Food and Drug Administration, HHS § 201.322

(2) The warning statement shall be accordance with the requirements of 40 clearly legible and conspicuous on the CFR part 82 and appear with such product, its immediate container, its prominence and conspicuousness as to outer packaging, or other labeling in render it likely to be read and under- accordance with the requirements of 40 stood by consumers under normal con- CFR part 82 and appear with such ditions of purchase. prominence and conspicuousness as to (d) This section does not replace or render it likely to be read and under- relieve a person from any requirements stood by consumers under normal con- imposed under 40 CFR part 82. ditions of purchase. [61 FR 20100, May 3, 1996] (3) If the warning statement in paragraph (b)(1) of this section is used, the § 201.322 Over-the-counter drug prod- following warning statement must be ucts containing internal analgesic/ placed on the package labeling in- antipyretic active ingredients; re- tended to be read by the physician quired alcohol warning. (physician package insert) after the (a) People who regularly consume ‘‘How supplied’’ section, which de- large quantities of alcohol (three or scribes special handling and storage more drinks every day) have an in- conditions on the physician labeling: creased risk of adverse effects (possible liver damage or gastrointestinal bleed- NOTE: The indented statement below is required by the Federal government’s Clean ing). OTC drug products containing in- Air Act for all products containing or manu- ternal analgesic/antipyretic active in- factured with chlorofluorocarbons (CFC’s) gredients may cause similar adverse ef- [or name of other class I substance, if appli- fects. FDA concludes that the labeling cable]: of OTC drug products containing inter- WARNING: Contains [or Manufactured with, nal analgesic/antipyretic active ingre- if applicable] [insert name of substance], a sub- dients should advise consumers with a stance which harms public health and the history of heavy alcohol use to consult environment by destroying ozone in the a physician. Accordingly, any OTC upper atmosphere. drug product, labeled for adult use, A notice similar to the above WARNING containing any internal analgesic/anti- has been placed in the information for the patient [or patient information leaflet, if ap- pyretic active ingredients (including, plicable] of this product under the Environ- but not limited to, acetaminophen, as- mental Protection Agency’s (EPA’s) regula- pirin, carbaspirin calcium, choline sa- tions. The patient’s warning states that the licylate, ibuprofen, ketoprofen, magne- patient should consult his or her physician if sium salicylate, naproxen sodium, and there are questions about alternatives. sodium salicylate) alone or in combina- (c)(1) For over-the-counter drug prod- tion shall bear an alcohol warning ucts for human use, the following al- statement in its labeling as follows: ternative warning statement may be (1) Acetaminophen. ‘‘Alcohol Warn- used: ing’’ [heading in boldface type]: ‘‘If you consume 3 or more alcoholic drinks NOTE: The indented statement below is re- every day, ask your doctor whether quired by the Federal government’s Clean you should take acetaminophen or Air Act for all products containing or manu- other pain relievers/fever reducers. Ac- factured with chlorofluorocarbons (CFC’s) [or other class I substance, if applicable]: etaminophen may cause liver damage.’’ (2) Nonsteroidal anti-inflammatory an- WARNING: Contains [or Manufactured with, if applicable] [insert name of substance], a sub- algesic/antipyretic active ingredients—in- stance which harms public health and envi- cluding but not limited to aspirin, ronment by destroying ozone in the upper at- carbaspirin calcium, choline salicylate, mosphere. ibuprofen, ketoprofen, magnesium salicy- CONSULT WITH YOUR PHYSICIAN OR late, naproxen sodium, and sodium salicy- HEALTH PROFESSIONAL IF YOU HAVE late. ‘‘Alcohol Warning’’ [heading in ANY QUESTION ABOUT THE USE OF THIS boldface type]: ‘‘If you consume 3 or PRODUCT. more alcoholic drinks every day, ask (2) The warning statement shall be your doctor whether you should take clearly legible and conspicuous on the [insert one nonsteroidal anti-inflam- product, its immediate container, its matory analgesic/antipyretic active in- outer packaging, or other labeling in gredient] or other pain relievers/fever

VerDate Mar<15>2010 08:48 May 17, 2010 Jkt 220068 PO 00000 Frm 00099 Fmt 8010 Sfmt 8010 Y:\SGML\220068.XXX 220068 wwoods2 on DSKDVH8Z91PROD with CFR § 201.323 21 CFR Ch. I (4–1–10 Edition)

reducers. [Insert one nonsteroidal anti- § 201.323 Aluminum in large and small inflammatory analgesic/antipyretic ac- volume parenterals used in total tive ingredient] may cause stomach parenteral nutrition. bleeding.’’ (a) The aluminum content of large (3) Combinations of acetaminophen with volume parenteral (LVP) drug products nonsteroidal anti-inflammatory analgesic/ used in total parenteral nutrition antipyretic active ingredients—including (TPN) therapy must not exceed 25 but not limited to aspirin, carbaspirin cal- micrograms per liter (μg/L). cium, choline salicylate, ibuprofen, (b) The package insert of LVP’s used ketoprofen, magnesium salicylate, in TPN therapy must state that the naproxen sodium, and sodium salicylate. drug product contains no more than 25 ‘‘Alcohol Warning’’ [heading in bold- μg/L of aluminum. This information face type]: ‘‘If you consume 3 or more must be contained in the ‘‘Pre- alcoholic drinks every day, ask your cautions’’ section of the labeling of all doctor whether you should take [insert large volume parenterals used in TPN acetaminophen and one nonsteroidal therapy. anti-inflammatory analgesic/anti- (c) Except as provided in paragraph pyretic active ingredient—including, (d) of this section, the maximum level but not limited to aspirin, carbaspirin of aluminum present at expiry must be calcium, choline salicylate, magnesium stated on the immediate container salicylate, or sodium salicylate] or label of all small volume parenteral other pain relievers/fever reducers. [Ac- (SVP) drug products and pharmacy etaminophen and (insert one nonste- bulk packages (PBPs) used in the prep- roidal anti-inflammatory analgesic/ aration of TPN solutions. The alu- antipyretic ingredient—including, but minum content must be stated as fol- not limited to aspirin, carbaspirin cal- lows: ‘‘Contains no more than ll μg/L cium, choline salicylate, magnesium of aluminum.’’ The immediate con- salicylate, or sodium salicylate] may tainer label of all SVP’s and PBP’s cause liver damage and stomach bleed- that are lyophilized powders used in ing.’’ the preparation of TPN solutions must (b) Requirements to supplement ap- contain the following statement: proved application. Holders of approved ‘‘When reconstituted in accordance applications for OTC drug products with the package insert instructions, that contain internal analgesic/anti- the concentration of aluminum will be pyretic active ingredients that are sub- no more than ll μg/L.’’ This max- ject to the requirements of paragraph imum level of aluminum must be stat- (a) of this section must submit supple- ed as the highest of: ments under § 314.70(c) of this chapter (1) The highest level for the batches to include the required warning in the produced during the last 3 years; product’s labeling. Such labeling may (2) The highest level for the latest be put into use without advance ap- five batches, or proval of FDA provided it includes the (3) The maximum historical level, exact information included in para- but only until completion of produc- graph (a) of this section. tion of the first five batches after July (c) Any drug product subject to this 26, 2004. section that is not labeled as required (d) If the maximum level of alu- and that is initially introduced or ini- minum is 25 μg/L or less, instead of tially delivered for introduction into stating the exact amount of aluminum interstate commerce after April 23, as required in paragraph (c) of this sec- 1999, is misbranded under section 502 of tion, the immediate container label the Federal Food, Drug, and Cosmetic may state: ‘‘Contains no more than 25 Act (21 U.S.C. 352) and is subject to reg- μg/L of aluminum.’’ If the SVP or PBP ulatory action. is a lyophilized powder, the immediate container label may state: ‘‘When re- [63 FR 56801, Oct. 23, 1998] constituted in accordance with the EFFECTIVE DATE NOTE: At 74 FR 19407, Apr. package insert instructions, the con- 29, 2009, § 201.322 was removed, effective Apr. centration of aluminum will be no 29, 2010. more than 25 μg/L’’.

VerDate Mar<15>2010 08:48 May 17, 2010 Jkt 220068 PO 00000 Frm 00100 Fmt 8010 Sfmt 8010 Y:\SGML\220068.XXX 220068 wwoods2 on DSKDVH8Z91PROD with CFR