21 CFR Ch. I (4–1–20 Edition) § 310.545

Home , Cetalkonium chloride, Chlorothen, Docusate, Merbromin, Nitromersol, Phenyltoloxamine

SUBCHAPTER D—DRUGS FOR HUMAN USE

PART 300—GENERAL presented for it, then formulation, labeling, or dosage changes may be pro- Subpart A [Reserved] posed and any resulting formulation may meet the appropriate criteria list- Subpart B—Combination Drugs ed in paragraph (a) of this section. (c) A fixed-combination prescription Sec. 300.50 Fixed-combination prescription drugs drug for humans that has been deter- for humans. mined to be effective for labeled indications by the Food and Drug Adminis- Subpart C—Substances Generally tration, based on evaluation of the Prohibited From Drugs NAS-NRC report on the combination, is considered to be in compliance with 300.100 Chlorofluorocarbon propellants. the requirements of this section. AUTHORITY: 21 U.S.C. 331, 351, 352, 355, 360b, 361, 371. [40 FR 13496, Mar. 27, 1975, as amended at 64 FR 401, Jan. 5, 1999] Subpart A [Reserved] Subpart C—Substances Generally Subpart B—Combination Drugs Prohibited From Drugs § 300.50 Fixed-combination prescrip- § 300.100 Chlorofluorocarbon propel- tion drugs for humans. lants. The Food and Drug Administration’s The use of chlorofluorocarbons in policy in administering the new-drug, human drugs as propellants in self- antibiotic, and other regulatory provi- pressurized containers is generally pro- sions of the Federal Food, Drug, and hibited except as provided by § 2.125 of Cosmetic Act regarding fixed combina- this chapter. tion dosage form prescription drugs for [43 FR 11317, Mar. 17, 1978] humans is as follows: (a) Two or more drugs may be combined in a single dosage form when PART 310—NEW DRUGS each component makes a contribution to the claimed effects and the dosage of Subpart A—General Provisions each component (amount, frequency, Sec. duration) is such that the combination 310.3 Definitions and interpretations. is safe and effective for a significant 310.4 Biologics; products subject to license patient population requiring such con- control. current therapy as defined in the label- 310.6 Applicability of ‘‘new drug’’ or safety ing for the drug. Special cases of this or effectiveness findings in drug efficacy general rule are where a component is study implementation notices and no- added: tices of opportunity for hearing to iden- (1) To enhance the safety or effec- tical, related, and similar drug products. tiveness of the principal active compo- Subpart B—Specific Administrative Rulings nent; and and Decisions (2) To minimize the potential for abuse of the principal active compo- 310.100 New drug status opinions; statement nent. of policy. (b) If a combination drug presently 310.103 New drug substances intended for the subject of an approved new-drug hypersensitivity testing. application has not been recognized as effective by the Commissioner of Food Subpart C—New Drugs Exempted From and Drugs based on his evaluation of Prescription-Dispensing Requirements the appropriate National Academy of 310.200 Prescription-exemption procedure. Sciences-National Research Council 310.201 Exemption for certain drugs limited panel report, or if substantial evidence by new drug applications to prescription of effectiveness has not otherwise been sale.

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Subpart D—Records and Reports 310.537 Drug products containing active ingredients offered over-the-counter (OTC) 310.303 Continuation of long-term studies, for oral administration for the treatment records, and reports on certain drugs for of fever blisters and cold sores. which new drug applications have been 310.538 Drug products containing active in- approved. gredients offered over-the-counter (OTC) 310.305 Records and reports concerning ad- for use for ingrown toenail relief. verse drug experiences on marketed pre- 310.540 Drug products containing active in- scription drugs for human use without gredients offered over-the-counter (OTC) approved new drug applications. for use as stomach acidifiers. 310.306 Notification of a permanent dis- 310.541 Over-the-counter (OTC) drug prod- continuance or an interruption in manu- ucts containing active ingredients of- facturing of marketed prescription drugs fered for use in the treatment of hypo- for human use without approved new phosphatemia. drug applications. 310.542 Over-the-counter (OTC) drug products containing active ingredients of- Subpart E—Requirements for Specific New fered for use in the treatment of hyper- Drugs or Devices phosphatemia. 310.543 Drug products containing active in- 310.501 Patient package inserts for oral con- gredients offered over-the-counter (OTC) traceptives. for human use in exocrine pancreatic in- 310.502 Certain drugs accorded new drug sta- sufficiency. tus through rulemaking procedures. 310.544 Drug products containing active in- 310.503 Requirements regarding certain ra- gredients offered over-the-counter (OTC) dioactive drugs. for use as a smoking deterrent. 310.509 Parenteral drug products in plastic 310.545 Drug products containing certain ac- containers. tive ingredients offered over-the-counter 310.515 Patient package inserts for estro- (OTC) for certain uses. gens. 310.546 Drug products containing active in- 310.517 Labeling for oral hypoglycemic gredients offered over-the-counter (OTC) drugs of the sulfonylurea class. for the treatment and/or prevention of 310.518 Drug products containing iron or nocturnal leg muscle cramps. iron salts. 310.547 Drug products containing quinine of- 310.519 Drug products marketed as over-the- fered over-the-counter (OTC) for the counter (OTC) daytime sedatives. treatment and/or prevention of malaria. 310.527 Drug products containing active in- 310.548 Drug products containing colloidal gredients offered over-the-counter (OTC) silver ingredients or silver salts offered for external use as hair growers or for over-the-counter (OTC) for the treatment hair loss prevention. and/or prevention of disease. 310.528 Drug products containing active ingredients offered over-the-counter (OTC) AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, for use as an aphrodisiac. 355, 360b–360f, 360j, 360hh–360ss, 361(a), 371, 374, 310.529 Drug products containing active in- 375, 379e, 379k–l; 42 U.S.C. 216, 241, 242(a), 262. gredients offered over-the-counter (OTC) for oral use as insect repellents. Subpart A—General Provisions 310.530 Topically applied hormone-containing drug products for over-the- § 310.3 Definitions and interpretations. counter (OTC) human use. 310.531 Drug products containing active in- As used in this part: gredients offered over-the-counter (OTC) (a) The term act means the Federal for the treatment of boils. Food, Drug, and Cosmetic Act, as 310.532 Drug products containing active in- amended (secs. 201–902, 52 Stat. 1040 et gredients offered over-the-counter (OTC) seq., as amended; 21 U.S.C. 321–392). to relieve the symptoms of benign prostatic hypertrophy. (b) Department means the Department 310.533 Drug products containing active in- of Health and Human Services. gredients offered over-the-counter (OTC) (c) Secretary means the Secretary of for human use as an anticholinergic in Health and Human Services. cough-cold drug products. (d) Commissioner means the Commis- 310.534 Drug products containing active in- sioner of Food and Drugs. gredients offered over-the-counter (OTC) (e) The term person includes individ- for human use as oral wound healing uals, partnerships, corporations, and agents. 310.536 Drug products containing active in- associations. gredients offered over-the-counter (OTC) (f) The definitions and interpreta- for use as a nailbiting or thumbsucking tions of terms contained in section 201 deterrent. of the act shall be applicable to such

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terms when used in the regulations in manufactured by other manufacturers: this part. and any other drug containing a com- (g) New drug substance means any ponent so related by chemical struc- substance that when used in the manu- ture or known pharmacological prop- facture, processing, or packing of a erties that, in the opinion of experts drug, causes that drug to be a new qualified by scientific training and ex- drug, but does not include intermedi- perience to evaluate the safety and ef- ates used in the synthesis of such sub- fectiveness of drugs, it is prudent to as- stance. sume or ascertain the liability of simi- (h) The newness of a drug may arise lar side effects and contraindications. by reason (among other reasons) of: (l) Special packaging as defined in sec- (1) The newness for drug use of any tion 2(4) of the Poison Prevention substance which composes such drug, Packaging Act of 1970 means packaging in whole or in part, whether it be an that is designed or constructed to be active substance or a menstruum, ex- significantly difficult for children cipient, carrier, coating, or other com- under 5 years of age to open or obtain ponent. a toxic or harmful amount of the sub- (2) The newness for a drug use of a stance contained therein within a rea- combination of two or more sub- sonable time and not difficult for nor- stances, none of which is a new drug. mal adults to use properly, but does (3) The newness for drug use of the not mean packaging which all such proportion of a substance in a combina- children cannot open or obtain a toxic tion, even though such combination or harmful amount within a reasonable containing such substance in other pro- time. portion is not a new drug. (m) [Reserved] (4) The newness of use of such drug in (n) The term radioactive drug means diagnosing, curing, mitigating, treat- any substance defined as a drug in sec- ing, or preventing a disease, or to af- tion 201(g)(1) of the Federal Food, fect a structure or function of the Drug, and Cosmetic Act which exhibits body, even though such drug is not a new drug when used in another disease spontaneous disintegration of unstable or to affect another structure or func- nuclei with the emission of nuclear tion of the body. particles or photons and includes any (5) The newness of a dosage, or meth- nonradioactive reagent kit or nuclide od or duration of administration or ap- generator which is intended to be used plication, or other condition of use pre- in the preparation of any such sub- scribed, recommended, or suggested in stance but does not include drugs such the labeling of such drug, even though as carbon-containing compounds or po- such drug when used in other dosage, tassium-containing salts which contain or other method or duration of admin- trace quantities of naturally occurring istration or application, or different radionuclides. The term ‘‘radioactive condition, is not a new drug. drug’’ includes a ‘‘radioactive biologi- (i) [Reserved] cal product’’ as defined in § 600.3(ee) of (j) The term sponsor means the per- this chapter. son or agency who assumes responsi- [39 FR 11680, Mar. 29, 1974, as amended at 39 bility for an investigation of a new FR 20484, June 11, 1974; 40 FR 31307, July 25, drug, including responsibility for com- 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. pliance with applicable provisions of 22, 1985] the act and regulations. The ‘‘sponsor’’ may be an individual, partnership, cor- § 310.4 Biologics; products subject to poration, or Government agency and license control. may be a manufacturer, scientific in- (a) If a drug has an approved license stitution, or an investigator regularly under section 351 of the Public Health and lawfully engaged in the investiga- Service Act (42 U.S.C. 262 et seq.) or tion of new drugs. under the animal virus, serum, and (k) The phrase related drug(s) includes toxin law of March 4, 1913 (21 U.S.C. 151 other brands, potencies, dosage forms, et seq.), it is not required to have an ap- salts, and esters of the same drug moi- proved application under section 505 of ety, including articles prepared or the act.

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(b) To obtain marketing approval for plicable. Any product not in compli- radioactive biological products for ance with an applicable drug efficacy human use, as defined in § 600.3(ee) of notice is in violation of section 505 this chapter, manufacturers must com- (new drugs) and/or section 502 (mis- ply with the provisions of § 601.2(a) of branding) of the act. this chapter. (b)(1) An identical, related, or similar drug includes other brands, potencies, [64 FR 56448, Oct. 20, 1999, as amended at 70 FR 14981, Mar. 24, 2005] dosage forms, salts, and esters of the same drug moiety as well as of any § 310.6 Applicability of ‘‘new drug’’ or drug moiety related in chemical struc- safety or effectiveness findings in ture or known pharmacological prop- drug efficacy study implementation erties. notices and notices of opportunity (2) Where experts qualified by sci- for hearing to identical, related, entific training and experience to and similar drug products. evaluate the safety and effectiveness of (a) The Food and Drug Administra- drugs would conclude that the findings tion’s conclusions on the effectiveness and conclusions, stated in a drug effi- of drugs are currently being published cacy notice or notice of opportunity for in the FEDERAL REGISTER as Drug Effi- hearing, that a drug product is a ‘‘new cacy Study Implementation (DESI) No- drug’’ or that there is a lack of evi- tices and as Notices of Opportunity for dence to show that a drug product is Hearing. The specific products listed in safe or effective are applicable to an these notices include only those that identical, related, or similar drug prod- were introduced into the market uct, such product is affected by the no- through the new drug procedures from tice. A combination drug product con- 1938–62 and were submitted for review taining a drug that is identical, re- by the National Academy of Sciences- lated, or similar to a drug named in a National Research Council (NAS-NRC), notice may also be subject to the find- Drug Efficacy Study Group. Many ings and conclusions in a notice that a products which are identical to, related drug product is a ‘‘new drug’’ or that to, or similar to the products listed in there is a lack of evidence to show that these notices have been marketed a drug product is safe or effective. under different names or by different (3) Any person may request an opin- firms during this same period or since ion on the applicability of such a no- 1962 without going through the new tice to a specific product by writing to drug procedures or the Academy re- the Food and Drug Administration at view. Even though these products are the address shown in paragraph (e) of not listed in the notices, they are cov- this section. ered by the new drug applications re- (c) Manufacturers and distributors of viewed and thus are subject to these drugs should review their products as notices. All persons with an interest in drug efficacy notices are published and a product that is identical, related, or assure that identical, related, or simi- similar to a drug listed in a drug effi- lar products comply with all applicable cacy notice or a notice of opportunity provisions of the notices. for a hearing will be given the same op- (d) The published notices and sum- portunity as the applicant to submit mary lists of the conclusions are of data and information, to request a particular interest to drug purchasing hearing, and to participate in any hear- agents. These agents should take par- ing. It is not feasible for the Food and ticular care to assure that the same Drug Administration to list all prod- purchasing policy applies to drug products which are covered by an NDA and ucts that are identical, related, or thus subject to each notice. However, similar to those named in the drug effi- it is essential that the findings and cacy notices. The Food and Drug Ad- conclusions that a drug product is a ministration applies the same regu- ‘‘new drug’’ or that there is a lack of latory policy to all such products. In evidence to show that a drug product is many instances a determination can safe or effective be applied to all iden- readily be made as to the applicability tical, related, and similar drug prod- of a drug efficacy notice by an indi- ucts to which they are reasonably ap- vidual who is knowledgeable about

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drugs and their indications for use. (Public Law 87–781; 76 Stat. 788–89). In Where the relationships are more sub- particular, when approval of a new tle and not readily recognized, the pur- drug application is withdrawn under chasing agent may request an opinion provisions of section 505(e) of the Fed- by writing to the Food and Drug Ad- eral Food, Drug, and Cosmetic Act, a ministration at the address shown in drug generally recognized as safe may paragraph (e) of this section. become a ‘‘new drug’’ within the mean- (e) Interested parties may submit to ing of section 201(p) of said act as the Food and Drug Administration, amended by the Kefauver-Harris Act on Center for Drug Evaluation and Re- October 10, 1962. This is of special im- search, Office of Compliance, 10903 New Hampshire Ave., Silver Spring, MD portance by reason of proposed actions 20993–0002, the names of drug products, to withdraw approval of new drug ap- and of their manufacturers or distribu- plications for lack of substantial evi- tors, that should be the subject of the dence of effectiveness as a result of re- same purchasing and regulatory poli- ports of the National Academy of cies as those reviewed by the Drug Effi- Sciences—National Research Council cacy Study Group. Appropriate action, on its review of drug effectiveness; for including referral to purchasing offi- example, see the notice published in cials of various government agencies, the FEDERAL REGISTER of January 23, will be taken. 1968 (33 FR 818), regarding rutin, quer- (f) This regulation does not apply to cetin, et al. OTC drugs identical, similar, or related (c) Any marketed drug is a ‘‘new to a drug in the Drug Efficacy Study drug’’ if any labeling change made unless there has been or is notification after October 9, 1962, recommends or in the FEDERAL REGISTER that a drug suggests new conditions of use under will not be subject to an OTC panel re- which the drug is not generally recog- view pursuant to §§ 330.10, 330.11, and nized as safe and effective by qualified 330.5 of this chapter. experts. Undisclosed or unreported side [39 FR 11680, Mar. 29, 1974, as amended at 48 effects as well as the emergence of new FR 2755, Jan. 21, 1983; 50 FR 8996, Mar. 6, 1985; knowledge presenting questions with 55 FR 11578, Mar. 29, 1990; 74 FR 13113, Mar. 26, 2009] respect to the safety or effectiveness of a drug may result in its becoming a Subpart B—Specific Administrative ‘‘new drug’’ even though it was previously considered ‘‘not a new drug.’’ Rulings and Decisions Any previously given informal advice § 310.100 New drug status opinions; that an article is ‘‘not a new drug’’ statement of policy. does not apply to such an article if it (a) Over the years since 1938 the Food has been changed in formulation, man- and Drug Administration has given in- ufacture control, or labeling in a way formal advice to inquirers as to the that may significantly affect the safety new drug status of preparations. These of the drug. drugs have sometimes been identified (d) For these reasons, all opinions only by general statements of composi- previously given by the Food and Drug tion. Generally, such informal opinions Administration to the effect that an were incorporated in letters that did article is ‘‘not a new drug’’ or is ‘‘no not explicitly relate all of the nec- longer a new drug’’ are hereby revoked. essary conditions and qualifications This does not mean that all articles such as the quantitative formula for that were the subjects of such prior the drug and the conditions under opinions will be regarded as new drugs. which it was prescribed, recommended, The prior opinions will be replaced by or suggested. This has contributed to opinions of the Food and Drug Admin- misunderstanding and misinterpreta- istration that are qualified and current tion of such opinions. on when an article is ‘‘not a new drug,’’ (b) These informal opinions that an as set forth in this subchapter. article is ‘‘not a new drug’’ or ‘‘no longer a new drug’’ require reexamina- [39 FR 11680, Mar. 29, 1974] tion under the Kefauver-Harris Act

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§ 310.103 New drug substances in- (c) This section does not apply to tended for hypersensitivity testing. drugs or their components that are (a) The Food and Drug Administra- subject to the licensing requirements tion is aware of the need in the prac- of the Public Health Service Act of tice of medicine for the ingredients of 1944, as amended. (See subchapter F— a new drug to be available for tests of Biologics, of this chapter.) hypersensitivity to such ingredients [39 FR 11680, Mar. 29, 1974, as amended at 55 and therefore will not object to the FR 11578, Mar. 29, 1990; 67 FR 4907, Feb. 1, shipment of a new drug substance, as 2002] defined in § 310.3(g), for such purpose if all of the following conditions are met: Subpart C—New Drugs Exempted (1) The shipment is made as a result From Prescription-Dispensing of a specific request made to the manu- Requirements facturer or distributor by a practitioner licensed by law to administer § 310.200 Prescription-exemption pro- such drugs, and the use of such drugs cedure. for patch testing is not promoted by (a) Duration of prescription require- the manufacturer or distributor. ment. Any drug limited to prescription (2) The new drug substance requested use under section 503(b)(1)(B) of the act is an ingredient in a marketed new remains so limited until it is exempted drug and is not one that is an ingre- as provided in paragraph (b) or (e) of dient solely in a new drug that is le- this section. gally available only under the inves- (b) Prescription-exemption procedure for tigational drug provisions of this part. drugs limited by a new drug application. (3) The label bears the following Any drug limited to prescription use prominently placed statements in lieu under section 503(b)(1)(B) of the act of adequate directions for use and in shall be exempted from prescription- addition to complying with the other dispensing requirements when the labeling provisions of the act: Commissioner finds such requirements (i) ‘‘Rx only’’; and are not necessary for the protection of (ii) ‘‘For use only in patch testing’’. the public health by reason of the (4) The quantity shipped is limited to drug’s toxicity or other potentiality an amount reasonable for the purpose for harmful effect, or the method of its of patch testing in the normal course use, or the collateral measures nec- of the practice of medicine and is used essary to its use, and he finds that the solely for such patch testing. drug is safe and effective for use in (5) The new drug substance is manu- self-medication as directed in proposed factured by the same procedures and labeling. A proposal to exempt a drug meets the same specifications as the from the prescription-dispensing re- component used in the finished dosage quirements of section 503(b)(1)(B) of the form. act may be initiated by the Commis- (6) The manufacturer or distributor sioner or by any interested person. Any maintains records of all shipments for interested person may file a petition this purpose for a period of 2 years seeking such exemption, which petition after shipment and will make them may be pursuant to part 10 of this available to the Food and Drug Admin- chapter, or in the form of a supplement istration on request. to an approved new drug application. (b) When the requested new drug sub- (c) New drug status of drugs exempted stance is intended for investigational from the prescription requirement. A drug use in humans or the substance is le- exempted from the prescription re- gally available only under the inves- quirement under the provisions of tigational drug provisions of part 312 of paragraph (b) of this section is a ‘‘new this chapter, the submission of an ‘‘In- drug’’ within the meaning of section vestigational New Drug Application’’ 201(p) of the act until it has been used (IND) is required. The Food and Drug to a material extent and for a material Administration will offer assistance to time under such conditions except as any practitioner wishing to submit an provided in paragraph (e) of this sec- Investigational New Drug Application. tion.

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(d) Prescription legend not allowed on (v) The preparation is labeled with exempted drugs. The use of the prescrip- adequate directions for use in minor tion caution statement quoted in sec- conditions as a simple analgesic. tion 503(b) (4) of the act, in the labeling (vi) The dosages of N-acetyl-p-amino- of a drug exempted under the provi- phenol recommended or suggested in sions of this section, constitutes mis- the labeling do not exceed: For adults, branding. Any other statement or sug- 0.65 gram (10 grains) per dose or 2.6 gestion in the labeling of a drug ex- grams (40 grains) per 24-hour period: for empted under this section, that such children 6 to 12 years of age, one-half of drug is limited to prescription use, the maximum adult dose or dosage; for may constitute misbranding. children 3 to 6 years of age, one-fifth of (e) Prescription-exemption procedure of the maximum adult dose or dosage. OTC drug review. A drug limited to pre- (vii) The labeling bears, in juxtaposi- scription use under section 503(b)(1)(B) tion with the dosage recommendations, of the act may also be exempted from a clear warning statement against ad- prescription-dispensing requirements ministration of the drug to children by the procedure set forth in § 330.13 of under 3 years of age and against use of this chapter. the drug for more than 10 days, unless such uses are directed by a physician. [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42 FR 4714, Jan. 25, (viii) If the article is offered for use 1977; 42 FR 15674, Mar. 22, 1977; 72 FR 15043, in arthritis or rheumatism, the label- Mar. 30, 2007] ing prominently bears a statement that the beneficial effects claimed are § 310.201 Exemption for certain drugs limited to the temporary relief of limited by new-drug applications to minor aches and pains of arthritis and prescription sale. rheumatism and, in juxtaposition with (a) The prescription-dispensing re- directions for use in such conditions, a quirements of section503(b)(1)(B) of the conspicuous warning statement, such Federal Food, Drug, and Cosmetic Act as ‘‘Caution: If pain persists for more are not necessary for the protection of than 10 days, or redness is present, or the public health with respect to the in conditions affecting children under following drugs subject to new drug ap- 12 years of age, consult a physician im- plications: mediately’’. (1) N-Acetyl-p-aminophenol (acetami- (2) Sodium gentisate (sodium-2, 5-di- nophen, p-hydroxy-acetanilid) prepara- hydroxybenzoate) preparations meet- tions meeting all the following condi- ing all the following conditions: tions: (i) The sodium gentisate is prepared, (i) The N-acetyl-p-aminophenol is with or without other drugs, in tablet prepared, with or without other drugs, or other dosage form suitable for oral in tablet or other dosage form suitable use in self-medication, and containing for oral use in self-medication, and no drug limited to prescription sale containing no drug limited to prescrip- under the provisions of section 503(b)(1) tion sale under the provisions of sec- of the act. tion 503(b)(1) of the act. (ii) The sodium gentisate and all (ii) The N-acetyl-p-aminophenol and other components of the preparation all other components of the prepara- meet their professed standards of iden- tion meet their professed standards of tity, strength, quality, and purity. identity, strength, quality, and purity. (iii) If the preparation is a new drug, (iii) If the preparation is a new drug, an application pursuant to section an application pursuant to section 505 505(b) of the act is approved for it. (b) of the act is approved for it. (iv) The preparation contains not (iv) The preparation contains not more than 0.5 gram (7.7 grains) of anhy- more than 0.325 gram (5 grains) of N- drous sodium gentisate per dosage acetyl-p-aminophenol per dosage unit, unit. or if it is in liquid form not more than (v) The preparation is labeled with 100 milligrams of N-acetyl-p-amino- adequate directions for use in minor phenol per milliliter. conditions as a simple analgesic.

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(vi) The dosages of sodium gentisate case of rectal bleeding, as this may in- recommended or suggested in the label- dicate serious disease. ing do not exceed: For adults, 0.5 gram (4) Phenyltoloxamine dihydrogen cit- (7.7 grains) per dose of 2.0 grams (31 rate (N,N-dimethyl-(a-phenyl-O-toloxy) grains) per 24-hour period; for children ethylamine dihydrogen citrate), prep- 6 to 12 years of age, one-half of the arations meeting all the following con- maximum adult dose or dosage. ditions: (vii) The labeling bears, in juxtaposi- (i) The phenyltoloxamine dihydrogen tion with the dosage recommendations, citrate is prepared, with or without a clear warning statement against ad- other drugs, in tablet or other dosage ministration of the drug to children form suitable for oral use in self-medi- under 6 years of age and against use of cation, and containing no drug limited the drug for a prolonged period, except to prescription sale under the provi- as such uses may be directed by a phy- sions of section 503(b)(1) of the act. sician. (ii) The phenyltoloxamine dihydro- (3) Isoamylhydrocupreine and zola- gen citrate and all other components of mine hydrochloride (N, N-dimethyl-N′- the preparation meet their professed 2-thiazolyl-N′-p-methoxybenzyl-ethyl- standards of identity, strength, qual- enediamine hydrochloride) prepara- ity, and purity. tions meeting all the following condi- (iii) If the preparation is a new drug, tions: an application pursuant to section (i) The isoamylhydrocupreine and zo- 505(b) of the act is approved for it. lamine hydrochloride are prepared in (iv) The preparation contains not dosage form suitable for self-medica- more than 88 milligrams of phenyl- tion as rectal suppositories or as an toloxamine dihydrogen citrate (equiva- ointment and containing no drug lim- lent to 50 milligrams of phenyltolox- ited to prescription sale under the pro- amine) per dosage unit. visions of section 503(b)(1) of the act. (v) The preparation is labeled with adequate directions for use in the tem- (ii) The isoamylhydrocupreine, zola- porary relief of the symptoms of hay amine hydrochloride, and all other fever and/or the symptoms of other components of the preparation meet minor conditions in which it is indi- their professed standards of identity, cated. strength, quality, and purity. (vi) The dosages recommended or (iii) If the preparation is a new drug, suggested in the labeling do not exceed: an application pursuant to section For adults, 88 milligrams of phenyl- 505(b) of the act is approved for it. toloxamine dihydrogen citrate (equiva- (iv) The preparation contains not lent to 50 milligrams of phenyltolox- more than 0.25 percent of isoamyl- amine) per dose or 264 milligrams of hydrocupreine and 1.0 percent of zola- phenyltoloxamine dihydrogen citrate mine hydrochloride. (equivalent to 150 milligrams of phen- (v) If the preparation is in supposi- yltoloxamine) per 24-hour period; for tory form, it contains not more than children 6 to 12 years of age, one-half of 5.0 milligrams of isoamylhydrocupreine the maximum adult dose or dosage. and not more than 20.0 milligrams of (vii) The labeling bears, in juxtaposi- zolamine hydrochloride per supposi- tion with the dosage recommendations: tory. (a) Clear warning statements against (vi) The preparation is labeled with administration of the drug to children adequate directions for use in the tem- under 6 years of age, except as directed porary relief of local pain and itching by a physician, and against driving a associated with hemorrhoids. car or operating machinery while using (vii) The directions provide for the the drug, since it may cause drowsi- use of not more than two suppositories ness. or two applications of ointment in a 24- (b) If the article is offered for tem- hour period. porary relief of the symptoms of colds, (viii) The labeling bears, in jux- a statement that continued adminis- taposition with the dosage rec- tration for such use should not exceed ommendations, a clear warning state- 3 days, except as directed by a physi- ment against use of the preparation in cian.

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(5)–(7) [Reserved] suitable for self-medication by external (8) Dicyclomine hydrochloride (1- application to the skin as a spray, and cyclohexylhexahydrobenzoic acid. b-di- containing no drug limited to prescrip- ethylaminoethyl ester hydrochloride; tion sale under the provisions of sec- diethylaminocarbethoxy-bicyclohexyl tion 503(b)(1) of the act. hydrochloride) preparations meeting (ii) The hexadenol and all other com- all the following conditions: ponents of the preparation meet their (i) The dicyclomine hydrochloride is professed standards of identity, prepared with suitable antacid and strength, quality, and purity. other components, in tablet or other (iii) If the preparation is a new drug, dosage form for oral use in self-medica- an application pursuant to section tion, and containing no drug limited to 505(b) of the act is approved for it. prescription sale under the provisions (iv) The preparation contains not of section 503(b)(1) of the act. more than 5 percent by weight of (ii) The dicyclomine hydrochloride hexadenol. and all other components of the prepa- (v) The preparation is labeled with ration meet their professed standards adequate directions for use by external of identity, strength, quality, and pu- application in the treatment of minor rity. burns and minor skin irritations. (iii) If the preparation is a new drug, (vi) The labeling bears, in juxtaposi- an application pursuant to section tion with the directions for use, clear 505(b) of the act is approved for it. warning statements against: (iv) The preparation contains not (a) Use on serious burns or skin con- more than 5 milligrams of dicyclomine ditions or prolonged use, except as dihydrochloride per dosage unit, or if it rected by a physician. is in liquid form not more than 0.5 mil- (b) Spraying the preparation in the ligram of dicyclomine hydrochloride vicinity of eyes, mouth, nose, or ears. per milliliter. (12) Sulfur dioxide preparations (v) The preparation is labeled with meeting all the following conditions: adequate directions for use only by adults and children over 12 years of (i) The sulfur dioxide is prepared with age, in the temporary relief of gastric or without other drugs, in an aqueous hyperacidity. solution packaged in a hermetic con- (vi) The dosages recommended or tainer suitable for use in self-medica- suggested in the directions for use do tion by external application to the not exceed 10 milligrams of dicyclo- skin, and containing no drug limited to mine hydrochloride per dose or 30 mil- prescription sale under the provisions ligrams in a 24-hour period. of section 503(b)(1) of the act. (vii) The labeling bears, in juxtaposi- (ii) The sulfur dioxide and all other tion with the dosage recommendations, components of the preparation meet clear warning statements against: their professed standards of identity, (a) Exceeding the recommended dos- strength, quality, and purity. age. (iii) If the preparation is a new drug, (b) Prolonged use, except as directed an application pursuant to section by a physician, since persistent or re- 505(b) of the act is approved for it. curring symptoms may indicate a seri- (iv) The preparation contains not ous disease requiring medical atten- more than 5 grams of sulfur dioxide per tion. 100 milliliters of solution. (c) Administration to children under (v) The preparation is labeled with 12 years of age except as directed by a adequate directions for use by external physician. application to the smooth skin in the (9)–(10) [Reserved] prevention or treatment of minor con- (11) Hexadenol (a mixture of tetra- ditions in which it is indicated. cosanes and their oxidation products) (vi) The directions for use rec- preparations meeting all the following ommend or suggest not more than two conditions: applications a day for not more than 1 (i) The hexadenol is prepared and week, except as directed by a physi- packaged, with or without other drugs, cian. solvents, and propellants, in a form (13)–(15) [Reserved]

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(16) Tuaminoheptane sulfate (2-ami- ester) preparations meeting all the fol- noheptane sulfate) preparations meet- lowing conditions. ing all the following conditions: (i) The vibesate is prepared and pack- (i) The tuaminoheptane sulfate is aged, with or without other drugs, sol- prepared, with or without other drugs, vents, and propellants, in a form suit- in an aqueous vehicle suitable for ad- able for self-medication by external ap- ministration in self-medication as nose plication to the skin as a spray, and drops, and containing no drug limited containing no drug limited to prescrip- to prescription sale under the provi- tion sale under the provisions of sec- sions of section 503(b)(1) of the act. tion 503(b)(1) of the act. (ii) The preparation is packaged with (ii) The vibesate and all other compo- a style of container or assembly suited nents of the preparation meet their to self-medication by the recommended professed standards of identity, route of administration, and delivering strength, quality, and purity. not more than 0.1 milliliter of the prep- (iii) If the preparation is a new drug, aration per drop. an application pursuant to section (iii) The tuaminoheptane sulfate and 505(b) of the act is approved for it. all other components of the prepara- (iv) The preparation contains not tion meet their professed standards of more than 13 percent by weight of vi- identity, strength, quality, and purity. besate. (iv) If the preparation is a new drug, (v) The preparation is labeled with an application pursuant to section adequate directions for use by external 505(b) of the act is approved for it. application as a dressing for minor (v) The tuaminoheptane sulfate con- burns, minor cuts, or other minor skin tent of the preparation does not exceed irritations. 10 milligrams per milliliter. (vi) The labeling bears in juxtaposi- (vi) The preparation is labeled with tion with the directions for use clear adequate directions for use in the tem- warning statements against: porary relief of nasal congestion. (a) Use on serious burns and on in- (vii) The dosages recommended or fected, deep, and puncture wounds un- suggested in the directions for use do less directed by a physician. not exceed the equivalent: For adults, 5 (b) Spraying the preparation near the drops of a 1 percent solution per nostril eyes or other mucous membranes. per dose, and 5 doses in a 24-hour pe- (c) Inhaling the preparation. riod; for children 1 to 6 years of age, 3 (d) Use near open flames. drops of a 1 percent solution per nostril (e) Puncturing the container or per dose, and 5 doses in a 24-hour pe- throwing the container into fire. riod; for infants under 1 year of age, 2 (19) Pramoxine hydrochloride (4-N- drops of a 1 percent solution per nostril butoxyphenyl g-morpholinopropyl per dose, and 5 doses in a 24-hour pe- ether hydrochloride) preparations riod. meeting all the following conditions: (viii) The labeling bears, in jux- (i) The pramoxine hydrochloride is taposition with the dosage rec- prepared, with or without other drugs, ommendations: in a dosage form suitable for use in (a) Clear warning statements against self-medication by external application use of more than 5 doses daily, and to the skin, and containing no drug against use longer than 4 days unless limited to prescription sale under the directed by a physician. provisions of section 503(b)(1) of the (b) A clear warning statement to the act. effect that frequent use may cause (ii) The pramoxine hydrochloride and nervousness or sleeplessness, and that all other components of the prepara- individuals with high blood pressure, tion meet their professed standards of heart disease, diabetes, or thyroid dis- identity, strength, quality, and purity. ease should not use the preparation un- (iii) If the preparation is a new drug, less directed by a physician. an application pursuant to section (17) [Reserved] 505(b) of the act is approved for it. (18) Vibesate (a mixture of copoly- (iv) The preparation contains not mers of hydroxy-vinyl chlorideacetate, more than 1.0 percent of pramoxine hy- sebacic acid, and modified maleic rosin drochloride.

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(v) The preparation is labeled with (i) The diphemanil methylsulfate is adequate directions for use by external prepared, with or without other drugs, application to the skin for the tem- in a dosage form suitable for use in porary relief of pain or itching due to self-medication by external application minor burns and sunburn, nonpoi- to the skin, and containing no drug sonous insect bites, and minor skin ir- limited to prescription sale under the ritations. provisions of section 503(b)(1) of the (vi) The directions for use rec- act. ommend or suggest not more than four (ii) The diphemanil methylsulfate applications of the preparation per day, and all other components of the prepa- unless directed by a physician. ration meet their professed standards (vii) The labeling bears, in juxtaposi- of identity, strength, quality, and pu- tion with the directions for use, clear rity. warning statements against: (iii) If the preparation is a new drug, (a) Prolonged use. an application pursuant to section (b) Application to large areas of the 505(b) of the act is approved for it. body. (iv) The preparation contains not (c) Continued use if redness, irrita- more than 2.0 percent of diphemanil tion, swelling, or pain persists or in- methylsulfate. creases, unless directed by a physician. (v) The preparation is labeled with (d) Use in the eyes or nose. adequate directions for use by external application to the skin for the relief of (20) [Reserved] symptoms of mild poison ivy, oak, and (21) Pamabrom (2-amino-2-methyl- sumac and other minor irritations and propanol-1-8-bromotheophyllinate) itching of the skin. preparations meeting all the following (vi) The directions for use rec- conditions: ommend or suggest not more than four (i) The pamabrom is prepared with applications of the preparation per day, appropriate amounts of a suitable an- unless directed by a physician. algesic and with or without other (vii) The labeling bears, in juxtaposi- drugs, in tablet or other dosage form tion with the directions for use, a clear suitable for oral use in self-medication, warning statement, such as: ‘‘Caution: and containing no drug limited to pre- If redness, irritation, swelling, or pain scription sale under the provisions of persists or increases, discontinue use section 503(b)(1) of the act. and consult physician.’’ (ii) The pamabrom and all other com- (23) Dyclonine hydrochloride (4-but- ponents of the preparation meet their oxy-3-piperidinopropiophenone hydro- professed standards of identity, chloride; 4-n-butoxy-b-piperidono- strength, quality, and purity. propiophenone hydrochloride) prepara- (iii) If the preparation is a new drug, tions meeting all the following condi- an application pursuant to section tions: 505(b) of the act is approved for it. (i) The dyclonine hydrochloride is (iv) The preparation contains not prepared, with or without other drugs, more than 50 milligrams of pamabrom in a dosage form suitable for use as a per dosage unit. cream or ointment in self-medication (v) The preparation is labeled with by external application to the skin, or adequate directions for use in the tem- rectally, and contains no drug limited porary relief of the minor pains and to prescription sale under the provi- discomforts that may occur a few days sions of section 503(b)(1) of the act. before and during the menstrual pe- (ii) The dyclonine hydrochloride and riod. all other components of the prepara- (vi) The dosages recommended or tion meet their professed standards of suggested in the labeling do not exceed identity, strength, quality, and purity. 50 milligrams of pamabrom per dose or (iii) If the preparation is a new drug, 200 milligrams per 24-hour period. an application pursuant to section (22) Diphemanil methylsulfate (4-di- 505(b) of the act is approved for it. phenylmethylene-1,1-dimethyl-piper- (iv) The preparation contains not idinium methylsulfate) preparations more than 1.0 percent of dyclonine hy- meeting all the following conditions: drochloride.

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(v) The preparation is labeled with half of the maximum adult dose or dos- adequate directions for use: age. (a) By external application to the (vii) The labeling bears, in juxtaposi- skin for the temporary relief of pain tion with the dosage recommendations: and itching in sunburn, nonpoisonous (a) Clear warning statements against insect bites, minor burns, cuts, abra- administration of the drug to children sions, and other minor skin irritations. under 6 years of age or exceeding the (b) [Reserved] recommended dosage, unless directed (c) In the prevention or treatment of by a physician, and against driving a other minor conditions in which it is car or operating machinery while using indicated. the drug, since it may cause drowsi- (vi) The labeling bears, in juxtaposi- ness. tion with the directions for use, clear (b) If the article is offered for the warning statements against: temporary relief of symptoms of colds, (a) Continued use if redness, irrita- a statement that continued adminis- tion, swelling, or pain persists or in- tration for such use should not exceed creases, unless directed by a physician. 3 days, unless directed by a physician. (b) Use in case of rectal bleeding, as (25) [Reserved] this may indicate serious disease. (26) Methoxyphenamine hydro- (c) Use in the eyes. chloride (b-(o-methoxyphenyl)-iso- (d) Prolonged use. propyl-methylamine hydrochloride; 1- (e) Application to large areas of the (o-methoxyphenyl)- 2-methylamino- body. propane hydrochloride) preparations (f) Use for deep or puncture wounds meeting all the following conditions: or serious burns. (i) The methoxyphenamine hydro- (24) Chlorothen citrate (chlorometha- chloride is prepared with appropriate pyrilene citrate; N,N-dimethyl-N′-(2- amounts of a suitable antitussive, with pyridyl)-N′-(5-chloro-2-thenyl) ethyl- or without other drugs, in a dosage enediamine citrate) preparations meet- form suitable for oral use in self-medi- ing all the following conditions: cation, and containing no drug limited (i) The chlorothen citrate is pre- to prescription sale under the provi- pared, with or without other drugs, in sions of section 503(b)(1) of the act. tablet or other dosage form suitable for (ii) The methoxyphenamine hydro- oral use in self-medication, and con- chloride and all other components of taining no drug limited to prescription the preparation meet their professed sale under the provisions of section standards of identity, strength, qual- 503(b)(1) of the act. ity, and purity. (ii) The chlorothen citrate and all (iii) If the preparation is a new drug, other components of the preparation an application pursuant to section meet their professed standards of iden- 505(b) of the act is approved for it. tity, strength, quality, and purity. (iv) The preparation contains not (iii) If the preparation is a new drug, more than 3.5 milligrams of methoxy- an application pursuant to section phenamine hydrochloride per milli- 505(b) of the act is approved for it. liter. (iv) The preparation contains not (v) The preparation is labeled with more than 25 milligrams of chlorothen adequate directions for use in the tem- citrate per dosage unit. porary relief of cough due to minor (v) The preparation is labeled with conditions in which it is indicated. adequate directions for use in the tem- (vi) The dosages recommended or porary relief of the symptoms of hay suggested in the labeling do not exceed: fever and/or the symptoms of other For adults, 35 milligrams of methoxy- minor conditions in which it is indi- phenamine hydrochloride per dose or cated. 140 milligrams of methoxyphenamine (vi) The dosages recommended or hydrochloride per 24-hour period; for suggested in the labeling do not exceed: children 6 to 12 years of age, one-half of For adults, 25 milligrams of chlorothen the maximum adult dose or dosage. citrate per dose or 150 milligrams of (vii) The label bears a conspicuous chlorothen citrate per 24-hour period; warning to keep the drug out of the for children 6 to 12 years of age, one- reach of children, and the labeling

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bears, in juxtaposition with the dosage afford adequate protection and be suit- recommendations: able for self-medication with a min- (a) A clear warning statement imum risk of contamination of the so- against administration of the drug to lution during use. Any dispensing unit children under 6 years of age, unless di- is sterile and so packaged as to main- rected by a physician. tain sterility until the package is (b) A clear warning statement to the opened. effect that frequent or prolonged use (iii) The tyloxapol, benzalkonium may cause nervousness, restlessness, or chloride, and other ingredients used to drowsiness, and that individuals with prepare the isotonic aqueous solution high blood pressure, heart disease, dia- meet their professed standards of iden- betes, or thyroid disease should not use tity, strength, quality, and purity. the preparation unless directed by a (iv) An application pursuant to sec- physician. tion 505(b) of the act is approved for (c) A clear warning statement the drug. against use of the drug in the presence (v) The preparation contains 0.25 per- of high fever or if cough persists, since cent of tyloxapol and 0.02 percent of persistent cough as well as high fever benzalkonium chloride. may indicate the presence of a serious (vi) The label bears a conspicuous condition. warning to keep the drug out of the (27) Biphenamine hydrochloride (b-di- reach of children and the labeling ethylaminoethyl-3-phenyl-2-hydroxy- bears, in juxtaposition with the dosage benzoate hydrochloride) preparations recommendations, a clear warning that meeting all the following conditions: if irritation occurs, persists, or in- (i) The biphenamine hydrochloride is creases, use of the drug should be dis- prepared in a form suitable for use as a continued and a physician consulted. shampoo and contains no drug limited The labeling includes a statement that to prescription sale under the provi- the dropper or other dispensing tip sions of section 503(b)(1) of the act. should not touch any surface, since (ii) The biphenamine hydrochloride this may contaminate the solution. meets its professed standards of iden- (29) [Reserved] tity, strength, quality, and purity. (b) [Reserved] (iii) If the preparation is a new drug, an application pursuant to section [39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977; 52 FR 15892, Apr. 30, 505(b) of the act is approved for it. 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, (iv) The preparation contains not Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR more than 1 percent of biphenamine 49898, Sept. 23, 1993; 59 FR 4218, Jan. 28, 1994; hydrochloride. 60 FR 52507, Oct. 6, 1995; 72 FR 15043, Mar. 30, (v) The preparation is labeled with 2007; 72 FR 67640, Nov. 30, 2007] adequate directions for use for the temporary relief of itching and scaling due Subpart D—Records and Reports to dandruff. (vi) The label bears a conspicuous § 310.303 Continuation of long-term warning to keep the drug out of the studies, records, and reports on cer- reach of children. tain drugs for which new drug ap- (28) Tyloxapol (an alkylarylpolyether plications have been approved. alcohol) and benzalkonium chloride (a) A new drug may not be approved ophthalmic preparations meeting all for marketing unless it has been shown the following conditions: to be safe and effective for its intended (i) The tyloxapol and benzalkonium use(s). After approval, the applicant is chloride are prepared, with other ap- required to establish and maintain propriate ingredients which are not records and make reports related to drugs limited to prescription sale clinical experience or other data or in- under the provisions of section 503(b)(1) formation necessary to make or facili- of the act, as a sterile, isotonic aque- tate a determination of whether there ous solution suitable for use in self- are or may be grounds under section medication on eye prostheses. 505(e) of the act for suspending or with- (ii) The preparation is so packaged as drawing approval of the application. to volume and type of container as to Some drugs, because of the nature of

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the condition for which they are in- the reporting requirements of para- tended, must be used for long periods of graph (c) of this section must also de- time—even a lifetime. To acquire nec- velop written procedures for the sur- essary data for determining the safety veillance, receipt, evaluation, and re- and effectiveness of long-term use of porting of postmarketing adverse drug such drugs, extensive animal and clin- experiences to FDA. ical tests are required as a condition of (b) Definitions. The following defini- approval. Nonetheless, the therapeutic tions of terms apply to this section: or prophylactic usefulness of such Adverse drug experience. Any adverse drugs may make it inadvisable in the event associated with the use of a drug public interest to delay the avail- in humans, whether or not considered ability of the drugs for widespread clin- drug related, including the following: ical use pending completion of such An adverse event occurring in the long-term studies. In such cases, the course of the use of a drug product in Food and Drug Administration may ap- professional practice; an adverse event prove the new drug application on con- occurring from drug overdose whether dition that the necessary long-term accidental or intentional; an adverse studies will be conducted and the re- event occurring from drug abuse; an sults recorded and reported in an orga- adverse event occurring from drug nized fashion. The procedures required withdrawal; and any failure of expected by paragraph (b) of this section will be pharmacological action. followed in order to list such a drug in Disability. A substantial disruption of § 310.304. a person’s ability to conduct normal (b) A proposal to require additional life functions. or continued studies with a drug for Individual case safety report (ICSR). A which a new drug application has been description of an adverse drug experi- approved may be made by the Commis- ence related to an individual patient or sioner on his own initiative or on the subject. petition of any interested person, pur- ICSR attachments. Documents related suant to part 10 of this chapter. Prior to the adverse drug experience de- to issuance of such a proposal, the ap- scribed in an ICSR, such as medical plicant will be provided an opportunity records, hospital discharge summaries, for a conference with representatives of or other documentation. the Food and Drug Administration. Life-threatening adverse drug experi- When appropriate, investigators or ence. Any adverse drug experience that other individuals may be invited to places the patient, in the view of the participate in the conference. All re- initial reporter, at immediate risk of quirements for special studies, records, death from the adverse drug experience and reports will be published in as it occurred, i.e., it does not include § 310.304. an adverse drug experience that, had it occurred in a more severe form, might [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 FR 15674, Mar. 22, have caused death. 1977] Serious adverse drug experience. Any adverse drug experience occurring at § 310.305 Records and reports con- any dose that results in any of the fol- cerning adverse drug experiences lowing outcomes: Death, a life-threat- on marketed prescription drugs for ening adverse drug experience, inpa- human use without approved new tient hospitalization or prolongation of drug applications. existing hospitalization, a persistent or (a) Scope. FDA is requiring manufac- significant disability/incapacity, or a turers, packers, and distributors of congenital anomaly/birth defect. Im- marketed prescription drug products portant medical events that may not that are not the subject of an approved result in death, be life-threatening, or new drug or abbreviated new drug ap- require hospitalization may be consid- plication to establish and maintain ered a serious adverse drug experience records and make reports to FDA of all when, based upon appropriate medical serious, unexpected adverse drug expe- judgment, they may jeopardize the pa- riences associated with the use of their tient or subject and may require med- drug products. Any person subject to ical or surgical intervention to prevent

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one of the outcomes listed in this defi- must be accompanied by the current nition. Examples of such medical content of labeling in electronic for- events include allergic bronchospasm mat as an ICSR attachment unless it is requiring intensive treatment in an already on file at FDA. emergency room or at home, blood (ii) A person identified in paragraph dyscrasias or convulsions that do not (c)(1)(i) of this section is not required result in inpatient hospitalization, or to submit a 15-day ‘‘Alert report’’ for the development of drug dependency or an adverse drug experience obtained drug abuse. from a postmarketing study (whether Unexpected adverse drug experience. or not conducted under an investiga- Any adverse drug experience that is tional new drug application) unless the not listed in the current labeling for applicant concludes that there is a rea- the drug product. This includes events sonable possibility that the drug that may be symptomatically and caused the adverse experience. pathophysiologically related to an (2) Postmarketing 15-day ‘‘Alert re- event listed in the labeling, but differ ports’’—followup. Each person identified from the event because of greater se- in paragraph (c)(1)(i) of this section verity or specificity. For example, must promptly investigate all serious, under this definition, hepatic necrosis unexpected adverse drug experiences would be unexpected (by virtue of that are the subject of these post- greater severity) if the labeling only marketing 15-day Alert reports and referred to elevated hepatic enzymes or must submit followup reports within 15 hepatitis. Similarly, cerebral thrombo- calendar days of receipt of new infor- embolism and cerebral vasculitis would mation or as requested by FDA. If addi- be unexpected (by virtue of greater tional information is not obtainable, specificity) if the labeling only listed records should be maintained of the un- cerebral vascular accidents. ‘‘Unex- successful steps taken to seek addi- pected,’’ as used in this definition, re- tional information. fers to an adverse drug experience that (3) Submission of reports. To avoid un- has not been previously observed (i.e., necessary duplication in the submis- included in the labeling) rather than sion of, and followup to, reports re- from the perspective of such experience quired in this section, a packer’s or dis- not being anticipated from the pharma- tributor’s obligations may be met by cological properties of the pharma- submission of all reports of serious ad- ceutical product. verse drug experiences to the manufac- (c) Reporting requirements. Each per- turer of the drug product. If a packer son identified in paragraph (c)(1)(i) of or distributor elects to submit these this section must submit to FDA ad- adverse drug experience reports to the verse drug experience information as manufacturer rather than to FDA, it described in this section. Except as must submit, by any appropriate provided in paragraph (e)(2) of this sec- means, each report to the manufac- tion, 15-day ‘‘Alert reports’’ and fol- turer within 5 calendar days of its re- lowup reports, including ICSRs and any ceipt by the packer or distributor, and ICSR attachments, must be submitted the manufacturer must then comply to the Agency in electronic format as with the requirements of this section described in paragraph (e)(1) of this even if its name does not appear on the section. label of the drug product. Under this (1) Postmarketing 15-day ‘‘Alert re- circumstance, the packer or distributor ports’’. (i) Any person whose name ap- must maintain a record of this action pears on the label of a marketed pre- which must include: scription drug product as its manufac- (i) A copy of each adverse drug expe- turer, packer, or distributor must re- rience report; port to FDA each adverse drug experi- (ii) The date the report was received ence received or otherwise obtained by the packer or distributor; that is both serious and unexpected as (iii) The date the report was sub- soon as possible, but no later than 15 mitted to the manufacturer; and calendar days from initial receipt of (iv) The name and address of the the information by the person whose manufacturer. name appears on the label. Each report (4) [Reserved]

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(5) A person identified in paragraph (5) Manufacturer, packer, or distributor (c)(1)(i) of this section is not required information. to resubmit to FDA adverse drug expe- (i) Manufacturer, packer, or dis- rience reports forwarded to that person tributor name and contact office ad- by FDA; however, the person must sub- dress; mit all followup information on such (ii) Telephone number; reports to FDA. (iii) Report source, such as sponta- (d) Information reported on ICSRs. neous, literature, or study; ICSRs include the following informa- (iv) Date the report was received by tion: manufacturer, packer, or distributor; (1) Patient information. (v) Whether the ICSR is a 15-day (i) Patient identification code; ‘‘Alert report’’; (ii) Patient age at the time of adverse (vi) Whether the ICSR is an initial drug experience, or date of birth; report or followup report; and (iii) Patient gender; and (vii) Unique case identification num- (iv) Patient weight. ber, which must be the same in the ini- (2) Adverse drug experience. tial report and any subsequent fol- (i) Outcome attributed to adverse lowup report(s). drug experience; (e) Electronic format for submissions. (1) (ii) Date of adverse drug experience; Each report required to be submitted (iii) Date of ICSR submission; to FDA under this section, including (iv) Description of adverse drug expe- the ICSR and any ICSR attachments, rience (including a concise medical must be submitted in an electronic for- narrative); mat that FDA can process, review, and (v) Adverse drug experience term(s); archive. FDA will issue guidance on (vi) Description of relevant tests, in- how to provide the electronic submis- cluding dates and laboratory data; and sion (e.g., method of transmission, (vii) Other relevant patient history, media, file formats, preparation and including preexisting medical condi- organization of files). tions. (2) Each person identified in para- (3) Suspect medical product(s). graph (c)(1)(i) of this section may re- (i) Name; quest, in writing, a temporary waiver (ii) Dose, frequency, and route of ad- of the requirements in paragraph (e)(1) ministration used; (iii) Therapy dates; of this section. These waivers will be (iv) Diagnosis for use (indication); granted on a limited basis for good (v) Whether the product is a com- cause shown. FDA will issue guidance bination product as defined in § 3.2(e) of on requesting a waiver of the require- this chapter; ments in paragraph (e)(1) of this sec- (vi) Whether the product is a pre- tion. scription or nonprescription product; (f) Patient privacy. Manufacturers, (vii) Whether adverse drug experience packers, and distributors should not in- abated after drug use stopped or dose clude in reports under this section the reduced; names and addresses of individual pa- (viii) Whether adverse drug experi- tients; instead, the manufacturer, ence reappeared after reintroduction of packer, and distributor should assign a drug; unique code for identification of the (ix) Lot number; patient. The manufacturer, packer, and (x) Expiration date; distributor should include the name of (xi) National Drug Code (NDC) num- the reporter from whom the informa- ber; and tion was received as part of the initial (xii) Concomitant medical products reporter information, even when the and therapy dates. reporter is the patient. The names of (4) Initial reporter information. patients, individual reporters, health (i) Name, address, and telephone care professionals, hospitals, and geo- number; graphical identifiers in adverse drug (ii) Whether the initial reporter is a experience reports are not releasable to health care professional; and the public under FDA’s public informa- (iii) Occupation, if a health care pro- tion regulations in part 20 of this chap- fessional. ter.

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(g) Recordkeeping. (1) Each manufac- make the notifications required under turer, packer, and distributor must § 314.81(b)(3)(iii) of this chapter and oth- maintain for a period of 10 years erwise comply with § 314.81(b)(3)(iii) of records of all adverse drug experiences this chapter. If the manufacturer of a required under this section to be re- product subject to this section fails to ported, including raw data and any cor- provide notification as required under respondence relating to the adverse § 314.81(b)(3)(iii), FDA will send a letter drug experiences, and the records re- to the manufacturer and otherwise fol- quired to be maintained under para- low the procedures set forth under graph (c)(3) of this section. § 314.81(b)(3)(iii)(e). (2) Manufacturers and packers may (c) Drug shortages list. FDA will in- retain the records required in para- clude on the drug shortages list re- graph (f)(1) of this section as part of its quired by § 314.81(b)(3)(iii)(d) drug prod- complaint files maintained under ucts that are subject to this section § 211.198 of this chapter. that it determines to be in shortage. (3) Manufacturers, packers, and dis- For such drug products, FDA will pro- tributors must permit any authorized vide the names of each manufacturer FDA employee, at all reasonable times, rather than the names of each appli- to have access to and copy and verify cant. With respect to information col- the records established and maintained lected under this paragraph, FDA will under this section. observe the confidentiality and disclo- (h) Disclaimer. A report or informa- sure provisions set forth in tion submitted by a manufacturer, § 314.81(b)(3)(iii)(d)(2). packer, or distributor under this section (and any release by FDA of that [80 FR 38938, July 8, 2015] report or information) does not necessarily reflect a conclusion by the Subpart E—Requirements for manufacturer, packer, or distributor, Specific New Drugs or Devices or by FDA, that the report or information constitutes an admission that the § 310.501 Patient package inserts for drug caused or contributed to an ad- oral contraceptives. verse effect. The manufacturer, packer, (a) Requirement for a patient package or distributor need not admit, and may insert. The safe and effective use of oral deny, that the report or information contraceptive drug products requires submitted under this section con- that patients be fully informed of the stitutes an admission that the drug benefits and the risks involved in their caused or contributed to an adverse ef- use. An oral contraceptive drug prod- fect. uct that does not comply with the re- [51 FR 24479, July 3, 1986, as amended at 52 quirements of this section is mis- FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, branded under section 502 of the Fed- 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, eral Food, Drug, and Cosmetic Act. June 25, 1997; 62 FR 52249, Oct. 7, 1997; 67 FR Each dispenser of an oral contraceptive 9585, Mar. 4, 2002; 74 FR 13113, Mar. 26, 2009; 79 drug product shall provide a patient FR 33087, June 10, 2014] package insert to each patient (or to § 310.306 Notification of a permanent an agent of the patient) to whom the discontinuance or an interruption product is dispensed, except that the in manufacturing of marketed pre- dispenser may provide the insert to the scription drugs for human use with- parent or legal guardian of a legally in- out approved new drug applica- competent patient (or to the agent of tions. either). The patient package insert is (a) Applicability. Marketed prescrip- required to be placed in or accompany tion drug products that are not the each package dispensed to the patient. subject of an approved new drug or ab- (b) Distribution requirements. (1) For breviated new drug application are sub- oral contraceptive drug products, the ject to this section. manufacturer and distributor shall pro- (b) Notification of a permanent dis- vide a patient package insert in or with continuance or an interruption in manu- each package of the drug product that facturing. The manufacturer of each the manufacturer or distributor in- product subject to this section must tends to be dispensed to a patient.

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(2) Patient package inserts for oral (ii) A statement concerning excretion contraceptives dispensed in acute-care of the drug in human milk and associ- hospitals or long-term care facilities ated risks to the nursing infant; will be considered to have been pro- (iii) A statement about laboratory vided in accordance with this section if tests which may be affected by oral provided to the patient before adminis- contraceptives; and tration of the first oral contraceptive (iv) A statement that identifies ac- and every 30 days thereafter, as long as tivities and drugs, foods, or other sub- the therapy continues. stances the patient should avoid be- (c) Contents of patient package insert. cause of their interactions with oral A patient package insert for an oral contraceptives. contraceptive drug product is required (11) Information about how to take to contain the following: oral contraceptives properly, including (1) The name of the drug. information about what to do if the pa- (2) A summary including a statement tient forgets to take the product, infor- concerning the effectiveness of oral mation about becoming pregnant after contraceptives in preventing preg- discontinuing use of the drug, a state- nancy, the contraindications to the ment that the drug product has been drug’s use, and a statement of the risks prescribed for the use of the patient and benefits associated with the drug’s and should not be used for other condi- use. tions or given to others, and a state- (3) A statement comparing the effec- ment that the patient’s pharmacist or tiveness of oral contraceptives to other practitioner has a more technical leaf- methods of contraception. let about the drug product that the pa- (4) A boxed warning concerning the tient may ask to review. increased risks associated with ciga- (12) A statement of the possible bene- rette smoking and oral contraceptive use. fits associated with oral contraceptive use. (5) A discussion of the contraindications to use, including information (13) The following information about that the patient should provide to the the drug product and the patient pack- prescriber before taking the drug. age insert: (6) A statement of medical conditions (i) The name and place of business of that are not contraindications to use the manufacturer, packer, or dis- but deserve special consideration in tributor, or the name and place of busi- connection with oral contraceptive use ness of the dispenser of the product. and about which the patient should in- (ii) The date, identified as such, of form the prescriber. the most recent revision of the patient (7) A warning regarding the most se- package insert placed prominently im- rious side effects of oral contracep- mediately after the last section of the tives. labeling. (8) A statement of other serious ad- (d) Other indications. The patient verse reactions and potential safety package insert may identify indica- hazards that may result from the use tions in addition to contraception that of oral contraceptives. are identified in the professional label- (9) A statement concerning common, ing for the drug product. but less serious side effects which may (e) Labeling guidance texts. The Food help the patient evaluate the benefits and Drug Administration issues infor- and risks from the use of oral contra- mal labeling guidance texts under ceptives. § 10.90(b)(9) of this chapter to provide (10) Information on precautions the assistance in meeting the requirements patients should observe while taking of this section. A request for a copy of oral contraceptives, including the fol- the guidance texts should be directed lowing: to the Center for Drug Evaluation and (i) A statement of risks to the moth- Research, Division of Reproductive and er and unborn child from the use of Urologic Products, Food and Drug Ad- oral contraceptives before or during ministration, 10903 New Hampshire early pregnancy; Ave., Silver Spring, MD 20993–0002.

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(f) Requirement to supplement approved (13) Thorium dioxide for drug use. application. Holders of approved appli- (14) Timed release dosage forms. cations for oral contraceptive drug (15) Vinyl chloride as an ingredient, products that are subject to the re- including propellant, in aerosol drug quirements of this section are required products. to submit supplements under § 314.70(c) (b) [Reserved] of this chapter to provide for the label- [62 FR 12084, Mar. 14, 1997, as amended at 64 ing required by this section. Such la- FR 401, Jan. 5, 1999; 84 FR 68334, Dec. 16, 2019] beling may be put into use without advance approval by the Food and Drug § 310.503 Requirements regarding cer- Administration. tain radioactive drugs. [54 FR 22587, May 25, 1989, as amended at 74 (a) On January 8, 1963 (28 FR 183), the FR 13113, Mar. 26, 2009] Commissioner of Food and Drugs exempted investigational radioactive new § 310.502 Certain drugs accorded new drugs from part 312 of this chapter pro- drug status through rulemaking vided they were shipped in complete procedures. conformity with the regulations issued (a) The drugs listed in this paragraph by the Nuclear Regulatory Commis- (a) have been determined by rule- sion. This exemption also applied to in- making procedures to be new drugs vestigational radioactive biologics. within the meaning of section 201(p) of (b) It is the opinion of the Nuclear the Federal Food, Drug, and Cosmetic Regulatory Commission, and the Food Act. An approved new drug application and Drug Administration that this ex- under section 505 of the Federal Food, emption should not apply for certain Drug, and Cosmetic Act and part 314 of specific drugs and that these drugs this chapter is required for marketing should be appropriately labeled for uses the following drugs: for which safety and effectiveness can (1) Aerosol drug products for human be demonstrated by new drug applica- use containing 1,1,1-trichloroethane. tions or through licensing under the (2) Aerosol drug products containing Public Health Service Act (42 U.S.C. 262 zirconium. et seq.) in the case of biologics. Contin- (3) Amphetamines (amphetamine, ued distribution under the investiga- dextroamphetamine, and their salts, tional exemption when the drugs are and levamfetamine and its salts) for intended for established uses will not human use. be permitted. (4) Camphorated oil drug products. (c) Based on its experience in regu- (5) Certain halogenated salicyl- lating investigational radioactive anilides (tribromsalan (TBS, 3,4′,5-tri- pharmaceuticals, the Nuclear Regu- bromosalicylanilide), dibromsalan latory Commission has compiled a list (DBS, 4′, 5-dibromosalicylanilide), of reactor-produced isotopes for which metabromsalan (MBS, 3, 5-dibromo- it considers that applicants may rea- salicylanilide), and 3,3′, 4,5′-tetra- sonably be expected to submit ade- chlorosalicylanilide (TC-SA)) as an in- quate evidence of safety and effective- gredient in drug products. ness for use as recommended in appro- (6) Chloroform used as an ingredient priate labeling. Such use may include, (active or inactive) in drug products. among others, the uses in this tabula- (7) Cobalt preparations intended for tion: use by man. (8) Intrauterine devices for human Isotope Chemical form Use use for the purpose of contraception Chromium 51 ... Chromate ...... Spleen scans. that incorporate heavy metals, drugs, Do ...... do ...... Placenta localiza- or other active substances. tion. (9) Oral prenatal drugs containing Do ...... do ...... Red blood cell labeling and survival fluorides intended for human use. studies. (10) Parenteral drug products in plas- Do ...... Labeled human Gastrointestinal pro- tic containers. serum albumin. tein loss studies. (11) [Reserved] Do ...... do ...... Placenta localiza- tion. (12) Sweet spirits of nitre drug prod- Do ...... Labeled red blood Do. ucts. cells.

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Isotope Chemical form Use Isotope Chemical form Use

Cobalt 58 or Labeled cyano- Intestinal absorption Krypton 85 ...... Gas ...... Diagnosis of cardiac Cobalt 60. cobalamin. studies. abnormalities. Gold 198 ...... Colloidal ...... Liver scans. Mercury 197 .... Chlormerodrin ...... Kidney scans. Do ...... do ...... Intracavitary treat- Do ...... do ...... Brain scans. ment of pleural ef- Mercury 203 1 ...... do ...... Kidney scans. fusions and/or as- Do ...... do ...... Brain scans. cites. Phosphorus 32 Soluble phosphate .. Treatment of poly- Do ...... do ...... Interstitial treatment cythemia vera. of cancer. Do ...... do ...... Treatment of leu- Iodine 131 ...... Iodide ...... Diagnosis of thyroid kemia and bone functions. metastasis. Do ...... do ...... Thyroid scans. Do ...... Colloidal chromic Intracavitary treat- Do ...... do ...... Treatment of hyper- phosphate. ment of pleural ef- thyroidism and/or fusions and/or as- cardiac dysfunc- cites. tion. Do ...... do ...... Interstitial treatment Do ...... do ...... Treatment of thyroid of cancer. carcinoma. Potassium 42 .. Chloride ...... Potassium space Do ...... Iodinated human Blood volume deter- studies. serum albumin. minations. Selenium 75 .... Labeled methionine Pancreas scans. Do ...... do ...... Cisternography. Strontium 85 .... Nitrate or chloride ... Bone scans on patients with diag- Do ...... do ...... Brain tumor localiza- nosed cancer. tion. Technetium Pertechnetate ...... Brain scans. Do ...... do ...... Placenta localiza- 99m. tion. Do ...... do ...... Thyroid scans. Do ...... do ...... Cardiac scans for Do ...... Sulfur colloid ...... Liver and spleen determination of scans. pericardial effu- Do ...... Pertechnetate ...... Placenta localiza- sions. tion. Do ...... Rose Bengal ...... Liver function stud- Do ...... do ...... Blood pool scans. ies. Do ...... do ...... Salivary gland Do ...... do ...... Liver scans. scans. Do ...... Iodopyracet, sodium Kidney function Do ...... Diethylenetri-amine Kidney scans. iodohippurate, so- studies and kid- pentaacetic acid dium diatrizoate, ney scans. (DTPA). diatrizoate methyl- Xenon 133 ...... Gas ...... Diagnosis of cardia glucamine, so- abnormalities. dium diprotrizoate, Cerebral blood- sodium acetri- flow studies. Pul- zoate, or sodium monary function iothalamate. studies. Muscle Do ...... Labeled fats and/or Fat absorption stud- bloodflow studies. fatty acids. ies. Do ...... Cholografin ...... Cardiac scans for 1 This item has been removed from the AEC list for kidney determination of scans but is included as the requirements of this order are applicable. pericardial effu- sions. (d)(1) In view of the extent of experi- Do ...... Macroaggregated io- Lung scans. dinated human ence with the isotopes listed in para- serum albumin. graph (c) of this section, the Nuclear Do ...... Colloidal micro- Liver scans. Regulatory Commission and the Food aggregated and Drug Administration conclude that human serum albumin. such isotopes should not be distributed Iodine 125 ...... Iodide ...... Diagnosis of thyroid under investigational-use labeling function. when they are actually intended for Do ...... Iodinated human Blood volume deter- serum albumin. minations. use in medical practice. Do ...... Rose Bengal ...... Liver function stud- (2) The exemption referred to in para- ies. graph (a) of this section, as applied to Do ...... Iodopyracet, sodium Kidney function any drug or biologic containing any of iodohippurate, so- studies. dium diatrizoate, the isotopes listed in paragraph (c) of diatrizoate methyl- this section, in the ‘‘chemical form’’ glucamine, so- and intended for the uses stated, is ter- dium diprotrizoate, sodium acetri- minated on March 3, 1972, except as zoate, or sodium provided in paragraph (d)(3) of this sec- iothalamate. tion. Do ...... Labeled fats and/or Fat absorption stud- (3) The exemption referred to in para- fatty acids. ies. Iron 59 ...... Chloride, citrate Iron turnover stud- graph (a) of this section, as applied to and/or sulfate. ies. any drug or biologic containing any of

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the isotopes listed in paragraph (c) of Drug Administration conclude that this section, in the ‘‘chemical form’’ they should not be distributed under and intended for the uses stated, for investigational-use labeling when they which drug a new drug application or a are actually intended for use in med- ‘‘Investigational New Drug Applica- ical practice. tion’’ was submitted prior to March 3, (3) Any manufacturer or distributor 1972, or for which biologic an applica- interested in continuing to ship in tion for product license or ‘‘Investiga- interstate commerce drugs containing tional New Drug Application’’ was sub- the isotopes listed in paragraph (f)(1) of mitted prior to March 3, 1972, is termi- this section for any of the indications nated on August 20, 1976, unless an ap- listed, shall submit, on or before Au- provable notice was issued on or before gust 25, 1975 to the Center for Drug August 20, 1976, in which case the ex- Evaluation and Research, Food and emption is terminated either upon the Drug Administration, 5600 Fishers subsequent issuance of a nonapprovable Lane, Rockville, MD 20857, a new drug notice for the new drug application or application or a ‘‘Investigational New on November 20, 1976, whichever occurs Drug Application’’ for each such drug first. for which the manufacturer or dis- (e) No exemption from section 505 of tributor does not have an approved new the act or from part 312 of this chapter drug application pursuant to section is in effect or has been in effect for ra- 505(b) of the act. If the drug is a bio- dioactive drugs prepared from accel- logic, a ‘‘Investigational New Drug Ap- erator-produced radioisotopes, natu- plication’’ or an application for a li- rally occurring isotopes, or nonradio- cense under section 351 of the Public active substances used in conjunction Health Service Act shall be submitted with isotopes. to the Food and Drug Administration, (f)(1) Based on its experience in regu- Center for Biologics Evaluation and lating investigational radioactive Research, Document Control Center, pharmaceuticals, the Nuclear Regu- latory Commission has compiled a list 10903 New Hampshire Ave., Bldg. 71, of reactor-produced isotopes for which Rm. G112, Silver Spring, MD 20993–0002, it considers that applicants may rea- in lieu of any submission to the Center sonably be expected to submit ade- for Drug Evaluation and Research. quate evidence of safety and effective- (4) The exemption referred to in para- ness for use as recommended in appro- graph (a) of this section, as applied to priate labeling; such use may include, any drug or biologic containing any of among others, the uses in this tabula- the isotopes listed in paragraph (f)(1) of tion: this section, in the ‘‘chemical form’’ and intended for the uses stated, is ter- Isotope Chemical form Use minated on August 26, 1975 except as Fluorine 18 ...... Fluoride ...... Bone imaging. provided in paragraph (f)(5) of this sec- Indium-113m ... Diethylenetriamine Brain imaging; kid- tion. pentaacetic acid ney imaging. (5)(i) Except as provided in paragraph (DTPA). Do ...... Chloride ...... Placenta imaging; (f)(5)(ii) of this section, the exemption blood pool imag- referred to in paragraph (a) of this sec- ing. tion, as applied to any drug containing Technetium Human serum albu- Lung imaging. 99m. min microspheres. any of the isotopes listed in paragraph Do ...... Diethylenetriamine Kidney imaging; kid- (f)(1) of this section, in the ‘‘chemical pentaacetic acid ney function stud- form’’ and intended for the uses stated, (Sn). ies. Do ...... do ...... Brain imaging. for which drug a new drug application Do ...... Polyphosphates ...... Bone imaging. or ‘‘Investigational New Drug Applica- Do ...... Technetated aggre- Lung imaging. tion’’ was submitted to the Center for gated albumin Drug Evaluation and Research on or (human). Do ...... Disodium etidronate Bone imaging. before August 25, 1975 is terminated on August 20, 1976, unless an approvable (2) In view of the extent of experience notice was issued on or before August with the isotopes listed in paragraph 20, 1976, in which case the exemption is (f)(1) of this section, the Nuclear Regu- terminated either upon the subsequent latory Commission and the Food and issuance of a nonapprovable notice for

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the new drug application or on Novem- graphs (d), (f), and (g) of this section, is ber 20, 1976, whichever occurs first. terminated on August 26, 1975. (ii) The exemption referred to in [39 FR 11680, Mar. 29, 1974, as amended at 40 paragraph (a) of this section, as applied FR 31307, July 25, 1975; 40 FR 44543, Sept. 29, to any biologic containing any of the 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, isotopes listed in paragraph (f)(1) of Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR this section in the ‘‘chemical form’’ 11578, Mar. 29, 1990; 64 FR 56449, Oct. 20, 1999; and intended for the uses stated, for 80 FR 18091, Apr. 3, 2015] which biologic an application for product license or ‘‘Investigational New § 310.509 Parenteral drug products in Drug Application’’ was submitted to plastic containers. the Center for Biologics Evaluation (a) Any parenteral drug product and Research on or before August 25, packaged in a plastic immediate con- 1975 is terminated on October 20, 1976, tainer is not generally recognized as unless an approvable notice was issued safe and effective, is a new drug within on or before October 20, 1976, in which the meaning of section 201(p) of the case the exemption is terminated ei- act, and requires an approved new drug ther upon the subsequent issuance of a application as a condition for mar- nonapprovable notice for the new drug keting. An ‘‘Investigational New Drug application or on January 20, 1977, Application’’ set forth in part 312 of whichever occurs first. this chapter is required for clinical in- (g) The exemption referred to in vestigations designed to obtain evi- paragraph (a) of this section, as applied dence of safety and effectiveness. to any drug intended solely for inves- (b) As used in this section, the term tigational use as part of a research ‘‘large volume parenteral drug prod- project, which use had been approved uct’’ means a terminally sterilized on or before July 25, 1975 in accordance aqueous drug product packaged in a with 10 CFR 35.11 (or equivalent regula- single-dose container with a capacity tion of an Agreement State) is termi- of 100 milliliters or more and intended nated on February 20, 1976 if the manu- to be administered or used intra- facturer of such drug or the sponsor of venously in a human. the investigation of such drug submits (c) Until the results of compatibility on or before August 25, 1975 to the Food studies are evaluated, a large volume and Drug Administration, Bureau of parenteral drug product for intra- Drugs, HFD–150, 5600 Fishers Lane, venous use in humans that is packaged Rockville, MD 20857, the following in- in a plastic immediate container on or formation: after April 16, 1979, is misbranded un- (1) The research project title; less its labeling contains a warning (2) A brief description of the purpose that includes the following informa- of the project; tion: (3) The name of the investigator re- (1) A statement that additives may sponsible; be incompatible. (4) The name and license number of (2) A statement that, if additive the institution holding the specific li- drugs are introduced into the paren- cense under 10 CFR 35.11 (or equivalent teral system, aseptic techniques should regulation of an Agreement State); be used and the solution should be (5) The name and maximum amount thoroughly mixed. per subject of the radionuclide used; (3) A statement that a solution con- (6) The number of subjects involved; taining an additive drug should not be and stored. (7) The date on which the administra- (d) This section does not apply to a tion of the radioactive drugs is ex- biological product licensed under the pected to be completed. Public Health Service Act of July 1, (h) The exemption referred to in 1944 (42 U.S.C. 201). paragraph (a) of this section, as applied [62 FR 12084, Mar. 14, 1997] to any drug not referred to in para-

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§ 310.515 Patient package inserts for drug product is required to contain the estrogens. following information: (a) Requirement for a patient package (1) The name of the drug. insert. FDA concludes that the safe and (2) The name and place of business of effective use of drug products con- the manufacturer, packer, or dis- taining estrogens requires that pa- tributor. tients be fully informed of the benefits (3) A statement regarding the bene- and risks involved in the use of these fits and proper uses of estrogens. drugs. Accordingly, except as provided (4) The contraindications to use, i.e., in paragraph (e) of this section, each when estrogens should not be used. estrogen drug product restricted to (5) A description of the most serious prescription distribution, including risks associated with the use of estro- products containing estrogens in fixed gens. combinations with other drugs, shall (6) A brief summary of other side ef- be dispensed to patients with a patient fects of estrogens. package insert containing information (7) Instructions on how a patient may concerning the drug’s benefits and reduce the risks of estrogen use. risks. An estrogen drug product that (8) The date, identified as such, of the does not comply with the requirements most recent revision of the patient of this section is misbranded under sec- package insert. tion 502(a) of the Federal Food, Drug, (d) Guidance language. The Food and and Cosmetic Act. Drug Administration issues informal (b) Distribution requirements. (1) For labeling guidance texts under estrogen drug products, the manufac- § 10.90(b)(9) of this chapter to provide turer and distributor shall provide a assistance in meeting the requirements patient package insert in or with each of paragraph (c) of this section. Re- package of the drug product that the quests for a copy of the guidance text manufacturer or distributor intends to should be directed to the Center for be dispensed to a patient. Drug Evaluation and Research, Divi- (2) In the case of estrogen drug prod- sion of Reproductive and Urologic ucts in bulk packages intended for Products, Food and Drug Administra- multiple dispensing, and in the case of tion, 10903 New Hampshire Ave., Silver injectables in multiple-dose vials, a Spring, MD 20993–0002. sufficient number of patient labeling (e) Exemptions. This section does not pieces shall be included in or with each apply to estrogen-progestogen oral con- package to assure that one piece can be traceptives. Labeling requirements for included with each package or dose dis- these products are set forth in § 310.501. pensed or administered to every pa- (f) Requirement to supplement approved tient. Each bulk package shall be la- application. Holders of approved appli- beled with instructions to the cations for estrogen drug products that dispensor to include one patient label- are subject to the requirements of this ing piece with each package dispensed section must submit supplements or, in the case of injectables, with each under § 314.70(c) of this chapter to pro- dose administered to the patient. This vide for the labeling required by para- section does not preclude the manufac- graph (a) of this section. Such labeling turer or labeler from distributing addi- may be put into use without advance tional patient labeling pieces to the approval by the Food and Drug Admin- dispensor. istration. (3) Patient package inserts for estro- [55 FR 18723, May 4, 1990, as amended at 74 gens dispensed in acute-care hospitals FR 13113, Mar. 26, 2009] or long-term care facilities will be considered to have been provided in ac- § 310.517 Labeling for oral hypo- cordance with this section if provided glycemic drugs of the sulfonylurea to the patient before administration of class. the first estrogen and every 30 days (a) The University Group Diabetes thereafter, as long as the therapy con- Program clinical trial has reported an tinues. association between the administration (c) Patient package insert contents. A of tolbutamide and increased cardio- patient package insert for an estrogen vascular mortality. The Food and Drug

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Administration has concluded that this class, in view of their close similarities in reported association provides adequate mode of action and chemical structure. basis for a warning in the labeling. In [49 FR 14331, Apr. 11, 1984] view of the similarities in chemical structure and mode of action, the Food § 310.518 Drug products containing and Drug Administration also believes iron or iron salts. it is prudent from a safety standpoint Drug products containing elemental to consider that the possible increased iron or iron salts as an active ingre- risk of cardiovascular mortality from dient in solid oral dosage form, e.g., tolbutamide applies to all other sulfo- tablets or capsules shall meet the fol- nylurea drugs as well. Therefore, the lowing requirements: labeling for oral hypoglycemic drugs of (a) Labeling. (1) The label of any drug the sulfonylurea class shall include a in solid oral dosage form (e.g., tablets warning concerning the possible in- or capsules) that contains iron or iron creased risk of cardiovascular mor- salts for use as an iron source shall tality associated with such use, as set bear the following statement: forth in paragraph (b) of this section. (b) Labeling for oral hypoglycemic WARNING: Accidental overdose or iron- drugs of the sulfonylurea class shall in- containing products is a leading cause of clude in boldface type at the beginning fatal poisoning in children under 6. Keep this product out of reach of children. In case of of the ‘‘Warnings’’ section of the label- accidental overdose, call a doctor or poison ing the following statement: control center immediately. (2)(i) The warning statement required SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY by paragraph (a)(1) of this section shall appear prominently and conspicuously The administration of oral hypoglycemic on the information panel of the imme- drugs has been reported to be associated diate container label. with increased cardiovascular mortality as compared to treatment with diet alone or (ii) If a drug product is packaged in diet plus insulin. This warning is based on unit-dose packaging, and if the imme- the study conducted by the University Group diate container bears labeling but not a Diabetes Program (UGDP), a long-term pro- label, the warning statement required spective clinical trial designed to evaluate by paragraph (a)(1) of this section shall the effectiveness of glucose-lowering drugs appear prominently and conspicuously in preventing or delaying vascular complica- on the immediate container labeling in tions in patients with non-insulin-dependent a way that maximizes the likelihood diabetes. The study involved 823 patients who were randomly assigned to one of four that the warning is intact until all of treatment groups (Diabetes, 19 (supp. 2): 747– the dosage units to which it applies are 830, 1970). used. UGDP reported that patients treated for 5 (3) Where the immediate container is to 8 years with diet plus a fixed dose of tol- not the retail package, the warning butamide (1.5 grams per day) had a rate of statement required by paragraph (a)(1) cardiovascular mortality approximately 21⁄2 of this section shall also appear promi- times that of patients treated with diet nently and conspicuously on the infor- alone. A significant increase in total mortality was not observed, but the use of tol- mation panel of the retail package butamide was discontinued based on the in- label. crease in cardiovascular mortality, thus lim- (4) The warning statement shall ap- iting the opportunity for the study to show pear on any labeling that contains an increase in overall mortality. Despite warnings. controversy regarding the interpretation of (5) The warning statement required these results, the findings of the UGDP study by paragraph (a)(1) of this section shall provide an adequate basis for this warning. The patient should be informed of the poten- be set off in a box by use of hairlines. tial risks and advantages of (name of drug) (b) The iron-containing inert tablets and of alternative modes of therapy. supplied in monthly packages of oral Although only one drug in the sulfonylurea contraceptives are categorically ex- class (tolbutamide) was included in this empt from the requirements of para- study, it is prudent from a safety standpoint graph (a) of this section. to consider that this warning may also apply to other oral hypoglycemic drugs in this [68 FR 59715, Oct. 17, 2003]

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§ 310.519 Drug products marketed as § 310.527 Drug products containing ac- over-the-counter (OTC) daytime tive ingredients offered over-the- sedatives. counter (OTC) for external use as hair growers or for hair loss pre- (a) Antihistamines, bromides, and vention. scopolamine compounds, either singly (a) Amino acids, aminobenzoic acid, or in combinations, have been mar- ascorbic acid, benzoic acid, biotin and keted as ingredients in over-the- all other B-vitamins, dexpanthenol, es- counter (OTC) drug products for use as tradiol and other topical hormones, daytime sedatives. The following jojoba oil, lanolin, nucleic acids, poly- claims have been made for daytime sorbate 20, polysorbate 60, sulfa- sedative products: ‘‘occasional simple nilamide, sulfur 1 percent on carbon in nervous tension,’’ ‘‘nervous irrita- a fraction of paraffinic hydrocarbons, bility,’’ ‘‘nervous tension headache,’’ tetracaine hydrochloride, urea, and ‘‘simple nervousness due to common wheat germ oil have been marketed as every day overwork and fatigue,’’ ‘‘a ingredients in OTC drug products for relaxed feeling,’’ ‘‘calming down and external use as hair growers or for hair relaxing,’’ ‘‘gently soothe away the loss prevention. There is a lack of ade- tension,’’ ‘‘calmative,’’ ‘‘resolving that quate data to establish general rec- irritability that ruins your day,’’ ognition of the safety and effectiveness ‘‘helps you relax,’’ ‘‘restlessness,’’ of these or any other ingredients in- ‘‘when you’re under occasional stress . tended for OTC external use as a hair . . helps you work relaxed.’’ Based on grower or for hair loss prevention. evidence presently available, there are Based on evidence currently available, no ingredients that can be generally all labeling claims for OTC hair grower recognized as safe and effective for use and hair loss prevention drug products as OTC daytime sedatives. for external use are either false, misleading, or unsupported by scientific (b) Any OTC drug product that is la- data. Therefore, any OTC drug product beled, represented, or promoted as an for external use containing an ingre- OTC daytime sedative (or any similar dient offered for use as a hair grower or or related indication) is regarded as a for hair loss prevention cannot be con- new drug within the meaning of section sidered generally recognized as safe 201(p) of the Federal Food, Drug, and and effective for its intended use. Cosmetic Act for which an approved (b) Any OTC drug product that is la- new drug application under section 505 beled, represented, or promoted for ex- of the act and part 314 of this chapter ternal use as a hair grower or for hair is required for marketing. loss prevention is regarded as a new (c) Clinical investigations designed drug within the meaning of section to obtain evidence that any drug prod- 201(p) of the Federal Food, Drug, and uct labeled, represented, or promoted Cosmetic Act (the act), for which an as an OTC daytime sedative (or any approved new drug application under similar or related indication) is safe section 505 of the act and part 314 of and effective for the purpose intended this chapter is required for marketing. must comply with the requirements In the absence of an approved new drug and procedures governing the use of in- application, such product is also mis- vestigational new drugs set forth in branded under section 502 of the act. part 312 of this chapter. (c) Clinical investigations designed (d) Any OTC daytime sedative drug to obtain evidence that any drug product labeled, represented, or promoted product introduced into interstate for OTC external use as a hair grower commerce after December 24, 1979, that or for hair loss prevention is safe and is not in compliance with this section effective for the purpose intended must is subject to regulatory action. comply with the requirements and pro- [44 FR 36380, June 22, 1979; 45 FR 47422, July cedures governing the use of investiga- 15, 1980, as amended at 55 FR 11579, Mar. 29, tional new drugs set forth in part 312 of 1990] this chapter. (d) After January 8, 1990, any such OTC drug product initially introduced

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or initially delivered for introduction In the absence of an approved new drug into interstate commerce that is not in application, such product is also mis- compliance with this section is subject branded under section 502 of the act. to regulatory action. (c) Clinical investigations designed to obtain evidence that any drug prod- [54 FR 28777, July 7, 1989] uct labeled, represented, or promoted § 310.528 Drug products containing ac- for OTC use as an aphrodisiac is safe tive ingredients offered over-the- and effective for the purpose intended counter (OTC) for use as an aphro- must comply with the requirements disiac. and procedures governing the use of in- (a) Any product that bears labeling vestigational new drugs set forth in claims that it will arouse or increase part 312 of this chapter. sexual desire, or that it will improve (d) After January 8, 1990, any such sexual performance, is an aphrodisiac OTC drug product initially introduced drug product. Anise, cantharides, don or initially delivered for introduction qual, estrogens, fennel, ginseng, golden into interstate commerce that is not in seal, gotu kola, Korean ginseng, lico- compliance with this section is subject rice, mandrake, methyltestosterone, to regulatory action. minerals, nux vomica, Pega Palo, sar- [54 FR 28786, July 7, 1989] saparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine hydro- § 310.529 Drug products containing ac- chloride, and yohimbinum have been tive ingredients offered over-the- present as ingredients in such drug counter (OTC) for oral use as insect products. Androgens (e.g., testosterone repellents. and methyltestosterone) and estrogens (a) Thiamine hydrochloride (vitamin are powerful hormones when adminis- B–1) has been marketed as an ingre- tered internally and are not safe for dient in over-the-counter (OTC) drug use except under the supervision of a products for oral use as an insect repel- physician. There is a lack of adequate lent (an orally administered drug prod- data to establish general recognition of uct intended to keep insects away). the safety and effectiveness of any of There is a lack of adequate data to es- these ingredients, or any other ingre- tablish the effectiveness of this, or any dient, for OTC use as an aphrodisiac. other ingredient for OTC oral use as an Labeling claims for aphrodisiacs for insect repellent. Labeling claims for OTC use are either false, misleading, or OTC orally administered insect repel- unsupported by scientific data. The fol- lent drug products are either false, lowing claims are examples of some misleading, or unsupported by sci- that have been made for aphrodisiac entific data. The following claims are drug products for OTC use: ‘‘acts as an examples of some that have been made aphrodisiac;’’ ‘‘arouses or increases for orally administered OTC insect re- sexual desire and improves sexual per- pellent drug products: ‘‘Oral mosquito formance;’’ ‘‘helps restore sexual vigor, repellent,’’ ‘‘mosquitos avoid you,’’ potency, and performance;’’ ‘‘improves ‘‘bugs stay away,’’ ‘‘keep mosquitos performance, staying power, and sexual away for 12 to 24 hours,’’ and ‘‘the new- potency;’’ and ‘‘builds virility and sex- est way to fight mosquitos.’’ Therefore, ual potency.’’ Based on evidence cur- any drug product containing ingredi- rently available, any OTC drug product ents offered for oral use as an insect re- containing ingredients for use as an pellent cannot be generally recognized aphrodisiac cannot be generally recog- as safe and effective. nized as safe and effective. (b) Any OTC drug product that is la- (b) Any OTC drug product that is labeled, represented, or promoted for oral beled, represented, or prompted for use use as an insect repellent is regarded as as an aphrodisiac is regarded as a new a new drug within the meaning of sec- drug within the meaning of section tion 201(p) of the Federal Food, Drug 201(p) of the Federal Food, Drug, and and Cosmetic Act for which an ap- Cosmetic Act, (the act), for which an proved new drug application under sec- approved new drug application under tion 505 of the act and part 314 of this section 505 of the act and part 314 of chapter is required for marketing. In this chapter is required for marketing. the absence of an approved new drug

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application, such product is also mis- the labeling indicating that ‘‘hor- branded under section 502 of the act. mones’’ are present in the product, or (c) Clinical investigations designed any statement that features or empha- to obtain evidence that any drug prod- sizes the presence of a hormone ingre- uct labeled, represented, or promoted dient in the product, will be considered OTC for oral use as an insect repellent to be a therapeutic claim for the prod- is safe and effective for the purpose in- uct, or a claim that the product will af- tended must comply with the require- fect the structure or function of the ments and procedures governing the body, and will consequently cause the use of investigational new drugs set product to be a drug. forth in part 312 of this chapter. (b) Any OTC drug product that is la- (d) Any such drug product in inter- beled, represented, or promoted as a state commerce after December 17, topically applied hormone-containing 1985, that is not in compliance with product for drug use, with the excep- this section is subject to regulatory action of those hormones identified in tion. paragraph (e) of this section, is re- [40 FR 25171, June 17, 1985, as amended at 55 garded as a new drug within the mean- FR 11579, Mar. 29, 1990] ing of section 201(p) of the act, for which an approved application or ab- § 310.530 Topically applied hormone- breviated application under section 505 containing drug products for over- of the act and part 314 of this chapter the-counter (OTC) human use. is required for marketing. In the ab- (a) The term ‘‘hormone’’ is used sence of an approved new drug applica- broadly to describe a chemical sub- tion or abbreviated new drug applica- stance formed in some organ of the tion, such product is also misbranded body, such as the adrenal glands or the under section 502 of the act. pituitary, and carried to another organ (c) Clinical investigations designed or tissue, where it has a specific effect. to obtain evidence that any drug prod- Hormones include, for example, estro- uct labeled, represented, or promoted gens, progestins, androgens, anabolic for OTC use as a topically applied hor- steroids, and adrenal corticosteroids, mone-containing drug product is safe and synthetic analogs. Estrogens, pro- and effective for the purpose intended gesterone, pregnenolone, and pregneno- must comply with the requirements lone acetate have been present as in- and procedures governing the use of ingredients in OTC drug products mar- vestigational new drugs set forth in keted for topical use as hormone part 312 of this chapter. creams. However, there is a lack of (d) After March 9, 1994, any such OTC adequate data to establish effective- drug product initially introduced or ness for any OTC drug use of these in- initially delivered for introduction into gredients. Therefore, with the excep- interstate commerce that is not in tion of those hormones identified in compliance with this section is subject paragraph (e) of this section, any OTC to regulatory action. drug product containing an ingredient (e) This section does not apply to hy- offered for use as a topically applied drocortisone and hydrocortisone ace- hormone cannot be considered gen- tate labeled, represented, or promoted erally recognized as safe and effective for OTC topical use in accordance with for its intended use. The intended use part 348 of this chapter. of the product may be inferred from [58 FR 47610, Sept. 9, 1993] the product’s labeling, promotional material, advertising, and any other § 310.531 Drug products containing ac- relevant factor. The use of the word tive ingredients offered over-the- ‘‘hormone’’ in the text of the labeling counter (OTC) for the treatment of or in the ingredient statement is an boils. implied drug claim. The claim implied (a) Aminacrine hydrochloride, benzo- by the use of this term is that the prod- caine, bismuth subnitrate, calomel, uct will have a therapeutic or some camphor, cholesterol, ergot fluid ex- other physiological effect on the body. tract, hexachlorophene, ichthammol, Therefore, reference to a product as a isobutamben, juniper tar (oil of cade), ‘‘hormone cream’’ or any statement in lanolin, magnesium sulfate, menthol,

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methyl salicylate, oxyguinoline sul- ichthammol, sulfur, or triclosan ini- fate, petrolatum, phenol, pine tar, tially introduced or initially delivered rosin, rosin cerate, sassafras oil, sulfur, for introduction into interstate com- thymol, triclosan, and zinc oxide have merce that is not in compliance with been present in OTC boil treatment this section is subject to regulatory ac- drug products. There is a lack of ade- tion. quate data to establish general rec- (f) This section does not apply to ognition of the safety and effectiveness drug products that contain benzocaine of these or any other ingredient for labeled, represented, or promoted for OTC use for the treatment of boils. OTC topical use in accordance with Treatment is defined as reducing the part 348 of this chapter. size of a boil or reducing an infection [58 FR 60336, Nov. 15, 1993] related to a boil. Treatment has involved the use of ‘‘drawing salves’’ for § 310.532 Drug products containing ac- these purposes. These ‘‘drawing salves’’ tive ingredients offered over-the- contained various ingredients. Based counter (OTC) to relieve the symp- on evidence currently available, any toms of benign prostatic hyper- OTC drug product offered for the treat- trophy. ment of boils cannot be considered gen- (a) The amino acids glycine, alanine, erally recognized as safe and effective. and glutamic acid (alone or in com- (b) Any OTC drug product that is la- bination) and the ingredient sabal have beled, represented, or promoted for the been present in over-the-counter (OTC) treatment of boils is regarded as a new drug products to relieve the symptoms drug within the meaning of section of benign prostatic hypertrophy, e.g., 201(p) of the Federal Food, Drug, and urinary urgency and frequency, exces- Cosmetic Act (the act), for which an sive urinating at night, and delayed approved application or abbreviated urination. There is a lack of adequate application under section 505 of the act data to establish general recognition of and part 314 of this chapter is required the safety and effectiveness of these or for marketing. In the absence of an ap- any other ingredients for OTC use in proved new drug application or abbre- relieving the symptoms of benign pros- viated new drug application, such prod- tatic hypertrophy. In addition, there is uct is also misbranded under section no definitive evidence that any drug 502 of the act. product offered for the relief of the (c) Clinical investigations designed symptoms of benign prostatic hyper- to obtain evidence that any OTC boil trophy would alter the obstructive or treatment drug product is safe and ef- inflammatory signs and symptoms of fective for the purpose intended must this condition. Therefore, self-medica- comply with the requirements and pro- tion with OTC drug products might un- cedures governing the use of investiga- necessarily delay diagnosis and treat- tional new drugs set forth in part 312 of ment of progressive obstruction and this chapter. secondary infections. Based on evi- (d) After May 7, 1991, any such OTC dence currently available, any OTC drug product that contains aminacrine drug product containing ingredients of- hydrochloride, bismuth subnitrate, cal- fered for use in relieving the symptoms omel, camphor, cholesterol, ergot fluid of benign prostatic hypertrophy cannot extract, hexachlorophene, isobu- be generally recognized as safe and ef- tamben, juniper tar (oil of cade), lan- fective. olin, magnesium sulfate, menthol, (b) Any OTC drug product that is la- methyl salicylate, oxyguinoline sul- beled, represented, or promoted to re- fate, petrolatum, phenol, pine tar, lieve the symptoms of benign prostatic rosin, rosin cerate, sassafras oil, thy- hypertrophy is regarded as a new drug mol, or zinc oxide initially introduced within the meaning of section 201(p) of or initially delivered for introduction the Federal Food, Drug, and Cosmetic into interstate commerce that is not in Act (the act), for which an approved compliance with this section is subject application under section 505 of the act to regulatory action. and part 314 of this chapter is required (e) After May 16, 1994, any such OTC for marketing. In the absence of an ap- drug product that contains benzocaine, proved application, such product is also

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misbranded under section 502 of the to establish general recognition of the act. safety and/or effectiveness or any of (c) Clinical investigations designed these ingredients, or any other ingre- to obtain evidence that any drug prod- dient, for OTC use as an anticho- uct labeled, represented, or promoted linergic in cough-cold drug products. for OTC use to relieve the symptoms of (b) Any OTC cough-cold drug product benign prostatic hypertrophy is safe that is labeled, represented, or pro- and effective for the purpose intended moted for use as an anticholinergic is must comply with the requirements regarded as a new drug within the and procedures governing the use of in- meaning of section 201(p) of the Fed- vestigational new drugs set forth in eral Food, Drug, and Cosmetic Act, for part 312 of this chapter. which an approved new drug applica- (d) After August 27, 1990, any such tion under section 505 of the act and OTC drug product initially introduced part 314 of this chapter is required for or initially delivered for introduction marketing. In the absence of an ap- into interstate commerce that is not in proved new drug application, such compliance with this section is subject product is also misbranded under sec- to regulatory action. tion 502 of the act. (c) Clinical investigations designed [55 FR 6930, Feb. 27, 1990] to obtain evidence that any cough-cold § 310.533 Drug products containing ac- drug product labeled, represented, or tive ingredients offered over-the- promoted for OTC use as an anticho- counter (OTC) for human use as an linergic is safe and effective for the anticholinergic in cough-cold drug purpose intended must comply with the products. requirements and procedures governing (a) Atropine sulfate, belladonna alka- the use of investigational new drugs loids, and belladonna alkaloids as con- set forth in part 312 of this chapter. tained in Atropa belladonna and Datu- (d) After the effective date of the ra stramonium have been present as in- final regulation, any such OTC cough- gredients in cough-cold drug products cold drug product that is labeled, rep- for use as an anticholinergic. Anticho- resented, or promoted for use as an linergic drugs have been marketed OTC anticholinergic may not be initially in- in cough-cold drug products to relieve troduced or initially delivered for in- excessive secretions of the nose and troduction into interstate commerce eyes, symptoms that are commonly as- unless it is the subject of an approved sociated with hay fever, allergy, rhi- new drug application. nitis, and the common cold. Atropine [50 FR 46587, Nov. 8, 1985, as amended at 55 sulfate for oral use as an anticho- FR 11579, Mar. 29, 1990] linergic is probably safe at dosages that have been used in marketed § 310.534 Drug products containing ac- cough-cold products (0.2 to 0.3 milli- tive ingredients offered over-the- gram); however, there are inadequate counter (OTC) for human use as data to establish general recognition of oral wound healing agents. the effectiveness of this ingredient. (a) Allantoin, carbamide peroxide in The belladonna alkaloids, which con- anhydrous glycerin, water soluble tain atropine (d, dl hyoscyamine) and chlorophyllins, and hydrogen peroxide scopolamine (l- hyoscine), are probably in aqueous solution have been present safe for oral use at dosages that have in oral mucosal injury drug products been used in marketed cough-cold for use as oral wound healing agents. products (0.2 milligram) but there are Oral wound healing agents have been inadequate data to establish general marketed as aids in the healing of recognition of the effectiveness of minor oral wounds by means other these ingredients as an anticholinergic than cleansing and irrigating, or by for cough-cold use. Belladonna alka- serving as a protectant. Allantoin, car- loids for inhalation use, as contained in bamide peroxide in anhydrous glycerin, Atropa belladonna and Datura stramo- water soluble chlorophyllins, and hy- nium, are neither safe nor effective as drogen peroxide in aqueous solution an OTC anticholinergic. There are in- are safe for use as oral wound healing adequate safety and effectiveness data agents, but there are inadequate data

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to establish general recognition of the is regarded as a new drug within the effectiveness of these ingredients as meaning of section 201(p) of the Fed- oral wound healing agents. eral Food, Drug, and Cosmetic Act (the (b) Any OTC drug product that is la- act) for which an approved application beled, represented, or promoted for use or abbreviated application under sec- as an oral wound healing agent is re- tion 505 of the act and part 314 of this garded as a new drug within the mean- chapter is required for marketing. In ing of section 201(p) of the Federal the absence of an approved new drug Food, Drug, and Cosmetic Act, for application or abbreviated new drug which an approved new drug applica- application, such product is also mis- tion under section 505 of the act and branded under section 502 of the act. part 314 of this chapter is required for (c) Clinical investigations designed marketing. In the absence of an ap- to obtain evidence that any drug prod- proved new drug application, such uct labeled, represented, or promoted product is also misbranded under sec- for OTC use as a nailbiting or thumb- tion 502 of the act. sucking deterrent is safe and effective (c) Clinical investigations designed for the purpose intended must comply to obtain evidence that any drug prod- with the requirements and procedures uct labeled, represented, or promoted governing the use of investigational for OTC use as an oral wound healing new drugs set forth in part 312 of this agent is safe and effective for the pur- chapter. pose intended must comply with the re- (d) After March 2, 1994, any such OTC quirements and procedures governing drug product initially introduced or the use of investigational new drugs initially delivered for introduction into set forth in part 312 of this chapter. interstate commerce that is not in (d) After the effective date of the compliance with this section is subject final regulation, any OTC drug product to regulatory action. that is labeled, represented, or pro- [58 FR 46754, Sept. 2, 1993] moted for use as an oral wound healing agent may not be initially introduced § 310.537 Drug products containing ac- or initially delivered for introduction tive ingredients offered over-the- into interstate commerce unless it is counter (OTC) for oral administra- the subject of an approved new drug ap- tion for the treatment of fever blis- plication. ters and cold sores. [51 FR 26114, July 18, 1986, as amended at 55 (a) L-lysine (lysine, lysine hydro- FR 11579, Mar. 29, 1990] chloride), Lactobacillus acidophilus, and Lactobacillus bulgaricus have been § 310.536 Drug products containing ac- present in orally administered OTC tive ingredients offered over-the- drug products to treat fever blisters counter (OTC) for use as a nail- and cold sores. There is a lack of ade- biting or thumbsucking deterrent. quate data to establish general rec- (a) Denatonium benzoate and sucrose ognition of the safety and effectiveness octaacetate have been present in OTC of these or any other orally adminis- nailbiting and thumbsucking deterrent tered ingredients for OTC use to treat drug products. There is a lack of ade- or relieve the symptoms or discomfort quate data to establish general rec- of fever blisters and cold sores. Based ognition of the safety and effectiveness on evidence currently available, any of these and any other ingredients OTC drug product for oral administra- (e.g., cayenne pepper) for OTC use as a tion containing ingredients offered for nailbiting or thumbsucking deterrent. use in treating or relieving the symp- Based on evidence currently available, toms or discomfort of fever blisters and any OTC drug product containing in- cold sores cannot be generally recog- gredients offered for use as a nailbiting nized as safe and effective. or thumbsucking deterrent cannot be (b) Any OTC drug product for oral ad- generally recognized as safe and effec- ministration that is labeled, rep- tive. resented, or promoted to treat or re- (b) Any OTC drug product that is la- lieve the symptoms or discomfort of beled, represented, and promoted as a fever blisters and cold sores is regarded nailbiting or thumbsucking deterrent as a new drug within the meaning of

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section 201(p) of the Federal Food, for marketing. In the absence of an ap- Drug, and Cosmetic Act (the act), for proved new drug application or abbre- which an approved application under viated new drug application, such prod- section 505 of the act and part 314 of uct is also misbranded under section this chapter is required for marketing. 502 of the act. In the absence of an approved applica- (c) Clinical investigations designed tion, such product is also misbranded to obtain evidence that any drug prod- under section 502 of the act. uct labeled, represented, or promoted (c) Clinical investigations designed for OTC use for ingrown toenail relief to obtain evidence that any drug prod- is safe and effective for the purpose in- uct for oral administration labeled, represented, or promoted for OTC use tended must comply with the require- to treat or relieve the symptoms or dis- ments and procedures governing the comfort of fever blisters and cold sores use of investigational new drugs set is safe and effective for the purpose in- forth in part 312 of this chapter. tended must comply with the require- (d) After March 9, 1994, any such OTC ments and procedures governing the drug product initially introduced or use of investigational new drugs set initially delivered for introduction into forth in part 312 of this chapter. interstate commerce that is not in (d) After December 30, 1992, any such compliance with this section is subject OTC drug product initially introduced to regulatory action. or initially delivered for introduction (e) This section does not apply to so- into interstate commerce that is not in dium sulfide labeled, represented, or compliance with this section is subject promoted for OTC topical use for in- to regulatory action. grown toenail relief in accordance with [57 FR 29173, June 30, 1992] part 358, subpart D of this chapter, after June 6, 2003. § 310.538 Drug products containing active ingredients offered over-the- [58 FR 47605, Sept. 9, 1993, as amended at 68 counter (OTC) for use for ingrown FR 24348, May 7, 2003] toenail relief. (a) Any product that bears labeling § 310.540 Drug products containing active ingredients offered over-the- claims such as for ‘‘temporary relief of counter (OTC) for use as stomach discomfort from ingrown toenails,’’ or acidifiers. ‘‘ingrown toenail relief product,’’ or ‘‘ingrown toenail reliever,’’ or similar (a) Betaine hydrochloride, glutamic claims is considered an ingrown toenail acid hydrochloride, diluted hydro- relief drug product. Benzocaine, chloro- chloric acid, and pepsin have been butanol, chloroxylenol, dibucaine, tan- present as ingredients in over-the- nic acid, and urea have been present as counter (OTC) drug products for use as ingredients in such products. There is stomach acidifiers. Because of the lack lack of adequate data to establish gen- of adequate data to establish the effec- eral recognition of the safety and effectiveness of these or any other ingredi- tiveness of these or any other ingredients for use in treating achlorhydria ents for OTC use for ingrown toenail and hypochlorhydria, and because such relief. Based on evidence currently conditions are asymptomatic, any OTC available, any OTC drug product con- drug product containing ingredients of- taining ingredients offered for use for fered for use as a stomach acidifier ingrown toenail relief cannot be gen- cannot be considered generally recog- erally recognized as safe and effective. nized as safe and effective. (b) Any OTC drug product that is la- (b) Any OTC drug product that is labeled, represented, or promoted for ingrown toenail relief is regarded as a beled, represented, or promoted for use new drug within the meaning of section as a stomach acidifier is regarded as a 201(p) of the Federal Food, Drug, and new drug within the meaning of section Cosmetic Act (the act), for which an 201(p) of the Federal Food, Drug, and approved application or abbreviated Cosmetic Act, for which an approved application under section 505 of the act new drug application under section 505 and part 314 of this chapter is required of the act and part 314 of this chapter

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is required for marketing. In the ab- drugs set forth in part 312 of his chap- sence of an approved new drug applica- ter. tion, such product is also misbranded (d) After November 12, 1990, any such under section 502 of the act. OTC drug product initially introduced (c) Clinical investigations designed or initially delivered for introduction to obtain evidence that any drug prod- into interstate commerce that is not in uct labeled, represented, or promoted compliance with this section is subject as a stomach acidifier for OTC use is to regulatory action. safe and effective for the purpose intended must comply with the require- [55 FR 19858, May 11, 1990] ments and procedures governing the use of investigational new drugs set § 310.542 Over-the-counter (OTC) drug products containing active ingredi- forth in part 312 of this chapter. ents offered for use in the treat- (d) After the effective date of the ment of hyperphosphatemia. final regulation, any such OTC drug product initially introduced or ini- (a) Hyperphosphatemia is a condition tially delivered for introduction into in which an abnormally high plasma interstate commerce that is not in level of phosphate occurs in the blood. compliance with this section is subject This condition in not amenable to self- to regulatory action. diagnosis or self-treatment. Treatment of this condition should be restricted [53 FR 31271, Aug. 17, 1988] to the supervision of a physician. For this reason, any drug product con- § 310.541 Over-the-counter (OTC) drug products containing active ingredi- taining ingredients offered for OTC use ents offered for use in the treat- in the treatment of hyperphosphatemia ment of hypophosphatemia. cannot be considered generally recog- (a) Hypophosphatemia is a condition nized as safe and effective. in which an abnormally low plasma (b) Any drug product that is labeled, level of phosphate occurs in the blood. represented, or promoted for OTC use This condition is not amenable to self- in the treatment of hyperphosphatemia diagnosis or self-treatment. Treatment is regarded as a new drug within the of this condition should be restricted meaning of section 201(p) of the Fed- to the supervision of a physician. For eral Food, Drug, and Cosmetic Act (the this reason, any drug product con- act), for which an approved application taining ingredients offered for OTC use under section 505 of the act and part 314 in the treatment of hypophosphatemia of this chapter is required for mar- cannot be considered generally recog- keting. In the absence of an approved nized as safe and effective. application, such product is also mis- (b) Any drug product that is labeled, branded under section 502 of the act. represented, or promoted for OTC use (c) Clinical investigations designed in the treatment of hypophosphatemia to obtain evidence that any drug prod- is regarded as a new drug within the uct labeled, represented, or promoted meaning of section 201(p) of the Fed- for use in the treatment of hyper- eral Food, Drug, and Cosmetic Act (the phosphatemia is safe and effective for act), for which an approved application the purpose intended must comply with under section 505 of the act and part 314 the requirements and procedures gov- of this chapter is required for mar- erning use of investigational new drugs keting. In the absence of an approved application, such product is also mis- set forth in part 312 of this chapter. branded under section 502 of the act. (d) After November 12, 1990, any such (c) Clinical investigations designed OTC drug product initially introduced to obtain evidence that any drug prod- or initially delivered for introduction uct labeled, represented, or promoted into interstate commerce that is not in for OTC use in the treatment of hypo- compliance with this section is subject phosphatemia is safe and effective for to regulatory action. the purpose intended must comply with [55 FR 19858, May 11, 1990] the requirements and procedures governing the use of investigational new

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§ 310.543 Drug products containing ac- and procedures governing the use of in- tive ingredients offered over-the- vestigational new drugs set forth in counter (OTC) for human use in part 312 of this chapter. exocrine pancreatic insufficiency. (d) After May 7, 1991, any such OTC (a) Hemicellulase, pancreatin, and drug product that contains hemi- pancrelipase have been present as in- cellulase initially introduced or ini- gredients in exocrine pancreatic insuf- tially delivered for introduction into ficiency drug products. Pancreatin and interstate commerce that is not in pancrelipase are composed of enzymes: compliance with this section is subject amylase, trypsin (protease), and lipase. to regulatory action. Significant differences have been (e) After October 24, 1995, any such shown in the bioavailability of mar- OTC drug product that contains pan- keted exocrine pancreatic insufficiency creatin or pancrelipase initially intro- drug products produced by different duced or initially delivered for intro- manufacturers. These differences raise duction into interstate commerce that a potential for serious risk to patients using these drug products. The bio- is not in compliance with this section availability of pancreatic enzymes is is subject to regulatory action. dependent on the process used to man- [60 FR 20165, Apr. 24, 1995] ufacture the drug products. Informa- tion on this process is not included in § 310.544 Drug products containing ac- an OTC drug monograph. Therefore, tive ingredients offered over-the- the safe and effective use of these en- counter (OTC) for use as a smoking zymes for treating exocrine pancreatic deterrent. insufficiency cannot be regulated ade- (a) Any product that bears labeling quately by an OTC drug monograph. claims that it ‘‘helps stop or reduce the Information on the product’s formula- cigarette urge,’’ ‘‘helps break the ciga- tion, manufacture, quality control pro- rette habit,’’ ‘‘helps stop or reduce cedures, and final formulation effec- smoking,’’ or similar claims is a smok- tiveness testing are necessary in an ap- ing deterrent drug product. Cloves, co- proved application to ensure that a riander, eucalyptus oil, ginger (Ja- company has the ability to manufac- maica), lemon oil (terpeneless), licorice ture a proper bioactive formulation. In root extract, lobeline (in the form of addition, continuous physician moni- lobeline sulfate or natural lobelia alka- toring of patients who take these drug loids or Lobelia inflata herb), menthol, products is a collateral measure nec- methyl salicylate, povidone-silver ni- essary to the safe and effective use of trate, quinine ascorbate, silver acetate, these enzymes, causing such products silver nitrate, and thymol have been to be available by prescription only. present as ingredients in such drug (b) Any drug product that is labeled, products. There is a lack of adequate represented, or promoted for OTC use data to establish general recognition of in the treatment of exocrine pancreatic the safety and effectiveness of these or insufficiency is regarded as a new drug within the meaning of section 201(p) of any other ingredients for OTC use as a the Federal Food, Drug, and Cosmetic smoking deterrent. Based on evidence Act (the act), for which an approved currently available, any OTC drug application under section 505 of the act product containing ingredients offered and part 314 of this chapter is required for use as a smoking deterrent cannot for marketing. In the absence of an ap- be generally recognized as safe and ef- proved application, such product is also fective. misbranded under section 502 of the (b) Any OTC drug product that is la- act. beled, represented, or promoted as a (c) Clinical investigations designed smoking deterrent is regarded as a new to obtain evidence that any drug prod- drug within the meaning of section uct labeled, represented, or promoted 201(p) of the Federal Food, Drug, and for OTC use in the treatment of exo- Cosmetic Act (the act), for which an crine pancreatic insufficiency is safe approved application or abbreviated and effective for the purpose intended application under section 505 of the act must comply with the requirements and part 314 of this chapter is required

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for marketing. In the absence of an ap- Chloroxylenol proved new drug application or abbre- Cloxyquin viated new drug application, such prod- Coal tar uct is also misbranded under section Dibenzothiophene Estrone 502 of the act. Magnesium aluminum silicate (c) Clinical investigations designed Magnesium sulfate to obtain evidence that any drug prod- Phenol uct labeled, represented, or promoted Phenolate sodium for OTC use as a smoking deterrent is Phenyl salicylate safe and effective for the purpose in- Povidone-iodine tended must comply with the require- Pyrilamine maleate ments and procedures governing the Resorcinol (as single ingredient) use of investigational new drugs set Resorcinol monoacetate (as single ingredient) forth in part 312 of this chapter. Salicylic acid (over 2 up to 5 percent) (d) After May 7, 1991, any such OTC Sodium borate drug product containing cloves, cori- Sodium thiosulfate ander, eucalyptus oil, ginger (Ja- Tetracaine hydrochloride maica), lemon oil (terpeneless), licorice Thymol root extract, menthol, methyl salicy- Vitamin E late, quinine ascorbate, silver nitrate, Zinc oxide and/or thymol initially introduced or Zinc stearate initially delivered for introduction into Zinc sulfide interstate commerce that is not in (2) Anticaries drug products—(i) Ap- compliance with this section is subject proved as of May 7, 1991. to regulatory action. After December 1, 1993, any such OTC drug product con- Hydrogen fluoride Sodium carbonate taining lobeline (in the form of lobeline Sodium monofluorophosphate (6 percent sulfate or natural lobelia alkaloids or rinse) Lobelia inflata herb), povidone-silver ni- Sodium phosphate trate, silver acetate, or any other ingredients initially introduced or ini- (ii) Approved as of October 7, 1996. tially delivered for introduction into Calcium sucrose phosphate interstate commerce that is not in Dicalcium phosphate dihydrate compliance with this section is subject Disodium hydrogen phosphate 1 to regulatory action. Phosphoric acid 1 Sodium dihydrogen phosphate [58 FR 31241, June 1, 1993] Sodium dihydrogen phosphate monohydrate Sodium phosphate, dibasic anhydrous rea- § 310.545 Drug products containing gent 1 certain active ingredients offered over-the-counter (OTC) for certain (3) Antidiarrheal drug products—(i) Ap- uses. proved as of May 7, 1991. (a) A number of active ingredients Aluminum hydroxide have been present in OTC drug prod- Atropine sulfate ucts for various uses, as described Calcium carbonate below. However, based on evidence cur- Carboxymethylcellulose sodium rently available, there are inadequate Glycine Homatropine methylbromide data to establish general recognition of Hyoscyamine sulfate the safety and effectiveness of these in- Lactobacillus acidophilus gredients for the specified uses: Lactobacillus bulgaricus (1) Topical acne drug products. Opium, powdered Opium tincture Alcloxa Paregoric Alkyl isoquinolinium bromide Phenyl salicylate Aluminum chlorohydrex Scopolamine hydrobromide Aluminum hydroxide Zinc phenolsulfonate Benzocaine Benzoic acid Boric acid 1 These ingredients are nonmonograph ex- Calcium polysulfide cept when used to prepare acidulated phos- Calcium thiosulfate phate fluoride treatment rinses identified in Camphor § 355.10(a)(3) of this chapter.

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(ii) Approved as of April 19, 2004; April Cedar leaf oil (topical) 18, 2005, for products with annual sales Creosote, beechwood (topical) less than $25,000. Ephedrine (oral) Ephedrine hydrochloride (oral) Attapulgite, activated Ephedrine sulfate (oral) Bismuth subnitrate Racephedrine hydrochloride (oral/topical) Calcium hydroxide Calcium polycarbophil (C) Approved as of April 11, 2007; Oc- Charcoal (activated) tober 11, 2007, for products with annual Pectin sales less than $25,000. Any ingre- Polycarbophil dient(s) labeled with claims or direc- Potassium carbonate tions for use for sinusitis or for relief Rhubarb fluidextract of nasal congestion associated with si- (4) Antiperspirant drug products—(i) nusitis. Ingredients—Approved as of May 7, 1991. (iii) Expectorant drug products. Alum, potassium Ammonium chloride Aluminum bromohydrate Antimony potassium tartrate Aluminum chloride (alcoholic solutions) Beechwood creosote Aluminum chloride (aqueous solution) (aer- Benzoin preparations (compound tincture of osol only) benzoin, tincture of benzoin) Aluminum sulfate Camphor Aluminum sulfate, buffered (aerosol only) Chloroform Sodium aluminum chlorohydroxy lactate Eucalyptol/eucalyptus oil (ii) Approved as of December 9, 2004; Horehound June 9, 2005, for products with annual Iodides (calcium iodide anyhydrous, hydroid- sales less than $25,000. ic acid syrup, iodized lime, potassium iodide) Aluminum sulfate buffered with sodium alu- Ipecac minum lactate Ipecac fluidextract Ipecac syrup (5) [Reserved] Menthol/peppermint oil (6) Cold, cough, allergy, bronchodilator, Pine tar preparations (extract white pine and antiasthmatic drug products—(i) compound, pine tar, syrup of pine tar, com- Antihistamine drug products—(A) Ingre- pound white pine syrup, white pine) dients. Potassium guaiacolsulfonate Sodium citrate Methapyrilene hydrochloride Squill preparations (squill, squill extract) Methapyrilene fumarate Terpin hydrate preparations (terpin hydrate, Thenyldiamine hydrochloride terpin hydrate elixir) (B) Ingredients. Tolu preparations (tolu, tolu balsam, tolu balsam tincture) Phenyltoloxamine dihydrogen citrate Turpentine oil (spirits of turpentine) Methapyrilene hydrochloride Methapyrilene fumarate (iv) Bronchodilator drug products—(A) Thenyldiamine hydrochloride Approved as of October 2, 1987. (ii) Nasal decongestant drug products— Aminophylline (A) Approved as of May 7, 1991. Belladonna alkaloids Euphorbia pilulifera Allyl isothiocyanate Metaproterenol sulfate Camphor (lozenge) Methoxyphenamine hydrochloride Creosote, beechwood (oral) Pseudoephedrine hydrochloride Eucalyptol (lozenge) Pseudoephedrine sulfate Eucalyptol (mouthwash) Theophylline, anhydrous Eucalyptus oil (lozenge) Theophylline calcium salicylate Eucalyptus oil (mouthwash) Menthol (mouthwash) Theophylline sodium glycinate Peppermint oil (mouthwash) (B) Approved as of January 29, 1996. Thenyldiamine hydrochloride Any combination drug product con- Thymol Thymol (lozenge) taining theophylline (e.g., theophylline Thymol (mouthwash) and ephedrine, or theophylline and Turpentine oil ephedrine and phenobarbital). (C) Approved as of June 19, 1996. Any (B) Approved as of August 23, 1995. ingredient(s) in a pressurized metered- Bornyl acetate (topical) dose inhaler container.

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(D) Approved as of October 29, 2001. Alcohol Any oral bronchodilator active ingre- Aluminum hydroxide dient (e.g., ephedrine, ephedrine hydro- Amylase Anise seed chloride, ephedrine sulfate, Aromatic powder racephedrine hydrochloride, or any Asafetida other ephedrine salt) in combination Aspergillus oryza enzymes (except lactase with any analgesic(s) or analgesic-anti- enzyme derived from Aspergillus oryzae) pyretic(s), anticholinergic, antihis- Bacillus acidophilus tamine, oral antitussive, or stimulant Bean active ingredient. Belladonna alkaloids (7) Dandruff/seborrheic dermatitis/psori- Belladonna leaves, powdered extract Betaine hydrochloride asis drug products. Bismuth subcarbonate Alkyl isoquinolinium bromide Bismuth subgallate Allantoin Black radish powder Benzalkonium chloride Blessed thistle (cnicus benedictus) Benzethonium chloride Buckthorn Boric acid Calcium gluconate Calcium undecylenate Capsicum Captan Capsicum, fluid extract of Chloroxylenol Carbon Colloidal oatmeal Cascara sagrada extract Cresol, saponated Catechu, tincture Ethohexadiol Catnip Eucalyptol Chamomile flowers Juniper tar Charcoal, wood Lauryl isoquinolinium bromide Chloroform Menthol Cinnamon oil Mercury oleate Cinnamon tincture Methylbenzethonium chloride Citrus pectin Methyl salicylate Diastase Phenol Diastase malt Phenolate sodium Dog grass Pine tar Elecampane Povidone-iodine Ether Resorcinol Fennel acid Sodium borate Galega Sodium salicylate Ginger Thymol Glycine Undecylenic acid Hydrastis canadensis (golden seal) Hectorite (8) Digestive aid drug products—(i) Ap- Horsetail proved as of May 7, 1991. Huckleberry Hydrastis fluid extract Bismuth sodium tartrate Hydrochloric acid Calcium carbonate Iodine Cellulase Iron ox bile Dehydrocholic acid Johnswort Dihydroxyaluminum sodium carbonate Juniper Duodenal substance Kaolin, colloidal Garlic, dehydrated Knotgrass Glutamic acid hydrochloride Lactic acid Hemicellulase Lactose Homatropine methylbromide Lavender compound, tincture of Magnesium hydroxide Linden Magnesium trisilicate Lipase Ox bile extract Lysine hydrochloride Pancreatin Mannitol Pancrelipase Mycozyme Papain Peppermint oil Myrrh, fluid extract of Pepsin Nettle Sodium bicarbonate Nickel-pectin Sodium citrate Nux vomica extract Sorbitol Orthophosphoric acid Papaya, natural (ii) Approved as of November 10, 1993. Pectin

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Peppermint Methapyrilene hydrochloride Peppermint spirit Methyl nicotinate Phenacetin Methyl salicylate Potassium bicarbonate Pectin Potassium carbonate Salicylamide Protease Strong ammonia solution Prolase Tannic acid Rhubarb fluid extract Thymol Senna Tripelennamine hydrochloride Sodium chloride Trolamine salicylate Sodium salicylate Turpentine oil Stem bromelain Zinc sulfate Strawberry Strychnine (vi) Insect bite and sting drug products. Tannic acid Alcohol Trillium Alcohol, ethoxylated alkyl Woodruff Benzalkonium chloride (iii) Charcoal, activated Calamine (9) [Reserved] Ergot fluidextract (10) External analgesic drug products— Ferric chloride Panthenol (i) Analgesic and anesthetic drug prod- Peppermint oil ucts. Pyrilamine maleate Aspirin Sodium borate Chloral hydrate Trolamine salicylate Chlorobutanol Turpentine oil Cyclomethycaine sulfate Zinc oxide Eugenol Zirconium oxide Hexylresorcinol (vii) Poison ivy, poison oak, and poison Methapyrilene hydrochloride Salicylamide sumac drug products. Thymol Alcohol (ii) Counterirritant drug products. Aspirin Benzethonium chloride Chloral hydrate Benzocaine (0.5 to 1.25 percent) Eucalyptus oil Bithionol Calamine (iii) Male genital desensitizer drug Cetalkonium chloride products. Chloral hydrate Benzyl alcohol Chlorobutanol Camphorated metacresol Chlorpheniramine maleate Ephedrine hydrochloride Creosote, beechwood Cyclomethycaine sulfate (iv) Diaper rash drug products. Any in- Dexpanthenol gredient(s) labeled with claims or di- Diperodon hydrochloride rections for use in the treatment and/ Eucalyptus oil or prevention of diaper rash. Eugenol (v) Fever blister and cold sore treatment Glycerin Glycol salicylate drug products. Hectorite Allyl isothiocyanate Hexylresorcinol Aspirin Hydrogen peroxide Bismuth sodium tartrate Impatiens biflora tincture Camphor (exceeding 3 percent) Iron oxide Capsaicin Isopropyl alcohol Capsicum Lanolin Capsicum oleoresin Lead acetate Chloral hydrate Merbromin Chlorobutanol Mercuric chloride Cyclomethycaine sulfate Methapyrilene hydrochloride Eucalyptus oil Panthenol Eugenol Parethoxycaine hydrochloride Glycol salicylate Phenyltoloxamine dihydrogen citrate Hexylresorcinol Povidone-vinylacetate copolymers Histamine dihydrochloride Pyrilamine maleate Menthol (exceeding 1 percent) Salicylamide

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Salicylic acid (C) Stimulant laxatives—Approved as of Simethicone November 5, 2002. Sulfur Tannic acid Aloe ingredients (aloe, aloe extract, aloe Thymol flower extract) Trolamine salicylate Cascara sagrada ingredients (casanthranol, Turpentine oil cascara fluidextract aromatic, cascara Zirconium oxide sagrada bark, cascara sagrada extract, cascara sagrada fluidextract). Zyloxin (11) [Reserved] (13) [Reserved] (14) Oral health care drug products (12) Laxative drug products—(i)(A) (nonantimicrobial). Bulk laxatives. Antipyrine Agar Camphor Carrageenan (degraded) Cresol Carrageenan (native) Dibucaine Guar gun Dibucaine hydrochloride (i)(B) Bulk laxatives—Approved as of Eucalyptol Lidocaine March 29, 2007. Lidocaine hydrochloride Granular dosage forms containing psyllium Methly salicylate (hemicellulose), psyllium hydrophilic Myrrh tincture mucilloid, psyllium seed, psyllium seed Pyrilamine maleate (blond), psyllium seed husks, plantago Sorbitol husks, or plantago seed including, but not Sugars limited to, any granules that are: Tetracaine (1) Swallowed dry prior to drinking liquid, Tetracaine hydrochloride (2) Dispersed, suspended, or partially dis- Thymol solved in liquid prior to swallowing, (15) Topical otic drug products—(i) For (3) Chewed, partially chewed, or unchewed, the prevention of swimmer’s ear and for and then washed down (or swallowed) with the drying of water-clogged ears, ap- liquid, or (4) Sprinkled over food. proved as of May 7, 1991. (ii) Saline laxative. Acetic acid (ii) For the prevention of swimmer’s ear, Tartaric acid approved as of August 15, 1995. (iii) Stool softener. Glycerin and anhydrous glycerin Poloxamer 188 Isopropyl alcohol (iv)(A) Stimulant laxatives—Approved (16) Poison treatment drug products. as of May 7, 1991. Ipecac fluidextract Aloin Ipecac tincture Bile salts/acids Zinc sulfate Calcium pantothenate (17) Skin bleaching drug products. Calomel Colocynth Mercury, ammoniated Elaterin resin (18) Skin protectant drug products— Frangula (i)(A) Ingredients—Approved as of May 7, Gamboge Ipomea 1991. Jalap Allantoin (wound healing claims only) Ox bile Sulfur Podophyllum resin Tannic acid Prune concentrate dehydrate Zinc acetate (wound healing claims only) Prune powder Rhubarb, Chinese (B) Ingredients—Approved as of June 4, Sodium Oleate 2004; June 6, 2005, for products with annual sales less than $25,000. (iv)(B) Stimulant laxatives—Approved as of January 29, 1999. Beeswax Bismuth subnitrate Danthron Boric acid Phenolphthalein Cetyl alcohol

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Glyceryl stearate (iv) Fever blister and cold sore treat- Isopropyl palmitate ment drug products. Live yeast cell derivative Shark liver oil Bismuth subnitrate Stearyl alcohol Boric acid Pyridoxine hydrochloride (ii) Astringent drug products. Sulfur Acetone Tannic acid Alcohol Topical starch Alum, ammonium Trolamine Alum, potassium Zinc sulfate Aluminum chlorhydroxy complex (v) Insect bite and sting drug products— Aromatics (A) Ingredients—Approved as of November Benzalkonium chloride Benzethonium chloride 10, 1993. Benzocaine Alcohol Benzoic acid Alcohol, ethoxylated alkyl Boric acid Ammonia solution, strong Calcium acetate (except calcium acetate Ammonium hydroxide monohydrate when combined with alu- Benzalkonium chloride minum sulfate tetradecahydrate to provide Camphor an aluminum acetate solution as described Ergot fluid extract in § 347.20(b) of this chapter) Ferric chloride Camphor gum Menthol Clove oil Peppermint oil Colloidal oatmeal Phenol Cresol Pyrilamine maleate Cupric sulfate Sodium borate Eucalyptus oil Trolamine Eugenol Turpentine oil Ferric subsulfate (Monsel’s Solution) Zirconium oxide Honey Isopropyl alcohol (B) Ingredients—Approved as of June 4, Menthol 2004; June 6, 2005, for products with an- Methyl salicylate nual sales less than $25,000. Oxyquinoline sulfate P-t-butyl-m-cresol Beeswax Peppermint oil Bismuth subnitrate Phenol Boric acid Polyoxeythylene laurate Cetyl alcohol Potassium ferrocyanide Glyceryl stearate Sage oil Isopropyl palmitate Silver nitrate Live yeast cell derivative Sodium borate Shark liver oil Sodium diacetate Stearyl alcohol Talc (vi) Poison ivy, poison oak, and poison Tannic acid glycerite sumac drug products—(A) Ingredients— Thymol Topical starch Approved as of November 10, 1993. Zinc chloride Alcohol Zinc oxide Anion and cation exchange resins buffered Zinc phenolsulfonate Benzethonium chloride Zinc stearate Benzocaine Zinc sulfate Benzyl alcohol (iii) Diaper rash drug products. Bismuth subnitrate Bithionol Aluminum hydroxide Boric acid Cocoa butter Camphor Cysteine hydrochloride Cetalkonium chloride Glycerin Chloral hydrate Protein hydrolysate Chlorpheniramine maleate Racemethionine Creosote Sulfur Diperodon hydrochloride Tannic acid Diphenhydramine hydrochloride Zinc acetate Eucalyptus oil Zinc carbonate Ferric chloride

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Glycerin Copper Hectorite Copper gluconate Hydrogen peroxide Corn oil Impatiens biflora tincture Corn syrup Iron oxide Corn silk, potassium extract Isopropyl alcohol Cupric sulfate Lanolin Cyanocobalamin (vitamin B12) Lead acetate Cystine Lidocaine Dextrose Menthol Docusate sodium Merbromin Ergocalciferol Mercuric chloride Ferric ammonium citrate Panthenol Ferric pyrophosphate Parethoxycaine hydrochloride Ferrous fumarate Phenol Ferrous gluconate Phenyltoloxamine dihydrogen citrate Ferrous sulfate (iron) Povidone-vinylacetate copolymers Flax seed Salicylic acid Folic acid Simethicone Fructose Tannic acid Guar gum Topical starch Histidine Trolamine Hydrastis canadensis Turpentine oil Inositol Zirconium oxide Iodine Zyloxin Isoleucine Juniper, potassium extract (B) Ingredients—Approved as of June 4, Karaya gum 2004; June 6, 2005, for products with an- Kelp nual sales less than $25,000. Lactose Lecithin Beeswax Leucine Bismuth subnitrate Liver concentrate Boric acid Lysine Cetyl alcohol Lysine hydrochloride Glyceryl stearate Magnesium Isopropyl palmitate Magnesium oxide Live yeast cell derivative Malt Shark liver oil Maltodextrin Stearyl alcohol Manganese citrate (19) [Reserved] Mannitol (20) Weight control drug products. Methionine Methylcellulose Alcohol Mono- and di-glycerides Alfalfa Niacinamide Alginic acid Organic vegetables Anise oil Pancreatin Arginine Pantothenic acid Ascorbic acid Papain Bearberry Papaya enzymes Biotin Pepsin Bone marrow, red Phenacetin Buchu Phenylalanine Buchu, potassium extract Phosphorus Caffeine Phytolacca Caffeine citrate Pineapple enzymes Calcium Plantago seed Calcium carbonate Potassium citrate Calcium caseinate Pyridoxine hydrochloride (vitamin B6) Calcium lactate Riboflavin Calcium pantothenate Rice polishings Carboxymethylcellulose sodium Saccharin Carrageenan Sea minerals Cholecalcierol Sesame seed Choline Sodium Chondrus Sodium bicarbonate Citric acid Sodium caseinate Cnicus benedictus Sodium chloride (salt)

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Soybean protein Dichlorophen Soy meal Menthol Sucrose Methylparaben Thiamine hydrochloride (vitamin B1) Oxyquinoline Thiamine mononitrate (vitamin B1 mono- Oxyquinoline sulfate nitrate) Phenol Threonine Phenolate sodium Tricalcium phosphate Phenyl salicylate Tryptophan Propionic acid Tyrosine Propylparaben Uva ursi, potassium extract Resorcinol Valine Salicylic acid Vegetable Sodium borate Vitamin A Sodium caprylate Vitamin A acetate Sodium propionate Vitamin A palmitate Sulfur Vitamin E Tannic acid Wheat germ Thymol Xanthan gum Tolindate Yeast Triacetin Zinc caprylate (21) Ophthalmic drug products. (i) Oph- Zinc propionate thalmic anesthetic drug products. (iii) Any ingredient(s) labeled with Antipyrine claims or directions for use on the Piperocaine hydrochloride scalp or on the nails. (ii) Ophthalmic anti-infective drug (iv) Ingredients. products. Camphorated metacresol Boric acid Chloroxylenol Mild silver protein m-cresol Yellow mercuric oxide Nystatin (iii) Ophthalmic astringent drug prod- (23) Internal analgesic drug products— ucts. (i) Approved as of November 10, 1993. Infusion of rose petals Aminobenzoic acid Antipyrine (iv) Ophthalmic demulcent drug prod- Aspirin, aluminum ucts. Calcium salicylate Codeine Polyethylene glycol 6000 Codeine phosphate (v) Ophthalmic vasoconstrictor drug Codeine sulfate products. Iodoantipyrine Lysine aspirin Phenylephrine hydrochloride (less than 0.08 Methapyrilene fumarate percent) Phenacetin (22) Topical antifungal drug products. Pheniramine maleate Pyrilamine maleate (i) Diaper rash drug products. Any ingre- Quinine dient(s) labeled with claims or direc- Salsalate tions for use in the treatment and/or Sodium aminobenzoate prevention of diaper rash. (ii) Approved as of February 22, 1999. (ii) Ingredients. Any atropine ingredient Alcloxa Any ephedrine ingredient Alum, potassium Aluminum sulfate (24) Orally administered menstrual drug Amyltricresols, secondary products—(i) Approved as of November 10, Basic fuchsin 1993. Benzethonium chloride Benzoic acid Alcohol Benzoxiquine Alfalfa leaves Boric acid Aloes Camphor Asclepias tuberosa Candicidin Asparagus Chlorothymol Barosma Coal tar Bearberry (extract of uva ursi)

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Bearberry fluidextract (extract of bearberry) Benzyl alcohol Blessed thistle (cnicus benedictus) Benzyl benzoate Buchu powdered extract (extract of buchu) Chlorophenothane (dichlorodiphenyl tri- Calcium lactate chloroethane) Calcium pantothenate Coconut oil soap, aqueous Capsicum oleoresin Copper oleate Cascara fluidextract, aromatic (extract of Docusate sodium cascara) Formic acid Chlorprophenpyridamine maleate Isobornyl thiocyanoacetate Cimicifuga racemosa Picrotoxin Codeine Propylene glycol Collinsonia (extract stone root) Sabadilla alkaloids Corn silk Sulfur, sublimed Couch grass Thiocyanoacetate Dog grass extract Ethyl nitrite (ii) Approved as of June 14, 1994. The Ferric chloride combination of pyrethrum extract (for- Ferrous sulfate merly named pyrethrins) and piperonyl Gentiana lutea (gentian) butoxide in an aerosol dosage formula- Glycyrrhiza (licorice) tion. Homatropine methylbromide (26) Anorectal drug products—(i) Anti- Hydrangea, powdered extract (extract of hy- cholinergic drug products. drangea) Hydrastis canadensis (golden seal) Atropine Hyoscyamine sulfate Belladonna extract Juniper oil (oil of juniper) Magnesium sulfate (ii) Antiseptic drug products. Methapyrilene hydrochloride Boric acid Methenamine Boroglycerin Methylene blue Hydrastis Natural estrogenic hormone Phenol Niacinamide Resorcinol Nutmeg oil (oil of nutmeg) Sodium salicylic acid phenolate Oil of erigeron Parsley (iii) Astringent drug products. Peppermint spirit Tannic acid Pepsin, essence Phenacetin (iv) Counterirritant drug products. Phenindamine tartrate Phenyl salicylate Camphor (greater than 3 to 11 percent) Piscidia erythrina Hydrastis Pipsissewa Menthol (1.25 to 16 percent) Potassium acetate Turpentine oil (rectified) (6 to 50 percent) Potassium nitrate (v) Keratolytic drug products. Riboflavin Saw palmetto Precipitated sulfur Senecio aureus Sublimed sulfur Sodium benzoate (vi) Local anesthetic drug products. Sodium nitrate Sucrose Diperodon Sulferated oils of turpentine Phenacaine hydrochloride Taraxacum officinale Theobromine sodium salicylate (vii) Other drug products. Theophylline Collinsonia extract Thiamine hydrochloride Escherichia coli vaccines Triticum Lappa extract Turpentine, venice (venice turpertine) Leptandra extract Urea Live yeast cell derivative (ii) Approved as of February 22, 1999. Mullein Any atropine ingredient (viii) Protectant drug products. Any ephedrine ingredient Bismuth oxide (25) Pediculicide drug products—(i) Ap- Bismuth subcarbonate proved as of November 10, 1993. Bismuth subgallate Bismuth subnitrate Benzocaine Lanolin alcohols

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(ix) Vasoconstrictor drug products. Tribromsalan Triclocarban Epinephrine undecylenate Triclosan (x) Wound healinq drug products. Triple Dye Undecoylium chloride iodine complex Cholecalciferol Cod liver oil (iv) Consumer antiseptic body wash Live yeast cell derivative drug products. Approved as of Sep- Peruvian balsam tember 6, 2017. Shark liver oil Cloflucarban Vitamin A Fluorosalan (xi) Combination drug products. Any Hexachlorophene combination drug product containing Hexylresorcinol hydrocortisone and pramoxine hydro- Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) chloride. Iodine tincture (27) Topical antimicrobial drug prod- Methylbenzethonium chloride ucts—(i) First aid antiseptic drug prod- Nonylphenoxypoly (ethyleneoxy) ucts. ethanoliodine Phenol (greater than 1.5 percent) Ammoniated mercury Phenol (less than 1.5 percent) Calomel (mercurous chloride) Poloxamer iodine complex Merbromin (mercurochrome) Povidone-iodine (5 to 10 percent) Mercufenol chloride (ortho- Secondary amyltricresols chloromercuriphenol, ortho- Sodium oxychlorosene hydroxyphenylmercuric chloride) Tribromsalan Mercuric chloride (bichloride of mercury, Triclocarban mercury chloride) Triclosan Mercuric oxide, yellow Triple Dye Mercuric salicylate Undecoylium chloride iodine complex Mercuric sulfide, red Mercury (v) [Reserved] Mercury oleate (vi) Health care personnel hand wash Mercury sulfide drug products. Approved as of December Nitromersol 20, 2018. Para-chloromercuriphenol Phenylmercuric nitrate Cloflucarban Thimerosal Fluorosalan Vitromersol Hexachlorophene Zyloxin Hexylresorcinol Iodine complex (ammonium ether sulfate (ii) Diaper rash drug products. and polyoxyethylene sorbitan monolaurate) Para-chloromercuriphenol Iodine complex (phosphate ester of Any other ingredient containing mercury alkylaryloxy polyethylene glycol) (iii) Consumer antiseptic hand wash Methylbenzethonium chloride drug products. Approved as of Sep- Nonylphenoxypoly (ethyleneoxy) tember 6, 2017. ethanoliodine Phenol Cloflucarban Poloxamer-iodine complex Fluorosalan Secondary amyltricresols Hexachlorophene Sodium oxychlorosene Hexylresorcinol Tribromsalan Iodine complex (ammonium ether sulfate Triclocarban and polyoxyethylene sorbitan Triclosan monolaurate) Undecoylium chloride iodine complex Iodine complex (phosphate ester of (vii) [Reserved] alkylaryloxy polyethylene glycol) (viii) Surgical hand scrub drug prod- Methylbenzethonium chloride ucts. Approved as of December 20, 2018. Nonylphenoxypoly (ethyleneoxy) ethanoliodine Cloflucarban Phenol (greater than 1.5 percent) Fluorosalan Phenol (less than 1.5 percent) Hexachlorophene Poloxamer iodine complex Hexylresorcinol Povidone-iodine (5 to 10 percent) Iodine complex (ammonium ether sulfate Secondary amyltricresols and polyoxyethylene sorbitan Sodium oxychlorosene monolaurate)

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Iodine complex (phosphate ester of (ii) Any ingredients labeled with any alkylaryloxy polyethylene glycol) of the following or similar claims. In- Methylbenzethonium chloride stant protection or protection imme- Nonylphenoxypoly (ethyleneoxy) diately upon application. ethanoliodine Phenol Claims for ‘‘all-day’’ protection or Poloxamer-iodine complex extended wear claims citing a specific Secondary amyltricresols number of hours of protection that is Sodium oxychlorosene inconsistent with the directions for ap- Tribromsalan plication in 21 CFR 201.327. Triclocarban Triclosan (30) [Reserved] Undecoylium chloride iodine complex (b) Any OTC drug product that is labeled, represented, or promoted for the (ix) [Reserved] uses specified and containing any ac- (x) Patient antiseptic skin preparation tive ingredient(s) as specified in para- drug products. Approved as of December graph (a) of this section is regarded as 20, 2018. a new drug within the meaning of sec- Cloflucarban tion 210(p) of the Federal Food, Drug, Fluorosalan and Cosmetic Act (the Act), for which Hexachlorophene an approved new drug application Hexylresorcinol under section 505 of the Act and part Iodine complex (phosphate ester of 314 of this chapter is required for mar- alkylaryloxy polyethylene glycol) Iodine tincture (USP) keting. In the absence of an approved Iodine topical solution (USP) new drug application, such product is Mercufenol chloride also misbranded under section 502 of Methylbenzethonium chloride the Act. Nonylphenoxypoly (ethyleneoxy) (c) Clinical investigations designed ethanoliodine to obtain evidence that any drug prod- Phenol uct labeled, represented, or promoted Poloxamer-iodine complex for the OTC uses and containing any Secondary amyltricresols active ingredient(s) as specified in Sodium oxychlorosene Tribromsalan paragraph (a) of this section is safe and Triclocarban effective for the purpose intended must Triclosan comply with the requirements and pro- Triple dye cedures governing the use of investiga- Undecoylium chloride iodine complex tional new drugs set forth in part 312 of Combination of calomel, oxyquinoline ben- this chapter. zoate, triethanolamine, and phenol deriva- (d) Any OTC drug product that is not tive in compliance with this section is sub- Combination of mercufenol chloride and secondary amyltricresols in 50 percent alcohol ject to regulatory action if initially in- (28) Vaginal contraceptive drug prod- troduced or initially delivered for in- ucts—(i) Approved as of October 22, 1998. troduction into interstate commerce after the dates specified in paragraphs Dodecaethylene glycol monolaurate (poly- (d)(1) through (d)(42) of this section. ethylene glycol 600 monolaurate) (1) May 7, 1991, for products subject Laureth 10S to paragraphs (a)(1) through (a)(2)(i), Methoxypolyoxyethyleneglycol 550 laurate (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), Phenylmercuric acetate Phenylmercuric nitrate (a)(6)(ii)(A), (a)(7) (except as covered by Any other ingredient containing mercury paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (ii) Approved as of November 5, 2002. (a)(12)(i)(A), (a)(12)(ii) through Octoxynol 9 (a)(12)(iv)(A), (a)(14) through (a)(15)(i), (29) Sunscreen drug products. (i) Ingre- (a)(16) through (a)(18)(i)(A), (a)(18)(ii) dients. (except as covered by paragraph (d)(22) of this section), (a)(18)(iii), (a)(18)(iv), Diethanolamine methoxycinnamate (a)(18)(v)(A), and (a)(18)(vi)(A) of this Digalloyl trioleate Ethyl 4-[bis(hydroxypropyl)] aminobenzoate section. Glyceryl aminobenzoate (2) February 10, 1992, for products Lawsone with dihydroxyacetone subject to paragraph (a)(20) of this sec- Red petrolatum tion.

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(3) December 4, 1992, for products sub- (15) September 23, 1994, for products ject to paragraph (a)(7) of this section subject to paragraph (a)(22)(iv) of this that contain menthol as an anti- section. pruritic in combination with the anti- (16) June 14, 1994, for products subject dandruff ingredient coal tar identified to paragraph (a)(25)(ii) of this section. in § 358.710(a)(1) of this chapter. This (17) April 19, 2004, for products sub- section does not apply to products al- ject to paragraph (a)(3)(ii) of this sec- lowed by § 358.720(b) of this chapter tion. April 18, 2005, for products with after April 5, 2007. annual sales less than $25,000. (4) February 28, 1990, for products (18) August 15, 1995, for products sub- subject to paragraph (a)(6)(iii) of this ject to paragraph (a)(15)(ii) of this sec- section, except those that contain ipe- tion. cac. (19) October 2, 1987, for products subject to paragraph (a)(6)(iv)(A) of this (5) September 14, 1993, for products section. subject to paragraph (a)(6)(iii) of this (20) January 29, 1996, for products section that contain ipecac. subject to paragraph (a)(6)(iv)(B) of (6) December 9, 1993, for products sub- this section. ject to paragraph (a)(6)(i)(B) of this (21) April 21, 1994, for products sub- section. ject to paragraph (a)(8)(iii) of this sec- (7) March 6, 1989, for products subject tion. to paragraph (a)(21) of this section, ex- (22) April 21, 1993, for products sub- cept those that contain ophthalmic ject to paragraph (a)(18)(ii) of this sec- anti-infective ingredients listed in tion that contain ferric subsulfate. paragraph (a)(21)(ii). (23) August 23, 1995, for products sub- (8) June 18, 1993, for products subject ject to paragraph (a)(6)(ii)(B) of this to paragraph (a)(21) of this section that section. contain ophthalmic anti-infective in- (24) October 7, 1996, for products sub- gredients. ject to paragraph (a)(2)(ii) of this sec- (9) June 18, 1993, for products subject tion. to paragraph (a)(10)(iv) of this section. (25) June 19, 1996, for products subject (10) June 18, 1993, for products subject to paragraph (a)(6)(iv)(C) of this sec- to paragraph (a)(22)(i) of this section. tion. (11) November 10, 1993, for products (26) February 22, 1999, for products subject to paragraphs (a)(8)(ii), subject to paragraphs (a)(23)(ii) and (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (a)(24)(ii) of this section. (except products that contain ferric (27) [Reserved] subsulfate as covered by paragraph (28) October 22, 1998, for products sub- (d)(22) of this section and except prod- ject to paragraphs (a)(27) and (a)(28)(i) ucts that contain calcium acetate of this section. monohydrate as covered by paragraph (29) January 29, 1999, for products subject to paragraph (a)(12)(iv)(B) of (d)(39) of this section) through this section. (a)(18)(v)(A), (a)(18)(vi)(A), (a)(22)(ii), (30) November 5, 2002, for products (a)(23)(i), (a)(24)(i), and (a)(25) of this subject to paragraph (a)(12)(iv)(C) of section. this section. (12) March 2, 1994, for products sub- (31) December 31, 2002, for products ject to paragraph (a)(22)(iii) of this sec- subject to paragraph (a)(29)(i) of this tion. section. (13) August 5, 1991, for products sub- (32) June 4, 2004, for products subject ject to paragraph (a)(26) of this section, to paragraphs (a)(18)(i)(B), (a)(18)(v)(B), except for those that contain live yeast and (a)(18)(vi)(B) of this section. June cell derivative and a combination of 6, 2005, for products with annual sales hydrocortisone and pramoxine hydro- less than $25,000. chloride. (33) October 29, 2001, for products sub- (14) September 2, 1994, for products ject to paragraph (a)(6)(iv)(D) of this subject to paragraph (a)(26)(vii) and section. (a)(26)(x) of this section that contain (34) December 9, 2004, for products live yeast cell derivative. subject to paragraph (a)(4)(ii) of this

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section. June 9, 2005, for products with used to treat or prevent this condition, annual sales less than $25,000. quinine sulfate has caused adverse (35) [Reserved] events such as transient visual and au- (36) November 5, 2002, for products ditory disturbances, dizziness, fever, subject to paragraph (a)(28)(ii) of this nausea, vomiting, and diarrhea. Qui- section. nine sulfate may cause unpredictable (37) September 25, 2003, for products serious and life-threatening hyper- subject to paragraph (a)(26)(xi) of this sensitivity reactions requiring medical section. intervention and hospitalization; fa- (38) October 1, 2007, for products sub- talities have been reported. The risk ject to paragraph (a)(12)(i)(B) of this section. associated with use of quinine sulfate, (39) September 6, 2010, for products in the absence of evidence of its effec- subject to paragraph (a)(18)(ii) of this tiveness, outweighs any potential ben- section that contain calcium acetate efit in treating and/or preventing this monohydrate, except as provided in benign, self-limiting condition. Based § 347.20(b) of this chapter. upon the adverse benefit-to-risk ratio, (40) December 17, 2012, for products any drug product containing quinine or subject to paragraph (a)(29)(ii) of this quinine sulfate cannot be considered section. December 17, 2013, for products generally recognized as safe for the with annual sales less than $25,000. treatment and/or prevention of noc- (41) September 6, 2017, for products turnal leg muscle cramps. subject to paragraph (a)(27)(iii) or (iv) (b) Any OTC drug product that is la- of this section. beled, represented, or promoted for the (42) December 20, 2018, for products treatment and/or prevention of noc- subject to paragraphs (a)(27)(vi) turnal leg muscle cramps is regarded as through (x) of this section. a new drug within the meaning of sec- [55 FR 46919, Nov. 7, 1990] tion 201(p) of the Federal Food, Drug, EDITORIAL NOTE: For FEDERAL REGISTER ci- and Cosmetic Act (the act), for which tations affecting § 310.545, see the List of CFR an approved application or abbreviated Sections Affected, which appears in the application under section 505 of the act Finding Aids section of the printed volume and part 314 of this chapter is required and at www.govinfo.gov. for marketing. In the absence of an ap- EFFECTIVE DATE NOTE: At 61 FR 9571, Mar. proved new drug application or abbre- 8, 1996, in § 310.545 in paragraph (a)(6)(ii)(B), viated new drug application, such prod- the entry for ‘‘l-desoxyephedrine (topical)’’ was stayed until further notice. uct is also misbranded under section 502 of the act. § 310.546 Drug products containing ac- (c) Clinical investigations designed tive ingredients offered over-the- to obtain evidence that any drug prod- counter (OTC) for the treatment uct labeled, represented, or promoted and/or prevention of nocturnal leg muscle cramps. for OTC use for the treatment and/or prevention of nocturnal leg muscle (a) Quinine sulfate alone or in com- cramps is safe and effective for the pur- bination with vitamin E has been pose intended must comply with the re- present in over-the-counter (OTC) drug quirements and procedures governing products for the treatment and/or prevention of nocturnal leg muscle the use of investigational new drugs cramps, i.e., a condition of localized set forth in part 312 of this chapter. pain in the lower extremities usually (d) After February 22, 1995, any such occurring in middle life and beyond OTC drug product initially introduced with no regular pattern concerning or initially delivered for introduction time or severity. There is a lack of ade- into interstate commerce that is not in quate data to establish general rec- compliance with this section is subject ognition of the safety and effectiveness to regulatory action. of quinine sulfate, vitamin E, or any other ingredients for OTC use in the [59 FR 43252, Aug. 22, 1994] treatment and/or prevention of nocturnal leg muscle cramps. In the doses

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§ 310.547 Drug products containing § 310.548 Drug products containing quinine offered over-the-counter colloidal silver ingredients or silver (OTC) for the treatment and/or pre- salts offered over-the-counter (OTC) vention of malaria. for the treatment and/or prevention of disease. (a) Quinine and quinine salts have been used OTC for the treatment and/or (a) Colloidal silver ingredients and silver salts have been marketed in prevention of malaria, a serious and over-the-counter (OTC) drug products potentially life-threatening disease. for the treatment and prevention of nu- Quinine is no longer the drug of choice merous disease conditions. There are for the treatment and/or prevention of serious and complicating aspects to most types of malaria. In addition, many of the diseases these silver ingre- there are serious and complicating as- dients purport to treat or prevent. Fur- pects of the disease itself and some po- ther, there is a lack of adequate data tentially serious and life-threatening to establish general recognition of the risks associated with the use of quinine safety and effectiveness of colloidal sil- at doses employed for the treatment of ver ingredients or silver salts for OTC malaria. There is a lack of adequate use in the treatment or prevention of data to establish general recognition of any disease. These ingredients and the safety of quinine drug products for salts include, but are not limited to, OTC use in the treatment and/or pre- silver proteins, mild silver protein, vention of malaria. Therefore, quinine strong silver protein, silver, silver ion, or quinine salts cannot be safely and silver chloride, silver cyanide, silver effectively used for the treatment and/ iodide, silver oxide, and silver phosphate. or prevention of malaria except under (b) Any OTC drug product containing the care and supervision of a doctor. colloidal silver ingredients or silver (b) Any OTC drug product containing salts that is labeled, represented, or quinine or quinine salts that is labeled, promoted for the treatment and/or pre- represented, or promoted for the treat- vention of any disease is regarded as a ment and/or prevention of malaria is new drug within the meaning of section regarded as a new drug within the 201(p) of the Federal Food, Drug, and meaning of section 201(p) of the act, for Cosmetic Act (the act) for which an ap- which an approved application or ab- proved application or abbreviated ap- breviated application under section 505 plication under section 505 of the act of the act and part 314 of this chapter and part 314 of this chapter is required is required for marketing. In the ab- for marketing. In the absence of an ap- sence of an approved new drug applica- proved new drug application or abbre- tion or abbreviated new drug applica- viated new drug application, such prod- tion, such product is also misbranded uct is also misbranded under section under section 502 of the act. 502 of the act. (c) Clinical investigations designed (c) Clinical investigations designed to obtain evidence that any drug prod- to obtain evidence that any drug product labeled, represented, or promoted uct containing colloidal silver or silver for OTC use for the treatment and/or salts labeled, represented, or promoted prevention of malaria is safe and effec- for any OTC drug use is safe and effective for the purpose intended must tive for the purpose intended must comply with the requirements and pro- comply with the requirements and procedures governing the use of investiga- cedures governing the use of investigational new drugs as set forth in part 312 tional new drugs set forth in part 312 of of this chapter. this chapter. (d) After September 16, 1999, any such (d) After April 20, 1998, any such OTC OTC drug product containing colloidal drug product initially introduced or silver or silver salts initially intro- initially delivered for introduction into duced or initially delivered for intro- interstate commerce that is not in duction into interstate commerce that compliance with this section is subject is not in compliance with this section to regulatory action. is subject to regulatory action. [63 FR 13528, Mar. 20, 1998] [64 FR 44658, Aug. 17, 1999]

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