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Home , Antacid, Magaldrate, Sodium bicarbonate

and Administration, HHS § 331.10

publish a notice of proposed rule- PART 331— PRODUCTS making to include the condition in FOR OVER-THE-COUNTER (OTC) § 310.502 of this chapter. HUMAN USE (5) Interested parties will have an op- portunity to submit comments and new Subpart A—General Provisions data. The agency will subsequently publish a final rule (or reproposal if Sec. 331.1 Scope. necessary) in the FEDERAL REGISTER. (h) Marketing. A condition submitted Subpart B—Active Ingredients under this section for consideration in the OTC drug monograph system may 331.10 Antacid active ingredients. 331.11 Listing of specific active ingredients. be marketed in accordance with an ap- 331.15 Combination with nonantacid active plicable final OTC drug monograph(s) ingredients. only after the agency determines that the condition is generally recognized as Subpart C—Testing Procedures safe and effective and includes it in the 331.20 Determination of percent contribu- appropriate OTC drug final mono- tion of active ingredients. graph(s), and the condition complies 331.21 Test Modifications. with paragraph (i) of this section. When an OTC drug monograph has not Subpart D—Labeling been finalized and finalization is not 331.30 Labeling of antacid products. imminent, after the agency has evalu- 331.80 Professional labeling. ated the comments to a proposed rule AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, to include a new condition in a ten- 360, 371. tative final monograph as generally SOURCE: 39 FR 19874, June 4, 1974, unless recognized as safe and effective and the otherwise noted. agency has not changed its position as a result of the comments, and the con- Subpart A—General Provisions dition complies with paragraph (i) of this section, the agency may publish a § 331.1 Scope. notice of enforcement policy that al- An over-the-counter antacid product lows marketing to begin pending com- in a form suitable for oral administra- pletion of the final monograph subject tion is generally recognized as safe and to the risk that the agency may, prior effective and is not misbranded if it to or in the final monograph, adopt a meets each of the following conditions different position that could require re- and each of the general conditions es- labeling, recall, or other regulatory ac- tablished in § 330.1 of this chapter. tion. (i) Compendial monograph. Any active Subpart B—Active Ingredients ingredient or botanical drug substance included in a final OTC drug mono- § 331.10 Antacid active ingredients. graph or the subject of an enforcement (a) The active antacid ingredients of notice described in paragraph (h) of the product consist of one or more of this section must be recognized in an the ingredients permitted in § 331.11 official USP-NF drug monograph that within any maximum daily dosage sets forth its standards of identity, limit established, each ingredient is in- strength, quality, and purity. Sponsors cluded at a level that contributes at must include an official or proposed least 25 percent of the total neu- compendial monograph as part of the tralizing capacity of the product, and safety and effectiveness data submis- the finished product contains at least 5 sion listed in § 330.10(a)(2) under item meq of acid neutralizing capacity as VII of the outline entitled ‘‘OTC DRUG measured by the procedure provided in the United States Pharmacopeia 23/Na- REVIEW INFORMATION.’’ tional Formulary 18. The method es- [67 FR 3074, Jan. 23, 2002] tablished in § 331.20 shall be used to de- termine the percent contribution of each antacid active ingredient.

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(b) This section does not apply to an (6) . antacid ingredient specifically added as (7) . a corrective to prevent a or (8) Magnesium trisilicate. constipating effect. (h) Milk solids, dried. [39 FR 19874, June 4, 1974, as amended at 61 (i) Phosphate-containing active in- FR 4822, Feb. 8, 1996] gredients: (1) Aluminum phosphate; maximum § 331.11 Listing of specific active in- daily dosage limit 8 grams. gredients. (2) Mono or dibasic ; (a) Aluminum-containing active in- maximum daily dosage limit 2 grams. gredients: (3) Tricalcium phosphate; maximum (1) Basic aluminum gel. daily dosage limit 24 grams. (2) Aluminum hydroxide (or as alu- minum hydroxide-hexitol stabilized (j) Potassium-containing active in- polymer, aluminum hydroxide-magne- gredients: sium carbonate codried gel, aluminum (1) Potassium (or car- hydroxide-magnesium trisilicate bonate when used as a component of an codried gel, aluminum-hydroxide su- effervescent preparation); maximum crose powder hydrated). daily dosage limit 200 mEq. of bicar- (3) Dihydroxyaluminum amino- bonate for persons up to 60 years and dihydroxyaluminum ami- old and 100 mEq. of bicarbonate ion for noacetic acid. persons 60 years or older. (4) Aluminum phosphate gel when (2) potassium tartrate. used as part of an antacid combination (k) Sodium-containing active ingre- product and contributing at least 25 dients: percent of the total acid neutralizing (1) (or carbonate capacity; maximum daily dosage limit when used as a component of an effer- is 8 grams. vescent preparation); maximum daily (5) Dihydroxyaluminum sodium car- dosage limit 200 mEq. of sodium for bonate. persons up to 60 years old and 100 mEq. (b) Bicarbonate-containing active in- of sodium for persons 60 years or older, gredients: Bicarbonate ion; maximum and 200 mEq. of bicarbonate ion for per- daily dosage limit 200 mEq. for persons sons up to 60 years old and 100 mEq. of up to 60 years old and 100 mEq. for per- sons 60 years or older. bicarbonate ion for persons 60 years or (c) Bismuth-containing active ingre- older. That part of the warning re- dients: quired by § 330.1(g), which states, ‘‘Keep (1) Bismuth aluminate. this and all out of the reach of (2) Bismuth carbonate. children’’ is not required on a product (3) Bismuth subcarbonate. which contains only sodium bicarbon- (4) Bismuth subgallate. ate powder and which is intended pri- (5) Bismuth subnitrate. marily for other than drug uses. (d) Calcium-containing active ingre- (2) Sodium potassium tartrate. dients: Calcium, as carbonate or phos- (l) Silicates: phate; maximum daily dosage limit 160 (1) Magnesium aluminosilicates. mEq. calcium (e.g., 8 grams calcium (2) Magnesium trisilicate. carbonate). (m) Tartrate-containing active ingre- (e) Citrate-containing active ingredi- dients. or its salts; max- ents: Citrate ion, as or salt; imum daily dosage limit 200 mEq. (15 maximum daily dosage limit 8 grams. grams) of tartrate. (f) Glycine (aminoacetic acid). (g) Magnesium-containing active in- [39 FR 19874, June 4, 1974, as amended at 51 gredients: FR 27763, Aug. 1, 1986; 55 FR 19859, May 11, (1) Hydrate magnesium aluminate ac- 1990] tivated sulfate. (2) . § 331.15 Combination with nonantacid (3) Magnesium aluminosilicates. active ingredients. (4) . (a) An antacid may contain any gen- (5) Magnesium glycinate. erally recognized as safe and effective

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nonantacid laxative ingredient to cor- submitted will be subject to the disclo- rect for caused by the ant- sure rules in part 20 of this chapter. acid. No labeling claim of the laxative [61 FR 4823, Feb. 8, 1996] effect may be used for such a product. (b) An antacid may contain any gen- erally recognized as safe and effective Subpart D—Labeling ingredient(s), if it is indi- cated for use solely for the concurrent § 331.30 Labeling of antacid products. symptoms involved, e.g., headache and (a) Statement of identity. The labeling acid , and is marketed in a of the product contains the established form intended for ingestion as a solu- name of the drug, if any, and identifies tion. the product as an ‘‘antacid.’’ (c) An antacid may contain any gen- (b) Indications. The labeling of the erally recognized as safe and effective product states, under the heading ‘‘In- antiflatulent ingredient if it is indi- dications,’’ the following: ‘‘For the re- cated for use solely for the concurrent lief of’’ (optional, any or all of the fol- symptoms of gas associated with heart- lowing:) ‘‘,’’ ‘‘sour stomach,’’ burn, sour stomach or acid indigestion. and/or ‘‘acid indigestion’’ (which may be followed by the optional statement:) Subpart C—Testing Procedures ‘‘and upset stomach associated with’’ (optional, as appropriate) ‘‘this symp- § 331.20 Determination of percent con- tom’’ or ‘‘these symptoms.’’ Other tribution of active ingredients. truthful and nonmisleading state- ments, describing only the indications To determine the percent contribu- for use that have been established and tion of an antacid active ingredient, listed in this paragraph (b), may also place an accurately weighed amount of be used, as provided in § 330.1(c)(2) of the antacid active ingredient equal to this chapter, subject to the provisions the amount present in a unit dose of of section 502 of the act relating to the product into a 250-milliliter (mL) misbranding and the prohibition in sec- beaker. If wetting is desired, add not tion 301(d) of the act against the intro- more than 5 mL of alcohol (neutralized duction or delivery for introduction to an apparent pH of 3.5), and mix to into interstate commerce of unap- wet the sample thoroughly. Add 70 mL proved new drugs in violation of sec- of water, and mix on a magnetic stirrer tion 505(a) of the act. at 300 ±30 r.p.m. for 1 minute. Analyze the acid neutralizing capacity of the (c) Warnings. The labeling of the sample according to the procedure pro- product contains the following warn- vided in the United States Pharma- ings, under the heading ‘‘Warnings’’, copeia 23/National Formulary 18 and which may be combined but not rear- calculate the percent contribution of ranged to eliminate duplicative words the antacid active ingredient in the or phrases if the resulting warning is total product as follows: clear and understandable: Percent contribution =(Total mEq. (1) ‘‘Do not take more than (max- Antacid Active Ingredient×100)/(Total imum recommended daily dosage, bro- mEq. Antacid Product). ken down by age groups if appropriate, expressed in units such as tablets or [61 FR 4823, Feb. 8, 1996] teaspoonfuls) in a 24–hour period, or use the maximum dosage of this prod- § 331.21 Test modifications. uct for more than 2 weeks, except The formulation or mode of adminis- under the advice and supervision of a tration of certain products may require physician.’’ a modification of the United States (2) For products which cause con- Pharmacopeia 23/National Formulary stipation in 5 percent or more of per- 18 acid neutralizing capacity test. Any sons who take the maximum rec- proposed modification and the data to ommended dosage: ‘‘May cause con- support it shall be submitted as a peti- stipation.’’ tion under the rules established in (3) For products which cause laxation § 10.30 of this chapter. All information in 5 percent or more of persons who

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take the maximum recommended dos- any of the labeling statements in this age: ‘‘May have laxative effect.’’ section. (4) For products containing more [39 FR 19874, June 4, 1974, as amended at 47 than 5 gm per day lactose in a max- FR 38484, Aug. 31, 1982; 51 FR 16266, May 1, imum daily dosage: ‘‘Do not use this 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, product except under advice and super- Mar. 13, 1987; 55 FR 11581, Mar. 29, 1990; 58 FR vision of a physician if you are allergic 45208, Aug. 26, 1993; 59 FR 60556, Nov. 25, 1994; to milk or milk products.’’ 61 FR 17806, Apr. 22, 1996; 64 FR 13295, Mar. 17, 1999; 69 FR 13734, Mar. 24, 2004] (d) precaution. The labeling of the product contains the § 331.80 Professional labeling. following statement ‘‘Ask a doctor or (a) The labeling of the product pro- pharmacist before use if you are [bul- vided to health professionals (but not 1 let] presently taking a prescription to the general public): drug. may interact with cer- (1) Shall contain the neutralizing ca- tain prescription drugs.’’ pacity of the product as calculated (e) Directions for use. The labeling of using the procedure set forth in United the product contains the recommended States Pharmacopeia 23/National For- dosage, under the heading ‘‘Direc- mulary 18 expressed in terms of the tions’’, per time interval (e.g., every 4 dosage recommended per minimum hours) or time period (e.g., 4 times a time interval or, if the labeling rec- day) broken down by age groups if ap- ommends more than one dosage, in propriate, followed by ‘‘or as directed terms of the minimum dosage rec- by a physician.’’ ommended per minimum time interval. (f) Exemption from the general acci- (2) May contain an indication for the dental overdose warning. The labeling symptomatic relief of hyperacidity as- for antacid drug products containing sociated with the diagnosis of peptic the active ingredients identified in ulcer, , peptic , gas- § 331.11(a), (b), and (d) through (m); per- tric hyperacidity, and hiatal hernia. mitted combinations of these ingredi- (3) For products containing basic alu- minum carbonate gel identified in ents provided for in § 331.10; and any of § 331.11(a)(1)—Indication. ‘‘For the these ingredients or combinations of treatment, control, or management of these ingredients in combination with hyperphosphatemia, or for use with a simethicone (identified in § 332.10 of low phosphate diet to prevent forma- this chapter and provided for in tion of phosphate urinary stones, § 331.15(c)), are exempt from the re- through the reduction of phosphates in quirement in § 330.1(g) of this chapter the serum and urine.’’ that the labeling bear the general (4) For products containing aluminum warning statement ‘‘In case of acci- identified in § 331.11(a)—Warnings. (i) dental overdose, seek professional as- Prolonged use of aluminum-containing sistance or contact a poison control antacids in patients with renal failure center immediately.’’ With the excep- may result in or worsen osteo- tion of sodium bicarbonate powder malacia. Elevated tissue aluminum products identified in § 331.11(k)(1), the levels contribute to the development of labeling must continue to bear the first the dialysis encephalopathy and osteo- part of the general warning in § 330.1(g) malacia syndromes. Small amounts of of this chapter, which states, ‘‘Keep aluminum are absorbed from the gas- this and all drugs out of the reach of trointestinal tract and renal children.’’ of aluminum is impaired in renal fail- (g) [Reserved] ure. Aluminum is not well removed by (h) The word ‘‘doctor’’ may be sub- dialysis because it is bound to albumin and transferrin, which do not cross di- stituted for the word ‘‘physician’’ in alysis membranes. As a result, alu- minum is deposited in , and dialy- sis osteomalacia may develop when large amounts of aluminum are in- gested orally by patients with impaired 1 See § 201.66(b)(4) of this chapter. renal function.

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(ii) Aluminum forms insoluble com- flatulent. Neither term should be con- plexes with phosphate in the gastro- sidered as describing the mechanism of intestinal tract, thus decreasing phos- action of the active ingredient con- phate absorption. Prolonged use of alu- tained in the product. minum-containing antacids by normo- [61 FR 8838, Mar. 5, 1996] phosphatemic patients may result in hypophosphatemia if phosphate intake is not adequate. In its more severe Subpart B—Active Ingredients forms, hypophosphatemia can lead to § 332.10 Antiflatulent active ingredi- anorexia, malaise, muscle weakness, ents. and osteomalacia. (b) Professional labeling for an ant- Simethicone; maximum daily dose acid-antiflatulent combination may 500 mg. There is no dosage limitation contain the information allowed for at this time for professional labeling. health professionals for antacids and antiflatulents. § 332.15 Combination with non-anti- flatulent active ingredients. [39 FR 19874, June 4, 1974. Redesignated and An antiflatulent may contain any amended at 55 FR 19859, May 11, 1990] generally recognized as safe and effec- tive antacid ingredient(s) if it is indi- PART 332—ANTIFLATULENT PROD- cated for use solely for the concurrent UCTS FOR OVER-THE-COUNTER symptoms of gas associated with heart- HUMAN USE burn, sour stomach or acid indigestion.

Subpart A—General Provisions Subpart C—Labeling Sec. 332.1 Scope. § 332.30 Labeling of antiflatulent drug 332.3 Definitions. products. (a) Statement of identity. The labeling Subpart B—Active Ingredients of the product contains the established 332.10 Antiflatulent active ingredients. name of the drug, if any, and identifies 332.15 Combination with non-antiflatulent the product as an ‘‘antiflatulent,’’ active ingredients. ‘‘antigas,’’ or ‘‘antiflatulent (antigas).’’ (b) Indications. The labeling of the Subpart C—Labeling product states, under the heading ‘‘In- 332.30 Labeling of antiflatulent products. dications,’’ one or more of the phrases 332.31 Professional labeling. listed in this paragraph (b), as appro- priate. Other truthful and nonmis- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, leading statements, describing only the 360, 371. indications for use that have been es- SOURCE: 39 FR 19877, June 4, 1974, unless tablished and listed in this paragraph otherwise noted. (b), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to Subpart A—General Provisions the provisions of section 502 of the Fed- eral Food, Drug, and Cosmetic Act (the § 332.1 Scope. act) relating to misbranding and the An over-the-counter antiflatulent prohibition in section 301(d) of the act product in a form suitable for oral ad- against the introduction or delivery for ministration is generally recognized as introduction into interstate commerce safe and effective and is not mis- of unapproved new drugs in violation of branded if it meets each of the fol- section 505(a) of the act. lowing conditions and each of the gen- (1) (Select one of the following: ‘‘Al- eral conditions established in § 330.1 of leviates or Relieves’’) ‘‘the symptoms this chapter. referred to as gas.’’ (2) (Select one of the following: ‘‘Al- § 332.3 Definitions. leviates’’ or ‘‘Relieves’’) (select one or As used in this part: more of the following: ‘‘,’’ Antigas. A term that may be used ‘‘pressure,’’ ‘‘fullness,’’ or ‘‘stuffed feel- interchangeably with the term anti- ing’’) ‘‘commonly referred to as gas.’’

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