Subpart E · 21 CFR Part 310

Contents

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.
310.517 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.

Subpart E · Subpart E—Requirements for Specific New Drugs or Devices

310.501Patient 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 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 § 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 Reproductive and Urologic Products, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.

(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 § 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.

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

(a)The drugs listed in this paragraph (a) have been determined by rulemaking procedures to be new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. An approved new drug application under section 505 of the Federal Food, Drug, and Cosmetic Act and part 314 of this chapter is required for marketing the following drugs:

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

(2)Aerosol drug products containing zirconium.

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

(4)Camphorated oil drug products.

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

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

(7)Cobalt preparations intended for use by man.

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

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

(10)Parenteral drug products in plastic containers.

(11)[Reserved]

(12)Sweet spirits of nitre drug products.

(13)Thorium dioxide for drug use.

(14)Timed release dosage forms.

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

(b)[Reserved]

310.503Requirements 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 albumin Gastrointestinal protein loss studies. Do ......do Placenta localization. Do Labeled red blood cells Do. Cobalt 58 or Cobalt 60 Labeled cyanocobalamin Intestinal absorption studies. Gold 198 Colloidal Liver scans. Do ......do Intracavitary treatment of pleural effusions and/or ascites. Do ......do Interstitial treatment of cancer. Iodine 131 Iodide Diagnosis of thyroid functions. Do ......do Thyroid scans. Do ......do Treatment of hyperthyroidism and/or cardiac dysfunction. Do ......do Treatment of thyroid carcinoma. Do Iodinated human serum albumin Blood volume determinations. Do ......do Cisternography. Do ......do Brain tumor localization. Do ......do Placenta localization. Do ......do Cardiac scans for determination of pericardial effusions. Do Rose Bengal Liver function studies. Do ......do Liver scans. Do Iodopyracet, sodium iodohippurate, sodium diatrizoate, diatrizoate methylglucamine, sodium diprotrizoate, sodium acetrizoate, or sodium iothalamate Kidney function studies and kidney scans. Do Labeled fats and/or fatty acids Fat absorption studies. Do Cholografin Cardiac scans for determination of pericardial effusions. Do Macroaggregated iodinated human serum albumin Lung scans. Do Colloidal microaggregated human serum albumin Liver scans. Iodine 125 Iodide Diagnosis of thyroid function. Do Iodinated human serum albumin Blood volume determinations. Do Rose Bengal Liver function studies. Do Iodopyracet, sodium iodohippurate, sodium diatrizoate, diatrizoate methyl-glucamine, sodium diprotrizoate, sodium acetrizoate, or sodium iothalamate Kidney function studies. Do Labeled fats and/or fatty acids Fat absorption studies. Iron 59 Chloride, citrate and/or sulfate Iron turnover studies. Krypton 85 Gas Diagnosis of cardiac abnormalities. Mercury 197 Chlormerodrin Kidney scans. Do ......do Brain scans. Mercury 203 1 ......do Kidney scans. Do ......do Brain scans. Phosphorus 32 Soluble phosphate Treatment of polycythemia vera. Do ......do Treatment of leukemia and bone metastasis. Do Colloidal chromic phosphate Intracavitary treatment of pleural effusions and/or ascites. Do ......do Interstitial treatment of cancer. Potassium 42 Chloride Potassium space studies. Selenium 75 Labeled methionine Pancreas scans. Strontium 85 Nitrate or chloride Bone scans on patients with diagnosed cancer. Technetium 99m Pertechnetate Brain scans. Do ......do Thyroid scans. Do Sulfur colloid Liver and spleen scans. Do Pertechnetate Placenta localization. Do ......do Blood pool scans. Do ......do Salivary gland scans. Do Diethylenetri-amine pentaacetic acid (DTPA) Kidney scans. Xenon 133 Gas Diagnosis of cardia abnormalities. Cerebral bloodflow studies. Pulmonary function studies. Muscle bloodflow studies. 1 This item has been removed from the AEC list for kidney scans but is included as the requirements of this order are applicable.

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

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

(3)The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the “chemical form” and intended for the uses stated, for which drug a new drug application or a “Investigational New Drug Application” was submitted prior to March 3, 1972, or for which biologic an application for product license or “Investigational New Drug Application” was submitted prior to March 3, 1972, is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first.

(e)No exemption from section 505 of the act or from part 312 of this chapter is in effect or has been in effect for radioactive drugs prepared from accelerator-produced radioisotopes, naturally occurring isotopes, or nonradioactive substances used in conjunction with isotopes.

(f)(1) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling; such use may include, among others, the uses in this tabulation: Isotope Chemical form Use Fluorine 18 Fluoride Bone imaging. Indium-113m Diethylenetriamine pentaacetic acid (DTPA) Brain imaging; kidney imaging. Do Chloride Placenta imaging; blood pool imaging. Technetium 99m Human serum albumin microspheres Lung imaging. Do Diethylenetriamine pentaacetic acid (Sn) Kidney imaging; kidney function studies. Do ......do Brain imaging. Do Polyphosphates Bone imaging. Do Technetated aggregated albumin (human) Lung imaging. Do Disodium etidronate Bone imaging.

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

(3)Any manufacturer or distributor interested in continuing to ship in interstate commerce drugs containing the isotopes listed in paragraph (f)(1) of this section for any of the indications listed, shall submit, on or before August 25, 1975 to the Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, a new drug application or a “Investigational New Drug Application” for each such drug for which the manufacturer or distributor does not have an approved new drug application pursuant to section 505(b) of the act. If the drug is a biologic, a “Investigational New Drug Application” or an application for a license under section 351 of the Public Health Service Act shall be submitted to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002, in lieu of any submission to the Center for Drug Evaluation and Research.

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

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

(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.

(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.

310.509Parenteral 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).

310.515Patient 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 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 § 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 Reproductive and Urologic Products, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.

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

310.517Labeling 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.

310.518Drug products containing iron or iron salts.#

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

(a)Labeling. (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 or iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.

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

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

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

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

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

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

310.519Drug 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.

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

(a)Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid, biotin and all other B-vitamins, dexpanthenol, estradiol and other topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20, polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat germ oil have been marketed as ingredients in OTC drug products for external use as hair growers or for hair loss prevention. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients intended for OTC external use as a hair grower or for hair loss prevention. Based on evidence currently available, all labeling claims for OTC hair grower and hair loss prevention drug products for external use are either false, misleading, or unsupported by scientific data. Therefore, any OTC drug product for external use containing an ingredient offered for use as a hair grower or for hair loss prevention cannot be considered generally recognized as safe and effective for its intended use.

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

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

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

310.528Drug 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.

310.529Drug 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.

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

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

(b)Any OTC drug product that is labeled, represented, or promoted as a topically applied hormone-containing product for drug use, with the exception of those hormones identified in paragraph (e) of this section, is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

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

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

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

310.531Drug 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.

310.532Drug 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.

310.533Drug 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 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.

310.534Drug 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.

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

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

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

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

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

310.537Drug 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.

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

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

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

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

(e)This section does not apply to sodium sulfide labeled, represented, or promoted for OTC topical use for ingrown toenail relief in accordance with part 358, subpart D of this chapter, after June 6, 2003.

310.540Drug 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.

310.541Over-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.

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

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

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

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

310.543Drug 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.

310.544Drug 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.

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

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

(1)Topical acne drug products. Alcloxa Alkyl isoquinolinium bromide Aluminum chlorohydrex Aluminum hydroxide Benzocaine Benzoic acid Boric acid Calcium polysulfide Calcium thiosulfate Camphor Chloroxylenol Cloxyquin Coal tar Dibenzothiophene Estrone Magnesium aluminum silicate Magnesium sulfate Phenol Phenolate sodium Phenyl salicylate Povidone-iodine Pyrilamine maleate Resorcinol (as single ingredient) Resorcinol monoacetate (as single ingredient) Salicylic acid (over 2 up to 5 percent) Sodium borate Sodium thiosulfate Tetracaine hydrochloride Thymol Vitamin E Zinc oxide Zinc stearate Zinc sulfide

(2)Anticaries drug products—(i) Approved as of May 7, 1991. Hydrogen fluoride Sodium carbonate Sodium monofluorophosphate (6 percent rinse) Sodium phosphate

(b)Any OTC drug product that is labeled, represented, or promoted for the uses specified and containing any active ingredient(s) as specified in paragraph (a) of this section is regarded as a new drug within the meaning of section 210(p) of the Federal Food, Drug, and Cosmetic Act (the Act), for which an approved new drug application under section 505 of the Act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the Act.

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

(d)Any OTC drug product that is not in compliance with this section is subject to regulatory action if initially introduced or initially delivered for introduction into interstate commerce after the dates specified in paragraphs (d)(1) through (d)(42) of this section.

(1)May 7, 1991, for products subject to paragraphs (a)(1) through (a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except as covered by paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (a)(12)(i)(A), (a)(12)(ii) through (a)(12)(iv)(A), (a)(14) through (a)(15)(i), (a)(16) through (a)(18)(i)(A), (a)(18)(ii) (except as covered by paragraph (d)(22) of this section), (a)(18)(iii), (a)(18)(iv), (a)(18)(v)(A), and (a)(18)(vi)(A) of this section.

(2)February 10, 1992, for products subject to paragraph (a)(20) of this section.

(3)December 4, 1992, for products subject to paragraph (a)(7) of this section that contain menthol as an antipruritic in combination with the antidandruff ingredient coal tar identified in § 358.710(a)(1) of this chapter. This section does not apply to products allowed by § 358.720(b) of this chapter after April 5, 2007.

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

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

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

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

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

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

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

(11)November 10, 1993, for products subject to paragraphs (a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except products that contain ferric subsulfate as covered by paragraph (d)(22) of this section and except products that contain calcium acetate monohydrate as covered by paragraph (d)(39) of this section) through (a)(18)(v)(A), (a)(18)(vi)(A), (a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) of this section.

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

(13)August 5, 1991, for products subject to paragraph (a)(26) of this section, except for those that contain live yeast cell derivative and a combination of hydrocortisone and pramoxine hydrochloride.

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

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

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

(17)April 19, 2004, for products subject to paragraph (a)(3)(ii) of this section. April 18, 2005, for products with annual sales less than $25,000.

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

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

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

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

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

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

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

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

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

(27)[Reserved]

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

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

(30)November 5, 2002, for products subject to paragraph (a)(12)(iv)(C) of this section.

(31)December 31, 2002, for products subject to paragraph (a)(29)(i) of this section.

(32)June 4, 2004, for products subject to paragraphs (a)(18)(i)(B), (a)(18)(v)(B), and (a)(18)(vi)(B) of this section. June 6, 2005, for products with annual sales less than $25,000.

(33)October 29, 2001, for products subject to paragraph (a)(6)(iv)(D) of this section.

(34)December 9, 2004, for products subject to paragraph (a)(4)(ii) of this section. June 9, 2005, for products with annual sales less than $25,000.

(35)[Reserved]

(36)November 5, 2002, for products subject to paragraph (a)(28)(ii) of this section.

(37)September 25, 2003, for products subject to paragraph (a)(26)(xi) of this section.

(38)October 1, 2007, for products subject to paragraph (a)(12)(i)(B) of this section.

(39)September 6, 2010, for products subject to paragraph (a)(18)(ii) of this section that contain calcium acetate monohydrate, except as provided in § 347.20(b) of this chapter.

(40)December 17, 2012, for products subject to paragraph (a)(29)(ii) of this section. December 17, 2013, for products with annual sales less than $25,000.

(41)September 6, 2017, for products subject to paragraph (a)(27)(iii) or (iv) of this section.

(42)December 20, 2018, for products subject to paragraphs (a)(27)(vi) through (x) of this section. Editorial Note:For Federal Register citations affecting § 310.545, see the List of CFR Sections Affected, which appears in the Finding Aids section of the printed volume and at www.govinfo.gov. Effective Date Note:At 61 FR 9571, Mar. 8, 1996, in § 310.545 in paragraph (a)(6)(ii)(B), the entry for “l-desoxyephedrine (topical)” was stayed until further notice.

(ii)Approved as of November 10, 1993. Alcohol Aluminum hydroxide Amylase Anise seed Aromatic powder Asafetida Aspergillus oryza enzymes (except lactase enzyme derived from Aspergillus oryzae) Bacillus acidophilus Bean Belladonna alkaloids Belladonna leaves, powdered extract Betaine hydrochloride Bismuth subcarbonate Bismuth subgallate Black radish powder Blessed thistle (cnicus benedictus) Buckthorn Calcium gluconate Capsicum Capsicum, fluid extract of Carbon Cascara sagrada extract Catechu, tincture Catnip Chamomile flowers Charcoal, wood Chloroform Cinnamon oil Cinnamon tincture Citrus pectin Diastase Diastase malt Dog grass Elecampane Ether Fennel acid Galega Ginger Glycine Hydrastis canadensis (golden seal) Hectorite Horsetail Huckleberry Hydrastis fluid extract Hydrochloric acid Iodine Iron ox bile Johnswort Juniper Kaolin, colloidal Knotgrass Lactic acid Lactose Lavender compound, tincture of Linden Lipase Lysine hydrochloride Mannitol Mycozyme Myrrh, fluid extract of Nettle Nickel-pectin Nux vomica extract Orthophosphoric acid Papaya, natural Pectin Peppermint Peppermint spirit Phenacetin Potassium bicarbonate Potassium carbonate Protease Prolase Rhubarb fluid extract Senna Sodium chloride Sodium salicylate Stem bromelain Strawberry Strychnine Tannic acid Trillium Woodruff

(3)Antidiarrheal drug products—(i) Approved as of May 7, 1991. Aluminum hydroxide Atropine sulfate Calcium carbonate Carboxymethylcellulose sodium Glycine Homatropine methylbromide Hyoscyamine sulfate Lactobacillus acidophilus Lactobacillus bulgaricus Opium, powdered Opium tincture Paregoric Phenyl salicylate Scopolamine hydrobromide Zinc phenolsulfonate

(4)Antiperspirant drug products—(i) Ingredients—Approved as of May 7, 1991. Alum, potassium Aluminum bromohydrate Aluminum chloride (alcoholic solutions) Aluminum chloride (aqueous solution) (aerosol only) Aluminum sulfate Aluminum sulfate, buffered (aerosol only) Sodium aluminum chlorohydroxy lactate

(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

(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.

(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 Pseudoephedrine sulfate Theophylline, anhydrous Theophylline calcium salicylate Theophylline sodium glycinate

(D)Approved as of October 29, 2001. Any oral bronchodilator active ingredient (e.g., ephedrine, ephedrine hydrochloride, ephedrine sulfate, racephedrine hydrochloride, or any other ephedrine salt) in combination with any analgesic(s) or analgesic-antipyretic(s), anticholinergic, antihistamine, oral antitussive, or stimulant active ingredient.

(7)Dandruff/seborrheic dermatitis/psoriasis drug products. Alkyl isoquinolinium bromide Allantoin Benzalkonium chloride Benzethonium chloride Boric acid Calcium undecylenate Captan Chloroxylenol Colloidal oatmeal Cresol, saponated Ethohexadiol Eucalyptol Juniper tar Lauryl isoquinolinium bromide Menthol Mercury oleate Methylbenzethonium chloride Methyl salicylate Phenol Phenolate sodium Pine tar Povidone-iodine Resorcinol Sodium borate Sodium salicylate Thymol Undecylenic acid

(8)Digestive aid drug products—(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

(i)(B) Bulk laxatives—Approved as of March 29, 2007. Granular dosage forms containing psyllium (hemicellulose), psyllium hydrophilic mucilloid, psyllium seed, psyllium seed (blond), psyllium seed husks, plantago husks, or plantago seed including, but not limited to, any granules that are: (1) Swallowed dry prior to drinking liquid, (2) Dispersed, suspended, or partially dissolved in liquid prior to swallowing, (3) Chewed, partially chewed, or unchewed, and then washed down (or swallowed) with liquid, or (4) Sprinkled over food.

(ii)Any ingredients labeled with any of the following or similar claims. Instant protection or protection immediately upon application. Claims for “all-day” protection or extended wear claims citing a specific number of hours of protection that is inconsistent with the directions for application in 21 CFR 201.327.

(16)Poison treatment drug products. Ipecac fluidextract Ipecac tincture Zinc sulfate

(17)Skin bleaching drug products. Mercury, ammoniated

(18)Skin protectant drug products—(i)(A) Ingredients—Approved as of May 7, 1991. Allantoin (wound healing claims only) Sulfur Tannic acid Zinc acetate (wound healing claims only)

(B)Ingredients—Approved as of June 4, 2004; June 6, 2005, for products with annual sales less than $25,000. Beeswax Bismuth subnitrate Boric acid Cetyl alcohol Glyceryl stearate Isopropyl palmitate Live yeast cell derivative Shark liver oil Stearyl alcohol

(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

(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 Isobornyl thiocyanoacetate Picrotoxin Propylene glycol Sabadilla alkaloids Sulfur, sublimed Thiocyanoacetate

(26)Anorectal drug products—(i) Anticholinergic drug products. Atropine Belladonna extract

(29)Sunscreen drug products. (i) Ingredients. Diethanolamine methoxycinnamate Digalloyl trioleate Ethyl 4-[bis(hydroxypropyl)] aminobenzoate Glyceryl aminobenzoate Lawsone with dihydroxyacetone Red petrolatum

(30)[Reserved]

(iii)Consumer antiseptic hand wash drug products. Approved as of September 6, 2017. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate) Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol (greater than 1.5 percent) Phenol (less than 1.5 percent) Poloxamer iodine complex Povidone-iodine (5 to 10 percent) Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Triple Dye Undecoylium chloride iodine complex

(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

(iv)Consumer antiseptic body wash drug products. Approved as of September 6, 2017. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Iodine tincture Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol (greater than 1.5 percent) Phenol (less than 1.5 percent) Poloxamer iodine complex Povidone-iodine (5 to 10 percent) Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Triple Dye Undecoylium chloride iodine complex

(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

(C)Stimulant laxatives—Approved as of November 5, 2002. Aloe ingredients (aloe, aloe extract, aloe flower extract) Cascara sagrada ingredients (casanthranol, cascara fluidextract aromatic, cascara sagrada bark, cascara sagrada extract, cascara sagrada fluidextract).

(13)[Reserved]

(14)Oral health care drug products (nonantimicrobial). Antipyrine Camphor Cresol Dibucaine Dibucaine hydrochloride Eucalyptol Lidocaine Lidocaine hydrochloride Methly salicylate Myrrh tincture Pyrilamine maleate Sorbitol Sugars Tetracaine Tetracaine hydrochloride Thymol

(15)Topical otic drug products—(i) For the prevention of swimmer's ear and for the drying of water-clogged ears, approved as of May 7, 1991. Acetic acid

(ix)[Reserved]

(v)[Reserved]

(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.

(vi)Health care personnel hand wash drug products. Approved as of December 20, 2018. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate) Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol Poloxamer-iodine complex Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Undecoylium chloride iodine complex

(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 B12) Cystine Dextrose Docusate sodium Ergocalciferol Ferric ammonium citrate Ferric pyrophosphate Ferrous fumarate Ferrous gluconate Ferrous sulfate (iron) Flax seed Folic acid Fructose Guar gum Histidine Hydrastis canadensis Inositol Iodine Isoleucine Juniper, potassium extract Karaya gum Kelp Lactose Lecithin Leucine Liver concentrate Lysine Lysine hydrochloride Magnesium Magnesium oxide Malt Maltodextrin Manganese citrate Mannitol Methionine Methylcellulose Mono- and di-glycerides Niacinamide Organic vegetables Pancreatin Pantothenic acid Papain Papaya enzymes Pepsin Phenacetin Phenylalanine Phosphorus Phytolacca Pineapple enzymes Plantago seed Potassium citrate Pyridoxine hydrochloride (vitamin B6) Riboflavin Rice polishings Saccharin Sea minerals Sesame seed Sodium Sodium bicarbonate Sodium caseinate Sodium chloride (salt) Soybean protein Soy meal Sucrose Thiamine hydrochloride (vitamin B1) Thiamine mononitrate (vitamin B1 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

(vii)[Reserved]

(11)[Reserved]

(12)Laxative drug products—(i)(A) Bulk laxatives. Agar Carrageenan (degraded) Carrageenan (native) Guar gun

(viii)Surgical hand scrub drug products. Approved as of December 20, 2018. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate) Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol Poloxamer-iodine complex Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Undecoylium chloride iodine complex

(x)Patient antiseptic skin preparation drug products. Approved as of December 20, 2018. Cloflucarban Fluorosalan Hexachlorophene Hexylresorcinol Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) Iodine tincture (USP) Iodine topical solution (USP) Mercufenol chloride Methylbenzethonium chloride Nonylphenoxypoly (ethyleneoxy) ethanoliodine Phenol Poloxamer-iodine complex Secondary amyltricresols Sodium oxychlorosene Tribromsalan Triclocarban Triclosan Triple dye Undecoylium chloride iodine complex Combination of calomel, oxyquinoline benzoate, triethanolamine, and phenol derivative Combination of mercufenol chloride and secondary amyltricresols in 50 percent alcohol

(28)Vaginal contraceptive drug products—(i) Approved as of October 22, 1998. Dodecaethylene glycol monolaurate (polyethylene glycol 600 monolaurate) Laureth 10S Methoxypolyoxyethyleneglycol 550 laurate Phenylmercuric acetate Phenylmercuric nitrate Any other ingredient containing mercury

(xi)Combination drug products. Any combination drug product containing hydrocortisone and pramoxine hydrochloride.

(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

310.546Drug 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.

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

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

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

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

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

310.548Drug 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.

United States Government work; public domain under 17 U.S.C. § 105.

Subpart E · Subpart E&#x2014;Requirements for Specific New Drugs or Devices

310.501Patient package inserts for oral contraceptives.#

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

310.503Requirements regarding certain radioactive drugs.#

310.509Parenteral drug products in plastic containers.#

310.515Patient package inserts for estrogens.#

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

310.518Drug products containing iron or iron salts.#

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Defined terms · 2

Key facts

History · 3 versions

Subpart E · Subpart E&#x2014;Requirements for Specific New Drugs or Devices

310.501Patient package inserts for oral contraceptives.#

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

310.503Requirements regarding certain radioactive drugs.#

310.509Parenteral drug products in plastic containers.#

310.515Patient package inserts for estrogens.#

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

310.518Drug products containing iron or iron salts.#

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Subpart E · Subpart E—Requirements for Specific New Drugs or Devices

Subpart E · Subpart E—Requirements for Specific New Drugs or Devices