Food and Drug Administration, HHS § 201.323
§ 201.322 Over-the-counter drug prod- ‘‘Alcohol Warning’’ [heading in bold- ucts containing internal analgesic/ face type]: ‘‘If you consume 3 or more antipyretic active ingredients; re- alcoholic drinks every day, ask your quired alcohol warning. doctor whether you should take [insert (a) People who regularly consume acetaminophen and one nonsteroidal large quantities of alcohol (three or anti-inflammatory analgesic/anti- more drinks every day) have an in- pyretic active ingredient—including, creased risk of adverse effects (possible but not limited to aspirin, carbaspirin liver damage or gastrointestinal bleed- calcium, choline salicylate, magnesium ing). OTC drug products containing in- salicylate, or sodium salicylate] or ternal analgesic/antipyretic active in- other pain relievers/fever reducers. [Ac- gredients may cause similar adverse ef- etaminophen and (insert one nonste- fects. FDA concludes that the labeling roidal anti-inflammatory analgesic/ of OTC drug products containing inter- antipyretic ingredient—including, but nal analgesic/antipyretic active ingre- not limited to aspirin, carbaspirin cal- dients should advise consumers with a cium, choline salicylate, magnesium history of heavy alcohol use to consult salicylate, or sodium salicylate] may a physician. Accordingly, any OTC cause liver damage and stomach bleed- drug product, labeled for adult use, ing.’’ containing any internal analgesic/anti- (b) Requirements to supplement ap- pyretic active ingredients (including, proved application. Holders of approved but not limited to, acetaminophen, as- applications for OTC drug products pirin, carbaspirin calcium, choline sa- that contain internal analgesic/anti- licylate, ibuprofen, ketoprofen, magne- pyretic active ingredients that are sub- sium salicylate, naproxen sodium, and ject to the requirements of paragraph sodium salicylate) alone or in combina- (a) of this section must submit supple- tion shall bear an alcohol warning ments under § 314.70(c) of this chapter statement in its labeling as follows: to include the required warning in the (1) Acetaminophen. ‘‘Alcohol Warn- product’s labeling. Such labeling may ing’’ [heading in boldface type]: ‘‘If you be put into use without advance ap- consume 3 or more alcoholic drinks proval of FDA provided it includes the every day, ask your doctor whether exact information included in para- you should take acetaminophen or graph (a) of this section. other pain relievers/fever reducers. Ac- (c) Any drug product subject to this etaminophen may cause liver damage.’’ section that is not labeled as required (2) Nonsteroidal anti-inflammatory an- and that is initially introduced or ini- algesic/antipyretic active ingredients—in- tially delivered for introduction into cluding but not limited to aspirin, interstate commerce after April 23, carbaspirin calcium, choline salicylate, 1999, is misbranded under section 502 of ibuprofen, ketoprofen, magnesium salicy- the Federal Food, Drug, and Cosmetic late, naproxen sodium, and sodium salicy- Act (21 U.S.C. 352) and is subject to reg- late. ‘‘Alcohol Warning’’ [heading in ulatory action. boldface type]: ‘‘If you consume 3 or more alcoholic drinks every day, ask [63 FR 56801, Oct. 23, 1998] your doctor whether you should take [insert one nonsteroidal anti-inflam- § 201.323 Aluminum in large and small matory analgesic/antipyretic active in- volume parenterals used in total parenteral nutrition. gredient] or other pain relievers/fever reducers. [Insert one nonsteroidal anti- (a) The aluminum content of large inflammatory analgesic/antipyretic ac- volume parenteral (LVP) drug products tive ingredient] may cause stomach used in total parenteral nutrition bleeding.’’ (TPN) therapy must not exceed 25 (3) Combinations of acetaminophen with micrograms per liter (µg/L). nonsteroidal anti-inflammatory analgesic/ (b) The package insert of LVP’s used antipyretic active ingredients—including in TPN therapy must state that the but not limited to aspirin, carbaspirin cal- drug product contains no more than 25 cium, choline salicylate, ibuprofen, µg/L of aluminum. This information ketoprofen, magnesium salicylate, must be contained in the ‘‘Pre- naproxen sodium, and sodium salicylate. cautions’’ section of the labeling of all
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large volume parenterals used in TPN tion of the method used and release therapy. data for several batches. Manufactur- (c) The maximum level of aluminum ers of parenteral drug products not present at expiry must be stated on the subject to an approved application immediate container label of all small must make assay methodology avail- volume parenteral (SVP) drug products able to FDA during inspections. Hold- and pharmacy bulk packages (PBP’s) ers of pending applications must sub- used in the preparation of TPN solu- mit an amendment under § 314.60 or tions. The aluminum content must be § 314.96 of this chapter. stated as follows: ‘‘Contains no more [65 FR 4110, Jan. 26, 2000] than l µg/L of aluminum.’’ The imme- diate container label of all SVP’s and EFFECTIVE DATE NOTE: At 65 FR 4110, Jan. PBP’s that are lyophilized powders 26, 2000, § 201.323 was added, effective Jan. 26, used in the preparation of TPN solu- 2001. tions must contain the following state- APPENDIX A TO PART 201—EXAMPLES OF ment: ‘‘When reconstituted in accord- GRAPHIC ENHANCEMENTS USED BY FDA ance with the package insert instruc- tions, the concentration of aluminum I. SECTION 201.66 STANDARD LABELING FORMAT l µ will be no more than g/L.’’ This A. Overall maximum level of aluminum must be stated as the highest of: 1. The ‘‘Drug Facts’’ labeling is set off in a (1) The highest level for the batches box or similar enclosure by the use of a barline with all black type printed on a produced during the last 3 years; white, color contrasting background. (2) The highest level for the latest five batches, or B. Typeface and size (3) The maximum historical level, 1. ‘‘Drug Facts’’ is set in 14 point Helvetica but only until completion of produc- Bold Italic, left justified. tion of the first five batches after Jan- 2. ‘‘Drug Facts (continued)’’ is set in 8 uary 26, 2001. point Helvetica Bold Italic for the words (d) The package insert for all LVP’s, ‘‘Drug Facts’’ and 8 point Helvetica Regular all SVP’s, and PBP’s used in TPN must for the word ‘‘(continued)’’ and is left justi- contain a warning statement. This fied. 3. The headings (e.g., ‘‘Directions’’) are set warning must be contained in the in 8 point Helvetica Bold Italic, left justified. ‘‘Warnings’’ section of the labeling. 4. The subheadings (e.g., ‘‘Ask a doctor or The warning must state: pharmacist before use if you are’’) are set in 6 point Helvetica Bold, left justified. WARNING: This product contains alu- 5. The information is set in 6 point minum that may be toxic. Aluminum may Helvetica Regular with 6.5 point leading, left reach toxic levels with prolonged parenteral justified. administration if kidney function is im- 6. The heading ‘‘Purpose’’ is right justified. paired. Premature neonates are particularly 7. The bullet is a 5-point solid square. at risk because their kidneys are immature, 8. Two em spacing separates bullets when and they require large amounts of calcium more than one bullet is on the same line. and phosphate solutions, which contain alu- 9. A table format is used for 3 or more dos- minum. age directions. Research indicates that patients with im- 10. A graphic appears at the bottom of the paired kidney function, including premature first panel leading the reader to the next neonates, who receive parenteral levels of panel. aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated C. Barlines and hairlines with central nervous system and bone tox- 1. A 2.5-point horizontal barline extends to icity. Tissue loading may occur at even each end of the ‘‘Drug Facts’’ box (or similar lower rates of administration. enclosure), providing separation between (e) Applicants and manufacturers each of the headings. must use validated assay methods to 2. A 0.5-point horizontal hairline extends determine the aluminum content in within 2 spaces on either side of the ‘‘Drug parenteral drug products. The assay Facts’’ box (or similar enclosure), imme- diately following the title and immediately methods must comply with current preceding the subheadings. good manufacturing practice require- 3. A 0.5-point horizontal hairline follows ments. Applicants must submit to the the title, immediately preceding the head- Food and Drug Administration valida- ing, when a heading appears on a subsequent
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