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(2) An active ingredient at a dosage level higher than that available in any OTC drug product on December 4, 1975, which ingredient and/or dosage level is classified by the panel in category III (conditions subject to $330.10(a)(6)(iii)), may be marketed only after:

(i) The Center for Drug Evaluation and Research or the Commissioner tentatively determines that the ingredient is generally recognized as safe and effective, and the Commissioner states by notice in the FEDERAL REGISTER (separately or as part of another document) that marketing under specified conditions will be permitted;

(ii) The ingredient is determined by the Commissioner to be generally recognized as safe and effective and is included in the appropriate published OTC drug final monograph; or

(iii) A new drug application for the product has been approved.

(41 FR 32582, Aug. 4, 1976, as amended at 47 FR 17739, Apr. 23, 1982; 50 FR 8996, Mar. 6, 1985; 55 FR 11581, Mar. 29, 1990)

may not accept

accept the

the panel's recommendation and may instead adopt a different position that may require relabeling, recall, or other regulatory action. The Commissioner may state such position at any time by notice in the FEDERAL REGISTER, either separately or as part of another document; appropriate regulatory action will commence immediately and will not await publication of a final monograph. Marketing of such a product with a formulation or labeling not in accord with a proposed monograph or tentative final monograph also may result in regulatory action against the product, the marketer, or both.

(c) An OTC drug product that contains: (1) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to $310.200 of this chapter, or

(2) An active ingredient at a dosage level higher than that available in any OTC drug product on December 4, 1975, which ingredient and/or dosage level is classified by the panel in category II (conditions subject to $330.10(a)(6)(ii)), may be marketed only after:

(i) The Center for Drug Evaluation and Research or the Commissioner tentatively determines that the ingredient is generally recognized as safe and effective, and the Commissioner states by notice in the FEDERAL REGISTER (separately or as part of another document) that marketing under specified conditions will be permitted;

(ii) The ingredient is determined by the Commissioner to be generally recognized as safe and effective and is included in the appropriate published OTC drug final monograph; or

(iii) A new drug application for the product has been approved.

(d) An OTC drug product that conta (1) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to $310.200 of this chapter, or

PART 331–ANTACID PRODUCTS

FOR OVER-THE-COUNTER (OTC) HUMAN USE

Subpart A-General Provisions

Sec. 331.1 Scope.

Subpart B-Active Ingredients

331.10 Antacid active ingredients. 331.11 Listing of specific active ingredients. 331.15 Combination with nonantacid active

ingredients.

Subpart C-Testing Procedures

331.20 Determination of percent contribu

tion of active ingredients. 331.21 Test Modifications.

Subpart D-Labeling

331.30 Labeling of antacid products. 331.80 Professional labeling.

AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

SOURCE: 39 FR 19874, June 4, 1974, unless otherwise noted.

Subpart A-General Provisions

§ 331.1 Scope.

An over-the-counter antacid product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the following conditions and each of the general conditions established in 8330.1 of this chapter.

Subpart B-Active Ingredients

$ 331.10 Antacid active ingredients.

(a) The active antacid ingredients of the product consist of one or more of the ingredients permitted in $331.11 within any maximum daily dosage limit established, each ingredient is included at a level that contributes at least 25 percent of the total acid neutralizing capacity of the product, and the finished product contains at least 5 med of acid neutralizing capacity as measured by the procedure provided in the United States Pharmacopeia 23/National Formulary 18. The method established in 8331.20 shall be used to determine the percent contribution of each antacid active ingredient.

(b) This section does not apply to an antacid ingredient specifically added as a corrective to prevent a laxative or constipating effect.

(5) Dihydroxyaluminum sodium carbonate.

(b) Bicarbonate-containing active ingredients: Bicarbonate ion; maximum daily dosage limit 200 mEq. for persons up to 60 years old and 100 mEq. for persons 60 years or older.

(c) Bismuth-containing active ingredients:

(1) Bismuth aluminate.
(2) Bismuth carbonate.
(3) Bismuth subcarbonate.
(4) Bismuth subgallate.
(5) Bismuth subnitrate.

(d) Calcium-containing active ingredients: Calcium, as carbonate or phosphate; maximum daily dosage limit 160 mEq. calcium (e.g., 8 grams calcium carbonate).

(e) Citrate-containing active ingredients: Citrate ion, as citric acid or salt; maximum daily dosage limit 8 grams.

(f) Glycine (aminoacetic acid).

(g) Magnesium-containing active ingredients:

(1) Hydrate magnesium aluminate activated sulfate.

(2) Magaldrate.
(3) Magnesium aluminosilicates.
(4) Magnesium carbonate.
(5) Magnesium glycinate.
(6) Magnesium hydroxide.
(7) Magnesium oxide.
(8) Magnesium trisilicate.
(h) Milk solids, dried.

(i) Phosphate-containing active ingredients:

(1) Aluminum phosphate; maximum daily dosage limit 8 grams.

(2) Mono or dibasic calcium salt; maximum daily dosage limit 2 grams.

(3) Tricalcium phosphate; maximum daily dosage limit 24 grams.

(j) Potassium-containing active ingredients:

(1) Potassium bicarbonate (or carbonate when used as a component of an effervescent preparation); maximum daily dosage limit 200 mEq. of bicarbonate ion for persons up to 60 years old and 100 mEq. of bicarbonate ion for persons 60 years or older.

(2) Sodium potassium tartrate.

(k) Sodium-containing active ingredients:

(1) Sodium bicarbonate (or carbonate when used as a component of an effervescent preparation); maximum daily dosage limit 200 mEq. of sodium for

[39 FR 19874, June 4, 1974, as amended at 61 FR 4822, Feb. 8, 1996)

331.11 Listing of specific active in

gredients. (a) Aluminum-containing active ingredients:

(1) Basic aluminum carbonate gel.

(2) Aluminum hydroxide (or as aluminum hydroxide-hexitol stabilized polymer, aluminum hydroxide-magnesium carbonate codried gel, aluminum hydroxide-magnesium

trisilicate codried gel, aluminum-hydroxide sucrose powder hydrated).

(3) Dihydroxyaluminum aminoacetate and dihydroxyaluminum aminoacetic acid.

(4) Aluminum phosphate gel when used as part of an antacid combination product and contributing at least 25 percent of the total acid neutralizing capacity; maximum daily dosage limit is 8 grams.

persons up to 60 years old and 100 mEq. of sodium for persons 60 years or older, and 200 mEq. of bicarbonate ion for persons up to 60 years old and 100 mEq. of bicarbonate ion for persons 60 years or older. That part of the warning required by $330.1(g), which states, “Keep this and all drugs out of the reach of children” is not required on a product which contains only sodium bicarbonate powder and which is intended primarily for other than drug uses.

(2) Sodium potassium tartrate.
(1) Silicates:
(1) Magnesium aluminosilicates.
(2) Magnesium trisilicate.

(m) Tartrate-containing active ingredients. Tartaric acid or its salts; maximum daily dosage limit 200 mEq. (15 grams) of tartrate.

to an apparent pH of 3.5), and mix to wet the sample thoroughly. Add 70 mL of water, and mix on a magnetic stirrer at 300_30 r.p.m. for 1 minute. Analyze the acid neutralizing capacity of the sample according to the procedure provided in the United States Pharmacopeia 23/National Formulary 18 and calculate the percent contribution of the antacid active ingredient in the total product as follows:

Percent contribution = (Total mEq. Antacid Active Ingredient x100)/(Total mEq. Antacid Product).

[61 FR 4823, Feb. 8, 1996)

(39 FR 19874, June 4, 1974, as amended at 51 FR 27763, Aug. 1, 1986; 55 FR 19859, May 11, 1990]

8331.21 Test modifications.

The formulation or mode of administration of certain products may require a modification of the United States Pharmacopeia 23/National Formulary 18 acid neutralizing capacity test. Any proposed modification and the data to support it shall be submitted as a petition under the rules established in $10.30 of this chapter. All information submitted will be subject to the disclosure rules in part 20 of this chapter.

(61 FR 4823, Feb. 8, 1996)

Subpart D-Labeling

$ 331.15 Combination with nonantacid

active ingredients. (a) An antacid may contain any generally recognized as safe and effective nonantacid laxative ingredient to correct for constipation caused by the antacid. No labeling claim of the laxative effect may be used for such a product.

(b) An antacid may contain any generally recognized as safe and effective analgesic ingredient(s), if it is indicated for use solely for the concurrent symptoms involved, e.g., headache and acid indigestion, and is marketed in a form intended for ingestion as a solution.

(c) An antacid may contain any generally recognized as safe and effective antiflatulent ingredient if it is indicated for use solely for the concurrent symptoms of gas associated with heartburn, sour stomach or acid indigestion.

$ 331.30 Labeling of antacid products.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an antacid."

(b) Indications. The labeling of the product states, under the heading “Indications,” the following: “For the relief of” (optional, any or all of the following:) "heartburn," "sour stomach, and/or "acid indigestion” (which may be followed by the optional statement:) “and upset stomach associated with" (optional, as appropriate) “this symptom" "these symptoms." Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in $330.1(c)(2) of this chapter, subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction

Subpart C-Testing Procedures

or

8331.20 Determination of percent con

tribution of active ingredients. To determine the percent contribution of an antacid active ingredient, place an accurately weighed amount of the antacid active ingredient equal to the amount present in a unit dose of the product into a 250-milliliter (mL) beaker. If wetting is desired, add not more than 5 mL of alcohol (neutralized

into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(c) Warnings. The labeling of the product contains the following warnings, under the heading "Warnings”, which may be combined but not rearranged to eliminate duplicative words or phrases if the resulting warning is clear and understandable:

(1) “Do not take more than (maximum recommended daily dosage, broken down by age groups if appropriate, expressed in units such as tablets or teaspoonfuls) in a 24-hour period, or use the maximum dosage of this product for more than 2 weeks, except under the advice and supervision of a physician.”

(2) For products which cause constipation in 5 percent or more of persons who take the maximum recommended dosage: “May cause constipation."

(3) For products which cause laxation in 5 percent or more of persons who take the maximum recommended dosage: “May have laxative effect."

(4) For products containing more than 50 mEq. of magnesium in the recommended daily dosage: “Do not use this product except under the advice and supervision of a physician if you have kidney disease."

(5) For products containing more than 25 mEq. potassium in the maximum recommended daily dose: “Do not use this product except under the advice and supervision of a physician if you have kidney disease."

(6) For products containing more than 5 gm per day lactose in a maximum daily dosage: “Do not use this product except under advice and supervision of a physician if you are allergic to milk or milk products.

(d) Drug interaction precaution. The labeling of the product contains the following statements under the heading “Drug Interaction Precaution": “Antacids may interact with certain prescription drugs. If you are presently taking a prescription drug, do not take this product without checking with your physician or other health professional.”

(e) Directions for use. The labeling of the product contains the recommended dosage, under the heading “Direc

tions”, per time interval (e.g., every 4 hours) or time period (e.g., 4 times a day) broken down by age groups if appropriate, followed by “or as directed by a physician."

(f) Exemption from the general accidental overdose warning. The labeling for antacid drug products containing the active ingredients identified in $331.11(a), (b), and (d) through (m); permitted combinations of these ingredients provided for in $331.10; and any of these ingredients or combinations of these ingredients in combination with simethicone (identified in 8332.10 of this chapter and provided for in 8331.15(c)), are exempt from the requirement in $330.1(g) of this chapter that the labeling bear the general warning statement "In case of accidental overdose, seek professional assistance or contact a poison control center immediately." With the exception of sodium bicarbonate powder products identified in $331.11(k)(1), the labeling must continue to bear the first part of the general warning in $330.1(g) of this chapter, which states, “Keep this and all drugs out of the reach of children."

(g) [Reserved]

(h) The word “doctor" may be substituted for the word “physician” in any of the labeling statements in this section.

[39 FR 19874, June 4, 1974, as amended at 47 FR 38484, Aug. 31, 1982; 51 FR 16266, May 1, 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, Mar. 13, 1987; 55 FR 11581, Mar. 29, 1990; 58 FR 45208, Aug. 26, 1993; 59 FR 60556, Nov. 25, 1994; 61 FR 17806, Apr. 22, 1996)

8331.80 Professional labeling.

(a) The labeling of the product provided to health professionals (but not to the general public):

(1) Shall contain the neutralizing capacity of the product as calculated using the procedure set forth in United States Pharmacopeia 23/National Formulary 18 expressed in terms of the dosage recommended per minimum time interval or, if the labeling recommends more than one dosage, in terms of the minimum dosage recommended per minimum time interval.

(2) May contain an indication for the symptomatic relief of hyperacidity associated with the diagnosis of peptic

ulcer, gastritis, peptic esophagitis, gas

332.3 Definitions. tric hyperacidity, and hiatal hernia. (3) For products containing basic alu

Subpart B-Active Ingredients minum carbonate gel identified in

332.10 Antiflatulent active ingredients. $ 331.11(a)(1)-Indication. "For the

332.15 Combination with non-antiflatulent treatment, control, or management of

active ingredients. hyperphosphatemia, or for use with a low phosphate diet to prevent forma

Subpart C-Labeling tion of phosphate urinary stones, through the reduction of phosphates in 332.30 Labeling of antiflatulent products. the serum and urine."

332.31 Professional labeling. (4) For products containing aluminum

AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, identified in $331.11(a)Warnings. (1)

360, 371. Prolonged use of aluminum-containing

SOURCE: 39 FR 19877, June 4, 1974, unless antacids in patients with renal failure

otherwise noted. may result in or worsen dialysis osteomalacia. Elevated tissue aluminum levels contribute to the development of Subpart A-General Provisions the dialysis encephalopathy and osteomalacia syndromes. Small amounts of

8 332.1 Scope. aluminum are absorbed from the gas- An over-the-counter antiflatulent trointestinal tract and renal excretion

product in a form suitable for oral adof aluminum is impaired in renal fail

ministration is generally recognized as ure. Aluminum is not well removed by

safe and effective and is not misdialysis because it is bound to albumin

branded if it meets each of the followand transferrin, which do not cross di

ing conditions and each of the general alysis membranes. As a result, alu

conditions established in $330.1 of this minum is deposited in bone, and dialy

chapter. sis osteomalacia may develop when large amounts of aluminum are in

8 332.3 Definitions. gested orally by patients with impaired renal function.

As used in this part: (ii) Aluminum forms insoluble com- Antigas. A term that may be used plexes with phosphate in the gastro- interchangeably with the term antiintestinal tract, thus decreasing phos- flatulent. Neither term should be conphate absorption. Prolonged use of alu- sidered as describing the mechanism of minum-containing antacids by normo- action of the active ingredient conphosphatemic patients may result in tained in the product. hypophosphatemia if phosphate intake is not adequate. In its more severe

(61 FR 8838, Mar. 5, 1996) forms, hypophosphatemia can lead to anorexia, malaise, muscle weakness, Subpart B-Active Ingredients and osteomalacia.

(b) Professional labeling for an ant- 8332.10 Antiflatulent active ingrediacid-antiflatulent combination may

ents. contain the information allowed for

Simethicone; maximum daily dose health professionals for antacids and

500 mg. There is no dosage limitation antiflatulents.

at this time for professional labeling. (39 FR 19874, June 4, 1974. Redesignated and amended at 55 FR 19859, May 11, 1990]

$ 332.15 Combination with non-anti

flatulent active ingredients. PART 332-ANTIFLATULENT PROD- An antiflatulent may contain any

UCTS FOR OVER-THE-COUNTER generally recognized as safe and effecHUMAN USE

tive antacid ingredient(s) if it is indi

cated for use solely for the concurrent Subpart A-General Provisions

symptoms of gas associated with heart

burn, sour stomach or acid indigestion. Sec. 332.1 Scope.

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