Food and Drug Administration, HHS § 201.323 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 ‘‘Alcohol Warning’’ [heading in bold- large volume parenterals used in TPN face type]: ‘‘If you consume 3 or more therapy. alcoholic drinks every day, ask your (c) Except as provided in paragraph doctor whether you should take [insert (d) of this section, the maximum level acetaminophen and one nonsteroidal of aluminum present at expiry must be anti-inflammatory analgesic/anti- stated on the immediate container pyretic active ingredient—including, label of all small volume parenteral but not limited to aspirin, carbaspirin (SVP) drug products and pharmacy 73 VerDate Aug<04>2004 12:59 Apr 25, 2005 Jkt 205068 PO 00000 Frm 00083 Fmt 8010 Sfmt 8010 Y:\SGML\205068.XXX 205068 Pt. 201, App. A 21 CFR Ch. I (4–1–05 Edition) bulk packages (PBPs) used in the prep- (f) Applicants and manufacturers aration of TPN solutions. The alu- must use validated assay methods to minum content must be stated as fol- determine the aluminum content in lows: ‘‘Contains no more than ll µg/L parenteral drug products. The assay of aluminum.’’ The immediate con- methods must comply with current tainer label of all SVP’s and PBP’s good manufacturing practice require- that are lyophilized powders used in ments. Applicants must submit to the the preparation of TPN solutions must Food and Drug Administration valida- contain the following statement: tion of the method used and release ‘‘When reconstituted in accordance data for several batches. Manufactur- with the package insert instructions, ers of parenteral drug products not the concentration of aluminum will be subject to an approved application no more than ll µg/L.’’ This max- must make assay methodology avail- imum level of aluminum must be stat- able to FDA during inspections. Hold- ed as the highest of: ers of pending applications must sub- (1) The highest level for the batches mit an amendment under § 314.60 or produced during the last 3 years; § 314.96 of this chapter. (2) The highest level for the latest [65 FR 4110, Jan. 26, 2000, as amended at 67 five batches, or FR 70691, Nov. 26, 2002; 68 FR 32981, June 3, (3) The maximum historical level, 2003] but only until completion of produc- APPENDIX A TO PART 201—EXAMPLES OF tion of the first five batches after July GRAPHIC ENHANCEMENTS USED BY FDA 26, 2004. (d) If the maximum level of alu- I. SECTION 201.66 STANDARD LABELING FORMAT µ minum is 25 g/L or less, instead of A. Overall stating the exact amount of aluminum as required in paragraph (c) of this sec- 1. The ‘‘Drug Facts’’ labeling is set off in a tion, the immediate container label box or similar enclosure by the use of a barline with all black type printed on a may state: ‘‘Contains no more than 25 white, color contrasting background. µg/L of aluminum.’’ If the SVP or PBP is a lyophilized powder, the immediate B. Typeface and size container label may state: ‘‘When re- 1. ‘‘Drug Facts’’ is set in 14 point Helvetica constituted in accordance with the Bold Italic, left justified. package insert instructions, the con- 2. ‘‘Drug Facts (continued)’’ is set in 8 centration of aluminum will be no point Helvetica Bold Italic for the words more than 25 µg/L’’. ‘‘Drug Facts’’ and 8 point Helvetica Regular for the word ‘‘(continued)’’ and is left justi- (e) The package insert for all LVP’s, fied. all SVP’s, and PBP’s used in TPN must 3. The headings (e.g., ‘‘Directions’’) are set contain a warning statement. This in 8 point Helvetica Bold Italic, left justified. warning must be contained in the 4. The subheadings (e.g., ‘‘Ask a doctor or ‘‘Warnings’’ section of the labeling. pharmacist before use if you are’’) are set in The warning must state: 6 point Helvetica Bold, left justified. 5. The information is set in 6 point WARNING: This product contains alu- Helvetica Regular with 6.5 point leading, left minum that may be toxic. Aluminum may justified. reach toxic levels with prolonged parenteral 6. The heading ‘‘Purpose’’ is right justified. administration if kidney function is im- 7. The bullet is a 5-point solid square. paired. Premature neonates are particularly 8. Two em spacing separates bullets when at risk because their kidneys are immature, more than one bullet is on the same line. and they require large amounts of calcium 9. A table format is used for 3 or more dos- and phosphate solutions, which contain alu- age directions. minum. 10. A graphic appears at the bottom of the Research indicates that patients with im- first panel leading the reader to the next paired kidney function, including premature panel. neonates, who receive parenteral levels of C. Barlines and hairlines aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated 1. A 2.5-point horizontal barline extends to with central nervous system and bone tox- each end of the ‘‘Drug Facts’’ box (or similar icity. Tissue loading may occur at even enclosure), providing separation between lower rates of administration. each of the headings. 74 VerDate Aug<04>2004 12:59 Apr 25, 2005 Jkt 205068 PO 00000 Frm 00084 Fmt 8010 Sfmt 8002 Y:\SGML\205068.XXX 205068.