21 CFR Part 310 — New Drugs

PART 310—NEW DRUGS Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 360j, 360hh-360ss, 361(a), 371, 374, 375, 379e, 379k-l; 42 U.S.C. 216, 241, 242(a), 262. Subpart A—General Provisions § 310.3 Definitions and interpretations. As used in this part: (a) The term act et seq., (b) Department (c) Secretary (d) Commissioner (e) The term person (f) The definitions and interpretations of terms contained in section 201 of the act shall be applicable to such terms when used in the regulations in this part. (g) New drug substance (h) The newness of a drug may arise by reason (among other reasons) of: (1) The newness for drug use of any substance which composes such drug, in whole or in part, whether it be an active substance or a menstruum, excipient, carrier, coating, or other component. (2) The newness for a drug use of a combination of two or more substances, none of which is a new drug. (3) The newness for drug use of the proportion of a substance in a combination, even though such combination containing such substance in other proportion is not a new drug. (4) The newness of use of such drug in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body. (5) The newness of a dosage, or method or duration of administration or application, or other condition of use prescribed, recommended, or suggested in the labeling of such drug, even though such drug when used in other dosage, or other method or duration of administration or application, or different condition, is not a new drug. (i) [Reserved] (j) The term sponsor (k) The phrase related drug(s) (l) Special packaging (m) [Reserved] (n) The term radioactive drug [39 FR 11680, Mar. 29, 1974, as amended at 39 FR 20484, June 11, 1974; 40 FR 31307, July 25, 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. 22, 1985] § 310.4 Biologics; products subject to license control. (a) If a drug has an approved license under section 351 of the Public Health Service Act (42 U.S.C. 262 et seq. et seq. (b) To obtain marketing approval for radioactive biological products for human use, as defined in § 600.3(ee) of this chapter, manufacturers must comply with the provisions of § 601.2(a) of this chapter. [64 FR 56448, Oct. 20, 1999, as amended at 70 FR 14981, Mar. 24, 2005] § 310.6 Applicability of “new drug” or safety or effectiveness findings in drug efficacy study implementation notices and notices of opportunity for hearing to identical, related, and similar drug products. (a) The Food and Drug Administration's conclusions on the effectiveness of drugs are currently being published in the Federal Register (b)(1) An identical, related, or similar drug includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety as well as of any drug moiety related in chemical structure or known pharmacological properties. (2) Where experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs would conclude that the findings and conclusions, stated in a drug efficacy notice or notice of opportunity for hearing, that a drug product is a “new drug” or that there is a lack of evidence to show that a drug product is safe or effective are applicable to an identical, related, or similar drug product, such product is affected by the notice. A combination drug product containing a drug that is identical, related, or similar to a drug named in a notice may also be subject to the findings and conclusions in a notice that a drug product is a “new drug” or that there is a lack of evidence to show that a drug product is safe or effective. (3) Any person may request an opinion on the applicability of such a notice to a specific product by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section. (c) Manufacturers and distributors of drugs should review their products as drug efficacy notices are published and assure that identical, related, or similar products comply with all applicable provisions of the notices. (d) The published notices and summary lists of the conclusions are of particular interest to drug purchasing agents. These agents should take particular care to assure that the same purchasing policy applies to drug products that are identical, related, or similar to those named in the drug efficacy notices. The Food and Drug Administration applies the same regulatory policy to all such products. In many instances a determination can readily be made as to the applicability of a drug efficacy notice by an individual who is knowledgeable about drugs and their indications for use. Where the relationships are more subtle and not readily recognized, the purchasing agent may request an opinion by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section. (e) Interested parties may submit to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Compliance, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, the names of drug products, and of their manufacturers or distributors, that should be the subject of the same purchasing and regulatory policies as those reviewed by the Drug Efficacy Study Group. Appropriate action, including referral to purchasing officials of various government agencies, will be taken. (f) This regulation does not apply to OTC drugs identical, similar, or related to a drug in the Drug Efficacy Study unless there has been or is notification in the Federal Register [39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990; 74 FR 13113, Mar. 26, 2009] Subpart B—Specific Administrative Rulings and Decisions § 310.100 New drug status opinions; statement of policy. (a) Over the years since 1938 the Food and Drug Administration has given informal advice to inquirers as to the new drug status of preparations. These drugs have sometimes been identified only by general statements of composition. Generally, such informal opinions were incorporated in letters that did not explicitly relate all of the necessary conditions and qualifications such as the quantitative formula for the drug and the conditions under which it was prescribed, recommended, or suggested. This has contributed to misunderstanding and misinterpretation of such opinions. (b) These informal opinions that an article is “not a new drug” or “no longer a new drug” require reexamination under the Kefauver-Harris Act (Public Law 87-781; 76 Stat. 788-89). In particular, when approval of a new drug application is withdrawn under provisions of section 505(e) of the Federal Food, Drug, and Cosmetic Act, a drug generally recognized as safe may become a “new drug” within the meaning of section 201(p) of said act as amended by the Kefauver-Harris Act on October 10, 1962. This is of special importance by reason of proposed actions to withdraw approval of new drug applications for lack of substantial evidence of effectiveness as a result of reports of the National Academy of Sciences—National Research Council on its review of drug effectiveness; for example, see the notice published in the Federal Register (c) Any marketed drug is a “new drug” if any labeling change made after October 9, 1962, recommends or suggests new conditions of use under which the drug is not generally recognized as safe and effective by qualified experts. Undisclosed or unreported side effects as well as the emergence of new knowledge presenting questions with respect to the safety or effectiveness of a drug may result in its becoming a “new drug” even though it was previously considered “not a new drug.” Any previously given informal advice that an article is “not a new drug” does not apply to such an article if it has been changed in formulation, manufacture control, or labeling in a way that may significantly affect the safety of the drug. (d) For these reasons, all opinions previously given by the Food and Drug Administration to the effect that an article is “not a new drug” or is “no longer a new drug” are hereby revoked. This does not mean that all articles that were the subjects of such prior opinions will be regarded as new drugs. The prior opinions will be replaced by opinions of the Food and Drug Administration that are qualified and current on when an article is “not a new drug,” as set forth in this subchapter. [39 FR 11680, Mar. 29, 1974] § 310.103 New drug substances intended for hypersensitivity testing. (a) The Food and Drug Administration is aware of the need in the practice of medicine for the ingredients of a new drug to be available for tests of hypersensitivity to such ingredients and therefore will not object to the shipment of a new drug substance, as defined in § 310.3(g), for such purpose if all of the following conditions are met: (1) The shipment is made as a result of a specific request made to the manufacturer or distributor by a practitioner licensed by law to administer such drugs, and the use of such drugs for patch testing is not promoted by the manufacturer or distributor. (2) The new drug substance requested is an ingredient in a marketed new drug and is not one that is an ingredient solely in a new drug that is legally available only under the investigational drug provisions of this part. (3) The label bears the following prominently placed statements in lieu of adequate directions for use and in addition to complying with the other labeling provisions of the act: (i) “Rx only”; and (ii) “For use only in patch testing”. (4) The quantity shipped is limited to an amount reasonable for the purpose of patch testing in the normal course of the practice of medicine and is used solely for such patch testing. (5) The new drug substance is manufactured by the same procedures and meets the same specifications as the component used in the finished dosage form. (6) The manufacturer or distributor maintains records of all shipments for this purpose for a period of 2 years after shipment and will make them available to the Food and Drug Administration on request. (b) When the requested new drug substance is intended for investigational use in humans or the substance is legally available only under the investigational drug provisions of part 312 of this chapter, the submission of an “Investigational New Drug Application” (IND) is required. The Food and Drug Administration will offer assistance to any practitioner wishing to submit an Investigational New Drug Application. (c) This section does not apply to drugs or their components that are subject to the licensing requirements of the Public Health Service Act of 1944, as amended. (See subchapter F—Biologics, of this chapter.) [39 FR 11680, Mar. 29, 1974, as amended at 55 FR 11578, Mar. 29, 1990; 67 FR 4907, Feb. 1, 2002] Subpart C—New Drugs Exempted From Prescription-Dispensing Requirements § 310.200 Prescription-exemption procedure. (a) Duration of prescription requirement. (b) Prescription-exemption procedure for drugs limited by a new drug application. (c) New drug status of drugs exempted from the prescription requirement. (d) Prescription legend not allowed on exempted drugs. (e) Prescription-exemption procedure of OTC drug review. [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42 FR 4714, Jan. 25, 1977; 42 FR 15674, Mar. 22, 1977; 72 FR 15043, Mar. 30, 2007] § 310.201 Exemption for certain drugs limited by new-drug applications to prescription sale. (a) The prescription-dispensing requirements of section503(b)(1)(B) of the Federal Food, Drug, and Cosmetic Act are not necessary for the protection of the public health with respect to the following drugs subject to new drug applications: (1) N p p (i) The N p (ii) The N p (iii) If the preparation is a new drug, an application pursuant to section 505 (b) of the act is approved for it. (iv) The preparation contains not more than 0.325 gram (5 grains) of N p N p (v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic. (vi) The dosages of N p (vii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against administration of the drug to children under 3 years of age and against use of the drug for more than 10 days, unless such uses are directed by a physician. (viii) If the article is offered for use in arthritis or rheumatism, the labeling prominently bears a statement that the beneficial effects claimed are limited to the temporary relief of minor aches and pains of arthritis and rheumatism and, in juxtaposition with directions for use in such conditions, a conspicuous warning statement, such as “Caution: If pain persists for more than 10 days, or redness is present, or in conditions affecting children under 12 years of age, consult a physician immediately”. (2) Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations meeting all the following conditions: (i) The sodium gentisate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The sodium gentisate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 0.5 gram (7.7 grains) of anhydrous sodium gentisate per dosage unit. (v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic. (vi) The dosages of sodium gentisate recommended or suggested in the labeling do not exceed: For adults, 0.5 gram (7.7 grains) per dose of 2.0 grams (31 grains) per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage. (vii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against administration of the drug to children under 6 years of age and against use of the drug for a prolonged period, except as such uses may be directed by a physician. (3) Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-N′-2-thiazolyl-N′- p (i) The isoamylhydrocupreine and zolamine hydrochloride are prepared in dosage form suitable for self-medication as rectal suppositories or as an ointment and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The isoamylhydrocupreine, zola-amine hydrochloride, and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 0.25 percent of isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride. (v) If the preparation is in suppository form, it contains not more than 5.0 milligrams of isoamylhydrocupreine and not more than 20.0 milligrams of zolamine hydrochloride per suppository. (vi) The preparation is labeled with adequate directions for use in the temporary relief of local pain and itching associated with hemorrhoids. (vii) The directions provide for the use of not more than two suppositories or two applications of ointment in a 24-hour period. (viii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against use of the preparation in case of rectal bleeding, as this may indicate serious disease. (4) Phenyltoloxamine dihydrogen citrate ( N,N a O (i) The phenyltoloxamine dihydrogen citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The phenyltoloxamine dihydrogen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dosage unit. (v) The preparation is labeled with adequate directions for use in the temporary relief of the symptoms of hay fever and/or the symptoms of other minor conditions in which it is indicated. (vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dose or 264 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 150 milligrams of phenyltoloxamine) per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage. (vii) The labeling bears, in juxtaposition with the dosage recommendations: ( a ( b (5)-(7) [Reserved] (8) Dicyclomine hydrochloride (1-cyclohexylhexahydrobenzoic acid. β-diethylaminoethyl ester hydrochloride; diethylaminocarbethoxy-bicyclohexyl hydrochloride) preparations meeting all the following conditions: (i) The dicyclomine hydrochloride is prepared with suitable antacid and other components, in tablet or other dosage form for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The dicyclomine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 5 milligrams of dicyclomine hydrochloride per dosage unit, or if it is in liquid form not more than 0.5 milligram of dicyclomine hydrochloride per milliliter. (v) The preparation is labeled with adequate directions for use only by adults and children over 12 years of age, in the temporary relief of gastric hyperacidity. (vi) The dosages recommended or suggested in the directions for use do not exceed 10 milligrams of dicyclomine hydrochloride per dose or 30 milligrams in a 24-hour period. (vii) The labeling bears, in juxtaposition with the dosage recommendations, clear warning statements against: ( a ( b ( c (9)-(10) [Reserved] (11) Hexadenol (a mixture of tetracosanes and their oxidation products) preparations meeting all the following conditions: (i) The hexadenol is prepared and packaged, with or without other drugs, solvents, and propellants, in a form suitable for self-medication by external application to the skin as a spray, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The hexadenol and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 5 percent by weight of hexadenol. (v) The preparation is labeled with adequate directions for use by external application in the treatment of minor burns and minor skin irritations. (vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against: ( a ( b (12) Sulfur dioxide preparations meeting all the following conditions: (i) The sulfur dioxide is prepared with or without other drugs, in an aqueous solution packaged in a hermetic container suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The sulfur dioxide and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 5 grams of sulfur dioxide per 100 milliliters of solution. (v) The preparation is labeled with adequate directions for use by external application to the smooth skin in the prevention or treatment of minor conditions in which it is indicated. (vi) The directions for use recommend or suggest not more than two applications a day for not more than 1 week, except as directed by a physician. (13)-(15) [Reserved] (16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations meeting all the following conditions: (i) The tuaminoheptane sulfate is prepared, with or without other drugs, in an aqueous vehicle suitable for administration in self-medication as nose drops, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The preparation is packaged with a style of container or assembly suited to self-medication by the recommended route of administration, and delivering not more than 0.1 milliliter of the preparation per drop. (iii) The tuaminoheptane sulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iv) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (v) The tuaminoheptane sulfate content of the preparation does not exceed 10 milligrams per milliliter. (vi) The preparation is labeled with adequate directions for use in the temporary relief of nasal congestion. (vii) The dosages recommended or suggested in the directions for use do not exceed the equivalent: For adults, 5 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period; for children 1 to 6 years of age, 3 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period; for infants under 1 year of age, 2 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period. (viii) The labeling bears, in juxtaposition with the dosage recommendations: ( a ( b (17) [Reserved] (18) Vibesate (a mixture of copolymers of hydroxy-vinyl chlorideacetate, sebacic acid, and modified maleic rosin ester) preparations meeting all the following conditions. (i) The vibesate is prepared and packaged, with or without other drugs, solvents, and propellants, in a form suitable for self-medication by external application to the skin as a spray, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The vibesate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 13 percent by weight of vibesate. (v) The preparation is labeled with adequate directions for use by external application as a dressing for minor burns, minor cuts, or other minor skin irritations. (vi) The labeling bears in juxtaposition with the directions for use clear warning statements against: ( a ( b ( c ( d ( e (19) Pramoxine hydrochloride (4- N (i) The pramoxine hydrochloride is prepared, with or without other drugs, in a dosage form suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The pramoxine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 1.0 percent of pramoxine hydrochloride. (v) The preparation is labeled with adequate directions for use by external application to the skin for the temporary relief of pain or itching due to minor burns and sunburn, nonpoisonous insect bites, and minor skin irritations. (vi) The directions for use recommend or suggest not more than four applications of the preparation per day, unless directed by a physician. (vii) The labeling bears, in juxtaposition with the directions for use, clear warning statements against: ( a ( b ( c ( d (20) [Reserved] (21) Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate) preparations meeting all the following conditions: (i) The pamabrom is prepared with appropriate amounts of a suitable analgesic and with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The pamabrom and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 50 milligrams of pamabrom per dosage unit. (v) The preparation is labeled with adequate directions for use in the temporary relief of the minor pains and discomforts that may occur a few days before and during the menstrual period. (vi) The dosages recommended or suggested in the labeling do not exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour period. (22) Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-piperidinium methylsulfate) preparations meeting all the following conditions: (i) The diphemanil methylsulfate is prepared, with or without other drugs, in a dosage form suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The diphemanil methylsulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 2.0 percent of diphemanil methylsulfate. (v) The preparation is labeled with adequate directions for use by external application to the skin for the relief of symptoms of mild poison ivy, oak, and sumac and other minor irritations and itching of the skin. (vi) The directions for use recommend or suggest not more than four applications of the preparation per day, unless directed by a physician. (vii) The labeling bears, in juxtaposition with the directions for use, a clear warning statement, such as: “Caution: If redness, irritation, swelling, or pain persists or increases, discontinue use and consult physician.” (23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone hydrochloride; 4- n (i) The dyclonine hydrochloride is prepared, with or without other drugs, in a dosage form suitable for use as a cream or ointment in self-medication by external application to the skin, or rectally, and contains no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The dyclonine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 1.0 percent of dyclonine hydrochloride. (v) The preparation is labeled with adequate directions for use: ( a ( b ( c (vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against: ( a ( b ( c ( d ( e ( f (24) Chlorothen citrate (chloromethapyrilene citrate; N,N N N (i) The chlorothen citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The chlorothen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 25 milligrams of chlorothen citrate per dosage unit. (v) The preparation is labeled with adequate directions for use in the temporary relief of the symptoms of hay fever and/or the symptoms of other minor conditions in which it is indicated. (vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 25 milligrams of chlorothen citrate per dose or 150 milligrams of chlorothen citrate per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage. (vii) The labeling bears, in juxtaposition with the dosage recommendations: ( a ( b (25) [Reserved] (26) Methoxyphenamine hydrochloride (β-( o o (i) The methoxyphenamine hydrochloride is prepared with appropriate amounts of a suitable antitussive, with or without other drugs, in a dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The methoxyphenamine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 3.5 milligrams of methoxyphenamine hydrochloride per milliliter. (v) The preparation is labeled with adequate directions for use in the temporary relief of cough due to minor conditions in which it is indicated. (vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 35 milligrams of methoxyphenamine hydrochloride per dose or 140 milligrams of methoxyphenamine hydrochloride per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage. (vii) The label bears a conspicuous warning to keep the drug out of the reach of children, and the labeling bears, in juxtaposition with the dosage recommendations: ( a ( b ( c (27) Biphenamine hydrochloride (β-diethylaminoethyl-3-phenyl-2-hydroxybenzoate hydrochloride) preparations meeting all the following conditions: (i) The biphenamine hydrochloride is prepared in a form suitable for use as a shampoo and contains no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The biphenamine hydrochloride meets its professed standards of identity, strength, quality, and purity. (iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it. (iv) The preparation contains not more than 1 percent of biphenamine hydrochloride. (v) The preparation is labeled with adequate directions for use for the temporary relief of itching and scaling due to dandruff. (vi) The label bears a conspicuous warning to keep the drug out of the reach of children. (28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium chloride ophthalmic preparations meeting all the following conditions: (i) The tyloxapol and benzalkonium chloride are prepared, with other appropriate ingredients which are not drugs limited to prescription sale under the provisions of section 503(b)(1) of the act, as a sterile, isotonic aqueous solution suitable for use in self-medication on eye prostheses. (ii) The preparation is so packaged as to volume and type of container as to afford adequate protection and be suitable for self-medication with a minimum risk of contamination of the solution during use. Any dispensing unit is sterile and so packaged as to maintain sterility until the package is opened. (iii) The tyloxapol, benzalkonium chloride, and other ingredients used to prepare the isotonic aqueous solution meet their professed standards of identity, strength, quality, and purity. (iv) An application pursuant to section 505(b) of the act is approved for the drug. (v) The preparation contains 0.25 percent of tyloxapol and 0.02 percent of benzalkonium chloride. (vi) The label bears a conspicuous warning to keep the drug out of the reach of children and the labeling bears, in juxtaposition with the dosage recommendations, a clear warning that if irritation occurs, persists, or increases, use of the drug should be discontinued and a physician consulted. The labeling includes a statement that the dropper or other dispensing tip should not touch any surface, since this may contaminate the solution. (29) [Reserved] (b) [Reserved] [39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977; 52 FR 15892, Apr. 30, 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR 49898, Sept. 23, 1993; 59 FR 4218, Jan. 28, 1994; 60 FR 52507, Oct. 6, 1995; 72 FR 15043, Mar. 30, 2007; 72 FR 67640, Nov. 30, 2007] Subpart D—Records and Reports § 310.305 Records and reports concerning adverse drug experiences on marketed prescription drugs for human use without approved new drug applications. (a) Scope. (b) Definitions. Adverse drug experience. Disability. Individual case safety report (ICSR). ICSR attachments. Life-threatening adverse drug experience. immediate i.e. Serious adverse drug experience. Unexpected adverse drug experience. i.e. (c) Reporting requirements. (1) Postmarketing 15-day “Alert reports”. (ii) A person identified in paragraph (c)(1)(i) of this section is not required to submit a 15-day “Alert report” for an adverse drug experience obtained from a postmarketing study (whether or not conducted under an investigational new drug application) unless the applicant concludes that there is a reasonable possibility that the drug caused the adverse experience. (2) Postmarketing 15-day “Alert reports”—followup. (3) Submission of reports. (i) A copy of each adverse drug experience report; (ii) The date the report was received by the packer or distributor; (iii) The date the report was submitted to the manufacturer; and (iv) The name and address of the manufacturer. (4) [Reserved] (5) A person identified in paragraph (c)(1)(i) of this section is not required to resubmit to FDA adverse drug experience reports forwarded to that person by FDA; however, the person must submit all followup (d) Information reported on ICSRs. (1) Patient information. (i) Patient identification code; (ii) Patient age at the time of adverse drug experience, or date of birth; (iii) Patient gender; and (iv) Patient weight. (2) Adverse drug experience. (i) Outcome attributed to adverse drug experience; (ii) Date of adverse drug experience; (iii) Date of ICSR submission; (iv) Description of adverse drug experience (including a concise medical narrative); (v) Adverse drug experience term(s); (vi) Description of relevant tests, including dates and laboratory data; and (vii) Other relevant patient history, including preexisting medical conditions. (3) Suspect medical product(s). (i) Name; (ii) Dose, frequency, and route of administration used; (iii) Therapy dates; (iv) Diagnosis for use (indication); (v) Whether the product is a combination product as defined in § 3.2(e) of this chapter; (vi) Whether the product is a prescription or nonprescription product; (vii) Whether adverse drug experience abated after drug use stopped or dose reduced; (viii) Whether adverse drug experience reappeared after reintroduction of drug; (ix) Lot number; (x) Expiration date; (xi) National Drug Code (NDC) number; and (xii) Concomitant medical products and therapy dates. (4) Initial reporter information. (i) Name, address, and telephone number; (ii) Whether the initial reporter is a health care professional; and (iii) Occupation, if a health care professional. (5) Manufacturer, packer, or distributor information. (i) Manufacturer, packer, or distributor name and contact office address; (ii) Telephone number; (iii) Report source, such as spontaneous, literature, or study; (iv) Date the report was received by manufacturer, packer, or distributor; (v) Whether the ICSR is a 15-day “Alert report”; (vi) Whether the ICSR is an initial report or followup report; and (vii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s). (e) Electronic format for submissions. (2) Each person identified in paragraph (c)(1)(i) of this section may request, in writing, a temporary waiver of the requirements in paragraph (e)(1) of this section. These waivers will be granted on a limited basis for good cause shown. FDA will issue guidance on requesting a waiver of the requirements in paragraph (e)(1) of this section. (f) Patient privacy. (g) Recordkeeping. (2) Manufacturers and packers may retain the records required in paragraph (f)(1) of this section as part of its complaint files maintained under § 211.198 of this chapter. (3) Manufacturers, packers, and distributors must permit any authorized FDA employee, at all reasonable times, to have access to and copy and verify the records established and maintained under this section. (h) Disclaimer. [51 FR 24479, July 3, 1986, as amended at 52 FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, June 25, 1997; 62 FR 52249, Oct. 7, 1997; 67 FR 9585, Mar. 4, 2002; 74 FR 13113, Mar. 26, 2009; 79 FR 33087, June 10, 2014] § 310.306 Notification of a permanent discontinuance or an interruption in manufacturing of marketed prescription drugs for human use without approved new drug applications. (a) Applicability. (b) Notification of a permanent discontinuance or an interruption in manufacturing. e (c) Drug shortages list. d d 2 [80 FR 38938, July 8, 2015] Subpart E—Requirements for Specific New Drugs or Devices § 310.501 Patient package inserts for oral contraceptives. (a) Requirement for a patient package insert. (b) Distribution requirements. (2) Patient package inserts for oral contraceptives dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before administration of the first oral contraceptive and every 30 days thereafter, as long as the therapy continues. (c) Contents of patient package insert. (1) The name of the drug. (2) A summary including a statement concerning the effectiveness of oral contraceptives in preventing pregnancy, the contraindications to the drug's use, and a statement of the risks and benefits associated with the drug's use. (3) A statement comparing the effectiveness of oral contraceptives to other methods of contraception. (4) A boxed warning concerning the increased risks associated with cigarette smoking and oral contraceptive use. (5) A discussion of the contraindications to use, including information that the patient should provide to the prescriber before taking the drug. (6) A statement of medical conditions that are not contraindications to use but deserve special consideration in connection with oral contraceptive use and about which the patient should inform the prescriber. (7) A warning regarding the most serious side effects of oral contraceptives. (8) A statement of other serious adverse reactions and potential safety hazards that may result from the use of oral contraceptives. (9) A statement concerning common, but less serious side effects which may help the patient evaluate the benefits and risks from the use of oral contraceptives. (10) Information on precautions the patients should observe while taking oral contraceptives, including the following: (i) A statement of risks to the mother and unborn child from the use of oral contraceptives before or during early pregnancy; (ii) A statement concerning excretion of the drug in human milk and associated risks to the nursing infant; (iii) A statement about laboratory tests which may be affected by oral contraceptives; and (iv) A statement that identifies activities and drugs, foods, or other substances the patient should avoid because of their interactions with oral contraceptives. (11) Information about how to take oral contraceptives properly, including information about what to do if the patient forgets to take the product, information about becoming pregnant after discontinuing use of the drug, a statement that the drug product has been prescribed for the use of the patient and should not be used for other conditions or given to others, and a statement that the patient's pharmacist or practitioner has a more technical leaflet about the drug product that the patient may ask to review. (12) A statement of the possible benefits associated with oral contraceptive use. (13) The following information about the drug product and the patient package insert: (i) The name and place of business of the manufacturer, packer, or distributor, or the name and place of business of the dispenser of the product. (ii) The date, identified as such, of the most recent revision of the patient package insert placed prominently immediately after the last section of the labeling. (d) Other indications. (e) Labeling guidance texts. (f) Requirement to supplement approved application. [54 FR 22587, May 25, 1989, as amended at 74 FR 13113, Mar. 26, 2009] § 310.502 Certain drugs accorded new drug status through rulemaking procedures. (a) The drugs listed in this paragraph (a) have been determined by rulemaking procedures to be new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. An approved new drug application under section 505 of the Federal Food, Drug, and Cosmetic Act and part 314 of this chapter is required for marketing the following drugs: (1) Aerosol drug products for human use containing 1,1,1-trichloroethane. (2) Aerosol drug products containing zirconium. (3) Amphetamines (amphetamine, dextroamphetamine, and their salts, and levamfetamine and its salts) for human use. (4) Camphorated oil drug products. (5) Certain halogenated salicylanilides (tribromsalan (TBS, 3,4′,5-tribromosalicylanilide), dibromsalan (DBS, 4′, 5-dibromosalicylanilide), metabromsalan (MBS, 3, 5-dibromosalicylanilide), and 3,3′, 4,5′-tetrachlorosalicylanilide (TC-SA)) as an ingredient in drug products. (6) Chloroform used as an ingredient (active or inactive) in drug products. (7) Cobalt preparations intended for use by man. (8) Intrauterine devices for human use for the purpose of contraception that incorporate heavy metals, drugs, or other active substances. (9) Oral prenatal drugs containing fluorides intended for human use. (10) Parenteral drug products in plastic containers. (11) [Reserved] (12) Sweet spirits of nitre drug products. (13) Thorium dioxide for drug use. (14) Timed release dosage forms. (15) Vinyl chloride as an ingredient, including propellant, in aerosol drug products. (b) [Reserved] [62 FR 12084, Mar. 14, 1997, as amended at 64 FR 401, Jan. 5, 1999; 84 FR 68334, Dec. 16, 2019] § 310.503 Requirements regarding certain radioactive drugs. (a) On January 8, 1963 (28 FR 183), the Commissioner of Food and Drugs exempted investigational radioactive new drugs from part 312 of this chapter provided they were shipped in complete conformity with the regulations issued by the Nuclear Regulatory Commission. This exemption also applied to investigational radioactive biologics. (b) It is the opinion of the Nuclear Regulatory Commission, and the Food and Drug Administration that this exemption should not apply for certain specific drugs and that these drugs should be appropriately labeled for uses for which safety and effectiveness can be demonstrated by new drug applications or through licensing under the Public Health Service Act (42 U.S.C. 262 et seq. (c) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling. Such use may include, among others, the uses in this tabulation: Isotope Chemical form Use Chromium 51 Chromate Spleen scans. Do ......do Placenta localization. Do ......do Red blood cell labeling and survival studies. Do Labeled human serum albumin Gastrointestinal protein loss studies. Do ......do Placenta localization. Do Labeled red blood cells Do. Cobalt 58 or Cobalt 60 Labeled cyanocobalamin Intestinal absorption studies. Gold 198 Colloidal Liver scans. Do ......do Intracavitary treatment of pleural effusions and/or ascites. Do ......do Interstitial treatment of cancer. Iodine 131 Iodide Diagnosis of thyroid functions. Do ......do Thyroid scans. Do ......do Treatment of hyperthyroidism and/or cardiac dysfunction. Do ......do Treatment of thyroid carcinoma. Do Iodinated human serum albumin Blood volume determinations. Do ......do Cisternography. Do ......do Brain tumor localization. Do ......do Placenta localization. Do ......do Cardiac scans for determination of pericardial effusions. Do Rose Bengal Liver function studies. Do ......do Liver scans. Do Iodopyracet, sodium iodohippurate, sodium diatrizoate, diatrizoate methylglucamine, sodium diprotrizoate, sodium acetrizoate, or sodium iothalamate Kidney function studies and kidney scans. Do Labeled fats and/or fatty acids Fat absorption studies. Do Cholografin Cardiac scans for determination of pericardial effusions. Do Macroaggregated iodinated human serum albumin Lung scans. Do Colloidal microaggregated human serum albumin Liver scans. Iodine 125 Iodide Diagnosis of thyroid function. Do Iodinated human serum albumin Blood volume determinations. Do Rose Bengal Liver function studies. Do Iodopyracet, sodium iodohippurate, sodium diatrizoate, diatrizoate methyl-glucamine, sodium diprotrizoate, sodium acetrizoate, or sodium iothalamate Kidney function studies. Do Labeled fats and/or fatty acids Fat absorption studies. Iron 59 Chloride, citrate and/or sulfate Iron turnover studies. Krypton 85 Gas Diagnosis of cardiac abnormalities. Mercury 197 Chlormerodrin Kidney scans. Do ......do Brain scans. Mercury 203 1 ......do Kidney scans. Do ......do Brain scans. Phosphorus 32 Soluble phosphate Treatment of polycythemia vera. Do ......do Treatment of leukemia and bone metastasis. Do Colloidal chromic phosphate Intracavitary treatment of pleural effusions and/or ascites. Do ......do Interstitial treatment of cancer. Potassium 42 Chloride Potassium space studies. Selenium 75 Labeled methionine Pancreas scans. Strontium 85 Nitrate or chloride Bone scans on patients with diagnosed cancer. Technetium 99m Pertechnetate Brain scans. Do ......do Thyroid scans. Do Sulfur colloid Liver and spleen scans. Do Pertechnetate Placenta localization. Do ......do Blood pool scans. Do ......do Salivary gland scans. Do Diethylenetri-amine pentaacetic acid (DTPA) Kidney scans. Xenon 133 Gas Diagnosis of cardia abnormalities. Cerebral bloodflow studies. Pulmonary function studies. Muscle bloodflow studies. 1 (d)(1) In view of the extent of experience with the isotopes listed in paragraph (c) of this section, the Nuclear Regulatory Commission and the Food and Drug Administration conclude that such isotopes should not be distributed under investigational-use labeling when they are actually intended for use in medical practice. (2) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the “chemical form” and intended for the uses stated, is terminated on March 3, 1972, except as provided in paragraph (d)(3) of this section. (3) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the “chemical form” and intended for the uses stated, for which drug a new drug application or a “Investigational New Drug Application” was submitted prior to March 3, 1972, or for which biologic an application for product license or “Investigational New Drug Application” was submitted prior to March 3, 1972, is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first. (e) No exemption from section 505 of the act or from part 312 of this chapter is in effect or has been in effect for radioactive drugs prepared from accelerator-produced radioisotopes, naturally occurring isotopes, or nonradioactive substances used in conjunction with isotopes. (f)(1) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling; such use may include, among others, the uses in this tabulation: Isotope Chemical form Use Fluorine 18 Fluoride Bone imaging. Indium-113m Diethylenetriamine pentaacetic acid (DTPA) Brain imaging; kidney imaging. Do Chloride Placenta imaging; blood pool imaging. Technetium 99m Human serum albumin microspheres Lung imaging. Do Diethylenetriamine pentaacetic acid (Sn) Kidney imaging; kidney function studies. Do ......do Brain imaging. Do Polyphosphates Bone imaging. Do Technetated aggregated albumin (human) Lung imaging. Do Disodium etidronate Bone imaging. (2) In view of the extent of experience with the isotopes listed in paragraph (f)(1) of this section, the Nuclear Regulatory Commission and the Food and Drug Administration conclude that they should not be distributed under investigational-use labeling when they are actually intended for use in medical practice. (3) Any manufacturer or distributor interested in continuing to ship in interstate commerce drugs containing the isotopes listed in paragraph (f)(1) of this section for any of the indications listed, shall submit, on or before August 25, 1975 to the Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, a new drug application or a “Investigational New Drug Application” for each such drug for which the manufacturer or distributor does not have an approved new drug application pursuant to section 505(b) of the act. If the drug is a biologic, a “Investigational New Drug Application” or an application for a license under section 351 of the Public Health Service Act shall be submitted to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002, in lieu of any submission to the Center for Drug Evaluation and Research. (4) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (f)(1) of this section, in the “chemical form” and intended for the uses stated, is terminated on August 26, 1975 except as provided in paragraph (f)(5) of this section. (5)(i) Except as provided in paragraph (f)(5)(ii) of this section, the exemption referred to in paragraph (a) of this section, as applied to any drug containing any of the isotopes listed in paragraph (f)(1) of this section, in the “chemical form” and intended for the uses stated, for which drug a new drug application or “Investigational New Drug Application” was submitted to the Center for Drug Evaluation and Research on or before August 25, 1975 is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first. (ii) The exemption referred to in paragraph (a) of this section, as applied to any biologic containing any of the isotopes listed in paragraph (f)(1) of this section in the “chemical form” and intended for the uses stated, for which biologic an application for product license or “Investigational New Drug Application” was submitted to the Center for Biologics Evaluation and Research on or before August 25, 1975 is terminated on October 20, 1976, unless an approvable notice was issued on or before October 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on January 20, 1977, whichever occurs first. (g) The exemption referred to in paragraph (a) of this section, as applied to any drug intended solely for investigational use as part of a research project, which use had been approved on or before July 25, 1975 in accordance with 10 CFR 35.11 (or equivalent regulation of an Agreement State) is terminated on February 20, 1976 if the manufacturer of such drug or the sponsor of the investigation of such drug submits on or before August 25, 1975 to the Food and Drug Administration, Bureau of Drugs, HFD-150, 5600 Fishers Lane, Rockville, MD 20857, the following information: (1) The research project title; (2) A brief description of the purpose of the project; (3) The name of the investigator responsible; (4) The name and license number of the institution holding the specific license under 10 CFR 35.11 (or equivalent regulation of an Agreement State); (5) The name and maximum amount per subject of the radionuclide used; (6) The number of subjects involved; and (7) The date on which the administration of the radioactive drugs is expected to be completed. (h) The exemption referred to in paragraph (a) of this section, as applied to any drug not referred to in paragraphs (d), (f), and (g) of this section, is terminated on August 26, 1975. [39 FR 11680, Mar. 29, 1974, as amended at 40 FR 31307, July 25, 1975; 40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990; 64 FR 56449, Oct. 20, 1999; 80 FR 18091, Apr. 3, 2015] § 310.509 Parenteral drug products in plastic containers. (a) Any parenteral drug product packaged in a plastic immediate container is not generally recognized as safe and effective, is a new drug within the meaning of section 201(p) of the act, and requires an approved new drug application as a condition for marketing. An “Investigational New Drug Application” set forth in part 312 of this chapter is required for clinical investigations designed to obtain evidence of safety and effectiveness. (b) As used in this section, the term “large volume parenteral drug product” means a terminally sterilized aqueous drug product packaged in a single-dose container with a capacity of 100 milliliters or more and intended to be administered or used intravenously in a human. (c) Until the results of compatibility studies are evaluated, a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or after April 16, 1979, is misbranded unless its labeling contains a warning that includes the following information: (1) A statement that additives may be incompatible. (2) A statement that, if additive drugs are introduced into the parenteral system, aseptic techniques should be used and the solution should be thoroughly mixed. (3) A statement that a solution containing an additive drug should not be stored. (d) This section does not apply to a biological product licensed under the Public Health Service Act of July 1, 1944 (42 U.S.C. 201). [62 FR 12084, Mar. 14, 1997] § 310.515 Patient package inserts for estrogens. (a) Requirement for a patient package insert. (b) Distribution requirements. (2) In the case of estrogen drug products in bulk packages intended for multiple dispensing, and in the case of injectables in multiple-dose vials, a sufficient number of patient labeling pieces shall be included in or with each package to assure that one piece can be included with each package or dose dispensed or administered to every patient. Each bulk package shall be labeled with instructions to the dispensor to include one patient labeling piece with each package dispensed or, in the case of injectables, with each dose administered to the patient. This section does not preclude the manufacturer or labeler from distributing additional patient labeling pieces to the dispensor. (3) Patient package inserts for estrogens dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before administration of the first estrogen and every 30 days thereafter, as long as the therapy continues. (c) Patient package insert contents. (1) The name of the drug. (2) The name and place of business of the manufacturer, packer, or distributor. (3) A statement regarding the benefits and proper uses of estrogens. (4) The contraindications to use, i.e. (5) A description of the most serious risks associated with the use of estrogens. (6) A brief summary of other side effects of estrogens. (7) Instructions on how a patient may reduce the risks of estrogen use. (8) The date, identified as such, of the most recent revision of the patient package insert. (d) Guidance language. (e) Exemptions. (f) Requirement to supplement approved application. [55 FR 18723, May 4, 1990, as amended at 74 FR 13113, Mar. 26, 2009] § 310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea class. (a) The University Group Diabetes Program clinical trial has reported an association between the administration of tolbutamide and increased cardiovascular mortality. The Food and Drug Administration has concluded that this reported association provides adequate basis for a warning in the labeling. In view of the similarities in chemical structure and mode of action, the Food and Drug Administration also believes it is prudent from a safety standpoint to consider that the possible increased risk of cardiovascular mortality from tolbutamide applies to all other sulfonylurea drugs as well. Therefore, the labeling for oral hypoglycemic drugs of the sulfonylurea class shall include a warning concerning the possible increased risk of cardiovascular mortality associated with such use, as set forth in paragraph (b) of this section. (b) Labeling for oral hypoglycemic drugs of the sulfonylurea class shall include in boldface type at the beginning of the “Warnings” section of the labeling the following statement: Special Warning on Increased Risk of Cardiovascular Mortality The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups ( Diabetes, UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 1/2 Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. [49 FR 14331, Apr. 11, 1984] § 310.518 Drug products containing iron or iron salts. Drug products containing elemental iron or iron salts as an active ingredient in solid oral dosage form, e.g., tablets or capsules shall meet the following requirements: (a) Labeling. WARNING: Accidental overdose or iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately. (2)(i) The warning statement required by paragraph (a)(1) of this section shall appear prominently and conspicuously on the information panel of the immediate container label. (ii) If a drug product is packaged in unit-dose packaging, and if the immediate container bears labeling but not a label, the warning statement required by paragraph (a)(1) of this section shall appear prominently and conspicuously on the immediate container labeling in a way that maximizes the likelihood that the warning is intact until all of the dosage units to which it applies are used. (3) Where the immediate container is not the retail package, the warning statement required by paragraph (a)(1) of this section shall also appear prominently and conspicuously on the information panel of the retail package label. (4) The warning statement shall appear on any labeling that contains warnings. (5) The warning statement required by paragraph (a)(1) of this section shall be set off in a box by use of hairlines. (b) The iron-containing inert tablets supplied in monthly packages of oral contraceptives are categorically exempt from the requirements of paragraph (a) of this section. [68 FR 59715, Oct. 17, 2003] § 310.519 Drug products marketed as over-the-counter (OTC) daytime sedatives. (a) Antihistamines, bromides, and scopolamine compounds, either singly or in combinations, have been marketed as ingredients in over-the-counter (OTC) drug products for use as daytime sedatives. The following claims have been made for daytime sedative products: “occasional simple nervous tension,” “nervous irritability,” “nervous tension headache,” “simple nervousness due to common every day overwork and fatigue,” “a relaxed feeling,” “calming down and relaxing,” “gently soothe away the tension,” “calmative,” “resolving that irritability that ruins your day,” “helps you relax,” “restlessness,” “when you're under occasional stress . . . helps you work relaxed.” Based on evidence presently available, there are no ingredients that can be generally recognized as safe and effective for use as OTC daytime sedatives. (b) Any OTC drug product that is labeled, represented, or promoted as an OTC daytime sedative (or any similar or related indication) is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted as an OTC daytime sedative (or any similar or related indication) is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) Any OTC daytime sedative drug product introduced into interstate commerce after December 24, 1979, that is not in compliance with this section is subject to regulatory action. [44 FR 36380, June 22, 1979; 45 FR 47422, July 15, 1980, as amended at 55 FR 11579, Mar. 29, 1990] § 310.527 Drug products containing active ingredients offered over-the-counter (OTC) for external use as hair growers or for hair loss prevention. (a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid, biotin and all other B-vitamins, dexpanthenol, estradiol and other topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20, polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat germ oil have been marketed as ingredients in OTC drug products for external use as hair growers or for hair loss prevention. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients intended for OTC external use as a hair grower or for hair loss prevention. Based on evidence currently available, all labeling claims for OTC hair grower and hair loss prevention drug products for external use are either false, misleading, or unsupported by scientific data. Therefore, any OTC drug product for external use containing an ingredient offered for use as a hair grower or for hair loss prevention cannot be considered generally recognized as safe and effective for its intended use. (b) Any OTC drug product that is labeled, represented, or promoted for external use as a hair grower or for hair loss prevention is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC external use as a hair grower or for hair loss prevention is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After January 8, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [54 FR 28777, July 7, 1989] § 310.528 Drug products containing active ingredients offered over-the-counter (OTC) for use as an aphrodisiac. (a) Any product that bears labeling claims that it will arouse or increase sexual desire, or that it will improve sexual performance, is an aphrodisiac drug product. Anise, cantharides, don qual, estrogens, fennel, ginseng, golden seal, gotu kola, Korean ginseng, licorice, mandrake, methyltestosterone, minerals, nux vomica, Pega Palo, sarsaparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are powerful hormones when administered internally and are not safe for use except under the supervision of a physician. There is a lack of adequate data to establish general recognition of the safety and effectiveness of any of these ingredients, or any other ingredient, for OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use are either false, misleading, or unsupported by scientific data. The following claims are examples of some that have been made for aphrodisiac drug products for OTC use: “acts as an aphrodisiac;” “arouses or increases sexual desire and improves sexual performance;” “helps restore sexual vigor, potency, and performance;” “improves performance, staying power, and sexual potency;” and “builds virility and sexual potency.” Based on evidence currently available, any OTC drug product containing ingredients for use as an aphrodisiac cannot be generally recognized as safe and effective. (b) Any OTC drug product that is labeled, represented, or prompted for use as an aphrodisiac is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the act), for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as an aphrodisiac is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After January 8, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [54 FR 28786, July 7, 1989] § 310.529 Drug products containing active ingredients offered over-the-counter (OTC) for oral use as insect repellents. (a) Thiamine hydrochloride (vitamin B-1) has been marketed as an ingredient in over-the-counter (OTC) drug products for oral use as an insect repellent (an orally administered drug product intended to keep insects away). There is a lack of adequate data to establish the effectiveness of this, or any other ingredient for OTC oral use as an insect repellent. Labeling claims for OTC orally administered insect repellent drug products are either false, misleading, or unsupported by scientific data. The following claims are examples of some that have been made for orally administered OTC insect repellent drug products: “Oral mosquito repellent,” “mosquitos avoid you,” “bugs stay away,” “keep mosquitos away for 12 to 24 hours,” and “the newest way to fight mosquitos.” Therefore, any drug product containing ingredients offered for oral use as an insect repellent cannot be generally recognized as safe and effective. (b) Any OTC drug product that is labeled, represented, or promoted for oral use as an insect repellent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug and Cosmetic Act for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted OTC for oral use as an insect repellent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) Any such drug product in interstate commerce after December 17, 1985, that is not in compliance with this section is subject to regulatory action. [40 FR 25171, June 17, 1985, as amended at 55 FR 11579, Mar. 29, 1990] § 310.530 Topically applied hormone-containing drug products for over-the-counter (OTC) human use. (a) The term “hormone” is used broadly to describe a chemical substance formed in some organ of the body, such as the adrenal glands or the pituitary, and carried to another organ or tissue, where it has a specific effect. Hormones include, for example, estrogens, progestins, androgens, anabolic steroids, and adrenal corticosteroids, and synthetic analogs. Estrogens, progesterone, pregnenolone, and pregnenolone acetate have been present as ingredients in OTC drug products marketed for topical use as hormone creams. However, there is a lack of adequate data to establish effectiveness for any OTC drug use of these ingredients. Therefore, with the exception of those hormones identified in paragraph (e) of this section, any OTC drug product containing an ingredient offered for use as a topically applied hormone cannot be considered generally recognized as safe and effective for its intended use. The intended use of the product may be inferred from the product's labeling, promotional material, advertising, and any other relevant factor. The use of the word “hormone” in the text of the labeling or in the ingredient statement is an implied drug claim. The claim implied by the use of this term is that the product will have a therapeutic or some other physiological effect on the body. Therefore, reference to a product as a “hormone cream” or any statement in the labeling indicating that “hormones” are present in the product, or any statement that features or emphasizes the presence of a hormone ingredient in the product, will be considered to be a therapeutic claim for the product, or a claim that the product will affect the structure or function of the body, and will consequently cause the product to be a drug. (b) Any OTC drug product that is labeled, represented, or promoted as a topically applied hormone-containing product for drug use, with the exception of those hormones identified in paragraph (e) of this section, is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a topically applied hormone-containing drug product is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After March 9, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. (e) This section does not apply to hydrocortisone and hydrocortisone acetate labeled, represented, or promoted for OTC topical use in accordance with part 348 of this chapter. [58 FR 47610, Sept. 9, 1993] § 310.531 Drug products containing active ingredients offered over-the-counter (OTC) for the treatment of boils. (a) Aminacrine hydrochloride, benzocaine, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, rosin cerate, sassafras oil, sulfur, thymol, triclosan, and zinc oxide have been present in OTC boil treatment drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredient for OTC use for the treatment of boils. Treatment is defined as reducing the size of a boil or reducing an infection related to a boil. Treatment has involved the use of “drawing salves” for these purposes. These “drawing salves” contained various ingredients. Based on evidence currently available, any OTC drug product offered for the treatment of boils cannot be considered generally recognized as safe and effective. (b) Any OTC drug product that is labeled, represented, or promoted for the treatment of boils is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any OTC boil treatment drug product is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After May 7, 1991, any such OTC drug product that contains aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, isobutamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, rosin cerate, sassafras oil, thymol, or zinc oxide initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. (e) After May 16, 1994, any such OTC drug product that contains benzocaine, ichthammol, sulfur, or triclosan initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. (f) This section does not apply to drug products that contain benzocaine labeled, represented, or promoted for OTC topical use in accordance with part 348 of this chapter. [58 FR 60336, Nov. 15, 1993] § 310.532 Drug products containing active ingredients offered over-the-counter (OTC) to relieve the symptoms of benign prostatic hypertrophy. (a) The amino acids glycine, alanine, and glutamic acid (alone or in combination) and the ingredient sabal have been present in over-the-counter (OTC) drug products to relieve the symptoms of benign prostatic hypertrophy, e.g., urinary urgency and frequency, excessive urinating at night, and delayed urination. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use in relieving the symptoms of benign prostatic hypertrophy. In addition, there is no definitive evidence that any drug product offered for the relief of the symptoms of benign prostatic hypertrophy would alter the obstructive or inflammatory signs and symptoms of this condition. Therefore, self-medication with OTC drug products might unnecessarily delay diagnosis and treatment of progressive obstruction and secondary infections. Based on evidence currently available, any OTC drug product containing ingredients offered for use in relieving the symptoms of benign prostatic hypertrophy cannot be generally recognized as safe and effective. (b) Any OTC drug product that is labeled, represented, or promoted to relieve the symptoms of benign prostatic hypertrophy is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use to relieve the symptoms of benign prostatic hypertrophy is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After August 27, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [55 FR 6930, Feb. 27, 1990] § 310.533 Drug products containing active ingredients offered over-the-counter (OTC) for human use as an anticholinergic in cough-cold drug products. (a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids as contained in Atropa belladonna and Datura stramonium have been present as ingredients in cough-cold drug products for use as an anticholinergic. Anticholinergic drugs have been marketed OTC in cough-cold drug products to relieve excessive secretions of the nose and eyes, symptoms that are commonly associated with hay fever, allergy, rhinitis, and the common cold. Atropine sulfate for oral use as an anticholinergic is probably safe at dosages that have been used in marketed cough-cold products (0.2 to 0.3 milligram); however, there are inadequate data to establish general recognition of the effectiveness of this ingredient. The belladonna alkaloids, which contain atropine ( d, dl l- (b) Any OTC cough-cold drug product that is labeled, represented, or promoted for use as an anticholinergic is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any cough-cold drug product labeled, represented, or promoted for OTC use as an anticholinergic is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After the effective date of the final regulation, any such OTC cough-cold drug product that is labeled, represented, or promoted for use as an anticholinergic may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved new drug application. [50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990] § 310.534 Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents. (a) Allantoin, carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, and hydrogen peroxide in aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing agents. Oral wound healing agents have been marketed as aids in the healing of minor oral wounds by means other than cleansing and irrigating, or by serving as a protectant. Allantoin, carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, and hydrogen peroxide in aqueous solution are safe for use as oral wound healing agents, but there are inadequate data to establish general recognition of the effectiveness of these ingredients as oral wound healing agents. (b) Any OTC drug product that is labeled, represented, or promoted for use as an oral wound healing agent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as an oral wound healing agent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After the effective date of the final regulation, any OTC drug product that is labeled, represented, or promoted for use as an oral wound healing agent may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved new drug application. [51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29, 1990] § 310.536 Drug products containing active ingredients offered over-the-counter (OTC) for use as a nailbiting or thumbsucking deterrent. (a) Denatonium benzoate and sucrose octaacetate have been present in OTC nailbiting and thumbsucking deterrent drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these and any other ingredients (e.g., cayenne pepper) for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a nailbiting or thumbsucking deterrent cannot be generally recognized as safe and effective. (b) Any OTC drug product that is labeled, represented, and promoted as a nailbiting or thumbsucking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a nailbiting or thumbsucking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After March 2, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [58 FR 46754, Sept. 2, 1993] § 310.537 Drug products containing active ingredients offered over-the-counter (OTC) for oral administration for the treatment of fever blisters and cold sores. (a) l Lactobacillus acidophilus, Lactobacillus bulgaricus (b) Any OTC drug product for oral administration that is labeled, represented, or promoted to treat or relieve the symptoms or discomfort of fever blisters and cold sores is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product for oral administration labeled, represented, or promoted for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After December 30, 1992, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [57 FR 29173, June 30, 1992] § 310.538 Drug products containing active ingredients offered over-the-counter (OTC) for use for ingrown toenail relief. (a) Any product that bears labeling claims such as for “temporary relief of discomfort from ingrown toenails,” or “ingrown toenail relief product,” or “ingrown toenail reliever,” or similar claims is considered an ingrown toenail relief drug product. Benzocaine, chlorobutanol, chloroxylenol, dibucaine, tannic acid, and urea have been present as ingredients in such products. There is lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use for ingrown toenail relief. Based on evidence currently available, any OTC drug product containing ingredients offered for use for ingrown toenail relief cannot be generally recognized as safe and effective. (b) Any OTC drug product that is labeled, represented, or promoted for ingrown toenail relief is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for ingrown toenail relief is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After March 9, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. (e) This section does not apply to sodium sulfide labeled, represented, or promoted for OTC topical use for ingrown toenail relief in accordance with part 358, subpart D of this chapter, after June 6, 2003. [58 FR 47605, Sept. 9, 1993, as amended at 68 FR 24348, May 7, 2003] § 310.540 Drug products containing active ingredients offered over-the-counter (OTC) for use as stomach acidifiers. (a) Betaine hydrochloride, glutamic acid hydrochloride, diluted hydrochloric acid, and pepsin have been present as ingredients in over-the-counter (OTC) drug products for use as stomach acidifiers. Because of the lack of adequate data to establish the effectiveness of these or any other ingredients for use in treating achlorhydria and hypochlorhydria, and because such conditions are asymptomatic, any OTC drug product containing ingredients offered for use as a stomach acidifier cannot be considered generally recognized as safe and effective. (b) Any OTC drug product that is labeled, represented, or promoted for use as a stomach acidifier is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted as a stomach acidifier for OTC use is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After the effective date of the final regulation, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [53 FR 31271, Aug. 17, 1988] § 310.541 Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hypophosphatemia. (a) Hypophosphatemia is a condition in which an abnormally low plasma level of phosphate occurs in the blood. This condition is not amenable to self-diagnosis or self-treatment. Treatment of this condition should be restricted to the supervision of a physician. For this reason, any drug product containing ingredients offered for OTC use in the treatment of hypophosphatemia cannot be considered generally recognized as safe and effective. (b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of hypophosphatemia is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use in the treatment of hypophosphatemia is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of his chapter. (d) After November 12, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [55 FR 19858, May 11, 1990] § 310.542 Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hyperphosphatemia. (a) Hyperphosphatemia is a condition in which an abnormally high plasma level of phosphate occurs in the blood. This condition in not amenable to self-diagnosis or self-treatment. Treatment of this condition should be restricted to the supervision of a physician. For this reason, any drug product containing ingredients offered for OTC use in the treatment of hyperphosphatemia cannot be considered generally recognized as safe and effective. (b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of hyperphosphatemia is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for use in the treatment of hyperphosphatemia is safe and effective for the purpose intended must comply with the requirements and procedures governing use of investigational new drugs set forth in part 312 of this chapter. (d) After November 12, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [55 FR 19858, May 11, 1990] § 310.543 Drug products containing active ingredients offered over-the-counter (OTC) for human use in exocrine pancreatic insufficiency. (a) Hemicellulase, pancreatin, and pancrelipase have been present as ingredients in exocrine pancreatic insufficiency drug products. Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin (protease), and lipase. Significant differences have been shown in the bioavailability of marketed exocrine pancreatic insufficiency drug products produced by different manufacturers. These differences raise a potential for serious risk to patients using these drug products. The bioavailability of pancreatic enzymes is dependent on the process used to manufacture the drug products. Information on this process is not included in an OTC drug monograph. Therefore, the safe and effective use of these enzymes for treating exocrine pancreatic insufficiency cannot be regulated adequately by an OTC drug monograph. Information on the product's formulation, manufacture, quality control procedures, and final formulation effectiveness testing are necessary in an approved application to ensure that a company has the ability to manufacture a proper bioactive formulation. In addition, continuous physician monitoring of patients who take these drug products is a collateral measure necessary to the safe and effective use of these enzymes, causing such products to be available by prescription only. (b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of exocrine pancreatic insufficiency is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use in the treatment of exocrine pancreatic insufficiency is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After May 7, 1991, any such OTC drug product that contains hemicellulase initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. (e) After October 24, 1995, any such OTC drug product that contains pancreatin or pancrelipase initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [60 FR 20165, Apr. 24, 1995] § 310.544 Drug products containing active ingredients offered over-the-counter (OTC) for use as a smoking deterrent. (a) Any product that bears labeling claims that it “helps stop or reduce the cigarette urge,” “helps break the cigarette habit,” “helps stop or reduce smoking,” or similar claims is a smoking deterrent drug product. Cloves, coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), licorice root extract, lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata (b) Any OTC drug product that is labeled, represented, or promoted as a smoking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a smoking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After May 7, 1991, any such OTC drug product containing cloves, coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), licorice root extract, menthol, methyl salicylate, quinine ascorbate, silver nitrate, and/or thymol initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. After December 1, 1993, any such OTC drug product containing lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata [58 FR 31241, June 1, 1993] § 310.545 Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. (a) A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses: (1) Topical acne drug products. Alcloxa Alkyl isoquinolinium bromide Aluminum chlorohydrex Aluminum hydroxide Benzocaine Benzoic acid Boric acid Calcium polysulfide Calcium thiosulfate Camphor Chloroxylenol Cloxyquin Coal tar Dibenzothiophene Estrone Magnesium aluminum silicate Magnesium sulfate Phenol Phenolate sodium Phenyl salicylate Povidone-iodine Pyrilamine maleate Resorcinol (as single ingredient) Resorcinol monoacetate (as single ingredient) Salicylic acid (over 2 up to 5 percent) Sodium borate Sodium thiosulfate Tetracaine hydrochloride Thymol Vitamin E Zinc oxide Zinc stearate Zinc sulfide (2) Anticaries drug products Approved as of May 7, 1991. Hydrogen fluoride Sodium carbonate Sodium monofluorophosphate (6 percent rinse) Sodium phosphate (ii) Approved as of October 7, 1996. Calcium sucrose phosphate Dicalcium phosphate dihydrate Disodium hydrogen phosphate 1 1 Phosphoric acid 1 Sodium dihydrogen phosphate Sodium dihydrogen phosphate monohydrate Sodium phosphate, dibasic anhydrous reagent 1 (3) Antidiarrheal drug products Approved as of May 7, 1991. Aluminum hydroxide Atropine sulfate Calcium carbonate Carboxymethylcellulose sodium Glycine Homatropine methylbromide Hyoscyamine sulfate Lactobacillus acidophilus Lactobacillus bulgaricus Opium, powdered Opium tincture Paregoric Phenyl salicylate Scopolamine hydrobromide Zinc phenolsulfonate (ii) Approved as of for products with annual sales less than $25,000. Attapulgite, activated Bismuth subnitrate Calcium hydroxide Calcium polycarbophil Charcoal (activated) Pectin Polycarbophil Potassium carbonate Rhubarb fluidextract (4) Antiperspirant drug products Ingredients Approved as of May 7, 1991. Alum, potassium Aluminum bromohydrate Aluminum chloride (alcoholic solutions) Aluminum chloride (aqueous solution) (aerosol only) Aluminum sulfate Aluminum sulfate, buffered (aerosol only) Sodium aluminum chlorohydroxy lactate (ii) Approved as of December 9, 2004; June 9, 2005, for products with annual sales less than $25,000. Aluminum sulfate buffered with sodium aluminum lactate (5) [Reserved] (6) Cold, cough, allergy, bronchodilator, and antiasthmatic drug products Antihistamine drug products Ingredients. Methapyrilene hydrochloride Methapyrilene fumarate Thenyldiamine hydrochloride (B) Ingredients. Phenyltoloxamine dihydrogen citrate Methapyrilene hydrochloride Methapyrilene fumarate Thenyldiamine hydrochloride (ii) Nasal decongestant drug products Approved as of May 7, 1991. Allyl isothiocyanate Camphor (lozenge) Creosote, beechwood (oral) Eucalyptol (lozenge) Eucalyptol (mouthwash) Eucalyptus oil (lozenge) Eucalyptus oil (mouthwash) Menthol (mouthwash) Peppermint oil (mouthwash) Thenyldiamine hydrochloride Thymol Thymol (lozenge) Thymol (mouthwash) Turpentine oil (B) Approved as of August 23, 1995. Bornyl acetate (topical) Cedar leaf oil (topical) Creosote, beechwood (topical) Ephedrine (oral) Ephedrine hydrochloride (oral) Ephedrine sulfate (oral) Racephedrine hydrochloride (oral/topical) (C) Approved as of April 11, 2007; October 11, 2007, for products with annual sales less than $25,000. Any ingredient(s) labeled with claims or directions for use for sinusitis or for relief of nasal congestion associated with sinusitis. (iii) Expectorant drug products. Ammonium chloride Antimony potassium tartrate Beechwood creosote Benzoin preparations (compound tincture of benzoin, tincture of benzoin) Camphor Chloroform Eucalyptol/eucalyptus oil Horehound Iodides (calcium iodide anyhydrous, hydroidic acid syrup, iodized lime, potassium iodide) Ipecac Ipecac fluidextract Ipecac syrup Menthol/peppermint oil Pine tar preparations (extract white pine compound, pine tar, syrup of pine tar, compound white pine syrup, white pine) Potassium guaiacolsulfonate Sodium citrate Squill preparations (squill, squill extract) Terpin hydrate preparations (terpin hydrate, terpin hydrate elixir) Tolu preparations (tolu, tolu balsam, tolu balsam tincture) Turpentine oil (spirits of turpentine) (iv) Bronchodilator drug products Approved as of October 2, 1987. Aminophylline Belladonna alkaloids Euphorbia pilulifera Metaproterenol sulfate Methoxyphenamine hydrochloride Pseudoephedrine hydrochloride Pseudoephedrine sulfate Theophylline, anhydrous Theophylline calcium salicylate Theophylline sodium glycinate (B) Approved as of January 29, 1996. Any combination drug product containing theophylline (e.g., theophylline and ephedrine, or theophylline and ephedrine and phenobarbital). (C) Approved as of June 19, 1996. Any ingredient(s) in a pressurized metered-dose inhaler container. (D) Approved as of October 29, 2001. Any oral bronchodilator active ingredient (e.g., ephedrine, ephedrine hydrochloride, ephedrine sulfate, racephedrine hydrochloride, or any other ephedrine salt) in combination with any analgesic(s) or analgesic-antipyretic(s), anticholinergic, antihistamine, oral antitussive, or stimulant active ingredient. (7) Dandruff/seborrheic dermatitis/psoriasis drug products. Alkyl isoquinolinium bromide Allantoin Benzalkonium chloride Benzethonium chloride Boric acid Calcium undecylenate Captan Chloroxylenol Colloidal oatmeal Cresol, saponated Ethohexadiol Eucalyptol Juniper tar Lauryl isoquinolinium bromide Menthol Mercury oleate Methylbenzethonium chloride Methyl salicylate Phenol Phenolate sodium Pine tar Povidone-iodine Resorcinol Sodium borate Sodium salicylate Thymol Undecylenic acid (8) Digestive aid drug products Approved as of May 7, 1991. Bismuth sodium tartrate Calcium carbonate Cellulase Dehydrocholic acid Dihydroxyaluminum sodium carbonate Duodenal substance Garlic, dehydrated Glutamic acid hydrochloride Hemicellulase Homatropine methylbromide Magnesium hydroxide Magnesium trisilicate Ox bile extract Pancreatin Pancrelipase Papain Peppermint oil Pepsin Sodium bicarbonate Sodium citrate Sorbitol (ii) Approved as of November 10, 1993. Alcohol Aluminum hydroxide Amylase Anise seed Aromatic powder Asafetida Aspergillus oryza enzymes (except lactase enzyme derived from Aspergillus oryzae Bacillus acidophilus Bean Belladonna alkaloids Belladonna leaves, powdered extract Betaine hydrochloride Bismuth subcarbonate Bismuth subgallate Black radish powder Blessed thistle (cnicus benedictus) Buckthorn Calcium gluconate Capsicum Capsicum, fluid extract of Carbon Cascara sagrada extract Catechu, tincture Catnip Chamomile flowers Charcoal, wood Chloroform Cinnamon oil Cinnamon tincture Citrus pectin Diastase Diastase malt Dog grass Elecampane Ether Fennel acid Galega Ginger Glycine Hydrastis canadensis (golden seal) Hectorite Horsetail Huckleberry Hydrastis fluid extract Hydrochloric acid Iodine Iron ox bile Johnswort Juniper Kaolin, colloidal Knotgrass Lactic acid Lactose Lavender compound, tincture of Linden Lipase Lysine hydrochloride Mannitol Mycozyme Myrrh, fluid extract of Nettle Nickel-pectin Nux vomica extract Orthophosphoric acid Papaya, natural Pectin Peppermint Peppermint spirit Phenacetin Potassium bicarbonate Potassium carbonate Protease Prolase Rhubarb fluid extract Senna Sodium chloride Sodium salicylate Stem bromelain Strawberry Strychnine Tannic acid Trillium Woodruff (iii) Charcoal, activated (9) [Reserved] (10) External analgesic drug products Analgesic and anesthetic drug products. Aspirin Chloral hydrate Chlorobutanol Cyclomethycaine sulfate Eugenol Hexylresorcinol Methapyrilene hydrochloride Salicylamide Thymol (ii) Counterirritant drug products. Chloral hydrate Eucalyptus oil (iii) Male genital desensitizer drug products. Benzyl alcohol Camphorated metacresol Ephedrine hydrochloride (iv) Diaper rash drug products. (v) Fever blister and cold sore treatment drug products. Allyl isothiocyanate Aspirin Bismuth sodium tartrate Camphor (exceeding 3 percent) Capsaicin Capsicum Capsicum oleoresin Chloral hydrate Chlorobutanol Cyclomethycaine sulfate Eucalyptus oil Eugenol Glycol salicylate Hexylresorcinol Histamine dihydrochloride Menthol (exceeding 1 percent) Methapyrilene hydrochloride Methyl nicotinate Methyl salicylate Pectin Salicylamide Strong ammonia solution Tannic acid Thymol Tripelennamine hydrochloride Trolamine salicylate Turpentine oil Zinc sulfate (vi) Insect bite and sting drug products. Alcohol Alcohol, ethoxylated alkyl Benzalkonium chloride Calamine Ergot fluidextract Ferric chloride Panthenol Peppermint oil Pyrilamine maleate Sodium borate Trolamine salicylate Turpentine oil Zinc oxide Zirconium oxide (vii) Poison ivy, poison oak, and poison sumac drug products. Alcohol Aspirin Benzethonium chloride Benzocaine (0.5 to 1.25 percent) Bithionol Calamine Cetalkonium chloride Chloral hydrate Chlorobutanol Chlorpheniramine maleate Creosote, beechwood Cyclomethycaine sulfate Dexpanthenol Diperodon hydrochloride Eucalyptus oil Eugenol Glycerin Glycol salicylate Hectorite Hexylresorcinol Hydrogen peroxide Impatiens biflora tincture Iron oxide Isopropyl alcohol Lanolin Lead acetate Merbromin Mercuric chloride Methapyrilene hydrochloride Panthenol Parethoxycaine hydrochloride Phenyltoloxamine dihydrogen citrate Povidone-vinylacetate copolymers Pyrilamine maleate Salicylamide Salicylic acid Simethicone Sulfur Tannic acid Thymol Trolamine salicylate Turpentine oil Zirconium oxide Zyloxin (11) [Reserved] (12) Laxative drug products Bulk laxatives. Agar Carrageenan (degraded) Carrageenan (native) Guar gun (i)(B) Bulk laxatives Approved as of Granular dosage forms containing psyllium (hemicellulose), psyllium hydrophilic mucilloid, psyllium seed, psyllium seed (blond), psyllium seed husks, plantago husks, or plantago seed including, but not limited to, any granules that are: ( 1 ( 2 ( 3 ( 4 (ii) Saline laxative. Tartaric acid (iii) Stool softener. Poloxamer 188 (iv)(A) Stimulant laxatives—Approved as of May 7, 1991. Aloin Bile salts/acids Calcium pantothenate Calomel Colocynth Elaterin resin Frangula Gamboge Ipomea Jalap Ox bile Podophyllum resin Prune concentrate dehydrate Prune powder Rhubarb, Chinese Sodium Oleate (iv)(B) Stimulant laxatives—Approved as of January 29, 1999. Danthron Phenolphthalein (C) Stimulant laxatives Approved as of Aloe ingredients (aloe, aloe extract, aloe flower extract) Cascara sagrada ingredients (casanthranol, cascara fluidextract aromatic, cascara sagrada bark, cascara sagrada extract, cascara sagrada fluidextract). (13) [Reserved] (14) Oral health care drug products (nonantimicrobial). Antipyrine Camphor Cresol Dibucaine Dibucaine hydrochloride Eucalyptol Lidocaine Lidocaine hydrochloride Methly salicylate Myrrh tincture Pyrilamine maleate Sorbitol Sugars Tetracaine Tetracaine hydrochloride Thymol (15) Topical otic drug products For the prevention of swimmer's ear and for the drying of water-clogged ears, approved as of May 7, 1991. Acetic acid (ii) For the prevention of swimmer's ear, approved as of August 15, 1995. Glycerin and anhydrous glycerin Isopropyl alcohol (16) Poison treatment drug products. Ipecac fluidextract Ipecac tincture Zinc sulfate (17) Skin bleaching drug products. Mercury, ammoniated (18) Skin protectant drug products Ingredients—Approved as of May 7, 1991. Allantoin (wound healing claims only) Sulfur Tannic acid Zinc acetate (wound healing claims only) (B) Ingredients—Approved as of for products with annual sales less than $25,000. Beeswax Bismuth subnitrate Boric acid Cetyl alcohol Glyceryl stearate Isopropyl palmitate Live yeast cell derivative Shark liver oil Stearyl alcohol (ii) Astringent drug products. Acetone Alcohol Alum, ammonium Alum, potassium Aluminum chlorhydroxy complex Aromatics Benzalkonium chloride Benzethonium chloride Benzocaine Benzoic acid Boric acid Calcium acetate (except calcium acetate monohydrate when combined with aluminum sulfate tetradecahydrate to provide an aluminum acetate solution as described in § 347.20(b) of this chapter) Camphor gum Clove oil Colloidal oatmeal Cresol Cupric sulfate Eucalyptus oil Eugenol Ferric subsulfate (Monsel's Solution) Honey Isopropyl alcohol Menthol Methyl salicylate Oxyquinoline sulfate P-t-butyl-m-cresol Peppermint oil Phenol Polyoxeythylene laurate Potassium ferrocyanide Sage oil Silver nitrate Sodium borate Sodium diacetate Talc Tannic acid glycerite Thymol Topical starch Zinc chloride Zinc oxide Zinc phenolsulfonate Zinc stearate Zinc sulfate (iii) Diaper rash drug products. Aluminum hydroxide Cocoa butter Cysteine hydrochloride Glycerin Protein hydrolysate Racemethionine Sulfur Tannic acid Zinc acetate Zinc carbonate (iv) Fever blister and cold sore treatment drug products. Bismuth subnitrate Boric acid Pyridoxine hydrochloride Sulfur Tannic acid Topical starch Trolamine Zinc sulfate (v) Insect bite and sting drug products Ingredients—Approved as of November 10, 1993. Alcohol Alcohol, ethoxylated alkyl Ammonia solution, strong Ammonium hydroxide Benzalkonium chloride Camphor Ergot fluid extract Ferric chloride Menthol Peppermint oil Phenol Pyrilamine maleate Sodium borate Trolamine Turpentine oil Zirconium oxide (B) Ingredients—Approved as of for products with annual sales less than $25,000. Beeswax Bismuth subnitrate Boric acid Cetyl alcohol Glyceryl stearate Isopropyl palmitate Live yeast cell derivative Shark liver oil Stearyl alcohol (vi) Poison ivy, poison oak, and poison sumac drug products Ingredients—Approved as of November 10, 1993. Alcohol Anion and cation exchange resins buffered Benzethonium chloride Benzocaine Benzyl alcohol Bismuth subnitrate Bithionol Boric acid Camphor Cetalkonium chloride Chloral hydrate Chlorpheniramine maleate Creosote Diperodon hydrochloride Diphenhydramine hydrochloride Eucalyptus oil Ferric chloride Glycerin Hectorite Hydrogen peroxide Impatiens biflora tincture Iron oxide Isopropyl alcohol Lanolin Lead acetate Lidocaine Menthol Merbromin Mercuric chloride Panthenol Parethoxycaine hydrochloride Phenol Phenyltoloxamine dihydrogen citrate Povidone-vinylacetate copolymers Salicylic acid Simethicone Tannic acid Topical starch Trolamine Turpentine oil Zirconium oxide Zyloxin (B) Ingredients—Approved as of for products with annual sales less than $25,000. Beeswax Bismuth subnitrate Boric acid Cetyl alcohol Glyceryl stearate Isopropyl palmitate Live yeast cell derivative Shark liver oil Stearyl alcohol (19) [Reserved] (20) Weight control drug products. Alcohol Alfalfa Alginic acid Anise oil Arginine Ascorbic acid Bearberry Biotin Bone marrow, red Buchu Buchu, potassium extract Caffeine Caffeine citrate Calcium Calcium carbonate Calcium caseinate Calcium lactate Calcium pantothenate Carboxymethylcellulose sodium Carrageenan Cholecalcierol Choline Chondrus Citric acid Cnicus benedictus Copper Copper gluconate Corn oil Corn syrup Corn silk, potassium extract Cupric sulfate Cyanocobalamin (vitamin B 12 Cystine Dextrose Docusate sodium Ergocalciferol Ferric ammonium citrate Ferric pyrophosphate Ferrous fumarate Ferrous gluconate Ferrous sulfate (iron) Flax seed Folic acid Fructose Guar gum Histidine Hydrastis canadensis Inositol Iodine Isoleucine Juniper, potassium extract Karaya gum Kelp Lactose Lecithin Leucine Liver concentrate Lysine Lysine hydrochloride Magnesium Magnesium oxide Malt Maltodextrin Manganese citrate Mannitol Methionine Methylcellulose Mono- and di-glycerides Niacinamide Organic vegetables Pancreatin Pantothenic acid Papain Papaya enzymes Pepsin Phenacetin Phenylalanine Phosphorus Phytolacca Pineapple enzymes Plantago seed Potassium citrate Pyridoxine hydrochloride (vitamin B 6 Riboflavin Rice polishings Saccharin Sea minerals Sesame seed Sodium Sodium bicarbonate Sodium caseinate Sodium chloride (salt) Soybean protein Soy meal Sucrose Thiamine hydrochloride (vitamin B 1 Thiamine mononitrate (vitamin B 1 Threonine Tricalcium phosphate Tryptophan Tyrosine Uva ursi, potassium extract Valine Vegetable Vitamin A Vitamin A acetate Vitamin A palmitate Vitamin E Wheat germ Xanthan gum Yeast (21) Ophthalmic drug products. Ophthalmic anesthetic drug products. Antipyrine Piperocaine hydrochloride (ii) Ophthalmic anti-infective drug products. Boric acid Mild silver protein Yellow mercuric oxide (iii) Ophthalmic astringent drug products. Infusion of rose petals (iv) Ophthalmic demulcent drug products. Polyethylene glycol 6000 (v) Ophthalmic vasoconstrictor drug products. Phenylephrine hydrochloride (less than 0.08 percent) (22) Topical antifungal drug products. Diaper rash drug products. (ii) Ingredients. Alcloxa Alum, potassium Aluminum sulfate Amyltricresols, secondary Basic fuchsin Benzethonium chloride Benzoic acid Benzoxiquine Boric acid Camphor Candicidin Chlorothymol Coal tar Dichlorophen Menthol Methylparaben Oxyquinoline Oxyquinoline sulfate Phenol Phenolate sodium Phenyl salicylate Propionic acid Propylparaben Resorcinol Salicylic acid Sodium borate Sodium caprylate Sodium propionate Sulfur Tannic acid Thymol Tolindate Triacetin Zinc caprylate Zinc propionate (iii) Any ingredient(s) labeled with claims or directions for use on the scalp or on the nails. (iv) Ingredients. Camphorated metacresol Chloroxylenol m Nystatin (23) Internal analgesic drug products Approved as of November 10, 1993. Aminobenzoic acid Antipyrine Aspirin, aluminum Calcium salicylate Codeine Codeine phosphate Codeine sulfate Iodoantipyrine Lysine aspirin Methapyrilene fumarate Phenacetin Pheniramine maleate Pyrilamine maleate Quinine Salsalate Sodium aminobenzoate (ii) Approved as of Any atropine ingredient Any ephedrine ingredient (24) Orally administered menstrual drug products Approved as of November 10, 1993. Alcohol Alfalfa leaves Aloes Asclepias tuberosa Asparagus Barosma Bearberry (extract of uva ursi) Bearberry fluidextract (extract of bearberry) Blessed thistle (cnicus benedictus) Buchu powdered extract (extract of buchu) Calcium lactate Calcium pantothenate Capsicum oleoresin Cascara fluidextract, aromatic (extract of cascara) Chlorprophenpyridamine maleate Cimicifuga racemosa Codeine Collinsonia (extract stone root) Corn silk Couch grass Dog grass extract Ethyl nitrite Ferric chloride Ferrous sulfate Gentiana lutea (gentian) Glycyrrhiza (licorice) Homatropine methylbromide Hydrangea, powdered extract (extract of hydrangea) Hydrastis canadensis (golden seal) Hyoscyamine sulfate Juniper oil (oil of juniper) Magnesium sulfate Methapyrilene hydrochloride Methenamine Methylene blue Natural estrogenic hormone Niacinamide Nutmeg oil (oil of nutmeg) Oil of erigeron Parsley Peppermint spirit Pepsin, essence Phenacetin Phenindamine tartrate Phenyl salicylate Piscidia erythrina Pipsissewa Potassium acetate Potassium nitrate Riboflavin Saw palmetto Senecio aureus Sodium benzoate Sodium nitrate Sucrose Sulferated oils of turpentine Taraxacum officinale Theobromine sodium salicylate Theophylline Thiamine hydrochloride Triticum Turpentine, venice (venice turpertine) Urea (ii) Approved as of Any atropine ingredient Any ephedrine ingredient (25) Pediculicide drug products Approved as of November 10, 1993. Benzocaine Benzyl alcohol Benzyl benzoate Chlorophenothane (dichlorodiphenyl trichloroethane) Coconut oil soap, aqueous Copper oleate Docusate sodium Formic acid Isobornyl thiocyanoacetate Picrotoxin Propylene glycol Sabadilla alkaloids Sulfur, sublimed Thiocyanoacetate (ii) Approved as of June 14, 1994. (26) Anorectal drug products Anticholinergic drug products. Atropine Belladonna extract (ii) Antiseptic drug products. Boric acid Boroglycerin Hydrastis Phenol Resorcinol Sodium salicylic acid phenolate (iii) Astringent drug products. Tannic acid (iv) Counterirritant drug products. Camphor (greater than 3 to 11 percent) Hydrastis Menthol (1.25 to 16 percent) Turpentine oil (rectified) (6 to 50 percent) (v) Keratolytic drug products. Precipitated sulfur Sublimed sulfur (vi) Local anesthetic drug products. Diperodon Phenacaine hydrochloride (vii) Other drug products. Collinsonia extract Escherichia coli vaccines Lappa extract Leptandra extract Live yeast cell derivative Mullein (viii) Protectant drug products. Bismuth oxide Bismuth subcarbonate Bismuth subgallate Bismuth subnitrate Lanolin alcohols (ix) Vasoconstrictor drug products. Epinephrine undecylenate (x) Wound healinq drug products. Cholecalciferol Cod liver oil Live yeast cell derivative Peruvian balsam Shark liver oil Vitamin A (xi) Combination drug products. (27) Topical antimicrobial drug products First aid antiseptic drug products. Ammoniated mercury Calomel (mercurous chloride) Merbromin (mercurochrome) Mercufenol chloride (ortho-chloromercuriphenol, ortho-hydroxyphenylmercuric chloride) Mercuric chloride (bichloride of mercury, mercury chloride) Mercuric oxide, yellow Mercuric salicylate Mercuric sulfide, red Mercury Mercury oleate Mercury sulfide Nitromersol Para-chloromercuriphenol Phenylmercuric nitrate Thimerosal Vitromersol Zyloxin (ii) Diaper rash drug products. Para-chloromercuriphenol Any other ingredient containing mercury (iii) Consumer antiseptic hand wash drug products. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate) Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol (greater than 1.5 percent) Phenol (less than 1.5 percent) Poloxamer iodine complex Povidone-iodine (5 to 10 percent) Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Triple Dye Undecoylium chloride iodine complex (iv) Consumer antiseptic body wash drug products. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Iodine tincture Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol (greater than 1.5 percent) Phenol (less than 1.5 percent) Poloxamer iodine complex Povidone-iodine (5 to 10 percent) Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Triple Dye Undecoylium chloride iodine complex (v) [Reserved] (vi) Health care personnel hand wash drug products. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate) Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol Poloxamer-iodine complex Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Undecoylium chloride iodine complex (vii) [Reserved] (viii) Surgical hand scrub drug products. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate) Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol Poloxamer-iodine complex Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Undecoylium chloride iodine complex (ix) [Reserved] (x) Patient antiseptic skin preparation drug products. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Iodine tincture (USP) Iodine topical solution (USP) Mercufenol chloride Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol Poloxamer-iodine complex Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Triple dye Undecoylium chloride iodine complex Combination of calomel, oxyquinoline benzoate, triethanolamine, and phenol derivative Combination of mercufenol chloride and secondary amyltricresols in 50 percent alcohol (28) Vaginal contraceptive drug products Approved as of October 22, 1998. Dodecaethylene glycol monolaurate (polyethylene glycol 600 monolaurate) Laureth 10S Methoxypolyoxyethyleneglycol 550 laurate Phenylmercuric acetate Phenylmercuric nitrate Any other ingredient containing mercury (ii) Approved as of November 5, 2002. Octoxynol 9 (29) Sunscreen drug products. Ingredients. Diethanolamine methoxycinnamate Digalloyl trioleate Ethyl 4-[bis(hydroxypropyl)] aminobenzoate Glyceryl aminobenzoate Lawsone with dihydroxyacetone Red petrolatum (ii) Any ingredients labeled with any of the following or similar claims. Instant protection or protection immediately upon application. Claims for “all-day” protection or extended wear claims citing a specific number of hours of protection that is inconsistent with the directions for application in 21 CFR 201.327. (30) [Reserved] (b) Any OTC drug product that is labeled, represented, or promoted for the uses specified and containing any active ingredient(s) as specified in paragraph (a) of this section is regarded as a new drug within the meaning of section 210(p) of the Federal Food, Drug, and Cosmetic Act (the Act), for which an approved new drug application under section 505 of the Act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the Act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for the OTC uses and containing any active ingredient(s) as specified in paragraph (a) of this section is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) Any OTC drug product that is not in compliance with this section is subject to regulatory action if initially introduced or initially delivered for introduction into interstate commerce after the dates specified in paragraphs (d)(1) through (d)(42) of this section. (1) May 7, 1991, for products subject to paragraphs (a)(1) through (a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except as covered by paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (a)(12)(i)(A), (a)(12)(ii) through (a)(12)(iv)(A), (a)(14) through (a)(15)(i), (a)(16) through (a)(18)(i)(A), (a)(18)(ii) (except as covered by paragraph (d)(22) of this section), (a)(18)(iii), (a)(18)(iv), (a)(18)(v)(A), and (a)(18)(vi)(A) of this section. (2) February 10, 1992, for products subject to paragraph (a)(20) of this section. (3) December 4, 1992, for products subject to paragraph (a)(7) of this section that contain menthol as an antipruritic in combination with the antidandruff ingredient coal tar identified in § 358.710(a)(1) of this chapter. This section does not apply to products allowed by § 358.720(b) of this chapter after April 5, 2007. (4) February 28, 1990, for products subject to paragraph (a)(6)(iii) of this section, except those that contain ipecac. (5) September 14, 1993, for products subject to paragraph (a)(6)(iii) of this section that contain ipecac. (6) December 9, 1993, for products subject to paragraph (a)(6)(i)(B) of this section. (7) March 6, 1989, for products subject to paragraph (a)(21) of this section, except those that contain ophthalmic anti-infective ingredients listed in paragraph (a)(21)(ii). (8) June 18, 1993, for products subject to paragraph (a)(21) of this section that contain ophthalmic anti-infective ingredients. (9) June 18, 1993, for products subject to paragraph (a)(10)(iv) of this section. (10) June 18, 1993, for products subject to paragraph (a)(22)(i) of this section. (11) November 10, 1993, for products subject to paragraphs (a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except products that contain ferric subsulfate as covered by paragraph (d)(22) of this section and except products that contain calcium acetate monohydrate as covered by paragraph (d)(39) of this section) through (a)(18)(v)(A), (a)(18)(vi)(A), (a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) of this section. (12) March 2, 1994, for products subject to paragraph (a)(22)(iii) of this section. (13) August 5, 1991, for products subject to paragraph (a)(26) of this section, except for those that contain live yeast cell derivative and a combination of hydrocortisone and pramoxine hydrochloride. (14) September 2, 1994, for products subject to paragraph (a)(26)(vii) and (a)(26)(x) of this section that contain live yeast cell derivative. (15) September 23, 1994, for products subject to paragraph (a)(22)(iv) of this section. (16) June 14, 1994, for products subject to paragraph (a)(25)(ii) of this section. (17) April 19, 2004, for products subject to paragraph (a)(3)(ii) of this section. April 18, 2005, for products with annual sales less than $25,000. (18) August 15, 1995, for products subject to paragraph (a)(15)(ii) of this section. (19) October 2, 1987, for products subject to paragraph (a)(6)(iv)(A) of this section. (20) January 29, 1996, for products subject to paragraph (a)(6)(iv)(B) of this section. (21) April 21, 1994, for products subject to paragraph (a)(8)(iii) of this section. (22) April 21, 1993, for products subject to paragraph (a)(18)(ii) of this section that contain ferric subsulfate. (23) August 23, 1995, for products subject to paragraph (a)(6)(ii)(B) of this section. (24) October 7, 1996, for products subject to paragraph (a)(2)(ii) of this section. (25) June 19, 1996, for products subject to paragraph (a)(6)(iv)(C) of this section. (26) February 22, 1999, for products subject to paragraphs (a)(23)(ii) and (a)(24)(ii) of this section. (27) [Reserved] (28) October 22, 1998, for products subject to paragraphs (a)(27) and (a)(28)(i) of this section. (29) January 29, 1999, for products subject to paragraph (a)(12)(iv)(B) of this section. (30) November 5, 2002, for products subject to paragraph (a)(12)(iv)(C) of this section. (31) December 31, 2002, for products subject to paragraph (a)(29)(i) of this section. (32) June 4, 2004, for products subject to paragraphs (a)(18)(i)(B), (a)(18)(v)(B), and (a)(18)(vi)(B) of this section. June 6, 2005, for products with annual sales less than $25,000. (33) October 29, 2001, for products subject to paragraph (a)(6)(iv)(D) of this section. (34) December 9, 2004, for products subject to paragraph (a)(4)(ii) of this section. June 9, 2005, for products with annual sales less than $25,000. (35) [Reserved] (36) November 5, 2002, for products subject to paragraph (a)(28)(ii) of this section. (37) September 25, 2003, for products subject to paragraph (a)(26)(xi) of this section. (38) October 1, 2007, for products subject to paragraph (a)(12)(i)(B) of this section. (39) September 6, 2010, for products subject to paragraph (a)(18)(ii) of this section that contain calcium acetate monohydrate, except as provided in § 347.20(b) of this chapter. (40) December 17, 2012, for products subject to paragraph (a)(29)(ii) of this section. December 17, 2013, for products with annual sales less than $25,000. (41) September 6, 2017, for products subject to paragraph (a)(27)(iii) or (iv) of this section. (42) December 20, 2018, for products subject to paragraphs (a)(27)(vi) through (x) of this section. [55 FR 46919, Nov. 7, 1990] Editorial Note: For Federal Register www.govinfo.gov. Effective Date Note: At 61 FR 9571, Mar. 8, 1996, in § 310.545 in paragraph (a)(6)(ii)(B), the entry for “l-desoxyephedrine (topical)” was stayed until further notice. § 310.546 Drug products containing active ingredients offered over-the-counter (OTC) for the treatment and/or prevention of nocturnal leg muscle cramps. (a) Quinine sulfate alone or in combination with vitamin E has been present in over-the-counter (OTC) drug products for the treatment and/or prevention of nocturnal leg muscle cramps, i.e. (b) Any OTC drug product that is labeled, represented, or promoted for the treatment and/or prevention of nocturnal leg muscle cramps is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for the treatment and/or prevention of nocturnal leg muscle cramps is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After February 22, 1995, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [59 FR 43252, Aug. 22, 1994] § 310.547 Drug products containing quinine offered over-the-counter (OTC) for the treatment and/or prevention of malaria. (a) Quinine and quinine salts have been used OTC for the treatment and/or prevention of malaria, a serious and potentially life-threatening disease. Quinine is no longer the drug of choice for the treatment and/or prevention of most types of malaria. In addition, there are serious and complicating aspects of the disease itself and some potentially serious and life-threatening risks associated with the use of quinine at doses employed for the treatment of malaria. There is a lack of adequate data to establish general recognition of the safety of quinine drug products for OTC use in the treatment and/or prevention of malaria. Therefore, quinine or quinine salts cannot be safely and effectively used for the treatment and/or prevention of malaria except under the care and supervision of a doctor. (b) Any OTC drug product containing quinine or quinine salts that is labeled, represented, or promoted for the treatment and/or prevention of malaria is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for the treatment and/or prevention of malaria is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) After April 20, 1998, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [63 FR 13528, Mar. 20, 1998] § 310.548 Drug products containing colloidal silver ingredients or silver salts offered over-the-counter (OTC) for the treatment and/or prevention of disease. (a) Colloidal silver ingredients and silver salts have been marketed in over-the-counter (OTC) drug products for the treatment and prevention of numerous disease conditions. There are serious and complicating aspects to many of the diseases these silver ingredients purport to treat or prevent. Further, there is a lack of adequate data to establish general recognition of the safety and effectiveness of colloidal silver ingredients or silver salts for OTC use in the treatment or prevention of any disease. These ingredients and salts include, but are not limited to, silver proteins, mild silver protein, strong silver protein, silver, silver ion, silver chloride, silver cyanide, silver iodide, silver oxide, and silver phosphate. (b) Any OTC drug product containing colloidal silver ingredients or silver salts that is labeled, represented, or promoted for the treatment and/or prevention of any disease is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. (c) Clinical investigations designed to obtain evidence that any drug product containing colloidal silver or silver salts labeled, represented, or promoted for any OTC drug use is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs as set forth in part 312 of this chapter. (d) After September 16, 1999, any such OTC drug product containing colloidal silver or silver salts initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. [64 FR 44658, Aug. 17, 1999]

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