available in the household for emergency treatment of poisonings, under medical supervision, and that the drug be appropriately packaged and labeled for this purpose.

(c) In view of the above recommendations, the Commissioner of Food and Drugs has determined that it is in the interest of the public health for ipecac syrup to be available for sale without prescription, provided that it is packaged in a quantity of 1 fluid ounce (30 milliliters), and its label bears, in addition to other required label information, the following, in a prominent and conspicuous manner:

(1) A statement conspicuously boxed and in red letters, to the effect: "For emergency use to cause vomiting in poisoning. Before using, call physician, the Poison Control Center, or hospital emergency room immediately for advice."

(2) A warning to the effect: "Warning-Keep out of reach of children. Do not use in unconscious persons. Ordinarily, this drug should not be used if strychnine, corrosives such as alkalies (lye) and strong acids, or petroleum distillates such as kerosine, gasoline, coal oil, fuel oil, paint thinner, or cleaning fluid have been ingested."

(3) Usual dosage: 1 tablespoon (15 milliliters) in persons over 1 year of age.

§ 201.309 Acetophenetidin

(phenacetin)

containing preparations; necessary warning statement.

(a) In 1961, the Food and Drug Administration, pursuant to its statutory

responsibility for the safety and effectiveness of drugs shipped in interstate commerce, began an active investigation of reports of possible toxic effects and renal damage due to misuse of the drug acetophenetidin. This study led to the decision that there was proba ble cause to conclude that misuse and prolonged use of the drug were in fact responsible for kidney lesions and disease. The Commissioner of Food and Drugs, in December 1963, appointed an ad hoc Advisory Committee of Inquiry on Possible Nephrotoxicity Associated With the Abuse of Acetophenetidin (Phenacetin)-Containing Preparations. This committee, composed of scientists in the fields of pharmacology and medicine, on April 23, 1964, submitted its findings and conclusions in the matter and recommended that all acetophenetidin (phenacetin)-containing preparations bear a warning as provided in section 502(f)(2) of the Federal Food, Drug, and Cosmetic Act.

(b) On the basis of the studies made by the Food and Drug Administration and the report of the Advisory Committee, the Commissioner of Food and Drugs has concluded that it is necessary for the protection of users that the label and labeling of all acetophenetidin (phenacetin)-containing preparations bear a warning statement to the following effect: "Warning-This medication may damage the kidneys when used in large amounts or for a long period of time. Do not take more than the recommended dosage, nor take regularly for longer than 10 days without consulting your physician.”

§ 201.310 Phenindione; labeling of drug preparations intended for use by man. (a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that phenindione, a synthetic anticoagulant drug, has caused a number of cases of agranulocytosis (with two fatalities). There are also reports implicating the drug in cases of hepatitis and hypersensitivity reactions. In view of the potentially serious effects found to be associated with preparations of this drug intended for use by man, the Commissioner of Food and Drugs will regard such preparations as misbrand