SUBCHAPTER D—DRUGS FOR HUMAN USE
PART 300—GENERAL priate National Academy of Sciences- National Research Council panel re- Subpart A—[Reserved] port, or if substantial evidence of effec- tiveness has not otherwise been pre- Subpart B—Combination Drugs sented for it, then formulation, label- ing, or dosage changes may be proposed Sec. 300.50 Fixed-combination prescription drugs and any resulting formulation may for humans. meet the appropriate criteria listed in paragraph (a) of this section. Subpart C—Substances Generally (c) A fixed-combination prescription Prohibited From Drugs drug for humans that has been deter- mined to be effective for labeled indica- 300.100 Chlorofluorocarbon propellants. tions by the Food and Drug Adminis- tration, based on evaluation of the Subpart A—[Reserved] NAS–NRC report on the combination, is considered to be in compliance with Subpart B—Combination Drugs the requirements of this section. [40 FR 13496, Mar. 27, 1975] AUTHORITY: Secs. 301, 501, 502, 505, 507, 512, 601, 701 of the Federal Food, Drug, and Cos- metic Act (21 U.S.C. 331, 351, 352, 355, 357, Subpart C—Substances Generally 360b, 361, 371). 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 humans is as follows: [43 FR 11317, Mar. 17, 1978] (a) Two or more drugs may be com- bined 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 or antibiotic monograph Subpart C—New Drugs Exempted From has not been recognized as effective by Prescription-Dispensing Requirements the Commissioner of Food and Drugs based on his evaluation of the appro- 310.200 Prescription-exemption procedure.
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310.201 Exemption for certain drugs limited 310.530 Topically applied hormone-contain- by new drug applications to prescription ing drug products for over-the-counter sale. (OTC) human use. 310.531 Drug products containing active in- Subpart D—Records and Reports gredients offered over-the-counter (OTC) for the treatment of boils. 310.303 Continuation of long-term studies, 310.532 Drug products containing active in- records, and reports on certain drugs for gredients offered over-the-counter (OTC) which new drug applications have been to relieve the symptoms of benign pros- approved. tatic hypertrophy. 310.305 Records and reports concerning ad- 310.533 Drug products containing active in- verse drug experiences on marketed pre- gredients offered over-the-counter (OTC) scription drugs for human use without for human use as an anticholinergic in approved new drug applications. cough-cold drug products. Subpart E—Requirements for Specific New 310.534 Drug products containing active in- gredients offered over-the-counter (OTC) Drugs or Devices for human use as oral wound healing 310.500 Digoxin products for oral use; condi- agents. tions for marketing. 310.536 Drug products containing active in- 310.501 Patient package inserts for oral con- gredients offered over-the-counter (OTC) traceptives. for use as a nailbiting or thumbsucking 310.502 Certain drugs accorded new drug sta- deterrent. tus through rulemaking procedures. 310.537 Drug products containing active in- 310.503 Requirements regarding certain ra- gredients offered over–the–counter (OTC) dioactive drugs. for oral administration for the treatment 310.504 Amphetamines (amphetamine, of fever blisters and cold sores. dextroamphetamine, and their salts and 310.538 Drug products containing active in- levamfetamine and its salts) for human gredients offered over-the-counter (OTC) use. for use for ingrown toenail relief. 310.506 Use of vinyl chloride as an ingredi- 310.540 Drug products containing active in- ent, including propellant, of aerosol drug gredients offered over-the-counter (OTC) products. for use as stomach acidifiers. 310.507 Aerosol drug products for human use 310.541 Over-the-counter (OTC) drug prod- containing 1,1,-1-trichloroethane. ucts containing active ingredients of- 310.508 Use of certain halogenated fered for use in the treatment of salicylanilides as an inactive ingredient hypophosphatemia. in drug products. 310.542 Over-the-counter (OTC) drug prod- 310.509 Parenteral drug products in plastic ucts containing active ingredients of- containers. fered for use in the treatment of 310.510 Use of aerosol drug products con- hyperphosphatemia. taining zirconium. 310.543 Drug products containing active in- 310.513 Chloroform, use as an ingredient (ac- gredients offered over-the-counter (OTC) tive or inactive) in drug products. for human use in exocrine pancreatic in- 310.515 Patient package inserts for sufficiency. estrogens. 310.544 Drug products containing active in- 310.516 Progestational drug products; label- gredients offered over-the-counter (OTC) ing directed to the patient. for use as a smoking deterrent. 310.517 Labeling for oral hypoglycemic 310.545 Drug products containing certain ac- drugs of the sulfonylurea class. tive ingredients offered over-the-counter 310.518 Drug products containing iron or (OTC) for certain uses. iron salts. 310.546 Drug products containing active in- 310.519 Drug products marketed as over-the- gredients offered over-the-counter (OTC) counter (OTC) daytime sedatives. for the treatment and/or prevention of 310.525 Sweet spirits of nitre drug products. nocturnal leg muscle cramps. 310.526 Camphorated oil drug products. 310.527 Drug products containing active in- AUTHORITY: Secs. 201, 301, 501, 502, 503, 505, gredients offered over-the-counter (OTC) 506, 507, 512–516, 520, 601(a), 701, 704, 705, 721 of for external use as hair growers or for the Federal Food, Drug, and Cosmetic Act hair loss prevention. (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 310.528 Drug products containing active in- 360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. gredients offered over-the-counter (OTC) 215, 301, 302(a), 351, 354–360F of the Public for use as an aphrodisiac. Health Service Act (42 U.S.C. 216, 241, 242(a), 310.529 Drug products containing active in- 262, 263b-263n). gredients offered over-the-counter (OTC) for oral use as insect repellents.
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Subpart A—General Provisions or other method or duration of admin- istration or application, or different § 310.3 Definitions and interpretations. condition, is not a new drug. As used in this part: (i) [Reserved] (a) The term act means the Federal (j) The term sponsor means the per- Food, Drug, and Cosmetic Act, as son or agency who assumes responsibil- amended (secs. 201–902, 52 Stat. 1040 et ity for an investigation of a new drug, seq., as amended; 21 U.S.C. 321–392). including responsibility for compliance (b) Department means the Department with applicable provisions of the act of Health and Human Services. and regulations. The ‘‘sponsor’’ may be (c) Secretary means the Secretary of an individual, partnership, corporation, Health and Human Services. or Government agency and may be a (d) Commissioner means the Commis- manufacturer, scientific institution, or sioner of Food and Drugs. an investigator regularly and lawfully (e) The term person includes individ- engaged in the investigation of new uals, partnerships, corporations, and drugs. associations. (k) The phrase related drug(s) includes (f) The definitions and interpreta- other brands, potencies, dosage forms, tions of terms contained in section 201 salts, and esters of the same drug moi- of the act shall be applicable to such ety, including articles prepared or 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 spontaneous disintegration of unstable new drug when used in another disease nuclei with the emission of nuclear or to affect another structure or func- particles or photons and includes any tion of the body. nonradioactive reagent kit or nuclide (5) The newness of a dosage, or meth- generator which is intended to be used od or duration of administration or ap- in the preparation of any such sub- plication, or other condition of use pre- stance but does not include drugs such scribed, recommended, or suggested in as carbon-containing compounds or po- the labeling of such drug, even though tassium-containing salts which contain such drug when used in other dosage, trace quantities of naturally occurring
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radionuclides. The term ‘‘radioactive tices and as Notices of Opportunity for drug’’ includes a ‘‘radioactive biologi- Hearing. The specific products listed in cal product’’ as defined in § 600.3(ee) of these notices include only those that this chapter. were introduced into the market [39 FR 11680, Mar. 29, 1974, as amended at 39 through the new drug procedures from FR 20484, June 11, 1974; 40 FR 31307, July 25, 1938–62 and were submitted for review 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. by the National Academy of Sciences- 22, 1985] National Research Council (NAS–NRC), Drug Efficacy Study Group. Many § 310.4 Biologics; products subject to products which are identical to, related license control. to, or similar to the products listed in (a) Except for radioactive biological these notices have been marketed products intended for human use, a under different names or by different new drug shall not be deemed to be firms during this same period or since subject to section 505 of the act if it is 1962 without going through the new a drug licensed under the Public Health drug procedures or the Academy re- Service Act of July 1, 1944 (58 Stat. 682, view. Even though these products are as amended (42 U.S.C. 201 et seq.)) or not listed in the notices, they are cov- under the animal virus, serum, and ered by the new drug applications re- toxin law of March 4, 1913 (37 Stat. 832 viewed and thus are subject to these (21 U.S.C. 151 et seq.)). notices. All persons with an interest in (b) A radioactive biological product a product that is identical, related, or (as defined in § 600.3(ee) of this chapter) similar to a drug listed in a drug effi- intended for human use is subject to cacy notice or a notice of opportunity section 505 of the act. Any license for for a hearing will be given the same op- such a radioactive biological product portunity as the applicant to submit which is issued under the Public Health data and information, to request a Service Act of July 1, 1944 (58 Stat. 682, hearing, and to participate in any hear- as amended (42 U.S.C. 201 et seq.)) and ing. It is not feasible for the Food and which has not been revoked or sus- Drug Administration to list all prod- pended as of August 25, 1975 shall con- ucts which are covered by an NDA and stitute an approved new drug applica- thus subject to each notice. However, tion in effect under the same terms and it is essential that the findings and conditions as set forth in such license conclusions that a drug product is a and such portions of the establishment ‘‘new drug’’ or that there is a lack of license relating to such product, which include data and information required evidence to show that a drug product is under part 314 of this chapter for a new safe or effective be applied to all iden- drug application. Any such radioactive tical, related, and similar drug prod- biological product for which licensure ucts to which they are reasonably ap- under the Public Health Service Act is plicable. Any product not in compli- pending on August 25, 1975 shall, upon ance with an applicable drug efficacy determination that it is acceptable for notice is in violation of section 505 licensure, be approved as a new drug (new drugs) and/or section 502 (mis- application in lieu of issuance of a bio- branding) of the act. logical product license. (b)(1) An identical, related, or similar drug includes other brands, potencies, [40 FR 31312, July 25, 1975] dosage forms, salts, and esters of the same drug moiety as well as of any § 310.6 Applicability of ‘‘new drug’’ or safety or effectiveness findings in drug moiety related in chemical struc- drug efficacy study implementation ture or known pharmacological prop- notices and notices of opportunity erties. for hearing to identical, related, (2) Where experts qualified by sci- and similar drug products. entific training and experience to (a) The Food and Drug Administra- evaluate the safety and effectiveness of tion’s conclusions on the effectiveness drugs would conclude that the findings of drugs are currently being published and conclusions, stated in a drug effi- in the FEDERAL REGISTER as Drug Effi- cacy notice or notice of opportunity for cacy Study Implementation (DESI) No- hearing, that a drug product is a ‘‘new
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drug’’ or that there is a lack of evi- of various government agencies, will be dence to show that a drug product is taken. safe or effective are applicable to an (f) This regulation does not apply to identical, related, or similar drug prod- OTC drugs identical, similar, or related uct, such product is affected by the no- to a drug in the Drug Efficacy Study tice. A combination drug product con- unless there has been or is notification taining a drug that is identical, relat- in the FEDERAL REGISTER that a drug ed, or similar to a drug named in a no- will not be subject to an OTC panel re- tice may also be subject to the findings view pursuant to §§ 330.10, 330.11, and and conclusions in a notice that a drug 330.5 of this chapter. product is a ‘‘new drug’’ or that there is a lack of evidence to show that a [39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983; 50 FR 8996, Mar. 6, 1985; drug product is safe or effective. 55 FR 11578, Mar. 29, 1990] (3) Any person may request an opin- ion on the applicability of such a no- tice to a specific product by writing to Subpart B—Specific Administrative the Food and Drug Administration at Rulings and Decisions the address shown in paragraph (e) of this section. § 310.100 New drug status opinions; (c) Manufacturers and distributors of statement of policy. drugs should review their products as (a) Over the years since 1938 the Food drug efficacy notices are published and and Drug Administration has given in- assure that identical, related, or simi- formal advice to inquirers as to the lar products comply with all applicable new drug status of preparations. These provisions of the notices. drugs have sometimes been identified (d) The published notices and sum- only by general statements of composi- mary lists of the conclusions are of tion. Generally, such informal opinions particular interest to drug purchasing were incorporated in letters that did agents. These agents should take par- not explicitly relate all of the nec- ticular care to assure that the same essary conditions and qualifications purchasing policy applies to drug prod- such as the quantitative formula for ucts that are identical, related, or the drug and the conditions under similar to those named in the drug effi- which it was prescribed, recommended, cacy notices. The Food and Drug Ad- or suggested. This has contributed to ministration applies the same regu- misunderstanding and misinterpreta- latory policy to all such products. In tion of such opinions. many instances a determination can (b) These informal opinions that an readily be made as to the applicability article is ‘‘not a new drug’’ or ‘‘no of a drug efficacy notice by an individ- longer a new drug’’ require reexamina- ual who is knowledgeable about drugs tion under the Kefauver-Harris Act and their indications for use. Where (Public Law 87–781; 76 Stat. 788–89). In the relationships are more subtle and particular, when approval of a new not readily recognized, the purchasing drug application is withdrawn under agent may request an opinion by writ- provisions of section 505(e) of the Fed- ing to the Food and Drug Administra- eral Food, Drug, and Cosmetic Act, a tion at the address shown in paragraph drug generally recognized as safe may (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, HFD–300, portance by reason of proposed actions 5600 Fishers Lane, Rockville, MD 20857, to withdraw approval of new drug ap- the names of drug products, and of plications for lack of substantial evi- their manufacturers or distributors, dence of effectiveness as a result of re- that should be the subject of the same ports of the National Academy of purchasing and regulatory policies as Sciences—National Research Council those reviewed by the Drug Efficacy on its review of drug effectiveness; for Study Group. Appropriate action, in- example, see the notice published in cluding referral to purchasing officials the FEDERAL REGISTER of January 23,
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1968 (33 FR 818), regarding rutin, quer- available only under the investiga- cetin, et al. tional drug provisions of this part. (c) Any marketed drug is a ‘‘new (3) The label bears the following drug’’ if any labeling change made prominently placed statements in lieu after October 9, 1962, recommends or of adequate directions for use and in suggests new conditions of use under addition to complying with the other which the drug is not generally recog- labeling provisions of the act: nized as safe and effective by qualified (i) ‘‘Caution: Federal law prohibits experts. Undisclosed or unreported side dispensing without a prescription’’; and effects as well as the emergence of new (ii) ‘‘For use only in patch testing’’. knowledge presenting questions with (4) The quantity shipped is limited to respect to the safety or effectiveness of an amount reasonable for the purpose a drug may result in its becoming a of patch testing in the normal course ‘‘new drug’’ even though it was pre- of the practice of medicine and is used viously considered ‘‘not a new drug.’’ solely for such patch testing. Any previously given informal advice (5) The new drug substance is manu- that an article is ‘‘not a new drug’’ factured by the same procedures and does not apply to such an article if it meets the same specifications as the has been changed in formulation, man- component used in the finished dosage ufacture control, or labeling in a way form. that may significantly affect the safety (6) The manufacturer or distributor of the drug. maintains records of all shipments for (d) For these reasons, all opinions this purpose for a period of 2 years previously given by the Food and Drug after shipment and will make them Administration to the effect that an available to the Food and Drug Admin- article is ‘‘not a new drug’’ or is ‘‘no istration on request. longer a new drug’’ are hereby revoked. (b) When the requested new drug sub- This does not mean that all articles stance is intended for investigational that were the subjects of such prior use in humans or the substance is le- opinions will be regarded as new drugs. gally available only under the inves- The prior opinions will be replaced by tigational drug provisions of part 312 of opinions of the Food and Drug Admin- this chapter, the submission of an ‘‘In- istration that are qualified and current vestigational New Drug Application’’ on when an article is ‘‘not a new drug,’’ (IND) is required. The Food and Drug as set forth in this subchapter. Administration will offer assistance to [39 FR 11680, Mar. 29, 1974] any practitioner wishing to submit an Investigational New Drug Application. § 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 and therefore will not object to the [39 FR 11680, Mar. 29, 1974, as amended at 55 FR 11578, Mar. 29, 1990] shipment of a new drug substance, as 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 practi- tioner 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)(C) 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 ingredi- as provided in paragraph (b) or (e) of ent solely in a new drug that is legally this section.
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(b) Prescription-exemption procedure for § 310.201 Exemption for certain drugs drugs limited by a new drug application. limited by new-drug applications to Any drug limited to prescription use prescription sale. under section 503(b)(1)(C) of the act (a) The prescription-dispensing re- shall be exempted from prescription- quirements of section 503(b)(1)(C) of the dispensing requirements when the Federal Food, Drug, and Cosmetic Act Commissioner finds such requirements are not necessary for the protection of are not necessary for the protection of the public health with respect to the the public health by reason of the following drugs subject to new drug ap- drug’s toxicity or other potentiality plications: for harmful effect, or the method of its (1) N-Acetyl-p-aminophenol use, or the collateral measures nec- (acetaminophen, p-hydroxy-acetanilid) essary to its use, and he finds that the preparations meeting all the following drug is safe and effective for use in conditions: self-medication as directed in proposed (i) The N-acetyl-p-aminophenol is labeling. A proposal to exempt a drug prepared, with or without other drugs, from the prescription-dispensing re- in tablet or other dosage form suitable quirements of section 503(b)(1)(C) of the for oral use in self-medication, and act may be initiated by the Commis- containing no drug limited to prescrip- tion sale under the provisions of sec- sioner or by any interested person. Any tion 503(b)(1) of the act. interested person may file a petition (ii) The N-acetyl-p-aminophenol and seeking such exemption, which petition all other components of the prepara- may be pursuant to part 10 of this tion meet their professed standards of chapter, or in the form of a supplement identity, strength, quality, and purity. to an approved new drug application. (iii) If the preparation is a new drug, (c) New drug status of drugs exempted an application pursuant to section 505 from the prescription requirement. A drug (b) of the act is approved for it. exempted from the prescription re- (iv) The preparation contains not quirement under the provisions of more than 0.325 gram (5 grains) of N- paragraph (b) of this section is a ‘‘new acetyl-p-aminophenol per dosage unit, drug’’ within the meaning of section or if it is in liquid form not more than 201(p) of the act until it has been used 100 milligrams of N-acetyl-p- to a material extent and for a material aminophenol per milliliter. time under such conditions except as (v) The preparation is labeled with provided in paragraph (e) of this sec- adequate directions for use in minor tion. conditions as a simple analgesic. (d) Prescription legend not allowed on (vi) The dosages of N-acetyl-p- exempted drugs. The use of the prescrip- aminophenol recommended or sug- tion caution statement quoted in sec- gested in the labeling do not exceed: tion 503(b) (4) of the act, in the labeling For adults, 0.65 gram (10 grains) per of a drug exempted under the provi- dose or 2.6 grams (40 grains) per 24-hour sions of this section, constitutes mis- period: for children 6 to 12 years of age, branding. Any other statement or sug- one-half of the maximum adult dose or gestion in the labeling of a drug ex- dosage; for children 3 to 6 years of age, empted under this section, that such one-fifth of the maximum adult dose or drug is limited to prescription use, dosage. may constitute misbranding. (vii) The labeling bears, in juxtaposi- tion with the dosage recommendations, (e) Prescription-exemption procedure of a clear warning statement against ad- OTC drug review. A drug limited to pre- ministration of the drug to children scription use under section 503(b)(1)(C) under 3 years of age and against use of of the act may also be exempted from the drug for more than 10 days, unless prescription-dispensing requirements such uses are directed by a physician. by the procedure set forth in § 330.13 of (viii) If the article is offered for use this chapter. in arthritis or rheumatism, the label- [39 FR 11680, Mar. 29, 1974, as amended at 41 ing prominently bears a statement FR 32582, Aug. 4, 1976; 42 FR 4714, Jan. 25, that the beneficial effects claimed are 1977; 42 FR 15674, Mar. 22, 1977] limited to the temporary relief of
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minor aches and pains of arthritis and ited to prescription sale under the pro- rheumatism and, in juxtaposition with visions of section 503(b)(1) of the act. directions for use in such conditions, a (ii) The isoamylhydrocupreine, zola- conspicuous warning statement, such amine hydrochloride, and all other as ‘‘Caution: If pain persists for more components of the preparation meet than 10 days, or redness is present, or their professed standards of identity, in conditions affecting children under strength, quality, and purity. 12 years of age, consult a physician im- (iii) If the preparation is a new drug, mediately’’. an application pursuant to section (2) Sodium gentisate (sodium-2, 5- 505(b) of the act is approved for it. dihydroxybenzoate) preparations meet- (iv) The preparation contains not ing all the following conditions: more than 0.25 percent of (i) The sodium gentisate is prepared, isoamylhydrocupreine and 1.0 percent with or without other drugs, in tablet of zolamine hydrochloride. or other dosage form suitable for oral (v) If the preparation is in supposi- use in self-medication, and containing tory form, it contains not more than no drug limited to prescription sale 5.0 milligrams of isoamylhydrocupreine under the provisions of section 503(b)(1) and not more than 20.0 milligrams of of the act. zolamine hydrochloride per supposi- (ii) The sodium gentisate and all tory. other components of the preparation (vi) The preparation is labeled with meet their professed standards of iden- adequate directions for use in the tem- tity, strength, quality, and purity. porary relief of local pain and itching (iii) If the preparation is a new drug, associated with hemorrhoids. an application pursuant to section (vii) The directions provide for the 505(b) of the act is approved for it. use of not more than two suppositories (iv) The preparation contains not or two applications of ointment in a 24- more than 0.5 gram (7.7 grains) of anhy- hour period. drous sodium gentisate per dosage (viii) The labeling bears, in jux- unit. taposition with the dosage rec- (v) The preparation is labeled with ommendations, a clear warning state- adequate directions for use in minor ment against use of the preparation in conditions as a simple analgesic. case of rectal bleeding, as this may in- (vi) The dosages of sodium gentisate dicate serious disease. recommended or suggested in the label- (4) Phenyltoloxamine dihydrogen cit- ing do not exceed: For adults, 0.5 gram rate (N,N-dimethyl-(a-phenyl-O-toloxy) (7.7 grains) per dose of 2.0 grams (31 ethylamine dihydrogen citrate), prep- grains) per 24-hour period; for children arations meeting all the following con- 6 to 12 years of age, one-half of the ditions: maximum adult dose or dosage. (i) The phenyltoloxamine dihydrogen (vii) The labeling bears, in juxtaposi- citrate is prepared, with or without tion with the dosage recommendations, other drugs, in tablet or other dosage a clear warning statement against ad- form suitable for oral use in self-medi- ministration of the drug to children cation, and containing no drug limited under 6 years of age and against use of to prescription sale under the provi- the drug for a prolonged period, except sions of section 503(b)(1) of the act. as such uses may be directed by a phy- (ii) The phenyltoloxamine sician. dihydrogen citrate and all other com- (3) Isoamylhydrocupreine and ponents of the preparation meet their zolamine hydrochloride (N, N-di- professed standards of identity, methyl-N′-2-thiazolyl-N′-p- strength, quality, and purity. methoxybenzyl-ethyl- enediamine hy- (iii) If the preparation is a new drug, drochloride) preparations meeting all an application pursuant to section the following conditions: 505(b) of the act is approved for it. (i) The isoamylhydrocupreine and (iv) The preparation contains not zolamine hydrochloride are prepared in more than 88 milligrams of dosage form suitable for self-medica- phenyltoloxamine dihydrogen citrate tion as rectal suppositories or as an (equivalent to 50 milligrams of ointment and containing no drug lim- phenyltoloxamine) per dosage unit.
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(v) The preparation is labeled with ligram of dicyclomine hydrochloride adequate directions for use in the tem- per milliliter. porary relief of the symptoms of hay (v) The preparation is labeled with fever and/or the symptoms of other adequate directions for use only by minor conditions in which it is indi- adults and children over 12 years of cated. age, in the temporary relief of gastric (vi) The dosages recommended or hyperacidity. suggested in the labeling do not exceed: (vi) The dosages recommended or For adults, 88 milligrams of suggested in the directions for use do phenyltoloxamine dihydrogen citrate not exceed 10 milligrams of (equivalent to 50 milligrams of dicyclomine hydrochloride per dose or phenyltoloxamine) per dose or 264 mil- 30 milligrams in a 24-hour period. ligrams of phenyltoloxamine (vii) The labeling bears, in juxtaposi- dihydrogen citrate (equivalent to 150 tion with the dosage recommendations, milligrams of phenyltoloxamine) per clear warning statements against: 24-hour period; for children 6 to 12 (a) Exceeding the recommended dos- years of age, one-half of the maximum age. adult dose or dosage. (b) Prolonged use, except as directed (vii) The labeling bears, in juxtaposi- by a physician, since persistent or re- tion with the dosage recommendations: curring symptoms may indicate a seri- (a) Clear warning statements against ous disease requiring medical atten- administration of the drug to children tion. under 6 years of age, except as directed (c) Administration to children under by a physician, and against driving a 12 years of age except as directed by a car or operating machinery while using physician. the drug, since it may cause drowsi- (9)–(10) [Reserved] ness. (11) Hexadenol (a mixture of (b) If the article is offered for tem- tetracosanes and their oxidation prod- porary relief of the symptoms of colds, ucts) preparations meeting all the fol- a statement that continued adminis- lowing conditions: tration for such use should not exceed 3 days, except as directed by a physi- (i) The hexadenol is prepared and cian. packaged, with or without other drugs, (5)–(7) [Reserved] solvents, and propellants, in a form (8) Dicyclomine hydrochloride (1- suitable for self-medication by external cyclohexylhexahydrobenzoic acid. β- application to the skin as a spray, and diethylaminoethyl ester hydrochloride; containing no drug limited to prescrip- diethylaminocarbethoxy-bicyclohexyl tion sale under the provisions of sec- hydrochloride) preparations meeting tion 503(b)(1) of the act. all the following conditions: (ii) The hexadenol and all other com- (i) The dicyclomine hydrochloride is ponents of the preparation meet their prepared with suitable antacid and professed standards of identity, other components, in tablet or other strength, quality, and purity. dosage form for oral use in self-medica- (iii) If the preparation is a new drug, tion, and containing no drug limited to an application pursuant to section prescription sale under the provisions 505(b) of the act is approved for it. of section 503(b)(1) of the act. (iv) The preparation contains not (ii) The dicyclomine hydrochloride more than 5 percent by weight of and all other components of the prepa- hexadenol. ration meet their professed standards (v) The preparation is labeled with of identity, strength, quality, and pu- adequate directions for use by external rity. application in the treatment of minor (iii) If the preparation is a new drug, burns and minor skin irritations. an application pursuant to section (vi) The labeling bears, in juxtaposi- 505(b) of the act is approved for it. tion with the directions for use, clear (iv) The preparation contains not warning statements against: more than 5 milligrams of dicyclomine (a) Use on serious burns or skin con- hydrochloride per dosage unit, or if it ditions or prolonged use, except as di- is in liquid form not more than 0.5 mil- rected by a physician.
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(b) Spraying the preparation in the (vi) The preparation is labeled with vicinity of eyes, mouth, nose, or ears. adequate directions for use in the tem- (12) Sulfur dioxide preparations porary relief of nasal congestion. meeting all the following conditions: (vii) The dosages recommended or (i) The sulfur dioxide is prepared with suggested in the directions for use do or without other drugs, in an aqueous not exceed the equivalent: For adults, 5 solution packaged in a hermetic con- drops of a 1 percent solution per nostril tainer suitable for use in self-medica- per dose, and 5 doses in a 24-hour pe- tion by external application to the riod; for children 1 to 6 years of age, 3 skin, and containing no drug limited to drops of a 1 percent solution per nostril prescription sale under the provisions per dose, and 5 doses in a 24-hour pe- of section 503(b)(1) of the act. riod; for infants under 1 year of age, 2 (ii) The sulfur dioxide and all other drops of a 1 percent solution per nostril components of the preparation meet per dose, and 5 doses in a 24-hour pe- their professed standards of identity, riod. strength, quality, and purity. (viii) The labeling bears, in jux- (iii) If the preparation is a new drug, taposition with the dosage rec- an application pursuant to section ommendations: 505(b) of the act is approved for it. (a) Clear warning statements against (iv) The preparation contains not use of more than 5 doses daily, and more than 5 grams of sulfur dioxide per against use longer than 4 days unless 100 milliliters of solution. directed by a physician. (v) The preparation is labeled with (b) A clear warning statement to the adequate directions for use by external effect that frequent use may cause application to the smooth skin in the nervousness or sleeplessness, and that prevention or treatment of minor con- individuals with high blood pressure, ditions in which it is indicated. heart disease, diabetes, or thyroid dis- (vi) The directions for use rec- ease should not use the preparation un- ommend or suggest not more than two less directed by a physician. applications a day for not more than 1 (17) [Reserved] week, except as directed by a physi- cian. (18) Vibesate (a mixture of copoly- (13)–(15) [Reserved] mers of hydroxy-vinyl chlorideacetate, (16) Tuaminoheptane sulfate (2- sebacic acid, and modified maleic rosin aminoheptane sulfate) preparations ester) preparations meeting all the fol- meeting all the following conditions: lowing conditions. (i) The tuaminoheptane sulfate is (i) The vibesate is prepared and prepared, with or without other drugs, packaged, with or without other drugs, in an aqueous vehicle suitable for ad- solvents, and propellants, in a form ministration in self-medication as nose suitable for self-medication by external drops, and containing no drug limited application to the skin as a spray, and to prescription sale under the provi- containing no drug limited to prescrip- sions of section 503(b)(1) of the act. tion sale under the provisions of sec- (ii) The preparation is packaged with tion 503(b)(1) of the act. a style of container or assembly suited (ii) The vibesate and all other compo- to self-medication by the recommended nents of the preparation meet their route of administration, and delivering professed standards of identity, not more than 0.1 milliliter of the prep- strength, quality, and purity. aration per drop. (iii) If the preparation is a new drug, (iii) The tuaminoheptane sulfate and an application pursuant to section all other components of the prepara- 505(b) of the act is approved for it. tion meet their professed standards of (iv) The preparation contains not identity, strength, quality, and purity. more than 13 percent by weight of (iv) If the preparation is a new drug, vibesate. an application pursuant to section (v) The preparation is labeled with 505(b) of the act is approved for it. adequate directions for use by external (v) The tuaminoheptane sulfate con- application as a dressing for minor tent of the preparation does not exceed burns, minor cuts, or other minor skin 10 milligrams per milliliter. irritations.
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(vi) The labeling bears in juxtaposi- preparations meeting all the following tion with the directions for use clear conditions: warning statements against: (i) The carbetanentane citrate is pre- (a) Use on serious burns and on in- pared, with or without other drugs, in fected, deep, and puncture wounds un- tablet or other dosage form suitable for less directed by a physician. oral use in self-medication, and con- (b) Spraying the preparation near the taining no drug limited to prescription eyes or other mucous membranes. sale under the provisions of section (c) Inhaling the preparation. 503(b)(1) of the act. (d) Use near open flames. (ii) The carbetapentane citrate and (e) Puncturing the container or all other components of the prepara- throwing the container into fire. tion meet their professed standards of (19) Pramoxine hydrochloride (4-N- identity, strength, quality, and purity. butoxyphenyl γ-morpholinopropyl (iii) If the preparation is a new drug, ether hydrochloride) preparations and application pursuant to section meeting all the following conditions: 505(b) of the act is approved for it. (i) The pramoxine hydrochloride is (iv) The preparation contains not prepared, with or without other drugs, more than 25 milligrams of in a dosage form suitable for use in carbetapentane citrate per dosage unit; self-medication by external application or if it is in liquid form, not more than to the skin, and containing no drug 1.5 milligrams of carbetapentane cit- limited to prescription sale under the rate per milliliter. provisions of section 503(b)(1) of the (v) The preparation is labeled with act. adequate directions for use in the tem- (ii) The pramoxine hydrochloride and porary relief of cough due to minor all other components of the prepara- conditions in which it is indicated. tion meet their professed standards of (vi) The dosages recommended or identity, strength, quality, and purity. suggested in the labeling do not exceed: For adults, 30 milligrams of (iii) If the preparation is a new drug, carbetapentane citrate per dose or 120 an application pursuant to section milligrams of carbetapentane citrate 505(b) of the act is approved for it. per 24-hour period; for children 4 to 12 (iv) The preparation contains not years of age, 7.5 milligrams per dose or more than 1.0 percent of pramoxine hy- 30 milligrams per 24-hour period; for drochloride. children 2 to 4 years of age, 4.0 milli- (v) The preparation is labeled with grams per dose or 16.0 milligrams per adequate directions for use by external 24-hour period. application to the skin for the tem- (vii) The label bears a conspicuous porary relief of pain or itching due to warning to keep the drug out of the minor burns and sunburn, nonpoison- reach of children, and the labeling ous insect bites, and minor skin irrita- bears, in juxtaposition with the dosage tions. recommendations: (vi) The directions for use rec- (a) A clear warning statement ommend or suggest not more than four against administration of the drug to applications of the preparation per day, children under 2 years of age, unless di- unless directed by a physician. rected by a physician. (vii) The labeling bears, in juxtaposi- (b) Clear warning statements against tion with the directions for use, clear use of the drug in the presence of high warning statements against: fever or if cough persists, since persist- (a) Prolonged use. ent cough as well as high fever may in- (b) Application to large areas of the dicate the presence of a serious condi- body. tion. (c) Continued use if redness, irrita- (21) Pamabrom (2-amino-2- tion, swelling, or pain persists or in- methylpropanol-1-8- creases, unless directed by a physician. bromotheophyllinate) preparations (d) Use in the eyes or nose. meeting all the following conditions: (20) Carbetapentane citrate (2-(2- (i) The pamabrom is prepared with diethylaminoethoxy)-ethyl-1-phenyl- appropriate amounts of a suitable anal- cyclopentyl-1-carboxylate citrate) gesic and with or without other drugs,
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in tablet or other dosage form suitable (vii) The labeling bears, in juxtaposi- for oral use in self-medication, and tion with the directions for use, a clear containing no drug limited to prescrip- warning statement, such as: ‘‘Caution: tion sale under the provisions of sec- If redness, irritation, swelling, or pain tion 503(b)(1) of the act. persists or increases, discontinue use (ii) The pamabrom and all other com- and consult physician.’’ ponents of the preparation meet their (23) Dyclonine hydrochloride (4- professed standards of identity, butoxy-3-piperidinopropiophenone hy- strength, quality, and purity. drochloride; 4-n-butoxy-β- (iii) If the preparation is a new drug, piperidonopropiophenone hydro- an application pursuant to section chloride) preparations meeting all the 505(b) of the act is approved for it. following conditions: (iv) The preparation contains not (i) The dyclonine hydrochloride is more than 50 milligrams of pamabrom prepared, with or without other drugs, per dosage unit. in a dosage form suitable for use as a (v) The preparation is labeled with cream or ointment in self-medication adequate directions for use in the tem- by external application to the skin, or porary relief of the minor pains and rectally, and contains no drug limited discomforts that may occur a few days to prescription sale under the provi- before and during the menstrual pe- sions of section 503(b)(1) of the act. riod. (ii) The dyclonine hydrochloride and (vi) The dosages recommended or all other components of the prepara- suggested in the labeling do not exceed tion meet their professed standards of 50 milligrams of pamabrom per dose or identity, strength, quality, and purity. 200 milligrams per 24-hour period. (iii) If the preparation is a new drug, (22) Diphemanil methylsulfate (4- an application pursuant to section diphenylmethylene-1,1-dimethyl- 505(b) of the act is approved for it. piperidinium methylsulfate) prepara- (iv) The preparation contains not tions meeting all the following condi- more than 1.0 percent of dyclonine hy- tions: drochloride. (i) The diphemanil methylsulfate is (v) The preparation is labeled with prepared, with or without other drugs, adequate directions for use: in a dosage form suitable for use in (a) By external application to the self-medication by external application skin for the temporary relief of pain to the skin, and containing no drug and itching in sunburn, nonpoisonous limited to prescription sale under the insect bites, minor burns, cuts, abra- provisions of section 503(b)(1) of the sions, and other minor skin irritations. act. (b) [Reserved] (ii) The diphemanil methylsulfate and all other components of the prepa- (c) In the prevention or treatment of ration meet their professed standards other minor conditions in which it is of identity, strength, quality, and pu- indicated. rity. (vi) The labeling bears, in juxtaposi- (iii) If the preparation is a new drug, tion with the directions for use, clear an application pursuant to section warning statements against: 505(b) of the act is approved for it. (a) Continued use if redness, irrita- (iv) The preparation contains not tion, swelling, or pain persists or in- more than 2.0 percent of diphemanil creases, unless directed by a physician. methylsulfate. (b) Use in case of rectal bleeding, as (v) The preparation is labeled with this may indicate serious disease. adequate directions for use by external (c) Use in the eyes. application to the skin for the relief of (d) Prolonged use. symptoms of mild poison ivy, oak, and (e) Application to large areas of the sumac and other minor irritations and body. itching of the skin. (f) Use for deep or puncture wounds (vi) The directions for use rec- or serious burns. ommend or suggest not more than four (24) Chlorothen citrate applications of the preparation per day, (chloromethapyrilene citrate; N,N-di- unless directed by a physician. methyl-N′-(2-pyridyl)-N ′-(5-chloro-2-
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thenyl) ethylenediamine citrate) prep- or without other drugs, in a dosage arations meeting all the following con- form suitable for oral use in self-medi- ditions: 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 an application pursuant to section methoxyphenamine hydrochloride per 505(b) of the act is approved for it. milliliter. (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 minor conditions in which it is indi- methoxyphenamine hydrochloride per cated. dose or 140 milligrams of (vi) The dosages recommended or methoxyphenamine hydrochloride per suggested in the labeling do not exceed: 24-hour period; for children 6 to 12 For adults, 25 milligrams of chlorothen years of age, one-half of the maximum citrate per dose or 150 milligrams of adult dose or dosage. chlorothen citrate per 24-hour period; (vii) The label bears a conspicuous for children 6 to 12 years of age, one- warning to keep the drug out of the half of the maximum adult dose or dos- reach of children, and the labeling age. bears, in juxtaposition with the dosage (vii) The labeling bears, in juxtaposi- recommendations: tion with the dosage recommendations: (a) A clear warning statement (a) Clear warning statements against against administration of the drug to administration of the drug to children children under 6 years of age, unless di- under 6 years of age or exceeding the rected by a physician. recommended dosage, unless directed (b) A clear warning statement to the by a physician, and against driving a effect that frequent or prolonged use car or operating machinery while using may cause nervousness, restlessness, or the drug, since it may cause drowsi- drowsiness, and that individuals with ness. high blood pressure, heart disease, dia- (b) If the article is offered for the betes, or thyroid disease should not use temporary relief of symptoms of colds, the preparation unless directed by a a statement that continued adminis- physician. tration for such use should not exceed (c) A clear warning statement 3 days, unless directed by a physician. against use of the drug in the presence (25) [Reserved] of high fever or if cough persists, since (26) Methoxyphenamine hydro- persistent cough as well as high fever chloride (β-(o-methoxyphenyl)-iso- may indicate the presence of a serious propyl-methylamine hydrochloride; 1- condition. (o-methoxyphenyl)-2-methylamino- (27) Biphenamine hydrochloride (β- propane hydrochloride) preparations diethylaminoethyl-3-phenyl-2-hydroxy- meeting all the following conditions: benzoate hydrochloride) preparations (i) The methoxyphenamine hydro- meeting all the following conditions: chloride is prepared with appropriate (i) The biphenamine hydrochloride is amounts of a suitable antitussive, with prepared in a form suitable for use as a
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shampoo and contains no drug limited the dropper or other dispensing tip to prescription sale under the provi- should not touch any surface, since sions of section 503(b)(1) of the act. this may contaminate the solution. (ii) The biphenamine hydrochloride (29) [Reserved] meets its professed standards of iden- (b) [Reserved] tity, strength, quality, and purity. [39 FR 11680, Mar. 29, 1974, as amended at 42 (iii) If the preparation is a new drug, FR 36994, July 19, 1977; 52 FR 15892, Apr. 30, an application pursuant to section 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, 505(b) of the act is approved for it. Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR (iv) The preparation contains not 49898, Sept. 23, 1993; 59 FR 4218, Jan. 28, 1994; more than 1 percent of biphenamine 60 FR 52507, Oct. 6, 1995] hydrochloride. (v) The preparation is labeled with Subpart D—Records and Reports adequate directions for use for the tem- porary relief of itching and scaling due § 310.303 Continuation of long-term to dandruff. studies, records, and reports on cer- (vi) The label bears a conspicuous tain drugs for which new drug ap- warning to keep the drug out of the plications have been approved. reach of children. (a) A new drug may not be approved (28) Tyloxapol (an alkylarylpolyether for marketing unless it has been shown alcohol) and benzalkonium chloride to be safe and effective for its intended ophthalmic preparations meeting all use(s). After approval, the applicant is the following conditions: required to establish and maintain (i) The tyloxapol and benzalkonium records and make reports related to chloride are prepared, with other ap- clinical experience or other data or in- propriate ingredients which are not formation necessary to make or facili- drugs limited to prescription sale tate a determination of whether there under the provisions of section 503(b)(1) are or may be grounds under section of the act, as a sterile, isotonic aque- 505(e) of the act for suspending or with- ous solution suitable for use in self- drawing approval of the application. medication on eye prostheses. Some drugs, because of the nature of (ii) The preparation is so packaged as the condition for which they are in- to volume and type of container as to tended, must be used for long periods of afford adequate protection and be suit- time—even a lifetime. To acquire nec- able for self-medication with a mini- essary data for determining the safety mum risk of contamination of the solu- and effectiveness of long-term use of tion during use. Any dispensing unit is such drugs, extensive animal and clini- sterile and so packaged as to maintain cal tests are required as a condition of sterility until the package is opened. approval. Nonetheless, the therapeutic (iii) The tyloxapol, benzalkonium or prophylactic usefulness of such chloride, and other ingredients used to drugs may make it inadvisable in the prepare the isotonic aqueous solution public interest to delay the availabil- meet their professed standards of iden- ity of the drugs for widespread clinical tity, strength, quality, and purity. use pending completion of such long- (iv) An application pursuant to sec- term studies. In such cases, the Food tion 505(b) of the act is approved for and Drug Administration may approve the drug. the new drug application on condition (v) The preparation contains 0.25 per- that the necessary long-term studies cent of tyloxapol and 0.02 percent of will be conducted and the results re- benzalkonium chloride. corded and reported in an organized (vi) The label bears a conspicuous fashion. The procedures required by warning to keep the drug out of the paragraph (b) of this section will be fol- reach of children and the labeling lowed in order to list such a drug in bears, in juxtaposition with the dosage § 310.304. recommendations, a clear warning that (b) A proposal to require additional if irritation occurs, persists, or in- or continued studies with a drug for creases, use of the drug should be dis- which a new drug application has been continued and a physician consulted. approved may be made by the Commis- The labeling includes a statement that sioner on his own initiative or on the
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petition of any interested person, pur- drug withdrawal; and any failure of ex- suant to part 10 of this chapter. Prior pected pharmacological action. to issuance of such a proposal, the ap- (3) Unexpected means an adverse drug plicant will be provided an opportunity experience that is not listed in the cur- for a conference with representatives of rent labeling for the drug product and the Food and Drug Administration. includes an event that may be sympto- When appropriate, investigators or matically and pathophysiologically re- other individuals may be invited to lated to an event listed in the labeling, participate in the conference. All re- but differs from the event because of quirements for special studies, records, greater severity or specificity. For ex- and reports will be published in ample, under this definition, hepatic § 310.304. necrosis would be unexpected (by vir- tue of greater severity) if the labeling [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 FR 15674, Mar. 22, only referred to elevated hepatic en- 1977] zymes or hepatitis. Similarly, cerebral thromboembolism and cerebral § 310.305 Records and reports concern- vasculitis would be unexpected (by vir- ing adverse drug experiences on tue of greater specificity) if the label- marketed prescription drugs for ing only listed cerebral vascular acci- human use without approved new dents. drug applications. (4) Serious means an adverse drug ex- (a) Scope. FDA is requiring manufac- perience that is fatal or life-threaten- turers, packers, and distributors of ing, is permanently disabling, requires marketed prescription drug products inpatient hospitalization, or is a con- that are not the subject of an approved genital anomaly, cancer, or overdose. new drug or abbreviated new drug ap- (5) Increased frequency means an in- plication to establish and maintain crease in the rate of occurrence of a records and make reports to FDA of: particular adverse drug experience, (1) All serious, unexpected adverse e.g., an increased number of reports of drug experiences associated with the a particular adverse drug experience use of their drug products; after appropriate adjustment for drug (2) Any significant increase in the exposure. frequency of a serious, expected ad- (c) Reporting requirements—15-day verse drug experience; and ‘‘Alert reports.’’ (1)(i) Any person whose (3) Any significant increase in the name appears on the label of a mar- frequency of therapeutic failure (lack keted prescription drug product as its of effect). manufacturer, packer, or distributor shall report to FDA each adverse drug These reports will enable FDA to pro- experience received or otherwise ob- tect the public health by helping to tained that is both serious and unex- monitor the safety of marketed drug pected as soon as possible but in any products and to ensure that these drug case within 15 working days of initial products are not adulterated or mis- receipt of the information. Each report branded. shall be accompanied by a copy of the (b) Definitions. The following defini- current labeling for the drug product. tions of terms apply to this section: (ii) A person identified in paragraph (1) FDA means the Food and Drug (c)(1)(i) of this section is not required Administration. to submit a 15-day ‘‘Alert report’’ for (2) Adverse drug experience means any an adverse drug experience obtained adverse event associated with the use from a postmarketing study (whether of a drug in humans, whether or not or not conducted under an investiga- considered drug related, including the tional new drug application) unless the following: an adverse event occurring applicant concludes that there is a rea- in the course of the use of a drug prod- sonable possibility that the drug uct in professional practice; an adverse caused the adverse experience. event occurring from drug overdose, (2) Each person identified in para- whether accidental or intentional; an graph (c)(1) of this section shall submit adverse event occurring from drug one copy of each report to the Division abuse; an adverse event occurring from of Epidemiology and Surveillance
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(HFD–730), Center for Drug Evaluation tributor shall maintain a record of this and Research, Food and Drug Adminis- action which shall include: tration, 5600 Fishers Lane, Rockville, (i) A copy of each drug experience re- MD 20857. port. (3) Each person identified in para- (ii) Date the report was received by graph (c)(1) of this section shall the packer or distributor. promptly investigate all serious, unex- (iii) Date the report was submitted to pected adverse drug experiences that the manufacturer. are the subject of these 15-day Alert re- (iv) Name and address of the manu- ports and shall submit followup reports facturer. within 15 working days of receipt of (6) Each report submitted to FDA new information or as requested by under this section shall bear prominent FDA. If additional information is not identification as to its contents, i.e., obtainable, a followup report may be ‘‘15-day Alert report’’ or ‘‘15-day Alert required that describes briefly the report—followup.’’ steps taken to seek additional informa- (d) Reporting form. (1) Except as pro- tion and the reasons why it could not vided in paragraph (d)(3) of this sec- be obtained. tion, each person identified in para- graph (c)(1) of this section shall submit (4) Each person identified in para- each report of a serious and unexpected graph (c)(1) of this section shall review adverse drug experience on a Form periodically (at least once each year) FDA-1639 (Adverse Reaction Report). the frequency of reports of adverse (2) Each completed Form FDA-1639 drug experiences that are both serious should pertain only to an individual and expected and reports of therapeutic patient. failure (lack of effect), received or oth- (3) Instead of using Form FDA–1639, a erwise obtained, and report any signifi- manufacturer, packer, or distributor cant increase in frequency as soon as may use a computer-generated FDA– possible but in any case within 15 1639 or other alternative format (e.g., a working days of determining that a computer-generated tape or tabular significant increase in frequency ex- listing) provided that: ists. Reports of a significant increase (i) The content of the alternative for- in frequency are required to be submit- mat is equivalent in all elements of in- ted in narrative form (including the formation to those specified in Form time period on which the increased fre- FDA–1639, and quency is based, the method of analy- (ii) The format is agreed to in ad- sis, and the interpretation of the re- vance by the Division of Epidemiology sults), rather than using Form FDA- and Surveillance (HFD–730). 1639. (4) Single copies of Form FDA–1639 (5) In order to avoid unnecessary du- may be obtained from the Division of plication in the submission of, and fol- Epidemiology and Surveillance (HFD– lowup to, reports required in this sec- 730), Center for Drug Evaluation and tion, including reports required by Research, Food and Drug Administra- paragraph (c)(4) of this section, a pack- tion, 5600 Fishers Lane, Rockville, MD er’s or distributor’s obligations may be 20857. Supplies of Form FDA–1639 may met by submission of all reports of se- be obtained from the PHS Forms and rious adverse drug experiences to the Publications Distribution Center, 12100 manufacturer of the drug product. If a Parklawn Dr., Rockville, MD 20857. packer or distributor elects to submit (e) Patient privacy. Manufacturers, these adverse drug experience reports packers, and distributors should not in- to the manufacturer rather than to clude in reports under this section the FDA, it shall submit each report to the names and addresses of individual pa- manufacturer within 3 working days of tients; instead, the manufacturer, its receipt by the packer or distributor, packer, and distributor should assign a and the manufacturer shall then com- unique code number to each report, ply with the requirements of this sec- preferably not more than eight char- tion even if its name does not appear acters in length. The manufacturer, on the label of the drug product. Under packer, and distributor should include this circumstance, the packer or dis- the name of the reporter from whom
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the information was received. Names of Subpart E—Requirements for patients, individual reporters, health Specific New Drugs or Devices care professionals, hospitals, and geo- graphical identifiers in adverse drug § 310.500 Digoxin products for oral experience reports are not releasable to use; conditions for marketing. the public under FDA’s public informa- (a) Studies have shown evidence of tion regulations in part 20 of this chap- clinically significant differences in bio- ter. availability in different batches of cer- (f) Recordkeeping. (1) Each manufac- tain marketed digoxin products for turer, packer, and distributor shall oral use from single manufacturers as maintain for a period of 10 years well as in batches of these products records of all adverse drug experiences produced by different manufacturers. required under this section to be re- These differences were observed despite ported or reviewed periodically for a the fact that the products met compendial specifications. Other stud- significant increase in frequency, in- ies have shown that there is a suffi- cluding raw data and any correspond- cient correlation between bioavailabil- ence relating to the adverse drug expe- ity in vivo and the dissolution rate of riences, and the records required to be digoxin tablets in vitro to make the maintained under paragraph (c)(5) of dissolution test an important addition this section. to the compendial standards. Because (2) Manufacturers and packers may of the potential for serious risk to car- retain the records required in para- diac patients using digoxin products graph (f)(1) of this section as part of its which may vary in bioavailability, the complaint files maintained under Commissioner of Food and Drugs has § 211.198 of this chapter. determined that immediate action (3) Manufacturers, packers, and dis- must be taken to assure the uniformity tributors shall permit any authorized of all digoxin products for oral use. The FDA employee, at all reasonable times, Commissioner is of the opinion that to have access to and copy and verify digoxin products for oral use are new the records established and maintained drugs within the meaning of section 201(p) of the Federal Food, Drug, and under this section. Cosmetic Act for which approved new (g) Disclaimer. A report or informa- drug applications are required. The tion submitted by a manufacturer, Commissioner has determined that, be- packer, or distributor under this sec- cause of questions raised regarding the tion (and any release by FDA of that bioavailability of digoxin products for report or information) does not nec- oral use, there is sufficient evidence to essarily reflect a conclusion by the invoke the authority under section manufacturer, packer, or distributor, 505(j) of the act to fully investigate or by FDA, that the report or informa- this question and to facilitate a deter- tion constitutes an admission that the mination of whether there is a ground drug caused or contributed to an ad- for withdrawal of approval of the drug verse effect. The manufacturer, packer, product under section 505(e) of the act. or distributor need not admit, and may Marketing of these products may be deny, that the report or information continued only under the following submitted under this section con- conditions: stitutes an admission that the drug (1) Digoxin products for oral use, caused or contributed to an adverse ef- other than tablets: Any person market- fect. ing digoxin products for oral use, other than tablets, shall submit to the Food (Collection of information requirements ap- and Drug Administration on or before proved by the Office of Management and February 21, 1974, an abbreviated new Budget under control number 0910–0210) drug application for these products. [51 FR 24779, July 3, 1986, as amended at 52 Any such drug product then on the FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, market which is not the subject of an 1990; 57 FR 17980, Apr. 28, 1993] application submitted for the drug
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product shall be subject to regulatory reviewed and either approved or its de- procedures under section 505 of the act. ficiencies delineated. In addition to the information speci- (b) Within 180 days after receiving no- fied in § 314.50 of this chapter, the appli- tification from the Food and Drug Ad- cation shall contain: ministration that the bioavailability (i) A full list of the articles used as protocol has been reviewed, submit to components of the digoxin product, the Food and Drug Administration the specifications for components, detailed results of the in vivo bioavailability identification and analytical proce- tests. dures used to assure that the compo- (2) Digoxin tablets: Any person mar- nents meet established specifications keting digoxin tablets, in addition to of identity, strength, quality, and pu- complying with all of the requirements rity and a complete description of the of paragraph (a)(1) of this section, shall manufacturing process. include in their abbreviated new drug (ii) The source of the digoxin used in application: the formulation including the name (i) A statement that the applicant and address of the supplier. will establish procedures to test each (iii) A statement that stability stud- lot of digoxin tablets prior to releasing ies will be conducted to establish a the batch for distribution to assure suitable expiration date for the digoxin that the batch meets all of The United product in the form in which it is dis- States Pharmacopeia (USP XVIII) re- tributed. quirements for digoxin tablets includ- (iv) A statement that the product ing, but not limited to, potency, con- label will contain a suitable expiration tent uniformity, and dissolution and date. In the absence of any stability either (a) that the quantity of digoxin test data, this expiration date shall be dissolved at one hour is not more than no longer than one year after the batch 95 percent of the assayed amount of is manufactured. If the expiration date digoxin or (b) that the quantity of is greater than one year, supporting digoxin dissolved at 15 minutes is not stability data shall be included in the more than 90 percent of the assayed application. amount of digoxin. (v) Labeling that is in compliance (ii) A statement that finished prod- with all requirements of the act and uct specifications shall be established regulations promulgated thereunder, to include provisions to assure that the the pertinent parts of which are as in- range of average one-hour dissolution dicated in paragraph (e) of this section. values among batches of digoxin tab- (vi) A statement that the applicant lets does not exceed 20 percent. will initiate recall of all stocks of the (3) Before releasing for distribution drug product outstanding when so re- any batch of digoxin tablets manufac- quested by the Food and Drug Adminis- tured after January 22, 1974, the manu- tration. facturer shall: (vii) A statement that the applicant (i) Test a sample of the batch to as- intends to conduct in vivo bioavailabil- sure that the batch meets all of the re- ity tests and that the applicant, under quirements of The United States Phar- the records and reports provisions of macopeia (USP XVIII) including but section 505(k) of the act, will: not limited to, potency, content uni- (a) Within 30 days after the submis- formity, and dissolution and either (a) sion of the application, submit to the that the quantity of digoxin dissolved Food and Drug Administration the pro- at one hour is not more than 95 percent tocol which the applicant proposes to of the assayed amount of digoxin or (b) follow in conducting these in vivo bio- that the quantity of digoxin dissolved availability tests. The protocol shall at 15 minutes is not more than 90 per- contain all of the essential elements cent of the assayed amount of digoxin. set forth in paragraph (d) of this sec- (ii) Submit a sample of the batch to tion. The tests shall not be initiated the Food and Drug Administration ac- prior to receiving notification from the cording to the procedures set forth in Food and Drug Administration that paragraph (g) of this section. Results of the bioavailability protocol has been tests conducted on the batch by or for
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the manufacturer and the batch pro- Drug Administration approval of the duction record shall accompany the supplement is required before the re- sample. formulated product is marketed. The (iii) Withhold the batch from dis- Food and Drug Administration rec- tribution until he is notified by the ommends that, where digoxin tablets Food and Drug Administration that are reformulated, manufacturers refor- the sample was tested and found to mulate their product to achieve dis- meet all of the requirements in The solution of 70 to 90 percent at one hour United States Pharmacopeia (USP when tested by all three methods (i.e., XVIII) for potency, content uniformity, the USP method, and the ‘‘paddle- and dissolution and either (a) that the water’’ and ‘‘paddle-acid’’ methods) de- quantity of digoxin dissolved at one scribed in paragraph (h) of this section. hour is not more than 95 percent of the (d) The protocol for the in vivo bio- assayed amount of digoxin or (b) that availability tests required in para- the quantity of digoxin dissolved at 15 graphs (a) and (c) of this section shall minutes is not more than 90 percent of employ a three-way crossover design the assayed amount of digoxin. using the digoxin test product; a ref- (iv) Submit a sample of each batch of erence digoxin tablet supplied, on re- digoxin tablets as provided for in para- quest, by the Food and Drug Adminis- graph (a)(3)(ii) of this section until he tration; and bulk digoxin USP in an is notified by the Food and Drug Ad- oral solution. Appropriate venous blood ministration that he is released from and urinary samples are to be collected the certification program. This notifi- and analyzed. The method shall be ca- cation will be made on the basis of pable of detecting the difference be- sample test results, inspectional find- tween the reference tablet and the ref- ings regarding compliance with current erence oral solution. Bioavailability of good manufacturing practice, and com- the test product shall be demonstrated pliance with all other requirements of if a mean absorption of at least 75 per- this section and any other directives cent of the combined mean of the two issued by the Food and Drug Adminis- reference standards is observed. Assist- tration as a condition for release from ance in developing a protocol for a par- the certification program. ticular dosage formulation may be ob- (4) Any manufacturer who has dis- tained by contacting the Food and tributed any batch of digoxin tablets Drug Administration, Center for Drug which does not meet the compendial Evaluation and Research (HFD–420), requirement for dissolution, when test- 5600 Fishers Lane, Rockville, MD 20857. ed by the method in The United States (e) Parts of the digoxin product label- Pharmacopeia (USP XVIII), shall initi- ing indicated below shall be as follows: ate recall of the subject batch when so DIGOXIN LABELING GUIDELINES requested by the Food and Drug Ad- ministration. (ADULT AND PEDIATRIC) (b) Failure of an applicant to submit DESCRIPTION the protocol and/or the results of the in vivo bioavailability tests showing ade- Digoxin is one of the cardiac (or digitalis) quate evidence of the product’s bio- glycosides, a closely related group of drugs having in common specific and powerful ef- availability within the times specified fects on the myocardium. These drugs are in paragraph (a)(1)(vii) of this section found in a number of plants. The term ‘‘digi- and/or to comply with all of the certifi- talis’’ is used to designate the whole group. cation requirements of paragraph (a)(3) Typically, the glycosides are composed of of this section shall be justification for three portions: a steroid nucleus, a lactone withdrawal of approval of the applica- ring, and a sugar (hence ‘‘glycosides’’). tion under section 505(e) of the act. (This section should include a chemical (c) Any product reformulation or and physical description of digoxin and the same quantitative ingredient information as change in manufacturing process will that required on the label.) require the submission of a supplement to the approved abbreviated new drug ACTION application containing adequate data The digitalis glycosides have qualitatively to demonstrate the bioavailability of the same therapeutic effects on the heart. the reformulated product. Food and They (1) increase the force of myocardial
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contraction, (2) increase the refractory pe- ure ensues or if atrial flutter is a frequent riod of the atrioventricular (A–V) node, and occurrence. (3) to a lesser degree, affect the sinoatrial 4. Paroxysmal atrial tachycardia. Oral (S–A) node and conduction system via the digoxin may be used, especially if the condi- parasympathetic and sympathetic nervous tion is resistant to lesser measures. Depend- systems. ing on the urgency, a more rapid acting par- Gastrointestinal absorption of digoxin is a enteral preparation may be preferable to ini- passive process. About 50–75 percent of tiate digitalization, although if heart failure digoxin in tablet form is absorbed. Digoxin is has ensued or paroxysms recur frequently, only 20–25 percent bound to plasma proteins digoxin should be maintained by oral admin- and is predominantly excreted by the kid- istration. neys unmetabolized unless there is signifi- Digoxin is not indicated in sinus tachy- cant renal failure. Renal excretion of digoxin cardia unless due to heart failure. is proportional to glomerular filtration rate 5. Cardiogenic shock. The drug is often em- and is largely independent of urine flow. ployed, especially when the condition is ac- Digoxin is not effectively removed from the companied by pulmonary edema. Digoxin body by dialysis, exchange transfusion, or seems to affect adversely shock due to septi- during cardiopulmonary bypass, presumably cemia from gram negative bacteria. because of tissue binding. In subjects with normal renal function, digoxin is excreted CONTRAINDICATIONS exponentially with an average half-life of 36 The presence of toxic effects (See AD- hours, resulting in the loss of 35–40 percent of VERSE REACTIONS section) induced by any the body stores daily. digitalis preparation is a contraindication to Serum levels and pharmacokinetics are es- all of the gylcosides. sentially unchanged by massive weight loss, Allergy, though rare, does occur. It may suggesting that lean body mass should be not extend to all preparations, and another used in dosage calculations. The peak blood may be tried. level from oral dosing with tablets occurs 1– Ventricular fibrillation. 3 hours after administration. The onset of therapeutic action of digoxin after oral tab- WARNINGS lets is 1–2 hours, with the peak therapeutic effect occurring 6–8 hours after dosing. Digitalis alone or with other drugs has been promoted for use in the treatment INDICATIONS of obesity. This use of digoxin or other digitalis glycosides is unwarranted. 1. Congestive heart failure, all degrees, is Moreover, since they may cause poten- the primary indication. The increased car- tially fatal arrhythmias or other adverse diac output due to digoxin results in diuresis effects, the use of these drugs in the and general amelioration of the disturbances treatment of obesity is dangerous. characteristic of right (venous congestion, edema) and left (dyspnea, orthopnea, cardiac Many of the arrhythmias for which digoxin asthma) heart failure. is advised closely resemble those reflecting Digoxin, generally, is most effective in digoxin intoxication. If the possibility of ‘‘low output’’ failure and less effective in digoxin intoxication cannot be excluded, car- ‘‘high output’’ (bronchopulmonary insuffi- diac glycosides should be temporarily with- ciency, infection, hyperthyroidism) heart held if permitted by the clinical situation. failure. The patient with congestive heart failure Digoxin should be continued after heart may complain of nausea and vomiting. These failure is abolished unless some known pre- symptoms may also be indications on cipitating factor is corrected. digoxin intoxication. A clinical determina- 2. Atrial fibrillation, especially when the tion of the cause of these symptoms must be ventricular rate is elevated. Digoxin rapidly attempted before further drug administra- reduces ventricular rates and eliminates the tion. pulse deficit. Palpitation, precordial distress Patients with renal insufficiency require or weakness are relieved and any concomi- smaller than usual doses of digoxin. See AC- tant congestive failure ameliorated. TION section for mechanism. Digoxin should be continued in doses nec- essary to maintain the desired ventricular PRECAUTIONS rate and other clinical effects. Atrial arrhythmias associated with 3. Atrial flutter. Digoxin slows the heart hypermetabolic states are particularly re- and regular sinus rhythm may appear. Fre- sistant to digoxin treatment. Care must be quently the flutter is converted to atrial fi- taken to avoid digoxin toxicity if digoxin is brillation with a slow ventricular rate. Stop- used to help the arrhythmia. ping digoxin at this point may be followed by Digoxin is not indicated for the treatment restoration of sinus rhythm, especially if the of ventricular tachycardia unless congestive flutter was of the paroxysmal type. It is pref- heart failure supervenes after a protracted erable, however, to continue digoxin if fail- episode not itself due to digoxin.
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Potassium depletion sensitizes the myo- Cardiac disturbances (arrhythmias): Ven- cardium to digoxin, and toxicity may de- tricular premature beats are the most com- velop even with the usual dosage. mon, except in infants and young children. Hypokalemia may also alter the rate of Paroxysmal and nonparoxysmal nodal onset and intensity of the positive inotropic rhythms, atrioventricular (interference) dis- effect of digoxin. Therefore, it is desirable to association and paroxysmal atrial tachy- maintain normal serum potassium levels in cardia (PAT) with block are also common ar- patients being treated with digoxin. rhythmias due to digoxin overdosage. Con- Potassium wastage may result from diu- duction disturbances: Excessive slowing of retic or corticosteriod therapy, the pulse is a clinical sign of digoxin over- hemodialysis, and from suction of gastro- dosage. Atrioventricular block of increasing intestinal secretions. It may accompany degree may proceed to complete heart block. malnutrition, diarrhea, prolonged vomiting, Note: The electrocardiogram is fundamental old age, and long-standing congestive heart in determining the presence and nature of failure. In general, rapid changes in serum these cardiac toxic disturbances. Digoxin potassium or other electrolytes are to be may also induce other changes (as of the ST avoided, and intravenous treatment with po- segment), but these provide no measure of tassium should be reserved only for special the degree of digitalization. circumstances as described below (see TREATMENT OF ARRHYTHMIAS PRO- TREATMENT OF ARRHYTHMIAS PRODUCED BY DUCED BY OVERDOSAGES section). OVERDOSAGES Patients with acute myocardial infarction, Digoxin should be discontinued until all severe pulmonary disease, or far advanced signs of toxicity are abolished. Discontinu- heart failure may be more sensitive to ation may be all that is necessary if toxic digoxin and more prone to disturbances of manifestations are not severe and appear rhythm. after the time for peak effect of the drug. Calcium affects contractility and excit- Potassium salts are commonly used. Po- ability of the heart in a manner similar to tassium chloride in divided oral doses total- that of digoxin. Calcium may produce seri- ing 4–6 grams for adults (see PEDIATRIC IN- ous arrhythmias in digitalized patients. FORMATION section for pediatric dosage) In myxedema the digoxin requirements are may be given provided renal function is ade- less because excretion rate is decreased and quate. blood levels are significantly higher. When correction of the arrhythmia is ur- In incomplete A–V block, especially in pa- gent and the serum potassium level is low or tients subject to Stokes-Adams attacks, ad- normal, potassium should be administered vanced or complete heart block may develop intravenously in a solution of 5 percent dex- if digoxin is given. Heart failure in these pa- trose in water. A total of 40–100 tients can usually be controlled by other milliequivalents (30 milliequivalents per 500 measures and by increasing the heart rate. milliliters) is given at the rate of 20 Patients with chronic constructive pericar- milliequivalents per hour unless limited by ditis may respond unfavorably to digoxin. pain due to local irritation. Patients with idiopathic hypertrophic sub- Additional amounts may be given if the ar- aortic stenosis must be managed extremely rhythmia is uncontrolled and the potassium carefully. Unless cardiac failure is severe, it well tolerated. is doubtful whether digoxin should be em- Continuous electrocardiographic monitor- ployed. ing should be performed to watch for any Renal insufficiency delays the excretion of evidence of potassium toxicity, e.g., peaking digoxin, and dosage must be adjusted accord- of T waves, and to observe the effect on the ingly in patients with renal disease. NOTE: arrhythmia so that the infusion may be This applies also to potassium administra- promptly stopped when the desired effect is tion should it become necessary. achieved. Electrical conversion of arrhythmias may CAUTION: Potassium should not be used and require reduction of digoxin dosage. may be dangerous for severe or complete heart block due to digoxin and not related to ADVERSE REACTIONS any tachycardia. Gynecomastia, uncommon. Other agents that have been approved for Overdosage or toxic effects. the treatment of digoxin intoxication in- Gastrointestinal: Anorexia, nausea, vomit- clude procainamide, lidocaine, and ing, diarrhea are the most common early propranolol. symptoms of overdosages in the adult (but rarely conspicuous in infants). Uncontrolled DOSAGE AND ADMINISTRATION heart failure may also produce such symp- Oral digoxin is administered slowly or rap- toms. idly as required until the desired therapeutic Central nervous system: Visual disturb- effect is obtained without symptoms of over- ances (blurred vision, yellow vision), head- dosage. The amount can be predicted ap- ache, weakness, apathy. proximately from the lean body mass of the
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patient with allowances made for excretion PEDIATRIC INFORMATION during the time taken to induce digitaliza- tion. WARNINGS Subsequent maintenance dosage is also de- Newborn infants display considerable vari- termined tentatively by the amount nec- ability in their tolerance to digoxin, depend- essary to sustain the desired therapeutic ef- ing on their degree of maturity. fect. Premature and immature infants are par- Recommended dosages are practical aver- ticularly sensitive, and dosage must be re- age figures that may require considerable duced and digitalization should be even more modification as dictated by individual sen- individualized and cautiously approached sitivity or associated conditions. Diminished than in more mature infants. Impaired renal function must also be carefully taken into renal function is the most important factor consideration. requiring modification of recommended or Congestive heart failure accompanying average doses. (See WARNINGS and PRE- acute glomerulonephritis requires extreme CAUTIONS sections.) care in digitalization. A relatively low total The average amount of digoxin that pa- dose administered in divided doses and con- tients must accumulate to be digitalized comitant use of antihypertensive drugs has with digoxin tablets is 1.0–1.5 milligrams. been recommended. ECG monitoring is es- Digitalization may be accomplished by any sential. Digoxin should be discontinued as of several approaches that vary in dosage soon as possible. and frequency of administration, but reach Patients with idiopathic hypertrophic sub- the same endpoint in terms of total amount aortic stenosis must be managed extremely accumulated. carefully. Unless cardiac failure is severe, it In previously undigitalized patients, a sin- is doubtful whether digoxin should be em- gle loading dose of 0.5–0.75 milligram orally ployed. usually produces a detectable effect in 1–2 Patients with rheumatic carditis, espe- hours that becomes maximal in 6–8 hours. cially when severe, are unusually sensitive to digoxin and prone to disturbances of Additional doses of 0.25–0.5 milligram may be rhythm. If heart failure develops, digitaliza- given cautiously at 6–8 hour intervals to full tion may be initiated with relatively low digitalization. doses; then it can be cautiously increased In previously undigitalized patients, insti- until a beneficial effect is obtained. If a tution of daily maintenance therapy (0.125– therapeutic trial does not result in improve- 0.5 milligram, see next paragraph) without a ment, the drug should be considered ineffec- loading dose results in development of a tive and be discontinued. steady-state plateau concentrations in about NOTE: Digitalis glycosides are an impor- 7 days in patients with normal renal func- tant cause of accidental poisoning in chil- tion. dren. The average daily oral maintenance dose is 0.125–0.5 milligram, usually 0.25 milligram. In PRECAUTIONS the elderly patient, 0.125–0.25 milligram Dosage must be carefully titrated and dif- should be considered the average mainte- ferences in the bioavailability of parenteral nance dose. preparations, elixirs, and tablets should be In patients with renal impairment, digoxin taken into account when switching patients excretion is impaired and serum half-life is from one preparation to another. prolonged (see ACTION section). Digitalizing Electrocardiographic monitoring may be and maintenance doses are lower than those necessary to avoid intoxication. recommended for patients with normal renal Premonitory signs of toxicity in the new- functions. Signs of digoxin toxicity develop born are undue slowing of the sinus rate, sinoatrial arrest, and prolongation of PR in- sooner in patients with renal impairment, terval. and it takes longer for toxic signs and symp- toms to disappear. Because of the prolonged ADVERSE REACTIONS half-life, a longer period of time is required Toxic signs differ from the adult in a num- to achieve an initial or new steady-state pla- ber of respects. Cardiac arrhythmias are the teau in patients with renal impairment than more reliable and frequent signs of toxicity. in patients with normal renal function. Vomiting and diarrhea, neurologic and vis- It cannot be overemphasized that the val- ual disturbances are rare as initial signs. ues given are averages and substantial indi- Premature ventricular systoles are rarely vidual variation can be expected. seen; nodal and atrial systoles are more fre- (If pediatric dosage is available, the label- quent. ing sections above should be expanded to in- Atrial arrhythmias, atrial ectopic clude the following information.) rhythms, and paroxysmal atrial tachycardia
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with A–V block particularly are more com- tion to be submitted to the Food and mon manifestations of toxicity in children. Drug Administration shall be handled Ventricular arrhythmias are rare. as follows: TREATMENT OF ARRHYTHMIAS PRODUCED BY (1) The sample shall consist of 6 sub- OVERDOSAGES samples of 1000 tablets each collected (See adult section for other recommenda- at random from throughout the manu- tions for the treatment of arrhythmias pro- facturing run. Each of the 6 subsamples duced by overdosages and for additional rec- shall be identified with the name of the ommendations and cautions regarding the product, the labeled potency, the date use of potassium.) Potassium preparations of manufacture, the batch number, and may be given orally in divided doses totaling the name and address of the manufac- 1–1.5 milliequivalents/kilogram (1 gram K turer. contains 13.4 milliequivalents). When correc- tion of the arrhythmia is urgent, approxi- (2) The sample together with the mately 0.5 milliequivalents/kilogram of po- batch production record and results of tassium per hour may be given, with careful all tests conducted by or for the manu- electrocardiographic monitoring, as a solu- facturer to determine the product’s tion of 20 milliequivalents or less per 500 mil- identity, strength, quality, and purity, liliters in 5 percent dextrose in water. The content uniformity and dissolution total dose should generally not exceed 2 shall be submitted to the Department milliequivalents of potassium/kilogram. of Health and Human Services, Public DOSAGE AND ADMINISTRATION Health Service, FDA National Center Digitalization must be individualized. Gen- for Drug Analysis, 1114 Market St., St. erally, premature and immature infants are Louis, MO 63101. The outer wrapper particularly sensitive, requiring reduced dos- shall be identified ‘‘SAMPLE— age that must be determined by careful ti- DIGOXIN CERTIFICATION.’’ tration. (h) The Food and Drug Administra- Oral Dosage. Beyond the immediate new- tion is aware of data with two in vitro born period, children require proportionally methods, in addition to that described greater doses than adults on the basis of in The United States Pharmacopeia body weight or surface area. The rec- ommended oral digitalizing dosages in chil- (USP XVIII), developed to measure dren with normal renal function are: digoxin tablets dissolution. These two Newborn infants (normal), up to 1 month, methods, the so-called ‘‘paddle-water’’ require 40–60 micrograms/kilogram. and ‘‘paddle-acid’’ methods, are de- Infants, 1 month to 2 years, require ap- scribed below and are identical with proximately 60–80 micrograms/kilogram. the exception of the nature of the dis- Children 2 years to 10 years, require 40–60 solution medium used in the proce- micrograms/kilogram. Children, over 10 years of age, require dures (i.e., distilled or deionized water adult dosages in proportion to their body vs. dilute hydrochloric acid (0.6 percent weight. volume/volume)). The dissolution appa- Maintenance therapy is 20–30 percent of ratus used in these two methods differs the digitalizing dose administered each day. significantly from the apparatus de- Long term use of digoxin is indicated in al- scribed in the method in the compen- most all infants who have been digitalized dium. The Food and Drug Administra- for acute congestive heart failure unless the cause is transient. Many favor maintaining tion is aware that the three methods digoxin until at least 2 years of age in all in- (i.e., USP, ‘‘paddle-water,’’ and ‘‘pad- fants with paroxysmal atrial tachycardia or dle-acid’’) show significant differences in those who show either definite or latent in dissolution in comparative tests on failure. some formulations. Definitive bioavail- Many children with severe inoperable con- ability data to compare the relative genital defects need digoxin throughout value of each of these methods to pre- childhood and often for life. dict bioavailability of the few formula- (f) Abbreviated new drug applications tions where the methods show signifi- shall be submitted to the Food and cant differences in dissolution rate are Drug Administration, Center for Drug not now available. Manufacturers who Evaluation and Research, Office of Ge- conduct research utilizing the ‘‘paddle- neric Drugs, 5600 Fishers Lane, Rock- water’’ and ‘‘paddle-acid’’ methods, ville, MD 20857. particularly in comparison with the (g) All samples of digoxin tablets re- method in The United States Pharma- quired by paragraph (a)(3) of this sec- copeia, shall submit any data obtained
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using these methods to the Food and this first solution to 100.0 milliliters Drug Administration pursuant to sec- with 95 percent ethanol and mix for the tion 505(k) of the act. second solution. Just prior to use, indi- (1) Dissolution apparatus. vidually dilute 1.0, 2.0, 3.0, 4.0, and 5.0 milliliter aliquots of the second solu- (NOTE: Throughout this procedure use scru- pulously clean glassware, which previously tion with dissolution medium to 50.0 has been rinsed with dilute hydrochloric milliliters. These solutions are equiva- acid, distilled or deionized water, then with lent to 20, 40, 60, 80, and 100 percent of alcohol, and carefully dried. Take pre- dissolution, respectively, for a 0.25 mil- cautions to prevent contamination from air- ligram digoxin tablet. borne, fluorescent particles and from metal (iii) Extraction solvent. Prepare a sol- and rubber surfaces.) The apparatus consists vent containing 6 volumes of chloro- of a suitable water bath, a 1000 milliliter glass vessel (Kimble Glass No. 26220 or equiv- form, analytical reagent grade, with 1 alent), a motor, and a polytetrafluoro- volume of n-propyl alcohol, analytical ethylene stirring blade (Sargent S–76637, Size reagent grade. B, 3 inch length; or equivalent) on a glass (iv) Ascorbic acid-methanol solution. stirring shaft (Sargent 5–76636, 14.5 inch Prepare a solution containing 2 milli- length; or equivalent). The water bath may grams of ascorbic acid, analytical rea- be of any convenient size that permits keep- gent grade, per 1 milliliter of meth- ° ing the water temperature uniformly at 37 anol, absolute, analytical reagent C. ±0.5° C. throughout the test. The vessel is spherical, and is provided with three ports at grade. the top, one of which is centered. The lower (v) Hydrochloric acid, concentrated rea- half of the vessel is 65 millimeters in inside gent grade. radius and the vessel’s nominal capacity is (vi) Hydrogen peroxide-methanol solu- 1000 milliliters. The glass stirring shaft from tion. On the day of use, dilute 2.0 milli- the motor is placed in the center port, and liters of recently assayed 30 percent one of the outer ports may be used for inser- hydrogen peroxide, reagent grade, with tion of a thermometer. Samples may be re- methanol, absolute, analytical reagent moved for analysis through the other port. The motor is fitted with a speed-regulating grade to 100.0 milliliters. Store in a re- device that allows the motor speed to be held frigerator. Just prior to use, dilute 2.0 at 50 rpm ±2 rpm. The motor is suspended milliliters of this solution with meth- above the vessel in such a way that it may be anol to 100.0 milliliters. raised or lowered to position the stirring (3) Procedure—(i) Dissolution. Place blade. The glass stirring shaft is 10 millime- 500 milliliters of dissolution medium in ters in diameter and about 37 centimeters in the vessel, immerse it in the constant- length. It must run true on the motor axis temperature bath set at 37°C.±0.5°C., without perceptible wobble. The polytetra- fluoroethylene stirring blade is 4 millimeters and allow the dissolution medium to thick and forms a section of a circle, whose assume the temperature of the bath. diameter is 83 millimeters and which is sub- Position the shaft so that there is a tended by parallel chords of 42 and 77 milli- distance of 2.5 centimeters ±0.2 centi- meters. The blade is positioned horizontally, meter between the midpoint of the bot- with the 42-millimeter edge down, 2.5 centi- tom of the blade and the bottom of the meters ±0.2 centimeter above the lowest vessel. With the stirrer operating at a inner surface of the vessel. speed of 50 rpm±2 rpm, place 1 tablet (2) Reagents—(i) Dissolution medium. into the flask. After 60 minutes, accu- For ‘‘paddle-water,’’ use distilled or rately timed, withdraw 25 milliliters, deionized water. For ‘‘paddle-acid,’’ use using a glass syringe connected to a dilute hydrochloric acid (0.6 percent glass sampling tube, of solution from a volume/volume). Use the same batch of point midway between the stirring dissolution medium throughout the shaft and the wall of the vessel, and ap- test. proximately midway in depth. Filter (ii) Standard solutions. Accurately the solution promptly after with- weigh approximately 25 milligrams of drawal, using a suitable membrane fil- The United States Pharmacopeia ter of not greater than 0.8 micron po- Digoxin Reference Standard, dissolve rosity (Millipore AAWP 025 00, or in a minimum amount of 95 percent equivalent), mounted in a suitable ethanol in a 500 milliliter volumetric holder (Millipore Swinnex SX00 025 00, flask and add 95 percent ethanol to vol- or equivalent), discarding the first 100 ume and mix. Dilute 10.0 milliliters of milliliters of filtrate. This is the test
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solution. Repeat the dissolution proce- percent of the assayed amount of dure on 5 additional tablets. digoxin are new drugs which may be (ii) Extraction. Transfer 10.0 milli- marketed only with an approved full liters of each of the six filtrates, 10.0 new drug application as provided for in milliliters of each of the five standard § 314.50 of this chapter. The application solutions, and 10.0 milliliters of dis- shall include, but not be limited to, solution medium, to provide a blank, in clinical studies establishing signifi- separate 60-milliliter separators. Ex- cantly greater bioavailability than tract each solution with two 10-milli- digoxin tablets meeting compendial re- liter portions of extraction solvent. quirements and dosage recommenda- Combine the extracts of each solution tions based on clinical studies estab- in separate, glass-stoppered, 50-milli- lishing the safe and effective use of the liter conical flasks, and evaporate on a bioavailable digoxin product. Market- steam bath with the aid of a stream of ing of these digoxin products will be al- nitrogen to dryness, rinsing the sides lowed only under a proprietary or trade of the flasks with extraction solvent. name, established name, and labeling Take care to ensure that all traces of which differs from that used for solvent are removed, but avoid pro- digoxin tablets that meet all of the re- longed heating. For convenience the quirements in The United States Phar- residues may be stored in a vacuum macopeia (USP XVIII) and that are for- desiccator overnight. mulated so that either (a) the quantity (iii) Measurement of fluorescence. of digoxin dissolved at one hour is not Begin with the standard solutions, and more than 95 percent of the assayed keep all flasks in the same sequence amount of digoxin or (b) the quantity throughout, so that the elapsed time of digoxin dissolved at 15 minutes is from addition of reagents to reading of not more than 90 percent of the as- fluorescence is the same for each. sayed amount of digoxin. New drug ap- Carry the test solutions, standard solu- plications for these digoxin products tions, and the blank through the deter- shall be submitted to the Food and mination in one group. Add the follow- Drug Administration, Center for Drug ing three reagents in as rapid a se- Evaluation and Research, Office of quence as possible, swirling after each Drug Evaluation I (HFD–100), 5600 Fish- addition, treating 1 flask at a time, in ers Lane, Rockville, MD 20857. the order named: 1.0 milliliter of ascor- [39 FR 11680, Mar. 29, 1974, as amended at 41 bic acid-methanol solution, 3.0 milli- FR 43137, Sept. 30, 1976; 41 FR 49482, Nov. 3, liters of concentrated hydrochloric 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, acid, and 1.0 milliliter of hydrogen per- Mar. 29, 1990] oxide-methanol solution. Insert the EFFECTIVE DATE NOTE: The provisions of 21 stoppers in the flasks, and after 2 CFR 310.500(a)(1) as they apply to the sub- hours, measure the fluorescence at mission of abbreviated new drug applications about 485 millimicrons, using exci- are stayed until 30 days after such time as a tation at about 372 millimicrons. In decision is reached regarding revision of the product labeling set forth in § 310.500(e). See order to provide a check on the stabil- 39 FR 9184, Mar. 8, 1974. However, the stay is ity of the fluorometer, reread one or removed insofar as it affects labeling re- more standard solutions. Correct each quirements for digoxin products. See 41 FR reading for the blank and plot a stand- 43136, Sept. 30, 1976. ard curve of fluorescence versus precentage dissolution. Determine the § 310.501 Patient package inserts for percentage dissolution of digoxin in the oral contraceptives. test solutions by reading from the (a) Requirement for a patient package standard graph. insert. The safe and effective use of oral (iv) Digoxin tablets formulated so contraceptive drug products requires that the quantity of digoxin dissolved that patients be fully informed of the at one hour, when tested by the method benefits and the risks involved in their in The United States Pharmacopeia use. An oral contraceptive drug prod- (USP XVIII), is greater than 95 percent uct that does not comply with the re- of the assayed amount of digoxin and quirements of this section is mis- so that the quantity of digoxin dis- branded under section 502 of the Fed- solved at 15 minutes is greater than 90 eral Food, Drug, and Cosmetic Act.
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Each dispenser of an oral contraceptive (8) A statement of other serious ad- drug product shall provide a patient verse reactions and potential safety package insert to each patient (or to hazards that may result from the use an agent of the patient) to whom the of oral contraceptives. product is dispensed, except that the (9) A statement concerning common, dispenser may provide the insert to the but less serious side effects which may parent or legal guardian of a legally in- help the patient evaluate the benefits competent patient (or to the agent of and risks from the use of oral contra- either). The patient package insert is ceptives. required to be placed in or accompany (10) Information on precautions the each package dispensed to the patient. patients should observe while taking (b) Distribution requirements. (1) For oral contraceptives, including the fol- oral contraceptive drug products, the lowing: manufacturer and distributor shall pro- (i) A statement of risks to the moth- vide a patient package insert in or with er and unborn child from the use of each package of the drug product that the manufacturer or distributor in- oral contraceptives before or during tends to be dispensed to a patient. early pregnancy; (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 fits associated with oral contraceptive use. use. (5) A discussion of the contraindica- tions 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 distribu- but deserve special consideration in tor, or the name and place of business connection with oral contraceptive use 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.
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(d) Other indications. The patient 3,3′, 4,5′-tetrachlorosalicylanilide (TC– package insert may identify indica- SA)) as an ingredient in drug products. tions in addition to contraception that (6) Chloroform used as an ingredient are identified in the professional label- (active or inactive) in drug products. ing for the drug product. (7) Cobalt preparations intended for (e) Labeling guidance texts. The Food use by man. and Drug Administration issues infor- (8) Intrauterine devices for human mal labeling guidance texts under use for the purpose of contraception § 10.90(b)(9) of this chapter to provide that incorporate heavy metals, drugs, assistance in meeting the requirements or other active substances. of this section. A request for a copy of (9) Oral prenatal drugs containing the guidance texts should be directed fluorides intended for human use. to the Center for Drug Evaluation and (10) Parenteral drug products in plas- Research, Division of Metabolism and tic containers. Endocrine Drug Products (HFD–510), (11) Sterilization of drugs by irradia- Food and Drug Administration, 5600 tion. Fishers Lane, Rockville, MD 20857. (12) Sweet spirits of nitre drug prod- (f) Requirement to supplement approved ucts. application. Holders of approved appli- (13) Thorium dioxide for drug use. cations for oral contraceptive drug (14) Timed release dosage forms. products that are subject to the re- (15) Vinyl chloride as an ingredient, quirements of this section are required including propellant, in aerosol drug to submit supplements under § 314.70(c) products. of this chapter to provide for the label- (b) Any drug listed in paragraph (a) ing required by this section. Such la- of this section, when composed wholly beling may be put into use without ad- or partly of any antibiotic drug, must vance approval by the Food and Drug be certified under section 507 of the act Administration. or exempted from certification under section 507 of the act for marketing. [54 FR 22587, May 25, 1989] [62 FR 12084, Mar. 14, 1997]
§ 310.502 Certain drugs accorded new EFFECTIVE DATE NOTE: At 62 FR 12084, Mar. drug status through rulemaking 14, 1997, § 310.502 was revised, effective Apr. procedures. 14, 1997. For the convenience of the user, the (a) The drugs listed in this paragraph superseded text is set forth as follows: (a) have been determined by rule- § 310.502 Intrauterine devices for human making procedures to be new drugs use for the purpose of contraception. within the meaning of section 201(p) of (a) New drug status of certain intrauterine de- the act. Except as provided in para- vices for human use for the purpose of contra- graph (b) of this section, an approved ception. (1) The Food and Drug Administra- new drug application under section 505 tion has become aware of the increased clini- of the act and part 314 of this chapter cal use for the purpose of contraception of intrauterine devices (IUD’s) that incorporate is required for marketing the following heavy metals, drugs, or other active sub- drugs: stances. The amount of local irritation (1) Aerosol drug products for human caused by such active materials has been re- use containing 1,1,1-trichloroethane. ported as being correlated, in animal studies, (2) Aerosol drug products containing to the efficacy of such devices in achieving zirconium. their contraceptive effect. Several investiga- tors have reported different pregnancy rates (3) Amphetamines (amphetamine, which appear to be dependent on the type of dextroamphetamine, and their salts, metal used and/or the amount of exposed sur- and levamfetamine and its salts) for face of the metal. Drugs have been incor- human use. porated with otherwise inert intrauterine de- (4) Camphorated oil drug products. vices to increase the contraceptive effect, de- (5) Certain halogenated crease adverse reactions, or provide in- salicylanilides (tribromsalan (TBS, creased medical acceptability. ′ (2) Intrauterine devices used for the pur- 3,4 ,5-tribromosalicylanilide), pose of contraception and incorporating dibromsalan (DBS, 4′, 5- heavy metals, drugs, or other active sub- dibromosalicylanilide), metabromsalan stances to increase the contraceptive effect, (MBS, 3, 5-dibromosalicylanilide), and to decrease adverse reactions, or to provide
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increased medical acceptability, are not gen- the endometrium, probably through foreign erally recognized as safe and effective for body reaction in the uterus. contraception and are new drugs within the meaning of section 201(p) of the Federal INDICATIONS AND USAGE Food, Drug, and Cosmetic Act. A completed The labeling may include indications and and signed ‘‘Investigational New Drug Appli- usages other than those stated below, pro- cation’’ set forth in part 312 of this chapter) vided that an approved new drug application must therefore be submitted to cover clini- is in effect. cal investigations to obtain evidence that (Name of drug IUD) is indicated for contra- such preparations are safe and effective for ception. this use. An approved new drug application is required for the marketing of such arti- CONTRAINDICATIONS cles. (b) Labeling of intrauterine contraceptive de- IUD’s should not be inserted when the fol- vices considered new drugs (drug IUD’s). The lowing conditions exist: intrauterine contraceptive device is a popu- 1. Pregnancy or suspicion of pregnancy. lar method of contraception used by several 2. Abnormalities of the uterus resulting in million women in the United States. Al- distortion of the uterine cavity. though this method of contraception is gen- 3. Acute pelvic inflammatory disease or a erally safe and effective, certain complica- history of repeated pelvic inflammatory dis- tions and side effects may result from its ease. use. A Food and Drug Administration review 4. Post partum endometritis or infected of the labeling of intrauterine contraceptive abortion in the past 3 months. devices currently marketed in the United 5. Known or suspected uterine or cervical States reveals that information necessary malignancy including unresolved, abnormal for the safe and effective use of these prod- ‘‘Pap’’ smear. ucts is not uniformly available to either the 6. Genital bleeding of unknown etiology. practitioner or the patient. Based on the re- 7. Untreated acute cervicitis until infec- view of the labeling and on the recommenda- tion is controlled. tions of the Ad Hoc Obstetric-Gynecology 8. Copper-containing IUD’s should not be Advisory Committee, the Commissioner has inserted in presence of diagnosed Wilson’s concluded that in the interest of safe and ef- Disease. fective use, and prevention of misleading la- 9. Known allergy to copper. (For copper- beling, there is a need to establish uniform containing IUD’s.) physician and patient labeling for such drugs. WARNINGS (1) Labeling accompanying each drug IUD 1. Pregnancy—a. Long-term effects.—Long- and directed to the physician shall be sub- term effects on the offspring when pregnancy stantially as follows, adjusted where appro- occurs with (name of drug IUD) in place are priate to the requirements of a particular unknown. drug IUD. b. Septic abortion. Reports have indicated an increased incidence of septic abortion as- DESCRIPTION sociated in some instances with septicemia, (To be supplied by manufacturer) septic shock, and death in patients becoming pregnant with an IUD in place. Most of these Description shall include the following in- reports have been associated with the mid- formation: trimester of pregnacy. In some cases, the ini- 1. Proprietary or established name of the tial symptoms have been insidious and not IUD. easily recognized. If pregnancy should occur 2. Major ingredients or composition. with an IUD in place, the IUD should be re- 3. Model. moved if the string is visible or, if removal 4. Physical dimensions (size and shape). proves to be or would be difficult, termi- 5. Description of components in package or nation of the pregnancy should be considered system. and offered the patient as an option bearing 6. A statement that the product is sterile. in mind that the risks associated with an 7. Other characteristics. elective abortion increase with gestational age. MODE OF ACTION OR PRINCIPLES OF IUD c. Continuation of pregnancy. If the patient DESIGN chooses to continue the pregnancy, she must be warned of the increased risk of sponta- (TO BE SUPPLIED BY THE MANUFACTURER) neous abortion and of the increased risk of The manufacturer shall include informa- sepsis, including death if the pregnancy con- tion on the mode of action or principles of tinues with the IUD in place. The patient the IUD’s design. At a minimum, the state- must be closely observed and she must be ad- ment should provide that IUD’s seem to vised to report all abnormal symptoms, such interfere in some manner with nidation in as flu-like syndrome, fever, abdominal
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cramping and pain, bleeding, or vaginal dis- patency of the endocervical canal and the in- charge immediately because generalized ternal os, and the direction and depth of the symptoms of septicemia may be insidious. uterine cavity. In occasional cases, severe 2. Ectopic pregnancy. a. A pregnancy that cervical stenosis may be encountered. Do not occurs with an IUD in place is more likely to use excessive force to overcome this resist- be ectopic than a pregnancy occurring with- ance. out an IUD in place. Accordingly, patients c. The uterus should sound to a depth of 6 who become pregnant while using the IUD to 8 centimeters (cm). Insertion of an IUD should be carefully evaluated for the possi- into a uterine cavity measuring less than 6.5 bility of an ectopic pregnancy. cm by sounding may increase the incidence b. Special attention should be directed to of expulsion, bleeding, and pain. patients with delayed menses, slight d. The possibility of insertion in the pres- metrorrhagia and/or unilateral pelvic pain ence of an existing undetermined pregnancy and to those patients who wish to terminate is reduced if insertion is performed during or a pregnancy because of IUD failure to deter- shortly following a menstrual period. The mine whether ectopic pregnancy has oc- IUD should not be inserted post partum or curred. postabortion until involution of the uterus is 3. Pelvic infection. Pelvic infection may completed. The incidence of perforation and occur with the IUD in place and at times re- expulsion is greater if involution is not com- sult in the development of tubo-ovarian ab- pleted. scesses or general peritonitis. Appropriate e. IUD’s should be used with caution in aerobic and anaerobic bacteriologocal stud- those patients who have an anemia or a his- ies should be done and antibiotic therapy ini- tory of menorrhagia or hypermenorrhea. Pa- tiated. If the infection does not show a tients experiencing menorrhagia and/or marked clinical improvement within 24 to 48 metrorrhagia following IUD insertion may hours, the IUD should be removed and the be at risk for the development of continuing treatment reassessed based upon hypochromic microcytic anemia. Also, IUD’s the results of culture and sensitivity tests. should be used with caution in patients re- 4. Embedment. Partial penetration or lodg- ceiving anticoagulants or having a ing of the IUD in the edometrium can result coagulopathy. in difficult removals. f. Syncope, bradycardia or other 5. Perforation. Partial or total perforation neurovascular episodes may occur during in- of the uterine wall or cervix may occur with sertion or removal of IUD’s especially in pa- the use of IUD’s. The possibility of perfora- tients with a previous disposition to these tion must be kept in mind during insertion conditions. and at the time of any subsequent examina- g. Patients with valvular or congenital tion. If perforation occurs, the IUD should be heart disease are more prone to develop removed. Adhesions, foreign body reactions, subacute bacterial endocarditis than pa- and intestinal obstruction may result if an tients who do not have valvular or congeni- IUD is left in the peritioneal cavity. tal heart disease. Use of an IUD in these pa- 6. Congenital anomalies. Systemically ad- tients may represent a potential source of ministered sex steroids, including septic emboli. progestational agents, have been associated h. Use of an IUD in those patients with with an increased risk of congenital anoma- acute cervicitis should be postponed until lies. It is not known whether such anomalies proper treatment has cleared up the infec- could occur when pregnancy is continued tion. with a progesterone-containing IUD in place. i. Since an IUD may be expelled or dis- placed, patients should be reexamined and PRECAUTIONS evaluated shortly after the first post- 1. Patient counseling. Prior to insertion the insertion menses, but definitely within 3 physician, nurse, or other trained health pro- months after insertion. Thereafter annual fessional must provide the patient with the examination with appropriate medical and Patient Brochure. The patient should be laboratory examination should be carried given the opportunity to read the brochure out. The IUD should be replaced every ---- and discuss fully any questions she may have years (information to be supplied by manu- concerning the IUD as well as other methods facturer). of contraception. j. The patient should be told that some 2. Patient evaluation and clinical consider- bleeding and cramps may occur during the ations. a. A complete medical history should first few weeks after insertion, but if her be obtained to determine conditions that symptoms continue or are severe she should might influence the selection of an IUD. report them to her physician. She should be Physical examination should include a pelvic instructed on how to check after each men- examination, ‘‘Pap’’ smear, gonorrhea cul- strual period to make certain that the ture and, if indicated, appropriate tests for thread still protrudes from the cervix, and other forms of venereal disease. she should be cautioned that there is no con- b. The uterus should be carefully sounded traceptive protection if the IUD is expelled. prior to insertion to determine the degree of She should be cautioned not to pull on the
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thread and displace the IUD. If partial expul- of sponsor) with the (name of drug IUD), use sion occurs, removal is indicated and a new effectiveness was determined as follows for IUD may be inserted. The patient should be parous and nulliparous women, as tabulated told to return in ---- years for replacement of by the life table method. (Rates are ex- the IUD. pressed as events per 100 women through 12 k. The use of medical diathermy (short- and 24 months of use.) This experience is wave and microwave) in patients with metal- based on (number) women/months of use, in- containing IUD’s may cause heat injury to cluding (number) women who completed 12 the surrounding tissue. Therefore, medical months of use and (number) women who diathermy to the abdominal and sacral areas completed 24 months of use. should not be used. l. Copper-containing IUD’s—A copper in- 12 mo 24 mo duced urticarial allergic skin reaction may Parous Nulliparous Parous Nulliparous develop in women wearing a copper-contain- ing IUD. If symptoms of such an allergic re- Pregnancy .. sponse occur, the patient should be in- Expulsion ... structed to tell the consulting physician Medical re- that a copper-bearing device is being worn. moval ...... Continuation ADVERSE REACTIONS rate ...... These adverse reactions are not listed in any order of frequency or severity. (2) Labeling, in sufficient quantities to be Reported adverse reactions include: endo- available to patients who express interest in metritis, spontaneous abortion, septic abor- IUD’s, shall accompany each drug IUD tion, septicemia, perforation of the uterus (packaged separately from the sterile pack- and cervix, embedment, fragmentation of the aging), be made available to the patient, and IUD, pelvic infection, vaginitis, leukorrhea, contain the following information: cervical erosion, pregnancy, ectopic preg- nancy, difficult removal, complete or partial PATIENT INFORMATION expulsion of the IUD, intermenstrual spot- This brochure provides information on the ting, prolongation of menstrual flow, ane- use of intrauterine contraceptive devices mia, pain and cramping, dysmenorrhea back- (IUD’s). There are other birth control meth- aches, dyspareunia, neurovascular episodes ods that may be suitable. Before deciding including bradycardia, and syncope second- which type of birth control method to use, ary to insertion. Perforation into the abdo- you should read this brochure and have the men has been followed by abdominal adhe- opportunity to discuss fully with your doctor sions, intestinal penetration, intestinal ob- any questions you may have about the IUD struction, and cystic masses in the pelvis and other methods of contraception. For copper-containing IUD’s the following adverse reaction should also be added: PREINSERTION INFORMATION urticarial allergic skin reaction. WHAT YOU SHOULD KNOW ABOUT THE IUD DIRECTIONS FOR USE IUD’s are small articles of various sizes (TO BE SUPPLIED BY MANUFACTURER) and shapes which are inserted into the uter- Directions for use shall include the follow- us (womb). The purpose of the IUD is to pre- ing: vent pregnancy. 1. Insertion technique. How the IUD prevents pregnancy is not 2. Requirements for replacement and re- completely understood. Several theories moval (including information on whether the have been suggested. IUD’s seem to interfere IUD should be replaced periodically and, if in some manner with the implantation of the so, how often). fertilized egg in the lining of the uterine cav- ity. The IUD does not prevent ovulation. CLINCIAL STUDIES The effectiveness of the IUD is measured Different event rates have been recorded by the pregnancy rate of women who use it with the use of different IUD’s. Inasmuch as and the rate of adverse reactions and side ef- these rates are usually derived from separate fects requiring removal of the IUD. studies conducted by different investigators USE-EFFECTIVENESS in several population groups, they cannot be compared with precision. Furthermore, Different pregnancy and adverse reaction event rates tend to be lower as clinical expe- rates have been reported with the use of dif- rience is expanded, possibly due to retention ferent IUD’s. Because these rates are usually in the clinical study of those patients who derived from separate studies conducted by accept the treatment regimen and do not dis- different investigators in several population continue due to adverse reactions or preg- groups, they cannot be compared with preci- nancy. In clincial trials conducted by (name sion.
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In clinical trials with (name of drug IUD), Prolonged or heavy menstrual flow. ——— patients completed ——— cycles or Septic abortion (infected miscarriage) fol- months in use. The incdience of unplanned lowed in some cases by blood poisoning pregnancies was ——— per 100 woman years (septicemia) which can lead to death. or ——— women out of 100 became pregnant Spontaneous abortion (miscarriage). in a year while using an IUD. The incidence Vaginal discharge and infection. of adverse reactions requiring medical re- If you decide on the IUD as your method of moval of the IUD is ——— per 100 woman birth control, read the following information years or ——— women out of 100 discontinued and instructions carefully. Please keep this using the IUD for medical reasons. brochure so that you may refer to it. If you WHAT YOU SHOULD TELL YOUR DOCTOR have any questions, consult your doctor. Before you have an IUD inserted, you POSTINSERTION INFORMATION should tell your doctor if you have ever had, or suspect you have ever had, any of the fol- DESCRIPTION lowing conditions which might make the (TO BE SUPPLIED BY MANUFACTURER) IUD unsuitable as a method of contraception for you: Description shall include the following in- formation: Abnormalities of the uterus (womb). 1. Proprietary or established name of the Allergy to copper. drug IUD. Anemia. 2. Model. Bleeding between periods. 3. Physical dimensions (size and shape). Cancer of the uterus (womb) or cervix. 4. Composition (metal or plastic). Fainting attacks. 5. Color and number of the tail or threads. Heart disease. 6. Other characteristics. Heart murmur. Heavy menstrual flow. DIRECTIONS FOR USE Infection of the uterus (womb) or cervix. Pelvic infection (plus in fallopian tubes). 1. Checking your IUD. A tail or thread is at- Prior IUD use. tached to the IUD so you can check to see if Prior uterine surgery. it is still in place since the IUD can come out Recent abortion or miscarriage. of the uterus (womb) without your knowing Recent pregnancy. it. This occurs most often during or right Severe mentstrual cramps. after a menstrual period. Suspected or possible pregnancy. Follow these steps to make sure your IUD Suspicious or abnormal ‘‘Pap’’ smear. is in place: Unexplained genital bleeding. a. Wash your hands. Vaginal discharge or infection. b. Assume the squatting postion or seat Venereal disease. yourself on the toilet. Wilson’s disease. c. Insert the index or middle finger high in vagina and locate the cervix (mouth of the ADVERSE REACTIONS uterus (womb)). The cervix feels firm like the tip of your nose. The following adverse reactions and side d. Feel for the tail or thread of the IUD, effects have been reported and may occur which should be in the cervix high in your after the IUD is inserted: vagina. Anemia. e. If your can feel the tail or thread it is Backache. likely that the IUD is in place and working. Blood poisoning (septicemia). You should not pull on the tail or thread. Bowel obstruction. This may displace the IUD. Cervical infection. f. After each menstrual period, you should Complete or partial expulsion. check to make sure the tail or thread is in Cysts on ovaries and tubes. place in the cervix. You may check for the Delayed menstruation. tail or thread more often if you wish. Difficult removal. g. If you think the IUD has come out or Embedment. has been displaced (e.g., you cannot feel the Fainting at the time of insertion or removal. tail or thread or you can feel the IUD itself), Fragmentation of the IUD. use another birth control method, such as Intermenstrual spotting. contraceptive vaginal foam, cream, or jelly, Internal abdominal adhesions. or condoms (rubbers), until you can be Pain and cramps. checked. (These alternative methods are not Painful intercourse. as effective as the IUD.) Call your doctor for Pelvic infection. an examination. Perforation of the uterus (womb) or cervix. h. You should return to see your doctor as Pregnancy outside the uterus (womb) (tubal soon as possible after your next menstrual or ovarian). period, after insertion of your IUD, but no
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later than 3 months after insertion. This will infection because use of an IUD in itself does allow the doctor to make sure that the IUD not prevent venereal disease. is in the correct position. d. Tail or thread disappearance. If you can- i. After your first checkup, you should be not feel the tail or thread coming through checked at least once a year by your doctor. the cervix, it is possible that the IUD has 2. Continuation and removal. While you are been expelled or displaced or that perfora- wearing the IUD, you may use tampons and tion has occurred. If any of these has oc- take douches, if this is your usual practice. curred, you are no longer protected from be- With some IUD’s, you may wear the IUD coming pregnant. Use another birth control until you wish to become pregnant. With method, such as contraceptive vaginal foam, other IUD’s it is necessary that they be re- cream, or jelly, or condoms (rubbers), until placed every year or so in order for you to you can be checked. (These alternative continue being protected against pregnancy. methods are not as effective as the IUD.) Check with your doctor concerning this. You 2. Do not undergo medical diathermy (in- should return to your doctor if you wish to cluding shortwave or microwave) treatments have the IUD removed. to the abdomen or lower back areas if you are wearing a metal IUD. These treatments SIDE EFFECTS may cause heat injury to the surrounding tissues. The following may occur during or after the IUD is inserted: SPECIAL WARNING ABOUT PREGNANCY WITH AN 1. Some bleeding occurs following insertion IUD IN PLACE in most women. Because of this, your doctor Some women become pregnant while using may choose to insert your IUD during or at an IUD. If you miss your menstrual period, the end of your menstrual period. This also or if you have a scanty flow during your pe- reduces the possibility that you are pregnant riod, or if you supect that you might be preg- at the time of IUD insertion. nant, see your doctor right away. Serious 2. Bleeding between menstrual periods, complication of sepsis (severe infection), sep- usually in the form of spotting, may occur tic abortion (infected miscarriage), and during the first 2 or 3 months after insertion. death have occurred when a pregnancy con- The first few menstrual periods after the in- tinues with an IUD in place. Most of the oc- sertion may be heavier and longer. If these currences of these serious complications conditions continue for longer than 2 or 3 have been reported in the middle third of months, consult your doctor. pregnancy. 3. Pain, usually in the form of uterine If your doctor confirms that you are preg- cramps or low backache, may occur at the nant, he should remove the IUD if the tail is time of insertion and last for a few days. visible. Removal of an IUD in pregnancy de- Simple pain medication usually relieves the creases the likelihood of serious complica- cramping. tions. 4. Fainting may occur at the time of inser- If removal of your IUD proves to be dif- tion or removal of an IUD. This passes quick- ficult, you and your doctor should discuss at ly and is not usually serious. that time the question of continuing the 5. The IUD may be expelled during the first pregnancy in view of the serious complica- two or three menstrual cycles following in- tions that may occur. In reaching a decision sertion. Expulsion increases the risk of an as to whether or not to have an abortion, it unplanned pregnancy. Although not as effec- should be remembered that the risks associ- tive as the IUD, the use of a second contra- ated with terminating a pregnancy increase ceptive method, such as a contraceptive vag- with the length of time you are pregnant. inal foam, cream, or jelly, or condoms (rub- bers) is recommended. (3) Any drug IUD that is not labeled as re- quired by this section and that is either in- WARNINGS troduced or delivered for introduction into interstate commerce, or held for sale after 1. Call your doctor for any of the following shipment in interstate commerce after No- reasons: vember 7, 1977, is misbranded pursuant to a. Severe or prolonged bleeding. If the flow is section 502 of the act. However, a drug IUD heavier and lasts much longer than your in the possession of an independent whole- usual menstrual flow, you may need to have saler, a retailer, or a licensed practitioner the IUD removed to prevent the development before November 7, 1977, is not misbranded if of anemia. labeling required by paragraph (b)(2) of this b. Pelvic pain and cramps. This could mean section is furnished to such independent an infection has developed requiring treat- wholesalers, retailers, or licensed practition- ment. ers in sufficient quantities to accompany c. Exposure to venereal disease (VD). If expo- each device in their possession. sure to venereal disease is suspected, report (4) The holder of an approved new drug ap- for examination and treatment promptly. plication for such device, as described in Failure to do so could result in serious pelvic paragraph (a)(2) of this section, shall submit
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a supplement to his application to provide sonably be expected to submit ade- for the labeling described in paragraphs (b) quate evidence of safety and effective- (1) and (2) of this section. The supplement ness for use as recommended in appro- shall be submitted before November 7, 1977, priate labeling. Such use may include, under the provisions of § 314.70 of this chap- ter. The labeling may be put into use with- among others, the uses in this tabula- out advance approval by the Food and Drug tion: Administration. (c) Applicability. Paragraphs (a) and (b) of Isotope Chemical form Use this section do not apply to the following Chromium 51 .. Chromate ...... Spleen scans. intrauterine contraceptive devices, which Do ...... do ...... Placenta localiza- are subject to the requirements of § 801.427 of tion. this chapter: Do ...... do ...... Red blood cell label- (1) Intrauterine devices fabricated solely ing and survival from inactive materials, e.g., inactive plas- studies. tics or metals. Do ...... Labeled human Gastrointestinal pro- (2) Intrauterine devices with substances serum albumin. tein loss studies. added to improve the physical characteris- Do ...... do ...... Placenta localiza- tics if such substances do not contribute to tion. contraception through chemical action on or Do ...... Labeled red blood Do. cells. within the body and are not dependent upon Cobalt 58 or Labeled Intestinal absorption being metabolized for the achievement of the Cobalt 60. cyanocobalamin. studies. contraceptive purpose. Gold 198 ...... Colloidal ...... Liver scans. (3) Intrauterine devices that contain a Do ...... do ...... Intracavitary treat- component, such as barium, added exclu- ment of pleural sively for the purpose of visualization by x- effusions and/or ray. ascites. Do ...... do ...... Interstitial treatment [42 FR 23777, May 10, 1977; 42 FR 25854, May of cancer. 20, 1977; 42 FR 35155, July 8, 1977; 55 FR 11578, Iodine 131 ...... Iodide ...... Diagnosis of thyroid Mar. 29. 1990] functions. Do ...... do ...... Thyroid scans. § 310.503 Requirements regarding cer- Do ...... do ...... Treatment of tain radioactive drugs. hyperthyroidism and/or cardiac (a) On January 8, 1963 (28 FR 183), the dysfunction. Commissioner of Food and Drugs ex- Do ...... do ...... Treatment of thyroid empted investigational radioactive new carcinoma. Do ...... Iodinated human Blood volume deter- drugs from part 312 of this chapter pro- serum albumin. minations. vided they were shipped in complete Do ...... do ...... Cisternography. conformity with the regulations issued Do ...... do ...... Brain tumor localiza- by the Nuclear Regulatory Commis- tion. Do ...... do ...... Placenta localiza- sion. This exemption also applied to in- tion. vestigational radioactive biologics. Do ...... do ...... Cardiac scans for (b) It is the opinion of the Nuclear determination of Regulatory Commission, and the Food pericardial effusions. and Drug Administration that this ex- Do ...... Rose Bengal ...... Liver function stud- emption should not apply for certain ies. specific drugs and that these drugs Do ...... do ...... Liver scans. should be appropriately labeled for uses Do ...... Iodopyracet, sodium Kidney function for which safety and effectiveness can iodohippurate, so- studies and kid- dium diatrizoate, ney scans. be demonstrated by new-drug applica- diatrizoate tions or through licensing by the Pub- methylglucamine, lic Health Service in the case of bio- sodium diprotrizoate, so- logics. Continued distribution under dium acetrizoate, the investigational exemption when or sodium the drugs are intended for established iothalamate. uses will not be permitted. Do ...... Labeled fats and/or Fat absorption stud- fatty acids. ies. (c) Based on its experience in regu- Do ...... Cholografin ...... Cardiac scans for lating investigational radioactive determination of pharmaceuticals, the Nuclear Regu- pericardial latory Commission has compiled a list effusions. Do ...... Macroaggregated Lung scans. of reactor-produced isotopes for which iodinated human it considers that applicants may rea- serum albumin.
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Isotope Chemical form Use Regulatory Commission and the Food and Drug Administration conclude that Do ...... Colloidal micro- Liver scans. aggregated such isotopes should not be distributed human serum al- under investigational-use labeling bumin. when they are actually intended for Iodine 125 ...... Iodide ...... Diagnosis of thyroid use in medical practice. function. Do ...... Iodinated human Blood volume deter- (2) The exemption referred to in para- serum albumin. minations. graph (a) of this section, as applied to Do ...... Rose Bengal ...... Liver function stud- any drug or biologic containing any of ies. Do ...... Iodopyracet, sodium Kidney function the isotopes listed in paragraph (c) of iodohippurate, so- studies. this section, in the ‘‘chemical form’’ dium diatrizoate, and intended for the uses stated, is ter- diatrizoate methyl- minated on March 3, 1972, except as glucamine, so- dium diprotrizoate, provided in paragraph (d)(3) of this sec- sodium tion. acetrizoate, or so- (3) The exemption referred to in para- dium iothalamate. Do ...... Labeled fats and/or Fat absorption stud- graph (a) of this section, as applied to fatty acids. ies. any drug or biologic containing any of Iron 59 ...... Chloride, citrate and/ Iron turnover stud- the isotopes listed in paragraph (c) of or sulfate. ies. this section, in the ‘‘chemical form’’ Krypton 85 ...... Gas ...... Diagnosis of cardiac abnormalities. and intended for the uses stated, for Mercury 197 ... Chlormerodrin ...... Kidney scans. which drug a new drug application or a Do ...... do ...... Brain scans. ‘‘Investigational New Drug Applica- Mercury 203 1 ...... do ...... Kidney scans. Do ...... do ...... Brain scans. tion’’ was submitted prior to March 3, Phosphorus 32 Soluble phosphate .. Treatment of poly- 1972, or for which biologic an applica- cythemia vera. tion for product license or ‘‘Investiga- Do ...... do ...... Treatment of leuke- tional New Drug Application’’ was sub- mia and bone me- tastasis. mitted prior to March 3, 1972, is termi- Do ...... Colloidal chromic Intracavitary treat- nated on August 20, 1976, unless an ap- phosphate. ment of pleural provable notice was issued on or before effusions and/or ascites. August 20, 1976, in which case the ex- Do ...... do ...... Interstitial treatment emption is terminated either upon the of cancer. subsequent issuance of a nonapprovable Potassium 42 .. Chloride ...... Potassium space notice for the new drug application or studies. Selenium 75 ... Labeled methionine Pancreas scans. on November 20, 1976, whichever occurs Strontium 85 ... Nitrate or chloride ... Bone scans on pa- first. tients with diag- (e) No exemption from section 505 of nosed cancer. the act or from part 312 of this chapter Technetium Pertechnetate ...... Brain scans. 99m. is in effect or has been in effect for ra- Do ...... do ...... Thyroid scans. dioactive drugs prepared from accelera- Do ...... Sulfur colloid ...... Liver and spleen tor-produced radioisotopes, naturally scans. Do ...... Pertechnetate ...... Placenta localiza- occurring isotopes, or nonradioactive tion. substances used in conjunction with Do ...... do ...... Blood pool scans. isotopes. Do ...... do ...... Salivary gland (f)(1) Based on its experience in regu- scans. Do ...... Diethylenetri-amine Kidney scans. lating investigational radioactive pentaacetic acid pharmaceuticals, the Nuclear Regu- (DTPA). latory Commission has compiled a list Xenon 133 ...... Gas ...... Diagnosis of cardia abnormalities. of reactor-produced isotopes for which Cerebral it considers that applicants may rea- bloodflow studies. sonably be expected to submit ade- Pulmonary func- quate evidence of safety and effective- tion studies. Mus- cle bloodflow ness for use as recommended in appro- studies. priate labeling; such use may include, 1 This item has been removed from the AEC list for kidney among others, the uses in this tabula- scans but is included as the requirements of this order are tion: applicable. (d)(1) In view of the extent of experi- Isotope Chemical form Use ence with the isotopes listed in para- Fluorine 18 ..... Fluoride ...... Bone imaging. graph (c) of this section, the Nuclear 39
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Isotope Chemical form Use provided in paragraph (f)(5) of this sec- tion. Indium-113m ... Diethylenetriamine Brain imaging; kid- pentaacetic acid ney imaging. (5)(i) Except as provided in paragraph (DTPA). (f)(5)(ii) of this section, the exemption Do ...... Chloride ...... Placenta imaging; referred to in paragraph (a) of this sec- blood pool imag- tion, as applied to any drug containing ing. any of the isotopes listed in paragraph Technetium Human serum albu- Lung imaging. 99m. min microspheres. (f)(1) of this section, in the ‘‘chemical Do ...... Diethylenetriamine Kidney imaging; kid- form’’ and intended for the uses stated, pentaacetic acid ney function stud- for which drug a new drug application (Sn). ies. or ‘‘Investigational New Drug Applica- Do ...... do ...... Brain imaging. Do ...... Polyphosphates ...... Bone imaging. tion’’ was submitted to the Center for Do ...... Technetated aggre- Lung imaging. Drug Evaluation and Research on or gated albumin before August 25, 1975 is terminated on (human). August 20, 1976, unless an approvable Do ...... Disodium etidronate Bone imaging. notice was issued on or before August 20, 1976, in which case the exemption is (2) In view of the extent of experience terminated either upon the subsequent with the isotopes listed in paragraph issuance of a nonapprovable notice for (f)(1) of this section, the Nuclear Regu- the new drug application or on Novem- latory Commission and the Food and ber 20, 1976, whichever occurs first. Drug Administration conclude that (ii) The exemption referred to in they should not be distributed under paragraph (a) of this section, as applied investigational-use labeling when they to any biologic containing any of the are actually intended for use in medi- isotopes listed in paragraph (f)(1) of cal practice. this section in the ‘‘chemical form’’ (3) Any manufacturer or distributor and intended for the uses stated, for interested in continuing to ship in which biologic an application for prod- interstate commerce drugs containing uct license or ‘‘Investigational New the isotopes listed in paragraph (f)(1) of Drug Application’’ was submitted to this section for any of the indications the Center for Biologics Evaluation listed, shall submit, on or before Au- and Research on or before August 25, gust 25, 1975 to the Center for Drug 1975 is terminated on October 20, 1976, Evaluation and Research, Food and unless an approvable notice was issued Drug Administration, 5600 Fishers on or before October 20, 1976, in which Lane, Rockville, MD 20857, a new drug case the exemption is terminated ei- application or a ‘‘Investigational New ther upon the subsequent issuance of a Drug Application’’ for each such drug nonapprovable notice for the new drug for which the manufacturer or distribu- application or on January 20, 1977, tor does not have an approved new drug whichever occurs first. application pursuant to section 505(b) (g) The exemption referred to in of the act. If the drug is a biologic, a paragraph (a) of this section, as applied ‘‘Investigational New Drug Applica- to any drug intended solely for inves- tion’’ or an application for a license tigational use as part of a research under section 351 of the Public Health project, which use had been approved Service Act shall be submitted to the on or before July 25, 1975 in accordance Center for Biologics Evaluation and with 10 CFR 35.11 (or equivalent regula- Research, Food and Drug Administra- tion of an Agreement State) is termi- tion, 8800 Rockville Pike, Bethesda, nated on February 20, 1976 if the manu- MD 20014, in lieu of any submission to facturer of such drug or the sponsor of the Center for Drug Evaluation and Re- the investigation of such drug submits search. on or before August 25, 1975 to the Food (4) The exemption referred to in para- and Drug Administration, Bureau of graph (a) of this section, as applied to Drugs, HFD–150, 5600 Fishers Lane, any drug or biologic containing any of Rockville, MD 20857, the following in- the isotopes listed in paragraph (f)(1) of formation: this section, in the ‘‘chemical form’’ (1) The research project title; and intended for the uses stated, is ter- (2) A brief description of the purpose minated on August 26, 1975 except as of the project;
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(3) The name of the investigator re- (2) In addition to those dosage forms sponsible; that were reviewed for efficacy by the (4) The name and license number of Academy, other dosage forms of am- the institution holding the specific li- phetamine drugs are on the market cense under 10 CFR 35.11 (or equivalent that were not cleared through the new regulation of an Agreement State); drug procedures. While certain amphet- (5) The name and maximum amount amines were marketed prior to enact- per subject of the radionuclide used; ment of the Federal Food, Drug, and (6) The number of subjects involved; Cosmetic Act in 1938, some of the con- and ditions of use subsequently prescribed, (7) The date on which the administra- recommended, or suggested in their la- tion of the radioactive drugs is ex- beling (for example, for the treatment pected to be completed. of obesity) differ from uses claimed for (h) The exemption referred to in the amphetamines before said enact- paragraph (a) of this section, as applied ment. Such uses have not been cleared to any drug not referred to in para- through the effectiveness provisions of graphs (d), (f), and (g) of this section, is the Drug Amendments of 1962 (Pub. L. terminated on August 26, 1975. 87–781 which amended the Federal Food, Drug, and Cosmetic Act). These [39 FR 11680, Mar. 29, 1974, as amended at 40 drugs are very extensively used in the FR 31307, July 25, 1975; 40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, treatment of obesity. The extent of use Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR for such purposes as narcolepsy and 11578, Mar. 29, 1990] minimal brain dysfunction in children is believed to be minor as compared § 310.504 Amphetamines (amphet- with the total usage of these drugs. Be- amine, dextroamphetamine, and cause of their stimulant effect on the their salts and levamfetamine and central nervous system, they have a its salts) for human use. potential for misuse by those to whom (a) Amphetamine and they are available through a physi- dextroamphetamine and their salts. (1) cian’s prescription, and their abuse by Pursuant to the drug efficacy require- those who obtain them through illicit ments of the Federal Food, Drug, and channels is well documented. Produc- Cosmetic Act, the National Academy of tion data indicate that amphetamines Sciences-National Research Council, have been produced and prescribed in Drug Efficacy Study Group, has evalu- quantities greatly in excess of dem- ated certain dosage forms of amphet- onstrated medical needs. amines and other sympathomimetic (3) Pursuant to a notice published in stimulant drugs intended for use in the the FEDERAL REGISTER of August 8, 1970 treatment of obesity and for other (35 FR 12652), which required the sub- uses. The Academy found that such mission of new drug applications as a drugs as a class have been shown to condition for continued marketing of have a generally short-term anorectic amphetamines, 106 new drug applica- action. They further commented that tions for amphetamines or amphet- clinical opinion on the contribution of amine-containing drug products were the sympathomimetic stimulants in a received. The data submitted in those weight reduction program varies wide- applications, and data obtained from ly, the anorectic effect of these drugs other sources concerning anorectic often plateaus or diminishes after a few drugs, generally supported the efficacy weeks, most studies of them are for of anorectic drugs. short periods, no available evidence (b) On the basis of currently avail- shows that use of anorectic alters the able evidence derived from short-term natural history of obesity, some evi- studies, the Commissioner concludes dence indicates that anorectic effects that single drug entity oral dosage may be strongly influenced by the sug- forms of amphetamine or gestibility of the patient, and reserva- dextroamphetamine are effective in the tions exist about the adequacy of the management of exogenous obesity as a controls in some of the clinical studies. short-term (a few weeks) adjunct in a Their significant potential for drug regimen of weight reduction, based on abuse was also cited. caloric restrictions, for patients in
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whom obesity is refractory to other men of weight reduction based on caloric re- measures. For purposes of this regula- striction, for patients in whom obesity is re- tion, a mixture of dextroamphetamine fractory to other measures. and amphetamine is ordinarily re- (3) Complete labeling guidelines are garded as a single drug entity. available from the Food and Drug Ad- (c) The Food and Drug Administra- ministration. tion is not aware of data providing sub- (h) Regulatory proceedings will be stantial evidence of the effectiveness of initiated with regard to any such drug levamfetamine and its salts and re- within the jurisdiction of the act which gards these preparations as new drugs is not in accord with this regulation. requiring approved full new drug appli- cations. [39 FR 11680, Mar. 29, 1974, as amended at 41 (d) In view of the well-documented FR 10885, Mar. 15, 1976; 55 FR 11578, Mar. 29, history of abuse of parenteral amphet- 1990] amines, the severe risk of drug depend- EFFECTIVE DATE NOTE: At 62 FR 12084, Mar. ence, and the availability of safer al- 14, 1997, § 310.504 was removed, effective Apr. ternative parenteral drugs which are 14, 1997. equally effective for recognized non- anorectic indications, the Food and § 310.506 Use of vinyl chloride as an Drug Administration regards paren- ingredient, including propellant, of aerosol drug products. teral amphetamines as lacking evi- dence of safety. (a) Vinyl chloride has been used as a (e) Any combination drug containing propellant in aerosol drug prepara- amphetamine or dextroamphetamine is tions. Evidence indicates that vinyl regarded as a new drug requiring an ap- chloride inhalation can result in acute proved full new drug application as a toxicity manifested by dizziness, head- condition for marketing. Data in new ache, disorientation, and unconscious- drug applications are required to fulfill ness where inhaled at high concentra- the criteria set forth in § 300.50 of this tions. Cardiac effects, bone changes, chapter governing fixed combination and degenerative changes in the brain, prescription drugs for humans. liver, and kidneys have been reported (f) New drug applications have been in animals. Studies also demonstrate received from persons marketing orally carcinogenic effects in animals as a re- administered single entity amphet- sult of inhalation exposure to vinyl amine or dextroamphetamine dosage chloride. Recently, vinyl chloride has forms. Any other person who intends to been linked to liver disease, including market such drug is required to submit liver cancer, in workers engaged in the to the Food and Drug Administration polymerization of vinyl chloride. an abbreviated application under (b) The Commissioner finds that § 314.55 of this chapter. there is a lack of general recognition (g) The labeling conditions for single by qualified experts of the safety or ef- entity oral dosage forms of amphet- fectiveness of aerosol drug prepara- amine and dextroamphetamine and tions containing vinyl chloride as an their salts are as follows: ingredient, including propellant. (1) The label shall bear the statement Therefore, any such product containing ‘‘Caution: Federal law prohibits dis- vinyl chloride is a new drug and a new pensing without prescription’’. drug application approved under sec- (2) The drug shall be labeled to com- tion 505 of the Federal Food, Drug, and ply with all requirements of the act Cosmetic Act is required for market- and regulations. The labeling shall ing. bear adequate information for safe and (c) Clinical investigations designed effective use of the drug. The indica- to obtain evidence that any aerosol tions for use are: drug preparation containing vinyl chlo- ride as an ingredient, including propel- Narcolepsy. lant, is safe and effective for the pur- Minimal brain dysfunction in children (hy- perkinetic behavior disorders), as an aid to pose intended, must comply with the general management. requirements and procedures governing Management of exogenous obesity as the use of investigational new drugs short-term (a few weeks) adjunct in a regi- set forth in part 312 of this chapter.
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(d) Any such drug within the jurisdic- is not in accord with this regulation on tion of the act which is not in accord January 16, 1978. with this regulation is subject to regu- [42 FR 63387, Dec. 16, 1977, as amended at 55 latory action. FR 11578, Mar. 29, 1990]
[39 FR 30830, Aug. 26, 1974, as amended at 55 EFFECTIVE DATE NOTE: At 62 FR 12084, Mar. FR 11578, Mar. 29, 1990] 14, 1997, § 310.507 was removed, effective Apr. 14, 1997. EFFECTIVE DATE NOTE: At 62 FR 12084, Mar. 14, 1997, § 310.506 was removed, effective Apr. 14, 1997. § 310.508 Use of certain halogenated salicylanilides as an inactive ingre- § 310.507 Aerosol drug products for dient in drug products. human use containing 1,1,1- (a) Halogenated salicylanilides trichloroethane. (tribromsalan (TBS, 3,4′,5– (a) Trichloroethane has been used in tribromosalicylanilide), dibromsalan ′ aerosol drug products as a solvent for (DBS, 4 , 5–dibromosalicylanilide), the active ingredients and to reduce metabromsalan (MBS, 3, 5– ′ ′ the vapor pressure of the propellants. dibromosalicylanilide), and 3,3 , 4,5 – tetrachlorosalicylanilide (TC–SA)) It is potentially toxic to the cardio- have been used as active or inactive in- vascular system, i.e., can sensitize the gredients in a number of over-the- heart to epinephrine. At a sufficiently counter (OTC) drug products, largely large concentration, it is a potent an- antibacterial soaps, for antimicrobial, esthetic agent. Deaths associated with preservative, and other purposes. These aerosol decongestant products intended halogenated salicylanilides are potent to be inhaled and containing photosensitizers and can cause dis- trichloroethane have been reported. abling skin disorders. In some in- Most of the deaths resulted from abuse stances the photosensitization may or gross misuse of the preparations. persist for prolonged periods as a se- (b) The Food and Drug Administra- vere reaction without further exposure tion finds that there is a lack of gen- to these chemicals. Safer alternative eral recognition by qualified experts of antimicrobial agents are available. the safety or effectiveness of (b) These halogenated salicylanilides trichloroethane in aerosol drug prod- are not generally recognized as safe ucts intended for inhalation either di- and effective for use as active or inac- rectly or indirectly. Any aerosol drug tive ingredients in any drug products. product containing trichloroethane and Therefore, any drug product containing labeled, represented, or advertised for such a halogenated salicylanilide as an use by inhalation is a new drug and ingredient at any level for any purpose subject to regulatory proceedings un- is a new drug within the meaning of less it is the subject of a new drug ap- section 201(p) of the Federal Food, plication approved pursuant to section Drug, and Cosmetic Act for which an approved new drug application pursu- 505 of the Federal Food, Drug, and Cos- ant to section 505 of the act and part metic Act. 314 of this chapter is required for mar- (c) Clinical investigations designed keting. to obtain evidence that any aerosol (c) Clinical investigations designed drug product containing to obtain evidence that any drug prod- trichloroethane and labeled, rep- uct containing a halogenated resented, or advertised for use by inha- salicylanilide as an ingredient at any lation either directly or indirectly is level for any purpose is safe and effec- safe and effective for the purposes in- tive for the purpose intended must tended must comply with the require- comply with the requirements and pro- ments and procedures governing the cedures governing the use of investiga- use of investigational new drugs set tional new drugs set forth in part 312 of forth in part 312 of this chapter. this chapter. (d) Regulatory proceedings will be (d) Any such drug product initially initiated with regard to any such drug introduced into interstate commerce within the jurisdiction of the act which after December 1, 1975, that is not in
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compliance with this section is subject § 310.509 Parenteral drug products in plas- to regulatory action. tic containers. (a) Any parenteral drug product packaged [40 FR 50530, Oct. 30, 1975, as amended at 55 in a plastic immediate container is not gen- FR 11578, Mar. 29, 1990] erally recognized as safe and effective, is a EFFECTIVE DATE NOTE: At 62 FR 12084, Mar. new drug within the meaning of section 14, 1997, § 310.508 was removed, effective Apr. 201(p) of the Federal Food, Drug, and Cos- 14, 1997. metic Act, and requires an approved new drug application as a condition for market- § 310.509 Parenteral drug products in ing. A ‘‘Investigational New Drug Applica- plastic containers. tion’’ set forth in part 312 of this chapter is required for clinical investigations designed (a) Any parenteral drug product to obtain evidence of safety and effective- packaged in a plastic immediate con- ness. tainer is not generally recognized as (b) It is common medical practice to add safe and effective, is a new drug within various drugs to containers of large volume the meaning of section 201(p) of the parenteral drug products for single adminis- act, and requires an approved new drug tration to the patient, although in many application as a condition for market- cases the safety and effectiveness of that practice has not been demonstrated. Accord- ing. An ‘‘Investigational New Drug Ap- ingly the Commissioner of Food and Drugs plication’’ set forth in part 312 of this concludes that reports of a full investigation chapter is required for clinical inves- of the compatibility of the immediate con- tigations designed to obtain evidence tainer of certain large volume parenteral of safety and effectiveness. drugs with certain other drugs that may be (b) As used in this section, the term added regularly to the parenteral delivery ‘‘large volume parenteral drug prod- system is necessary under section 505(k) of uct’’ means a terminally sterilized the act to determine whether there is ground for requiring revision of the labeling to pro- aqueous drug product packaged in a vide for safer use of the large volume paren- single-dose container with a capacity teral drug products or ground for withdraw- of 100 milliliters or more and intended ing approval, under section 505(e) of the act, to be administered or used intra- of any of the approved new drug applications venously in a human. for the products. As used in this section, the (c) Until the results of compatibility term ‘‘large volume parenteral drug prod- studies are evaluated, a large volume uct’’ means a terminally sterilized aqueous parenteral drug product for intra- drug product packaged in a single-dose con- tainer with a capacity of 100 milliliters or venous use in humans that is packaged more and intended to be administered or in a plastic immediate container on or used intravenously in a human. after April 16, 1979, is misbranded un- (c) Each holder of an approved new drug less its labeling contains a warning application (NDA) for a large volume paren- that includes the following informa- teral drug product for intravenous use in hu- tion: mans that is packaged in a plastic container (1) A statement that additives may shall submit the following to the Food and be incompatible. Drug Administration: (1) The protocol that the NDA holder pro- (2) A statement that, if additive poses to follow in conducting compatibility drugs are introduced into the paren- studies for its large volume parenteral drug teral system, aseptic techniques should product and each additive drug listed in be used and the solution should be paragraph (d) of this section, on or before thoroughly mixed. April 16, 1979. (3) A statement that a solution con- (2) A status report of the ongoing studies 9 taining an additive drug should not be months after the applicant has received writ- stored. ten acceptance of the protocol from the Food and Drug Administration. (d) This section does not apply to a (3) The final report at the completion of biological product licensed under the the compatibility studies within 24 months Public Health Service Act of July 1, following acceptance of the protocol by the 1944 (42 U.S.C. 201). Food and Drug Administration. (d) Reports of compatibility studies with [62 FR 12084, Mar. 14, 1997] each of the following drugs shall be submit- EFFECTIVE DATE NOTE: At 62 FR 12084, Mar. ted under paragraph (c) of this section for 14, 1997, § 310.509 was revised, effective Apr. each large volume parenteral drug product 14, 1997. For the convenience of the user, the for intravenous use in humans that is superseded text is set forth as follows: packaged in a plastic immediate container,
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unless a waiver is granted under paragraph tic techniques should be used and the solu- (e) of this section for a specific drug product: tion should be thoroughly mixed. (3) A statement that a solution containing Aminophylline an additive drug should not be stored. Amphotericin Ampicillin (g) After February 13, 1979, the Food and Calcium gluconate Drug Administration shall approve a new Carbenicillin drug application for a large volume paren- Cephalosporins teral drug product for intravenous use in hu- Chloramphenicol mans that is packaged in a plastic imme- Chloramphenicol sodium succinate diate container if all of the following condi- Clindamycin phosphate tions are met: Cyclophosphamide (1) The application is otherwise approv- Cytarabine able. Diphenhydramine (2) The application contains the results of Erythromicins studies to determine the compatibility of the Fluorouracil large volume parenteral drug product’s plas- Gentamicin tic container with drugs that may be added Heparin regularly to the parenteral delivery system. Hydrocortisone sodium succinate (h) After February 13, 1979, the Food and Insulin Drug Administration shall approve a new Isoproterenol drug application for a drug product intended Kanamycin to be added to a parenteral delivery system Levarterenol that includes a large volume parenteral drug Lidocaine product for intravenous use in humans that Lincomycin is packaged in a plastic immediate container Magnesium sulfate if all of the following conditions are met: Metaraminol (1) The application is otherwise approv- Methicillin able. Methotrexate (2) The application contains the results of Methyldopa studies to determine the compatibility of the Oxacillin additive drug product with the plastic imme- Oxytocin diate container of marketed large volume Penicillin G parenteral drug products for intravenous use Potassium chloride in humans. Sodium bicarbonate (i) Holders of new drug applications for Sodium chloride large volume parenteral drug products that Tetracyclines are subject to this section and who must sub- Vitamins (single-entity and multiple vita- mit supplements under § 314.70(c)(2) of this min products) chapter to provide for the labeling required (e) The required submission of a report of under paragraph (f) of this section may put a compatibility study of a large volume par- the labeling into use without advance ap- enteral drug product packaged in plastic and proval by the Food and Drug Administra- any additive drug listed in paragraph (d) of tion. this section may be waived upon a showing (j) This section does not apply to a biologi- that the report is unnecessary or techniques cal product licensed under the Public Health are not available for conducting a compat- Service Act of July 1, 1944 (42 U.S.C. 201). ibility study that would produce meaningful [43 FR 58562, Dec. 15, 1978, as amended at 50 data. A request for a waiver shall be submit- FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, ted to the Director of the Division of Sur- 1990] gical-Dental Drug Products (HFD–160), Cen- ter for Drug Evaluation and Research, Food § 310.510 Use of aerosol drug products and Drug Administration, Department of containing zirconium. Health and Human Services, 5600 Fishers Lane, Rockville, MD 20857. (a) Aerosol products containing zir- (f) Until the results of the compatibility conium have been used in over-the- studies are evaluated, a large volume paren- counter drug products as teral drug product for intravenous use in hu- antiperspirants. Based upon the lack of mans that is packaged in a plastic imme- toxicological data adequate to estab- diate container on or after April 16, 1979 is lish a safe level for use and the adverse misbranded unless its labeling contains a benefit-to-risk ratio, such aerosol prod- warning that includes the following informa- ucts containing zirconium cannot be tion: (1) A statement that additives may be in- considered generally recognized as safe compatible. for use in drug products. The benefit (2) A statement that, if additive drugs are from using aerosol drug products con- introduced into the parenteral system, asep- taining zirconium is insignificant when
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compared to the risk. Safer alternative (c) Any holder of an approved new antiperspirant products are available. drug application for a drug product (b) Any aerosol drug product contain- containing chloroform as an ingredient ing zirconium is a new drug within the shall submit to the Food and Drug Ad- meaning of section 201(p) of the Fed- ministration on or before July 29, 1976 eral Food, Drug, and Cosmetic Act for a supplemental application providing which an approved new drug applica- for a revised formulation removing tion pursuant to section 505 of the act chloroform as an ingredient. and part 314 of this chapter is required (1) The supplemental application for marketing. shall contain: (c) Clinical investigations designed (i) A full list of articles used as com- to obtain evidence that any aerosol ponents and a full statement of the drug product containing zirconium is composition of the drug product. safe for the purpose intended must (ii) The date that the composition of comply with the requirements and pro- the drug product will be changed. cedures governing the use of investiga- (iii) Data showing that the change in tional new drugs set forth in part 312 of composition does not interfere with this chapter. any assay or other control procedures (d) Any such drug product introduced used in manufacturing the drug prod- in interstate commerce after Septem- uct, or that the assay and other control ber 15, 1977 that is not in compliance procedures are revised to make them with this section is subject to regu- adequate. latory action. (iv) Data available to establish the [42 FR 41376, Aug. 16, 1977, as amended at 55 stability of the revised formulation FR 11579, Mar. 29, 1990] and, if the data are too limited to sup- port a conclusion that the drug will re- EFFECTIVE DATE NOTE: At 62 FR 12085, Mar. 14, 1997, § 310.510 was removed, effective Apr. tain its declared potency for a reason- 14, 1997. able marketing period, a commitment from the applicant: § 310.513 Chloroform, use as an ingre- (a) To test the stability of marketed dient (active or inactive) in drug batches at reasonable intervals; products. (b) To submit the data as they be- (a) Chloroform has been used as an come available; and ingredient in drug products, such as (c) To recall from the market any cough preparations, liniments, and batch found to fall outside the ap- toothpastes. Although considered safe proved specifications for the drug. for many years, recent information has (v) Copies of the label and all other become available associating chloro- labeling to be used for the drug product form with carcinogenic effects in ani- (a total of 12 copies if in final printed mals. Studies conducted by the Na- form, 4 copies if in draft form). tional Cancer Institute have dem- (2) If such drug product now contains onstrated that the oral administration more than one percent chloroform, the of chloroform to mice and rats induced revised formulation containing no hepatocellular carcinomas (liver can- chloroform shall not be marketed be- cer) in mice and renal tumors in male fore the receipt of written notice of ap- rats. proval of the supplemental application (b) Any drug product containing by the Food and Drug Administration. chloroform as an ingredient is a new (3) If such drug product now contains drug within the meaning of section one percent or less chloroform, the re- 201(p) of the act and misbranded and is vised formulation containing no chlo- subject to regulatory action under sec- roform may be marketed, subject to tions 301, 502, and 505 of the act. Any the conditions of § 314.70(c) of this chap- drug product containing chloroform in ter, after submission of the supple- residual amounts from its use as a mental application but prior to the re- processing solvent during manufacture, ceipt of written notice of its approval or as a byproduct from the synthesis of by the Food and Drug Administration. an ingredient, is not, for the purpose of (d) Any sponsor of a ‘‘Investigational this section, considered to contain New Drug Application’’ (IND) for a chloroform as an ingredient. drug product containing chloroform as
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an ingredient shall amend the IND on beled with instructions to the or before July 29, 1976 to revise the for- dispensor to include one patient label- mulation removing chloroform as an ing piece with each package dispensed ingredient. or, in the case of injectables, with each (e) The Commissioner will initiate dose administered to the patient. This action to withdraw approval of an ap- section does not preclude the manufac- plication or terminate an IND in ac- turer or labeler from distributing addi- cordance with the applicable provisions tional patient labeling pieces to the of section 505 of the act and parts 312 dispensor. and 314 of this chapter upon failure of (3) Patient package inserts for a holder of an approved new drug appli- estrogens dispensed in acute-care hos- cation or sponsor of an IND to comply pitals or long-term care facilities will with the provisions of paragraph (c) or be considered to have been provided in (d) of this section. accordance with this section if pro- [41 FR 26845, June 29, 1976, as amended at 55 vided to the patient before administra- FR 11579, Mar. 29, 1990] tion of the first estrogen and every 30 EFFECTIVE DATE NOTE: At 62 FR 12085, Mar. days thereafter, as long as the therapy 14, 1997, § 310.513 was removed, effective Apr. continues. 14, 1997. (c) Patient package insert contents. A patient package insert for an estrogen § 310.515 Patient package inserts for estrogens. drug product is required to contain the following information: (a) Requirement for a patient package (1) The name of the drug. insert. FDA concludes that the safe and effective use of drug products contain- (2) The name and place of business of ing estrogens requires that patients be the manufacturer, packer, or distribu- fully informed of the benefits and risks tor. involved in the use of these drugs. Ac- (3) A statement regarding the bene- cordingly, except as provided in para- fits and proper uses of estrogens. graph (e) of this section, each estrogen (4) The contraindications to use, i.e., drug product restricted to prescription when estrogens should not be used. distribution, including products con- (5) A description of the most serious taining estrogens in fixed combina- risks associated with the use of tions with other drugs, shall be dis- estrogens. pensed to patients with a patient pack- (6) A brief summary of other side ef- age insert containing information con- fects of estrogens. cerning the drug’s benefits and risks. (7) Instructions on how a patient may An estrogen drug product that does not reduce the risks of estrogen use. comply with the requirements of this (8) The date, identified as such, of the section is misbranded under section most recent revision of the patient 502(a) of the Federal Food, Drug, and package insert. Cosmetic Act. (b) Distribution requirements. (1) For (d) Guidance language. The Food and estrogen drug products, the manufac- Drug Administration issues informal turer and distributor shall provide a labeling guidance texts under patient package insert in or with each § 10.90(b)(9) of this chapter to provide package of the drug product that the assistance in meeting the requirements manufacturer or distributor intends to of paragraph (c) of this section. Re- be dispensed to a patient. quests for a copy of the guidance text (2) In the case of estrogen drug prod- should be directed to the Center for ucts in bulk packages intended for Drug Evaluation and Research, Divi- multiple dispensing, and in the case of sion of Metabolism and Endocrine Drug injectables in multiple-dose vials, a Products (HFD–510), Food and Drug Ad- sufficient number of patient labeling ministration, 5600 Fishers Lane, Rock- pieces shall be included in or with each ville, MD 20857. package to assure that one piece can be (e) Exemptions. This section does not included with each package or dose dis- apply to estrogen-progestogen oral con- pensed or administered to every pa- traceptives. Labeling requirements for tient. Each bulk package shall be la- these products are set forth in § 310.501.
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(f) Requirement to supplement approved (c) The patient labeling shall be application. Holders of approved appli- printed in accordance with the follow- cations for estrogen drug products that ing specifications: are subject to the requirements of this (1) The minimum letter size shall be section must submit supplements one-sixteenth of an inch in height. under § 314.70(c) of this chapter to pro- (2) Letter heights pertain to the vide for the labeling required by para- lower-case letter ‘‘o’’ or its equivalent graph (a) of this section. Such labeling that shall meet the minumim height may be put into use without advance standard. approval by the Food and Drug Admin- (3) Type used shall conform to the istration. minimum letter height. The body copy shall contain 1-point leading, noncon- [55 FR 18723, May 4, 1990] densed type, and shall not contain any § 310.516 Progestational drug prod- light-face type or small capital letters. ucts; labeling directed to the pa- (d) This section does not apply to a tient. progestogen-containing product in- tended for contraception, which shall (a) The Commissioner of Food and be labeled according to the require- Drugs concludes that the safe and ef- ments of § 310.501. fective use of any progestational drug (e)(1) Patient labeling for each product requires that patients be in- progestational drug product shall be formed that there is an increased risk provided in or with each package in- of birth defects in children whose tended to be dispensed to the patient. mothers have taken this drug during Patient labeling for drug products dis- the first 4 months of pregnancy. Ac- pensed in acute-care hospitals or long- cordingly, except as provided by para- term care facilities will be considered graph (d) of this section, any to have been provided in accordance progestational drug product that is the with this section if provided to the pa- subject of a new drug application ap- tient before first administration of the proved either before or after October 9, drug and every 30 days thereafter, as 1962 and all identical, related, or simi- long as the therapy continues. lar drug products as defined in § 310.6, (2) In the case of progestational drug whether or not the subject of an ap- products in bulk packages intended for proved new drug application, shall be multiple dispensing, a sufficient num- dispensed to patients with labeling in ber of patient-labeling pieces shall be lay language containing such a warn- included in or shall accompany each ing. The patient labeling shall be pro- bulk package to assure that one can be vided as a separate printed leaflet inde- included with each package dispensed pendent of any additional materials. to every patient. Each bulk package (b) The patient labeling shall specifi- shall be labeled with instructions to cally include the following: the dispenser to include one patient-la- (1) Name of the drug. beling piece with each package dis- (2) Name and place of business of the pensed to the patient. This section does manufacturer, packer, or distributor. not preclude the manufacturer or label- (3) A warning that there is an in- er from distributing additional patient- creased risk of birth defects in children labeling pieces to the dispenser. whose mothers take this drug during (3) In the case of progestational drug the first 4 months of pregnancy. products for injection, each package (4) A brief discussion of the nature of shall include a sufficient number of pa- the risks of birth defects resulting tient-labeling pieces for the volume of from the use of these drugs during the the vial, and instructions to the practi- first 4 months of pregnancy. tioner administering the drug to give (5) A brief statement that these drugs one patient-labeling piece to each are no longer considered safe as a test premenopausal woman, except those in for pregnancy. whom childbearing is impossible, re- (6) A statement that the patient ceiving the drug. should inform her physician as soon as (4) This section does not apply to oral possible if she discovers that she was dosage forms labeled solely for the pregnant when she took the drug. treatment of advanced cancer.
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(5) Any progestational drug product, structure and mode of action, the Food except as noted in paragraphs (d) and and Drug Administration also believes (e)(4) of this section, that is not labeled it is prudent from a safety standpoint as required by this section and is either to consider that the possible increased introduced or delivered for introduc- risk of cardiovascular mortality from tion into interstate commerce, or held tolbutamide applies to all other for sale after shipment in interstate sulfonylurea drugs as well. Therefore, commerce, is misbranded under section the labeling for oral hypoglycemic 502 of the Federal Food, Drug, and Cos- drugs of the sulfonylurea class shall in- metic Act. However, a progestational clude a warning concerning the pos- drug product in the possession of a sible increased risk of cardiovascular wholesaler or retailer before December mortality associated with such use, as 12, 1978, is not misbranded if adequate set forth in paragraph (b) of this sec- numbers of copies of the patient label- tion. ing are furnished to the wholesaler or (b) Labeling for oral hypoglycemic retailer to permit any retail purchaser drugs of the sulfonylurea class shall in- after that date to obtain such labeling clude in boldface type at the beginning with the product. The requirement of the ‘‘Warnings’’ section of the label- that any progestational drug product ing the following statement: be dispensed with patient labeling, as applied to physicians who dispense or SPECIAL WARNING ON INCREASED RISK administer the drug, will not be effec- OF CARDIOVASCULAR MORTALITY tive for supplies in their possession on the effective date, but will apply only The administration of oral hypoglycemic to supplies received thereafter. drugs has been reported to be associated (f) The Food and Drug Administra- with increased cardiovascular mortality as tion has available guideline patient la- compared to treatment with diet alone or diet plus insulin. This warning is based on beling for progestational drug products the study conducted by the University Group that includes information responsive to Diabetes Program (UGDP), a long-term pro- all items specified in paragraph (b) of spective clinical trial designed to evaluate this section. This labeling was pub- the effectiveness of glucose-lowering drugs lished in a separate notice appearing in in preventing or delaying vascular complica- the FEDERAL REGISTER of January 12, tions in patients with non-insulin-dependent 1989. Any person may rely on this la- diabetes. The study involved 823 patients beling as complying with paragraph (b) who were randomly assigned to one of four treatment groups (Diabetes, 19 (supp. 2): 747– of this section. 830, 1970). (g) Holders of approved new drug ap- UGDP reported that patients treated for 5 plications for progestational drug prod- to 8 years with diet plus a fixed dose of tol- ucts that are subject to the require- butamide (1.5 grams per day) had a rate of ments of this section shall submit sup- cardiovascular mortality approximately 21⁄2 plements under § 314.70(c) of this chap- times that of patients treated with diet ter to provide for the labeling required alone. A significant increase in total mortal- by paragraph (a) of this section. ity was not observed, but the use of tol- butamide was discontinued based on the in- [43 FR 47181, Oct. 13, 1978, as amended at 46 crease in cardiovascular mortality, thus lim- FR 53657, Oct. 30, 1981; 54 FR 1163, Jan. 12, iting the opportunity for the study to show 1989] an increase in overall mortality. Despite controversy regarding the interpretation of § 310.517 Labeling for oral hypo- these results, the findings of the UGDP study glycemic drugs of the sulfonylurea provide an adequate basis for this warning. class. The patient should be informed of the poten- (a) The University Group Diabetes tial risks and advantages of (name of drug) and of alternative modes of therapy. Program clinical trial has reported an Although only one drug in the sulfonylurea association between the administration class (tolbutamide) was included in this of tolbutamide and increased cardio- study, it is prudent from a safety standpoint vascular mortality. The Food and Drug to consider that this warning may also apply Administration has concluded that this to other oral hypoglycemic drugs in this reported association provides adequate class, in view of their close similarities in basis for a warning in the labeling. In mode of action and chemical structure. view of the similarities in chemical [49 FR 14331, Apr. 11, 1984]
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§ 310.518 Drug products containing (ii) If a drug product is packaged in iron or iron salts. unit-dose packaging, and if the imme- Drug products containing elemental diate container bears labeling but not a iron or iron salts as an active ingredi- label, the warning statement required by paragraph (c)(1) of this section shall ent in solid oral dosage form, e.g., tab- appear prominently and conspicuously lets or capsules shall meet the follow- on the immediate container labeling in ing requirements: a way that maximizes the likelihood (a) Packaging. If the product contains that the warning is intact until all of 30 milligrams or more of iron per dos- the dosage units to which it applies are age unit, it shall be packaged in unit- used. dose packaging. ‘‘Unit-dose packaging’’ (3) Where the immediate container is means a method of packaging a prod- not the retail package, the warning uct into a nonreusable container de- statement required by paragraph (c)(1) signed to hold a single dosage unit in- of this section shall also appear promi- tended for administration directly nently and conspicuously on the infor- from that container, irrespective of mation panel of the retail package whether the recommended dose is one label. or more than one of these units. The (4) The warning statement shall ap- term ‘‘dosage unit’’ means the individ- pear on any labeling that contains ual physical unit of the product, e.g., warnings. tablet or capsule. Iron-containing (5) The warning statement required drugs that are subject to this regula- by paragraph (c)(1) of this section shall tion are also subject to child-resistant be set off in a box by use of hairlines. special packaging requirements in 16 (d) The iron-containing inert tablets CFR parts 1700, 1701, and 1702. supplied in monthly packages of oral (b) Temporary exemption. (1) Drug contraceptives are categorically ex- products offered in solid oral dosage empt from the requirements of para- form (e.g., tablets or capsules), and graphs (a) and (c) of this section. containing 30 milligrams or more of iron per dosage unit, are exempt from [62 FR 2250, Jan. 15, 1997; 62 FR 15111, Mar. 31, 1997] the provisions of paragraph (a) of this section until January 15, 1998, if the EFFECTIVE DATE NOTE: At 62 FR 2250, Jan. sole source of iron in the drug product 15, 1997, § 310.518 was added, effective July 15, is carbonyl iron that meets the speci- 1997. At 62 FR 15111, Mar. 31, 1997, in § 310.518 paragraphs (b)(2) and (c)(5) were corrected, fications of § 184.1375 of this chapter. effective July 15, 1997. (2) If this temporary exemption is not extended or made permanent, such § 310.519 Drug products marketed as drug products shall be in compliance over-the-counter (OTC) daytime with the provisions of paragraph (a) of sedatives. this section on or before July 15, 1998. (a) Antihistamines, bromides, and (c) Labeling. (1) The label of any drug scopolamine compounds, either singly in solid oral dosage form (e.g., tablets or in combinations, have been mar- or capsules) that contains iron or iron keted as ingredients in over-the- salts for use as an iron source shall counter (OTC) drug products for use as bear the following statement: daytime sedatives. The following claims have been made for daytime WARNING: Accidental overdose of sedative products: ‘‘occasional simple iron-containing products is a leading nervous tension,’’ ‘‘nervous irritabil- cause of fatal poisoning in children ity,’’ ‘‘nervous tension headache,’’ under 6. Keep this product out of reach ‘‘simple nervousness due to common of children. In case of accidental over- every day overwork and fatigue,’’ ‘‘a dose, call a doctor or poison control relaxed feeling,’’ ‘‘calming down and center immediately. relaxing,’’ ‘‘gently soothe away the (2)(i) The warning statement required tension,’’ ‘‘calmative,’’ ‘‘resolving that by paragraph (c)(1) of this section shall irritability that ruins your day,’’ appear prominently and conspicuously ‘‘helps you relax,’’ ‘‘restlessness,’’ on the information panel of the imme- ‘‘when you’re under occasional stress . diate container label. . . helps you work relaxed.’’ Based on
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evidence presently available, there are any use is safe and effective for the no ingredients that can be generally purpose intended must comply with the recognized as safe and effective for use requirements and procedures governing as OTC daytime sedatives. the use of investigational new drugs (b) Any OTC drug product that is la- set forth in part 312 of this chapter. beled, represented, or promoted as an (d) Any drug product containing OTC daytime sedative (or any similar sweet spirits of nitre in interstate com- or related indication) is regarded as a merce after June 27, 1980, that is not in new drug within the meaning of section compliance with this section is subject 201(p) of the Federal Food, Drug, and to regulatory action. Cosmetic Act for which an approved [45 FR 43401, June 27, 1980, as amended at 55 new drug application under section 505 FR 11579, Mar. 29, 1990] of the act and Part 314 of this chapter is required for marketing. EFFECTIVE DATE NOTE: At 62 FR 12085, Mar. 14, 1997, § 310.525 was removed, effective Apr. (c) Clinical investigations designed 14, 1997. to obtain evidence that any drug prod- uct labeled, represented, or promoted § 310.526 Camphorated oil drug prod- as an OTC daytime sedative (or any ucts. similar or related indication) is safe (a) Historically, camphorated oil and effective for the purpose intended (also known as camphor liniment), a must comply with the requirements solution of 20 percent camphor in cot- and procedures governing the use of in- tonseed oil, has been marketed as an vestigational new drugs set forth in over-the-counter (OTC) drug product part 312 of this chapter. for various uses, primarily as a topical (d) Any OTC daytime sedative drug counterirritant or liniment. A large product introduced into interstate number of accidental ingestions of commerce after December 24, 1979, that camphorated oil, often mistaken for is not in compliance with this section castor oil, cod liver oil, mineral oil, is subject to regulatory action. olive oil, cough medicine, or other drug [44 FR 36380, June 22, 1979; 45 FR 47422, July products, have been reported and tox- 15, 1980, as amended at 55 FR 11579, Mar. 29, icity has often resulted, primarily in 1990] infants and young children. Because of the potential hazard for poisoning to § 310.525 Sweet spirits of nitre drug occur, the benefit from using any drug products. product containing camphor in oil or (a) Historically, sweet spirits of nitre from using any camphor-containing has been present as an ingredient in drug product that is labeled as over-the-counter (OTC) drug products ‘‘camphorated oil’’ or ‘‘camphor for various uses. Based upon the lack of liniment,’’ or any similar name such as adequate data to establish effective- ‘‘camphor oil’’ or ‘‘camphorated ness for any use and the adverse bene- liniment,’’ for any use, is insignificant fit-to-risk ratio, sweet spirits of nitre when compared to the risk. Based upon drug products cannot be considered the adverse benefit-to-risk ratio, generally recognized as safe and effec- camphorated oil, any drug product con- tive. The benefit from using sweet spir- taining camphor in oil, or any other its of nitre for any use is insignificant drug product containing camphor that when compared to the risk. is represented, suggested, or purported (b) Any drug product containing to be camphorated oil, such as a prod- sweet spirits of nitre is misbranded uct labeled ‘‘camphor liniment,’’ ‘‘cam- under section 502 of the Federal Food, phor oil,’’ ‘‘camphorated liniment,’’ or Drug, and Cosmetic Act and is a new any similar name, cannot be considered drug within the meaning of section generally recognized as safe. 201(p) of the act for which an approved (b) Any camphorated oil drug prod- new drug application under section 505 uct, any drug product containing cam- of the act and part 314 of this chapter phor in oil, or any other drug product is required for marketing. containing camphor that is rep- (c) Clinical investigations designed resented, suggested or purported to be to obtain evidence that any drug prod- camphorated oil, e.g., ‘‘camphor uct containing sweet spirits of nitre for liniment,’’ ‘‘camphor oil,’’
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‘‘camphorated liniment,’’ is mis- leading, or unsupported by scientific branded under section 502 of the Fed- data. Therefore, any OTC drug product eral Food, Drug, and Cosmetic Act and for external use containing an ingredi- is a new drug within the meaning of ent offered for use as a hair grower or section 201(p) of the act for which an for hair loss prevention cannot be con- approved new drug application under sidered generally recognized as safe section 505 of the act and part 314 of and effective for its intended use. this chapter is required for marketing. (b) Any OTC drug product that is la- (c) Clinical investigations designed beled, represented, or promoted for ex- to obtain evidence that any ternal use as a hair grower or for hair camphorated oil drug product, any loss prevention is regarded as a new drug product containing camphor in drug within the meaning of section oil, or any other drug product contain- 201(p) of the Federal Food, Drug, and ing camphor that is represented, sug- Cosmetic Act (the act), for which an gested, or purported to be camphorated approved new drug application under oil, e.g., ‘‘camphor liniment,’’ ‘‘cam- section 505 of the act and part 314 of phor oil,’’ ‘‘camphorated liniment,’’ is this chapter is required for marketing. safe for the purpose intended must In the absence of an approved new drug comply with the requirements and pro- application, such product is also mis- cedures governing the use of investiga- branded under section 502 of the act. tional new drugs set forth in part 312 of (c) Clinical investigations designed this chapter. to obtain evidence that any drug prod- (d) Any such drug product in inter- uct labeled, represented, or promoted state commerce after September 21, for OTC external use as a hair grower 1982 that is not in compliance with this or for hair loss prevention is safe and section is subject to regulatory action. effective for the purpose intended must comply with the requirements and pro- [47 FR 41720, Sept. 21, 1982, as amended at 55 FR 11579, Mar. 29, 1990] cedures governing the use of investiga- tional new drugs set forth in Part 312 of EFFECTIVE DATE NOTE: At 62 FR 12085, Mar. this chapter. 14, 1997, § 310.526 was removed, effective Apr. (d) After January 8, 1990, any such 14, 1997. OTC drug product initially introduced § 310.527 Drug products containing ac- or initially delivered for introduction tive ingredients offered over-the- into interstate commerce that is not in counter (OTC) for external use as compliance with this section is subject hair growers or for hair loss pre- to regulatory action. vention. [54 FR 28777, July 7, 1989] (a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid, biotin and § 310.528 Drug products containing ac- all other B-vitamins, dexpanthenol, es- tive ingredients offered over-the- tradiol and other topical hormones, counter (OTC) for use as an aphro- jojoba oil, lanolin, nucleic acids, disiac. polysorbate 20, polysorbate 60, sulfa- (a) Any product that bears labeling nilamide, sulfur 1 percent on carbon in claims that it will arouse or increase a fraction of paraffinic hydrocarbons, sexual desire, or that it will improve tetracaine hydrochloride, urea, and sexual performance, is an aphrodisiac wheat germ oil have been marketed as drug product. Anise, cantharides, don ingredients in OTC drug products for qual, estrogens, fennel, ginseng, golden external use as hair growers or for hair seal, gotu kola, Korean ginseng, lico- loss prevention. There is a lack of ade- rice, mandrake, methyltestosterone, quate data to establish general rec- minerals, nux vomica, Pega Palo, sar- ognition of the safety and effectiveness saparilla, strychnine, testosterone, vi- of these or any other ingredients in- tamins, yohimbine, yohimbine hydro- tended for OTC external use as a hair chloride, and yohimbinum have been grower or for hair loss prevention. present as ingredients in such drug Based on evidence currently available, products. Androgens (e.g., testosterone all labeling claims for OTC hair grower and methyltestosterone) and estrogens and hair loss prevention drug products are powerful hormones when adminis- for external use are either false, mis- tered internally and are not safe for
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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 ingredi- tablish the effectiveness of this, or any ent, for OTC use as an aphrodisiac. La- other ingredient for OTC oral use as an beling claims for aphrodisiacs for OTC insect repellent. Labeling claims for use are either false, misleading, or un- OTC orally administered insect repel- supported 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 la- beled, 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 In the absence of an approved new drug application, such product is also mis- application, such product is also mis- branded under section 502 of the act. branded under section 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 prod- uct labeled, represented, or promoted uct labeled, represented, or promoted OTC for oral use as an insect repellent for OTC use as an aphrodisiac is safe is safe and effective for the purpose in- and effective for the purpose intended tended must comply with the require- must comply with the requirements ments and procedures governing the and procedures governing the use of in- use of investigational new drugs set vestigational new drugs set forth in forth in part 312 of this chapter. part 312 of this chapter. (d) Any such drug product in inter- (d) After January 8, 1990, any such state commerce after December 17, OTC drug product initially introduced 1985, that is not in compliance with or initially delivered for introduction this section is subject to regulatory ac- into interstate commerce that is not in tion. compliance with this section is subject [40 FR 25171, June 17, 1985, as amended at 55 to regulatory action. FR 11579, Mar. 29, 1990] [54 FR 28786, July 7, 1989] § 310.530 Topically applied hormone- § 310.529 Drug products containing ac- containing drug products for over- tive ingredients offered over-the- the-counter (OTC) human use. counter (OTC) for oral use as insect (a) The term ‘‘hormone’’ is used repellents. broadly to describe a chemical sub- (a) Thiamine hydrochloride (vitamin stance formed in some organ of the B–1) has been marketed as an ingredi- body, such as the adrenal glands or the ent in over-the-counter (OTC) drug pituitary, and carried to another organ
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or tissue, where it has a specific effect. (c) Clinical investigations designed Hormones include, for example, to obtain evidence that any drug prod- estrogens, progestins, androgens, ana- uct labeled, represented, or promoted bolic steroids, and adrenal for OTC use as a topically applied hor- corticosteroids, and synthetic analogs. mone-containing drug product is safe Estrogens, progesterone, pregnenolone, and effective for the purpose intended and pregnenolone acetate have been must comply with the requirements present as ingredients in OTC drug and procedures governing the use of in- products marketed for topical use as vestigational new drugs set forth in hormone creams. However, there is a part 312 of this chapter. lack of adequate data to establish ef- (d) After March 9, 1994, any such OTC fectiveness for any OTC drug use of drug product initially introduced or these ingredients. Therefore, with the initially delivered for introduction into exception of those hormones identified interstate commerce that is not in in paragraph (e) of this section, any compliance with this section is subject OTC drug product containing an ingre- to regulatory action. (e) This section does not apply to hy- dient offered for use as a topically ap- drocortisone and hydrocortisone ace- plied hormone cannot be considered tate labeled, represented, or promoted generally recognized as safe and effec- for OTC topical use in accordance with tive for its intended use. The intended part 348 of this chapter. use of the product may be inferred from the product’s labeling, pro- [58 FR 47610, Sept. 9, 1993] motional material, advertising, and any other relevant factor. The use of § 310.531 Drug products containing ac- tive ingredients offered over-the- the word ‘‘hormone’’ in the text of the counter (OTC) for the treatment of labeling or in the ingredient statement boils. is an implied drug claim. The claim im- (a) Aminacrine hydrochloride, plied by the use of this term is that the benzocaine, bismuth subnitrate, calo- product will have a therapeutic or mel, camphor, cholesterol, ergot fluid some other physiological effect on the extract, hexachlorophene, ichthammol, body. Therefore, reference to a product isobutamben, juniper tar (oil of cade), as a ‘‘hormone cream’’ or any state- lanolin, magnesium sulfate, menthol, ment in the labeling indicating that methyl salicylate, oxyguinoline sul- ‘‘hormones’’ are present in the product, fate, petrolatum, phenol, pine tar, or any statement that features or em- rosin, rosin cerate, sassafras oil, sulfur, phasizes the presence of a hormone in- thymol, triclosan, and zinc oxide have gredient in the product, will be consid- been present in OTC boil treatment ered to be a therapeutic claim for the drug products. There is a lack of ade- product, or a claim that the product quate data to establish general rec- will affect the structure or function of ognition of the safety and effectiveness the body, and will consequently cause of these or any other ingredient for the product to be a drug. OTC use for the treatment of boils. (b) Any OTC drug product that is la- Treatment is defined as reducing the beled, represented, or promoted as a size of a boil or reducing an infection topically applied hormone-containing related to a boil. Treatment has in- product for drug use, with the excep- volved the use of ‘‘drawing salves’’ for tion of those hormones identified in these purposes. These ‘‘drawing salves’’ paragraph (e) of this section, is re- contained various ingredients. Based garded as a new drug within the mean- on evidence currently available, any ing of section 201(p) of the act, for OTC drug product offered for the treat- which an approved application or ab- ment of boils cannot be considered gen- breviated application under section 505 erally recognized as safe and effective. of the act and part 314 of this chapter (b) Any OTC drug product that is la- is required for marketing. In the ab- beled, represented, or promoted for the sence of an approved new drug applica- treatment of boils is regarded as a new tion or abbreviated new drug applica- drug within the meaning of section tion, such product is also misbranded 201(p) of the Federal Food, Drug, and under section 502 of the act. Cosmetic Act (the act), for which an
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approved application or abbreviated sive urinating at night, and delayed application under section 505 of the act urination. There is a lack of adequate and part 314 of this chapter is required data to establish general recognition of for marketing. In the absence of an ap- the safety and effectiveness of these or proved new drug application or abbre- any other ingredients for OTC use in viated new drug application, such prod- relieving the symptoms of benign pros- uct is also misbranded under section tatic hypertrophy. In addition, there is 502 of the act. no definitive evidence that any drug (c) Clinical investigations designed product offered for the relief of the to obtain evidence that any OTC boil symptoms of benign prostatic hyper- treatment drug product is safe and ef- trophy would alter the obstructive or fective for the purpose intended must inflammatory signs and symptoms of comply with the requirements and pro- this condition. Therefore, self-medica- cedures governing the use of investiga- tion with OTC drug products might un- tional new drugs set forth in part 312 of this chapter. necessarily delay diagnosis and treat- (d) After May 7, 1991, any such OTC ment of progressive obstruction and drug product that contains aminacrine secondary infections. Based on evi- hydrochloride, bismuth subnitrate, cal- dence currently available, any OTC omel, camphor, cholesterol, ergot fluid drug product containing ingredients of- extract, hexachlorophene, fered for use in relieving the symptoms isobutamben, juniper tar (oil of cade), of benign prostatic hypertrophy cannot lanolin, magnesium sulfate, menthol, be generally recognized as safe and ef- methyl salicylate, oxyguinoline sul- fective. fate, petrolatum, phenol, pine tar, (b) Any OTC drug product that is la- rosin, rosin cerate, sassafras oil, thy- beled, represented, or promoted to re- mol, or zinc oxide initially introduced lieve the symptoms of benign prostatic or initially delivered for introduction hypertrophy is regarded as a new drug into interstate commerce that is not in within the meaning of section 201(p) of compliance with this section is subject the Federal Food, Drug, and Cosmetic to regulatory action. Act (the act), for which an approved (e) After May 16, 1994, any such OTC application under section 505 of the act drug product that contains benzocaine, and part 314 of this chapter is required ichthammol, sulfur, or triclosan ini- for marketing. In the absence of an ap- tially introduced or initially delivered proved application, such product is also for introduction into interstate com- misbranded under section 502 of the merce that is not in compliance with act. this section is subject to regulatory ac- tion. (c) Clinical investigations designed (f) This section does not apply to to obtain evidence that any drug prod- drug products that contain benzocaine uct labeled, represented, or promoted labeled, represented, or promoted for for OTC use to relieve the symptoms of OTC topical use in accordance with benign prostatic hypertrophy is safe part 348 of this chapter. and effective for the purpose intended must comply with the requirements [58 FR 60336, Nov. 15, 1993] and procedures governing the use of in- vestigational new drugs set forth in § 310.532 Drug products containing ac- tive ingredients offered over-the- part 312 of this chapter. counter (OTC) to relieve the symp- (d) After August 27, 1990, any such toms of benign prostatic hyper- OTC drug product initially introduced trophy. or initially delivered for introduction (a) The amino acids glycine, alanine, into interstate commerce that is not in and glutamic acid (alone or in com- compliance with this section is subject bination) and the ingredient sabal have to regulatory action. been present in over-the-counter (OTC) drug products to relieve the symptoms [55 FR 6930, Feb. 27, 1990] of benign prostatic hypertrophy, e.g., urinary urgency and frequency, exces-
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§ 310.533 Drug products containing ac- drug product labeled, represented, or tive ingredients offered over-the- promoted for OTC use as an counter (OTC) for human use as an anticholinergic is safe and effective for anticholinergic in cough-cold drug the purpose intended must comply with products. the requirements and procedures gov- (a) Atropine sulfate, belladonna alka- erning the use of investigational new loids, and belladonna alkaloids as con- drugs set forth in part 312 of this chap- tained in Atropa belladonna and ter. Datura stramonium have been present (d) After the effective date of the as ingredients in cough-cold drug prod- final regulation, any such OTC cough- ucts for use as an anticholinergic. cold drug product that is labeled, rep- Anticholinergic drugs have been mar- resented, or promoted for use as an keted OTC in cough-cold drug products anticholinergic may not be initially in- to relieve excessive secretions of the troduced or initially delivered for in- nose and eyes, symptoms that are com- troduction into interstate commerce monly associated with hay fever, al- unless it is the subject of an approved lergy, rhinitis, and the common cold. new drug application. Atropine sulfate for oral use as an [50 FR 46587, Nov. 8, 1985, as amended at 55 anticholinergic is probably safe at dos- FR 11579, Mar. 29, 1990] ages that have been used in marketed cough-cold products (0.2 to 0.3 milli- § 310.534 Drug products containing ac- gram); however, there are inadequate tive ingredients offered over-the- data to establish general recognition of counter (OTC) for human use as the effectiveness of this ingredient. oral wound healing agents. The belladonna alkaloids, which con- (a) Allantoin, carbamide peroxide in tain atropine (d, dl hyoscyamine) and anhydrous glycerin, water soluble scopolamine (l- hyoscine), are probably chlorophyllins, and hydrogen peroxide safe for oral use at dosages that have in aqueous solution have been present been used in marketed cough-cold in oral mucosal injury drug products products (0.2 milligram) but there are for use as oral wound healing agents. inadequate data to establish general Oral wound healing agents have been recognition of the effectiveness of marketed as aids in the healing of these ingredients as an anticholinergic minor oral wounds by means other for cough-cold use. Belladonna alka- than cleansing and irrigating, or by loids for inhalation use, as contained in serving as a protectant. Allantoin, car- Atropa belladonna and Datura stramo- bamide peroxide in anhydrous glycerin, nium, are neither safe nor effective as water soluble chlorophyllins, and hy- an OTC anticholinergic. There are in- drogen peroxide in aqueous solution adequate safety and effectiveness data are safe for use as oral wound healing to establish general recognition of the agents, but there are inadequate data safety and/or effectiveness or any of to establish general recognition of the these ingredients, or any other ingredi- effectiveness of these ingredients as ent, for OTC use as an anticholinergic oral wound healing agents. in cough-cold drug products. (b) Any OTC drug product that is la- (b) Any OTC cough-cold drug product beled, represented, or promoted for use that is labeled, represented, or pro- as an oral wound healing agent is re- moted for use as an anticholinergic is garded as a new drug within the mean- regarded as a new drug within the ing of section 201(p) of the Federal meaning of section 201(p) of the Fed- Food, Drug, and Cosmetic Act, for eral Food, Drug, and Cosmetic Act, for which an approved new drug applica- which an approved new drug applica- tion under section 505 of the act and tion under section 505 of the act and part 314 of this chapter is required for part 314 of this chapter is required for marketing. In the absence of an ap- marketing. In the absence of an ap- proved new drug application, such proved new drug application, such product is also misbranded under sec- product is also misbranded under sec- tion 502 of the act. tion 502 of the act. (c) Clinical investigations designed (c) Clinical investigations designed to obtain evidence that any drug prod- to obtain evidence that any cough-cold uct labeled, represented, or promoted
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for OTC use as an oral wound healing cedures governing the use of investiga- agent is safe and effective for the pur- tional new drugs set forth in part 312 of pose intended must comply with the re- this chapter. quirements and procedures governing (d) After March 2, 1994, any such OTC the use of investigational new drugs drug product initially introduced or set forth in part 312 of this chapter. initially delivered for introduction into (d) After the effective date of the interstate commerce that is not in final regulation, any OTC drug product compliance with this section is subject that is labeled, represented, or pro- to regulatory action. moted for use as an oral wound healing agent may not be initially introduced [58 FR 46754, Sept. 2, 1993] or initially delivered for introduction into interstate commerce unless it is § 310.537 Drug products containing ac- tive ingredients offered over-the- the subject of an approved new drug ap- counter (OTC) for oral administra- plication. tion for the treatment of fever blis- [51 FR 26114, July 18, 1986, as amended at 55 ters and cold sores. FR 11579, Mar. 29, 1990] (a) L-lysine (lysine, lysine hydro- chloride), Lactobacillus acidophilus, and § 310.536 Drug products containing ac- tive ingredients offered over-the- Lactobacillus bulgaricus have been counter (OTC) for use as a present in orally administered OTC nailbiting or thumbsucking deter- drug products to treat fever blisters rent. and cold sores. There is a lack of ade- (a) Denatonium benzoate and sucrose quate data to establish general rec- octaacetate have been present in OTC ognition of the safety and effectiveness nailbiting and thumbsucking deterrent of these or any other orally adminis- drug products. There is a lack of ade- tered ingredients for OTC use to treat quate data to establish general rec- or relieve the symptoms or discomfort ognition of the safety and effectiveness of fever blisters and cold sores. Based of these and any other ingredients on evidence currently available, any (e.g., cayenne pepper) for OTC use as a OTC drug product for oral administra- nailbiting or thumbsucking deterrent. tion containing ingredients offered for Based on evidence currently available, use in treating or relieving the symp- any OTC drug product containing in- toms or discomfort of fever blisters and gredients offered for use as a nailbiting cold sores cannot be generally recog- or thumbsucking deterrent cannot be nized as safe and effective. generally recognized as safe and effec- (b) Any OTC drug product for oral ad- tive. ministration that is labeled, rep- (b) Any OTC drug product that is la- resented, or promoted to treat or re- beled, represented, and promoted as a lieve the symptoms or discomfort of nailbiting or thumbsucking deterrent fever blisters and cold sores is regarded is regarded as a new drug within the as a new drug within the meaning of meaning of section 201(p) of the Fed- section 201(p) of the Federal Food, eral Food, Drug, and Cosmetic Act (the Drug, and Cosmetic Act (the act), for act) for which an approved application which an approved application under or abbreviated application under sec- section 505 of the act and part 314 of tion 505 of the act and part 314 of this this chapter is required for marketing. chapter is required for marketing. In In the absence of an approved applica- the absence of an approved new drug tion, such product is also misbranded application or abbreviated new drug under section 502 of the act. application, such product is also mis- (c) Clinical investigations designed branded under section 502 of the act. to obtain evidence that any drug prod- (c) Clinical investigations designed uct for oral administration labeled, to obtain evidence that any drug prod- represented, or promoted for OTC use uct labeled, represented, or promoted to treat or relieve the symptoms or dis- for OTC use as a nailbiting or comfort of fever blisters and cold sores thumbsucking deterrent is safe and ef- is safe and effective for the purpose in- fective for the purpose intended must tended must comply with the require- comply with the requirements and pro- ments and procedures governing the
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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 into interstate commerce that is not in [58 FR 47605, Sept. 9, 1993] compliance with this section is subject to regulatory action. § 310.540 Drug products containing ac- tive ingredients offered over-the- [57 FR 29173, June 30, 1992] counter (OTC) for use as stomach acidifiers. § 310.538 Drug products containing ac- tive ingredients offered over-the- (a) Betaine hydrochloride, glutamic counter (OTC) for use for ingrown acid hydrochloride, diluted hydro- toenail relief. chloric acid, and pepsin have been (a) Any product that bears labeling present as ingredients in over-the- claims such as for ‘‘temporary relief of counter (OTC) drug products for use as discomfort from ingrown toenails,’’ or stomach acidifiers. Because of the lack ‘‘ingrown toenail relief product,’’ or of adequate data to establish the effec- ‘‘ingrown toenail reliever,’’ or similar tiveness of these or any other ingredi- claims is considered an ingrown toenail ents for use in treating achlorhydria relief drug product. Benzocaine, and hypochlorhydria, and because such chlorobutanol, chloroxylenol, dibu- conditions are asymptomatic, any OTC caine, sodium sulfide, tannic acid, and drug product containing ingredients of- urea have been present as ingredients fered for use as a stomach acidifier in such products. There is lack of ade- cannot be considered generally recog- quate data to establish general rec- nized as safe and effective. ognition of the safety and effectiveness (b) Any OTC drug product that is la- of these or any other ingredients for beled, represented, or promoted for use OTC use for ingrown toenail relief. as a stomach acidifier is regarded as a Based on evidence currently available, new drug within the meaning of section any OTC drug product containing in- gredients offered for use for ingrown 201(p) of the Federal Food, Drug, and toenail relief cannot be generally rec- Cosmetic Act, for which an approved ognized as safe and effective. new drug application under section 505 (b) Any OTC drug product that is la- of the act and part 314 of this chapter beled, represented, or promoted for in- is required for marketing. In the ab- grown toenail relief is regarded as a sence of an approved new drug applica- new drug within the meaning of section tion, such product is also misbranded 201(p) of the Federal Food, Drug, and under section 502 of the act. Cosmetic Act (the act), for which an (c) Clinical investigations designed approved application or abbreviated to obtain evidence that any drug prod- application under section 505 of the act uct labeled, represented, or promoted and part 314 of this chapter is required as a stomach acidifier for OTC use is for marketing. In the absence of an ap- safe and effective for the purpose in- proved new drug application or abbre- tended must comply with the require- viated new drug application, such prod- ments and procedures governing the uct is also misbranded under section use of investigational new drugs set 502 of the act. forth in part 312 of this chapter. (c) Clinical investigations designed (d) After the effective date of the to obtain evidence that any drug prod- final regulation, any such OTC drug uct labeled, represented, or promoted product initially introduced or ini- for OTC use for ingrown toenail relief is safe and effective for the purpose in- tially delivered for introduction into tended must comply with the require- interstate commerce that is not in ments and procedures governing the compliance with this section is subject use of investigational new drugs set to regulatory action. forth in part 312 of this chapter. [53 FR 31271, Aug. 17, 1988] (d) After March 9, 1994, any such OTC drug product initially introduced or
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§ 310.541 Over-the-counter (OTC) drug the treatment of hyperphosphatemia products containing active ingredi- cannot be considered generally recog- ents offered for use in the treat- nized as safe and effective. ment of hypophosphatemia. (b) Any drug product that is labeled, (a) Hypophosphatemia is a condition represented, or promoted for OTC use in which an abnormally low plasma in the treatment of hyperphosphatemia level of phosphate occurs in the blood. is regarded as a new drug within the This condition is not amenable to self- meaning of section 201(p) of the Fed- diagnosis or self-treatment. Treatment eral Food, Drug, and Cosmetic Act (the of this condition should be restricted act), for which an approved application to the supervision of a physician. For under section 505 of the act and part 314 this reason, any drug product contain- of this chapter is required for market- ing ingredients offered for OTC use in ing. In the absence of an approved ap- the treatment of hypophosphatemia plication, such product is also mis- cannot be considered generally recog- branded under section 502 of the act. nized as safe and effective. (c) Clinical investigations designed (b) Any drug product that is labeled, to obtain evidence that any drug prod- represented, or promoted for OTC use uct labeled, represented, or promoted in the treatment of hypophosphatemia for use in the treatment of is regarded as a new drug within the hyperphosphatemia is safe and effec- meaning of section 201(p) of the Fed- tive for the purpose intended must eral Food, Drug, and Cosmetic Act (the comply with the requirements and pro- act), for which an approved application cedures governing use of investiga- under section 505 of the act and part 314 tional new drugs set forth in part 312 of of this chapter is required for market- this chapter. ing. In the absence of an approved ap- (d) After November 12, 1990, any such plication, such product is also mis- OTC drug product initially introduced branded under section 502 of the act. or initially delivered for introduction (c) Clinical investigations designed into interstate commerce that is not in to obtain evidence that any drug prod- compliance with this section is subject uct labeled, represented, or promoted to regulatory action. for OTC use in the treatment of [55 FR 19858, May 11, 1990] hypophosphatemia is safe and effective for the purpose intended must comply § 310.543 Drug products containing ac- with the requirements and procedures tive ingredients offered over-the- governing the use of investigational counter (OTC) for human use in new drugs set forth in part 312 of his exocrine pancreatic insufficiency. chapter. (a) Hemicellulase, pancreatin, and (d) After November 12, 1990, any such pancrelipase have been present as in- OTC drug product initially introduced gredients in exocrine pancreatic insuf- or initially delivered for introduction ficiency drug products. Pancreatin and into 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 [55 FR 19858, May 11, 1990] shown in the bioavailability of mar- keted exocrine pancreatic insufficiency § 310.542 Over-the-counter (OTC) drug drug products produced by different products containing active ingredi- manufacturers. These differences raise ents offered for use in the treat- a potential for serious risk to patients ment of hyperphosphatemia. using these drug products. The bio- (a) Hyperphosphatemia is a condition availability of pancreatic enzymes is in which an abnormally high plasma dependent on the process used to man- level of phosphate occurs in the blood. ufacture the drug products. Informa- This condition in not amenable to self- tion on this process is not included in diagnosis or self-treatment. Treatment an OTC drug monograph. Therefore, of this condition should be restricted the safe and effective use of these en- to the supervision of a physician. For zymes for treating exocrine pancreatic this reason, any drug product contain- insufficiency cannot be regulated ade- ing ingredients offered for OTC use in quately by an OTC drug monograph.
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Information on the product’s formula- rette habit,’’ ‘‘helps stop or reduce tion, manufacture, quality control pro- smoking,’’ or similar claims is a smok- cedures, and final formulation effec- ing deterrent drug product. Cloves, co- tiveness testing are necessary in an ap- riander, eucalyptus oil, ginger (Ja- proved application to ensure that a maica), lemon oil (terpeneless), licorice company has the ability to manufac- root extract, lobeline (in the form of ture a proper bioactive formulation. In lobeline sulfate or natural lobelia alka- addition, continuous physician mon- loids or Lobelia inflata herb), menthol, itoring of patients who take these drug methyl salicylate, povidone-silver ni- products is a collateral measure nec- trate, quinine ascorbate, silver acetate, essary to the safe and effective use of silver nitrate, and thymol have been these enzymes, causing such products present as ingredients in such drug to be available by prescription only. products. There is a lack of adequate (b) Any drug product that is labeled, data to establish general recognition of represented, or promoted for OTC use the safety and effectiveness of these or in the treatment of exocrine pancreatic any other ingredients for OTC use as a insufficiency is regarded as a new drug smoking deterrent. Based on evidence within the meaning of section 201(p) of currently available, any OTC drug the Federal Food, Drug, and Cosmetic product containing ingredients offered Act (the act), for which an approved for use as a smoking deterrent cannot application under section 505 of the act be generally recognized as safe and ef- and part 314 of this chapter is required fective. for marketing. In the absence of an ap- (b) Any OTC drug product that is la- proved application, such product is also beled, represented, or promoted as a misbranded under section 502 of the smoking deterrent is regarded as a new act. drug within the meaning of section (c) Clinical investigations designed 201(p) of the Federal Food, Drug, and to obtain evidence that any drug prod- Cosmetic Act (the act), for which an uct labeled, represented, or promoted approved application or abbreviated for OTC use in the treatment of application under section 505 of the act exocrine pancreatic insufficiency is and part 314 of this chapter is required safe and effective for the purpose in- for marketing. In the absence of an ap- tended must comply with the require- proved new drug application or abbre- ments and procedures governing the viated new drug application, such prod- use of investigational new drugs set uct is also misbranded under section forth in part 312 of this chapter. 502 of the act. (d) After May 7, 1991, any such OTC (c) Clinical investigations designed drug product that contains to obtain evidence that any drug prod- hemicellulase initially introduced or uct labeled, represented, or promoted initially delivered for introduction into for OTC use as a smoking deterrent is interstate commerce that is not in safe and effective for the purpose in- compliance with this section is subject tended must comply with the require- to regulatory action. ments and procedures governing the (e) After October 24, 1995, any such use of investigational new drugs set OTC drug product that contains pan- forth in part 312 of this chapter. creatin or pancrelipase initially intro- (d) After May 7, 1991, any such OTC duced or initially delivered for intro- drug product containing cloves, cori- duction into interstate commerce that ander, eucalyptus oil, ginger (Ja- is not in compliance with this section maica), lemon oil (terpeneless), licorice is subject to regulatory action. root extract, menthol, methyl salicy- [60 FR 20165, Apr. 24, 1995] late, quinine ascorbate, silver nitrate, and/or thymol initially introduced or § 310.544 Drug products containing ac- initially delivered for introduction into tive ingredients offered over-the- interstate commerce that is not in counter (OTC) for use as a smoking compliance with this section is subject deterrent. to regulatory action. After December 1, (a) Any product that bears labeling 1993, any such OTC drug product con- claims that it ‘‘helps stop or reduce the taining lobeline (in the form of lobeline cigarette urge,’’ ‘‘helps break the ciga- sulfate or natural lobelia alkaloids or
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Lobelia inflata herb), povidone-silver ni- Sodium phosphate trate, silver acetate, or any other in- (ii) Approved as of October 7, 1996. gredients initially introduced or ini- tially delivered for introduction into Calcium sucrose phosphate interstate commerce that is not in Dicalcium phosphate dihydrate Disodium hydrogen phosphate1 compliance with this section is subject Phosphoric acid1 to regulatory action. Sodium dihydrogen phosphate [58 FR 31241, June 1, 1993] Sodium dihydrogen phosphate monohydrate Sodium phosphate, dibasic anhydrous rea- § 310.545 Drug products containing gent1 certain active ingredients offered (3) Antidiarrheal drug products. over-the-counter (OTC) for certain uses. Aluminum hydroxide Atropine sulfate (a) A number of active ingredients Calcium carbonate have been present in OTC drug prod- Carboxymethylcellulose sodium ucts for various uses, as described Glycine below. However, based on evidence cur- Homatropine methylbromide rently available, there are inadequate Hyoscyamine sulfate data to establish general recognition of Lactobacillus acidophilus the safety and effectiveness of these in- Lactobacillus bulgaricus gredients for the specified uses: Opium, powdered Opium tincture (1) Topical acne drug products. Paregoric Alcloxa Phenyl salicylate Alkyl isoquinolinium bromide Scopolamine hydrobromide Aluminum chlorohydrex Zinc phenolsulfonate Aluminum hydroxide (4) Antiperspirant drug products. Benzocaine Benzoic acid Alum, potassium Boric acid Aluminum bromohydrate Calcium polysulfide Aluminum chloride (alcoholic solutions) Calcium thiosulfate Aluminum chloride (aqueous solution) (aero- Camphor sol only) Chloroxylenol Aluminum sulfate Cloxyquin Aluminum sulfate, buffered (aerosol only) Coal tar Sodium aluminum chlorohydroxy lactate Dibenzothiophene Estrone (5) [Reserved] Magnesium aluminum silicate (6) Cold, cough, allergy, bronchodilator, Magnesium sulfate and antiasthmatic drug products—(i) Phenol Antihistamine drug products—(A) Ingre- Phenolate sodium dients. Phenyl salicylate Povidone-iodine Methapyrilene hydrochloride Pyrilamine maleate Methapyrilene fumarate Resorcinol (as single ingredient) Thenyldiamine hydrochloride Resorcinol monoacetate (as single ingredi- ent) (B) Ingredients. Salicylic acid (over 2 up to 5 percent) Phenyltoloxamine dihydrogen citrate Sodium borate Methapyrilene hydrochloride Sodium thiosulfate Methapyrilene fumarate Tetracaine hydrochloride Thenyldiamine hydrochloride Thymol Vitamin E (ii) Nasal decongestant drug products— Zinc oxide (A) Approved as of May 7, 1991. Zinc stearate Zinc sulfide Allyl isothiocyanate Camphor (lozenge) (2) Anticaries drug products—(i) Ap- Creosote, beechwood (oral) proved as of May 7, 1991. Hydrogen fluoride 1 These ingredients are nonmonograph ex- Sodium carbonate cept when used to prepare acidulated phos- Sodium monofluorophosphate (6 percent phate fluoride treatment rinses identified in rinse) § 355.10(a)(3) of this chapter.
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Eucalyptol (lozenge) taining theophylline (e.g., theophylline Eucalyptol (mouthwash) and ephedrine, or theophylline and Eucalyptus oil (lozenge) ephedrine and phenobarbital). Eucalyptus oil (mouthwash) (C) Approved as of June 19, 1996. Any Menthol (mouthwash) Peppermint oil (mouthwash) ingredient(s) in a pressurized metered- Thenyldiamine hydrochloride dose inhaler container. Thymol (7) Dandruff/seborrheic dermatitis/psori- Thymol (lozenge) asis drug products. Thymol (mouthwash) Turpentine oil Alkyl isoquinolinium bromide Allantoin (B) Approved as of August 23, 1995. Benzalkonium chloride Benzethonium chloride Bornyl acetate (topical) Boric acid Cedar leaf oil (topical) Calcium undecylenate Creosote, beechwood (topical) Captan l-desoxyephedrine (topical) Chloroxylenol Ephedrine (oral) Colloidal oatmeal Ephedrine hydrochloride (oral) Cresol, saponated Ephedrine sulfate (oral) Ethohexadiol Racephedrine hydrochloride (oral/topical) Eucalyptol (iii) Expectorant drug products. Juniper tar Lauryl isoquinolinium bromide Ammonium chloride Menthol Antimony potassium tartrate Mercury oleate Beechwood creosote Methylbenzethonium chloride Benzoin preparations (compound tincture of Methyl salicylate benzoin, tincture of benzoin) Phenol Camphor Phenolate sodium Chloroform Pine tar Eucalyptol/eucalyptus oil Povidone-iodine Horehound Resorcinol Iodides (calcium iodide anyhydrous, Sodium borate hydroidic acid syrup, iodized lime, potas- Sodium salicylate sium iodide) Thymol Ipecac Undecylenic acid Ipecac fluidextract (8) Digestive aid drug products—(i) Ap- Ipecac syrup Menthol/peppermint oil proved as of May 7, 1991. Pine tar preparations (extract white pine Bismuth sodium tartrate compound, pine tar, syrup of pine tar, Calcium carbonate compound white pine syrup, white pine) Cellulase Potassium guaiacolsulfonate Dehydrocholic acid Sodium citrate Dihydroxyaluminum sodium carbonate Squill preparations (squill, squill extract) Duodenal substance Terpin hydrate preparations (terpin hydrate, Garlic, dehydrated terpin hydrate elixir) Glutamic acid hydrochloride Tolu preparations (tolu, tolu balsam, tolu Hemicellulase balsam tincture) Homatropine methylbromide Turpentine oil (spirits of turpentine) Magnesium hydroxide Magnesium trisilicate (iv) Bronchodilator drug products—(A) Ox bile extract Approved as of October 2, 1987. Pancreatin Aminophylline Pancrelipase Belladonna alkaloids Papain Euphorbia pilulifera Peppermint oil Metaproterenol sulfate Pepsin Methoxyphenamine hydrochloride Sodium bicarbonate Pseudoephedrine hydrochloride Sodium citrate Pseudoephedrine sulfate Sorbitol Theophylline, anhydrous (ii) Approved as of November 10, 1993. Theophylline calcium salicylate Theophylline sodium glycinate Alcohol Aluminum hydroxide (B) Approved as of January 29, 1996. Amylase Any combination drug product con- Anise seed
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Aromatic powder Potassium carbonate Asafetida Protease Aspergillus oryza enzymes (except lactase Prolase enzyme derived from Aspergillus oryzae) Rhubarb fluid extract Bacillus acidophilus Senna Bean Sodium chloride Belladonna alkaloids Sodium salicylate Belladonna leaves, powdered extract Stem bromelain Betaine hydrochloride Strawberry Bismuth subcarbonate Strychnine Bismuth subgallate Tannic acid Black radish powder Trillium Blessed thistle (cnicus benedictus) Woodruff Buckthorn (iii) Charcoal, activated Calcium gluconate Capsicum (9) [Reserved] Capsicum, fluid extract of (10) External analgesic drug products— Carbon (i) Analgesic and anesthetic drug prod- Cascara sagrada extract ucts. Catechu, tincture Catnip Aspirin Chamomile flowers Chloral hydrate Charcoal, wood Chlorobutanol Chloroform Cyclomethycaine sulfate Cinnamon oil Eugenol Cinnamon tincture Hexylresorcinol Citrus pectin Methapyrilene hydrochloride Diastase Salicylamide Diastase malt Thymol Dog grass (ii) Counterirritant drug products. Elecampane Ether Chloral hydrate Fennel acid Eucalyptus oil Galega (iii) Male genital desensitizer drug Ginger Glycine products. Hydrastis canadensis (golden seal) Benzyl alcohol Hectorite Camphorated metacresol Horsetail Ephedrine hydrochloride Huckleberry Hydrastis fluid extract (iv) Diaper rash drug products. Hydrochloric acid Any ingredient(s) labeled with claims Iodine or directions for use in the treatment Iron ox bile and/or prevention of diaper rash. Johnswort (v) Fever blister and cold sore treatment Juniper Kaolin, colloidal drug products. Knotgrass Allyl isothiocyanate Lactic acid Aspirin Lactose Bismuth sodium tartrate Lavender compound, tincture of Camphor (exceeding 3 percent) Linden Capsaicin Lipase Capsicum Lysine hydrochloride Capsicum oleoresin Mannitol Chloral hydrate Mycozyme Chlorobutanol Myrrh, fluid extract of Cyclomethycaine sulfate Nettle Eucalyptus oil Nickel-pectin Eugenol Nux vomica extract Glycol salicylate Orthophosphoric acid Hexylresorcinol Papaya, natural Histamine dihydrochloride Pectin Menthol (exceeding 1 percent) Peppermint Methapyrilene hydrochloride Peppermint spirit Methyl nicotinate Phenacetin Methyl salicylate Potassium bicarbonate Pectin
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Salicylamide Thymol Strong ammonia solution Trolamine salicylate Tannic acid Turpentine oil Thymol Zirconium oxide Tripelennamine hydrochloride Zyloxin Trolamine salicylate Turpentine oil (11) [Reserved] Zinc sulfate (12) Laxative drug products—(i) Bulk laxatives. (vi) Insect bite and sting drug products. Agar Alcohol Carrageenan (degraded) Alcohol, ethoxylated alkyl Carrageenan (native) Benzalkonium chloride Guar gun Calamine Ergot fluidextract (ii) Saline laxative. Ferric chloride Tartaric acid Panthenol Peppermint oil (iii) Stool softener. Pyrilamine maleate Sodium borate Poloxamer 188 Trolamine salicylate (iv) Stimulant laxatives. Turpentine oil Zinc oxide Aloin Zirconium oxide Bile salts/acids Calcium pantothenate (vii) Poison ivy, poison oak, and poison Calomel sumac drug products. Colocynth Alcohol Elaterin resin Aspirin Frangula Benzethonium chloride Gamboge Benzocaine (0.5 to 1.25 percent) Ipomea Bithionol Jalap Ox bile Calamine Podophyllum resin Cetalkonium chloride Prune concentrate dehydrate Chloral hydrate Prune powder Chlorobutanol Rhubarb, Chinese Chlorpheniramine maleate Sodium Oleate Creosote, beechwood Cyclomethycaine sulfate (13) [Reserved] Dexpanthenol (14) Oral health care drug products Diperodon hydrochloride (nonantimicrobial). Eucalyptus oil Eugenol Antipyrine Glycerin Camphor Glycol salicylate Cresol Hectorite Dibucaine Hexylresorcinol Dibucaine hydrochloride Hydrogen peroxide Eucalyptol Impatiens biflora tincture Lidocaine Iron oxide Lidocaine hydrochloride Isopropyl alcohol Methly salicylate Lanolin Myrrh tincture Lead acetate Pyrilamine maleate Merbromin Sorbitol Mercuric chloride Sugars Methapyrilene hydrochloride Tetracaine Panthenol Tetracaine hydrochloride Parethoxycaine hydrochloride Thymol Phenyltoloxamine dihydrogen citrate (15) Topical otic drug products for the Povidone-vinylacetate copolymers prevention of swimmer’s ear and for the Pyrilamine maleate Salicylamide drying of water-clogged ears—(i) Ap- Salicylic acid proved as of May 7, 1991. Simethicone Acetic acid Sulfur Tannic acid (ii) Approved as of August 15, 1995.
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Glycerin and anhydrous glycerin Cocoa butter Isopropyl alcohol Cysteine hydrochloride Glycerin (16) Poison treatment drug products. Protein hydrolysate Ipecac fluidextract Racemethionine Ipecac tincture Sulfur Zinc sulfate Tannic acid Zinc acetate (17) Skin bleaching drug products. Zinc carbonate Mercury, ammoniated (iv) Fever blister and cold sore treat- (18) Skin protectant drug products. (i) ment drug products. Ingredients. Bismuth subnitrate Boric acid Allantoin (wound healing claims only) Pyridoxine hydrochloride Sulfur Sulfur Tannic acid Tannic acid Zinc acetate (wound healing claims only) Topical starch (ii) Astringent drug products. Trolamine Zinc sulfate Acetone Alcohol (v) Insect bite and sting drug products. Alum, ammonium Alcohol Alum, potassium Alcohol, ethoxylated alkyl Aluminum chlorhydroxy complex Ammonia solution, strong Aromatics Ammonium hydroxide Benzalkonium chloride Benzalkonium chloride Benzethonium chloride Camphor Benzocaine Ergot fluidextract Benzoic acid Ferric chloride Boric acid Menthol Calcium acetate Peppermint oil Camphor gum Phenol Clove oil Pyrilamine maleate Colloidal oatmeal Sodium borate Cresol Trolamine Cupric sulfate Turpentine oil Eucalyptus oil Zirconium oxide Eugenol Ferric subsulfate (Monsel’s Solution) (vi) Poison ivy, poison oak, and poison Honey sumac drug products. Isopropyl alcohol Alcohol Menthol Anion and cation exchange resins buffered Methyl salicylate Benzethonium chloride Oxyquinoline sulfate Benzocaine P-t-butyl-m-cresol Benzyl alcohol Peppermint oil Bismuth subnitrate Phenol Bithionol Polyoxeythylene laurate Boric acid Potassium ferrocyanide Camphor Sage oil Cetalkonium chloride Silver nitrate Chloral hydrate Sodium borate Chlorpheniramine maleate Sodium diacetate Creosote Talc Diperodon hydrochloride Tannic acid glycerite Diphenhydramine hydrochloride Thymol Eucalyptus oil Topical starch Ferric chloride Zinc chloride Glycerin Zinc oxide Hectorite Zinc phenolsulfonate Hydrogen peroxide Zinc stearate Impatiens biflora tincture Zinc sulfate Iron oxide (iii) Diaper rash drug products. Isopropyl alcohol Lanolin Aluminum hydroxide Lead acetate
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Lidocaine Hydrastis canadensis Menthol Inositol Merbromin Iodine Mercuric chloride Isoleucine Panthenol Juniper, potassium extract Parethoxycaine hydrochloride Karaya gum Phenol Kelp Phenyltoloxamine dihydrogen citrate Lactose Povidone-vinylacetate copolymers Lecithin Salicylic acid Leucine Simethicone Liver concentrate Tannic acid Lysine Topical starch Lysine hydrochloride Trolamine Magnesium Turpentine oil Magnesium oxide Zirconium oxide Malt Zyloxin Maltodextrin 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) Copper Soybean protein Copper gluconate Soy meal Corn oil Sucrose Corn syrup Thiamine hydrochloride (vitamin B1) Thiamine mononitrate (vitamin B mono- Corn silk, potassium extract 1 nitrate) Cupric sulfate Threonine Cyanocobalamin (vitamin B ) 12 Tricalcium phosphate Cystine Tryptophan Dextrose Tyrosine Docusate sodium Uva ursi, potassium extract Ergocalciferol Valine Ferric ammonium citrate Vegetable Ferric pyrophosphate Vitamin A Ferrous fumarate Vitamin A acetate Ferrous gluconate Vitamin A palmitate Ferrous sulfate (iron) Vitamin E Flax seed Wheat germ Folic acid Xanthan gum Fructose Yeast Guar gum Histidine (21) Ophthalmic drug products.
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(i) Ophthalmic anesthetic drug prod- Zinc propionate ucts. (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 Chloroxylenol Boric acid m-cresol Mild silver protein Nystatin Yellow mercuric oxide (23) Internal analgesic drug products. (iii) Ophthalmic astringent drug prod- ucts. Aminobenzoic acid Antipyrine Infusion of rose petals Aspirin, aluminum (iv) Ophthalmic demulcent drug prod- Calcium salicylate Codeine ucts. Codeine phosphate Polyethylene glycol 6000 Codeine sulfate Iodoantipyrine (v) Ophthalmic vasoconstrictor drug Lysine aspirin products. Methapyrilene fumarate Phenacetin Phenylephrine hydrochloride (less than 0.08 Pheniramine maleate percent) Pyrilamine maleate (22) Topical antifungal drug products. Quinine (i) Diaper rash drug products. Any in- Salsalate gredient(s) labeled with claims or di- Sodium aminobenzoate rections for use in the treatment and/ (24) Orally administered menstrual drug or prevention of diaper rash. products. (ii) Ingredients. Alcohol Alcloxa Alfalfa leaves Alum, potassium Aloes Aluminum sulfate Asclepias tuberosa Amyltricresols, secondary Asparagus Basic fuchsin Barosma Benzethonium chloride Bearberry (extract of uva ursi) Benzoic acid Bearberry fluidextract (extract of bearberry) Benzoxiquine Blessed thistle (cnicus benedictus) Boric acid Buchu powdered extract (extract of buchu) Camphor Calcium lactate Candicidin Calcium pantothenate Chlorothymol Capsicum oleoresin Coal tar Cascara fluidextract, aromatic (extract of Dichlorophen cascara) Menthol Chlorprophenpyridamine maleate Methylparaben Cimicifuga racemosa Oxyquinoline Codeine Oxyquinoline sulfate Collinsonia (extract stone root) Phenol Corn silk Phenolate sodium Couch grass Phenyl salicylate Dog grass extract Propionic acid Ethyl nitrite Propylparaben Ferric chloride Resorcinol Ferrous sulfate Salicylic acid Gentiana lutea (gentian) Sodium borate Glycyrrhiza (licorice) Sodium caprylate Homatropine methylbromide Sodium propionate Hydrangea, powdered extract (extract of hy- Sulfur drangea) Tannic acid Hydrastis canadensis (golden seal) Thymol Hyoscyamine sulfate Tolindate Juniper oil (oil of juniper) Triacetin Magnesium sulfate Zinc caprylate Methapyrilene hydrochloride
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Methenamine Sodium salicylic acid phenolate Methylene blue Natural estrogenic hormone (iii) Astringent drug products. Niacinamide Tannic acid Nutmeg oil (oil of nutmeg) Oil of erigeron (iv) Counterirritant drug products. Parsley Camphor (greater than 3 to 11 percent) Peppermint spirit Hydrastis Pepsin, essence Menthol (1.25 to 16 percent) Phenacetin Turpentine oil (rectified) (6 to 50 percent) Phenindamine tartrate Phenyl salicylate (v) Keratolytic drug products. Piscidia erythrina Pipsissewa Precipitated sulfur Potassium acetate Sublimed sulfur Potassium nitrate (vi) Local anesthetic drug products. Riboflavin Saw palmetto Diperodon Senecio aureus Phenacaine hydrochloride Sodium benzoate Sodium nitrate (vii) Other druq products. Sucrose Collinsonia extract Sulferated oils of turpentine Escherichia coli vaccines Taraxacum officinale Lappa extract Theobromine sodium salicylate Leptandra extract Theophylline Live yeast cell derivative Thiamine hydrochloride Mullein Triticum Turpentine, venice (venice turpertine) (viii) Protectant druq products. Urea Bismuth oxide (25) Pediculicide drug products—(i) Ap- Bismuth subcarbonate proved as of November 10, 1993. Bismuth subgallate Bismuth subnitrate Benzocaine Lanolin alcohols Benzyl alcohol Benzyl benzoate (ix) Vasoconstrictor druq products. Chlorophenothane (dichlorodiphenyl Epinephrine undecylenate trichloroethane) Coconut oil soap, aqueous (x) Wound healinq druq products. Copper oleate Cholecalciferol Docusate sodium Cod liver oil Formic acid Live yeast cell derivative Isobornyl thiocyanoacetate Peruvian balsam Picrotoxin Shark liver oil Propylene glycol Vitamin A Sabadilla alkaloids Sulfur, sublimed (b) Any OTC drug product that is la- Thiocyanoacetate beled, represented, or promoted for the (ii) Approved as of June 14, 1994. The uses specified and containing any ac- combination of pyrethrum extract (for- tive ingredient(s) as specified in para- merly named pyrethrins) and piperonyl graph (a) of this section is regarded as butoxide in an aerosol dosage formula- a new drug within the meaning of sec- tion. tion 210(p) of the Federal Food, Drug, (26) Anorectal druq products—(i) and Cosmetic Act (the Act), for which Anticholinergic drug products. an approved new drug application under section 505 of the Act and part Atropine 314 of this chapter is required for mar- Belladonna extract keting. In the absence of an approved (ii) Antiseptic drug products. new drug application, such product is also misbranded under section 502 of Boric acid Boroglycerin the Act. Hydrastis (c) Clinical investigations designed Phenol to obtain evidence that any drug prod- Resorcinol uct labeled, represented, or promoted
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for the OTC uses and containing any section, except products that contain active ingredient(s) as specified in ferric subsulfate. paragraph (a) of this section is safe and (12) March 2, 1994, for products sub- effective for the purpose intended must ject to paragraph (a)(22)(iii) of this sec- comply with the requirements and pro- tion. cedures governing the use of investiga- (13) August 5, 1991, for products sub- tional new drugs set forth in part 312 of ject to paragraphs (a)(26) of this sec- this chapter. tion, except for those that contain live (d) Any OTC drug product that is not yeast cell derivative. in compliance with this section is sub- (14) September 2, 1994, for products ject to regulatory action if initially in- subject to paragraph (a)(26)(vii) and troduced or initially delivered for in- (a)(26)(x) of this section that contain troduction into interstate commerce after the dates specified in paragraphs live yeast cell derivative. (d)(1) through (d)(25) of this section. (15) September 23, 1994, for products (1) May 7, 1991, for products subject subject to paragraph (a)(22)(iv) of this to paragraphs (a)(1) through (a)(2)(i), section. (a)(3) through (a)(4), (a)(6)(i)(A), (16) June 14, 1994, for products subject (a)(6)(ii)(A), (a)(7) (except as covered by to paragraph (a)(25)(ii) of this section. paragraph (d)(3) of this section), (17) [Reserved] (a)(8)(i), (a)(9) through (a)(10)(iii), (18) August 15, 1995, for products sub- (a)(12)(i) through (a)(12)(iv), (a)(14) ject to paragraph (a)(15)(ii) of this sec- through (a)(15)(i), and (a)(16) through tion. (a)(18)(i) of this section. (19) October 2, 1987, for products sub- (2) February 10, 1992, for products ject to paragraph (a)(6)(iv)(A) of this subject to paragraph (a)(20) of this sec- section. tion. (20) January 29, 1996, for products (3) December 4, 1992, for products sub- subject to paragraph (a)(6)(iv)(B) of ject to paragraph (a)(7) of this section this section. that contain menthol as an (21) April 21, 1994, for products sub- antipruritic in combination with the ject to paragraph (a)(8)(iii) of this sec- antidandruff ingredient coal tar identi- tion. fied in § 358.710(a)(1) of this chapter. (22) April 21, 1993, for products sub- (4) February 28, 1990, for products ject to paragraph (a)(18)(ii) of this sec- subject to paragraph (a)(6)(iii) of this tion that contain ferric subsulfate. section, except those that contain ipe- (23) August 23, 1995, for products sub- cac. ject to paragraph (a)(6)(ii)(B) of this (5) September 14, 1993, for products section. subject to paragraph (a)(6)(iii) of this section that contain ipecac. (24) October 7, 1996, for products sub- ject to paragraph (a)(2)(ii) of this sec- (6) December 9, 1993, for products sub- ject to paragraph (a)(6)(i)(B) of this tion. section. (25) June 19, 1996, for products subject (7) March 6, 1989, for products subject to paragraph (a)(6)(iv)(C) of this sec- to paragraph (a)(21) of this section, ex- tion. cept those that contain ophthalmic [55 FR 46919, Nov. 7, 1990] anti–infective ingredients listed in paragraph (a)(21)(ii). EDITORIAL NOTE: For FEDERAL REGISTER ci- tations affecting § 310.545, see the List of CFR (8) June 18, 1993, for products subject Sections Affected in the Finding Aids sec- to paragraph (a)(21) of this section that tion of this volume. contain ophthalmic anti–infective in- gredients. EFFECTIVE DATE NOTES: 1. At 60 FR 42436, (9) June 18, 1993, for products subject Aug. 16, 1995, in § 310.545, paragraph (a)(15)(ii) was stayed for topical otic drug products for to paragraph (a)(10)(iv) of this section. the drying of water-clogged ears. (10) June 18, 1993, for products subject 2. At 61 FR 9571, Mar. 8, 1996, in § 310.545 in to paragraph (a)(22)(i) of this section. paragraph (a)(6)(ii)(B), the entry for ‘‘l- (11) November 10, 1993, for products desoxyephedrine (topical)’’ was stayed until subject to paragraph (a)(18)(ii) of this further notice.
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§ 310.546 Drug products containing ac- uct labeled, represented, or promoted tive ingredients offered over-the- for OTC use for the treatment and/or counter (OTC) for the treatment prevention of nocturnal leg muscle and/or prevention of nocturnal leg cramps is safe and effective for the pur- muscle cramps. pose intended must comply with the re- (a) Quinine sulfate alone or in com- quirements and procedures governing bination with vitamin E has been the use of investigational new drugs present in over-the-counter (OTC) drug set forth in part 312 of this chapter. products for the treatment and/or pre- (d) After February 22, 1995, any such vention of nocturnal leg muscle OTC drug product initially introduced cramps, i.e., a condition of localized or initially delivered for introduction pain in the lower extremities usually into interstate commerce that is not in occurring in middle life and beyond compliance with this section is subject with no regular pattern concerning to regulatory action. time or severity. There is a lack of ade- quate data to establish general rec- [59 FR 43252, Aug. 22, 1994] ognition of the safety and effectiveness of quinine sulfate, vitamin E, or any PART 312—INVESTIGATIONAL NEW other ingredients for OTC use in the DRUG APPLICATION treatment and/or prevention of noc- turnal leg muscle cramps. In the doses Subpart A—General Provisions used to treat or prevent this condition, quinine sulfate has caused adverse Sec. 312.1 Scope. events such as transient visual and au- 312.2 Applicability. ditory disturbances, dizziness, fever, 312.3 Definitions and interpretations. nausea, vomiting, and diarrhea. Qui- 312.6 Labeling of an investigational new nine sulfate may cause unpredictable drug. serious and life-threatening 312.7 Promotion and charging for investiga- hypersensitivity reactions requiring tional drugs. medical intervention and hospitaliza- 312.10 Waivers. tion; fatalities have been reported. The risk associated with use of quinine sul- Subpart B—Investigational New Drug fate, in the absence of evidence of its Application (IND) effectiveness, outweighs any potential 312.20 Requirement for an IND. benefit in treating and/or preventing 312.21 Phases of an investigation. this benign, self-limiting condition. 312.22 General principles of the IND submis- Based upon the adverse benefit-to-risk sion. ratio, any drug product containing qui- 312.23 IND content and format. nine or quinine sulfate cannot be con- 312.30 Protocol amendments. sidered generally recognized as safe for 312.31 Information amendments. the treatment and/or prevention of 312.32 IND safety reports. nocturnal leg muscle cramps. 312.33 Annual reports. (b) Any OTC drug product that is la- 312.34 Treatment use of an investigational beled, represented, or promoted for the new drug. treatment and/or prevention of noc- 312.35 Submissions for treatment use. 312.36 Emergency use of an investigational turnal leg muscle cramps is regarded as new drug. a new drug within the meaning of sec- 312.38 Withdrawal of an IND. tion 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which Subpart C—Administrative Actions an approved application or abbreviated application under section 505 of the act 312.40 General requirements for use of an in- and part 314 of this chapter is required vestigational new drug in a clinical in- vestigation. for marketing. In the absence of an ap- 312.41 Comment and advice on an IND. proved new drug application or abbre- 312.42 Clinical holds and requests for modi- viated new drug application, such prod- fication. uct is also misbranded under section 312.44 Termination. 502 of the act. 312.45 Inactive status. (c) Clinical investigations designed 312.47 Meetings. to obtain evidence that any drug prod- 312.48 Dispute resolution.
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