[Code of Federal Regulations]

[Title 21, Volume 5, Parts 300 to 499]

[Revised as of April 1, 2000]

From the U.S. Government Printing Office via GPO Access[CITE: 21CFR310]

[Page 5-58]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION,DEPARTMENT OF HEALTH AND HUMAN SERVICES--Continued

PART 310--NEW DRUGS

Subpart A--General Provisions

Sec.

310.3 Definitions and interpretations.

310.4 Biologics; products subject to license control.

310.6 Applicability of ``new drug'' or safety or effectiveness findings in drug efficacy study implementation notices and notices of opportunity for hearing to identical, related, and similar drug products.

Subpart B--Specific Administrative Rulings and Decisions

310.100 New drug status opinions; statement of policy.

310.103 New drug substances intended for hypersensitivity testing.

Subpart C--New Drugs Exempted From Prescription-Dispensing Requirements

310.200 Prescription-exemption procedure.

310.201 Exemption for certain drugs limited by new drug applications to prescription sale.

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Subpart D--Records and Reports

310.303 Continuation of long-term studies, records, and reports on certain drugs for which new drug applications have been approved.

310.305 Records and reports concerning adverse drug experiences on marketed prescription drugs for human use without approved new drug applications.

Subpart E--Requirements for Specific New Drugs or Devices

310.500 Digoxin products for oral use; conditions for marketing.

310.501 Patient package inserts for oral contraceptives.

310.502 Certain drugs accorded new drug status through rulemaking procedures.

310.503 Requirements regarding certain radioactive drugs.

310.509 Parenteral drug products in plastic containers.

310.515 Patient package inserts for estrogens.

310.516 Progestational drug products; labeling directed to the patient.

310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea class.

310.518 Drug products containing iron or iron salts.

310.519 Drug products marketed as over-the-counter (OTC) daytime sedatives.

310.527 Drug products containing active ingredients offered over-the- counter (OTC) for external use as hair growers or for hair loss prevention

310.528 Drug products containing active ingredients offered over-the- counter (OTC) for use as an aphrodisiac

310.529 Drug products containing active ingredients offered over-the- counter (OTC) for oral use as insect repellents

310.530 Topically applied hormone-containing drug products for over- the-counter (OTC) human use

310.531 Drug products containing active ingredients offered over-the- counter (OTC) for the treatment of boils

310.532 Drug products containing active ingredients offered over-the- counter (OTC) to relieve the symptoms of benign prostatic hypertrophy

310.533 Drug products containing active ingredients offered over-the- counter (OTC) for human use as an anticholinergic in cough- cold drug products

310.534 Drug products containing active ingredients offered over-the- counter (OTC) for human use as oral wound healing agents.

310.536 Drug products containing active ingredients offered over-the- counter (OTC) for use as a nailbiting or thumbsucking deterrent.

310.537 Drug products containing active ingredients offered over-the- counter (OTC) for oral administration for the treatment of fever blisters and cold sores.

310.538 Drug products containing active ingredients offered over-the- counter (OTC) for use for ingrown toenail relief.

310.540 Drug products containing active ingredients offered over-the- counter (OTC) for use as stomach acidifiers.

310.541 Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hypophosphatemia.

310.542 Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hyperphosphatemia.

310.543 Drug products containing active ingredients offered over-the- counter (OTC) for human use in exocrine pancreatic insufficiency.

310.544 Drug products containing active ingredients offered over-the- counter (OTC) for use as a smoking deterrent.

310.545 Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses.

310.546 Drug products containing active ingredients offered over-the- counter (OTC) for the treatment and/or prevention of nocturnal leg muscle cramps.

310.547 Drug products containing quinine offered over-the-counter (OTC) for the treatment and/or prevention of malaria.

310.548 Drug products containing colloidal silver ingredients or silver salts offered over-the-counter (OTC) for the treatment and/or prevention of disease.

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 263b-263n.

Subpart A--General Provisions

Sec. 310.3 Definitions and interpretations.

As used in this part:

(a) The term act means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

(b) Department means the Department of Health and Human Services.

(c) Secretary means the Secretary of Health and Human Services.

(d) Commissioner means the Commissioner of Food and Drugs.

(e) The term person includes individuals, partnerships, corporations, and associations.

(f) The definitions and interpretations of terms contained in section 201 of the act shall be applicable to such

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terms when used in the regulations in this part.

(g) New drug substance means any substance that when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance.

(h) The newness of a drug may arise by reason (among other reasons) of:

(1) The newness for drug use of any substance which composes such drug, in whole or in part, whether it be an active substance or a menstruum, excipient, carrier, coating, or other component.

(2) The newness for a drug use of a combination of two or more substances, none of which is a new drug.

(3) The newness for drug use of the proportion of a substance in a combination, even though such combination containing such substance in other proportion is not a new drug.

(4) The newness of use of such drug in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body.

(5) The newness of a dosage, or method or duration of administration or application, or other condition of use prescribed, recommended, or suggested in the labeling of such drug, even though such drug when used in other dosage, or other method or duration of administration or application, or different condition, is not a new drug.

(i) [Reserved]

(j) The term sponsor means the person or agency who assumes responsibility for an investigation of a new drug, including responsibility for compliance with applicable provisions of the act and regulations. The ``sponsor'' may be an individual, partnership, corporation, or Government agency and may be a manufacturer, scientific institution, or an investigator regularly and lawfully engaged in the investigation of new drugs.

(k) The phrase related drug(s) includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety, including articles prepared or manufactured by other manufacturers: and any other drug containing a component so related by chemical structure or known pharmacological properties that, in the opinion of experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, it is prudent to assume or ascertain the liability of similar side effects and contraindications.

(l) Special packaging as defined in section 2(4) of the Poison Prevention Packaging Act of 1970 means packaging that is designed or constructed to be significantly difficult for children under 5 years of age to open or obtain a toxic or harmful amount of the substance contained therein within a reasonable time and not difficult for normal adults to use properly, but does not mean packaging which all such children cannot open or obtain a toxic or harmful amount within a reasonable time.

(m) [Reserved]

(n) The term radioactive drug means any substance defined as a drug in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act which exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons and includes any nonradioactive reagent kit ornuclide generator which is intended to be used in the preparation of any such substance but does not include drugs such as carbon-containing compounds or potassium-containing salts which contain trace quantities of naturally occurring radionuclides. The term ``radioactive drug'' includes a ``radioactive biological product'' as defined in Sec. 600.3(ee) of this chapter.

[39 FR 11680, Mar. 29, 1974, as amended at 39 FR 20484, June 11, 1974; 40 FR 31307, July 25, 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. 22, 1985]

Sec. 310.4 Biologics; products subject to license control.

(a) If a drug has an approved license under section 351 of the Public Health Service Act (42 U.S.C. 262 et seq.) or under the animal virus, serum, and toxin law of March 4, 1913 (21 U.S.C. 151 et seq.), it is not required to have an approved application under section 505 of the act.

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(b) To obtain marketing approval for radioactive biological products for human use, as defined in Sec. 600.3(ee) of this chapter, manufacturers must comply with the provisions of 601.2(b) of this chapter.

[64 FR 56448, Oct. 20, 1999]

Sec. 310.6 Applicability of ``new drug'' or safety or effectiveness findings in drug efficacy study implementation notices and notices of opportunity for hearing to identical, related, and similar drug products.

(a) The Food and Drug Administration's conclusions on the effectiveness of drugs are currently being published in the Federal Register as Drug Efficacy Study Implementation (DESI) Notices and as Notices of Opportunity for Hearing. The specific products listed in these notices include only those that were introduced into the market through the new drug procedures from 1938-62 and were submitted for review by the National Academy of Sciences-National Research Council (NAS-NRC), Drug Efficacy Study Group. Many products which are identical to, related to, or similar to the products listed in these notices have been marketed under different names or by different firms during this same period or since 1962 without going through the new drug procedures or the Academy review. Even though these products are not listed in the notices, they are covered by the new drug applications reviewed and thus are subject to these notices. All persons with an interest in a product that is identical, related, or similar to a drug listed in a drug efficacy notice or a notice of opportunity for a hearing will be given the same opportunity as the applicant to submit data and information, to request a hearing, and to participate in any hearing. It is not feasible for the Food and Drug Administration to list all products which are covered by an NDA and thus subject to each notice. However, it is essential that the findings and conclusions that a drug product is a ``new drug'' or that there is a lack of evidence to show that a drug product is safe or effective be applied to all identical, related, and similar drug products to which they are reasonably applicable. Any product not in compliance with an applicable drug efficacy notice is in violation of section 505 (new drugs) and/or section 502 (misbranding) of the act.

(b)(1) An identical, related, or similar drug includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety as well as of any drug moiety related in chemical structure or known pharmacological properties.

(2) Where experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs would conclude that the findings and conclusions, stated in a drug efficacy notice or notice of opportunity for hearing, that a drug product is a ``new drug'' or that there is a lack of evidence to show that a drug product is safe or effective are applicable to an identical, related, or similar drug product, such product is affected by the notice. A combination drug product containing a drug that is identical, related, or similar to a drug named in a notice may also be subject to the findings and conclusions in a notice that a drug product is a ``new drug'' or that there is a lack of evidence to show that a drug product is safe or effective.

(3) Any person may request an opinion on the applicability of such a notice to a specific product by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section.

(c) Manufacturers and distributors of drugs should review their products as drug efficacy notices are published and assure that identical, related, or similar products comply with all applicable provisions of the notices.

(d) The published notices and summary lists of the conclusions are of particular interest to drug purchasing agents. These agents should take particular care to assure that the same purchasing policy applies to drug products that are identical, related, or similar to those named in the drug efficacy notices. The Food and Drug Administration applies the same regulatory policy to all such products. In many instances a determination can readily be made as to the applicability of a drug efficacy notice by an individual who is knowledgeable about drugs and their indications for use.

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Where the relationships are more subtle and not readily recognized, the purchasing agent may request an opinion by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section.

(e) Interested parties may submit to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Compliance, HFD-300, 5600 Fishers Lane, Rockville, MD 20857, the names of drug products, and of their manufacturers or distributors, that should be the subject of the same purchasing and regulatory policies as those reviewed by the Drug Efficacy Study Group. Appropriate action, including referral to purchasing officials of various government agencies, will be taken.

(f) This regulation does not apply to OTC drugs identical, similar, or related to a drug in the Drug Efficacy Study unless there has been or is notification in the Federal Register that a drug will not be subject to an OTC panel review pursuant to Secs. 330.10, 330.11, and 330.5 of this chapter.

[39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990]

Subpart B--Specific Administrative Rulings and Decisions

Sec. 310.100 New drug status opinions; statement of policy.

(a) Over the years since 1938 the Food and Drug Administration has given informal advice to inquirers as to the new drug status of preparations. These drugs have sometimes been identified only by general statements of composition. Generally, such informal opinions were incorporated in letters that did not explicitly relate all of the necessary conditions and qualifications such as the quantitative formula for the drug and the conditions under which it was prescribed, recommended, or suggested. This has contributed to misunderstanding and misinterpretation of such opinions.

(b) These informal opinions that an article is ``not a new drug'' or ``no longer a new drug'' require reexamination under the Kefauver-Harris Act (Public Law 87-781; 76 Stat. 788-89). In particular, when approval of a new drug application is withdrawn under provisions of section 505(e) of the Federal Food, Drug, and Cosmetic Act, a drug generally recognized as safe may become a ``new drug'' within the meaning of section 201(p) of said act as amended by the Kefauver-Harris Act on October 10, 1962. This is of special importance by reason of proposed actions to withdraw approval of new drug applications for lack of substantial evidence of effectiveness as a result of reports of the National Academy of Sciences--National Research Council on its review of drug effectiveness; for example, see the notice published in the Federal Register of January 23, 1968 (33 FR 818), regarding rutin, quercetin, et al.

(c) Any marketed drug is a ``new drug'' if any labeling change made after October 9, 1962, recommends or suggests new conditions of use under which the drug is not generally recognized as safe and effective by qualified experts. Undisclosed or unreported side effects as well as the emergence of new knowledge presenting questions with respect to the safety or effectiveness of a drug may result in its becoming a ``new drug'' even though it was previously considered ``not a new drug.'' Any previously given informal advice that an article is ``not a new drug'' does not apply to such an article if it has been changed in formulation, manufacture control, or labeling in a way that may significantly affect the safety of the drug.

(d) For these reasons, all opinions previously given by the Food and Drug Administration to the effect that an article is ``not a new drug'' or is ``no longer a new drug'' are hereby revoked. This does not mean that all articles that were the subjects of such prior opinions will be regarded as new drugs. The prior opinions will be replaced by opinions of the Food and Drug Administration that are qualified and current on when an article is ``not a new drug,'' as set forth in this subchapter.

[39 FR 11680, Mar. 29, 1974]

Sec. 310.103 New drug substances intended for hypersensitivity testing.

(a) The Food and Drug Administration is aware of the need in the practice of medicine for the ingredients of

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a new drug to be available for tests of hypersensitivity to such ingredients and therefore will not object to the shipment of a new drug substance, as defined in Sec. 310.3(g), for such purpose if all of the following conditions are met:

(1) The shipment is made as a result of a specific request made to the manufacturer or distributor by a practitioner licensed by law to administer such drugs, and the use of such drugs for patch testing is not promoted by the manufacturer or distributor.

(2) The new drug substance requested is an ingredient in a marketed new drug and is not one that is an ingredient solely in a new drug that is legally available only under the investigational drug provisions of this part.

(3) The label bears the following prominently placed statements in lieu of adequate directions for use and in addition to complying with the other labeling provisions of the act:

(i) ``Caution: Federal law prohibits dispensing without a prescription''; and

(ii) ``For use only in patch testing''.

(4) The quantity shipped is limited to an amount reasonable for the purpose of patch testing in the normal course of the practice of medicine and is used solely for such patch testing.

(5) The new drug substance is manufactured by the same procedures and meets the same specifications as the component used in the finished dosage form.

(6) The manufacturer or distributor maintains records of all shipments for this purpose for a period of 2 years after shipment and will make them available to the Food and Drug Administration on request.

(b) When the requested new drug substance is intended for investigational use in humans or the substance is legally available only under the investigational drug provisions of part 312 of this chapter, the submission of an ``Investigational New Drug Application'' (IND) is required. The Food and Drug Administration will offer assistance to any practitioner wishing to submit an Investigational New Drug Application.

(c) This section does not apply to drugs or their components that are subject to the licensing requirements of the Public Health Service Act of 1944, as amended. (See subchapter F--Biologics, of this chapter.)

[39 FR 11680, Mar. 29, 1974, as amended at 55 FR 11578, Mar. 29, 1990]

Subpart C--New Drugs Exempted From Prescription-Dispensing Requirements

Sec. 310.200 Prescription-exemption procedure.

(a) Duration of prescription requirement. Any drug limited to prescription use under section 503(b)(1)(C) of the act remains so limited until it is exempted as provided in paragraph (b) or (e) of this section.

(b) Prescription-exemption procedure for drugs limited by a new drug application. Any drug limited to prescription use under section 503(b)(1)(C) of the act shall be exempted from prescription-dispensing requirements when the Commissioner finds such requirements are not necessary for the protection of the public health by reason of the drug's toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, and he finds that the drug is safe and effective for use in self-medication as directed in proposed labeling. A proposal to exempt a drug from the prescription-dispensing requirements of section 503(b)(1)(C) of the act may be initiated by the Commissioner or by any interested person. Any interested person may file a petition seeking such exemption, which petition may be pursuant to part 10 of this chapter, or in the form of a supplement to an approved new drug application.

(c) New drug status of drugs exempted from the prescription requirement. A drug exempted from the prescription requirement under the provisions of paragraph (b) of this section is a ``new drug'' within the meaning of section 201(p) of the act until it has been used to a material extent and for a material time under such conditions except as provided in paragraph (e) of this section.

(d) Prescription legend not allowed on exempted drugs. The use of the prescription caution statement quoted in section 503(b) (4) of the act, in the labeling

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of a drug exempted under the provisions of this section, constitutes misbranding. Any other statement or suggestion in the labeling of a drug exempted under this section, that such drug is limited to prescription use, may constitute misbranding.

(e) Prescription-exemption procedure of OTC drug review. A drug limited to prescription use under section 503(b)(1)(C) of the act may also be exempted from prescription-dispensing requirements by the procedure set forth in Sec. 330.13 of this chapter.

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42 FR 4714, Jan. 25, 1977; 42 FR 15674, Mar. 22, 1977]

Sec. 310.201 Exemption for certain drugs limited by new-drug applications to prescription sale.

(a) The prescription-dispensing requirements of section 503(b)(1)(C) of the Federal Food, Drug, and Cosmetic Act are not necessary for the protection of the public health with respect to the following drugs subject to new drug applications:

(1) N-Acetyl-p-aminophenol (acetaminophen, p-hydroxy-acetanilid) preparations meeting all the following conditions:

(i) The N-acetyl-p-aminophenol is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The N-acetyl-p-aminophenol and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505 (b) of the act is approved for it.

(iv) The preparation contains not more than 0.325 gram (5 grains) of N-acetyl-p-aminophenol per dosage unit, or if it is in liquid form not more than 100 milligrams of N-acetyl-p-aminophenol per milliliter.

(v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic.

(vi) The dosages of N-acetyl-p-aminophenol recommended or suggested in the labeling do not exceed: For adults, 0.65 gram (10 grains) per dose or 2.6 grams (40 grains) per 24-hour period: for children 6 to 12 years of age, one-half of the maximum adult dose or dosage; for children 3 to 6 years of age, one-fifth of the maximum adult dose or dosage.

(vii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against administration of the drug to children under 3 years of age and against use of the drug for more than 10 days, unless such uses are directed by a physician.

(viii) If the article is offered for use in arthritis or rheumatism, the labeling prominently bears a statement that the beneficial effects claimed are limited to the temporary relief of minor aches and pains of arthritis and rheumatism and, in juxtaposition with directions for use in such conditions, a conspicuous warning statement, such as ``Caution: If pain persists for more than 10 days, or redness is present, or in conditions affecting children under 12 years of age, consult a physician immediately''.

(2) Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations meeting all the following conditions:

(i) The sodium gentisate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The sodium gentisate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 0.5 gram (7.7 grains) of anhydrous sodium gentisate per dosage unit.

(v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic.

(vi) The dosages of sodium gentisate recommended or suggested in the labeling do not exceed: For adults, 0.5 gram (7.7 grains) per dose of 2.0 grams (31 grains) per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.

(vii) The labeling bears, in juxtaposition with the dosage recommendations,

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a clear warning statement against administration of the drug to children under 6 years of age and against use of the drug for a prolonged period, except as such uses may be directed by a physician.

(3) Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-N'-2-thiazolyl-N'-p-methoxybenzyl-ethyl- enediamine hydrochloride) preparations meeting all the following conditions:

(i) The isoamylhydrocupreine and zolamine hydrochloride are prepared in dosage form suitable for self-medication as rectal suppositories or as an ointment and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The isoamylhydrocupreine, zola-amine hydrochloride, and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 0.25 percent of isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride.

(v) If the preparation is in suppository form, it contains not more than 5.0 milligrams of isoamylhydrocupreine and not more than 20.0 milligrams of zolamine hydrochloride per suppository.

(vi) The preparation is labeled with adequate directions for use in the temporary relief of local pain and itching associated with hemorrhoids.

(vii) The directions provide for the use of not more than two suppositories or two applications of ointment in a 24-hour period.

(viii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against use of the preparation in case of rectal bleeding, as this may indicate serious disease.

(4) Phenyltoloxamine dihydrogen citrate (N,N-dimethyl-(a-phenyl-O-toloxy) ethylamine dihydrogen citrate), preparations meeting all the following conditions:

(i) The phenyltoloxamine dihydrogen citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The phenyltoloxamine dihydrogen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dosage unit.

(v) The preparation is labeled with adequate directions for use in the temporary relief of the symptoms of hay fever and/or the symptoms of other minor conditions in which it is indicated.

(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dose or 264 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 150 milligrams of phenyltoloxamine) per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.

(vii) The labeling bears, in juxtaposition with the dosage recommendations:

(a) Clear warning statements against administration of the drug to children under 6 years of age, except as directed by a physician, and against driving a car or operating machinery while using the drug, since it may cause drowsiness.

(b) If the article is offered for temporary relief of the symptoms of colds, a statement that continued administration for such use should not exceed 3 days, except as directed by a physician.

(5)-(7) [Reserved]

(8) Dicyclomine hydrochloride (1-cyclohexylhexahydrobenzoic acid. <greek-b>-diethylaminoethyl ester hydrochloride; diethylaminocarbethoxy-bicyclohexyl hydrochloride) preparations meeting all the following conditions:

(i) The dicyclomine hydrochloride is prepared with suitable antacid and other components, in tablet or other

[[Page 13]]

dosage form for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The dicyclomine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 5 milligrams of dicyclomine hydrochloride per dosage unit, or if it is in liquid form not more than 0.5 milligram of dicyclomine hydrochloride per milliliter.

(v) The preparation is labeled with adequate directions for use only by adults and children over 12 years of age, in the temporary relief of gastric hyperacidity.

(vi) The dosages recommended or suggested in the directions for use do not exceed 10 milligrams of dicyclomine hydrochloride per dose or 30 milligrams in a 24-hour period.

(vii) The labeling bears, in juxtaposition with the dosage recommendations, clear warning statements against:

(a) Exceeding the recommended dosage.

(b) Prolonged use, except as directed by a physician, since persistent or recurring symptoms may indicate a serious disease requiring medical attention.

(c) Administration to children under 12 years of age except as directed by a physician.

(9)-(10) [Reserved]

(11) Hexadenol (a mixture of tetracosanes and their oxidation products) preparations meeting all the following conditions:

(i) The hexadenol is prepared and packaged, with or without other drugs, solvents, and propellants, in a form suitable for self-medication by external application to the skin as a spray, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The hexadenol and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 5 percent by weight of hexadenol.

(v) The preparation is labeled with adequate directions for use by external application in the treatment of minor burns and minor skin irritations.

(vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:

(a) Use on serious burns or skin conditions or prolonged use, except as directed by a physician.

(b) Spraying the preparation in the vicinity of eyes, mouth, nose, or ears.

(12) Sulfur dioxide preparations meeting all the following conditions:

(i) The sulfur dioxide is prepared with or without other drugs, in an aqueous solution packaged in a hermetic container suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The sulfur dioxide and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 5 grams of sulfur dioxide per 100 milliliters of solution.

(v) The preparation is labeled with adequate directions for use by external application to the smooth skin in the prevention or treatment of minor conditions in which it is indicated.

(vi) The directions for use recommend or suggest not more than two applications a day for not more than 1 week, except as directed by a physician.

(13)-(15) [Reserved]

(16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations meeting all the following conditions:

(i) The tuaminoheptane sulfate is prepared, with or without other drugs, in an aqueous vehicle suitable for administration in self-medication as nose drops, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

[[Page 14]]

(ii) The preparation is packaged with a style of container or assembly suited to self-medication by the recommended route of administration, and delivering not more than 0.1 milliliter of the preparation per drop.

(iii) The tuaminoheptane sulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iv) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(v) The tuaminoheptane sulfate content of the preparation does not exceed 10 milligrams per milliliter.

(vi) The preparation is labeled with adequate directions for use in the temporary relief of nasal congestion.

(vii) The dosages recommended or suggested in the directions for use do not exceed the equivalent: For adults, 5 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period; for children 1 to 6 years of age, 3 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period; for infants under 1 year of age, 2 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period.

(viii) The labeling bears, in juxtaposition with the dosage recommendations:

(a) Clear warning statements against use of more than 5 doses daily, and against use longer than 4 days unless directed by a physician.

(b) A clear warning statement to the effect that frequent use may cause nervousness or sleeplessness, and that individuals with high blood pressure, heart disease, diabetes, or thyroid disease should not use the preparation unless directed by a physician.

(17) [Reserved]

(18) Vibesate (a mixture of copolymers of hydroxy-vinyl chlorideacetate, sebacic acid, and modified maleic rosin ester) preparations meeting all the following conditions.

(i) The vibesate is prepared and packaged, with or without other drugs, solvents, and propellants, in a form suitable for self-medication by external application to the skin as a spray, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The vibesate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 13 percent by weight of vibesate.

(v) The preparation is labeled with adequate directions for use by external application as a dressing for minor burns, minor cuts, or other minor skin irritations.

(vi) The labeling bears in juxtaposition with the directions for use clear warning statements against:

(a) Use on serious burns and on infected, deep, and puncture wounds unless directed by a physician.

(b) Spraying the preparation near the eyes or other mucous membranes.

(c) Inhaling the preparation.

(d) Use near open flames.

(e) Puncturing the container or throwing the container into fire.

(19) Pramoxine hydrochloride (4-N-butoxyphenyl <greek-g>-morpholinopropyl ether hydrochloride) preparations meeting all the following conditions:

(i) The pramoxine hydrochloride is prepared, with or without other drugs, in a dosage form suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The pramoxine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 1.0 percent of pramoxine hydrochloride.

(v) The preparation is labeled with adequate directions for use by external application to the skin for the temporary relief of pain or itching due to minor burns and sunburn, nonpoisonous insect bites, and minor skin irritations.

(vi) The directions for use recommend or suggest not more than four

[[Page 15]]

applications of the preparation per day, unless directed by a physician.

(vii) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:

(a) Prolonged use.

(b) Application to large areas of the body.

(c) Continued use if redness, irritation, swelling, or pain persists or increases, unless directed by a physician.

(d) Use in the eyes or nose.

(20) Carbetapentane citrate (2-(2-diethylaminoethoxy)-ethyl-1-phenyl- cyclopentyl-1-carboxylate citrate) preparations meeting all the following conditions:

(i) The carbetanentane citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The carbetapentane citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, and application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 25 milligrams of carbetapentane citrate per dosage unit; or if it is in liquid form, not more than 1.5 milligrams of carbetapentane citrate per milliliter.

(v) The preparation is labeled with adequate directions for use in the temporary relief of cough due to minor conditions in which it is indicated.

(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 30 milligrams of carbetapentane citrate per dose or 120 milligrams of carbetapentane citrate per 24-hour period; for children 4 to 12 years of age, 7.5 milligrams per dose or 30 milligrams per 24-hour period; for children 2 to 4 years of age, 4.0 milligrams per dose or 16.0 milligrams per 24-hour period.

(vii) The label bears a conspicuous warning to keep the drug out of the reach of children, and the labeling bears, in juxtaposition with the dosage recommendations:

(a) A clear warning statement against administration of the drug to children under 2 years of age, unless directed by a physician.

(b) Clear warning statements against use of the drug in the presence of high fever or if cough persists, since persistent cough as well as high fever may indicate the presence of a serious condition.

(21) Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate) preparations meeting all the following conditions:

(i) The pamabrom is prepared with appropriate amounts of a suitable analgesic and with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The pamabrom and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 50 milligrams of pamabrom per dosage unit.

(v) The preparation is labeled with adequate directions for use in the temporary relief of the minor pains and discomforts that may occur a few days before and during the menstrual period.

(vi) The dosages recommended or suggested in the labeling do not exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour period.

(22) Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-piperidinium methylsulfate) preparations meeting all the following conditions:

(i) The diphemanil methylsulfate is prepared, with or without other drugs, in a dosage form suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The diphemanil methylsulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

[[Page 16]]

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 2.0 percent of diphemanil methylsulfate.

(v) The preparation is labeled with adequate directions for use by external application to the skin for the relief of symptoms of mild poison ivy, oak, and sumac and other minor irritations and itching of the skin.

(vi) The directions for use recommend or suggest not more than four applications of the preparation per day, unless directed by a physician.

(vii) The labeling bears, in juxtaposition with the directions for use, a clear warning statement, such as: ``Caution: If redness, irritation, swelling, or pain persists or increases, discontinue use and consult physician.''

(23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone hydrochloride; 4-n-butoxy-<greek-b>-piperidonopropiophenone hydrochloride) preparations meeting all the following conditions:

(i) The dyclonine hydrochloride is prepared, with or without other drugs, in a dosage form suitable for use as a cream or ointment in self-medication by external application to the skin, or rectally, and contains no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The dyclonine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 1.0 percent of dyclonine hydrochloride.

(v) The preparation is labeled with adequate directions for use:

(a) By external application to the skin for the temporary relief of pain and itching in sunburn, nonpoisonous insect bites, minor burns, cuts, abrasions, and other minor skin irritations.

(b) [Reserved]

(c) In the prevention or treatment of other minor conditions in which it is indicated.

(vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:

(a) Continued use if redness, irritation, swelling, or pain persists or increases, unless directed by a physician.

(b) Use in case of rectal bleeding, as this may indicate serious disease.

(c) Use in the eyes.

(d) Prolonged use.

(e) Application to large areas of the body.

(f) Use for deep or puncture wounds or serious burns.

(24) Chlorothen citrate (chloromethapyrilene citrate; N,N-dimethyl-N'-(2-pyridyl)-N'-(5-chloro-2-thenyl) ethylenediamine citrate) preparations meeting all the following conditions:

(i) The chlorothen citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The chlorothen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 25 milligrams of chlorothen citrate per dosage unit.

(v) The preparation is labeled with adequate directions for use in the temporary relief of the symptoms of hay fever and/or the symptoms of other minor conditions in which it is indicated.

(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 25 milligrams of chlorothen citrate per dose or 150 milligrams of chlorothen citrate per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.

(vii) The labeling bears, in juxtaposition with the dosage recommendations:

(a) Clear warning statements against administration of the drug to children under 6 years of age or exceeding the recommended dosage, unless directed by a physician, and against driving a car or operating machinery while using

[[Page 17]]

the drug, since it may cause drowsiness.

(b) If the article is offered for the temporary relief of symptoms of colds, a statement that continued administration for such use should not exceed 3 days, unless directed by a physician.

(25) [Reserved]

(26) Methoxyphenamine hydrochloride (<greek-b>-(o-methoxyphenyl)-isopropyl-methylamine hydrochloride; 1-(o-methoxyphenyl)- 2-methylamino-propane hydrochloride) preparations meeting all the following conditions:

(i) The methoxyphenamine hydrochloride is prepared with appropriate amounts of a suitable antitussive, with or without other drugs, in a dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The methoxyphenamine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 3.5 milligrams of methoxyphenamine hydrochloride per milliliter.

(v) The preparation is labeled with adequate directions for use in the temporary relief of cough due to minor conditions in which it is indicated.

(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 35 milligrams of methoxyphenamine hydrochloride per dose or 140 milligrams of methoxyphenamine hydrochloride per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.

(vii) The label bears a conspicuous warning to keep the drug out of the reach of children, and the labeling bears, in juxtaposition with the dosage recommendations:

(a) A clear warning statement against administration of the drug to children under 6 years of age, unless directed by a physician.

(b) A clear warning statement to the effect that frequent or prolonged use may cause nervousness, restlessness, or drowsiness, and that individuals with high blood pressure, heart disease, diabetes, or thyroid disease should not use the preparation unless directed by a physician.

(c) A clear warning statement against use of the drug in the presence of high fever or if cough persists, since persistent cough as well as high fever may indicate the presence of a serious condition.

(27) Biphenamine hydrochloride (<greek-b>-diethylaminoethyl- 3-phenyl-2-hydroxybenzoate hydrochloride) preparations meeting all the following conditions:

(i) The biphenamine hydrochloride is prepared in a form suitable for use as a shampoo and contains no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The biphenamine hydrochloride meets its professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 1 percent of biphenamine hydrochloride.

(v) The preparation is labeled with adequate directions for use for the temporary relief of itching and scaling due to dandruff.

(vi) The label bears a conspicuous warning to keep the drug out of the reach of children.

(28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium chloride ophthalmic preparations meeting all the following conditions:

(i) The tyloxapol and benzalkonium chloride are prepared, with other appropriate ingredients which are not drugs limited to prescription sale under the provisions of section 503(b)(1) of the act, as a sterile, isotonic aqueous solution suitable for use in self-medication on eye prostheses.

(ii) The preparation is so packaged as to volume and type of container as to afford adequate protection and be suitable for self-medication with a minimum risk of contamination of the solution during use. Any dispensing unit is sterile and so packaged as to maintain sterility until the package is opened.

(iii) The tyloxapol, benzalkonium chloride, and other ingredients used to prepare the isotonic aqueous solution

[[Page 18]]

meet their professed standards of identity, strength, quality, and purity.

(iv) An application pursuant to section 505(b) of the act is approved for the drug.

(v) The preparation contains 0.25 percent of tyloxapol and 0.02 percent of benzalkonium chloride.

(vi) The label bears a conspicuous warning to keep the drug out of the reach of children and the labeling bears, in juxtaposition with the dosage recommendations, a clear warning that if irritation occurs, persists, or increases, use of the drug should be discontinued and a physician consulted. The labeling includes a statement that the dropper or other dispensing tip should not touch any surface, since this may contaminate the solution.

(29) [Reserved]

(b) [Reserved]

[39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977; 52 FR 15892, Apr. 30, 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR 49898, Sept. 23, 1993; 59 FR 4218, Jan. 28, 1994; 60 FR 52507, Oct. 6, 1995]

Subpart D--Records and Reports

Sec. 310.303 Continuation of long-term studies, records, and reports on certain drugs for which new drug applications have been approved.

(a) A new drug may not be approved for marketing unless it has been shown to be safe and effective for its intended use(s). After approval, the applicant is required to establish and maintain records and make reports related to clinical experience or other data or information necessary to make or facilitate a determination of whether there are or may be grounds under section 505(e) of the act for suspending or withdrawing approval of the application. Some drugs, because of the nature of the condition for which they are intended, must be used for long periods of time--even a lifetime. To acquire necessary data for determining the safety and effectiveness of long-term use of such drugs, extensive animal and clinical tests are required as a condition of approval. Nonetheless, the therapeutic or prophylactic usefulness of such drugs may make it inadvisable in the public interest to delay the availability of the drugs for widespread clinical use pending completion of such long-term studies. In such cases, the Food and Drug Administration may approve the new drug application on condition that the necessary long-term studies will be conducted and the results recorded and reported in an organized fashion. The procedures required by paragraph (b) of this section will be followed in order to list such a drug in Sec. 310.304.

(b) A proposal to require additional or continued studies with a drug for which a new drug application has been approved may be made by the Commissioner on his own initiative or on the petition of any interested person, pursuant to part 10 of this chapter. Prior to issuance of such a proposal, the applicant will be provided an opportunity for a conference with representatives of the Food and Drug Administration. When appropriate, investigators or other individuals may be invited to participate in the conference. All requirements for special studies, records, and reports will be published in Sec. 310.304.

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 FR 15674, Mar. 22, 1977]

Sec. 310.305 Records and reports concerning adverse drug experiences on marketed prescription drugs for human use without approved new drug applications.

(a) Scope. FDA is requiring manufacturers, packers, and distributors of marketed prescription drug products that are not the subject of an approved new drug or abbreviated new drug application to establish and maintain records and make reports to FDA of all serious, unexpected adversedrug experiences associated with the use of their drug products. Any person subject to the reporting requirements of paragraph (c) of this section shall also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA.

(b) Definitions. The following definitions of terms apply to this section:- Adverse drug experience. Any adverse event associated with the use of a drug in humans, whether or not considered

[[Page 19]]

drug related, including the following: An adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action. Disability. A substantial disruption of a person's ability to conduct normal life functions. Life-threatening adverse drug experience. Any adverse drug experience that places the patient, in the view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred, i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have caused death. Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. Unexpected adverse drug experience. Any adverse drug experience that is not listed in the current labeling for the drug product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differ from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents. ``Unexpected,'' as used in this definition, refers to an adverse drug experience that has not been previously observed (i.e., included in the labeling) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.

(c) Reporting requirements. Each person identified in paragraph (c)(1)(i) of this section shall report to FDA adverse drug experience information as described in this section and shall submit one copy of each report to the Division of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

(1) Postmarketing 15-day ``Alert reports''. (i) Any person whose name appears on the label of a marketed prescription drug product as its manufacturer, packer, or distributor shall report to FDA each adverse drug experience received or otherwise obtained that is both serious and unexpected as soon as possible, but in no case later than 15 calendar days of initial receipt of the information by the person whose name appears on the label. Each report shall be accompanied by a copy of the current labeling for the drug product.

(ii) A person identified in paragraph (c)(1)(i) of this section is not required to submit a 15-day ``Alert report'' for an adverse drug experience obtained from a postmarketing study (whether or not conducted under an investigational new drug application) unless the applicant concludes that there is a reasonable possibility that the drug caused the adverse experience.

(2) Postmarketing 15-day ``Alert reports''--followup. Each person identified in paragraph (c)(1)(i) of this section shall promptly investigate all serious, unexpected adverse drug experiences that are the subject of these postmarketing 15-day Alert reports and shall submit followup reports within 15

[[Page 20]]

calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information. Postmarketing 15-day Alert reports and followups to them shall be submitted under separate cover.

(3) Submission of reports. To avoid unnecessary duplication in the submission of, and followup to, reports required in this section, a packer's or distributor's obligations may be met by submission of all reports of serious adverse drug experiences to the manufacturer of the drug product. If a packer or distributor elects to submit these adverse drug experience reports to the manufacturer rather than to FDA, it shall submit each report to the manufacturer within 5 calendar days of its receipt by the packer or distributor, and the manufacturer shall then comply with the requirements of this section even if its name does not appear on the label of the drug product. Under this circumstance, the packer or distributor shall maintain a record of this action which shall include:

(i) A copy of each adverse drug experience report;

(ii) The date the report was received by the packer or distributor;

(iii) The date the report was submitted to the manufacturer; and

(iv) The name and address of the manufacturer.

(4) Each report submitted to FDA under this section shall bear prominent identification as to its contents, i.e., ``15-day Alert report,'' or ``15-day Alert report-followup.''

(5) A person identified in paragraph (c)(1)(i) of this section is not required to resubmit to FDA adverse drug experience reports forwarded to that person by FDA; however, the person must submit all followup information on such reports to FDA.

(d) Reporting form. (1) Except as provided in paragraph (d)(3) of this section, each person identified in paragraph (c)(1)(i) of this section shall submit each report of a serious and unexpected adverse drug experience on an FDA Form 3500A (foreign events may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form).

(2) Each completed FDA Form 3500A should pertain only to an individual patient.

(3) Instead of using Form FDA Form 3500A, a manufacturer, packer, or distributor may use a computer-generated FDA Form 3500A or other alternative format (e.g., a computer-generated tape or tabular listing) provided that:

(i) The content of the alternative format is equivalent in all elements of information to those specified in FDA Form 3500A, and

(ii) The format is agreed to in advance by MedWatch: The FDA Medical Products Reporting Program.

(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the instructions for completing the form may be obtained from the Division of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. More than 10 copies of the form may be obtained by writing to the Consolidated Forms and Publications Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.

(e) Patient privacy. Manufacturers, packers, and distributors should not include in reports under this section the names and addresses of individual patients; instead, the manufacturer, packer, and distributor should assign a unique code number to each report, preferably not more than eight characters in length. The manufacturer, packer, and distributor should include the name of the reporter from whom the information was received. Names of patients, individual reporters, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not releasable to the public under FDA's public information regulations in part 20 of this chapter.

(f) Recordkeeping. (1) Each manufacturer, packer, and distributor shall maintain for a period of 10 years records of all adverse drug experiences required under this section to be reported, including raw data and any correspondence relating to the adverse

[[Page 21]]

drug experiences, and the records required to be maintained under paragraph (c)(4) of this section.

(2) Manufacturers and packers may retain the records required in paragraph (f)(1) of this section as part of its complaint files maintained under Sec. 211.198 of this chapter.

(3) Manufacturers, packers, and distributors shall permit any authorized FDA employee, at all reasonable times, to have access to and copy and verify the records established and maintained under this section.

(g) Disclaimer. A report or information submitted by a manufacturer, packer, or distributor under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the manufacturer, packer, or distributor, or by FDA, that the report or information constitutes an admission that the drug caused or contributed to an adverse effect. The manufacturer, packer, or distributor need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the drug caused or contributed to an adverse effect.

(Collection of information requirements approved by the Office of Management and Budget under control number 0910-0210)

[51 FR 24479, July 3, 1986, as amended at 52 FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, June 25, 1997; 62 FR 52249, Oct. 7, 1997]

Subpart E--Requirements for Specific New Drugs or Devices

Sec. 310.500 Digoxin products for oral use; conditions for marketing.

(a) Studies have shown evidence of clinically significant differences in bio-availability in different batches of certain marketed digoxin products for oral use from single manufacturers as well as in batches of these products produced by different manufacturers. These differences were observed despite the fact that the products met compendial specifications. Other studies have shown that there is a sufficient correlation between bioavailability in vivo and the dissolution rate of digoxin tablets in vitro to make the dissolution test an important addition to the compendial standards. Because of the potential for serious risk to cardiac patients using digoxin products which may vary in bioavailability, the Commissioner of Food and Drugs has determined that immediate action must be taken to assure the uniformity of all digoxin products for oral use. The Commissioner is of the opinion that digoxin products for oral use are new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act for which approved new drug applications are required. The Commissioner has determined that, because of questions raised regarding the bioavailability of digoxin products for oral use, there is sufficient evidence to invoke the authority under section 505(j) of the act to fully investigate this question and to facilitate a determination of whether there is a ground for withdrawal of approval of the drug product under section 505(e) of the act. Marketing of these products may be continued only under the following conditions:

(1) Digoxin products for oral use, other than tablets: Any person marketing digoxin products for oral use, other than tablets, shall submit to the Food and Drug Administration on or before February 21, 1974, an abbreviated new drug application for these products. Any such drug product then on the market which is not the subject of an application submitted for the drug product shall be subject to regulatory procedures under section 505 of the act. In addition to the information specified in Sec. 314.50 of this chapter, the application shall contain:

(i) A full list of the articles used as components of the digoxin product, specifications for components, detailed identification and analytical procedures used to assure that the components meet established specifications of identity, strength, quality, and purity and a complete description of the manufacturing process.

(ii) The source of the digoxin used in the formulation including the name and address of the supplier.

(iii) A statement that stability studies will be conducted to establish a suitable expiration date for the digoxin product in the form in which it is distributed.

[[Page 22]]

(iv) A statement that the product label will contain a suitable expiration date. In the absence of any stability test data, this expiration date shall be no longer than one year after the batch is manufactured. If the expiration date is greater than one year, supporting stability data shall be included in the application.

(v) Labeling that is in compliance with all requirements of the act and regulations promulgated thereunder, the pertinent parts of which are as indicated in paragraph (e) of this section.

(vi) A statement that the applicant will initiate recall of all stocks of the drug product outstanding when so requested by the Food and Drug Administration.

(vii) A statement that the applicant intends to conduct in vivo bioavailability tests and that the applicant, under the records and reports provisions of section 505(k) of the act, will:

(a) Within 30 days after the submission of the application, submit to the Food and Drug Administration the protocol which the applicant proposes to follow in conducting these in vivo bioavailability tests. The protocol shall contain all of the essential elements set forth in paragraph (d) of this section. The tests shall not be initiated prior to receiving notification from the Food and Drug Administration that the bioavailability protocol has been reviewed and either approved or its deficiencies delineated.

(b) Within 180 days after receiving notification from the Food and Drug Administration that the bioavailability protocol has been reviewed, submit to the Food and Drug Administration the results of the in vivo bioavailability tests.

(2) Digoxin tablets: Any person marketing digoxin tablets, in addition to complying with all of the requirements of paragraph (a)(1) of this section, shall include in their abbreviated new drug application:

(i) A statement that the applicant will establish procedures to test each lot of digoxin tablets prior to releasing the batch for distribution to assure that the batch meets all of The United States Pharmacopeia (USP XVIII) requirements for digoxin tablets including, but not limited to, potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin.

(ii) A statement that finished product specifications shall be established to include provisions to assure that the range of average one-hour dissolution values among batches of digoxin tablets does not exceed 20 percent.

(3) Before releasing for distribution any batch of digoxin tablets manufactured after January 22, 1974, the manufacturer shall:

(i) Test a sample of the batch to assure that the batch meets all of the requirements of The United States Pharmacopeia (USP XVIII) including but not limited to, potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin.

(ii) Submit a sample of the batch to the Food and Drug Administration according to the procedures set forth in paragraph (g) of this section. Results of tests conducted on the batch by or for the manufacturer and the batch production record shall accompany the sample.

(iii) Withhold the batch from distribution until he is notified by the Food and Drug Administration that the sample was tested and found to meet all of the requirements in The United States Pharmacopeia (USP XVIII) for potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin.

(iv) Submit a sample of each batch of digoxin tablets as provided for in paragraph (a)(3)(ii) of this section until he is notified by the Food and Drug Administration that he is released from

[[Page 23]]

the certification program. This notification will be made on the basis of sample test results, inspectional findings regarding compliance with current good manufacturing practice, and compliance with all other requirements of this section and any other directives issued by the Food and Drug Administration as a condition for release from the certification program.

(4) Any manufacturer who has distributed any batch of digoxin tablets which does not meet the compendial requirement for dissolution, when tested by the method in The United States Pharmacopeia (USP XVIII), shall initiate recall of the subject batch when so requested by the Food and Drug Administration.

(b) Failure of an applicant to submit the protocol and/or the results of the in vivo bioavailability tests showing adequate evidence of the product's bioavailability within the times specified in paragraph (a)(1)(vii) of this section and/or to comply with all of the certification requirements of paragraph (a)(3) of this section shall be justification for withdrawal of approval of the application under section 505(e) of the act.

(c) Any product reformulation or change in manufacturing process will require the submission of a supplement to the approved abbreviated new drug application containing adequate data to demonstrate the bioavailability of the reformulated product. Food and Drug Administration approval of the supplement is required before the reformulated product is marketed. The Food and Drug Administration recommends that, where digoxin tablets are reformulated, manufacturers reformulate their product to achieve dissolution of 70 to 90 percent at one hour when tested by all three methods (i.e., the USP method, and the ``paddle-water'' and ``paddle-acid'' methods) described in paragraph (h) of this section.

(d) The protocol for the in vivo bioavailability tests required in paragraphs (a) and (c) of this section shall employ a three-way crossover design using the digoxin test product; a reference digoxin tablet supplied, on request, by the Food and Drug Administration; and bulk digoxin USP in an oral solution. Appropriate venous blood and urinary samples are to be collected and analyzed. The method shall be capable of detecting the difference between the reference tablet and the reference oral solution. Bioavailability of the test product shall be demonstrated if a mean absorption of at least 75 percent of the combined mean of the two reference standards is observed. Assistance in developing a protocol for a particular dosage formulation may be obtained by contacting the Food and Drug Administration, Center for Drug Evaluation and Research (HFD-420), 5600 Fishers Lane, Rockville, MD 20857.

(e) Parts of the digoxin product labeling indicated below shall be as follows:

Digoxin Labeling Guidelines

(adult and pediatric)

description

Digoxin is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific and powerful effects on the myocardium. These drugs are found in a number of plants. The term ``digitalis'' is used to designate the whole group. Typically, the glycosides are composed of three portions: a steroid nucleus, a lactone ring, and a sugar (hence ``glycosides'').

(This section should include a chemical and physical description of digoxin and the same quantitative ingredient information as that required on the label.)

Action

The digitalis glycosides have qualitatively the same therapeutic effects on the heart. They (1) increase the force of myocardial contraction, (2) increase the refractory period of the atrioventricular (A-V) node, and (3) to a lesser degree, affect the sinoatrial (S-A) node and conduction system via the parasympathetic and sympathetic nervous systems. Gastrointestinal absorption of digoxin is a passive process. About 50-75 percent of digoxin in tablet form is absorbed. Digoxin is only 20-25 percent bound to plasma proteins and is predominantly excreted by the kidneys unmetabolized unless there is significant renal failure. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely independent of urine flow. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass, presumably because of tissue binding. In subjects with normal renal function, digoxin is excreted exponentially with an average half-life of 36 hours, resulting in the loss of 35-40 percent of the body stores daily. Serum levels and pharmacokinetics are essentially unchanged by massive weight loss,

[[Page 24]]

suggesting that lean body mass should be used in dosage calculations. The peak blood level from oral dosing with tablets occurs 1-3 hours after administration. The onset of therapeutic action of digoxin after oral tablets is 1-2 hours, with the peak therapeutic effect occurring 6-8 hours after dosing.

indications

1. Congestive heart failure, all degrees, is the primary indication. The increased cardiac output due to digoxin results in diuresis and general amelioration of the disturbances characteristic of right (venous congestion, edema) and left (dyspnea, orthopnea, cardiac asthma) heart failure. Digoxin, generally, is most effective in ``low output'' failure and less effective in ``high output'' (bronchopulmonary insufficiency, infection, hyperthyroidism) heart failure. Digoxin should be continued after heart failure is abolished unless some known precipitating factor is corrected. 2. Atrial fibrillation, especially when the ventricular rate is elevated. Digoxin rapidly reduces ventricular rates and eliminates the pulse deficit. Palpitation, precordial distress or weakness are relieved and any concomitant congestive failure ameliorated. Digoxin should be continued in doses necessary to maintain the desired ventricular rate and other clinical effects. 3. Atrial flutter. Digoxin slows the heart and regular sinus rhythm may appear. Frequently the flutter is converted to atrial fibrillation with a slow ventricular rate. Stopping digoxin at this point may be followed by restoration of sinus rhythm, especially if the flutter was of the paroxysmal type. It is preferable, however, to continue digoxin if failure ensues or if atrial flutter is a frequent occurrence. 4. Paroxysmal atrial tachycardia. Oral digoxin may be used, especially if the condition is resistant to lesser measures. Depending on the urgency, a more rapid acting parenteral preparation may be preferable to initiate digitalization, although if heart failure has ensued or paroxysms recur frequently, digoxin should be maintained by oral administration. Digoxin is not indicated in sinus tachycardia unless due to heart failure. 5. Cardiogenic shock. The drug is often employed, especially when the condition is accompanied by pulmonary edema. Digoxin seems to affect adversely shock due to septicemia from gram negative bacteria.

contraindications

The presence of toxic effects (See ADVERSE REACTIONS section) induced by any digitalis preparation is a contraindication to all of the gylcosides. Allergy, though rare, does occur. It may not extend to all preparations, and another may be tried. Ventricular fibrillation.

Warnings

Digitalis alone or with other drugs has been promoted for use in the treatment of obesity. This use of digoxin or other digitalis glycosides is unwarranted. Moreover, since they may cause potentially fatal arrhythmias or other adverse effects, the use of these drugs in the treatment of obesity is dangerous.

Many of the arrhythmias for which digoxin is advised closely resemble those reflecting digoxin intoxication. If the possibility of digoxin intoxication cannot be excluded, cardiac glycosides should be temporarily withheld if permitted by the clinical situation. The patient with congestive heart failure may complain of nausea and vomiting. These symptoms may also be indications on digoxin intoxication. A clinical determination of the cause of these symptoms must be attempted before further drug administration. Patients with renal insufficiency require smaller than usual doses of digoxin. See ACTION section for mechanism.

precautions

Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment. Care must be taken to avoid digoxin toxicity if digoxin is used to help the arrhythmia. Digoxin is not indicated for the treatment of ventricular tachycardia unless congestive heart failure supervenes after a protracted episode not itself due to digoxin. Potassium depletion sensitizes the myocardium to digoxin, and toxicity may develop even with the usual dosage. Hypokalemia may also alter the rate of onset and intensity of the positive inotropic effect of digoxin. Therefore, it is desirable to maintain normal serum potassium levels in patients being treated with digoxin. Potassium wastage may result from diuretic or corticosteriod therapy, hemodialysis, and from suction of gastrointestinal secretions. It may accompany malnutrition, diarrhea, prolonged vomiting, old age, and long-standing congestive heart failure. In general, rapid changes in serum potassium or other electrolytes are to be avoided, and intravenous treatment with potassium should be reserved only for special circumstances as described below (see TREATMENT OF ARRHYTHMIAS PRODUCED BY OVERDOSAGES section). Patients with acute myocardial infarction, severe pulmonary disease, or far advanced heart failure may be more sensitive to digoxin and more prone to disturbances of rhythm.

[[Page 25]]

Calcium affects contractility and excitability of the heart in a manner similar to that of digoxin. Calcium may produce serious arrhythmias in digitalized patients. In myxedema the digoxin requirements are less because excretion rate is decreased and blood levels are significantly higher. In incomplete A-V block, especially in patients subject to Stokes-Adams attacks, advanced or complete heart block may develop if digoxin is given. Heart failure in these patients can usually be controlled by other measures and by increasing the heart rate. Patients with chronic constructive pericarditis may respond unfavorably to digoxin. Patients with idiopathic hypertrophic subaortic stenosis must be managed extremely carefully. Unless cardiac failure is severe, it is doubtful whether digoxin should be employed. Renal insufficiency delays the excretion of digoxin, and dosage must be adjusted accordingly in patients with renal disease. Note: This applies also to potassium administration should it become necessary. Electrical conversion of arrhythmias may require reduction of digoxin dosage.

adverse reactions

Gynecomastia, uncommon. Overdosage or toxic effects. Gastrointestinal: Anorexia, nausea, vomiting, diarrhea are the most common early symptoms of overdosages in the adult (but rarely conspicuous in infants). Uncontrolled heart failure may also produce such symptoms. Central nervous system: Visual disturbances (blurred vision, yellow vision), headache, weakness, apathy. Cardiac disturbances (arrhythmias): Ventricular premature beats are the most common, except in infants and young children. Paroxysmal and nonparoxysmal nodal rhythms, atrioventricular (interference) disassociation and paroxysmal atrial tachycardia (PAT) with block are also common arrhythmias due to digoxin overdosage. Conduction disturbances: Excessive slowing of the pulse is a clinical sign of digoxin overdosage. Atrioventricular block of increasing degree may proceed to complete heart block. Note: The electrocardiogram is fundamental in determining the presence and nature of these cardiac toxic disturbances. Digoxin may also induce other changes (as of the ST segment), but these provide no measure of the degree of digitalization.

treatment of arrhythmias produced by overdosages

Digoxin should be discontinued until all signs of toxicity are abolished. Discontinuation may be all that is necessary if toxic manifestations are not severe and appear after the time for peak effect of the drug. Potassium salts are commonly used. Potassium chloride in divided oral doses totaling 4-6 grams for adults (see PEDIATRIC INFORMATION section for pediatric dosage) may be given provided renal function is adequate. When correction of the arrhythmia is urgent and the serum potassium level is low or normal, potassium should be administered intravenously in a solution of 5 percent dextrose in water. A total of 40-100 milliequivalents (30 milliequivalents per 500 milliliters) is given at the rate of 20 milliequivalents per hour unless limited by pain due to local irritation. Additional amounts may be given if the arrhythmia is uncontrolled and the potassium well tolerated. Continuous electrocardiographic monitoring should be performed to watch for any evidence of potassium toxicity, e.g., peaking of T waves, and to observe the effect on the arrhythmia so that the infusion may be promptly stopped when the desired effect is achieved. Caution: Potassium should not be used and may be dangerous for severe or complete heart block due to digoxin and not related to any tachycardia. Other agents that have been approved for the treatment of digoxin intoxication include procainamide, lidocaine, and propranolol.

dosage and administration

Oral digoxin is administered slowly or rapidly as required until the desired therapeutic effect is obtained without symptoms of overdosage. The amount can be predicted approximately from the lean body mass of the patient with allowances made for excretion during the time taken to induce digitalization. Subsequent maintenance dosage is also determined tentatively by the amount necessary to sustain the desired therapeutic effect. Recommended dosages are practical average figures that may require considerable modification as dictated by individual sensitivity or associated conditions. Diminished renal function is the most important factor requiring modification of recommended or average doses. (See WARNINGS and PRECAUTIONS sections.) The average amount of digoxin that patients must accumulate to be digitalized with digoxin tablets is 1.0-1.5 milligrams. Digitalization may be accomplished by any of several approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount accumulated. In previously undigitalized patients, a single loading dose of 0.5-0.75 milligram orally usually produces a detectable effect in 1-2 hours that becomes maximal in 6-8 hours.

[[Page 26]]

Additional doses of 0.25-0.5 milligram may be given cautiously at 6-8 hour intervals to full digitalization. In previously undigitalized patients, institution of daily maintenance therapy (0.125-0.5 milligram, see next paragraph) without a loading dose results in development of a steady-state plateau concentrations in about 7 days in patients with normal renal function. The average daily oral maintenance dose is 0.125-0.5 milligram, usually 0.25 milligram. In the elderly patient, 0.125-0.25 milligram should be considered the average maintenance dose. In patients with renal impairment, digoxin excretion is impaired and serum half-life is prolonged (see ACTION section). Digitalizing and maintenance doses are lower than those recommended for patients with normal renal functions. Signs of digoxin toxicity develop sooner in patients with renal impairment, and it takes longer for toxic signs and symptoms to disappear. Because of the prolonged half-life, a longer period of time is required to achieve an initial or new steady-state plateau in patients with renal impairment than in patients with normal renal function. It cannot be overemphasized that the values given are averages and substantial individual variation can be expected.

(If pediatric dosage is available, the labeling sections above should be expanded to include the following information.)

pediatric information

warnings

Newborn infants display considerable variability in their tolerance to digoxin, depending on their degree of maturity. Premature and immature infants are particularly sensitive, and dosage must be reduced and digitalization should be even more individualized and cautiously approached than in more mature infants. Impaired renal function must also be carefully taken into consideration. Congestive heart failure accompanying acute glomerulonephritis requires extreme care in digitalization. A relatively low total dose administered in divided doses and concomitant use of antihypertensive drugs has been recommended. ECG monitoring is essential. Digoxin should be discontinued as soon as possible. Patients with idiopathic hypertrophic subaortic stenosis must be managed extremely carefully. Unless cardiac failure is severe, it is doubtful whether digoxin should be employed. Patients with rheumatic carditis, especially when severe, are unusually sensitive to digoxin and prone to disturbances of rhythm. If heart failure develops, digitalization may be initiated with relatively low doses; then it can be cautiously increased until a beneficial effect is obtained. If a therapeutic trial does not result in improvement, the drug should be considered ineffective and be discontinued. Note: Digitalis glycosides are an important cause of accidental poisoning in children.

precautions

Dosage must be carefully titrated and differences in the bioavailability of parenteral preparations, elixirs, and tablets should be taken into account when switching patients from one preparation to another. Electrocardiographic monitoring may be necessary to avoid intoxication. Premonitory signs of toxicity in the newborn are undue slowing of the sinus rate, sinoatrial arrest, and prolongation of PR interval.

adverse reactions

Toxic signs differ from the adult in a number of respects. Cardiac arrhythmias are the more reliable and frequent signs of toxicity. Vomiting and diarrhea, neurologic and visual disturbances are rare as initial signs. Premature ventricular systoles are rarely seen; nodal and atrial systoles are more frequent. Atrial arrhythmias, atrial ectopic rhythms, and paroxysmal atrial tachycardia with A-V block particularly are more common manifestations of toxicity in children. Ventricular arrhythmias are rare.

treatment of arrhythmias produced by overdosages

(See adult section for other recommendations for the treatment of arrhythmias produced by overdosages and for additional recommendations and cautions regarding the use of potassium.) Potassium preparations may be given orally in divided doses totaling 1-1.5 milliequivalents/kilogram (1 gram K contains 13.4 milliequivalents). When correction of the arrhythmia is urgent, approximately 0.5 milliequivalents/kilogram of potassium per hour may be given, with careful electrocardiographic monitoring, as a solution of 20 milliequivalents or less per 500 milliliters in 5 percent dextrose in water. The total dose should generally not exceed 2 milliequivalents of potassium/kilogram.

dosage and administration

Digitalization must be individualized. Generally, premature and immature infants are particularly sensitive, requiring reduced dosage that must be determined by careful titration. Oral Dosage. Beyond the immediate newborn period, children require proportionally greater doses than adults on the basis of

[[Page 27]]

body weight or surface area. The recommended oral digitalizing dosages in children with normal renal function are: Newborn infants (normal), up to 1 month, require 40-60 micrograms/kilogram. Infants, 1 month to 2 years, require approximately 60-80 micrograms/kilogram. Children 2 years to 10 years, require 40-60 micrograms/kilogram. Children, over 10 years of age, require adult dosages in proportion to their body weight. Maintenance therapy is 20-30 percent of the digitalizing dose administered each day. Long term use of digoxin is indicated in almost all infants who have been digitalized for acute congestive heart failure unless the cause is transient. Many favor maintaining digoxin until at least 2 years of age in all infants with paroxysmal atrial tachycardia or in those who show either definite or latent failure. Many children with severe inoperable congenital defects need digoxin throughout childhood and often for life.

(f) Abbreviated new drug applications shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, 5600 Fishers Lane, Rockville, MD 20857.

(g) All samples of digoxin tablets required by paragraph (a)(3) of this section to be submitted to the Food and Drug Administration shall be handled as follows:

(1) The sample shall consist of 6 subsamples of 1000 tablets each collected at random from throughout the manufacturing run. Each of the 6 subsamples shall be identified with the name of the product, the labeled potency, the date of manufacture, the batch number, and the name and address of the manufacturer.

(2) The sample together with the batch production record and results of all tests conducted by or for the manufacturer to determine the product's identity, strength, quality, and purity, content uniformity and dissolution shall be submitted to the Department of Health and Human Services, Public Health Service, FDA National Center for Drug Analysis, 1114 Market St., St. Louis, MO 63101. The outer wrapper shall be identified ``SAMPLE--DIGOXIN CERTIFICATION.''

(h) The Food and Drug Administration is aware of data with two in vitro methods, in addition to that described in The United States Pharmacopeia (USP XVIII), developed to measure digoxin tablets dissolution. These two methods, the so-called ``paddle-water'' and ``paddle-acid'' methods, are described below and are identical with the exception of the nature of the dissolution medium used in the procedures (i.e., distilled or deionized water vs. dilute hydrochloric acid (0.6 percent volume/volume)). The dissolution apparatus used in these two methods differs significantly from the apparatus described in the method in the compendium. The Food and Drug Administration is aware that the three methods (i.e., USP, ``paddle-water,'' and ``paddle-acid'') show significant differences in dissolution in comparative tests on some formulations. Definitive bioavailability data to compare the relative value of each of these methods to predict bioavailability of the few formulations where the methods show significant differences in dissolution rate are not now available. Manufacturers who conduct research utilizing the ``paddle-water'' and ``paddle-acid'' methods, particularly in comparison with the method in The United States Pharmacopeia, shall submit any data obtained using these methods to the Food and Drug Administration pursuant to section 505(k) of the act.

(1) Dissolution apparatus.

(Note: Throughout this procedure use scrupulously clean glassware, which previously has been rinsed with dilute hydrochloric acid, distilled or deionized water, then with alcohol, and carefully dried. Take precautions to prevent contamination from airborne, fluorescent particles and from metal and rubber surfaces.) The apparatus consists of a suitable water bath, a 1000 milliliter glass vessel (Kimble Glass No. 26220 or equivalent), a motor, and a polytetrafluoroethylene stirring blade (Sargent S-76637, Size B, 3 inch length; or equivalent) on a glass stirring shaft (Sargent 5-76636, 14.5 inch length; or equivalent). The water bath may be of any convenient size that permits keeping the water temperature uniformly at 37 deg. C. <SUP>plus-minus</SUP>0.5 deg. C. throughout the test. The vessel is spherical, and is provided with three ports at the top, one of which is centered. The lower half of the vessel is 65 millimeters in inside radius and the vessel's nominal capacity is 1000 milliliters. The glass stirring shaft from the motor is placed in the center port, and one of the outer ports may be used for insertion of a thermometer. Samples may be removed for analysis through the other port. The motor is fitted with a speed-regulating

[[Page 28]]

device that allows the motor speed to be held at 50 rpm <SUP>plus-minus</SUP>2 rpm. The motor is suspended above the vessel in such a way that it may be raised or lowered to position the stirring blade. The glass stirring shaft is 10 millimeters in diameter and about 37 centimeters in length. It must run true on the motor axis without perceptible wobble. The polytetrafluoroethylene stirring blade is 4 millimeters thick and forms a section of a circle, whose diameter is 83 millimeters and which is subtended by parallel chords of 42 and 77 millimeters. The blade is positioned horizontally, with the 42-millimeter edge down, 2.5 centimeters <SUP>plus-minus</SUP>0.2 centimeter above the lowest inner surface of the vessel.

(2) Reagents--(i) Dissolution medium. For ``paddle-water,'' use distilled or deionized water. For ``paddle-acid,'' use dilute hydrochloric acid (0.6 percent volume/volume). Use the same batch of dissolution medium throughout the test.

(ii) Standard solutions. Accurately weigh approximately 25 milligrams of The United States Pharmacopeia Digoxin Reference Standard, dissolve in a minimum amount of 95 percent ethanol in a 500 milliliter volumetric flask and add 95 percent ethanol to volume and mix. Dilute 10.0 milliliters of this first solution to 100.0 milliliters with 95 percent ethanol and mix for the second solution. Just prior to use, individually dilute 1.0, 2.0, 3.0, 4.0, and 5.0 milliliter aliquots of the second solution with dissolution medium to 50.0 milliliters. These solutions are equivalent to 20, 40, 60, 80, and 100 percent of dissolution, respectively, for a 0.25 milligram digoxin tablet.

(iii) Extraction solvent. Prepare a solvent containing 6 volumes of chloroform, analytical reagent grade, with 1 volume of n-propyl alcohol, analytical reagent grade.

(iv) Ascorbic acid-methanol solution. Prepare a solution containing 2 milligrams of ascorbic acid, analytical reagent grade, per 1 milliliter of methanol, absolute, analytical reagent grade.

(v) Hydrochloric acid, concentrated reagent grade.

(vi) Hydrogen peroxide-methanol solution. On the day of use, dilute 2.0 milliliters of recently assayed 30 percent hydrogen peroxide, reagent grade, with methanol, absolute, analytical reagent grade to 100.0 milliliters. Store in a refrigerator. Just prior to use, dilute 2.0 milliliters of this solution with methanol to 100.0 milliliters.

(3) Procedure--(i) Dissolution. Place 500 milliliters of dissolution medium in the vessel, immerse it in the constant-temperature bath set at 37 deg.C.<SUP>plus-minus</SUP>0.5 deg.C., and allow the dissolution medium to assume the temperature of the bath. Position the shaft so that there is a distance of 2.5 centimeters <SUP>plus-minus</SUP>0.2 centimeter between the midpoint of the bottom of the blade and the bottom of the vessel. With the stirrer operating at a speed of 50 rpm<SUP>plus-minus</SUP>2 rpm, place 1 tablet into the flask. After 60 minutes, accurately timed, withdraw 25 milliliters, using a glass syringe connected to a glass sampling tube, of solution from a point midway between the stirring shaft and the wall of the vessel, and approximately midway in depth. Filter the solution promptly after withdrawal, using a suitable membrane filter of not greater than 0.8 micron porosity (Millipore AAWP 025 00, or equivalent), mounted in a suitable holder (Millipore Swinnex SX00 025 00, or equivalent), discarding the first 100 milliliters of filtrate. This is the test solution. Repeat the dissolution procedure on 5 additional tablets.

(ii) Extraction. Transfer 10.0 milliliters of each of the six filtrates, 10.0 milliliters of each of the five standard solutions, and 10.0 milliliters of dissolution medium, to provide a blank, in separate 60-milliliter separators. Extract each solution with two 10-milliliter portions of extraction solvent. Combine the extracts of each solution in separate, glass-stoppered, 50-milliliter conical flasks, and evaporate on a steam bath with the aid of a stream of nitrogen to dryness, rinsing the sides of the flasks with extraction solvent. Take care to ensure that all traces of solvent are removed, but avoid prolonged heating. For convenience the residues may be stored in a vacuum desiccator overnight.

(iii) Measurement of fluorescence. Begin with the standard solutions, and keep all flasks in the same sequence throughout, so that the elapsed time from addition of reagents to reading of fluorescence is the same for each.

[[Page 29]]

Carry the test solutions, standard solutions, and the blank through the determination in one group. Add the following three reagents in as rapid a sequence as possible, swirling after each addition, treating 1 flask at a time, in the order named: 1.0 milliliter of ascorbic acid-methanol solution, 3.0 milliliters of concentrated hydrochloric acid, and 1.0 milliliter of hydrogen peroxide-methanol solution. Insert the stoppers in the flasks, and after 2 hours, measure the fluorescence at about 485 millimicrons, using excitation at about 372 millimicrons. In order to provide a check on the stability of the fluorometer, reread one or more standard solutions. Correct each reading for the blank and plot a standard curve of fluorescence versus precentage dissolution. Determine the percentage dissolution of digoxin in the test solutions by reading from the standard graph.

(iv) Digoxin tablets formulated so that the quantity of digoxin dissolved at one hour, when tested by the method in The United States Pharmacopeia (USP XVIII), is greater than 95 percent of the assayed amount of digoxin and so that the quantity of digoxin dissolved at 15 minutes is greater than 90 percent of the assayed amount of digoxin are new drugs which may be marketed only with an approved full new drug application as provided for in Sec. 314.50 of this chapter. The application shall include, but not be limited to, clinical studies establishing significantly greater bioavailability than digoxin tablets meeting compendial requirements and dosage recommendations based on clinical studies establishing the safe and effective use of the bioavailable digoxin product. Marketing of these digoxin products will be allowed only under a proprietary or trade name, established name, and labeling which differs from that used for digoxin tablets that meet all of the requirements in The United States Pharmacopeia (USP XVIII) and that are formulated so that either (a) the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin. New drug applications for these digoxin products shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Drug Evaluation I (HFD-100), 5600 Fishers Lane, Rockville, MD 20857.

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 43137, Sept. 30, 1976; 41 FR 49482, Nov. 3, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990]

Sec. 310.501 Patient package inserts for oral contraceptives.

(a) Requirement for a patient package insert. The safe and effective use of oral contraceptive drug products requires that patients be fully informed of the benefits and the risks involved in their use. An oral contraceptive drug product that does not comply with the requirements of this section is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act. Each dispenser of an oral contraceptive drug product shall provide a patient package insert to each patient (or to an agent of the patient) to whom the product is dispensed, except that the dispenser may provide the insert to the parent or legal guardian of a legally incompetent patient (or to the agent of either). The patient package insert is required to be placed in or accompany each package dispensed to the patient.

(b) Distribution requirements. (1) For oral contraceptive drug products, the manufacturer and distributor shall provide a patient package insert in or with each package of the drug product that the manufacturer or distributor intends to be dispensed to a patient.

(2) Patient package inserts for oral contraceptives dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before administration of the first oral contraceptive and every 30 days thereafter, as long as the therapy continues.

(c) Contents of patient package insert. A patient package insert for an oral contraceptive drug product is required to contain the following:

(1) The name of the drug.

(2) A summary including a statement concerning the effectiveness of oral contraceptives in preventing pregnancy, the contraindications to the

[[Page 30]]

drug's use, and a statement of the risks and benefits associated with the drug's use.

(3) A statement comparing the effectiveness of oral contraceptives to other methods of contraception.

(4) A boxed warning concerning the increased risks associated with cigarette smoking and oral contraceptive use.

(5) A discussion of the contraindications to use, including information that the patient should provide to the prescriber before taking the drug.

(6) A statement of medical conditions that are not contraindications to use but deserve special consideration in connection with oral contraceptive use and about which the patient should inform the prescriber.

(7) A warning regarding the most serious side effects of oral contraceptives.

(8) A statement of other serious adverse reactions and potential safety hazards that may result from the use of oral contraceptives.

(9) A statement concerning common, but less serious side effects which may help the patient evaluate the benefits and risks from the use of oral contraceptives.

(10) Information on precautions the patients should observe while taking oral contraceptives, including the following:

(i) A statement of risks to the mother and unborn child from the use of oral contraceptives before or during early pregnancy;

(ii) A statement concerning excretion of the drug in human milk and associated risks to the nursing infant;

(iii) A statement about laboratory tests which may be affected by oral contraceptives; and

(iv) A statement that identifies activities and drugs, foods, or other substances the patient should avoid because of their interactions with oral contraceptives.

(11) Information about how to take oral contraceptives properly, including information about what to do if the patient forgets to take the product, information about becoming pregnant after discontinuing use of the drug, a statement that the drug product has been prescribed for the use of the patient and should not be used for other conditions or given to others, and a statement that the patient's pharmacist or practitioner has a more technical leaflet about the drug product that the patient may ask to review.

(12) A statement of the possible benefits associated with oral contraceptive use.

(13) The following information about the drug product and the patient package insert:

(i) The name and place of business of the manufacturer, packer, or distributor, or the name and place of business of the dispenser of the product.

(ii) The date, identified as such, of the most recent revision of the patient package insert placed prominently immediately after the last section of the labeling.

(d) Other indications. The patient package insert may identify indications in addition to contraception that are identified in the professional labeling for the drug product.

(e) Labeling guidance texts. The Food and Drug Administration issues informal labeling guidance texts under Sec. 10.90(b)(9) of this chapter to provide assistance in meeting the requirements of this section. A request for a copy of the guidance texts should be directed to the Center for Drug Evaluation and Research, Division of Metabolism and Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

(f) Requirement to supplement approved application. Holders of approved applications for oral contraceptive drug products that are subject to the requirements of this section are required to submit supplements under Sec. 314.70(c) of this chapter to provide for the labeling required by this section. Such labeling may be put into use without advance approval by the Food and Drug Administration.

[54 FR 22587, May 25, 1989]

Sec. 310.502 Certain drugs accorded new drug status through rulemaking procedures.

(a) The drugs listed in this paragraph have been determined by rulemaking procedures to be new drugs within the meaning of section 201(p) of the act. An approved new drug application under

[[Page 31]]

section 505 of the act and part 314 of this chapter is required for marketing the following drugs:

(1) Aerosol drug products for human use containing 1,1,1-trichloroethane.

(2) Aerosol drug products containing zirconium.

(3) Amphetamines (amphetamine, dextroamphetamine, and their salts, and levamfetamine and its salts) for human use.

(4) Camphorated oil drug products.

(5) Certain halogenated salicylanilides (tribromsalan (TBS, 3,4',5-tribromosalicylanilide), dibromsalan (DBS, 4', 5-dibromosalicylanilide), metabromsalan (MBS, 3, 5-dibromosalicylanilide), and 3,3', 4,5'-tetrachlorosalicylanilide (TC-SA)) as an ingredient in drug products.

(6) Chloroform used as an ingredient (active or inactive) in drug products.

(7) Cobalt preparations intended for use by man.

(8) Intrauterine devices for human use for the purpose of contraception that incorporate heavy metals, drugs, or other active substances.

(9) Oral prenatal drugs containing fluorides intended for human use.

(10) Parenteral drug products in plastic containers.

(11) Sterilization of drugs by irradiation.

(12) Sweet spirits of nitre drug products.

(13) Thorium dioxide for drug use.

(14) Timed release dosage forms.

(15) Vinyl chloride as an ingredient, including propellant, in aerosol drug products.

(b) [Reserved]

[62 FR 12084, Mar. 14, 1997, as amended at 64 FR 401, Jan. 5, 1999]

Sec. 310.503 Requirements regarding certain radioactive drugs.

(a) On January 8, 1963 (28 FR 183), the Commissioner of Food and Drugs exempted investigational radioactive new drugs from part 312 of this chapter provided they were shipped in complete conformity with the regulations issued by the Nuclear Regulatory Commission. This exemption also applied to investigational radioactive biologics.

(b) It is the opinion of the Nuclear Regulatory Commission, and the Food and Drug Administration that this exemption should not apply for certain specific drugs and that these drugs should be appropriately labeled for uses for which safety and effectiveness can be demonstrated by new drug applications or through licensing under the Public Health Service Act (42 U.S.C. 262 et seq.) in the case of biologics. Continued distribution under the investigational exemption when the drugs are intended for established uses will not be permitted.

(c) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling. Such use may include, among others, the uses in this tabulation:

-----------------------------------------

------------------------------------------------------------------------

Isotope Chemical form Use

------------------------------------------------------------------------

Chromium 51........... Chromate............... Spleen scans.

Do................ ......do............... Placenta localization.

Do................ ......do............... Red blood cell labeling

and survival studies.

Do................ Labeled human serum Gastrointestinal

albumin. protein loss studies.

Do................ ......do............... Placenta localization.

Do................ Labeled red blood cells Do.

Cobalt 58 or Cobalt 60 Labeled cyanocobalamin. Intestinal absorption

studies.

Gold 198.............. Colloidal.............. Liver scans.

Do................ ......do............... Intracavitary treatment

of pleural effusions

and/or ascites.

Do................ ......do............... Interstitial treatment

of cancer.

Iodine 131............ Iodide................. Diagnosis of thyroid

functions.

Do................ ......do............... Thyroid scans.

Do................ ......do............... Treatment of

hyperthyroidism and/or

cardiac dysfunction.

Do................ ......do............... Treatment of thyroid

carcinoma.

Do................ Iodinated human serum Blood volume

albumin. determinations.

Do................ ......do............... Cisternography.

Do................ ......do............... Brain tumor

localization.

Do................ ......do............... Placenta localization.

Do................ ......do............... Cardiac scans for

determination of

pericardial effusions.

[[Page 32]]

Do................ Rose Bengal............ Liver function studies.

Do................ ......do............... Liver scans.

Do................ Iodopyracet, sodium Kidney function studies

iodohippurate, sodium and kidney scans.

diatrizoate,

diatrizoate

methylglucamine,

sodium diprotrizoate,

sodium acetrizoate, or

sodium iothalamate.

Do................ Labeled fats and/or Fat absorption studies.

fatty acids.

Do................ Cholografin............ Cardiac scans for

determination of

pericardial effusions.

Do................ Macroaggregated Lung scans.

iodinated human serum

albumin.

Do................ Colloidal Liver scans.

microaggregated human

serum albumin.

Iodine 125............ Iodide................. Diagnosis of thyroid

function.

Do................ Iodinated human serum Blood volume

albumin. determinations.

Do................ Rose Bengal............ Liver function studies.

Do................ Iodopyracet, sodium Kidney function

iodohippurate, sodium studies.

diatrizoate,

diatrizoate methyl-

glucamine, sodium

diprotrizoate, sodium

acetrizoate, or sodium

iothalamate.

Do................ Labeled fats and/or Fat absorption studies.

fatty acids.

Iron 59............... Chloride, citrate and/ Iron turnover studies.

or sulfate.

Krypton 85............ Gas.................... Diagnosis of cardiac

abnormalities.

Mercury 197........... Chlormerodrin.......... Kidney scans.

Do................ ......do............... Brain scans.

Mercury 203 \1\....... ......do............... Kidney scans.

Do................ ......do............... Brain scans.

Phosphorus 32......... Soluble phosphate...... Treatment of

polycythemia vera.

Do................ ......do............... Treatment of leukemia

and bone metastasis.

Do................ Colloidal chromic Intracavitary treatment

phosphate. of pleural effusions

and/or ascites.

Do................ ......do............... Interstitial treatment

of cancer.

Potassium 42.......... Chloride............... Potassium space

studies.

Selenium 75........... Labeled methionine..... Pancreas scans.

Strontium 85.......... Nitrate or chloride.... Bone scans on patients

with diagnosed cancer.

Technetium 99m........ Pertechnetate.......... Brain scans.

Do................ ......do............... Thyroid scans.

Do................ Sulfur colloid......... Liver and spleen scans.

Do................ Pertechnetate.......... Placenta localization.

Do................ ......do............... Blood pool scans.

Do................ ......do............... Salivary gland scans.

Do................ Diethylenetri-amine Kidney scans.

pentaacetic acid

(DTPA).

Xenon 133............. Gas.................... Diagnosis of cardia

abnormalities.

Cerebral bloodflow

studies. Pulmonary

function studies.

Muscle bloodflow

studies.

------------------------------------------------------------------------

\1\ This item has been removed from the AEC list for kidney scans but is included as the requirements of this order are applicable. Start time Tuesday, April 20, 1999 16:55:11

(d)(1) In view of the extent of experience with the isotopes listed in paragraph (c) of this section, the Nuclear Regulatory Commission and the Food and Drug Administration conclude that such isotopes should not be distributed under investigational-use labeling when they are actually intended for use in medical practice.

(2) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the ``chemical form'' and intended for the uses stated, is terminated on March 3, 1972, except as provided in paragraph (d)(3) of this section.

(3) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the ``chemical form'' and intended for the uses stated, for which drug a new drug application or a ``Investigational New Drug Application'' was submitted prior to March 3, 1972, or for which biologic an application for product license or

``Investigational New Drug Application'' was submitted prior to March 3, 1972, is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first.

(e) No exemption from section 505 of the act or from part 312 of is in effect or has been in effect for radioactive drugs prepared from accelerator-produced radioisotopes, naturally occurring isotopes, or

nonradioactive substances used in conjunction with isotopes.

(f)(1) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that

applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling; such use may include, among others, the uses in this tabulation:

------------------------------------------------------------------------

Isotope Chemical form Use

------------------------------------------------------------------------

Fluorine 18........... Fluoride............... Bone imaging.

Indium-113m........... Diethylenetriamine Brain imaging; kidney

pentaacetic acid imaging.

(DTPA).

Do................ Chloride............... Placenta imaging; blood

pool imaging.

Technetium 99m........ Human serum albumin Lung imaging.

microspheres.

Do................ Diethylenetriamine Kidney imaging; kidney

pentaacetic acid (Sn). function studies.

Do................ ......do............... Brain imaging.

Do................ Polyphosphates......... Bone imaging.

Do................ Technetated aggregated Lung imaging.

albumin (human).

Do................ Disodium etidronate.... Bone imaging.

------------------------------------------------------------------------

(2) In view of the extent of experience with the isotopes listed in paragraph (f)(1) of this section, the Nuclear Regulatory Commission and the Food and Drug Administration conclude that they should not be distributed under investigational-use labeling when they are actually intended for use in medical practice.

(3) Any manufacturer or distributor interested in continuing to ship in interstate commerce drugs containing the isotopes listed in paragraph (f)(1) of this section for any of the indications listed, shall submit, on or before August 25, 1975 to the Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, a new drug application or a ``Investigational New Drug Application'' for each such drug for which the manufacturer or distributor does not have an approved new drug application pursuant to section 505(b) of the act. If the drug is a biologic, a ``Investigational New Drug Application'' or an application for a license under section 351 of the Public Health Service Act shall be submitted to the Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20014, in lieu of any submission to the Center for Drug Evaluation and Research.

(4) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (f)(1) of this section, in the ``chemical form'' and intended for the uses stated, is terminated on August 26, 1975 except as provided in paragraph (f)(5) of this section.

(5)(i) Except as provided in paragraph (f)(5)(ii) of this section, the exemption referred to in paragraph (a) of this section, as applied to any drug containing any of the isotopes listed in paragraph (f)(1) of this section, in the ``chemical form'' and intended for the uses stated, for which drug a new drug application or ``Investigational New Drug Application'' was submitted to the Center for Drug Evaluation and Research on or before August 25, 1975 is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first.

(ii) The exemption referred to in paragraph (a) of this section, as applied to any biologic containing any of the isotopes listed in paragraph (f)(1) of this section in the ``chemical form'' and intended for the uses stated, for which biologic an application for product license or ``Investigational New Drug Application'' was submitted to the Center for Biologics Evaluation and Research on or before August 25, 1975 is terminated on October 20, 1976, unless an approvable notice was issued on or before October 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on January 20, 1977, whichever occurs first.

[[Page 34]]

(g) The exemption referred to in paragraph (a) of this section, as applied to any drug intended solely for investigational use as part of a research project, which use had been approved on or before July 25, 1975 in accordance with 10 CFR 35.11 (or equivalent regulation of an Agreement State) is terminated on February 20, 1976 if the manufacturer of such drug or the sponsor of the investigation of such drug submits on or before August 25, 1975 to the Food and Drug Administration, Bureau of Drugs, HFD-150, 5600 Fishers Lane, Rockville, MD 20857, the following information:

(1) The research project title;

(2) A brief description of the purpose of the project;

(3) The name of the investigator responsible;

(4) The name and license number of the institution holding the specific license under 10 CFR 35.11 (or equivalent regulation of an Agreement State);

(5) The name and maximum amount per subject of the radionuclide used;

(6) The number of subjects involved; and

(7) The date on which the administration of the radioactive drugs is expected to be completed.

(h) The exemption referred to in paragraph (a) of this section, as applied to any drug not referred to in paragraphs (d), (f), and (g) of this section, is terminated on August 26, 1975.

[39 FR 11680, Mar. 29, 1974, as amended at 40 FR 31307, July 25, 1975; 40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990; 64 FR 56449, Oct. 20, 1999]

Sec. 310.509 Parenteral drug products in plastic containers.

(a) Any parenteral drug product packaged in a plastic immediate container is not generally recognized as safe and effective, is a new drug within the meaning of section 201(p) of the act, and requires an approved new drug application as a condition for marketing. An ``Investigational New Drug Application'' set forth in part 312 of this chapter is required for clinical investigations designed to obtain evidence of safety and effectiveness.

(b) As used in this section, the term ``large volume parenteral drug product'' means a terminally sterilized aqueous drug product packaged in a single-dose container with a capacity of 100 milliliters or more and intended to be administered or used intravenously in a human.

(c) Until the results of compatibility studies are evaluated, a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or after April 16, 1979, is misbranded unless its labeling contains a warning that includes the following information:

(1) A statement that additives may be incompatible.

(2) A statement that, if additive drugs are introduced into the parenteral system, aseptic techniques should be used and the solution should be thoroughly mixed.

(3) A statement that a solution containing an additive drug should not be stored.

(d) This section does not apply to a biological product licensed under the Public Health Service Act of July 1, 1944 (42 U.S.C. 201).

[62 FR 12084, Mar. 14, 1997]

Sec. 310.515 Patient package inserts for estrogens.

(a) Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed of the benefits and risks involved in the use of these drugs. Accordingly, except as provided in paragraph (e) of this section, each estrogen drug product restricted to prescription distribution, including products containing estrogens in fixed combinations with other drugs, shall be dispensed to patients with a patient package insert containing information concerning the drug's benefits and risks. An estrogen drug product that does not comply with the requirements of this section is misbranded under section 502(a) of the Federal Food, Drug, and Cosmetic Act.

(b) Distribution requirements. (1) For estrogen drug products, the manufacturer and distributor shall provide a patient package insert in or with each package of the drug product that the

[[Page 35]]

manufacturer or distributor intends to be dispensed to a patient.

(2) In the case of estrogen drug products in bulk packages intended for multiple dispensing, and in the case of injectables in multiple-dose vials, a sufficient number of patient labeling pieces shall be included in or with each package to assure that one piece can be included with each package or dose dispensed or administered to every patient. Each bulk package shall be labeled with instructions to the dispensor to include one patient labeling piece with each package dispensed or, in the case of injectables, with each dose administered to the patient. This section does not preclude the manufacturer or labeler from distributing additional patient labeling pieces to the dispensor.

(3) Patient package inserts for estrogens dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before administration of the first estrogen and every 30 days thereafter, as long as the therapy continues.

(c) Patient package insert contents. A patient package insert for an estrogen drug product is required to contain the following information:

(1) The name of the drug.

(2) The name and place of business of the manufacturer, packer, or distributor.

(3) A statement regarding the benefits and proper uses of estrogens.

(4) The contraindications to use, i.e., when estrogens should not be used.

(5) A description of the most serious risks associated with the use of estrogens.

(6) A brief summary of other side effects of estrogens.

(7) Instructions on how a patient may reduce the risks of estrogen use.

(8) The date, identified as such, of the most recent revision of the patient package insert.

(d) Guidance language. The Food and Drug Administration issues informal labeling guidance texts under Sec. 10.90(b)(9) of this chapter to provide assistance in meeting the requirements of paragraph (c) of this section. Requests for a copy of the guidance text should be directed to the Center for Drug Evaluation and Research, Division of Metabolism and Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

(e) Exemptions. This section does not apply to estrogen-progestogen oral contraceptives. Labeling requirements for these products are set forth in Sec. 310.501.

(f) Requirement to supplement approved application. Holders of approved applications for estrogen drug products that are subject to the requirements of this section must submit supplements under Sec. 314.70(c) of this chapter to provide for the labeling required by paragraph (a) of this section. Such labeling may be put into use without advance approval by the Food and Drug Administration.

[55 FR 18723, May 4, 1990]

Sec. 310.516 Progestational drug products; labeling directed to the patient.

(a) The Commissioner of Food and Drugs concludes that the safe and effective use of any progestational drug product requires that patients be informed that there is an increased risk of birth defects in children whose mothers have taken this drug during the first 4 months of pregnancy. Accordingly, except as provided by paragraph (d) of this section, any progestational drug product that is the subject of a new drug application approved either before or after October 9, 1962 and all identical, related, or similar drug products as defined in Sec. 310.6, whether or not the subject of an approved new drug application, shall be dispensed to patients with labeling in lay language containing such a warning. The patient labeling shall be provided as a separate printed leaflet independent of any additional materials.

(b) The patient labeling shall specifically include the following:

(1) Name of the drug.

(2) Name and place of business of the manufacturer, packer, or distributor.

(3) A warning that there is an increased risk of birth defects in children whose mothers take this drug during the first 4 months of pregnancy.

(4) A brief discussion of the nature of the risks of birth defects resulting

[[Page 36]]

from the use of these drugs during the first 4 months of pregnancy.

(5) A brief statement that these drugs are no longer considered safe as a test for pregnancy.

(6) A statement that the patient should inform her physician as soon as possible if she discovers that she was pregnant when she took the drug.

(c) The patient labeling shall be printed in accordance with the following specifications:

(1) The minimum letter size shall be one-sixteenth of an inch in height.

(2) Letter heights pertain to the lower-case letter ``o'' or its equivalent that shall meet the minumim height standard.

(3) Type used shall conform to the minimum letter height. The body copy shall contain 1-point leading, noncondensed type, and shall not contain any light-face type or small capital letters.

(d) This section does not apply to a progestogen-containing product intended for contraception, which shall be labeled according to the requirements of Sec. 310.501.

(e)(1) Patient labeling for each progestational drug product shall be provided in or with each package intended to be dispensed to the patient. Patient labeling for drug products dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before first administration of the drug and every 30 days thereafter, as long as the therapy continues.

(2) In the case of progestational drug products in bulk packages intended for multiple dispensing, a sufficient number of patient-labeling pieces shall be included in or shall accompany each bulk package to assure that one can be included with each package dispensed to every patient. Each bulk package shall be labeled with instructions to the dispenser to include one patient-labeling piece with each package dispensed to the patient. This section does not preclude the manufacturer or labeler from distributing additional patient-labeling pieces to the dispenser.

(3) In the case of progestational drug products for injection, each package shall include a sufficient number of patient-labeling pieces for the volume of the vial, and instructions to the practitioner administering the drug to give one patient-labeling piece to each premenopausal woman, except those in whom childbearing is impossible, receiving the drug.

(4) This section does not apply to oral dosage forms labeled solely for the treatment of advanced cancer.

(5) Any progestational drug product, except as noted in paragraphs (d) and (e)(4) of this section, that is not labeled as required by this section and is either introduced or delivered for introduction into interstate commerce, or held for sale after shipment in interstate commerce, is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act. However, a progestational drug product in the possession of a wholesaler or retailer before December 12, 1978, is not misbranded if adequate numbers of copies of the patient labeling are furnished to the wholesaler or retailer to permit any retail purchaser after that date to obtain such labeling with the product. The requirement that any progestational drug product be dispensed with patient labeling, as applied to physicians who dispense or administer the drug, will not be effective for supplies in their possession on the effective date, but will apply only to supplies received thereafter.

(f) The Food and Drug Administration has available guideline patient labeling for progestational drug products that includes information responsive to all items specified in paragraph (b) of this section. This labeling was published in a separate notice appearing in the Federal Register of January 12, 1989. Any person may rely on this labeling as complying with paragraph (b) of this section.

(g) Holders of approved new drug applications for progestational drug products that are subject to the requirements of this section shall submit supplements under Sec. 314.70(c) of this chapter to provide for the labeling required by paragraph (a) of this section.

[43 FR 47181, Oct. 13, 1978, as amended at 46 FR 53657, Oct. 30, 1981; 54 FR 1163, Jan. 12, 1989; 64 FR 62112, Nov. 16, 1999]

Effective Date Note: At 64 FR 62112, Nov. 16, 1999, Sec. 310.516 was removed, effective Nov. 16, 2000.

[[Page 37]]

Sec. 310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea class.

(a) The University Group Diabetes Program clinical trial has reported an association between the administration of tolbutamide and increased cardiovascular mortality. The Food and Drug Administration has concluded that this reported association provides adequate basis for a warning in the labeling. In view of the similarities in chemical structure and mode of action, the Food and Drug Administration also believes it is prudent from a safety standpoint to consider that the possible increased risk of cardiovascular mortality from tolbutamide applies to all other sulfonylurea drugs as well. Therefore, the labeling for oral hypoglycemic drugs of the sulfonylurea class shall include a warning concerning the possible increased risk of cardiovascular mortality associated with such use, as set forth in paragraph (b) of this section.

(b) Labeling for oral hypoglycemic drugs of the sulfonylurea class shall include in boldface type at the beginning of the ``Warnings'' section of the labeling the following statement:

Special Warning on Increased Risk of Cardiovascular Mortality

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 (supp. 2): 747-830, 1970). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2\1/2\ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of (name of drug) and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

[49 FR 14331, Apr. 11, 1984]

Sec. 310.518 Drug products containing iron or iron salts.

Drug products containing elemental iron or iron salts as an active ingredient in solid oral dosage form, e.g., tablets or capsules shall meet the following requirements:

(a) Packaging. If the product contains 30 milligrams or more of iron per dosage unit, it shall be packaged in unit-dose packaging. ``Unit-dose packaging'' means a method of packaging a product into a nonreusable container designed to hold a single dosage unit intended for administration directly from that container, irrespective of whether the recommended dose is one or more than one of these units. The term ``dosage unit'' means the individual physical unit of the product, e.g., tablet or capsule. Iron-containing drugs that are subject to this regulation are also subject to child-resistant special packaging requirements in 16 CFR parts 1700, 1701, and 1702.

(b) Temporary exemption. (1) Drug products offered in solid oral dosage form (e.g., tablets or capsules), and containing 30 milligrams or more of iron per dosage unit, are exempt from the provisions of paragraph (a) of this section until January 15, 1998, if the sole source of iron in the drug product is carbonyl iron that meets the specifications of Sec. 184.1375 of this chapter.

(2) If this temporary exemption is not extended or made permanent, such drug products shall be in compliance with the provisions of paragraph (a) of this section on or before July 15, 1998.

(c) Labeling. (1) The label of any drug in solid oral dosage form (e.g., tablets or capsules) that contains iron or iron salts for use as an iron source shall bear the following statement:

WARNING: Accidental overdose of iron-containing products is a leading

[[Page 38]]

cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

(2)(i) The warning statement required by paragraph (c)(1) of this section shall appear prominently and conspicuously on the information panel of the immediate container label.

(ii) If a drug product is packaged in unit-dose packaging, and if the immediate container bears labeling but not a label, the warning statement required by paragraph (c)(1) of this section shall appear prominently and conspicuously on the immediate container labeling in a way that maximizes the likelihood that the warning is intact until all of the dosage units to which it applies are used.

(3) Where the immediate container is not the retail package, the warning statement required by paragraph (c)(1) of this section shall also appear prominently and conspicuously on the information panel of the retail package label.

(4) The warning statement shall appear on any labeling that contains warnings.

(5) The warning statement required by paragraph (c)(1) of this section shall be set off in a box by use of hairlines.

(d) The iron-containing inert tablets supplied in monthly packages of oral contraceptives are categorically exempt from the requirements of paragraphs (a) and (c) of this section.

[62 FR 2250, Jan. 15, 1997; 62 FR 15111, Mar. 31, 1997]

Sec. 310.519 Drug products marketed as over-the-counter (OTC) daytime sedatives.

(a) Antihistamines, bromides, and scopolamine compounds, either singly or in combinations, have been marketed as ingredients in over-the-counter (OTC) drug products for use as daytime sedatives. The following claims have been made for daytime sedative products: ``occasional simple nervous tension,'' ``nervous irritability,'' ``nervous tension headache,'' ``simple nervousness due to common every day overwork and fatigue,'' ``a relaxed feeling,'' ``calming down and relaxing,'' ``gently soothe away the tension,'' ``calmative,'' ``resolving that irritability that ruins your day,'' ``helps you relax,'' ``restlessness,'' ``when you're under occasional stress . . . helps you work relaxed.'' Based on evidence presently available, there are no ingredients that can be generally recognized as safe and effective for use as OTC daytime sedatives.

(b) Any OTC drug product that is labeled, represented, or promoted as an OTC daytime sedative (or any similar or related indication) is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted as an OTC daytime sedative (or any similar or related indication) is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) Any OTC daytime sedative drug product introduced into interstate commerce after December 24, 1979, that is not in compliance with this section is subject to regulatory action.

[44 FR 36380, June 22, 1979; 45 FR 47422, July 15, 1980, as amended at 55 FR 11579, Mar. 29, 1990]

Sec. 310.527 Drug products containing active ingredients offered over- the-counter (OTC) for external use as hair growers or for hair loss prevention.

(a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid, biotin and all other B-vitamins, dexpanthenol, estradiol and other topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20, polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat germ oil have been marketed as ingredients in OTC drug products for external use as hair growers or for hair loss prevention. There is a lack of adequate data to establish general recognition of the safety and effectiveness

[[Page 39]]

of these or any other ingredients intended for OTC external use as a hair grower or for hair loss prevention. Based on evidence currently available, all labeling claims for OTC hair grower and hair loss prevention drug products for external use are either false, misleading, or unsupported by scientific data. Therefore, any OTC drug product for external use containing an ingredient offered for use as a hair grower or for hair loss prevention cannot be considered generally recognized as safe and effective for its intended use.

(b) Any OTC drug product that is labeled, represented, or promoted for external use as a hair grower or for hair loss prevention is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC external use as a hair grower or for hair loss prevention is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After January 8, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[54 FR 28777, July 7, 1989]

Sec. 310.528 Drug products containing active ingredients offered over- the-counter (OTC) for use as an aphrodisiac.

(a) Any product that bears labeling claims that it will arouse or increase sexual desire, or that it will improve sexual performance, is an aphrodisiac drug product. Anise, cantharides, don qual, estrogens, fennel, ginseng, golden seal, gotu kola, Korean ginseng, licorice, mandrake, methyltestosterone, minerals, nux vomica, Pega Palo, sarsaparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are powerful hormones when administered internally and are not safe for use except under the supervision of a physician. There is a lack of adequate data to establish general recognition of the safety and effectiveness of any of these ingredients, or any other ingredient, for OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use are either false, misleading, or unsupported by scientific data. The following claims are examples of some that have been made for aphrodisiac drug products for OTC use: ``acts as an aphrodisiac;'' ``arouses or increases sexual desire and improves sexual performance;'' ``helps restore sexual vigor, potency, and performance;'' ``improves performance, staying power, and sexual potency;'' and ``builds virility and sexual potency.'' Based on evidence currently available, any OTC drug product containing ingredients for use as an aphrodisiac cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or prompted for use as an aphrodisiac is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the act), for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as an aphrodisiac is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After January 8, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[54 FR 28786, July 7, 1989]

[[Page 40]]

Sec. 310.529 Drug products containing active ingredients offered over- the-counter (OTC) for oral use as insect repellents.

(a) Thiamine hydrochloride (vitamin B-1) has been marketed as an ingredient in over-the-counter (OTC) drug products for oral use as an insect repellent (an orally administered drug product intended to keep insects away). There is a lack of adequate data to establish the effectiveness of this, or any other ingredient for OTC oral use as an insect repellent. Labeling claims for OTC orally administered insect repellent drug products are either false, misleading, or unsupported by scientific data. The following claims are examples of some that have been made for orally administered OTC insect repellent drug products: ``Oral mosquito repellent,'' ``mosquitos avoid you,'' ``bugs stay away,'' ``keep mosquitos away for 12 to 24 hours,'' and ``the newest way to fight mosquitos.'' Therefore, any drug product containing ingredients offered for oral use as an insect repellent cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted for oral use as an insect repellent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug and Cosmetic Act for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted OTC for oral use as an insect repellent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) Any such drug product in interstate commerce after December 17, 1985, that is not in compliance with this section is subject to regulatory action.

[40 FR 25171, June 17, 1985, as amended at 55 FR 11579, Mar. 29, 1990]

Sec. 310.530 Topically applied hormone-containing drug products for over-the-counter (OTC) human use.

(a) The term ``hormone'' is used broadly to describe a chemical substance formed in some organ of the body, such as the adrenal glands or the pituitary, and carried to another organ or tissue, where it has a specific effect. Hormones include, for example, estrogens, progestins, androgens, anabolic steroids, and adrenal corticosteroids, and synthetic analogs. Estrogens, progesterone, pregnenolone, and pregnenolone acetate have been present as ingredients in OTC drug products marketed for topical use as hormone creams. However, there is a lack of adequate data to establish effectiveness for any OTC drug use of these ingredients. Therefore, with the exception of those hormones identified in paragraph (e) of this section, any OTC drug product containing an ingredient offered for use as a topically applied hormone cannot be considered generally recognized as safe and effective for its intended use. The intended use of the product may be inferred from the product's labeling, promotional material, advertising, and any other relevant factor. The use of the word ``hormone'' in the text of the labeling or in the ingredient statement is an implied drug claim. The claim implied by the use of this term is that the product will have a therapeutic or some other physiological effect on the body. Therefore, reference to a product as a ``hormone cream'' or any statement in the labeling indicating that ``hormones'' are present in the product, or any statement that features or emphasizes the presence of a hormone ingredient in the product, will be considered to be a therapeutic claim for the product, or a claim that the product will affect the structure or function of the body, and will consequently cause the product to be a drug.

(b) Any OTC drug product that is labeled, represented, or promoted as a topically applied hormone-containing product for drug use, with the exception of those hormones identified in paragraph (e) of this section, is regarded as a new drug within the meaning of section 201(p) of the act, for

[[Page 41]]

which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a topically applied hormone-containing drug product is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After March 9, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(e) This section does not apply to hydrocortisone and hydrocortisone acetate labeled, represented, or promoted for OTC topical use in accordance with part 348 of this chapter.

[58 FR 47610, Sept. 9, 1993]

Sec. 310.531 Drug products containing active ingredients offered over- the-counter (OTC) for the treatment of boils.

(a) Aminacrine hydrochloride, benzocaine, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, rosin cerate, sassafras oil, sulfur, thymol, triclosan, and zinc oxide have been present in OTC boil treatment drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredient for OTC use for the treatment of boils. Treatment is defined as reducing the size of a boil or reducing an infection related to a boil. Treatment has involved the use of ``drawing salves'' for these purposes. These ``drawing salves'' contained various ingredients. Based on evidence currently available, any OTC drug product offered for the treatment of boils cannot be considered generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted for the treatment of boils is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any OTC boil treatment drug product is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After May 7, 1991, any such OTC drug product that contains aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, isobutamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, rosin cerate, sassafras oil, thymol, or zinc oxide initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(e) After May 16, 1994, any such OTC drug product that contains benzocaine, ichthammol, sulfur, or triclosan initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(f) This section does not apply to drug products that contain benzocaine labeled, represented, or promoted for OTC topical use in accordance with part 348 of this chapter.

[58 FR 60336, Nov. 15, 1993]

[[Page 42]]

Sec. 310.532 Drug products containing active ingredients offered over- the-counter (OTC) to relieve the symptoms of benign prostatic hypertrophy.

(a) The amino acids glycine, alanine, and glutamic acid (alone or in combination) and the ingredient sabal have been present in over-the-counter (OTC) drug products to relieve the symptoms of benign prostatic hypertrophy, e.g., urinary urgency and frequency, excessive urinating at night, and delayed urination. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use in relieving the symptoms of benign prostatic hypertrophy. In addition, there is no definitive evidence that any drug product offered for the relief of the symptoms of benign prostatic hypertrophy would alter the obstructive or inflammatory signs and symptoms of this condition. Therefore, self-medication with OTC drug products might unnecessarily delay diagnosis and treatment of progressive obstruction and secondary infections. Based on evidence currently available, any OTC drug product containing ingredients offered for use in relieving the symptoms of benign prostatic hypertrophy cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted to relieve the symptoms of benign prostatic hypertrophy is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use to relieve the symptoms of benign prostatic hypertrophy is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After August 27, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[55 FR 6930, Feb. 27, 1990]

Sec. 310.533 Drug products containing active ingredients offered over- the-counter (OTC) for human use as an anticholinergic in cough-cold drug products.

(a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids as contained in Atropa belladonna and Datura stramonium have been present as ingredients in cough-cold drug products for use as an anticholinergic. Anticholinergic drugs have been marketed OTC in cough-cold drug products to relieve excessive secretions of the nose and eyes, symptoms that are commonly associated with hay fever, allergy, rhinitis, and the common cold. Atropine sulfate for oral use as an anticholinergic is probably safe at dosages that have been used in marketed cough-cold products (0.2 to 0.3 milligram); however, there are inadequate data to establish general recognition of the effectiveness of this ingredient. The belladonna alkaloids, which contain atropine (d, dl hyoscyamine) and scopolamine (l- hyoscine), are probably safe for oral use at dosages that have been used in marketed cough-cold products (0.2 milligram) but there are inadequate data to establish general recognition of the effectiveness of these ingredients as an anticholinergic for cough-cold use. Belladonna alkaloids for inhalation use, as contained in Atropa belladonna and Datura stramonium, are neither safe nor effective as an OTC anticholinergic. There are inadequate safety and effectiveness data to establish general recognition of the safety and/or effectiveness or any of these ingredients, or any other ingredient, for OTC use as an anticholinergic in cough-cold drug products.

(b) Any OTC cough-cold drug product that is labeled, represented, or promoted for use as an anticholinergic is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for

[[Page 43]]

which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any cough-cold drug product labeled, represented, or promoted for OTC use as an anticholinergic is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After the effective date of the final regulation, any such OTC cough-cold drug product that is labeled, represented, or promoted for use as an anticholinergic may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved new drug application.

[50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990]

Sec. 310.534 Drug products containing active ingredients offered over- the-counter (OTC) for human use as oral wound healing agents.

(a) Allantoin, carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, and hydrogen peroxide in aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing agents. Oral wound healing agents have been marketed as aids in the healing of minor oral wounds by means other than cleansing and irrigating, or by serving as a protectant. Allantoin, carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, and hydrogen peroxide in aqueous solution are safe for use as oral wound healing agents, but there are inadequate data to establish general recognition of the effectiveness of these ingredients as oral wound healing agents.

(b) Any OTC drug product that is labeled, represented, or promoted for use as an oral wound healing agent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as an oral wound healing agent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After the effective date of the final regulation, any OTC drug product that is labeled, represented, or promoted for use as an oral wound healing agent may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved new drug application.

[51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29, 1990]

Sec. 310.536 Drug products containing active ingredients offered over- the-counter (OTC) for use as a nailbiting or thumbsucking deterrent.

(a) Denatonium benzoate and sucrose octaacetate have been present in OTC nailbiting and thumbsucking deterrent drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these and any other ingredients (e.g., cayenne pepper) for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a nailbiting or thumbsucking deterrent cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, and promoted as a nailbiting or thumbsucking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

[[Page 44]]

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a nailbiting or thumbsucking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After March 2, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[58 FR 46754, Sept. 2, 1993]

Sec. 310.537 Drug products containing active ingredients offered over- the-counter (OTC) for oral administration for the treatment of fever blisters and cold sores.

(a) l-lysine (lysine, lysine hydrochloride), Lactobacillus acidophilus, and Lactobacillus bulgaricus have been present in orally administered OTC drug products to treat fever blisters and cold sores. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other orally administered ingredients for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores. Based on evidence currently available, any OTC drug product for oral administration containing ingredients offered for use in treating or relieving the symptoms or discomfort of fever blisters and cold sores cannot be generally recognized as safe and effective.

(b) Any OTC drug product for oral administration that is labeled, represented, or promoted to treat or relieve the symptoms or discomfort of fever blisters and cold sores is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product for oral administration labeled, represented, or promoted for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After December 30, 1992, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[57 FR 29173, June 30, 1992]

Sec. 310.538 Drug products containing active ingredients offered over- the-counter (OTC) for use for ingrown toenail relief.

(a) Any product that bears labeling claims such as for ``temporary relief of discomfort from ingrown toenails,'' or ``ingrown toenail relief product,'' or ``ingrown toenail reliever,'' or similar claims is considered an ingrown toenail relief drug product. Benzocaine, chlorobutanol, chloroxylenol, dibucaine, sodium sulfide, tannic acid, and urea have been present as ingredients in such products. There is lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use for ingrown toenail relief. Based on evidence currently available, any OTC drug product containing ingredients offered for use for ingrown toenail relief cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted for ingrown toenail relief is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for ingrown toenail relief

[[Page 45]]

is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After March 9, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[58 FR 47605, Sept. 9, 1993]

Sec. 310.540 Drug products containing active ingredients offered over- the-counter (OTC) for use as stomach acidifiers.

(a) Betaine hydrochloride, glutamic acid hydrochloride, diluted hydrochloric acid, and pepsin have been present as ingredients in over-the-counter (OTC) drug products for use as stomach acidifiers. Because of the lack of adequate data to establish the effectiveness of these or any other ingredients for use in treating achlorhydria and hypochlorhydria, and because such conditions are asymptomatic, any OTC drug product containing ingredients offered for use as a stomach acidifier cannot be considered generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted for use as a stomach acidifier is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted as a stomach acidifier for OTC use is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After the effective date of the final regulation, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[53 FR 31271, Aug. 17, 1988]

Sec. 310.541 Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hypophosphatemia.

(a) Hypophosphatemia is a condition in which an abnormally low plasma level of phosphate occurs in the blood. This condition is not amenable to self-diagnosis or self-treatment. Treatment of this condition should be restricted to the supervision of a physician. For this reason, any drug product containing ingredients offered for OTC use in the treatment of hypophosphatemia cannot be considered generally recognized as safe and effective.

(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of hypophosphatemia is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use in the treatment of hypophosphatemia is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of his chapter.

(d) After November 12, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[55 FR 19858, May 11, 1990]

Sec. 310.542 Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hyperphosphatemia.

(a) Hyperphosphatemia is a condition in which an abnormally high plasma level of phosphate occurs in the blood. This condition in not amenable to self-diagnosis or self-treatment. Treatment

[[Page 46]]

of this condition should be restricted to the supervision of a physician. For this reason, any drug product containing ingredients offered for OTC use in the treatment of hyperphosphatemia cannot be considered generally recognized as safe and effective.

(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of hyperphosphatemia is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for use in the treatment of hyperphosphatemia is safe and effective for the purpose intended must comply with the requirements and procedures governing use of investigational new drugs set forth in part 312 of this chapter.

(d) After November 12, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[55 FR 19858, May 11, 1990]

Sec. 310.543 Drug products containing active ingredients offered over- the-counter (OTC) for human use in exocrine pancreatic insufficiency.

(a) Hemicellulase, pancreatin, and pancrelipase have been present as ingredients in exocrine pancreatic insufficiency drug products. Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin (protease), and lipase. Significant differences have been shown in the bioavailability of marketed exocrine pancreatic insufficiency drug products produced by different manufacturers. These differences raise a potential for serious risk to patients using these drug products. The bioavailability of pancreatic enzymes is dependent on the process used to manufacture the drug products. Information on this process is not included in an OTC drug monograph. Therefore, the safe and effective use of these enzymes for treating exocrine pancreatic insufficiency cannot be regulated adequately by an OTC drug monograph. Information on the product's formulation, manufacture, quality control procedures, and final formulation effectiveness testing are necessary in an approved application to ensure that a company has the ability to manufacture a proper bioactive formulation. In addition, continuous physician monitoring of patients who take these drug products is a collateral measure necessary to the safe and effective use of these enzymes, causing such products to be available by prescription only.

(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of exocrine pancreatic insufficiency is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use in the treatment of exocrine pancreatic insufficiency is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After May 7, 1991, any such OTC drug product that contains hemicellulase initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(e) After October 24, 1995, any such OTC drug product that contains pancreatin or pancrelipase initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[60 FR 20165, Apr. 24, 1995]

[[Page 47]]

Sec. 310.544 Drug products containing active ingredients offered over- the-counter (OTC) for use as a smoking deterrent.

(a) Any product that bears labeling claims that it ``helps stop or reduce the cigarette urge,'' ``helps break the cigarette habit,'' ``helps stop or reduce smoking,'' or similar claims is a smoking deterrent drug product. Cloves, coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), licorice root extract, lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata herb), menthol, methyl salicylate, povidone-silver nitrate, quinine ascorbate, silver acetate, silver nitrate, and thymol have been present as ingredients in such drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use as a smoking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a smoking deterrent cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted as a smoking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a smoking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After May 7, 1991, any such OTC drug product containing cloves, coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), licorice root extract, menthol, methyl salicylate, quinine ascorbate, silver nitrate, and/or thymol initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. After December 1, 1993, any such OTC drug product containing lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata herb), povidone-silver nitrate, silver acetate, or any other ingredients initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[58 FR 31241, June 1, 1993]

Sec. 310.545 Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses.

(a) A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses:

(1) Topical acne drug products.

Alcloxa

Alkyl isoquinolinium bromide

Aluminum chlorohydrex

Aluminum hydroxide

Benzocaine

Benzoic acid

Boric acid

Calcium polysulfide

Calcium thiosulfate

Camphor

Chloroxylenol

Cloxyquin

Coal tar

Dibenzothiophene

Estrone

Magnesium aluminum silicate

Magnesium sulfate

Phenol

Phenolate sodium

Phenyl salicylate

Povidone-iodine

Pyrilamine maleate

Resorcinol (as single ingredient)

Resorcinol monoacetate (as single ingredient)

Salicylic acid (over 2 up to 5 percent)

Sodium borate

Sodium thiosulfate

Tetracaine hydrochloride

Thymol

Vitamin E

Zinc oxide

Zinc stearate

[[Page 48]]

Zinc sulfide

(2) Anticaries drug products--(i) Approved as of May 7, 1991.

Hydrogen fluoride

Sodium carbonate

Sodium monofluorophosphate (6 percent rinse)

Sodium phosphate

(ii) Approved as of October 7, 1996.

Calcium sucrose phosphate

Dicalcium phosphate dihydrate

Disodium hydrogen phosphate\1\

---------------------------------------------------------------------------

\1\ These ingredients are nonmonograph except when used to prepare

acidulated phosphate fluoride treatment rinses identified in

Sec. 355.10(a)(3) of this chapter.

---------------------------------------------------------------------------

Phosphoric acid<SUP>1</SUP>

Sodium dihydrogen phosphate

Sodium dihydrogen phosphate monohydrate

Sodium phosphate, dibasic anhydrous reagent<SUP>1</SUP>

(3) Antidiarrheal drug products.

Aluminum hydroxide

Atropine sulfate

Calcium carbonate

Carboxymethylcellulose sodium

Glycine

Homatropine methylbromide

Hyoscyamine sulfate

Lactobacillus acidophilus

Lactobacillus bulgaricus

Opium, powdered

Opium tincture

Paregoric

Phenyl salicylate

Scopolamine hydrobromide

Zinc phenolsulfonate

(4) Antiperspirant drug products.

Alum, potassium

Aluminum bromohydrate

Aluminum chloride (alcoholic solutions)

Aluminum chloride (aqueous solution) (aerosol only)

Aluminum sulfate

Aluminum sulfate, buffered (aerosol only)

Sodium aluminum chlorohydroxy lactate

(5) [Reserved]

(6) Cold, cough, allergy, bronchodilator, and antiasthmatic drug

products--(i) Antihistamine drug products--(A) Ingredients.

Methapyrilene hydrochloride

Methapyrilene fumarate

Thenyldiamine hydrochloride

(B) Ingredients.

Phenyltoloxamine dihydrogen citrate

Methapyrilene hydrochloride

Methapyrilene fumarate

Thenyldiamine hydrochloride

(ii) Nasal decongestant drug products--(A) Approved as of May 7,

1991.

Allyl isothiocyanate

Camphor (lozenge)

Creosote, beechwood (oral)

Eucalyptol (lozenge)

Eucalyptol (mouthwash)

Eucalyptus oil (lozenge)

Eucalyptus oil (mouthwash)

Menthol (mouthwash)

Peppermint oil (mouthwash)

Thenyldiamine hydrochloride

Thymol

Thymol (lozenge)

Thymol (mouthwash)

Turpentine oil

(B) Approved as of August 23, 1995.

Bornyl acetate (topical)

Cedar leaf oil (topical)

Creosote, beechwood (topical)

Ephedrine (oral)

Ephedrine hydrochloride (oral)

Ephedrine sulfate (oral)

Racephedrine hydrochloride (oral/topical)

(iii) Expectorant drug products.

Ammonium chloride

Antimony potassium tartrate

Beechwood creosote

Benzoin preparations (compound tincture of benzoin, tincture of benzoin)

Camphor

Chloroform

Eucalyptol/eucalyptus oil

Horehound

Iodides (calcium iodide anyhydrous, hydroidic acid syrup, iodized lime,

potassium iodide)

Ipecac

Ipecac fluidextract

Ipecac syrup

Menthol/peppermint oil

Pine tar preparations (extract white pine compound, pine tar, syrup of

pine tar, compound white pine syrup, white pine)

Potassium guaiacolsulfonate

Sodium citrate

Squill preparations (squill, squill extract)

Terpin hydrate preparations (terpin hydrate, terpin hydrate elixir)

Tolu preparations (tolu, tolu balsam, tolu balsam tincture)

Turpentine oil (spirits of turpentine)

(iv) Bronchodilator drug products--(A) Approved as of October 2,

1987.

Aminophylline

Belladonna alkaloids

Euphorbia pilulifera

Metaproterenol sulfate

Methoxyphenamine hydrochloride

Pseudoephedrine hydrochloride

[[Page 49]]

Pseudoephedrine sulfate

Theophylline, anhydrous

Theophylline calcium salicylate

Theophylline sodium glycinate

(B) Approved as of January 29, 1996. Any combination drug product

containing theophylline (e.g., theophylline and ephedrine, or

theophylline and ephedrine and phenobarbital).

(C) Approved as of June 19, 1996. Any ingredient(s) in a pressurized

metered-dose inhaler container.

(7) Dandruff/seborrheic dermatitis/psoriasis drug products.

Alkyl isoquinolinium bromide

Allantoin

Benzalkonium chloride

Benzethonium chloride

Boric acid

Calcium undecylenate

Captan

Chloroxylenol

Colloidal oatmeal

Cresol, saponated

Ethohexadiol

Eucalyptol

Juniper tar

Lauryl isoquinolinium bromide

Menthol

Mercury oleate

Methylbenzethonium chloride

Methyl salicylate

Phenol

Phenolate sodium

Pine tar

Povidone-iodine

Resorcinol

Sodium borate

Sodium salicylate

Thymol

Undecylenic acid

(8) Digestive aid drug products--(i) Approved as of May 7, 1991.

Bismuth sodium tartrate

Calcium carbonate

Cellulase

Dehydrocholic acid

Dihydroxyaluminum sodium carbonate

Duodenal substance

Garlic, dehydrated

Glutamic acid hydrochloride

Hemicellulase

Homatropine methylbromide

Magnesium hydroxide

Magnesium trisilicate

Ox bile extract

Pancreatin

Pancrelipase

Papain

Peppermint oil

Pepsin

Sodium bicarbonate

Sodium citrate

Sorbitol

(ii) Approved as of November 10, 1993.

Alcohol

Aluminum hydroxide

Amylase

Anise seed

Aromatic powder

Asafetida

Aspergillus oryza enzymes (except lactase enzyme derived from

Aspergillus oryzae)

Bacillus acidophilus

Bean

Belladonna alkaloids

Belladonna leaves, powdered extract

Betaine hydrochloride

Bismuth subcarbonate

Bismuth subgallate

Black radish powder

Blessed thistle (cnicus benedictus)

Buckthorn

Calcium gluconate

Capsicum

Capsicum, fluid extract of

Carbon

Cascara sagrada extract

Catechu, tincture

Catnip

Chamomile flowers

Charcoal, wood

Chloroform

Cinnamon oil

Cinnamon tincture

Citrus pectin

Diastase

Diastase malt

Dog grass

Elecampane

Ether

Fennel acid

Galega

Ginger

Glycine

Hydrastis canadensis (golden seal)

Hectorite

Horsetail

Huckleberry

Hydrastis fluid extract

Hydrochloric acid

Iodine

Iron ox bile

Johnswort

Juniper

Kaolin, colloidal

Knotgrass

Lactic acid

Lactose

Lavender compound, tincture of

Linden

Lipase

Lysine hydrochloride

Mannitol

Mycozyme

Myrrh, fluid extract of

Nettle

Nickel-pectin

Nux vomica extract

[[Page 50]]

Orthophosphoric acid

Papaya, natural

Pectin

Peppermint

Peppermint spirit

Phenacetin

Potassium bicarbonate

Potassium carbonate

Protease

Prolase

Rhubarb fluid extract

Senna

Sodium chloride

Sodium salicylate

Stem bromelain

Strawberry

Strychnine

Tannic acid

Trillium

Woodruff

(iii) Charcoal, activated

(9) [Reserved]

(10) External analgesic drug products--(i) Analgesic and anesthetic

drug products.

Aspirin

Chloral hydrate

Chlorobutanol

Cyclomethycaine sulfate

Eugenol

Hexylresorcinol

Methapyrilene hydrochloride

Salicylamide

Thymol

(ii) Counterirritant drug products.

Chloral hydrate

Eucalyptus oil

(iii) Male genital desensitizer drug products.

Benzyl alcohol

Camphorated metacresol

Ephedrine hydrochloride

(iv) Diaper rash drug products.

Any ingredient(s) labeled with claims or directions for use in the

treatment and/or prevention of diaper rash.

(v) Fever blister and cold sore treatment drug products.

Allyl isothiocyanate

Aspirin

Bismuth sodium tartrate

Camphor (exceeding 3 percent)

Capsaicin

Capsicum

Capsicum oleoresin

Chloral hydrate

Chlorobutanol

Cyclomethycaine sulfate

Eucalyptus oil

Eugenol

Glycol salicylate

Hexylresorcinol

Histamine dihydrochloride

Menthol (exceeding 1 percent)

Methapyrilene hydrochloride

Methyl nicotinate

Methyl salicylate

Pectin

Salicylamide

Strong ammonia solution

Tannic acid

Thymol

Tripelennamine hydrochloride

Trolamine salicylate

Turpentine oil

Zinc sulfate

(vi) Insect bite and sting drug products.

Alcohol

Alcohol, ethoxylated alkyl

Benzalkonium chloride

Calamine

Ergot fluidextract

Ferric chloride

Panthenol

Peppermint oil

Pyrilamine maleate

Sodium borate

Trolamine salicylate

Turpentine oil

Zinc oxide

Zirconium oxide

(vii) Poison ivy, poison oak, and poison sumac drug products.

Alcohol

Aspirin

Benzethonium chloride

Benzocaine (0.5 to 1.25 percent)

Bithionol

Calamine

Cetalkonium chloride

Chloral hydrate

Chlorobutanol

Chlorpheniramine maleate

Creosote, beechwood

Cyclomethycaine sulfate

Dexpanthenol

Diperodon hydrochloride

Eucalyptus oil

Eugenol

Glycerin

Glycol salicylate

Hectorite

Hexylresorcinol

Hydrogen peroxide

Impatiens biflora tincture

Iron oxide

Isopropyl alcohol

Lanolin

Lead acetate

Merbromin

Mercuric chloride

Methapyrilene hydrochloride

Panthenol

Parethoxycaine hydrochloride

Phenyltoloxamine dihydrogen citrate

[[Page 51]]

Povidone-vinylacetate copolymers

Pyrilamine maleate

Salicylamide

Salicylic acid

Simethicone

Sulfur

Tannic acid

Thymol

Trolamine salicylate

Turpentine oil

Zirconium oxide

Zyloxin

(11) [Reserved]

(12) Laxative drug products--(i) Bulk laxatives.

Agar

Carrageenan (degraded)

Carrageenan (native)

Guar gun

(ii) Saline laxative.

Tartaric acid

(iii) Stool softener.

Poloxamer 188

(iv)(A) Stimulant laxatives--Approved as of May 7, 1991.

Aloin

Bile salts/acids

Calcium pantothenate

Calomel

Colocynth

Elaterin resin

Frangula

Gamboge

Ipomea

Jalap

Ox bile

Podophyllum resin

Prune concentrate dehydrate

Prune powder

Rhubarb, Chinese

Sodium Oleate

(iv)(B) Stimulant laxatives--Approved as of January 29, 1999.

Danthron

Phenolphthalein

(13) [Reserved]

(14) Oral health care drug products (nonantimicrobial).

Antipyrine

Camphor

Cresol

Dibucaine

Dibucaine hydrochloride

Eucalyptol

Lidocaine

Lidocaine hydrochloride

Methly salicylate

Myrrh tincture

Pyrilamine maleate

Sorbitol

Sugars

Tetracaine

Tetracaine hydrochloride

Thymol

(15) Topical otic drug products for the prevention of swimmer's ear

and for the drying of water-clogged ears--(i) Approved as of May 7,

1991.

Acetic acid

(ii) Approved as of August 15, 1995.

Glycerin and anhydrous glycerin

Isopropyl alcohol

(16) Poison treatment drug products.

Ipecac fluidextract

Ipecac tincture

Zinc sulfate

(17) Skin bleaching drug products.

Mercury, ammoniated

(18) Skin protectant drug products. (i) Ingredients.

Allantoin (wound healing claims only)

Sulfur

Tannic acid

Zinc acetate (wound healing claims only)

(ii) Astringent drug products.

Acetone

Alcohol

Alum, ammonium

Alum, potassium

Aluminum chlorhydroxy complex

Aromatics

Benzalkonium chloride

Benzethonium chloride

Benzocaine

Benzoic acid

Boric acid

Calcium acetate

Camphor gum

Clove oil

Colloidal oatmeal

Cresol

Cupric sulfate

Eucalyptus oil

Eugenol

Ferric subsulfate (Monsel's Solution)

Honey

Isopropyl alcohol

Menthol

Methyl salicylate

Oxyquinoline sulfate

P-t-butyl-m-cresol

Peppermint oil

Phenol

Polyoxeythylene laurate

Potassium ferrocyanide

Sage oil

Silver nitrate

Sodium borate

[[Page 52]]

Sodium diacetate

Talc

Tannic acid glycerite

Thymol

Topical starch

Zinc chloride

Zinc oxide

Zinc phenolsulfonate

Zinc stearate

Zinc sulfate

(iii) Diaper rash drug products.

Aluminum hydroxide

Cocoa butter

Cysteine hydrochloride

Glycerin

Protein hydrolysate

Racemethionine

Sulfur

Tannic acid

Zinc acetate

Zinc carbonate

(iv) Fever blister and cold sore treatment drug products.

Bismuth subnitrate

Boric acid

Pyridoxine hydrochloride

Sulfur

Tannic acid

Topical starch

Trolamine

Zinc sulfate

(v) Insect bite and sting drug products.

Alcohol

Alcohol, ethoxylated alkyl

Ammonia solution, strong

Ammonium hydroxide

Benzalkonium chloride

Camphor

Ergot fluidextract

Ferric chloride

Menthol

Peppermint oil

Phenol

Pyrilamine maleate

Sodium borate

Trolamine

Turpentine oil

Zirconium oxide

(vi) Poison ivy, poison oak, and poison sumac drug products.

Alcohol

Anion and cation exchange resins buffered

Benzethonium chloride

Benzocaine

Benzyl alcohol

Bismuth subnitrate

Bithionol

Boric acid

Camphor

Cetalkonium chloride

Chloral hydrate

Chlorpheniramine maleate

Creosote

Diperodon hydrochloride

Diphenhydramine hydrochloride

Eucalyptus oil

Ferric chloride

Glycerin

Hectorite

Hydrogen peroxide

Impatiens biflora tincture

Iron oxide

Isopropyl alcohol

Lanolin

Lead acetate

Lidocaine

Menthol

Merbromin

Mercuric chloride

Panthenol

Parethoxycaine hydrochloride

Phenol

Phenyltoloxamine dihydrogen citrate

Povidone-vinylacetate copolymers

Salicylic acid

Simethicone

Tannic acid

Topical starch

Trolamine

Turpentine oil

Zirconium oxide

Zyloxin

(19) [Reserved]

(20) Weight control drug products.

Alcohol

Alfalfa

Alginic acid

Anise oil

Arginine

Ascorbic acid

Bearberry

Biotin

Bone marrow, red

Buchu

Buchu, potassium extract

Caffeine

Caffeine citrate

Calcium

Calcium carbonate

Calcium caseinate

Calcium lactate

Calcium pantothenate

Carboxymethylcellulose sodium

Carrageenan

Cholecalcierol

Choline

Chondrus

Citric acid

Cnicus benedictus

Copper

Copper gluconate

Corn oil

Corn syrup

Corn silk, potassium extract

Cupric sulfate

Cyanocobalamin (vitamin B<INF>12</INF>)

Cystine

[[Page 53]]

Dextrose

Docusate sodium

Ergocalciferol

Ferric ammonium citrate

Ferric pyrophosphate

Ferrous fumarate

Ferrous gluconate

Ferrous sulfate (iron)

Flax seed

Folic acid

Fructose

Guar gum

Histidine

Hydrastis canadensis

Inositol

Iodine

Isoleucine

Juniper, potassium extract

Karaya gum

Kelp

Lactose

Lecithin

Leucine

Liver concentrate

Lysine

Lysine hydrochloride

Magnesium

Magnesium oxide

Malt

Maltodextrin

Manganese citrate

Mannitol

Methionine

Methylcellulose

Mono- and di-glycerides

Niacinamide

Organic vegetables

Pancreatin

Pantothenic acid

Papain

Papaya enzymes

Pepsin

Phenacetin

Phenylalanine

Phosphorus

Phytolacca

Pineapple enzymes

Plantago seed

Potassium citrate

Pyridoxine hydrochloride (vitamin B<INF>6</INF>)

Riboflavin

Rice polishings

Saccharin

Sea minerals

Sesame seed

Sodium

Sodium bicarbonate

Sodium caseinate

Sodium chloride (salt)

Soybean protein

Soy meal

Sucrose

Thiamine hydrochloride (vitamin B<INF>1</INF>)

Thiamine mononitrate (vitamin B<INF>1</INF> mononitrate)

Threonine

Tricalcium phosphate

Tryptophan

Tyrosine

Uva ursi, potassium extract

Valine

Vegetable

Vitamin A

Vitamin A acetate

Vitamin A palmitate

Vitamin E

Wheat germ

Xanthan gum

Yeast

(21) Ophthalmic drug products.

(i) Ophthalmic anesthetic drug products.

Antipyrine

Piperocaine hydrochloride

(ii) Ophthalmic anti-infective drug products.

Boric acid

Mild silver protein

Yellow mercuric oxide

(iii) Ophthalmic astringent drug products.

Infusion of rose petals

(iv) Ophthalmic demulcent drug products.

Polyethylene glycol 6000

(v) Ophthalmic vasoconstrictor drug products.

Phenylephrine hydrochloride (less than 0.08 percent)

(22) Topical antifungal drug products.

(i) Diaper rash drug products. Any ingredient(s) labeled with claims

or directions for use in the treatment and/or prevention of diaper rash.

(ii) Ingredients.

Alcloxa

Alum, potassium

Aluminum sulfate

Amyltricresols, secondary

Basic fuchsin

Benzethonium chloride

Benzoic acid

Benzoxiquine

Boric acid

Camphor

Candicidin

Chlorothymol

Coal tar

Dichlorophen

Menthol

Methylparaben

Oxyquinoline

Oxyquinoline sulfate

Phenol

Phenolate sodium

[[Page 54]]

Phenyl salicylate

Propionic acid

Propylparaben

Resorcinol

Salicylic acid

Sodium borate

Sodium caprylate

Sodium propionate

Sulfur

Tannic acid

Thymol

Tolindate

Triacetin

Zinc caprylate

Zinc propionate

(iii) Any ingredient(s) labeled with claims or directions for use on

the scalp or on the nails.

(iv) Ingredients.

Camphorated metacresol

Chloroxylenol

m-cresol

Nystatin

(23) Internal analgesic drug products. (i) Approved as of November

10, 1993.

Aminobenzoic acid

Antipyrine

Aspirin, aluminum

Calcium salicylate

Codeine

Codeine phosphate

Codeine sulfate

Iodoantipyrine

Lysine aspirin

Methapyrilene fumarate

Phenacetin

Pheniramine maleate

Pyrilamine maleate

Quinine

Salsalate

Sodium aminobenzoate

(ii) Approved as of February 22, 1999.

Any atropine ingredient

Any ephedrine ingredient

(24) Orally administered menstrual drug products. (i) Approved as of

November 10, 1993.

Alcohol

Alfalfa leaves

Aloes

Asclepias tuberosa

Asparagus

Barosma

Bearberry (extract of uva ursi)

Bearberry fluidextract (extract of bearberry)

Blessed thistle (cnicus benedictus)

Buchu powdered extract (extract of buchu)

Calcium lactate

Calcium pantothenate

Capsicum oleoresin

Cascara fluidextract, aromatic (extract of cascara)

Chlorprophenpyridamine maleate

Cimicifuga racemosa

Codeine

Collinsonia (extract stone root)

Corn silk

Couch grass

Dog grass extract

Ethyl nitrite

Ferric chloride

Ferrous sulfate

Gentiana lutea (gentian)

Glycyrrhiza (licorice)

Homatropine methylbromide

Hydrangea, powdered extract (extract of hydrangea)

Hydrastis canadensis (golden seal)

Hyoscyamine sulfate

Juniper oil (oil of juniper)

Magnesium sulfate

Methapyrilene hydrochloride

Methenamine

Methylene blue

Natural estrogenic hormone

Niacinamide

Nutmeg oil (oil of nutmeg)

Oil of erigeron

Parsley

Peppermint spirit

Pepsin, essence

Phenacetin

Phenindamine tartrate

Phenyl salicylate

Piscidia erythrina

Pipsissewa

Potassium acetate

Potassium nitrate

Riboflavin

Saw palmetto

Senecio aureus

Sodium benzoate

Sodium nitrate

Sucrose

Sulferated oils of turpentine

Taraxacum officinale

Theobromine sodium salicylate

Theophylline

Thiamine hydrochloride

Triticum

Turpentine, venice (venice turpertine)

Urea

(ii) Approved as of February 22, 1999.

Any atropine ingredient

Any ephedrine ingredient

(25) Pediculicide drug products--(i) Approved as of November 10,

1993.

Benzocaine

Benzyl alcohol

Benzyl benzoate

Chlorophenothane (dichlorodiphenyl trichloroethane)

Coconut oil soap, aqueous

Copper oleate

Docusate sodium

Formic acid

[[Page 55]]

Isobornyl thiocyanoacetate

Picrotoxin

Propylene glycol

Sabadilla alkaloids

Sulfur, sublimed

Thiocyanoacetate

(ii) Approved as of June 14, 1994. The combination of pyrethrum

extract (formerly named pyrethrins) and piperonyl butoxide in an aerosol

dosage formulation.

(26) Anorectal druq products--(i) Anticholinergic drug products.

Atropine

Belladonna extract

(ii) Antiseptic drug products.

Boric acid

Boroglycerin

Hydrastis

Phenol

Resorcinol

Sodium salicylic acid phenolate

(iii) Astringent drug products.

Tannic acid

(iv) Counterirritant drug products.

Camphor (greater than 3 to 11 percent)

Hydrastis

Menthol (1.25 to 16 percent)

Turpentine oil (rectified) (6 to 50 percent)

(v) Keratolytic drug products.

Precipitated sulfur

Sublimed sulfur

(vi) Local anesthetic drug products.

Diperodon

Phenacaine hydrochloride

(vii) Other druq products.

Collinsonia extract

Escherichia coli vaccines

Lappa extract

Leptandra extract

Live yeast cell derivative

Mullein

(viii) Protectant druq products.

Bismuth oxide

Bismuth subcarbonate

Bismuth subgallate

Bismuth subnitrate

Lanolin alcohols

(ix) Vasoconstrictor druq products.

Epinephrine undecylenate

(x) Wound healinq druq products.

Cholecalciferol

Cod liver oil

Live yeast cell derivative

Peruvian balsam

Shark liver oil

Vitamin A

(27) Topical antimicrobial drug products--(i) First aid antiseptic

drug products.

Ammoniated mercury

Calomel (mercurous chloride)

Merbromin (mercurochrome)

Mercufenol chloride (ortho-chloromercuriphenol, ortho-

hydroxyphenylmercuric chloride)

Mercuric chloride (bichloride of mercury, mercury chloride)

Mercuric oxide, yellow

Mercuric salicylate

Mercuric sulfide, red

Mercury

Mercury oleate

Mercury sulfide

Nitromersol

Para-chloromercuriphenol

Phenylmercuric nitrate

Thimerosal

Vitromersol

Zyloxin

(ii) Diaper rash drug products.

Para-chloromercuriphenol

Any other ingredient containing mercury

(28) Vaginal contraceptive drug products.

Dodecaethylene glycol monolaurate (polyethylene glycol 600 monolaurate)

Laureth 10S

Methoxypolyoxyethyleneglycol 550 laurate

Phenylmercuric acetate

Phenylmercuric nitrate

Any other ingredient containing mercury

(29) Sunscreen drug products.

Diethanolamine methoxycinnamate

Digalloyl trioleate

Ethyl 4-[bis(hydroxypropyl)] aminobenzoate

Glyceryl aminobenzoate

Lawsone with dihydroxyacetone

Red petrolatum

(b) Any OTC drug product that is labeled, represented, or promoted for the uses specified and containing any active ingredient(s) as specified in paragraph (a) of this section is regarded as a new drug within the meaning of section 210(p) of the Federal Food, Drug, and Cosmetic Act (the Act), for which an approved new drug application under section 505 of the Act and part 314 of this chapter is required for marketing. In the absence of an approved

[[Page 56]]

new drug application, such product is also misbranded under section 502 of the Act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for the OTC uses and containing any active ingredient(s) as specified in paragraph (a) of this section is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) Any OTC drug product that is not in compliance with this section is subject to regulatory action if initially introduced or initially delivered for introduction into interstate commerce after the dates specified in paragraphs (d)(1) through (d)(31) of this section.

(1) May 7, 1991, for products subject to paragraphs (a)(1) through (a)(2)(i), (a)(3) through (a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except as covered by paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv)(A), (a)(14) through (a)(15)(i), and (a)(16) through (a)(18) of this section.

(3) December 4, 1992, for products subject to paragraph (a)(7) of this section that contain menthol as an antipruritic in combination with the antidandruff ingredient coal tar identified in Sec. 358.710(a)(1) of this chapter.

(4) February 28, 1990, for products subject to paragraph (a)(6)(iii) of this section, except those that contain ipecac.

(5) September 14, 1993, for products subject to paragraph (a)(6)(iii) of this section that contain ipecac.

(6) December 9, 1993, for products subject to paragraph (a)(6)(i)(B) of this section.

(7) March 6, 1989, for products subject to paragraph (a)(21) of this section, except those that contain ophthalmic anti-infective ingredients listed in paragraph (a)(21)(ii).

(8) June 18, 1993, for products subject to paragraph (a)(21) of this section that contain ophthalmic anti-infective ingredients.

(9) June 18, 1993, for products subject to paragraph (a)(10)(iv) of this section.

(10) June 18, 1993, for products subject to paragraph (a)(22)(i) of this section.

(11) November 10, 1993, for products subject to paragraphs (a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except products that contain ferric subsulfate) through (a)(18)(vi), (a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) of this section.

(12) March 2, 1994, for products subject to paragraph (a)(22)(iii) of this section.

(13) August 5, 1991, for products subject to paragraphs (a)(26) of this section, except for those that contain live yeast cell derivative.

(14) September 2, 1994, for products subject to paragraph (a)(26)(vii) and (a)(26)(x) of this section that contain live yeast cell derivative.

(15) September 23, 1994, for products subject to paragraph (a)(22)(iv) of this section.

(16) June 14, 1994, for products subject to paragraph (a)(25)(ii) of this section.

(17) [Reserved]

(18) August 15, 1995, for products subject to paragraph (a)(15)(ii) of this section.

(19) October 2, 1987, for products subject to paragraph (a)(6)(iv)(A) of this section.

(20) January 29, 1996, for products subject to paragraph (a)(6)(iv)(B) of this section.

(21) April 21, 1994, for products subject to paragraph (a)(8)(iii) of this section.

(22) April 21, 1993, for products subject to paragraph (a)(18)(ii) of this section that contain ferric subsulfate.

(23) August 23, 1995, for products subject to paragraph (a)(6)(ii)(B) of this section.

(24) October 7, 1996, for products subject to paragraph (a)(2)(ii) of this section.

(25) June 19, 1996, for products subject to paragraph (a)(6)(iv)(C) of this section.

(26) February 22, 1999, for products subject to paragraphs (a)(23)(ii) and (a)(24)(ii) of this section.

(27) [Reserved]

(28) October 22, 1998, for products subject to paragraphs (a)(27) and (a)(28) of this section.

(29) January 29, 1999, for products subject to paragraph (a)(12)(iv)(B) of this section.

(30) [Reserved]

[[Page 57]]

(31) May 21, 2001 for products subject to paragraph (a)(29) of this section.-

[55 FR 46919, Nov. 7, 1990]

Editorial Note: For Federal Register citations affecting Sec. 310.545, see the List of CFR Sections Affected in the Finding Aids section of this volume.

Effective Date Notes: 1. At 60 FR 42436, Aug. 16, 1995, in Sec. 310.545, paragraph (a)(15)(ii) was stayed for topical otic drug products for the drying of water-clogged ears. 2. At 61 FR 9571, Mar. 8, 1996, in Sec. 310.545 in paragraph (a)(6)(ii)(B), the entry for ``l-desoxyephedrine (topical)'' was stayed until further notice. 3. At 64 FR 27687, May 21, 1999, in Sec. 310.545 paragraph (a)(29) was added, (d) introductory text was revised, paragraph (d)(30) was added and reserved, and paragraph (d)(31) was added, effective May 21, 2001. For the convenience of the user, the revised text is set forth as follows:

Sec. 310.545 Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses.

(a) * * *

* * * * *

(d) Any OTC drug product that is not in compliance with this section is subject to regulatory action if initially introduced or initially delivered for introduction into interstate commerce after the dates specified in paragraphs (d)(1) through (d)(29) of this section.

* * * * *

Sec. 310.546 Drug products containing active ingredients offered over- the-counter (OTC) for the treatment and/or prevention of nocturnal leg muscle cramps.

(a) Quinine sulfate alone or in combination with vitamin E has been present in over-the-counter (OTC) drug products for the treatment and/or prevention of nocturnal leg muscle cramps, i.e., a condition of localized pain in the lower extremities usually occurring in middle life and beyond with no regular pattern concerning time or severity. There is a lack of adequate data to establish general recognition of the safety and effectiveness of quinine sulfate, vitamin E, or any other ingredients for OTC use in the treatment and/or prevention of nocturnal leg muscle cramps. In the doses used to treat or prevent this condition, quinine sulfate has caused adverse events such as transient visual and auditory disturbances, dizziness, fever, nausea, vomiting, and diarrhea. Quinine sulfate may cause unpredictable serious and life-threatening hypersensitivity reactions requiring medical intervention and hospitalization; fatalities have been reported. The risk associated with use of quinine sulfate, in the absence of evidence of its effectiveness, outweighs any potential benefit in treating and/or preventing this benign, self-limiting condition. Based upon the adverse benefit-to-risk ratio, any drug product containing quinine or quinine sulfate cannot be considered generally recognized as safe for the treatment and/or prevention of nocturnal leg muscle cramps.

(b) Any OTC drug product that is labeled, represented, or promoted for the treatment and/or prevention of nocturnal leg muscle cramps is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for the treatment and/or prevention of nocturnal leg muscle cramps is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After February 22, 1995, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[59 FR 43252, Aug. 22, 1994]

Sec. 310.547 Drug products containing quinine offered over-the-counter (OTC) for the treatment and/or prevention of malaria.

(a) Quinine and quinine salts have been used OTC for the treatment and/or

[[Page 58]]

prevention of malaria, a serious and potentially life-threatening disease. Quinine is no longer the drug of choice for the treatment and/or prevention of most types of malaria. In addition, there are serious and complicating aspects of the disease itself and some potentially serious and life-threatening risks associated with the use of quinine at doses employed for the treatment of malaria. There is a lack of adequate data to establish general recognition of the safety of quinine drug products for OTC use in the treatment and/or prevention of malaria. Therefore, quinine or quinine salts cannot be safely and effectively used for the treatment and/or prevention of malaria except under the care and supervision of a doctor.

(b) Any OTC drug product containing quinine or quinine salts that is labeled, represented, or promoted for the treatment and/or prevention of malaria is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for the treatment and/or prevention of malaria is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After April 20, 1998, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[63 FR 13528, Mar. 20, 1998]

Sec. 310.548 Drug products containing colloidal silver ingredients or silver salts offered over-the-counter (OTC) for the treatment and/or prevention of disease.

(a) Colloidal silver ingredients and silver salts have been marketed in over-the-counter (OTC) drug products for the treatment and prevention of numerous disease conditions. There are serious and complicating aspects to many of the diseases these silver ingredients purport to treat or prevent. Further, there is a lack of adequate data to establish general recognition of the safety and effectiveness of colloidal silver ingredients or silver salts for OTC use in the treatment or prevention of any disease. These ingredients and salts include, but are not limited to, silver proteins, mild silver protein, strong silver protein, silver, silver ion, silver chloride, silver cyanide, silver iodide, silver oxide, and silver phosphate.

(b) Any OTC drug product containing colloidal silver ingredients or silver salts that is labeled, represented, or promoted for the treatment and/or prevention of any disease is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product containing colloidal silver or silver salts labeled, represented, or promoted for any OTC drug use is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs as set forth in part 312 of this chapter.

(d) After September 16, 1999, any such OTC drug product containing colloidal silver or silver salts initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

[64 FR 44658, Aug. 17, 1999]