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

(1) A statement that additives may be incompatible.

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

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

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

[62 FR 12084, Mar. 14, 1997]

§ 310.515 Patient package inserts for estrogens.

(a) Requirement for a patient package insert. 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 Metabolism and Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

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

[55 FR 18723, May 4, 1990]

prod

§ 310.516 Progestational drug ucts; labeling directed to the patient.

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

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

(1) Name of the drug.

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

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

(4) A brief discussion of the nature of the risks of birth defects resulting from the use of these drugs during the first 4 months of pregnancy.

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

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

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

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

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

(3) Type used shall conform to the minimum letter height. The body copy shall contain 1-point leading, noncondensed type, and shall not contain any light-face type or small capital letters. (d) This section does not apply to a progestogen-containing product intended for contraception, which shall be labeled according to the requirements of §310.501.

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

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

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

whom childbearing is impossible, receiving the drug.

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

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

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

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

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

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

(a) The University Group Diabetes Program clinical trial has reported an association between the administration of tolbutamide and increased cardio

vascular 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): 747830, 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 21⁄2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of (name of drug) and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply

to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

[49 FR 14331, Apr. 11, 1984]

§310.518 Drug products containing iron or iron salts.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(a) Antihistamines, bromides, and scopolamine compounds, either singly or in combinations, have been marketed as ingredients in over-thecounter (OTC) drug products for use as daytime The sedatives. following claims have been made for daytime sedative products: “occasional simple nervous tension," "nervous irritability," "nervous tension headache, "simple nervousness due to common every day overwork and fatigue," "a relaxed feeling," "calming down and relaxing," "gently soothe away the tension," "calmative," "resolving that irritability that ruins your day," "helps you relax," "restlessness,' "when you're under occasional stress

helps you work relaxed." Based on

evidence presently available, there are no ingredients that can be generally recognized as safe and effective for use as OTC daytime sedatives.

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

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

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

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

§310.527 Drug products containing ac

tive ingredients offered over-thecounter (OTC) for external use as hair growers or for hair loss prevention.

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

for external use are either false, misleading, or unsupported by scientific data. Therefore, any OTC drug product for external use containing an ingredient offered for use as a hair grower or for hair loss prevention cannot be considered generally recognized as safe and effective for its intended use.

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

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

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

[54 FR 28777, July 7, 1989]

§310.528 Drug products containing ac

tive ingredients offered over-thecounter (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