21 C.F.R. Subpart G—Specific Labeling Requirements for Specific Drug Products
Title 21 - Food and Drugs
(a) Under date of December 4, 1941, in a notice to manufacturers of glandular preparations, the Food and Drug Administration expressed the opinion that preparations of inert glandular materials intended for medicinal use should, in view of the requirement of section 201(n) of the Federal Food, Drug, and Cosmetic Act (52 Stat. 1041; 21 U.S.C. 321(n)), be labeled with a statement of the material fact that there is no scientific evidence that the articles contain any therapeutic or physiologically active constituents. Numerous preparations of such inert glandular materials were subsequently marketed with disclaimers of the type suggested. The term inert glandular materials means preparations incapable of exerting an action or effect of some significant or measurable benefit in one way or another, i.e., in the diagnosis, cure, mitigation, treatment, or prevention of disease, or in affecting the structure or any function of the body. (b) Manufacturers have heretofore taken advantage of §201.100 permitting omission of directions for use when the label bears the prescription legend. Section 201.100(c) requires that the labeling of the drug, which may include brochures readily available to licensed practitioners, bear information as to the use of the drug by practitioners licensed by law to administer it. Obviously, information adequate for the use of an inert glandular preparation is not available to practitioners licensed by law. (c) The Department of Health and Human Services is of the opinion that inert glandular materials may not be exempted from the requirements of section 502(f)(1) of the act that they bear adequate directions for use; and, accordingly, that their labeling must include among other things, representations as to the conditions for which such articles are intended to be used or as to the structure or function of the human body that they are intended to affect. Since any such representations offering these articles for use as drugs would be false or misleading, such articles will be considered to be misbranded if they are distributed for use as drugs. (d) The amended regulations provide also that in the case of drugs intended for parenteral administration there shall be no exemption from the requirement that their labelings bear adequate directions for use. Such inert glandular materials for parenteral use are therefore subject to the same comment as applies to those intended for oral administration. Some drug preparations fabricated wholly or in part from estradiol and labeled as to potency in terms of international units or in terms of international units of estrone activity have been marketed. The international unit of the estrus-producing hormone was established by the International Conference on the Standardization of Sex Hormones at London, England, on August 1, 1932. This unit was defined as “the specific estrus-producing activity contained in 0.1 gamma (=0.0001 mg.) of the standard” hydroxyketonic hormone found in urine (estrone). The International Conference declared that it did not recommend the determination of the activity of nonhydroxyketonic forms of estrogenic hormones in units of estrone because of the varying ratios between the activity of such nonhydroxyketonic estrogenic hormones and estrone, when measured by different methods on test animals. There is no international unit for measuring the activity of estradiol and no accepted relationship between its activity and that of estrone, either in test animals or in humans. The declaration of potency of estradiol in terms of international units or in terms of international units of estrone activity is therefore considered misleading, within the meaning of 21 U.S.C. 352(a). The declaration of the estradiol content of an estrogenic hormone preparation in terms of weight is considered appropriate. (a) In the past few years research studies have altered medical opinion as to the usefulness and harmfulness of mineral oil in the human body. These studies have indicated that when mineral oil is used orally near mealtime it interferes with absorption from the digestive tract of provitamin A and the fat-soluble vitamins A, D, and K, and consequently interferes with the utilization of calcium and phosphorus, with the result that the user is left liable to deficiency diseases. When so used in pregnancy it predisposes to hemorrhagic disease of the newborn. (b) There is accumulated evidence that the indiscriminate administration of mineral oil to infants may be followed by aspiration of the mineral oil and subsequent “lipoid pneumonia.” (c) In view of these facts, the Department of Health and Human Services will regard as misbranded under the provisions of the Federal Food, Drug, and Cosmetic Act a drug for oral administration consisting in whole or in part of mineral oil, the labeling of which encourages its use in pregnancy or indicates or implies that such drug is for administration to infants. (d) It is also this Department's view that the act requires the labelings of such drugs to bear a warning against consumption other than at bedtime and against administration to infants. The following form of warning is suggested: “Caution: To be taken only at bedtime. Do not use at any other time or administer to infants, except upon the advice of a physician.” (e) This statement of interpretation does not in any way exempt mineral oil or preparations containing mineral oil from complying in all other respects with the requirements of the Federal Food, Drug, and Cosmetic Act. (a) Because methyl salicylate (wintergreen oil) manifests no toxicity in the minute amounts in which it is used as a flavoring, it is mistakenly regarded by the public as harmless even when taken in substantially larger amounts. Actually, it is quite toxic when taken in quantities of a teaspoonful or more. Wintergreen oil and preparations containing it have caused a number of deaths through accidental misuse by both adults and children. Children are particularly attracted by the odor and are likely to swallow these products when left within reach. (b) To safeguard against fatalities from this cause, the Department of Health and Human Services will regard as misbranded under the provisions of the Federal Food, Drug, and Cosmetic Act any drug containing more than 5 percent methyl salicylate (wintergreen oil), the labeling of which fails to warn that use otherwise than as directed therein may be dangerous and that the article should be kept out of reach of children to prevent accidental poisoning. (c) This statement of interpretation in no way exempts methyl salicylate (wintergreen oil) or its preparations from complying in all other respects with the requirements of the Federal Food, Drug, and Cosmetic Act. (a) It has become a widespread practice for tannic acid to be added to barium enemas to improve X-ray pictures. Tannic acid is capable of causing diminished liver function and severe liver necrosis when absorbed in sufficient amounts. The medical literature reports a number of deaths associated with the addition of tannic acid to barium enemas. There is a lack of scientific evidence to establish the conditions, if any, under which tannic acid is safe and effective for use in enemas. Tannic acid for rectal use to enhance X-ray visualization is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. (b) In view of the hazards involved when tannic acid is used in barium enemas, any shipments of tannic acid labeled to come within the exemptions under 502(f) of the Act containing such phrases as: “Caution: For manufacturing, processing, or repackaging,” “For prescription compounding,” or “Diagnostic reagent—For professional use only” will be regarded by the Commissioner of Food and Drugs as misbranded within the meaning of section 502(f) of the Federal Food, Drug, and Cosmetic Act unless the label and the labeling bear conspicuously a warning to the effect: “Warning— Not for use in enemas.” (c) Any tannic acid intended for use by man and found within the jurisdiction of the Federal Food, Drug, and Cosmetic Act labeled contrary to this section after 60 days from the date of its publication in the (a) Accumulating reports have been received by the Food and Drug Administration and have appeared in the medical literature of severe paradoxical bronchoconstriction associated with repeated, excessive use of isoproterenol inhalation preparations in the treatment of bronchial asthma and other chronic bronchopulmonary disorders. The cause of this paradoxical reaction is unknown; it has been observed, however, that patients have not responded completely to other forms of therapy until use of the isoproterenol inhalation preparation was discontinued. In addition, sudden unexpected deaths have been associated with the excessive use of isoproterenol inhalation preparations. The mechanism of these deaths and their relationship, if any, to the cases of severe paradoxical bronchospasm are not clear. Cardiac arrest was noted in several of these cases of sudden death. (b) On the basis of the above information and after discussion with and concurrence of the Respiratory and Anesthetic Drugs Advisory Committee for Food and Drug Administration, the Commissioner of Food and Drugs concludes that in order for the labeling of such drugs to bear adequate information for their safe use, as required by §201.100, such labeling must include the following:
Warning: Occasional patients have been reported to develop severe paradoxical airway resistance with repeated, excessive use of isoproterenol inhalation preparations. The cause of this refractory state is unknown. It is advisable that in such instances the use of this preparation be discontinued immediately and alternative therapy instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn. Deaths have been reported following excessive use of isoproterenol inhalation preparations and the exact cause is unknown. Cardiac arrest was noted in several instances. (c)(1) The Commissioner also concludes that in view of the manner in which these preparations are self-administered for relief of attacks of bronchial asthma and other chronic bronchopulmonary disorders, it is necessary for the protection of users that warning information to patients be included as a part of the label and as part of any instructions to patients included in the package dispensed to the patient as follows:
Warning: Do not exceed the dose prescribed by your physician. If difficulty in breathing persists, contact your physician immediately. (2) The warning on the label may be accomplished (i) by including it on the immediate container label with a statement directed to pharmacists not to remove the label or (ii) by including in the package a printed warning with instructions to pharmacists to place the warning on the container prior to dispensing. (d) The marketing of isoproterenol inhalation preparations may be continued if all the following conditions are met: (1) Within 30 days following the date of publication of this section in the (i) The label and labeling of such preparations shipped within the jurisdiction of the act are in accordance with paragraphs (b) and (c) of this section. (ii) The holder of an approved new-drug application for such preparation submits a supplement to his new-drug application to provide for appropriate labeling changes as described in paragraphs (b) and (c) of this section. (2) Within 90 days following the date of publication of this section in the (3) The applicant submits additional information required for the approval of the application as may be specified in a written communication from the Food and Drug Administration. (e) After 270 days following expiration of said 90 days, regulatory proceedings based on section 505(a) of the Federal Food, Drug, and Cosmetic Act may be initiated with regard to any such drug shipped within the jurisdiction of the act for which an approved new-drug application is not in effect. [40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990] (a) The Food and Drug Administration will initiate no regulatory action with respect to the continued marketing of coated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet provided all the following conditions are met: (1) Within 30 days from the date of publication of this statement of policy in the (i) The labeling of the drug bears the prescription caution statement quoted in section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act; (ii) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the “full disclosure” labeling requirements of §201.100 of this chapter, including the following warning statement:
Warning—There have been several reports, published and unpublished, concerning nonspecific small-bowel lesions consisting of stenosis, with or without ulceration, associated with the administration of enteric-coated thiazides with potassium salts. These lesions may occur with enteric-coated potassium tablets alone or when they are used with nonenteric-coated thiazides, or certain other oral diuretics. These small-bowel lesions have caused obstruction, hemorrhage, and perforation. Surgery was frequently required and deaths have occurred. Based on a large survey of physicians and hospitals, both United States and foreign, the incidence of these lesions is low, and a causal relationship in man has not been definitely established. Available information tends to implicate enteric-coated potassium salts, although lesions of this type also occur spontaneously. Therefore, coated potassium-containing formulations should be administered only when indicated, and should be discontinued immediately if abdominal pain, distention, nausea, vomiting, or gastrointestinal bleeding occur. Coated potassium tablets should be used only when adequate dietary supplementation is not practicable. (Although the warning statement includes references to enteric-coated potassium salt preparations, it applies to any capsule or coated tablet of a potassium salt intended for oral ingestion without prior dilution with an adequate volume of liquid to preclude gastrointestinal injury.) (iii) Any other labeling or additional advertising for the drug conforms to the labeling described in paragraph (a)(1)(ii) of this section, in accordance with §§202.1 and 201.100 of this chapter. (2) Within 90 days from the date of publication of this statement of policy in the (b) The Food and Drug Administration may initiate regulatory proceedings after 30 days from the date of publication of this section, with respect to the marketing of uncoated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet or with respect to liquid preparations containing potassium chloride or other potassium salts which supply 20 milligrams or more of potassium per milliliter, labeled or intended for human use, unless all the following conditions are met: (1) The labeling of the drug bears the prescription statement quoted in section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act; and (2) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the “full disclosure” labeling requirements of §201.100 of this chapter, including a recommendation that patients be directed to dissolve any such tablets in an appropriate amount of liquid and to dilute any such liquid preparations adequately to assure against gastrointestinal injury associated with the oral ingestion of concentrated potassium salt preparations. [40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990; 67 FR 4906, Feb. 1, 2002] (a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that multiple container sizes of sodium phosphates oral solution available in the marketplace have caused consumer confusion and appear to have been involved in several consumer deaths. Sodium phosphates oral solution has been marketed in 45-milliliter (mL), 90-mL, and 240-mL container sizes. The 45-mL and 90-mL container sizes of sodium phosphates oral solution are often recommended and prescribed by physicians for bowel cleansing prior to surgery and diagnostic procedures of the colon. Sodium phosphates oral solution (adult dose 20 mL to 45 mL) is also used as an over-the-counter (OTC) laxative for the relief of occasional constipation. Accidental overdosing and deaths have occurred because the 240-mL container was mistakenly used instead of the 45-mL or 90-mL container. The Food and Drug Administration is limiting the amount of sodium phosphates oral solution to not more than 90 mL (3 ounces (oz)) per OTC container because of the serious health risks associated with the ingestion of larger than intended doses of this product. Further, because an overdose of either oral or rectal enema sodium phosphates can cause an electrolyte imbalance, additional warning and direction statements are required for the safe use of any OTC laxative drug product containing sodium phosphates. (b) Any OTC drug product for laxative or bowel cleansing use containing sodium phosphates as an active ingredient when marketed as described in paragraph (a) of this section is misbranded within the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless packaged and labeled as follows: (1) Package size limitation for sodium phosphates oral solution: Container shall not contain more than 90 mL (3 oz). (2) Warnings. The following sentences shall appear in boldface type as the first statement under the heading “Warnings.” (i) Oral dosage forms. “Taking more than the recommended dose in 24 hours can be harmful.” (ii) Rectal enema dosage forms. “Using more than one enema in 24 hours can be harmful.” (3) Directions—(i) The labeling of all orally or rectally administered OTC drug products containing sodium phosphates shall contain the following directions in boldface type immediately preceding the dosage information: “Do not” (“take” or “use”) “more unless directed by a doctor. See Warnings.” (ii) For products containing dibasic sodium phosphate/monobasic sodium phosphate identified in §334.16(d) marketed as a solution. Adults and children 12 years of age and over: Oral dosage is dibasic sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium phosphate 9.1 to 20.2 g (20 to 45 mL dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a single daily dose. “Do not take more than 45 mL (9 teaspoonfuls or 3 tablespoonfuls) in a 24-hour period.” Children 10 and 11 years of age: Oral dosage is dibasic sodium phosphate 1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1 g (10 to 20 mL dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a single daily dose. “Do not take more than 20 mL (4 teaspoonfuls) in a 24-hour period.” Children 5 to 9 years of age: Oral dosage is dibasic sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to 5.05 g (5 to 10 mL dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a single daily dose. “Do not take more than 10 mL (2 teaspoonfuls) in a 24-hour period.” Children under 5 years of age: ask a doctor. (c) After June 22, 1998, for package size limitation and September 18, 1998, for labeling in accord with paragraph (b) of this section, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce, or any such drug product that is repackaged or relabeled after these dates regardless of the date the product was manufactured, initially introduced, or initially delivered for introduction into interstate commerce, that is not in compliance with this section is subject to regulatory action. [63 FR 27843, May 21, 1998] (a) It is estimated that each year about 500,000 accidental poisonings occur in the United States and result in approximately 1,500 deaths, of which over 400 are children. In the emergency treatment of these poisonings, ipecac syrup is considered the emetic of choice. The immediate availability of this drug for use in such situations is critical, since rapid treatment may be the difference between life and death. The restriction of this drug to prescription sale limits its availability in emergencies. On the other hand, it is the consensus of informed medical opinion that ipecac syrup should be used only under medical supervision in the emergency treatment of poisonings. In view of these facts, the question of whether ipecac syrup labeled as an emergency treatment for use in poisonings should be available over the counter has been controversial. (b) In connection with its study of this problem, the Food and Drug Administration has obtained the views of medical authorities. It is the unanimous recommendation of the American Academy of Pediatrics, the American Association of Poison Control Centers, the American Medical Association, and the Medical Advisory Board of the Food and Drug Administration that ipecac syrup in 1 fluid ounce containers be permitted to be sold without prescription so that it will be readily available in the household for emergency treatment of poisonings, under medical supervision, and that the drug be appropriately packaged and labeled for this purpose. (c) In view of the above recommendations, the Commissioner of Food and Drugs has determined that it is in the interest of the public health for ipecac syrup to be available for sale without prescription, provided that it is packaged in a quantity of 1 fluid ounce (30 milliliters), and its label bears, in addition to other required label information, the following, in a prominent and conspicuous manner: (1) A statement conspicuously boxed and in red letters, to the effect: “For emergency use to cause vomiting in poisoning. Before using, call physician, the Poison Control Center, or hospital emergency room immediately for advice.” (2) A warning to the effect: “Warning—Keep out of reach of children. Do not use in unconscious persons. Ordinarily, this drug should not be used if strychnine, corrosives such as alkalies (lye) and strong acids, or petroleum distillates such as kerosine, gasoline, coal oil, fuel oil, paint thinner, or cleaning fluid have been ingested.” (3) Usual dosage: 1 tablespoon (15 milliliters) in persons over 1 year of age. (a) In 1961, the Food and Drug Administration, pursuant to its statutory responsibility for the safety and effectiveness of drugs shipped in interstate commerce, began an active investigation of reports of possible toxic effects and renal damage due to misuse of the drug acetophenetidin. This study led to the decision that there was probable cause to conclude that misuse and prolonged use of the drug were in fact responsible for kidney lesions and disease. The Commissioner of Food and Drugs, in December 1963, appointed an ad hoc Advisory Committee of Inquiry on Possible Nephrotoxicity Associated With the Abuse of Acetophenetidin (Phenacetin)-Containing Preparations. This committee, composed of scientists in the fields of pharmacology and medicine, on April 23, 1964, submitted its findings and conclusions in the matter and recommended that all acetophenetidin (phenacetin)-containing preparations bear a warning as provided in section 502(f)(2) of the Federal Food, Drug, and Cosmetic Act. (b) On the basis of the studies made by the Food and Drug Administration and the report of the Advisory Committee, the Commissioner of Food and Drugs has concluded that it is necessary for the protection of users that the label and labeling of all acetophenetidin (phenacetin)-containing preparations bear a warning statement to the following effect: “Warning—This medication may damage the kidneys when used in large amounts or for a long period of time. Do not take more than the recommended dosage, nor take regularly for longer than 10 days without consulting your physician.” (a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that phenindione, a synthetic anticoagulant drug, has caused a number of cases of agranulocytosis (with two fatalities). There are also reports implicating the drug in cases of hepatitis and hypersensitivity reactions. In view of the potentially serious effects found to be associated with preparations of this drug intended for use by man, the Commissioner of Food and Drugs will regard such preparations as misbranded within the meaning of section 502(f) (1) and (2) of the Federal Food, Drug, and Cosmetic Act, unless the label and labeling on or within the package from which the drug is to be dispensed, and any other labeling furnishing or purporting to furnish information for use of the drug, bear a conspicuous warning statement to the following effect: “Warning: Agranulocytosis and hepatitis have been associated with the use of phenindione. Patients should be instructed to report promptly prodromal symptoms such as marked fatigue, chill, fever, and sore throat. Periodic blood studies and liver function tests should be performed. Use of the drug should be discontinued if leukopenia occurs or if evidence of hypersensitivity, such as dermatitis or fever, appears.” (b) Regulatory action may be initiated with respect to preparations of phenindione intended for use by man found within the jurisdiction of the act on or after November 25, 1961, unless such preparations are labeled in accordance with paragraph (a) of this section.
Title 21: Food and Drugs
PART 201—LABELING
Subpart G—Specific Labeling Requirements for Specific Drug Products
§ 201.300 Notice to manufacturers, packers, and distributors of glandular preparations.
§ 201.301 Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.
§ 201.302 Notice to manufacturers, packers, and distributors of drugs for internal use which contain mineral oil.
§ 201.303 Labeling of drug preparations containing significant proportions of wintergreen oil.
§ 201.304 Tannic acid and barium enema preparations.
§ 201.305 Isoproterenol inhalation preparations (pressurized aerosols, nebulizers, powders) for human use; warnings.
§ 201.306 Potassium salt preparations intended for oral ingestion by man.
§ 201.307 Sodium phosphates; package size limitation, warnings, and directions for over-the-counter sale.
§ 201.308 Ipecac syrup; warnings and directions for use for over-the-counter sale.
§ 201.309 Acetophenetidin (phenacetin)-containing preparations; necessary warning statement.
§ 201.310 Phenindione; labeling of drug preparations intended for use by man.
§ 201.311 [Reserved]
§ 201.312 Magnesium sulfate heptahydrate; label declaration on drug products.
Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or usual name.
§ 201.313 Estradiol labeling.
The article presently recognized in The National Formulary under the heading “Estradiol” and which is said to be “17-cis-beta estradiol” is the same substance formerly recognized in the United States Pharmacopeia under the designation “Alpha Estradiol.” The substance should no longer be referred to in drug labeling as “Alpha Estradiol.” The Food and Drug Administration would not object to label references to the article as simply “Estradiol”; nor would it object if the label of a preparation containing this substance referred to the presence of “Estradiol (formerly known as Alpha Estradiol).”
§ 201.314 Labeling of drug preparations containing salicylates.
(a) The label of any oral drug preparation intended for sale without prescription and which contains any salicylate ingredient (including aspirin, salicylamide, other salicylates, and combinations) must conspicuously bear, on a clearly contrasting background, the warning statement: “Keep out of reach of children [highlighted in bold type]. In case of overdose, get medical help or contact a Poison Control Center right away,” or “Keep out of reach of children [highlighted in bold type],” except that if the article is an aspirin preparation, it shall bear the first of these warning statements. Such a warning statement is required for compliance with section 502(f)(2) of the Federal Food, Drug, and Cosmetic Act and is intended to guard against accidental poisonings. Safety closures that prevent access to the drug by young children are also recommended to guard against accidental poisonings.
(b) Effervescent preparations and preparations containing para-aminosalicylate as the only salicylate ingredient are exempted from this labeling requirement.
(c) Aspirin tablets sold as such and containing no other active ingredients, except tablets which cannot be readily subdivided into a child's dose because of their coating or size, should always bear dosage directions for each age group down to 3 years of age, with a statement such as “For children under 3 years of age, consult your physician.” It is recommended that:
(1) Aspirin tablets especially made for pediatric use be produced only in 1
(2) By June 1, 1967, manufacturers and distributors of 1
(3) The flavoring of 5-grain aspirin tablets or other “adult aspirin tablets” be discontinued; and
(4) Labeling giving undue emphasis to the pleasant flavor of flavored aspirin tablets be discontinued.
(d) Salicylate preparations other than aspirin tablets sold as such may, at the option of the distributor, be labeled for use by adults only. If their labeling and advertising clearly offer them for administration to adults only.
(e)(1) It is the obligation of the distributor who labels a salicylate preparation for administration to children to make certain that the article is suitable for such use and labeled with adequate directions for use in the age group for which it is offered, but in no case should such an article bear directions for use in children under 3 years of age. If the directions provide for administration to children as young as 3 years of age, the label should bear the statement, “For children under 3 years of age consult your physician.” However, if the directions provide for administration to children only of an age greater than 3 years (for example, the dosage instructions provide for administration of the article to children only down to age 6), the label should bear a statement such as, “For younger children consult your physician.”
(2) A statement such as, “For children under 3 years of age consult your physician” or “For younger children consult your physician” is not required on the label of an article clearly offered for administration to adults only.
(f) If the labeling or advertising of a salicylate preparation offers it for use in arthritis or rheumatism, the label and labeling should clearly state that the beneficial effects claimed are limited to: “For the temporary relief of minor aches and pains of arthritis and rheumatism.” The qualifying phrase “for the temporary relief of minor aches and pains” should appear with the same degree of prominence and conspicuousness as the phrase “arthritis and rheumatism”. The label and labeling should bear in juxtaposition with such directions for use conspicuous warning statements to the effect: “Caution: If pain persists for more than 10 days, or redness is present, or in conditions affecting children under 12 years of age, consult a physician immediately.” The salicylate dosage should not exceed 60 grains in a 24-hour period or 10 grains in a 4-hour period. If the article contains other analgesics, the salicylate dosage should be appropriately reduced.
(g)(1) The label of any drug containing more than 5 percent methyl salicylate (wintergreen oil) should bear a conspicuous warning such as: “Do not use otherwise than as directed.” These drug products must also include the “Keep out of reach of children” warning and the accidental ingestion warning as required in §330.1(g) of this chapter.
(2) If the preparation is a counterirritant or rubefacient, it should also bear a caution such as, “Caution: Discontinue use if excessive irritation of the skin develops. Avoid getting into the eyes or on mucous membranes.” (See also §201.303.)
(h)(1) The labeling of orally or rectally administered over-the-counter drug products containing aspirin or nonaspirin salicylates as active ingredients subject to this paragraph is required to prominently bear the following warning: “Reye's syndrome [subheading in bold type]: Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye's syndrome, a rare but serious illness.”
(2) This warning statement shall appear on the immediate container labeling. In cases where the immediate container is not the retail package, the retail package also must bear the warning statement. In addition, the warning statement shall appear on any labeling that contains warnings and, in such cases, the warning statement shall be the first warning statement under the heading “Warnings.”
(3) Over-the-counter drug products subject to this paragraph and labeled solely for use by children (pediatric products) shall not recommend the product for use in treating flu or chicken pox.
(4) Any product subject to paragraphs (h)(1), (h)(2), and (h)(3) of this section that is not labeled as required by these paragraphs and that is initially introduced or initially delivered for introduction into interstate commerce after the following dates is misbranded under sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and Cosmetic Act.
(i) Compliance by October 18, 2004, for OTC drug products containing aspirin and nonaspirin salicylates as an active ingredient and marketed under a new drug application or abbreviated new drug application.
(ii) Compliance by April 19, 2004, for OTC antidiarrheal and overindulgence drug products that contain bismuth subsalicylate as an active ingredient and have annual sales greater than $25,000.
(iii) Compliance by April 18, 2005, for OTC antidiarrheal and overindulgence drug products that contain bismuth subsalicylate as an active ingredient and have annual sales less than $25,000.
(iv) Compliance dates for all other OTC drug products containing aspirin and nonaspirin salicylates as an active ingredient and marketed under an OTC drug monograph (for internal analgesic, antipyretic, and antirheumatic drug products, or for menstrual drug products) will be established when the final monographs for those products are published in a future issue of the
[40 FR 13998, Mar. 27, 1985, as amended at 51 FR 8182, Mar. 7, 1986; 53 FR 21637, June 9, 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, Mar. 17, 1999; 65 FR 8, Jan. 3, 2000; 68 FR 18869, Apr. 17, 2003]
§ 201.315 Over-the-counter drugs for minor sore throats; suggested warning.
The Food and Drug Administration has studied the problem of the labeling of lozenges or troches containing a local anesthetic, chewing gum containing aspirin, various mouth washes and gargles and other articles sold over the counter for the relief of minor irritations of the mouth or throat. It will not object to the labeling of suitable articles of this type “For the temporary relief of minor sore throats”, provided this is immediately followed in the labeling with a warning statement in prominent type essentially as follows: “Warning—Severe or persistent sore throat or sore throat accompanied by high fever, headache, nausea, and vomiting may be serious. Consult physician promptly. Do not use more than 2 days or administer to children under 3 years of age unless directed by physician.”
§ 201.316 Drugs with thyroid hormone activity for human use; required warning.
(a) Drugs with thyroid hormone activity have been promoted for, and continue to be dispensed and prescribed for, use in the treatment of obesity, although their safety and effectiveness for that use have never been established.
(b) Drugs for human use with thyroid hormone activity are misbranded within the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless their labeling bears the following boxed warning at the beginning of the “Warnings” section:
Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have been used for the treatment of obesity. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.
[43 FR 22009, May 23, 1978]
§ 201.317 Digitalis and related cardiotonic drugs for human use in oral dosage forms; required warning.
(a) Digitalis and related cardiotonic drugs for human use in oral dosage forms have been promoted for, and continue to be dispensed and prescribed for, use in the treatment of obesity, although their safety and effectiveness for that use have never been established.
(b) Digitalis and related cardiotonic drugs for human use in oral dosage forms are misbranded within the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless their labeling bears the following boxed warning at the beginning of the “Warnings” section:
Digitalis alone or with other drugs has been used in the treatment of obesity. This use of digoxin or other digitalis glycosides is unwarranted. Moreover, since they may cause potentially fatal arrhythmias or other adverse effects, the use of these drugs in the treatment of obesity is dangerous.
(c) This section does not apply to digoxin products for oral use, which shall be labeled according to the requirements of §310.500 of this chapter.
[43 FR 22009, May 23, 1978]
§ 201.319 Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids (including, but not limited to agar, alginic acid, calcium polycarbophil, carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil tragacanth, and xanthan gum) as active ingredients; required warnings and directions.
(a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that esophageal obstruction and asphyxiation have been associated with the ingestion of water-soluble gums, hydrophilic gums, and hydrophilic mucilloids including, but not limited to, agar, alginic acid, calcium polycarbophil, carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil, tragacanth, and xanthan gum. Esophageal obstruction and asphyxiation due to orally-administered drug products containing water-soluble gums, hydrophilic gums, and hydrophylic mucilloids as active ingredients are significant health risks when these products are taken without adequate fluid or when they are used by individuals with esophageal narrowing or dysfunction, or with difficulty in swallowing. Additional labeling is needed for the safe and effective use of any OTC drug product for human use containing a water-soluble gum, hydrophilic gum, or hydrophilic mucilloid as an active ingredient when marketed in a dry or incompletely hydrated form to include, but not limited to, the following dosage forms: capsules, granules, powders, tablets, and wafers.
(b) Any drug products for human use containing a water-soluble gum, hydrophilic gum, or hydrophilic mucilloid as an active ingredient in an oral dosage form when marketed in a dry or incompletely hydrated form as described in paragraph (a) of this section are misbranded within the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless their labeling bears the following warnings (under the subheading “Choking”) and directions:
“‘Choking’ [highlighted in bold type]: Taking this product without adequate fluid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty in swallowing. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek immediate medical attention;” and
“‘Directions’ [highlighted in bold type]:” (Select one of the following, as appropriate: “Take” or “Mix”) “this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning.”
(c) After February 28, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce, or any such drug product that is repackaged or relabeled after this date regardless of the date the product was manufactured, initially introduced, or initially delivered for introduction into interstate commerce, that is not in compliance with this section is subject to regulatory action.
[58 FR 45201, Aug. 26, 1993, as amended at 64 FR 13292, Mar. 17, 1999]
§ 201.320 Warning statements for drug products containing or manufactured with chlorofluorocarbons or other ozone-depleting substances.
(a)(1) All drug products containing or manufactured with chlorofluorocarbons, halons, carbon tetrachloride, methyl chloride, or any other class I substance designated by the Environmental Protection Agency (EPA) shall, except as provided in paragraph (b) or (c) of this section, bear the following warning statement:
Warning: Contains [or Manufactured with, if applicable] [insert name of substance], a substance which harms public health and the environment by destroying ozone in the upper atmosphere.
(2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase.
(b)(1) For prescription drug products for human use, the following alternative warning statement may be used:
Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or name of other class I substance, if applicable]:
This product contains [or is manufactured with, if applicable] [insert name of substance], a substance which harms the environment by destroying ozone in the upper atmosphere.
Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.
(2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase.
(3) If the warning statement in paragraph (b)(1) of this section is used, the following warning statement must be placed on the package labeling intended to be read by the physician (physician package insert) after the “How supplied” section, which describes special handling and storage conditions on the physician labeling:
Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or name of other class I substance, if applicable]:
A notice similar to the above WARNING has been placed in the information for the patient [or patient information leaflet, if applicable] of this product under the Environmental Protection Agency's (EPA's) regulations. The patient's warning states that the patient should consult his or her physician if there are questions about alternatives.
(c)(1) For over-the-counter drug products for human use, the following alternative warning statement may be used:
Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or other class I substance, if applicable]:
CONSULT WITH YOUR PHYSICIAN OR HEALTH PROFESSIONAL IF YOU HAVE ANY QUESTION ABOUT THE USE OF THIS PRODUCT.
(2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase.
(d) This section does not replace or relieve a person from any requirements imposed under 40 CFR part 82.
[61 FR 20100, May 3, 1996]
§ 201.322 Over-the-counter drug products containing internal analgesic/antipyretic active ingredients; required alcohol warning.
(a) People who regularly consume large quantities of alcohol (three or more drinks every day) have an increased risk of adverse effects (possible liver damage or gastrointestinal bleeding). OTC drug products containing internal analgesic/antipyretic active ingredients may cause similar adverse effects. FDA concludes that the labeling of OTC drug products containing internal analgesic/antipyretic active ingredients should advise consumers with a history of heavy alcohol use to consult a physician. Accordingly, any OTC drug product, labeled for adult use, containing any internal analgesic/antipyretic active ingredients (including, but not limited to, acetaminophen, aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate) alone or in combination shall bear an alcohol warning statement in its labeling as follows:
(1) Acetaminophen. “Alcohol Warning” [heading in boldface type]: “If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen may cause liver damage.”
(2) Nonsteroidal anti-inflammatory analgesic/antipyretic active ingredients—including but not limited to aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate. “Alcohol Warning” [heading in boldface type]: “If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take [insert one nonsteroidal anti-inflammatory analgesic/antipyretic active ingredient] or other pain relievers/fever reducers. [Insert one nonsteroidal anti-inflammatory analgesic/antipyretic active ingredient] may cause stomach bleeding.”
(3) Combinations of acetaminophen with nonsteroidal anti-inflammatory analgesic/antipyretic active ingredients—including but not limited to aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate. “Alcohol Warning” [heading in boldface type]: “If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take [insert acetaminophen and one nonsteroidal anti-inflammatory analgesic/antipyretic active ingredient—including, but not limited to aspirin, carbaspirin calcium, choline salicylate, magnesium salicylate, or sodium salicylate] or other pain relievers/fever reducers. [Acetaminophen and (insert one nonsteroidal anti-inflammatory analgesic/antipyretic ingredient—including, but not limited to aspirin, carbaspirin calcium, choline salicylate, magnesium salicylate, or sodium salicylate] may cause liver damage and stomach bleeding.”
(b) Requirements to supplement approved application. Holders of approved applications for OTC drug products that contain internal analgesic/antipyretic active ingredients that are subject to the requirements of paragraph (a) of this section must submit supplements under §314.70(c) of this chapter to include the required warning in the product's labeling. Such labeling may be put into use without advance approval of FDA provided it includes the exact information included in paragraph (a) of this section.
(c) Any drug product subject to this section that is not labeled as required and that is initially introduced or initially delivered for introduction into interstate commerce after April 23, 1999, is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 352) and is subject to regulatory action.
[63 FR 56801, Oct. 23, 1998]
§ 201.323 Aluminum in large and small volume parenterals used in total parenteral nutrition.
(a) The aluminum content of large volume parenteral (LVP) drug products used in total parenteral nutrition (TPN) therapy must not exceed 25 micrograms per liter (µg/L).
(b) The package insert of LVP's used in TPN therapy must state that the drug product contains no more than 25 µg/L of aluminum. This information must be contained in the “Precautions” section of the labeling of all large volume parenterals used in TPN therapy.
(c) Except as provided in paragraph (d) of this section, the maximum level of aluminum present at expiry must be stated on the immediate container label of all small volume parenteral (SVP) drug products and pharmacy bulk packages (PBPs) used in the preparation of TPN solutions. The aluminum content must be stated as follows: “Contains no more than __ µg/L of aluminum.” The immediate container label of all SVP's and PBP's that are lyophilized powders used in the preparation of TPN solutions must contain the following statement: “When reconstituted in accordance with the package insert instructions, the concentration of aluminum will be no more than __ µg/L.” This maximum level of aluminum must be stated as the highest of:
(1) The highest level for the batches produced during the last 3 years;
(2) The highest level for the latest five batches, or
(3) The maximum historical level, but only until completion of production of the first five batches after July 26, 2004.
(d) If the maximum level of aluminum is 25 µg/L or less, instead of stating the exact amount of aluminum as required in paragraph (c) of this section, the immediate container label may state: “Contains no more than 25 µg/L of aluminum.” If the SVP or PBP is a lyophilized powder, the immediate container label may state: “When reconstituted in accordance with the package insert instructions, the concentration of aluminum will be no more than 25 µg/L”.
(e) The package insert for all LVP's, all SVP's, and PBP's used in TPN must contain a warning statement. This warning must be contained in the “Warnings” section of the labeling. The warning must state:
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
(f) Applicants and manufacturers must use validated assay methods to determine the aluminum content in parenteral drug products. The assay methods must comply with current good manufacturing practice requirements. Applicants must submit to the Food and Drug Administration validation of the method used and release data for several batches. Manufacturers of parenteral drug products not subject to an approved application must make assay methodology available to FDA during inspections. Holders of pending applications must submit an amendment under §314.60 or §314.96 of this chapter.
[65 FR 4110, Jan. 26, 2000, as amended at 67 FR 70691, Nov. 26, 2002; 68 FR 32981, June 3, 2003]
Appendix A to Part 201—Examples of Graphic Enhancements Used by FDA
I. Section 201.66 Standard Labeling Format
A. Overall
1. The “Drug Facts” labeling is set off in a box or similar enclosure by the use of a barline with all black type printed on a white, color contrasting background.
B. Typeface and size
1. “Drug Facts” is set in 14 point Helvetica Bold Italic, left justified.
2. “Drug Facts (continued)” is set in 8 point Helvetica Bold Italic for the words “Drug Facts” and 8 point Helvetica Regular for the word “(continued)” and is left justified.
3. The headings (e.g., “Directions”) are set in 8 point Helvetica Bold Italic, left justified.
4. The subheadings (e.g., “Ask a doctor or pharmacist before use if you are”) are set in 6 point Helvetica Bold, left justified.
5. The information is set in 6 point Helvetica Regular with 6.5 point leading, left justified.
6. The heading “Purpose” is right justified.
7. The bullet is a 5-point solid square.
8. Two em spacing separates bullets when more than one bullet is on the same line.
9. A table format is used for 3 or more dosage directions.
10. A graphic appears at the bottom of the first panel leading the reader to the next panel.
C. Barlines and hairlines
1. A 2.5-point horizontal barline extends to each end of the “Drug Facts” box (or similar enclosure), providing separation between each of the headings.
2. A 0.5-point horizontal hairline extends within 2 spaces on either side of the “Drug Facts” box (or similar enclosure), immediately following the title and immediately preceding the subheadings.
3. A 0.5-point horizontal hairline follows the title, immediately preceding the heading, when a heading appears on a subsequent panel immediately after the “Drug Facts (continued)” title.
D. Box or Enclosure
1. All information is enclosed by a 2.5-point barline.
II. Section 201.66 Modified Labeling Format
A. Overall
1. The “Drug Facts” labeling is presented in all black type printed on a white color contrasting background.
B. Typeface and size
1. “Drug Facts” is set in 9 point Helvetica Bold Italic, left justified.
2. The headings (e.g., “Directions”) are set in 8 point Helvetica Bold Italic, left justified.
3. The subheadings (e.g., “Ask a doctor or pharmacist before use if you are”) are set in 6 point Helvetica Bold, left justified.
4. The information is set in 6 point Helvetica Regular with 6.5 point leading, left justified.
5. The heading “Purpose” is right justified.
6. The bullet is a 5-point solid square.
7. Bulleted information may start on same line as headings (except for the “Warnings” heading) and subheadings, with 2 em spacing separating bullets, and need not be vertically aligned.
C. Barlines and hairlines
1. A 2.5-point horizontal barline extends to each end of the “Drug Facts” box (or similar enclosure), providing separation between each of the headings.
2. A 0.5-point horizontal hairline extends within 2 spaces on either side of the “Drug Facts” box (or similar enclosure), immediately following the title and immediately preceding the subheadings.
D. Box or Enclosure
1. All information is set off by color contrast. No barline is used.
III. Examples of §201.66 Standard Labeling and Modified Labeling Formats
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