13996 RULES AND REGULATIONS

Title 21-Food and Drugs Old New Old New PART 200-GENERAL Section Section Section Section Subpart A--General Provislons CHAPTER I-FOOD AND DRUG ADMIN- 133.11 ---- 211.58 3.509 ----- 201.314 Sec. ISTRATION, DEPARTMENT OF HEALTH, 133.12 ---- 211.110 3.510 ----- 201.315 200.5 Mailing of important information EDUCATION, AND WELFARE 133.13 ---- 211.60 3.512 ----- 200.31 about drugs. 133.14 ---- 211.62 [Recodification Docket No. 9] 3.513 ----- 200.7 200.7 Supplying pharmacists with Indi- ---- 211.115 3.514 ----- 201.55 133.15 cations and dosage information. SUBCHAPTER C-DRUGS: GENERAL 133.100 ____ 225.1 3.515 ----- 201.160 con- --- 22520 200.10 Contract facilities (including 3.516 ----- 250.105 133.101 sulting laboratories) Utilized as Reorganization and Republication --- 225.30 3.518 ----- 201.161 133.102 extramural facilities by pharma- 133.103 --- 225.10 The Commissioner of Food and Drugs, 132.1 ----- 207.3 ceutical manufacturer=. 133.104 --- 225A2 for the purposes of establishing an 132.2 ----- 207.20 200.11 Use of octadecylamine in steam of informative reg- 132.3 ----- 207.21 133.105 --- 225.102 lines of drug establishments. orderly development 133.106 --- 225.40 ulations for the Food and Drug Admin- 132.4 ---- 207.22 200.15 Definition of term "Insulin." 132.5 ----- 207.25 133.107 --- 225.80 istration, furnishing ample room for ..... 200.18 Use of secondhand containers for 132.6 ----- 207.30 133.108 225.58 the shipment or storage of food expansion of such regulations in years 225.110 132.7 ----- 207.31 133.109 and animal feed. ahead, and providing the public and af- 132.8 ----- 207.35 133.110 --- 225.115 --- Subpart B-ManufacturnlProcedures Affecting fected industries with regulations that 132.9 ----- 207.37 133.200 226.1 Novi DrugStatus are easy to find, read, and understand, 132.10 ---- 207.26 133.201 --- 226.20 has initiated a recodification program for 132.11 ---- 207.39 133.202 --- 226.30 200.30 Sterilization of drugs by irradia- the Code of Fed- 132.31 ---- 207.40 133.203 --- 226.10 tion. Chapter I of Title 21 of --- eral Regulations. 132.51 ---- 207.65 133.204 226.2 200.31 Timed release dosage forms. 133.1 ----- 210.3 133.205 --- 226.102 This is the ninth document in a series Subpart C--Requirements for Specific Classes or 133.2 ----- 211.1 133.206 -.... 226A0 Drugs of recodification documents that will 133.3 ----- 211.20 133.207 -- 226.80 eventually include all regulations ad- 133.4 ---- 211.30 133.208 226.58 200.50 Ophthalmic preparations and dis- ministered by the Food and Drug Ad- 133.5 ----- 211.10 133.209 --- 226.110 pensers, ministration. 133.6 ------211.42 133.210 --- 226.115 Subpart D-Sutability of Specific Drug This recodiflcation document repre- 133.7 ----- 211.101 133.300 --- 229.25 Components re- 133.8 ----- 211.40 138.1 ----- 299.3 200.100 Use of on bile from condemned sents a reorganization of material ----- Subchapter C-Drugs that 133.9 211.55 138.2 299.20 livers from slaughtered animals maining in ---- has general applicability, rather than 133.10 211.80 in the manufacture of drugs. 200.101 Suprarenal glands from hog car- strictly human or animal use. In addi- ' The changes being made are nonsub- casses prior to final inspection, tion certain related sections under Parts stantive in nature and for this reason 1 and 3 have been redesignated as part notice and public procedure are not pre- AuTnoRITy: Sec. 701, 52 Stat. 1055; 21 of the revised Subchapter C-Drugs: requisites to this promulgation. For the U.S.C. 371, unless otherwise noted. General. convenience of the user, the entire text of Subpart A-General Provisions The following table shows the relation- Parts 200, 201, 202, 207, 210, 211, 225, 226, ship of the CFR section numbers inder 229, 250, 290, and 299 of Subehapter C § 200.5 Mailing of important inforniu- tion about drugs. the former Subchapters A and C to their is set forth below. redesignation reflected in the new Parts Manufacturers and distributors of Dated: March 21, 1975. 200 through 299: drugs and the Food and Drug Adminis- Old New Old New S A D. FINE, tration occasionally are required to mal Section Section Section Section Associate Commissioner for Important Information about drugs to 1.100 ----- 299.5 3.21 ------250.102 Compliance. physicians and others responsible for public interest, such 1.101 -----.- 201.6 3.22 ------200.101 Therefore, 21 CFR is amended by re- patient care. In the 1.101a ---- 201.60 3.27 ------250.203 mail should be distinctive In appearance of Parts 1 and 3 1.102 ----- 201.50 3.28 ------200.50 designating portions so that It will be prolnptly recognized and Parts 132, 133, and 1.102a ---- 201.61 3.29 ------201.307 of Subehapter A and read. The Food and Drug Administration 1.102b ---- 201.1 3.30 ------201.308 138 of Subchapter C as Parts 200, 201, will make such mailings In accordance 226, 229, 250, 290, 1.102c ------201.51 3.35 ------201.303 202, 207, 210, 211, 225, with the specifications set forth In this 1.102d ---- 201.62 3.36 ------250.103 and 299 of Subchapter C-Drugs: Gen- section. Manufacturers and distributors 1.103 ------201.15 3.37 ------201.309 eral, and republished to read as follows: 1.104 ----- 201.10 3.40 ------250.201 of drugs are asked to make such mailings 1.105 ---- 202.1 33.------201.310 SUBCHAPTER C-DRUGS: GENERAL as prescribed by-this section and not to 1,106(a) --- 201.5 3.44 ------201.311 Part use the distinctive envelopes for ordinary --- 1.106(b) 201.100 3.45 ------200.30 200-General mall. 1.106(c) --- 201.105 3.48 ------250.106 (a) Use first class mail and No. 10 1.106(d) --- 201.109 3.50 ------250.104 201-Labeling white envelopes. ---- 1.106(f) 201.110 3.52 ------250.107 (b) The name and address of the 1.106(g) --- 201.115 3.53 ------250.10 202-Prescription Drug Advertising or dis- 1.106(h) - 201.116 3.56 ------201A05 207-Registration of Producers of Drugs and agency or the drug manufacturer 1.106(1) ---- 201.117 3.61 ------200.18 Listing of Drugs in Commercial DIs- tributor Is to appear In the upper left 1.106(J) ---- 201.119 3.62 ------2994 tribution corner of the envelope. 1.106(k) --- 201.120 3.63 ------250.11 (c) The following statements are to 1.106(1) ---- 201.122 3.64 ------250.12 210-Current Good Manufacturing Practices in Manufacturing, Processing, Pack- appear in the far left third of the en- 1.106(m) --- 201.125 3.67 ------201.305 ing, or Holding of Drugs: General velope front, in the type and size indi- - 1.106(n) 201.127 3.71 ------250.100 In a rectangular spabo 1.105(o) --- 201.128 3.74 ------201.56 cated, centered 211-Current Good Manufacturing Practice approximately 3 inches wide and 22/ 1.107 ----- 201.150 3.76 ------200.10 for Finished Pharmaceuticals 1.108(a) 3.77 ------290.35 Inches high with an approximately %- & (b) ---- 201.16 3.81 ------201.200 225--Current Good Manufacturing Practice Inch-wide border in the color indicated: 1.108(c) ---- 290.6 3.84 ------201.410 for Medicated Feeds (1) When the information concerns 1.109 ----- 290.5 3.90 ------250.300 226-Current Good Manufacturing Practice a significant hazard to health, the state- 1.110 ----- 290.10 3.91 ------250.250 for Medicated Premixes ment: r ----- 200.15 250.109 1.115 3.94 ------IMAPORTANT 201.300 229-Current Good Manufacturing Practice 3.3 ------3.95 ------250.110 DRUG 3.4 ------201.302 3.501 ----- 200.5 for Certain Other Drug Products WARNZING 3.7------250.108 3.502 ----- 201.19 250-Special Requirements for Specific Hu- 3.8 ------250.101 3.503 ----- 201.312 man Drugs The statement shall be In three lines, all 3.11 ------201.301 3.505 ----- 201.313 capitals, and centered. "Important" shall Drugs 3.12 ------201.304 3.506 ----- 200.11 290-Controlled be in 36 point Gothic Bold type. "Drug" 3.15 ------201.306 3.507 _- ---201.17 29-Drugs; Official Names and Established and "Warning" shall be in 38 point 3.16 ------200.100 3.508 ----- 201.18 Names Gotl e Condensed type. The rectangle's

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 13996 1975 RULES AND REGULATIONS 13997 border-and -the statement therein shall Claimed Exemption for Investigational (b) The Commissloner concludes that be red. New Drug (IND), any information ob- such dangerous or potentially dangerous (2) When the information concerns tained during the inspection of an extra- practices include, but are not limited to, important changes In drug package mural facility having a specific bearing the following: labeling, the statement: on the compliance of the manufacturer's, (1) 'Some vegetable growers and IMPORTA.NT applicant's, or sponsor's product with packers employ used poultry crates for PRESCRIBING the Federal Food, Drug, and Cosmetic shipment of fresh vegetables, including INFORMATION Act. The Food and Drug Administration's cabbage and celery. Salmonella orga- The statement shall be in three lines, all position is that by the acceptance of such nisms are commonly present on dressed capitals, contract work, the extramural facility poultry and in excreta and fluid exu- and centered. "Important" shall authorizes such disclosures. dates from dressed birds. Thus wooden be in 36 point Gothic Bold type. 'Pre- (d) Food and Drug Administra- scribing" and "Information" shall be in .The crates in which dressed poultry has been 36 point Gothic Condensed tion does not consider results of valida- Iced and packed are potential sources of type. The tion studies of analytical- and assay Salmonella or other enteropathogenfe rectangle's border and the statement methods -therein shall be blue. and control procedures to be microorganisms that may contaminate (3) When the information concerns a trade secrets that may be withheld from fresh vegetables which are frequently correction of prescription drug advertis- the drug manufacturer by the contracted consumed without heat treatment ing or labeling, the statement: extramural facility. (2) Some potato growers and pro- (Sics. 501. 505, 704(a), 52 Stat. 1049-50, as ducers of animal feeds use secondhand IMPORTANT amended, 1052-53, as amended, 67 Stat. 477, bags for shipment of these articles. Such CORRECTION as amended, 76 Stat. 2l OF DRUG 792: U.S.C. 351, 355, bags may have originally been used for INFORMATION 374(a)) shipping or storing pesticlde-treated seed Use or other articles bearing or containing The statement § 200.11 of octadecylamie insteanm shall be ifi four lines, all lines of drug cstablilslunents. poisonous substances. Thus these sec- capitals, and centered. "Important" shall ondlhnd bags are potential sources of be in 36 point Gothic Bold type. "Correc- The Food and Drug Administration contamination of the food or animal tion." "Of Drug," and "Information" will not object to the use of octadecyla- feed stored or shipped therein. bshall be in 36 point Gothic Condensed mine in steam lines where the steam may be used for autoclaving surgical In- (c) In a policy statement Issued type. The rectangle's border and the April 11, 1968, the Food and Drug Ad- statement therein shall be brown. struments and gauze If the octadecyla- ministration declared adufterated within (Sem. 705(b), 52 Stat. 1058; 21 U.S.C. $75(b)) mine in the steam Is not more than 2.4 parts per million. the meaning of section 402(a) of the § 200.7 Supplying pharmacists with in- Federal Food, Drug, and Cosmetic Act dications and dosage information. (See. 502, 52 Stat. 1051; 21 U.S.C. 352) shipments of vegetables or other edible § 200.15 Definition of term "insulin." food In used crates or containers that There are presently no regulations may render the contents Injurious to under the Federal Food, Drug, and Cos- For, the purposes of sections 502(k) health. Thlspolicy statement Is extended metic Act that prevent a manufacturer and 506 of the act: so that the Food and Drug Administra- of prescription drugs from sending the (a) The term "Insulin" a' used therein tion will regard as adulterated within pharmacist data he needs on indications means the active principle of pancreas the meaning of section 402(a) of the act and dosage in exercising his Important which affects the metabolism of carbo- shipments of vegetables, other edible professional function of checking against hydrate in the animal body and which food, or animal feed in used crates, bags, possible mistakes in a prescription. The is of value in the treatment of diabetes or other containers that may render the Food and Drug Administration believes mellitus. ,contents injurious to health. manufacturers should be encouraged to (b) The following substances, when supply such printed matter to the phar- they are intended for use in the manu- (Sees. 402(a), 52 Stat. 1046, -as amended; 21 macist for his professional information. facture Of Insulin-containing drugs that US.C. 342(a)) Obviously, such printed matter should will subsequently be submitted for certi- Subpart B-Manufacturing Procedures not be displayed to prospective pur- fication, shall not be considered to be Affecting New Mrg Status chasers to promote over-the-counter sale subject to certification as "drugs com- § 200.30 Sterilization of drugs by irra- of pfescription drugs. posed wholly or partly of insulin": diation. (Sees. 502(f) (1). 503(b) (1) (B).'52 Stat. 1051. (1)Pancreas glands; and 52 Stat. 1052. as amended 65 Stat. 648, 649; (2) Materials prepared from pan- There Is a current interest in the uti- 21 U.S.C. 352(f) (1), 353(b) (1) (B)) creas glands, such as "salt cake" and lization of newly developed sources of radiation for the sterilization of drugs § 200.10 Contract facilities (including "isoelectric precipitate," which materials' must be subjected to further purification Prior to the marketing of a drug steri- consulting laboratories) utilized as lized by such means, It is necessary in extramural facilities by pharmaceu- in order to meet the standards of purity established by Part 429 of this chapter. the interest of protecting the public tical manufacturers. health to establish by adequate investi- (a) Section 704(a) of -the Federal (Sec. 506, 55 Stat. 851; 21 U.S.C. 356) gations that the Irradiation treatment Food, Drug, and Cosmetic Act specifically § 200.18 Use of secondhand containers does not cause the drug to become un- authorizes inspection of consulting for the shipment or storage of food safe or otherwise unsuitable for use. Ac- laboratories as well as any factory, ware- and animal feed. cordlngly, all drug products, including house, or establishment in which pre- (a) Investigations by the Food and Injections, ophthalmic solutions, surgi- scription drugs are manufactured, proc- Drug Administration, the National Com- cal sutures, and surgical dressings ster- essed, packed, or held. municable Disease Center of thesU.S. ilized by means of irradiation are (b) The Food and Drug Administra- Public Health Service, the Consumer and regarded as new drugs within the mean- tion is aware that many manufacturers Marketing Service of the U.S. Depart- tg of section 201(p) of the Federal Food, of pharmaceutical products utilize ex- ment of Agriculture, and by various State Drug, and Cosmetic Act. An effective tramural independent contract facilities, public health agencies have revealed new-drug application pursuant to sec- such as testing laboratories, contract practices whereby food and animal feed tion 505 of the act is therefore a pre- packers or labelers, and custom grinders, stored or shipped in secondhand con- requisite to interstate shipment of such and regards extramural facilities as an tainers have been rendered dangerous to articles, except as provided by section extension of the manufacturer's own health. Such contamination has been 505(1). facility. the result of the original use of these (Smes. 201. 505, 52 Stat. 1040, as amended, (c) The Food and Drug Administra- containers for the storage and shipment 1052. as amended: 21 U.S.C. 321, 355) tion reserves the right to disclose to the 200.31 pharmaceutical manufacturer, or to the of articles containing or bearing disea.se § Timed release dosage forrs. applicant of a new drug applicatiod organisms or poisonous or deleterious (a) Many drugs are now being offered (NDA) or to the sponsor of a Notice of substances. in dosage forms that are designed to re-

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 13997 1975 13998 RULES AND REGULATIONS

lease the active ingredients over a pro- the act. This ruling is extended to af- tity of contents in the container (for ex- longed period. There is a possibility of fect all preparations for ophthalmic use. ample, "50 gallons") and the name and unsafe overdosage if such products are (3) The containers of ophthalmic address of the manufacturer, packer, or improperly made and the active ingre- preparations shall be sterile at the time shipper. dients are released at one time or over too of filling and closing, and the container (c) Bile from the condemned livers of short a time interval. Any such dosage or individual carton shall be.so sealed sheep and goats also may be released, form that contains per dosage unit (for that the contents cannot be used with- under the same conditions as outlined In example, capsule or tablet), a quantity out destroying the seal. To provide time the preceding paragraph, except that of active drug ingredients which is not for validation of sterility tests and the words "Sheep Bile" or "Goat Bile," generally recognized as safe for ad- changes to sterile production procedures, as the case may be, shall be substituted ministration as a single dose under the this ruling will be effective for non- for the words "Ox Bile" upon the label, conditions suggested in Its labeling, is antitbiotic 'ophthalmic ointment prepa- In the case of mixtures of bile from any regarded as a new drug within the mean- rations recognized in the official com- two or all three of the sources mentioned, ing of section 201(p) of the Federal Food, pendia (U.S.P. and N.F.) on the dates the label shall indicate the sources of Drug. and Cosmetic Act. specified in such official compendia. For such bile. (b) The fact that the labling of this all other ophthalmic ointments, this rul- § 200.101 Suprarenal glands from hog type of drug may claim delayed or pro- ing will be effective 12 months after the carcasses prior lo final inspection. longed release of all or s6me of the active date of publication in the FEDERAL REGIS- ingredients does not affect the new-drug TER (10-28-72). (a) The Agricultural Research Serv- status of such articles. A new-drug (b) Liquid ophthalmic preparations ice of the U.S. Department of Agricul- application is required in any such case packed in multiple-dose containers ture has informed the Food and Drug to demonstrate that the drug is in fact should: Administration of the Department of safe because it is properly made and con- (1) Contain one or more suitable and Health, Education, and Welfare that, trolled to release the total dose at a safe harmless substances that will inhibit the under appropriate conditions, it will per- rate. It should be noted particularly that growth of microorganisms-; or mit the removal of suprarenal glands such dosage forms are regarded as new (2) Be so packaged as to volume and from hogs that have not been finally In- drugs even when the total daily dosage type of container and so labeled as to spected by Federal Inspectors. The recommended in the labeling is generally duration of use and with such necessary glands to be so obtained are Intended for recognized as safe. For example, a cap- warnings as to afford adequate protec- use in manufacturing extracts contain- sule containing 50 milligrams of pyrila- tion and minimize the hazard of injury ing one or more of the therapeutically mine maleate and 15 milligrams of resulting from contamination during use. useful constituents of suparenal glands. phenylephrine hydrochloride, offered for (c) Eye cups, eye droppers, and other (b) Under the conditions specified In sale without prescription, is regarded as dispensers intended for ophthalmic use this section, the Secretary of Health, a new drug for which the distributor should be sterile, and may be regarded Education, and Welfare has determined should have an effective new-drug ap- as falling below their professed standard that the public healthi will be adequately plication, even though the directions call of purity or quality if they are not sterile. protected from any danger from the use for taking no more than two capsules They should be so packaged as to main- of drugs, made in whole or In part from daily. While the daily intake under such tain sterility until the package is opened suprarenal glands of hogs that may be directions is within the range regarded and be so labeled, on or within the retail condemned by Federal Inspectors of the as safe for use in self-medication, the package, as to afford adequate directions Department of Agriculture after re- single dose is too high for such use unless and necessary warnings to minimize the moval of such glands from the carcasses, the release of the drug is sufficiently pro- hazard of injury resulting from con- arising from any abnormality of such longed. Itis obvious that, In filing anew- tamination during use. carcasses if such glands are subjected to drug the application for such an article, par- Subpart D-Suitability of Specific Drug following prescribed treatment, ticular attention should be given to data Components which will destroy or eliminate any ml. which establish that the active ingredi- crodrganiss or toxins that might be ents are released over a period of time. § 200.100 Use of ox bile from con- present in the glands: as )epresented in'he labeling. demned 'livers from slaughtered ani- (c) The glands are subjected to quick mals in the manufacture of drugs. (Sec. 201(p), 52 Stat. 1042; 21 U.S.C. 321(p)) freezing promptly upon removal from (a) Conferences have recently been the carcasses and maintained in a frozen Subpart C-Requirements for Special held between members of the Depart- state until they are ground and Im. Classes of Drugs ment of Health, Education, and Welfare mersed in 95 percent to 100 percent ace- § 200.50 Ophthalmic preparations and and representatives of the Agricultural tone. The ground tissues remain in the dispensers. -Research Service, Department of Agri-, acetone for a period of not less than a culture, concerning requests made to days, the mixture is filtered, and thO (a) (1) Informed medical opinion is in residue is burned. agreement that all preparations offered that agency for the release of ox bile or intended for ophthalmic use, includ- from condemned livers of slaughtered ing contact lens animals for use in the manufacture of solutions and prepara- drugs. PART 201-LABELING tions for cleansing the eyes, should be certain sterile. It is further evident that such (W The Secretary of Health, Educa- Subpart A--General Labeling Provlsiong preparations purport to tion, and Welfare has given careful con- Sec. be of such purity sideration and quality as to be suitable for safe -use to this problem and has 201.1 Drugs and devices; namo and place in the eye. reached the conclusion that no hazard to of buslne.s of manufacturer, (2) The Food and Dxug Administration public health will be involved in the re- packer or dtstributor. concludes that all such preparations, if lease of such ox bile, after the addition to 201.5 Drugs and dovices; adequate direc- they are not sterile, fall below their it of sufficient sodium hydroxide to give tions for us3. pro- the fessed standard of purity or quality and mixture a sodium hydroxide content 201.6 Drugs and dc-Ices; misleaflng may be unsafe. In a statement of policy of not less than 5 percent, the mixture statements. Issued on September then being allowed to stand at least 24 201.10 Drugs; statement of Ingredlents, 1, 1964, the Food hours. This and Drug Administration ruled that Department will not regard 201.15 Drugs and devices; prominence of liquid preparations offered as in violation of the provisions of the required label statements. or intended Federal for ophthalmic use that are not sterile Food, Drug, and Cosmetic Act 201.16 Drugs and devices; Spanish- may be regarded as adulterated within such alkalized and aged ox bile, if labeled language version of certain re- the meaning of section 501(c) of the "Ox Bile and Sodium Hydroxide (or Ox quired statements. Federal Food, Drug, and Cosmetic Act, Bile and Sodiuni Hydroxide Solution). 201.17 Drugs; location of expiration date. and, further, may be deemed misbranded Sodium hydroxide not less than 5 percent 201.18 Drugs; significance of control within the meaning of section 502(j) of by weight. For manufacturing use only," number. together with a statement of the quan- 201.19 Drugs; use of term "infant".

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- Subpart B-Labeling Requirements for Sec, Directions Prescription for use may be inadequate Drugs and/or Insulin 201.312 Magnesium sulfate beptahydrate; because (among other reasons) label declaration on of.omls- Sec. drug prod- Sion, in whole or in part, or incorrect 201.50 Statement of Identity. ucts. specification of: 201.51 Declaration of net quantity of con- 201.313 Estradlol labeling. tents. 201.314 Labeling of drug preparations con- (a) Statements of all conditions, pur- 201.55 Statement of-dosage. taining salcylates. poses, or uses for which such drug or 201.56 Content and format of labeling. 201.315 Over-the-counter drugs for minor device is Intended, Including conditions, Subpart C-Labeling Requirements for Over-the- sore throats: suggested warning. purposes, or uses for which- It is pre- Counter Drugs and Devices Subpart H-Special Requirements for scribed, recommended, or suggested In Specific Devices its oral. written, 201.60 Principal display panel. printed, or graphic ad- 201.61 Statement of identity. 201.405 Labeling of articles Intended for vertising, and conditions, purposes, or 201.62 Declaration of net quantity of con- lay use In the repairing and/or uses for which the drug or device Is tents. refitting of dentures. commonly used; except that such state- 201.410 Use of Impact-resistant Subpart D-Exemptions from Adequate lenses In ments shall not refer to conditions, Directions for Use eyeglasses and sunglasses. uses, or purposes for which the drug or 201.100 Prescription drugs for human use. Aur-orrY: Sec. 701. 52 Stat. 1055--1056 as device can be safely used only under 201.105 Veterinary drugs. amended; 21 U.S.C. 371, unless otherwise the supervision of a practitioner licensed 201.109 Prescription devices. noted. by law and for which it is advertised 201.110 Retail exemption for veterinary Subpart A--General Labeling Provisions solely to such practitioner. drugs-and prescription devices. (b) Quantity of'dose (including usual 201.115 New drugs or new animal drugs. § 201.1 Drugs and devices; name and quantities for each of the uses for which 201.116 Drugs and devices having commonly place of business of nmnufacturer, It Is Intended and usual quantities for known directions. packer or distributor. persons 201.117 Inactive ingredients. of different ages and different 201.119 In vitro diagnostic products. (a) The label of a drug or device in physical conditions). 201.120 Prescription chemicals and other package form shall specify conspicuously (c) Frequency of administration or prescription components. the name and place of business of the application. 201.122 Drugs and devices for processing, manufacturer, packer, or distributor. (d) Duration of administration or ap- - repacking, or manufacturing. (b) The requirement for declaration of plication. 201.125 Drugs and devices for use in teach- the name of the manufacturer, packer, (e) Time or administration or appli- ing, law enforcement, research, cation (in relation to time of meals, time and analysis. or distributor shall be deemed to be satis- 201.127 Drugs fied, in the case of a corporation, only by of onset of symptoms, or other time fac- and devices; expiration of tors). exemptions. - the actual corpbmte name which may be 201.128 Meaning of "Intended uses". preceded or followed by the name of the (f) Route or method of administra- tlon or application. Subpart E-Other Exemptions particular division of the corporation. Abbreviations for "Company," "Incor- (g) Preparation for use (shaking, di- 201.150 Drugs'and devices; processing, label- porated." etc., may be used and "'Ihe" lution, adjustment of temperature, or ing, or repacking. may be omitted. other manipulation or process) 201.160 Drugs; information commonly In the case of an in- known. dividual, partnership, or association, the § 201.6 Drugs and devices; misleading 201.161 Carbon dixide and certain other name under which the business is con- statements. gases. ducted shall be used. (c) Where a drug or device is not (a) Among representations in the la- Subpart F-Labeling Claims for Drugs iii beling Drug manufactured by the person whose name of a drug or device which render Efficacy Study such drug or device misbranded Is a false 201.200 Disclosure of drug efficacy study appears on the label, the name shall be qualified by a phrase that reveals the or misleadingyepresentation with respect evaluations in labeling and adver- to another tising. I connection such person has with such drug or device or a food or drug or device; such as, "Manufactured. cosmetic. Subpart G--Specific Labeling Requirements (b) The labeling of a drug which con- for Specific Drug Products for - ", "Distributed by -----", or any other wording that expresses the taIns two or more ingredients may be 201.300 Notice to manufacturers, packers, misleading by reason and distributors of glandular facts. (among other rea- preparations. (d)The statement of the place sons) of the designation of such drug In of busi- such labeling 201.301 Notice to manufacturers, packers, ness shall, include the street address, by a name which Includes and distributors of estrogenic city. State, and ZIP Code; however, the or suggests the name of one or more but hormone preparations. street address may be omitted if It Is not all such Ingredients, even though 201.302 Notice to manufacturers, packers, shown In a current city directory or tele- tWe names of all such Ingredients are and distributors of drugs for in- t ted elsewhere In the labeling. ternal use ,which contain mineral phone directory. The requirement for in- clusion of the ZIP Code shall apply only (See. 502.52 Stat. 1050. as amended; 21 US.C. oil 352) 201.303 Labeling-of drug preparations con- to consumer commodity labels developed taining significant proportions of or revised after thfe effective date of this § 201.10 Drugs; statement of ingredi- wintergreen oil. section. In the' case of nonconsumer ents. 201.304 'Tannic acid and barium enema packages, the ZIP 'Code shall appear preparations. either on the label or the labeling (in- (a) The Ingredient information re- 201.305 Isoproterenol inhalation prepara- cluding the invoice). quired by section 502(e) of the Federal tions (pressurized aerosols, neb- (e) If a person Food, Drug, and Cosmetic Act shall ap- ulizers, powders) for human manufactures, packs, use; or distributes a drug or device at a place pear together, without any intervening warnings. written, printed, 201.306 Potassium salt preparations In- other than his principal place of busi- or graphic matter, ex- tended for oral Ingestion by man. ness, the label may state the principal cept the proprietary names of ingredi- 201.307 Chlorcyclizine, cyclizine, meclizine; place of business In lleu of the actual ents. which may be Included with the warnings; labeling requirements. place where such drug or device was listing of established names, and such 201.308 Ipecac syrup; -warnings and direc- manufactured or packed or Is to be dis- Statements as "Warning-May be habit tions for use for over-the-counter tributed, unless such statement would be forming" that are specifically required sale. misleading. for certain ingredients by the act or 201.309 Acetophenetidin (phenacetin) - regulations in this chapter. containihg preparations; neces- § 201.5 Drugs and devices; adequate (b) The term "ingredient" applies to Ssary warning statement. directions for use. 201.310 Phenindione; labeling of drug any substance In the drug. whether added preparations intended for use by "Adequate directions for use" means to the formulation as a single substance man. directions under which the layman or in admixture with other substances. 201.311 Anminopyrine or dipyrone drug prep- can use a drug or device safely and (c) The labeling of a drug may be arations for human use; direc- for the purposes for which It is Intended misleading by reason (among otherrea- Stions and warnings. (Section 201.128 defines "intended use.") sons) of:

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(1) The order in which the names (g) (1) If the label or' labeling of a name or designation for such mixture of the Ingredients present in the drug prescription drug bears a proprietary and there is no established name corre- appear in the labeling, or the relative name or designation for the drug or any sponding to such proprietary name or prominence otherwise given such names. Ingredient thereof, the established name, designation, the quantitative ingredient (2) Failure to reveal the proportion If such there be, corresponding to such information required on the label by sec- of, or other fact with respect to, an proprietary name or designation shall tion 502(e) of the act shall be placed in ingredient present in such drug, when accompany such proprietary name or direct conjunction with the most promi- such proportion orlother fact is material designation each time it Is featured on nent display of the proprietary name or in the light of the representation that the label or in the labeling for the drug; designation. The prominence of the such ingredient is present in such drug. but, except as provided in this sub- quantitative ingredient information shall (3) The employment of a fanciful paragraph, the established name need bear a reasonable relationship to the proprietary name for a drug or ingre- not be used with the proprietary name prominence of the proprietary name. dient in such a manner as-to imply that or designation in the running text of the (2) If the drug is packaged in a con- the drug or ingredient has some uniclue label or labeling. On any label or page of tainer too small to bear the quantitative effectiveness or composition when, in labeling In which the roprletary name ingredient information on the main dis- fact, the drug or ingredient is a common or designation is not featured but is used play panel, the quantitative ingredient substance, the limitations of which are in the running text, the established name information required by section 502(o) readily fecognized when the drug or in- shall be used at least once In the running of the act may appear elsewhere on the gredient is listed by its established name. text In association with such proprietary label, even though the proprietary name (4) The featuring, in the labeling of name or designation and in the same or designation appears on the main dis- inert or inactive ingredients in a manner type size used in such running text: Pro- play panel of the label; but side- or back- that creates an impression of value vided, however, That if the proprietary panel placement shall in this case be so greater than their true functional role name or designation is used in the run- arranged and printed as to provide size in the formulation. ning text in larger size type, the estab- and prominence of display reasonably (5) Designation of a drug or ingredi- lished name shall be used at least once related to the size and prominence of the ent by a proprietary name that, because in association with, and in type at least front-panel display. of similarity in spelling or pronuncia- half as large as the type used for, the (I) A drug packaged in a container too tion. may be confused with the proprie- most prominent presentation of the pro- small or otherwise unable to accommo- tary name or the established name of a prietary name or designation in such date a label with suffielent space to bear different drug or ingredient. running text. If any labeling includes a the information required for compliance (d) (1 If the drug-is in tablet or cap- column with running text containing de- with section 502(e) (1) (A) (it) and (B) sule form or other unit dosage form, any tailed information as -to composition, of the act shall be exempt from compli- statement of the quantity of an ingre- prescribing, side effects, or contraindica- ance with those clauses: Provided, That: dient contained therein shall express the tions and the proprietary name or desig- (1) Thelabel bears: quantity of such ingredient in each such nation is used In such column but Is not (1) The proprietary name of the drug: unit. If th6 drug i not in unit dosage featured above or below the column, the (ii) The estabflshed name, If such form, any statement of the quantity of established name shall be used at least there be. of the drug: an ingredient contained therein shall ex- once in such column of running text in (ill) An identifying lot or control press the amount of such ingredient in association with such proprietary name number: and a specified unit of weight or measure of or designation and in the same type size (Wiv)The name of the manufacturer, the drug, or the percentage of such in- used in such column of running text: packer, or distributor of the drug; and gredient in such drug. Such statements Provided, however, That if the pro- (2) All the Information required to shall be in terms that are informative to prietary name or designation is used in appear on the label by the act and the licensed practitioners, in the case of a .such column of running text in larger regulations in this chapter appears on prescription drug. and to the layman, in' size type, the established name shall be the carton or other outer container or the case of a nonprescription drug. used at least once in association with, wrapper if such carton, outer container, (2) A statement of the percentage of and in type at least half as large as the or wrapper has sufficient space to bear an ingredient in a drug shall, if the type used for, the most prominent pres- such Information, or such complete label term "percent" is used without quali- entation of the proprietary name or information appears on a leaflet with the fication, mean percent weight-in-weight. designation in such column of running package. if the ingredient and the drug are both text. Where the established name is re- § 201.15 Drugs and devices; prominence solids, or if the ingredient is a liquid and quired to accompany or to be used In as- of required label statements. the drug is a solid; percent weight in sociation with the proprietary name or volume at 680 F. (20° C.), if the in- designation, the established name shall (a) A word, statement, or other in- gredient is a solid and the drug is a be placed in direct conjunction withthe formation required by or under authority liquid; and percent volume in volume at proprietary name or designation, and the of the act to appear on the label may lack 68- F. (20 C.), if both the ingredient relationship between the proprietary that prominence and conspicuousness re- and the drug are liquids, except that name or designation and the established quired by section 502(c) of the act by alcohol shall be stated in terms of per- name shall be made clear by use of a reason (among other reasons) of: cent volume of absolute alcohol at 60' phrase such as "brand of" preceding the (1) The failure of such word, state- F. (15.56 C.). established name, by brackets surround- ment, or information to appear on the (e) A derivative or preparation of a ing the established name, or by other part or panel of the label which is pre- substance named in section 502(e) of the suitable means. sented or, displayed under customary act is an article derived or prepared from (2) The established name shall be conditions of purchase; such substance by any method, includ- printed in letters that are at least half (2) The failure of such word, state- ing actual or theoretical chemical action as large as the letters comprising the ment, or information to appear on two (f) If an ingredient is a derivative or proprietary name or designation with or more parts or panels of the label, each preparation of a substance specifically which it is joined, and the established of which has sufficient space therefor, named in section 502(e) of the act and name shall have a prominence commen- and each of which is so designed as to the established name of such ingredient surate with the prominence with which render It likely to be, under customary does not indicate that It is a derivative such proprietary name or designation conditions of purchase, the part or panel or preparation of the parent substance appears, taking into account all perti- displayed; named in section 502(e) of the act, the nent factors. including typography, lay- (3) The failure of the label to extend labeling shall, in conjunction with the out. contrast, and other printing over the area of the container or package listing of the established name of such features. available for such extension, so as to ingredient, declare that such article is a (h) (1) In the case of a prescription provide sufficient label space for the derivative or preparation of such parent drug containing two or more active in- prominent placing of such word. state- substance. gredients, if the label bears a proprietary ment, or information;

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(4) Insufficiency of label space (for translation must convey the meaning the drug. An Insulin-containing drug the prominent placing of such word. properly, in order to avoid confusion and shall be further Identified by placement statement, oI information) resulting dilution of the purposes of the warnings. on the outside container or wrapper of the package, and on the label of the from the use of label space for any word, The Commissioner of Food and DrugB 5 statement, design, or device which is not hereby adopts the following Spanish- Immediate container, of the dlstingulsh required by or under authority of the act language versions as the accepted equiv- Ing color(s) required by § 429.12 of this to appear on the label; alents of the English wording of the -chapter. In -the cas3 "of a prescription (5) Insufficiency 6f label space (for following: drug that is a mixture and that has no the prominent placing of such word, (a) Section 503(b)C4) of the Federal established name, the requirement for statement, or information) resulting Food, Drug, and Cosmetic Act requires statement of identity shall be deemed from the use of label space to give ma- the statement "Caution: Federal law to be satisfied by a listing of the quanti- terially greater conspicuousness to any. prohibits dispensing without prescrip- tative ingredient information as pre- other word, statement, or information, tion." The Spanish version of this shall scribed by § 201.10. or to any design or device; or be: "Precaucion: La Icy Federal prohlbe (c) The statement of Identity of a (6) Smallness or style of type in su despacho sin prescrlpcion facultativa:' prescription drug shall also comply with which such word, statement, or informa- Cb) Section 502(d) of the Federal the placement, size and prominence re- tion appears. insufficient background 'Food, Drug, and Cosmetic Act requires quirements of § 201.10. contrast, obscuring designs or vignettes.* the statement 'Warning-May be habit § 201.51 Declaration of net quantity of or crowding with other written, printed, forming" on habit-forming drugs. The contents. or graphic mattef. Spanish version of this shall be: "Avso-- (b) No exemption depending on in- Puede formar habito o viclo:' (a) The label of a prescription or in- label space, as prescribed sulln-containing drug in package form sufficiency of § 201.17 Drugs; location of expiration shall bear a declaration of the net quan- in regulations promulgated under sec- date. tion 502 Cb) or (e) of the act, shall apply tty of contents. This shall be expressed if such insufficiency is caused by:- Drugs which require an expiration in the terms of weight, measure, numeri- (1) The use of label space for any date should show the expiration date cal count, or a combination of numerical word. statement, design, or device which on the immediate container. When the count and weight or measure. The state- is not required by or under authority of Immediate container is packaged In an ment of quantity of drugs In tablet, cap- the act to appear on -the label; individual carton, the expiration date sule, ampule, or other unit dosage form (2) The use of label space to give should also be placed on the carton. shall be expressed In terms of numerical greater conspicuousness to any word. Whbn single-dose containers are packed count; the statement of-quantity for statement, or-other infoxmation than is in individual cartons, the expiration date drugs in, other dosage forms shall be In required by section 502 (c) of the act; or may properly appear on the carton only. terms of weight If the drug is solid, semi- (3) The use of label space for any (Sees. 505, 605, 507,52 Stat. 1052. as amended. solid, or viscous, or in terms of fluid representation in a foreign language. 55 Stat. 851.59 Stat. 463. 01 Stat. 12, 63 Stat. measure if the drug Is liquid. When the . (c)(1) All words, statements, and 409; 21 U.S.C. 355, 350, 357) drug quantity statement Is in terms of or under the numerical count of the drug units, it other information required by § 201.18 Drugs; significance of control shall be augmented to give the weight authority of the act to appear on the numbers. or measure of the drug units or the quan- label or libeling shall appear thereon in The lot number on the label of a drug tity of each active Ingredent n each drug the Engl4h language: Provided, how- should be capable of yl.Iding the com- unit or, when quantity does not ac- ever, That in the case of articles distrib- plete manufacturing history of the pack- uted solely in the Commonwealth of curately reflect drug potency, a statement age. An incorrect lot number may be of the drug potency. Puerto Rico or in a Territory where the regarded as causing the article to be (b) Statements of weight of the con- predominant language is one other than misbranded. English. the predominant language may tents shall in the case of prescription (Se. 502, 52 Stat. 1050; 21 U.S.O. 352) drugs be expressed in terms of avoirdu- be substituted for English. pois pound, ounce, and grain or of kilo- (2) If the label contains any repre- § 201.19 Drugs; use of term "infant". gram, gram, and subdivisions thereof. A sentation in a foreign language, all The regulations affecting special die- statement of liquid measure of the con- words, statements, and other informa- tary foods § 125.1(d) of this chapter) tents shall in the case of prescription tion required by' or under authority of define an infant as a child not more drugs be expressed In terms of the U.S. the act to appear on the label shall than 12 months old. Apart from this, gallon of 231 cubic Inches and quart, appear thereon in the foreign language. the Food and Drug Administration has pint, fluid-ounce, and fluid-dram sub- (3) If the labeling contains any repre- not established any definition of the divisions thereof, or of the liter and mlM- sentation in a foreign language, all term "Infant." Some question has arisen liter, or cubic centimeter, and shall ex- words, statements, and'other informa- whether, for the purposes of drug label- press the volume at 680 F. (200 C.). A tion required by or under authority of ing, an infant means a child up to 1 year statement of the liquid measure of the the act to appear on the label or labeling of age or a child up to 2 years of age. contents in the case of Insulin-contain- shall appear on the labeling in the for- Until the term is more precisely defined lug drugs shall be expressed in terms of eign language. .by legislation or formal regulation, the liter and milliliter, or cubic centi- (Sec. 502, 52 Stat. 1050, as amended; 21 where the exact meaning of the term meter. and shall express the volume at U.S.C. 352) is significant, maufacturers should 680 F. (200 C.). §201.16 Drugs and devices; Spanish- qualify any reference to "Infant" to in- c) The declaration shall contain only language version of certain required dicate whether it refers to a child who such fractions as are generally used in statements. is not more than 1 year of age, or a child expressing the quantity of the drug. A not more than 2 years of age. common fraction shall be reduced to its An ncreasing number oftmedlcations (Sec. 502, 52 Stat.,1051; 21 U.S.C. 352) lowest terms; a decimal fraction shall restricted to prescription use only are not be carried out to more than three being labeled solely in Spanish for dis- Subpart B-Labeling Requirements for places, except In the case of a statement tribution in the Commonwealth of Puerto Prescription Drugs and/or Insulin of the quantity of an active ingredient Rico where Spanish is the predominant in a unit of a drug. language. Such labeling is authorized § 201.50 Statement 6f identity. d) The declaration shall appear as under § 201.15(c). Two required warn- (a) The label of prescription and in- a distinct item on the label and, in-the ings. the wording of which is fixed by sulin-contalning drugs in package form case of large volume parenterals, may law in the English. language, are pres- shall bear as one of Its principal features be embossed on the glass. ently being translated in various ways, (e) The declaration shall accurately from literal translation to loose Inter- a statement of the Identity of the drug. reveal the quantity of drug in the pack- pretation. The statutory nature of Cb) Such statement of Identity shall age exclusive of wrappers and other ma- these two statements requires that the be in terms of the established name of terial packed therewith.

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(f) A statement of the quantity of a safe and effective use of a drug, as re- obvious "principal display panel" such as prescription or insulin-containing drug quired under § 201.100, §hould ordinarily the top of a triangular or circular pack- in terms of weight or measure applicable contain information in substantially the age, the area shall consist of the entire to such drug, under the provisions of format and order and with the section top surface. paragraph (a) of this section, shall ex- headings as follows: In determining the area of the principal press with prominence and conspicuous- DESCanTIroN display panel, exclude tops, bottoms, ness the number of the largest whole ACTIONS flanges at the tops and bottoms of cans, unit, as- specified in paragraph (b) of INDICATIONS and shoulders and necks of bottles or this section, that are contained in the CONTRAINDICATIONS Jars. In the case of cylindrical or nearly package. Any remainder shall be ex- WARNINGS PRECAUTIONS cylindrical containers, information re- pressed in terms of common or decimal ADVERSE REACTIONS quired by this part to appear on the prin- fractions of such unit or In terms of the D OSAGE AND ADmInISTRATION cipal display panel shall appear within next smaller whole unit and common or OVERDOSAGE (WHERE APPLICABLE) that 40 percent of the circumference decimal fractions thereof. *How SUPPLIED which is most likely to be displayed, (g) The declaration of net quantity, of (b) The following sections are optional. presented, shown, or examined under contents shall express an accurate state- If used, they should be placed after the customary conditions bf display for re- ment of the quantity of contents of the tail sale. package. Reasonable variations caused information described above. by loss or gain of moisture during the AN=AL PHARACOLOGY AND TOXICOLOGY § 201.61 Statement of identity. course of good distribution practice or CLINICA.I STDIRES (a) The principal display panel of an by unavoidable deviations in good manu- REFERENCES over-the-counter drug or device in pack- facturing practice will be recognized. (c) Although ordinarily prescription age form shall bear as one of Its princi- Variations from stated quantity of con- drug labeling should employ the format, pal features a statement of the identity tents shall not be unreasonably large. In order, and section headings described of the commodity. the case of a liquid drug in ampules or in paragraphs (a) and (b) of this sec- (b) Such statement of Identity shall vials, intended for injection, the declara- tion, in the case of some drugs special be in terms of the established name of tion shall be considered to express the warnings may be required to appear con- if any there be, or common minimum quantity and the variation spicuously in the beginning of the label- the drug, special attention by physicians name of the device followed by an ac- above the stated measure shall comply ing for curate statement of the general phar- with the excess volume prescribed by for the safety of patients. In the case of of the drug the National Formulary -or the U.S. a drug for which there is no information macological category(les) Pharmacopela for filling of anipules. In applicable to a section heading described or the principal intended action(s) of the the case of a solid drug in ampules or in paragraph (a) of this section, sucl drug or device. In the case of an over- heading and section may be omitted. the-counter drug that is a mixture and vials, the declaration shall be considered that has no established name, this re- to express the accurate net weight. (Secs. 502, 503, 52 Stat. 1050-52, as amended; quirement shall be deemed to be satisfied Variations shall comply with the limita- 21 U.S.C. 352, 353) by a prominent and conspicuous state- tions provided In the U.S. Pharmacopela Subpart C-Labeling Requirements for ment of the general pharmacological ac- or the National Formulary. Over-the-Counter Drugs and Devices tion(s) of the mixture or of Its principal (h) A drug-shall be exempt from com- intended action(s) In terms that are pliance with the net quantity declara- , 201.60 Principal display panel. meaningful to the layman. Such state- tion.required by this section If it is an The term "principal display panel," as ments shall be placed in direct conjunc- ointment labeled "sample", "physician's It applies to over-the-counter drugs and tion with the most prominent display of sample", or a substantially similar state- devices in package form and as used in the proprietary name or designation and ment and the contents of the package do this part, means the part of a label that shall employ terms descriptive of general not 6xceed 8 grams. - is most likely to be displayed, presented, pharmacological category(les) or prin- § 201.55 -Statement of dosage. shown, or examined under customary cipal Intended action(s): for example, sale. The Section 201.100(b)(2) requires that conditions of display for retail "antacid," "analgesic,"' "decongestant," labels for prescription drugs -bear a principal display panel shall be large "antihistaminic," etc. The Indications for statement of -the recommended or enough to accommodate all the manda- use shall be Included in the directions tory label information required to be for use of the drug, as required by sec- usual dosage. Since the dosage for clarity some prescription drugs varies within placed thereon-by this part with tion 502(f) (1) of the act and by the extremely wide limits, depending upon and conspicuousness and without obscur- regulations in this part. the conditiong being treated, it may ing designs, vignettes, or crowding. (c) The statement of Identity shall be not be possible in all cases to pre- Where packages bear alternate principal presented in bold face type on rhe prin- sent an informative or useful statement display panels, information required to cipal display panel, shall be in a size of the recommended or usual dosage in be placed on the principal display panel reasonably related to the most prominent the space available on the label or carton shall be duplicated on each principal dis- printed matter on such panel, and shall of the package. It is the view of the play panel. For the purpose of obtaining be in lines generally parallel to the base uniform type size in declaring the quan- on which the package rests as It Is de- Food and Drug Administration that tity of contents -for all packages of sub- when such a situdtion prevails, compli- stantially the same size, the term "area signed to be displayed. ance with this requirement would be met § 201.62 . Declaration of net qutifty of by a statement such as "See package in- of the principal display panel" means sert for dosage information", where the 'the area of the side or surface that bears contents. detailed information is contained in such the principal display panel, which area (a) The label of an over-the-counter insert. However. If an informative. shall be: drug or device In package form shall bear realistic, recommended or usual dosage (a) In the case of a rectangular pack- a declaration of the net quantity of con- can readily be set forth on the label, it age where one entire side properly can tents. This shall be expressed in the should appear thereon. be considered to be the principal display terms of weight, measure, numerical panel side, the product of the height count, or a combination or numerical § 201.56 Content and format of labeling. times the width of that side; count and weight, measure, or size. The (a) To be most useful to practitioners, (b) In th6 case of a cylindrical or statement of quantity of drugs in tablet, labeling information for prescription nearly cylindrical container. 40 percent capsule, ampule, or other unit form and drugs should be orderly and-uniform in of the product of the height of the con- the quantity of devices shall be expressed the sequence and kinds of information tainer times the circumference; and in terms of numerical count; the state- presented. For this reason, the Food and (c) In the case of any other shape of ment of .quantlty for drugs In other Drug Administtion recommends that container, 40 percent of the total surface dosage forms shall be in terms of weight prescription drug labeling purporting to of the container: Provided, however, if the drug is solid, cemisolid, or viscous, furnish adequate information for the That where such container presents an or In terms of fluid measure If the drug

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The drug quantity statement space equal to the height of the lettering (3) When fractions are used, each shall be augmented when necessary to used in the declaration) from other component numeral shall meet one-half give accurate information as to the -printed label information appearing the minimum height standards- strength of such drug in the package; for above or below the declaration and (by (h) The declaration shall be In letters example, to differentiate between several at least a space equal to twice the width and numerals In a type size established strengths of the same drug "100 tablets, of the letter '"' of the style of type In relationship to the area of the prin- 5 grains each" or "100 capsules, 125 mil- used in the quantity of contents state- cipal display panel of the package and ligrams each" or "100 capsules, 250 milli- ment) from other printed label informa- shall be uniform for all packages of sub- grams each": Provided,That: tion appearing to the left or right of the stantially the same size by complying (1) In the case of a firmly established, declaration. It shall not include any with the following type specifications: general consumer usage and trade cus- term qualifying a unit of weight, meas- (1) Not less than one-sixteenth Inch tom of declaring the quantity of a drug ure, or count (such as "giant pint" and in height on packages the principal dis- or device in terms of linear measure or "full quart") that tends to exaggerate play panel of which has an area of 5 measure of area, such respective term the amount of the drug in the con- square inches or less. may be used. Such term shall be" aug- taifer. It shall be placed on the principal (2) Not less than one-eighth inch in mented when necessary for accuracy of display panel within the bottom 30 per- height on packages the principal display information by a statement of the weight, cent of the area of the label panel in panel of which has an area of more than measure, or size of the individual units or lines generally parallel to the base on ave but not more than 25 square inches. of the entire drug or device; for example, which the package rests as it is de- (3) Not less than three-sixteenths Inch the net quantity of adhesive tape in pack- signed to be displayed: Provided, That: n height on packages the principal dis- age form shall be expressed in terms of (1) On packages having a principal play panel of which has an area of more linear 'measure augmented by a -state- display panel of 5 square inches or less than 25 but not more than 100 square ment of its width. the requirement for placement within Inches. (2) If the declaration of contents for the bottom 30 percent of the area of the (4) Not less than one-fourth inch in a device by numerical count does not give label panel shall not apply when the dec- height on packages the principal display accurate information as to the.quantity laration of net quantity of contents 100 square inches, except not less than of the device in the package, it shall be meets the other requirements of this one-half inch In height if the area Is augmented by such statement of *eight, part; and more than 400 square inches. measure, or size of the individual units (2) In the case of a drug that Is or of the total weight, measure, or size of marketed with both outer and inner re- Where the declaration Is blown, em- the device as will give such information; bossed, or molded on a glass or plastic tail containers bearing the mandatory surface rather than by printing, typing. for exampl6, "100 tongue depressors, label information required by this part or coloring, adult size," "1 rectal syringe, adult size," ahd the inner container is not intended the lettering sizes specified etc. Whenever the Commissioner deter- to be sold separately, the net quantity of in iaragraphs (h) (1) through (4) of mines for a specific packaged drug or contents placement requirement of this this section shall be increased by one-- device that an existing -practice .of de- section applicable to such inner container sixteenth of an Inch claring net quantity of cohtents by Is waived. (1) On packages containing less than weight, measure, numerical count, or a (3) The principal display panel of a 4 pounds or 1 gallon and labeled In terms combination of these does not facilitate drug marketed on a display card to which of weight or fluid measure: value comparisons by consumers, he shall the immediate container Is affixed may (1) The declaration shall be expressed by regulation designate the appropriate be consldei-ed to be the display panel of both in ounces. with Identification by term or terms to be used for such article. the card, and the type sIze of the net weight or by liquid measure and, If appli- (b)Statements of weight of the con- quantity of contents statement s gov- cable (1 pound or I pint or more) tents shall be expressed in terms of erned by the dimensions of the display followed in parentheses by a declaration avoirdupois pound and ounce. A state- card. In pounds for weight units, with any re- ment of liquid measure of the contents (f) The declaration shall accurately mainder in terms of ounces or common shall be expressed in terms of the U.S. reveal the quantity of drug or device in or decimal fractions of the pound (see gallon of 231 cubic, inches and quart, the package exclusive of wrappers and examples set forth in paragraph (k) pint, and 'luid-ounce subdivisions there- other material packed therewith: Pro- (1) and (2) of this section), or in the -of, and shall express the volume at 68° F. vided, That in the case of 'drugs packed case of liquid measure, in the largest (20' C.) (see also paragraph (p)of this In containers designed to deliver the drug whole units (quarts. quarts and pints, or section). under pressure, the declaration shall pints, as appropriate) with any re-, (c)The declaration may contain com- state the net quantity of the contents mainder In terms of fluid ounces or mon or decimal fractions. A common that will be expelled when the Instruc- common or decimal fractions of the pint fraction shall be in terms of halves, tions for use as shown on the container or quart (see examples set forth in para- quarters, eighths, sixteenths, or thirty- are followed. The propellant Is included graph (Wr(3) and (4) of this section). seconds; except that if there exists a In the net quantity declaration. If the net weight of the package is less firmly established, general consumer (g) The declaration shall appear In panel of which has an area of more than usage .and trade custom of employing conspicuous and easily legible boldface than 1 ounce avoirdupois or the net fluid different common fractions in the net print or type in distinct contrast (by measure is less than 1 fluid ounce, the quantity declaration of a particular com- typography, layout, color, embossing, or declaration shall be In terms of common modity, they may be employed. A com- molding) to other matter on the pack- or decimal fractions of the respective mon fraction shall be reduced to its age; except that a declaration of net ounce and not in terms of drams. lowest terms; a decimal fraction shall quantity blown, embossed, or molded on (2) The declaration may appear in not be carried out to more a glass or plastic surface is permissible more than one line. The term "net than two weight" shall be used when stating the places.,A statement that includes small when all label information s so formed net fractions of an ounce shall be deemed to on the surface. Requirements of con- quantity of contents in terms of permit smaller variations than one spicuousness and legibility shall include weight. Use of the terms "net" or "net -which does not include such fractions. the specifications that: contents" in terms of fluid measure or (d) The declaration shall be located (1)The ratio of height to width (of numerical count Is optional. It Is suf- on the principal display panel of the ,the letter) shall not exceed a differential cient to distinguish avoirdupois ounce label, and with respect to packages bear- of 3 units to I unit (no more than 3 times from fluid ounce through association of ing alternate principal panels it shall be %shigh as it Is wide) terms; for example. "Net wt. 6 oz." or "6 duplicated on each principal display (2) Letter heights pertain to upper oz- net wt.," and "6 fi. oz." or "net con- case or capital letters. tents 6 fl. oz."' panel. When upper and () (e) The declaration shall appear as a lower case or all lower case letters are On packages cortainlng 4 pounds or 1 gallon or more and distinct item on the principal display used, It Is the lower case letter "o" or Its labeled in terms equivalent that shall meet the minimum of weight or fluid measure, the declara- lanel, shall be separated (by at least a "standards. tion shall be expresseo In pounds for

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MSARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14003 1975 14004 RULES AND REGULATIONS weight units with any remainder in or decimal fractions of the square foot (2) The recommended or usual dos- terms of ounces or common or decimal or square yard; for example, "158 sq. age, and fractions of the pound; in the case of inches (1 sq. ft. 14 sq. in.)." (3) The route of administration, If fluid measure, it shall be expressed in (o) Nothing in this section shall pro- it Is not for oral use; and the largest whole unit (gallons, fQllowed hibit supplemental statements at loca-. (4) The quantity or proportion of by common or decimal fractions of a tions other than the principal display each active ingredient, as well as the gallon or by the next smaller whole unit panel(s), describing in nondeceptive informati6n required by section 502 (d) or units (quarts or quarts and pints)) terms the net quantity of contents, pro- and (e) ; and with any remainder in terms of fluid vided that such supplemental statements (5) If it is for other than oral use, the ounces or common oi decimal fractions of net quantity of contents shall not in- names of all inactive ingredients, except of the pint or quart (see paragraph (W) clude any term qualifying a unit of that: (5) of this section). weight, measure, or count that tends to (i) Flavorings and perfumes may be (k) Examples: exaggerate the amount of the drug or designated as such without naming their (1) A declaration of 1% pounds weight device contained in the package; for components. shall be expressed as "Net wt. 24 oz. example, "giant pint" and "full quart." (ii) Color additives may be designated (Q lb. 8 oz.),"."Net wt. 24 oz. (i lb.)" Dual or combination declarations of net as coloring without naming specific color or "Net wt. 24 oz. (1.5 lb.) ." quantity of contents as provided for In components unless the naming of such (2) A declaration of three-fourths paragraphs (a) and (I) of this section components is required by a color addi- pound avoirdupois weight shall be ex- are not regarded as supplemental net tive regulation prescribed In Part 8 of pressed as "Net wt. 12 oz." quantity statements and shall be located this chapter, (3) A declaration of 1 quart liquid 'on the principal display panel. (iii) Trace amounts of harmless sub- measure shall be expressed as "Net con- (p) A separate statement of net quan- stances added solely for individual prod- tents 32 fi. oz. l. qt.) ." (1 qt.)" or "32 oz. (1 tity of contents in terms of the metric uct identification need not be named. system of weight or measure Is not re- If It is Intended for adnifinistratIon by (4) A declaration Of 13 quarts liquid garded as a supplemental statement and parenteral injection, the quantity or measure shall be expressed as "Net con- an accurate statement of.the net quan- proportion of all inactive Ingredients, tents 56 fl.oz. (1 qt. 1 pt. 8 oz.)" or "Net -tity of contents in terms of the metric except that Ingredients added to adjust contents 56 fl.oz. (1 qt. 1.5 pt.)," but system of weight or measure may also the pH or to make the drug Isotonic may not in terms of quart and ounce such as appear on the principal display panel or be declared by name and a statement of "Net 56 fl.oz. (Iqt. 24 oz.)." on other panels. their effect; and if the vehicle Is water (5) A declaration of 2% gallons liquid (q) The declaration of net quantity for injection it need not be named. measure shall be expressed as "Net con- of contents shall express an accurate (6) An Identifying lot'or control num- tents 2 gal. 2 qt.," "Net contents 2.5 statement of the quantity of contents of ber from which it Is possible to determine gallons," or "Net contents 2Y2 gal.' but the package. Reasonable variations the complete manufacturing history of not as "2 gal. 4 pt." caused by loss or gain of moisture during the package of the drug; (1) For quantities, the following ab- the course of good distribution practice breviations and none other may be Provided. however, That in the case of or by unavoidable deviations in good containers too small or otherwise unable employed (periods and plural forms are manufacturing practice will be recog- optional): to accommodate a label with sufflclent nized. Variations from stated quantity space to bear all such Information, but gallon gal. millilter mL of contents shall not be unreasonably quart qt. cubic centimeter cc. which are packaged within an outer con- large. tainer from which they are removed for pint pt. yard yd. (r) A drug shall be exempt from ounce oz. feet or foot ft. com- dispensing or use, the information re- pound lb. inch in. pliance with the net quantity declara- quired by paragraph (b) (2), (3) and grain gr. meter m. tion required by this section if It is an (5) of this section may be contained kilogram kg. centimeter cm. ointment labeled "sample," "physician's In other labeling on or within the pack- gram g. milimeter mm sample," or a substantially similar state- age from which It Is to be dlspensd, and milligram mg. fluid fl. ment and the contents of the package do the information referred to in paragraph microgram mcg. square sq. not exceed 8 grams. ' liter 1. ,weightwt. (b) (1) of this section may be placed on Subpart D-Exemptions From Adequate such outer container only, and the In- (m) On packages labeled in terms of Directions for Use formation required by paragraph (b) (6) linear measure, the declaration shall be of this section may be on the crimp of expressed both in tehns of inches and, if § 201.100 Prescription drugs for human Use. the dispensing tube. applicable (1 foot or more), the largest (c) (1) Labeling on or within the whole units (yards, yards and feet, feet). A drug subject to the requirements of Package from which the drug is to be The declaration in terms of the largest section 503 (b) (1) of the act shall be dispensed bears adequate Information for whole units shall be in parentheses fol- exempt from section 502 (f) (1) if all Its use, including Indications, effects, lowing the declaration in terms of inches the following conditions are met: dosages, routes, methods, and frequency and any remainder shall be in terms of (a) ,The drug is: and duration of administration, and any inches or common or decimal fractions of (1) () In the possession of a person relevant hazards. contraindications, side the foot or yard; if applicable (as In the (or his agents or employees) regularly effects, and precautions under which case of adhesive tape), the initial declar- and lawfully engaged in the manufac- Practitioners licensed by law to admin- ation in linear inches shall be preceded ture, transportation, storage, or whole- ister the drug can use the drug safely and by a statement of the width. Examples sale distribution of prescription drugs: for the purposes for which it is intended, of linear measure are "86 inches (2 yd. 1 or Including all purposes for which it is ft. 2 in.)," "90 inches (2'A yd.)," "30 (ii) In the possession of a retail, hos- advertised or represented: and Inches (2.5 ft.)." "/ inch by 36 In. (1 pital. or clinic pharmacy, -or a public (2) If the article is subject to section yd.) ,"etc. health agency, regularly and lawfully 505, 506, or 507 of the act, the labeling (n) On packages labeled in teris of engaged In dispensing prescription. bearing such Information Is the labeling area measure, the declaration shall be ex- drugs: or authorized by the approved new-drug ap- pressed both in terms of square inches (iII) In the possession of a practitioner olication or required as a condition for and, if applicable (1 square foot or more), licensed by law to admirdster or prescribe, the certification or the exemption from the largest whole square unit (square such drugs: and certification requirements applicable to yards, square yards and square feet. (2) It is to be dispensed in accordance preparations of insulin or antibiotic square feet). The declaration In terms of with section 503(b). drugs: Provided, however, That the in- the largest whole units shall be in paren- (b) The label of the drug bears: formation required by paragraph (c) (1) theses following the declaration In terms (1) The statement "Caution: Federal of this section may be omitted from the of square inches and any remainder shall law nrnhibiLs disponslng without pre- dispensing package if, but only If, the be in terms of square inches or common 'crivtion": and article is a drug for which directions,

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14004 1975 RULES AND REGULATIONS 14005 hazards, warnings, and use informa- § 201.105 Veterinary drugs. such outer container only, and the in- formation required by paragraph (b) (6) tion are commonly known to practi- A drug intended for veterinary use tioners licensed by law to administer -the of this section may be on the crimp of which, because of toxicity or other po- d drug. Upon written request, stating rea- tentiality for harmful effect, or the the ensing tube. sonable grounds therefor, the Commis- (c) (1) Labeling on or within the pack- method of its use, is not safe for animal age from which the drug Is to be dis- sioner will offer an opinion on a proposal use except under the supervision of a to-omit such information from the dis- licensed veterinarlqn, and hence for pensed bears adequate information for pensing package under this proviso.' its use, Including Indications, effects, which "adequate directions for use" can- dosages, routes, methods, and frequency- (d) Any labeling, as defined in section not be prepared, shall be exempt from 201(m) of thp act, whether or not It is section 502(f) (1) of the act if all the and duration of administration, and any on" or within a package from which the following conditions are met: relevant hazards, contraindations, side ' ug is to be dispensed, distributed by (a) The drug is: effects, and precautions under which vet- or on behalf of the manufadturer, erinarians licensed by law to administer (1) In the possession of a person (or the drug can use the drug safely and for packer, or distributor of the drug, that his agents or employees) regularly and furnishes or purorts to furnish infor- lawfully engaged In the, manufacture, the purposes for which It is intended, n- mation for use or which prescribes, rec- transportation, storage, or wholesale or cluding all purposes for which It Is ommends, or suggests a dosage for the retail distributlon or veterinary drugB advertised or represented; and use of the drug (other than dose ihfor- and is to be sold only to or on the pre- (2) If the article is subject to section mation required by paragraph (b) (2) of scription or other order of a licensed 512 of the act, the labeling bearing such this section dnd § 201.105(b) (2)) con- veterinarian for use in the course of his Information is the labeling. authorized tains: professional practice: or by the approved new animal drug appli- (1) Adequate information for such (2) In the possession of a licensed cation or required as a condition for the use, including indications, effects, dos- veterinarian for use In the course of his certification or the exemption from ages, routes, methods, and frequency and professional practice. certification requirements applicable to duration of administration and any rel- (b) The label of the drug bears: preparations of antibiotic drugs: Pro- evant warnings, hazards, contraindica- (1) The statement "Caution: Federal vided, however, That the information tions, side effects, and precautions, under law restricts this drug to use by or on required by paragraph (c)()- of this which practitioners licensed bY. law to the order of a licensed veterinarian": section may be omitted from the dis- administer the drug can use the drug and pensing package if, but only if, the safely and for the purposes for which it (2) The recommended or usual dos- article is a drug for which directions, is intended including all conditions for age: and hazards, warnings, and use information- which it is advertised Or represented; and (3) The route of administration, if it are commonly known to veterinarians If the article is subject to section 505 or is not for oral use: and licensed by law to administer the drug. 507 of the act, the parts of the labeling (4) The quantity or proportion of Upon written request, stating reasonable providing such information are the same each active ingredient as well as the In- mounds therefor, the Commissioner will In language and emphasis as labeling ap- formation required by section 502(e) of offer an opinion on a proposal to omit proved or permitted under the provisions the act: and such information from the dispensing of section 505 or 507, respectiVely, and (5) If it is for other than oral use, uackage under this proviso. any other parts of the labeling are con- the names of all inactive ingredients. d) Any labeling, as defined in-section sistent with and not contrary to such except that: 201 (m) of the act. whether or not It is, approved or permitted labeling; and (I) Flavorings and perfumes may be on or within a package from which the (2) The same information concerning designated as such without naming drug is to be dispensed, distributed by or the ingredients of the drug as appears on their components. on behalf of the manufacturer, packer. the label and labeling on or Within the (il) Color additives may be designated or distributor of the drug, that furnishes package from which the drug is to be as coloring without naming specific or purports to furnish information for dispensed: Provided, however, That the color components unless the naming of use or which prescribes, recommends, or information required by paragraph (d) such components Is required by a suggests a dosage for the use of the drug (1) and (2) of this section is not re- color additive regulation prescribed In (other than dose information required quired on the so-called reminder-piece Part 8 of this chapter. by paragraph (b) (2) of this section and labeling which calls attention to the (11) Trace amounts of harmless sub- §201.100(b) (2)) contains: name of the drug but does not include stances added solely for Individual prod- (1) Adequate information for such use, indications or dosage recommendations uct Identification need not be named. including indications, effects, dosages, for use of the drug: And provided, how- routes, methods, and frequency and ever, That reminder-piece labeling is not If it is intended for administration by duration of administration, and any rel- permitted for a drug for which an an- parenteral injection, the quantity or evant warnings, hazards, contraindica- nouncement has been published by the proportion, of all inactive Ingredients, tons, side effects, and precautions, and Food and Drug Administration pursuant except that ingredients added to adjust Including information relevant to com- to a refiew of the labeling claims for the the pH or to make the drug Isotonic may pliance with the new animal drug provi- drug by the National Academy of Sci- be declared by name and a statement of sions of the act, under which veterinar- ences-National Research Council, Drug their effect: and if the vehicle is water ians licensed by law to administer the Efficacy Study Group, and for which no for injection. It need not be named. drug can use the drug safely and for the claim has been evaluated as higher than (6) An Idenitifying lot or control purposes for which It Is intended, includ- 'possibly effective." If the Commissioner number from which it is possible to de- ing all conditions for which it is adver- find the circumstances are such that re- termine the complete manufacturing tised or represented; and if the article is minder-piece labeling may be mislead- history of the package ef the drug: subject to section 512 of the act, the ing to prescribers of drugs subject to Provided, however. That in the case of parts of the labeling providing such In- NAS-NRC evaluation, such reminder labeling will not be allowed and the containers too small or otherwise unable formation are the same In language and to accommodate a label with sufilcient emphasis as labeling approved or per- manufacturer, packer, or distributor will space to bear all such Information. but mltted under the provisions of section be notified either in the publication of which are packaged within an outer 512, and any other parts of the labeling the conclusions on the effectiveness of container from which they are removed are consistent with and not contrary to the drug or .byletter. for dispensing or use, the information such approved or permitted labeling; (e)All labeling, except labels and car- required bf'paragraph (b) (2), (3), and and tons, bearing information for use of the (5) of this section may be contained in, (2) The same information concerning other labeling on or within the package the Ingredients of the drug as appears drug also bears the date of the issuance from which it is to be so dispensed, and on the label and labeling on or within or the date of the latest revision of such the information referred to in paragraph the package from which the drug is to labeling. (b) (1) of this section may be placed on be dispensed;

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HeinOnline -- 40 Fed. Reg. 14005 1975 14006 RULES AND REGULATIONS

Provided,however, That the Information such Information from the dispensing empt from section 502 (f) (1) of the act, required by paragraph (d) (1) and (2) package under this proviso. This exemption shall not apply to any of this section is not required on the (d) Any labeling, as defined in section substance intended for a use which ro- so-called reminder-piece labeling which 201(m) of the act, whether or not it is suits in the preparation of a new drug, calls attention to the name of the drug on or within a package from which the unless an approved new-drug application but does not include indications or dos- device is to be dispensed, distributed by provides for such use. age recommendations for use of the drug. or on behalf of the manufacturer, packer, § 201.119 In vitro liagnostic productq. (e) All labeling, except labels and or distributor of the device, that fur- cartons, bearing information for use of nishes or purports to furnish informa- A product intended for use In the the drug also bears the date-of the is- tion for use of the device contains ade- diagnosis of disease and which Is an suance or the date of the latest revision quate Information for such use, includ- in vitro diagnostic product as defined in of such labeling. ing Indications, effects, routes, methods, § 328.3(a) of this chaptor shall be deemed' (f) A prescription drug intended for and frequency and duration of admin- to be in compliance with the require- both human and veterinary use shall istration and any relevant hazards, con- ments of this section and section 502(f) comply with paragraphs (e) and (f) of traindications, side effects, and precau- (1) of the act if It meets the require- this section and § 201.100. tions, under which practitioners licensed ments of Part 328 of this chapter. § 201.109 Prescription devices. by law to employ the device can use the § 201.120 Prescription chemicals and device safely and for the purposes for other prescription components. A device which, because of any poten- which it. is intended, including all pur- tiality for harmful effect, or the method poses for which it is advertised or repre- A- drug prepared, packaged, and pri- of its use, or the collateral measures sented. This information will not be marily sold as a prescription chemical or necessary to its use is not safe except required on so-called reminder-piece other component for use by registered under the supervision of a practitioner labeling which calls attention to the pharmacists in compounding prescrip- licensed by law to direct the use of name of the device but does not Include tions or for dispensing in dosage unit such device, and hence for which "ade- indications dr other use information. form upon prescriptions shall be exempt quate directions for use" cannot be pre- (e) All labeling, except labels and car- from section 502(f) (1) of the act if all pared, shall be exempt from section 502 tons, bearing information for use of the the following conditions are met: (f) (1) of the act if all the following device also bears the date of the issuance (a) The drug Is an official liquid acid conditions are met: or the date of the latest revision of such or official liquid alkali, or Is not a liquid (a) The device is: labeling. solution, emulsion, suspension, tablet, (1) (i) In the possession of a person capsule, or other dosago unit form; and (or his agents or employees) regularly § 201.110 Retail exemption for veteri- (b) The label of the drug bears: and lawfully engaged in the manufac- nary drugs and prescription devices. (1) The statement "For prescription ture, transportation, storage, or whole- A drug or device subject to §§ 201.105 compounding": and sale or retail distribution of such device, or 201.109 shall be exempt at the time (2) If in substantially all dosage forms or of delivery to the ultimate purchaser in which it may be dispensed It is subject (i) In the possession of a practitioner, or user from section 502(f) (1) of the act to section 503 (b) (1) of the act, the such as physicians, dentists, and veteri- if It is delivered by a licensed practi- statement "Caution: Federal law prohib- narians, licensed by law to use or order tioner in the course of his professional its dispensing without prescription"; or the use of such device: and practice or upon a prescription or other (3) If it is not subject to section 503 (2) Is to Ile sold only to or on the order lawfully issued in the course of his. (b) (1) of the act and is by custom prescription or other, order of such prac- professional practice, with labeling bear- among retail pharmacists sold in or from titioner for use in the course of his pro- ing the name ana address of such li- the interstate package for use by con- fessional practice. censed practitioner and the directions sumers, "adequate directions for use" In (b) The label of the device (other than for use and cautionary statements, if the conditions for which it is so sold. surgical instruments) bearst any, contained in such order. (1) The statement "Caution: Federal Provided, however, That the information law restricts this device to sale by or on § 201.115 News drugs or new animal referred to In paragraph (b) (3) of this the order of a ------", the blank drugs. section may be contained In the labeling to be filled with the on or within the package from which It word "physician", A new drug shall be exempt from sec- is to be dispensed. "dentist", "veterinarian", or with the tion 502(f) (1) of the act: descriptive designation (c) This exemption shall not apply to of any other (a) To the extent to which such ex- any substance intended for usa in com- practitioner licensed by the law of the emption is claimed in an approved appli- State in which pounding which results in a new drug, he practices to use or cation with respect to such drug under unless an approved new-drug application order the use of the device; and section 505 or 512 of the act; or (2) The method of its application or covers such use of the drug in compound- (b) If no application under section ing prescriptions. use. 505 of the act is approved with respect to (c) Labeling on or within the package such drug but It complies with section § 201.122 Drugs and devices for process- from which the device is to be dispensed 505 (1) or 512 of the act and regulations ing, repacking, or manufacturing. bears Information for use, including in- thereunder. A drug in a bulk package (except dications, effects, routes, methods, and No exemption shall apply to any other tablets, capsules, or other dosage unit frequency and duration of administra- forms) or a device intended for proces- tion, and any relevant hazards, drug which would be a new drug if Its contrain- labeling bore representations for its in- ing, repacking, or use in the manufac- dications, side effects, and precautions tended uses. ture of another drug or device shall be under which practitioners licensed by exempt from section 502(f) (1) of the law to administer the device can use § 201.116 Drugs and' devices having act if its label beam the statement the device safely and for the purpose commonly known directions. "Caution: For manufacturing, proc- for which It is intended, including all A drug or device shall be exempt from essing, or repacking"; and, If in sub- purposes for which It Is advertised or section 502(f) (1) of the act insofar as stantially all dosage forms In which it represented: Provided, however, That adequate directions for common uses may be dispensed it Is subject to section such information may be omitted from thereof are known to the ordinary in- 503 (b) (1). the statement "Caution: the dispensing package if, but only if, dividual. Federal law prohibits dispensing without the article is a device for which direc- prescription". Thtk exemption and the tions, hazards, warnings, and other in- § 201.117 Inactive ingredients. formation are commonly known to prac- exemption under § 201.120 may be .A harmless drug that is ordinarily claimed for the same article. But the titioners licensed by law to use the device. used as an inactive ingredient, such as a Upon written request, stating reasonable coloring, emulsifier, excipient, flavoring. exemption shall not apply to a substance grounds therefor, the Commissioner will lubricant, preservative, or solvent, in the intended for a 'use in manufacture, offer an opinion on a proposal to omit preparation of other drugs shall be ex- processing, or repacking which causes

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the finished article to be a new drug, of the article. This objective intent employee of the Department who re- unless: I may, for example, be shown by labeling quests them. (a) An approved new-drug application claims, advertising matter, or oral or (b) An exemption of a shipment or or new ni- drug application held by written statements by such persons or other delivery of a drug or device under the person preparing the dosage form or their representatives. It may be shown paragraph (a) (1) of this section shall, drug for dispensing covers the production by the circumstances that the article Is, at the beginning of the act of removing and delivery to him of such substance; or with the knowledge of such persons or such shipment or delivery, or any part - (b) If no application is approved with their representatives, offered and used thereof, from such establishment, be- respect to such new drug or new animal for a purpose for which it is neither come void ab initio If the drug or de- drug, the label statement "Caution: For labeled nor advertised. The Intended vice comprising such shipment, delivery, manufacturing, processing, or repacking" uses of an article may change after It has or part Is adulterated or misbranded Is. immediately supplemented by the been introduced into interstate com- within the meaning of the act when so words "in the preparation bf a new drug merce by Its manufacturer. If, for ex- removed. or new animal.drug limited- by Federal ample, a packer, distributor, or seller (c) An exemption of a shipment or law to investigational use", and the deliv- intends an article for different uses than other delivery of a drug or deviceunder ery is made for use only in the manufac- those Intended by the person from whom paragraph (a) (2) of this section shall ture of suchi new dru ornew animal drug he received the drug, such packer, dis- become void ab inItio with respect to the limited to investigational use as provided tributor, or seller Is required to supply person who Introduced such shilpment or in § 312.1 or § 51171 of this chapter. adequate labeling in accordance with the delivery into interstate commerce upon § 201.125 Drugs and devices for use in new Intended uses. But if a manufac- refusal by such person to make available teacting, law enforcement, research, turer knows, or has knowledge of facts for inspection a copy of the agreement, and analysis. that would give him notice, that a drug as required by such subparagraph. or device introduced into interstate com- (d) An exemption of a shipment or A drug or device subject to §§ 201.100, merce by him is to be used for conditions. other delivery of a drug or device under 2Q.1.105, or 201.109 shall be exempt from purposes, or uses bther than the ones for paragraph (a) (2) of this section shalL section 502(f) (1) of the act if shipped or which he offers It,he Is required to pro- expire: sold to, or in the possession of, persons' vide adequate labeling for such a drug (1) At the beginning of the act of re- regularly and lawfully engaged in in- which accords with such other uses to moving such shipment or delivery, or struction, in pharmacy, chemistry, or which the article is to be put. any part thereof, from such establish- medicine not involving clinical use, or (Secs. 201 (n). 502, 505, 507, 701, 52 Stat. 1041, ment if the drug or device comprising engaged in -law enforcement, or in re- such shiprpent, delivery, or part is adul- search not involving 1050-53 as amended, 1055-58 as amended by clinical use, or in 70 Stat. 919 and 72 Stat. 948, 59 Stat. 463 as terated or misbranded within the mean- chemical analysis, or physical testing, amended; 21 U.S.C. 321(n), 352,355,357, 701) ing of the act when so removed; or and is to be used only for such instruc- (2) Upon refusal by the operator of tion, law enforcement, research, analy- Subpart E-Other Exemptions the establishment where such drug or sis, or testing. § 201.150 Drugs and devices; process- device is to be processed, labeled, or re- § 201.127 Drugs and devices; expiration ing, labelingj or repacking. packed, to make available for inspection . of exemptions. (a) Except as provided by paragraphs a copy of the agreement, as required by (b) and (c)of this section. a shipment such clause. (a) If a shipment or delivery, or any (e) Except as provided in paragraphs part thereof, of a drug or device which is or other delivery of a drug or device exempt under. the regulations in this which Is, in accordance with the prac- (g) and (h) of this section, a shipment section tice of the trade, to be processed, labeled, or other delivery of a drug which is sub- is made to a person in whose pos- Ject to section 507 of the act and which session the article Is not exempt, or is or repacked in substantial quantity at an establishment other is, in accordance with the practice of the made for any purpose other than those than that where trade, to be processed or repacked in-a specified, such exemption shall expire, originally processed or packed, shall be substantial quantity at an establishment with respect to such shipment or de- exempt, during the time of introduction other than that where originally proc- livery or part thereof, at the beginning into and movement in Interstate com- merce essed or packed shall be exempt from of that shipment or delivery. The caus- and the time of holding in such compliance with th6 labeling require- ing of an exemption to expire shall be establishment, from compliance with the labeling ments of section 502 (f of the act during considered an act which results in such and packaging requirements of the time such drug is also exempt from drug or device being misbranded unless sections 501(b) and 502 (b), (d), (e), (f. the requirements of section 502 (1) of it is disposed of under circumstances in and (g) of the act if: the act or, in the case of a new animal which it ceases to be a drug or device. (1) The person who Introduced such shipment or delivery into interstate com- drug, is exempt from certification under (b) The exemptions conferred by section 512(n) of the act under the provi- §§ 201.117,-201.119, 201.120, 201.122, and merce s the operator of the establish- ment where such drug or device Is sions of § 433.15 or § 433.16 of this 201.125 shall continue until the drugs to be chapter. or devices are used for the purposes processed, labeled, or repacked; or (2) In case such person Is not such M Except aisprovided by paragraphs for which they are- exempted, or until (g) and (h) of this section, a shipment they are relabeled to comply with sec- operator, such shipment or delivery is made to such establishment under a or other delivery of a drug which is sub- tion 502 (f (1) of the act. If.however, Ject to section 507 of the act and which the drug is converted, compounded, or vwrtten agreement, signed by and con- taining the post-ofme addresses of such Is, in accordance with the practice of manufactured into a dosage form limited the trade, to be labeled in substantial to prescription dispensing, no exemption person and such operator, and contain- ing such specifications for the processing, quantity at an establishment other than shall thereafter apply to the article un- that where originally processed or less the labelng, or repacking, as the case may be, dosage form is labeled as re- of such drug or device in such establish- packed shall be exempt from compli- quired by section 503(b) and §§ 201.100, ance with the labeling requirements of 201.105, or 201.109. ment as will insure, if such specifications are followed, that such drug or device section 502 (b). (e) and (f of the act § 201.128 eManing of "Intended uses". will not be adulterated or misbranded during the time such drug is also exempt from the requirements of section 502 (1y The words "intended uses" or words within the meaning of the act upon com- pletion of such processing, labeling, or of the act or, in the case of a new animal of simir import in §§ 201.5, 201.115, drug, Is exempt from certification under 201.117, 201.119, 201.120, and 201.122 repacking. Such person and such opera- tor shall eachkeep a copy of such agree- section.512(n) of the act under § 433.12 refer to the objective intent of the per- of this chapter, if the words, statements, sons legally responsible for the labeling ment until 2 years after the final ship- ment or delivery of such drug or device and other Information required by sec- of. drugs and devices. The intent is tion 502 (b) and (e) of the act appear-an -determined by such persons' expres-, from such establishment, and shall make each shipping container of such drug. sions or may be shown by the circum- such copies available for Inspection at (g) In case the person who intro- stances surrounding the distribution any reasonable hour to any offer or duced such shipment or other delivery

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14007 1975 14008 RULES AND REGULATIONS

Into interstate commerce is the oper- (Secs. 501(c), 602(a),'503, 701(a), 52 Stat. Epinephrineinjection, 1: 1,000. ator of the establishment where such 1049, 1050, 1051, 1055; 21 U.S.C. 351(c), 352 (a), 371 (a)) Erythrityl tetranitrate.For oral use, not drug is to be processed, labeled, or re- in excess of 30 milligrams per dosage packed, an exemption of such shipment § 201.160 Drugs; information com- unit. or delivery under paragraph (e) or (f) monly known. Homatropine methylbromide. For oral -bf this section shall become void at the use, not in excess of 5 milligrams per beginning of the act of removing such (a) Section 201.100(c) of this chap- ter provides that in the dosage unit. shipment or delivery or any part thereof case of certain Hyoscyahine hydrobromide. drugs for which directions, hazards, For oral from such establishment if the drug use, not in excess of 1 milligram per comprising such shipment, delivery, or warnings, and use information are com- dosage unit. part is adulterated or misbranded within monly known to practitioners licensed by Hyoscyamine law, such information may be omitted sulfate. For oral use, not the meaning of the act when so removed. in excess of 1 milligram per dosage (h) In case the person who introduced from the dispensing package. Under this unit. such shipment or delivery into interstate proviso, the Commissioner of Food and Hyoscyamus Drugs will offer an opinion, upon tincture. For oral use, not commerce is not the operator of the es- written in excess of 2 millbliters per dosage tablishment where such drug is to be request, stating reasonable grounds unit. processed, labeled, or repacked, an ex- therefor, on a proposal to omit such in- Mannitol formation from hexanitrate. For oral use, not emption of a shipment or other delivery the dispensing package. in excess of 32 milligrams per dosage of such drug under paragraph (e) or (f) (b) The Commissioner of Food and unit. of this section shall expire at the be- Drugs has considered submitted mate- rial covering Methenamine. For oral use, not in ex- ginning of the act of removing such a number of drug products cess of 1 gram per dosage unit. shipment or delivery or any part thereof and has offered the 'opinion that the following drugs, Morphine phosphate.For oral use, not in from such establishment -if the drug when Intended for excess; of 33 mIlligrams per dosage comprising such shipment, delivery, or those human uses for which they are now generally unit; for injection, not in excess of .33 part is adulterated or misbrandea employed by the medical milligrams per dosage unit. within the meaning of the act when so profession, should be exempt from the requirements Morphine sulfate. For oral use, not In removed. of § 201.100(c) of this excess (I) As It Is a chapter, provided that they of 33 milligrams per dosage common industry prac- meet the unit; for injection, not In excess tice to manufacture' and/or assemble, conditions prescribed in this paragraph. of package, and Preparations that are not in dosage 33 milligrams per dosage unit. fully label a device as sterile unit Nitroglycerin. For oral use, not in at one establishment and then ship such form (for example, solutions) will be excess regarded as meeting of 0.65 milligram per dosage unit. device in interstate commerce to another the conditions with Pentaerythritol establishment respect to the maximum quantity of tetranitrate. For oral or to a contract sterilizer use, not in excess of 20 milligrams per for sterilization, the Food and Drug Ad- drug per dosage unit if they are pre- pared In a manner.that enables dosage unit. ministration will initiate no regulatory accurate Pentaerythritol action against the device as misbranded and ready administration of a quantity tetranitratewith pheno- of drug not in excess of the stated barbital. For oral use, not in excess or adulterated when the nonsterile device maxi- of 20 milligrams is labeled sterile, provided all mum per dosage unit: of pentaerythrltol the follow- tetranitrate and 35 milligrams of ing conditions are met: Aminophylline. For oral use, not In ex- (1) There phenobarbital. is in effect a written agree- cess of 200 milligrams per dosage unit, Quinidine sulfate. For oral use, not In ment which: with or without not in excess of 33 excess of 325 milligrams per dosage (I) Contains the names and post office milligrams of phenobarbital. unit. addresses of the firms involved and is Atropine methyl nitrate. For oral use, signed by the person Scopolamine methylbromde. For oral authorizing such not in excess of 1.0 milligram per use, not in excess of 2.5 milligrams per shipment and the operator or person in dosage unit. dosage unit. charge of the establishment receiving the Atropine sulfate. For oral use, not in Sodium chloride injection. devices for sterilization. excess of 0.54 milligram per dosage (ii) Provides Sodium nitrite. For oral use, not In instructions for maintain- unit; for injection, not in excess of excess of 60 milligrams per dosage ing proper rdcords or otherwise account- 0.54 milligram (Ym-grain) per dos- ing for the number unit. of units in each ship- age unit. Theobromine. For oral use, not in ex- ment to insure that the number of units Barbiturates. For oral use, not in ex- shipped cess of 325 milligrams per dosage unit. is the same as the number re- cess of 100 milligrams per dosage Thyroid. For oral use, not in excess of ceived and sterilized. unit; for use as suppositories, not In (iiI) Acknowledges 220 milligrams per dosage unit. that the device is excess of 130 milligrams per supposi- Water for injection, sterile. nonsterile and is being shipped for fur- tory. ther processing, and Chioral hydrate. For oral use, not In § 201.161 Carbon dioxide and certain (iv) States in detail the sterilization excess of 500 milligrams per dosage other gases. process, the gaseous mixture or other unit; for use as suppositories, not in (a) Carbon dioxide, cyclopropane, media, the equipment, and the testing excess of 1.0 gram per suppository. - ethylene, helium, and nitrous oxide gases method or quality controls o be used by Codeine phosphate. For oral use, not intended for drug use are exempted from the contract sterilizer to assure that the in excess of 65 milligrams per dosage the requirements of § 201.100(b) (2), device will be brought into full compli- unit; for injection, not in excess of (3), and (c) (1) provided the labeling ance with the Federal Food, Drug, and 65 milligrams per dosage unit. bears, in addition to may other Informa- Cosmetic Act. Codeine sulfate. For oral use, not in tion required by the Federal Food, Drug; (2) Each pallet, carton, or other excess of 65 milligrams per dosage and Cosmetic Act, the following: designated unit is conspicuously marked unit; for injection,-not in excess of (1) to The warning statement "Warn- show Its nonsterile nature when it is 65 milligrams per dosage unit. ing-,Administration of (name of gas) Introduced Into and is moving in inter- Digitalis. Preparations of whole leaf may Nbe hazardous or contraindicated. state commerce, and while it Is being digitalis including forms such as digi- held For use only by or under the supervision prior to sterilization. Following talis tincture. For oral use, contain- of a licensed practitioner who Is experi- sterilization, and until such time as it is ing the equivalent of not more than established that enced in the use and administration of the device is sterile and 1 U.S.?. digitalis unit per dosage unit. (name of gas) and is familiar with the can be released from quarantine, each Dihydroeodeinone bitartrate. For oral Indications, effects, dosages, methods, pallet, carton, or other designated unit use, not in excess of 10 milligrams per is conspicuously marked to show that it dosage unit. and frequency and duration of adminis- has not been released from quarantine, Dlhydromorphinonehydrochloride. For tration, and with the hazards, contrain- e.g. "sterilized-awaiting test results" or oral use, not in excess of 4 milligrams dications, and side effects and the pro- an equivalent designation. per dosage unit. / cautions to be taken"; and

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14008 1975 RULES AND REGULATIONS 14009 (2) Aii needed directions concerning establishes that there Is a material tion and be in the following format: the conditions for storage and warnings weight of opinion among qualified ex- against the inherent dangers in the perts contrary to the representation handling of'the specific compressed gas. made or suggested In the labeling, and (b) This labeling exemption does not Baztd on a review of this drug by failure to reveal this fact causes such the National Academy of Sclences- apply'to mixtures of any one or more of labeling to be misleading. National Recearch Concil- and/or these gases with oxygen or with each (c) Therefore, after publication in the other Information, FDA. has cla=sfled other. FEDERAL REMSE"R of a Drug Efficacy the lndicaton(s) as follow3: (c) Regulatory. action may be initi- Study Implementation notice on a pre- Effective: (list or state In paragraph ated with respect to any article shipped scription drug, unless exempted or other- form). within the jurisdiction of the Act con- wise provided for In the notice, all "Probably" effective: (list or state trary to the provisions of this section in prgraph form). package labeling (other than the Imme- "Po-Ably" effective: (lst or state In after 60 days following publication of diate container or carton label, unless paragraph form). this section in the FEDERAL REGISTER. such labeling contains information re- Final clavifleation of the les,-than- (See. 502(f), 52 Stat. 1051; 21 U.S.C. 352(f)) quired by § 201.100(c) (1) in leu of a effective indications requires further nve"tlgatlon. Subpart F-Labeling Claims for Drugs in package insert). "promotional labeling, - Drug Efficacy Study and advertisements shall include, as part of the information for practi- (2) Or theindcation(s) forwhich the §201.200 Disclosure of drug efficacy tioners under which the drug can drug has been found effective may appear stud-' evaluations in labeling and ad. be safely and effectivef used, an ap- outside the boxed statement and be fol- vertising. propriate qualification of all claims lowed immediately by the following boxed (a) (1) The National Academy of Sci- evaluated as other than "effective" by statement: ences-National Research Council, Drug a panel of the National Academy of Sei- Efficacy Study Group, has completed an cinces-National Research Council, Ding exhaustive review of labeling claims made Efficacy Study Group, if such claims Bazed on a review of this drug by for drugs marketed under new-drug and continue to be included in either the the National Academy of Sciences- labeling or advertisements. However, this National Eesearch Councl and/or antibiotic drug procedures between 1938 other Information, FDA has dlassifled and 1962. The results are compiled in qualifying Information will be required the other Indicaton(s) as follows: 'Drug Efficacy Study, A Report to the In advertisements only If promotional "Probably" effective: (list or state In Commissioner of Food and Drugs from material Is included therein for claims paragraph form). -the National Academy of Sciences evaluated as less than "effective" or if Tozibly" effective: (list or state In (1969) ." As the report notes, this review such claims are included in the indica- paragraph form). has made "an audit of the state of the art tions section of the portion of the ad- Final clasalfication of the less-than- vertisement containing the information effective Indications requires further of drug usage that has been uniquely ex- nvezt1gatIon. tensive in scope and uniquely intensive required in brief summary by § 202.1 in time" and is applicable to more than 80 (e) (1) of this chapter. When, however. percent of the currently marketed drugs. the Food and Drug Administration clas- (3) In drug labeling (other than that The report further notes that the quality sification of such claim Is "effective" (for example, which Is required by § 201.100(c) (1) of the evidence of efficacy, as well as the on the basis of revision which may contain a promotional mes- quality of the labeling claims, is poor. of the language of the claim or sub- mission or existence of adequate data), sage, the promotional message shall be Labeling and other promotional claims keyed to the boxed statement by the have been evaluated as "effective," "prob- such qualification Is not necessary. When the Food and Drug Administration clas- same means as those provided for ad- ably effective," "possibly effective," "in- vertisements In paragraph (fI (2) of this effective," "ineffective as a fixed combi- sification of the claim, as stated in the implementation notice, differs from that section. nation," and "effective but," and a report (f) Qualifying Information required for each drug in the study has been sub- of the Academy but is other than "effec- mitted to the Commissioner. tive," the qualifying statement shall In prescription drug advertising by para- refer to this classification in lieu of the graph (c) of this section shall contain a (2) The Food and Drug Administra- prominent boxed statement of the ad- tion is processing the reports, seeking Academy's classification. (d) For new drugs and antibiotics, sup- vertised indication(s) and of the limita- voluntary action on the part. of the drug tions of effectiveness using the same for- manufacturers and distributors in the plements to provide for revised labeling mat, language, and emphasis as that re- elimination or modification of unsup- in accord with paragraph (c) of this sec- tion shall be submitted under the quired in labeling by paragraph (e) of ported promotional claims, and initiating provi- this section. administrative actions as necessary to sions of § 314.8 (d) and (e) and § 514.50 require product and labeling changes. of thli chapter within 90 days after pub- (1) The boxed statement shall appear (3) Delays have been encountered in lication of the Implementation notice in In (or next to) the information required bringing to the attention of the pre- the FEDERAL RECsTER or by May 15, 1972, in brief summary by § 202.1(e) (1) of this scribers of prescription items the conclu- for those drugs for which notices have chapter and shall have prominence at least equal to that provided for other sions 9f the expert panels that reviewed. been published and such labeling shall be the promotional claims. put into use as soon as possible but not information presented in the brief sum- (b) The Commissioner of Food and later than the end of the time period al- mary and shall have type size, captions, Drugs concludes that: lowed for submitting supplements to pro- color, and other physical characteristics vide for revised labeling. comparable to the information required (1) The failureto disclose in the label- in the brief summary. ing of a drug and in other promotional (e) Qualifying information required in drug labeling by paragraph (c) of this (2) Less-than-effective ndicationCs) material the conclusions of the Academy in the promotional experts that -a claim is "ineffective," section in order to advise prescribers of message of an adver- a drug of the findings made by a panel tisement which is a single page or less "possibly effective," "probably effective," shall be keyed to the boxed statement or "ineffective as a fixed combination," of the Academy In evaluating a claim as other than "effective" shall be at least of by asterisk, by an appropriate statement, while labeling and promotional material or by other suitable means providing ade- bearing any such claim are being used, the same size and color and degree of prominence as other printing in the quate-emphasis on the boxed statement. is a failure to disclose facts that are ma- On each page where less-than-effective terial'in light of the representations made labeling and shall be Presented In a prominent box using one of the follow- indication(s) appear in a mutiple page and causes the drug to- be misbranded. advertisement, an asterisk shalibe placed (2) The Academy 'classification of a Ing formats and procedures: after the most prominent mention of the drug as other than "effective" for a claim (1) In drug labeling the box statement indication(s); If the degree of promi- for which such drug is recommended may entirely replace the indications sec- nence does not vary, an asterisk shall be

FEDERAL REGISTER, VOL 40, NO. 60--THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14009 1975 14010 RULES AND REGULATIONS label bears the prescription legend. Sec- § 201.302 Notice to manufacturers, placed after the first mention of the in- packers, and distributors of drugs for dication. The asterisk shall refer to a tion 201.100(c) requires that the labeling of the drug, which may include brochures internal use *hich contain mineral notation at the bottom of the page-which oil. shall state "This drug has been evaluated readily available to licensed practi- as probably effective (or possibly effective tioners, bear information as to the use (a) In the past few years research whichever is appropriate) for this Indi- of the drug by practitioners licensed by studies have altered medical opinion cation" and "See Brief Summary" or law to administer it. Obviously, infor- as to the usefulne;s and harmfulnes "See Prescribing Information," the latter mation adequate for the use of an inert of mineral oil in the human body. legend to be used only if the advertise- glandular preparation is not available to These studies have indicated that ment carries the required Information for practitioners licensed by law. when mineral oil is used orally professional use as set forth in § 201.100 (c) The Department of Health, Educa- near mealtime it Interferes with (c) (1). tion, and Welfare is of the opinion that absorption from the digestive tract (3) For less-than-effective indications inert glandular materials may not be of provitamin A and the fat-soluble vita- which are ncluded n the advertisement exempted from the requirementd of sec- mins A, D, and K, and consequently in- only as a part of the information re- tion 502 (f) (1) of the act that they bear terferes with the utilization of calcium quired in brief summary, the disclosure adequate directions for use; and, accord- and phosphorus, with the result that the Information shall appear in this portion ingly, that their labeling must include user is left liable to deficiency diseases. of the advertisement in the same manner among other things, representations as When so used In pregnancy It predisposes as is specified for labeling in paragraph to the conditions for which such articles to hemorrhagic disease of the newborn. (e) of this section. are intended to be used or as to the struc- (b) There Is accumulated evidence (g) The-Commissioner may find cir- ture or function of the human body that that the Indiscriminate administration of cumstances are such that, while the they are intended to affect. Since any mineral oil to Infants may be followed by elimination of claims evaluated as other such representations offering these arti- aspiration of the mineral oil and subse- than effective will generally eliminate cles for use as drugs would be false or quent "lipoid pneumonia." the need for disclosure about such claims, misleading, such articles will be consid- (c)In view of these facts, the Depart- there will be Instances in which the ered to be misbranded if they are dis- ment of Health, Education, and Welfare change in the prescribing or promotional tributed for use as drugs. will regard as misbranded under the pro- profile of the drug is so substantial as (d) The amended regulations provide visions of the Federal Food, Drug, and to require a disclosure of the reason for also that in the case of drugs intended for Cosmetic Act a drug for oral administra- the change so that the purchaser or pre- parenteral administration there shall be tion consisting In whole or in part of scriber is not misled by being left un- no exemption from the requirement that mineral oil, the labeling of which en- aware through the sponsor's silence that their labelings bear adequate directions courages its use in pregnancy or Indi- a basic change has taken place. The for use. Such Inert glandular materials cates or, implies that such drug Is for Food and Drug Administration will for parenteral use are therefore subject administration to infants. identify these situations in direct cor- to the same comment as applies to those (d) It is also this Department's view respondence with the drug promoters, intended for oral administration. that the act requires the labelings of such after which the failure to make the dis- § 201.301 Notice , t6 manufacturers, drugs to bear a warning against con- closure will be regarded as misleading packers, and distributors of estro- sumption other than at bedtime and and appropriate action will be taken. genic hormone preparations. against administration to infants. The (Sees. 201(n), 502, 505, 607, 62 Stat. 1041, following form of warning Is suggested: Some drug preparations fabricated "Caution: To be taken only at bedtime. 1050-53 as amended, 1056, as amended by 70 wholly or in part from estrndlol and la- Stat. 919 and 72 Stat. 948, 59 Stat. 463 as Do not use at any other time or admin- 321 (n), 352, 355,357, 701) beled as to potency in terms of interna- ister to infants, except upon the advice amended; 21 U.S.C. tional units or in terms of international Labeling Require- of a physician." Subpart G-Specific units of estrone activity have been mar- of interpretation ments for Specific Drug Products international unit of the (e) This statement keted. The does not In any way exempt mineral oil or § 201.300 Notice to manufacturers, estrus-producing hormone was estab- lished by the International Conference preparations containing mineral oil from packers, and distributors of glandular complying in all other respects with the preparations. on the Standardization of Sex Hormones at London, England, on August 1, 1932. requirements of the Federal Food, Drug, (a) Under dateof December 4, 1941, in This unit was defined as "the specific and Cosmetic Act. a notice to manufacturers of glandular estrus-producing activity contained in § 201.303 Labeling of drug preparations preparations, the Food and Drug Admin- 0.1 gamma (=0.0001 mg.) of the stand- containing significant proportions of istration expressed the opinion that ard" hydroxyketonie hormone found in wintergreen oil. preparations of inert glandular materials urine (estrone). The International Con- (a) Because methyl zailcylate (winter- intended for medicinal use should, in ference declared that it did not recom- section 201(n) green oil) manifests no toxicity In the view of the requirement of mend the determination of the activity minute amounts in which It Is used as a of the Federal Food. Drug, and Cosmetic of nonhydroxyketonlc forms of estro- mistakenly regarded by Act (52 Stat. 1041; 21 U.S.C. 321(n) ), be flavoring, it Is genic hormones in units of estrone be- the public as harmless even when taken labeled with a statement of the material cause of the varying ratios between the in substantially larger amounts. Actu- fact that there Is no scientific evidence activity bf such nonhydroxyketonic es- taken In quan- contain any therapeutic ally. It is quite toxic when that the articles trogenic hormones and estrone, when tities of a teaspoonful or more. Winter- or physiologically active constituents. measured by different methods on test of such inert green oil and preparations containing It Numerous preparations animals. There is no International unit have caused a number of deaths through glandular materials were subsequently for measuring the activity of estradiol accidental misuse by both adults and marketed with disclaimers of the type and no accepted relationship between its at- glandular children. Children are particularly suggested. The term "inert activity and that of estrone. either in test Iracted by the odor and are likely to materials" means preparations incapable animals or in humans. The declaration swallow these products when left within of exerting an action or effect of some of potency of estradiol in terms of inter- reach. significant or measurable benefit in one national units or in terms of interna- way or another, I.e., in the diagnosis. (b) To safeguard against fatalities tional units of estrone activity is there- from this cause, the Department of cure, mitigation, treatment, or preven- fore considered misleading, within the tion of disease, or in affecting the struc- Health, Education, and Welfare will re- meaning of 21 U.S.C. 359(a). The dec- gard as misbranded under the provisions ture or any function of the body. estradol content of an (b) Manufacturers have heretofore laration of the of the Federal Food, Drug, and Cosmetic taken advantage of § 201.100 permitting estrogenic hormone preparation In terms Act any drug containing more than 5 omission of directions for use when the -of weight is considered appropriate. percent methyl salicylate (wintergreen

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14010 1975 RULES AND REGULATIONS ,14011 oil), the labeling of which fails to warn with the excessive use of isoproterenol containing satisfactory information of that use otherwise than as directed inhalation preparations. The mechanism the kinds required by Items 4, 5, 6, 7, 8, therein may be dangerous and that the of these deaths and their relationship, and 9 of the new-drug application form article should be kept out of reach of if any, to the cases of severe paradoxical (form FD-356H set forth in § 314.1(c) (2) children to prevent accidential poisoning. bronchospasm are not clear. Cardiac of this chapter), including appropriate (c) This statement of interpretation arrest was noted in several of these labeling as described in paragraphs (b) in no way exempts methyl salicylate cases of sudden death. and (c)of this section. (wintergreen oil) or its preparations (b) On the basis of the above infor- (3) The applicant submits additional from complying in all other respects with mation and after dicusslon with and lnformatibn required for the approval of the requirements of the Federal Food, concurrence of the Respiratory and An- the application as may be specified in a Drug, and Cosmetic Act. esthetic Drugs Advisory Committee for written communication from the Food (Sec. 502, 52 Stat, 1050, as amended; 21 Food and Drug Administration, the and Drug Administration. U.S.C. 352) Commissioner of Food and Drugs con- (e)After 270 days following expira- cludes that in order for the labeling of tion of said 90 days, regulatory proceed- § 201.304 Tannic acid -and barium en- 505(a) of the ema preparations. ,such drugs to bear adequate Information ings based on section for their safe use, as required by Federal Food, Drug, and Cosmetic Act (a) It has become-a widespread pirac- § 201.100, such labeling must include the may be initiated with regard to any such tice for tannic acid to be added to barium following: drug shipped within the Jurisdiction of enemas to improve X-raypictfires. Tan- Warning: Occasional patients have been the act for which an approved new-drug nic acid is capable of causing diminished reported to develop severe paradoxical air- application is not in effect. liver function and severe liver necrosis way resistance with repeated, excesive use (Seca. 502 (f), (j), 505, 52 Stat 1051-53, as when absorbed in sufficient amounts. of isoproterenol Inhalation preparations. The amended; 21 U.S.C. 352 (f), (j), 355) The medical literature reports a number cause of this refractory state is unknown. It of deaths associated with the addition is advisable that In such Instances the use § 201.306 Potassium salt preparations of tannic acid to barium enemas. There of this preparation be discontinued Immedi- intended for oral ingestion by man. Is a lack of scientific evidence to estab- ately and alternative therapy Instituted. aince In the reported cases the patients did not re- (a) The Food and Drug Administra- lish the conditions, If any. under which spond to other forms of therapy until the tion will Initiate no regulatory action tannic acid is safe and effective for use drug was withdrawn. with respect to the continued marketing in enemas. Tannio acid for rectal use to Deaths have been reported following exces- of coated tablets containing potassium enhance X-ray visualization is regarded sive use of lsoproterenol Whalation prepara- chloride or other potassium salts which as a new drug within the meaning of sec- tions and the erect cause Is unknown. Car- supply 100 milligrams or more of potas- tion 201(p) of the Federal Food, Drug, diac arrest was noted n several instances. sium per tablet provided all the follow- and-Cosmetic Act. (o) (1) The Commissioner also con- ing conditions are met: (b) In view- of the hazards Involved cludes that in view of the manner in (1) Within 30 days from the date of .when tannic acid is used- In barium which these preparations are self-admin- publication of this statement of policy enemas,- any shipments of tannic acid istered for relief of attacks of bronchial in the F=zrAL RGcISrE: labeled to come within the exemptions asthma and other chronic bronchopul- CI) The labeling of the drug bears the under 502(f) of the Act containing such monary disorders, It Is necessary for the prescription caution statement quoted in phrases as: "Caution: For mahufactur- protection of users that warning infor- section 503(b) (4) of the Federal Food, ing.- processing, or repackaging,"' ' or mation to patients be included as a part Drug, and Cosmetic Act;, prescription compounding," or 'Diag- of the label and as part of any instTuc- (I) The labeling on or within the nostic reagent-For professional use tions to patients included in the package package from which the drug is to be only" will be regarded by the Commis- dispensed to the patient as follows: dispensed bears adequate information sioner of Food and Drugs as misbranded for Its use by practitioners in accord with Warning: Do not -exceed the does within the meaning of section 502(f) of pre- the "full disclosure" labeling require- the Federal scribed by your physician. If dilIculty In Food, Drug, and Cosmestlc breathing persists, contact your physician ments of § 201.100 of this chapter, in- Act unless the label and the labeling bear immediately. cluding the following warning statement: conspicuously a warning to the effect: "Warning-There have been several re- "Warning-Not for use in enemas." (2) The warning o4 the label may be ports, published and unpublished, con- (c) Any tannic acid intended for use accomplished (1) by including It on the cerning nonspecific small-bowel lesions by man and-found within the jurisdiction immediate container label with a state- consisting of stenosis, with or without of the Federal Food, Drug, and Cosmetic ment directed to pharmacists not to re- ulceration, associated with the admin- Act labeled-contrary to this'section after move the label or (i) by including in the istration of enterfc-coated thlazides with 60 days from the date of Its publication package a printed warning with Instruc- potassium salts. These lesions may oc- In the FEDEm REGrsTE may be made tions to pharmacists to place the warn- cur with enteric-coated potassium tab- the subject of regulatory proceedings. ing on the container prior ta dispensing. lets alone or when they are used with (Sec. 502,52 Stat. 105,0, as amended; 21 U.S.C. (d) The marketing of isoproterenol in- nonenteric-coated thiazides, or certain 352) halation preparations may be continued other oral diuretics. These small-bowel if all the following conditions are met: § 201.305 Isoproterenolinhalation prep- lesions have caused obstruction, hemor- (1) Within 30 days following the date rhage, and perforation. Surgery was arations (pressurized aerosols, neb- of publication of this section in the FD- ulizers, powders) for human use; frequently required and deaths have oc- warnings. ERAL REGIS=m: curred. Based on a large survey of (I) The label and labeling of such physicians and hospitals, both United (a) Accumulating reports have been preparations shipped within the Juris- States and foreign, the incidence of these received by the Food and Drug Admin- diction of the act are in accordance with lesions is low, and a causal relationship istration and have appeared in the medi- paragraphs (b) and (c) of this section. in man has not been definitely estab- cal literature of severe paradoxical (iD The holder of an approved new- lished. Available information tends to bronchoconstriction associated with re- drug application for such preparation Implicate enteric-coated potassium salts, peated, excessive use of isoproterenol in- submits a supplement to his new-drug although lesions of this type-also occur halation preparations in the treatment application to provide for appropriate spontaneously. Therefore, coated po- of bronchial asthma and other chronic labeling changes as described In para- tasslum-containing formulations should bronchopulmonary disorders. The cause graphs '(b) and (c) of this section. be administered only when indicated, of this paradoxical reaction is unknown; (2) Within 90 days following the date and should be discontinued immediately it has been observed, -however, that of publication of this section in the FED- if abdominal pain, distention, nausea, patients have not responded completely ERAL REGISTER, the manufacturer, packer, vomiting, or gastrointestinal bleeding oc- to other.forms of therapy until use of or distributor of any drug -containing the isoproterenol Inhalation preparation isoproterenol intended forinhalatlon for cur. Coatedpotassium tablets should be was discontinued. In addition, sudden which a new-drug approval is not in used only when adequate dietary sup- unexpected deaths have been associated effect submits a new-drug application plementation is not practicable."'

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14011 1975 14012 RULES AND REGULATIONS

(Although the warning statement In- teratogenicity in animals administered tential. In any case, the dosago and dura- cludes references to enteric-coated po-- tion of treatment should be kept to a these drugs to Justify warnings against minimum. tassium salt preparations, it applies to their use in pregnancy except on advice any capsule or coated tablet of a potas- of a physician. An Ad Hoc Advisory This statement shall be followed with sium salt intended for oral ingestion Committee on the Teratogenic Effect of an appropriate summary of the perti- without prior dilution with an adequate Certain Drugs, comprised of scientists in nent animal studies and adverso clini- volume of liquid to preclude gastroin- various branches of medicine concerned cal experiences, with adequate refer- testinal injury.) tith the problem, has submitted its ences to the scientific literature. Also, (Ill) Any other labeling or additional findings and conclusions to the Commis- the labeling shall contain, in Juxtaposi- advertising for the drug conforms to the sioner of Food and Drugs and has rec- tion with any representation for use in labeling described in paragraph (a) (1) ommended that all over-the-counter the treatment of nausea and vomiting (ii) of this section, in accordance* with preparations containing chlorcyclizine, in pregnancy, the followint statement: §§ 202.1 and 201.100 of this chapter. cyclizine, or meclizine or thelr salts bear The effectiveness of ---- for the pro- (2) Within 90 days from the date of a warning. vention and treatment of nausea and vomit- publication of this statement of policy (b) On the basis of studies made by Ing of pregnancy has not been established, in the FEDERAL REGISTER, the manufac- the Food and Drug Administration and and the decision to use - should be turer, packer, or distributor Of the drug on the recommendations of the Advisory based on the seriousnezs of the situation, shall submit a new-drug application con- Committee, the Commissioner of Food remembering that while this drug ha boon taining satisfactory information of the and Drugs has concluded that it is neces- used clinically for a decade, there are yet kind required by Items 2, 3, 4, 6, 7, and no controlled studies to demonstrate Ito sary for the protection of users that the usefulness in an objective fashion. In most 9 of the new-drug application form con- label and labeling of all over-the-counter tained in cases, nausea and vomiting of pregnancy § 314.1(c) of this chapter, with preparations containing chlorcyclizine, may be unpleasant but do not present a appropriate labeling as described in this cyclizine, or meclizine or their salts bear serious threat to the health'of the patient paragraph. a statement to the following effect: or to the progress of her pregnancy. In (b) The Food and Drug Administra- "Waring-Not for use by women who view of the desirability of keeping the ad- tion may Initiate regulatory proceedings are pregnant or who may possibly be- ministration of all drugs to a minimum dur- after 30 days from the date of publication come pregnant, unless directed by a ing pregnancy, management by physiologic of this section, with respect means such as proper nutrition and by to the mar- physician, since this drug may have the psychologic support Is preferable to anti- keting of uncoated tablets containing potentiality of injuring the unborn emetic therapy. potassium chloride or other potassium child."- - salts which supply 100 milligrams or (c) The marketing of oral and pa- (2) Within 30 days from the date of more of potassium per tablet or with re- renteral drugs containing chlorcyclizine, publication of this statement of policy spect to liquid preparations containing cyclizine, or meclizine or their salts may in the FEDERAL REoSTER, the applicant potassium chloride or other potassium be continued provided that all the fol- under an approved new-drug application salts which supply 20 milligrams or more lowing conditions are met: for A drug containing chloroyclizine, of potassium per milliliter, labeled or in- (1) Within 30 days from the date of cyclizine, or meclzine or their salts shall tended for human use, unless all the fol- publication of this statement in the submit a supplement to his new-drug ap- lowing conditions are met: FEDERAL REGISTER. plication, providing for appropriate (1) The labeling of the drug bears the' (D The label and applicable labeling labeling changes as described in para- prescription caution statement quoted in of druas containing chlorcyclizine, cycli- graph (c) (1) (i)or (ii) of this section. section 603 (b) (4) of the Federal Food. zine, or meclizine or their salts at ac- (3) Within 90 days from the date of Drug, and Cosmetic Act; 'and ceptable levels for over-the-counter dis- publication of this statement of policy (2) The labeling on or within the pack- tribution, shall prominently and con- in the FEDAmL REGISTER, the manu- age from, which the drug is to be dis- spicuously display the statement: facturer, packer, or dlstributor of any pensed bears adequate information for "Warning-Not for use by women who drug colitaining chlorcyclizine, cyclizine, Its use by practitioners in accord with are pregnant or who may possibly be- or meclizine or their salts for which a the "full disclosure" labeling require- come pregnant, unless directed by a new-drug approval is not in effect shall ments of § 201.100 of this chapter, physician, since this drug may have the submit a new-drug application contain- Including a recommendation that pa- potentiality of injuring the unborn ing satisfactory Information of the kinds tients be directed to disslove any such child." required in. the new-drug application tablets -in an appropriate amount of (ii) The package labeling and other form contained In § 314.1(c) of this liquid and to dilute any such liquid prep- labeling providing professional use in- chapter, including appropriate labeling arations adequately to assure against formation concerning prescription drugs as described in paragraph (c) (1) (i)or gastrointestinal injury associated with containing chlorcyclizine, cyclizine, or (ii) of this section. the oral ingestion of concentrated potas- meclizine or-their salts and not contra- (d) In view of the fact that no sub- sium salt preparations. indicated for use in pregnancy because stantial evidence has been offered for (Sees. 602(f). 503(b) (4). 505: 52 Stat. 1051, Of some other ingredient, shall bear, in the effectiveness of chiorcyclizIne, cycli- 1052; 21 U.S.C. 352(f), 353(b), 355) accordance with § 201.100" of this chap- zine, and meclizine or their salts in the 201.307 Chlorcyclizine, cyclizine, mcc- ter, a section under "Adverse Reactions" prevention and treatment of nausea and lizine; warnings; labeling require- headed "Use in Pregnancy," as follows: vomiting of pregnancy, but mindful of ments. The following information should be the fact that some practicing physicians taken into account in determining whether believe that these drugs exert a bene- (a) The Food and Drug Administra- the potential benefits of [chlorcyclizine, ficial effect upon this condition, the Food tion, pursuant to its responsibility for cycliszne, mecliaine, or their salts] outweigh and Drug Administration will permit a the safety and effectiveness of drugs, has the risks of their use in women of child- modified claim in Indications for this conducted active investigations of re- bearing age and particularly during preg- use for a period not exceeding 2 years. ports of available animal data which nancy. A review of available animal data reveals that this drug However, this modified Indication for use reveal that chlorcyclizine hydrochloride. exerts a teratogenic of these drugs In the prevention and cyclizine response in the [rat, mouse, rabbit, pig, dog]. hydrochloride and lactate, and While available clinical data are inconclu- treatment of nausea and vomiting of meclizine hydrochloride exert a terato- sivb, scientific experts are of the opinion pregnancy will be deleted from the label- genic response in animals such as the that this drug may possess a potential for ing unless substantial evidence Is offered rat, mouse, rabbit, pig, and dog. While adverse effects on the human fetus. Conse- before the expiration of this period of clinical studies to date are inconclusive, quently. consideration should be given to time. The Food and Drug Administra- scientific etperts are of the opinion that Initial use of a nonphenothiazine agent that tion will also continue to follow the these drugs may possess a potential foi is not uspected of having a teratogenic po- large-scale surveys of clinical experience adverse effects on the human fetus. In- and any reports of adverse reaction that vestigations have led to the conclusion *Section 202.1 will require that prescrip- may be due to the use of these drugs that there exists sufficient evidence of tion drug advertising contain this warning. under the revised labeling.

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14012 1975 RULES AND REGULATIONS 14013

§ 201.308 Ipecac syrup; warnings and commerce, began an active investiga- phenindlone intended for use by man directions- for - use for over-the- tion of reports of possible toxic effects found within the Jurisdiction of the act counter sale. and renal damage due to misuse of the on or after November 25, 1961, unless (a) It is estimated that each year drug acetophenetidin. This study led to such preparations are labeled in ac- about 500,000 accidental poisonings occur the decision that there was probable cordance with paragraph (a) of this in the United States and result In ap- cause to conclude that misuse and pro- section. proximately 1,500 deaths, of which over longed use of the drug were in fact (Sees. 502(f), 52 Stat. 1051, 21 US.C. 352(f)) responsible for kidney lesions and 400 are children. In the emergency § 201.311 Aminopyrine or dipyrone treatment of -these poisonings. Ipecac disease. The Commissioner of Food and Drugs, in December 1963. appointed an drug preparations for human use; di- syrup is considered the emetic of choice. rections and warnings. The-immediate availability of this drug ad hoc Advisory Committee of Inquiry on for use in such situations Is critical, since Possible Nephrotoxieity Associated With (a) Because'of the Increasing number rapid treatment may be the difference the Abuse of Acetophenetidin (Phen- of reports of fatal agranulocytosis asso- between life and death. The restriction acetin) -Containing Preparations. This ciated with the use of aminopyrine (4- of this drug to prescription sale limits committee, composed of scientists in the dimethylamino - 2,3-dlmethyl-l-phenyl- its availability 14 emergencies. On the fields of pharmacology and medicine, on 3-pyrazolin-5-one) and dipyrone (1- other hand, it is the consensus of in- April 23, 1964, submitted its findings and phenyl - 2,3 - dimethyl- 5-pyrazolone-4- formedmedical opinion that Ipecac syrup conclusions In the matter and recom- methylaminomethanesulfonate sodium). should be used only under medical super,. mended that all acetophenetidin (phen- the Commissioner of Food and Drugs vision in the emergency treatment of acetin) -containing preparations bear a convened an ad hoc Committee on Ami- poisonings. In view of these facts, the- warning as provided in section 502(f) (2) nopyrine and Dipyrone. The members question of whether Ipecac syrup labeled of the Federal Food, Drug, and Cos- of the committee conslited of authorities as an emergency treatment for use In metic Act. In the fields of hematology, internal poisonings should be available over the (b) On the basis of the studies made medicine, neurology, pediatrics, and counter has ibeen controversial. by the Food and Drug Administration pharmacology. This committee consid- (b) In connection with its study of and the report of the Advisory Commit- ered the questions of safety and effective- this problem, the Food and-Drug Admin- tee, the Commissioner of Food and Drugs ness of aminopyrine and dpyrone and istration has obtained the views of medi- has concluded that It Is necessary for the reported Its findings and recommenda- cal authorities. It is the unanimous protection of users that the label and tions to the Commissioner of Food and' recommendation of the American Acad- labeling of all acetophenetidin (phena- Drugs. Copies of the committee's report emy of Pediatrics, the Anierican Associa- cetin) -containing preparations bear a and recommendations are available upon tion of Poison Control Centers, the warning statement to the following ef- request, directed to the office of the As- American Medical Associationand the fect: "Warning-This medication may sistant Commissioner for Public Affairs, Medical Advisory Board of the Food and damage the kidneys when used In large 5600 Fishers Lane, Rockvllle, MD 20852. Drug Administration that ipecac syrup amounts or for a long period of time. The committee found: in 1 fluid ounce containers be permitted Do not take more than the recommended (1) Aminopyrine and dipyrone, a de- to be sold without prescription so that It dosage, nor take regularly for longer rivative of aminopyrine, are capable of will be readily available in the household than 10 days without consulting your causing and have caused fatal agranulo- for emergency treatment of poisonings, physician." cytosis. under medical supervision, and that the § 201.310 Phenindione; labeling of drug (2) Relatively small amounts of these drug be appropriately packaged and preparations intended for use by drugs given intermittently over a period labeled for this purpose. man. of time, as well as regular and continued (c) In view of the above recommenda- administration, can precipitate the re- (a) Reports in the medical literature action of agraulocytosis. tions, the. Commissioner of Food and and data accumulated "(3) In most instances, Drugs has determined that It is in,the by the Food and other anti- Drug Administration Indicate that phen- pyretics and analgesics that are much interest of the public health for ipecac ndone, a synthetic anticoagulant drug, syrup to be available for sale without safer -should be used in preferencF to prescription, provided that it is packaged has caused a number of cases of aminopyrine or dipyrone. agranulocytosis (with two fatalities). (4) The only conditions in which ami- In a quantity.of 1 fluid ounce (30 milM- There are also reports liters), and its label bears, in addition Implicating the nopyrine pr dipyrone are known to be drug in cases of hepatitis and hyper- possibly indicated are febrile convulsions to other required label information, the sensitivity reactions. following, in a prominent and con- In view of .the in children, where a parenteral anti- spicuousimanner: potentially serious effects found to be pyretic may be needed, and in rare in- (1) associated with preparations of this drug stances of Hodgkin's disease and similar A statement conspicuously boxed intended and in red letters, to the effect: "For for use by man, the Commis- malignant -diseases in which the fever sioner of Food and Drugs will regard cannot be controlled emergency use to cause vomiting in such preparations by any other means. poisoning. Before using, call physician. as misbranded within (b) The committee summarized its the Poison Control Center, or hospital the meaning of section 502(f) (1) and recommendations as follows: emergency r6om (2) of the Federal Food, Drug, and Cos- immediately for advice." metic Act, unless the label and labeling 1. It in recommended that aminopyrine and (2) A warning to the effect: "Warn- dipyrone for the present be retained on the ing-Keep out of reach of children. Do on or within the package from which the market, but that the following statementa- drug is to be dispensed, and any other be included In the labeling of the drugs: ndt use'in unconscious persons. Ordi- labeling furnishing or purporting narily, this drug should not be used if to All brochures, maling pieces, detallpieces. strychnine, corrosives such as alkalies furnish information for use of the drug, advertising, and other labeling should con- (lye) and strong acids, or pttroleum dfs- bear a conspicuous warning statement tain the following paragraphs, In this order: to the following effect: 'Warnjng: Warnfng--THIS DRUG MAY CAUSE FATAL tillates such as kerosine, gasoline, coal Agranulocytosis and hepatitis -have been AGRANUILOCTOSIS. (This should Imme- oil, fuel oil, paint thinner, or cleaning diately foUow the name of the drug.) fluid have been ingested." associated with the use of phenindione. Cauti-on-This drug should be used only in (3) Usual dosage: 1 tablespoon (15 Patients should be instructed to report those conditions in which It Is specifically milliliters) in persons over 1 year of age. promptly prodromal symptoms such as indicated and In which other less toxic drugs marked fatigue, chill, fever, and sore have proved ineffective or are not tolerated. § 201.309 Acetophenetidin (phenacectin)- throat. Periodic blood studies and liver The potential benefit accruing from the containing preparations; necessary function tests should be prformed. Use ue of this drug must be weighed against the warning statement, of the drug should be discontinued if pocaiblty of fatal agranulocytcsls. leukopenla occurs or If evidence of Indfcatf n or use. Aminopyrdneandami- -(a) In 1961, the Food and Drug nopyrine derivates (dIpyrone preparations) Administration, pursuant to its statutory hypersensitivity, such as dermatitis or should be restricted for use In serious or life- fever, appears." threatening situations where sallcylates or responsibility for the safety and effec- (b) Regulatory action may be initi- of- stim ar drugs are known to be ineffective or tiveness drugs shipped in interstate ated with respect to preparations of are contraindicated or not tolerated.

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 197S

HeinOnline -- 40 Fed. Reg. 14013 1975 RULES AND REGULATIONS

DuFationof administration. Fatal agranl- (i) The label and labeling of the drug satisfactory information of the kinds re- locytosis has been reported after short-term contains prominently and conspicuously. quired by Items 4, 5, 6, 7, and 8 of the use, intermittent use, and after long-term immediately following the trade name of new-drug application form set forth In administration. Therefore, the use of these the drug, without any intervening § 314.1(c) (2) of this chapter. agents should be as brief as possible. written, printed or graphic matter, the (6) Regulatory proceedings may be Precautions. Frequent white blood cell initiated with regard to the interstate differential counts should be carried out. following: and (a) A quantitative declaration of the shipment of any such preparations for However, it Is emphasized that agranu- application Is not ap- locytosis may occur precipitously without aminopyrine content; or which a new-drug prior warning.' The drug should be dis- (b) A quantitative declaration of the proved or which Is labeled or advertised continued at the first evidence of any altera dipyrone content with the name "dl- contrary to the labeling approved In such tion of the blood count or sign of agranu- pyrone" followed immediately and con- application consistent with this state- locytosis, and the patient should be spicuously in parentheses by the declara- ment of policy. instructed to discontinue use of the drug at tion "aminopyrine derivative"; and (Sec. 502 .(f), (j); 62 Stat. 1051; 21 U.S.o. the first Indication of sore throat or sign of other Infection In the mouth or throat (pain, (c) The statement "Warning:-This 352 (f), (j)) swelling, tenderness, ulceration). drug may cause fatal agranulocytosis." § 201.312 Magneslum sulfate heplahy- Dosage. Adults: The usual antipyretc (ii) Labeling on or within the package drale; label declaration on drug dose should not exceed 2 to 1 gram per from which the drug is to be dispensed products. dose, nor should more than 3 grams total and any other labeling for the drug that daily dosage be used. If the desired effect furnishes or purports to furnish informa- Magnesium sulfate heptahydrato Is not achieved within a very few days, tion for use, or which prescribes, recom- should be listed on the label of a drug use of the drug should be discontinued. mends, or suggest§ a dosage for the use product as epsom salt, which Is Its com- Children: 250 to 500 milligrams per dose, mon or usual name. repeated in 3 to 4 hours if necessary. Use of the drug, bears, in addition to the of the drug should be as brief as possible. information required in this subpara- (Sec. 502, 52 Stat. 1051; 21 U.S.C. 352) 2. It Is recommended that every effort be graph, information to the following § 201.313 Estradiol labeling. made through educational media to empha- effect: size the Identical nature of aminopyrine and CAUSE The article presently recognized In The dipyrone Insofar as toxicity is concerned. WARNING-THIS DRUG MAY AGRAlUqLOOYTOSIS. National Formulary under the heading 3. It Is further recommended that the FATAL "Estradiol" and which is said to be "17- official name of dipyrone be changed to CAUTION: This drug should be used only Is the same substance aminopyrinesulfonate sodium, if possible. in those conditions in which it is specifically cis-beta estradlol" The purpose of this is to achieve the objec- indicated and In which other less toxic drugs formerly recognized in the United States tive of Item 2 above. have proved ineffective or are not tolerated. Pharmacopela under the designation 4. The committee suggests that the panel. The potential benefit accruing from the use "Alpha Estradiol." The substance should be recalled by the Commissioner of the Food of this drug must be-welghed against the no longer be referred to in drug labeling and Drug Administration within approxi- possibility of fatal agranulocytosis. as "Alpha Estradlol." The Food and mately one year after these recommendations Indications for use. Aminopyrine and Drug Administration would not object to have been fully implemented. The purpose eminopyrine derivatives (dipyrone prepa- label references to the article os simply of such a meeting would be to ascertain- rations) should be restricted to use for "Estradior'; nor would It object if the whether the use of dipyrone and Ainopy- their antipyretic effect In serious or life- label of a preparation containing this rine and the cases of fatal agranulocytosis as- threatening situations where salicylates or sociated with the use of these drugs had been similar drugs are known to be ineffective or substance referred to the presence of noticeably reduced by the method proposed. are contraindicated or not tolerated. "Estradlol (formerly known as Alpha If the recommended labeling changes do not Duration of administration. Fatal agran- Estradiol)." have the desired effect, other recommenda- ulocytosis has been reported after short- (Sees. 201, 502, 52 Stat. 1040, 1051: 21 U. S. 0. tions would need to be considered at that term use, intermittent use, and after long- time. term administration. Therefore, the use of 321,352) these agents should be as brief as possible. § 201.314 Labelingof drug preparations (c) The committee also decided that Precautions. Frequent white blood cell . containing salicylates. a letter should be sent to all physicians and differential counts should be carried out. to remind them of the close similarity However, it is emphasized that agranulocy- (a) The label of any oral drug and toxicity of aminopyrine and di- tosis may occur precipitously without prior preparation Intended for sale without pyrone. warning. The drug should be discontinued prescription and which contains any at the first evidence of any alteration of the salicylate ingredient (including aspirin, (d) On the basis of the available blood count or sign of agranulocytosts, and salicylamlde, other sallcylates, and com- evidence, including the findings and the patient should be instructed to discon- binations) must bear a conspicuous recommendations of the committee, the tinue use of the drug at the first ndication block type on Drugs finds of sore throat or sign of other infection in warning statement in heavy Commissioner of Food and clearly contrasting background, such as: and determines with respect to any the mouth or throat (pain, swelling, tender- ness, ulceration). "Warning-Keep this and all medicines drug preparation intended for admin- case of ac- amino- Dosage. Adults: The usual antipyreto out of children's reach, In istration to man that contains dose should not exceed 1/2to 1 gram per dose, Cidental overdose, contact a physician pyrine or dipyrone: nor should more than 3 grams total daily immediately," or "Warning-Keep out (1) Such drugs are unsafe and are dosage be used. If the desired effect Is not of the reach of children," except that regarded as misbranded within the achieved within a very few days, use of the if the article is an aspirin preparation, it meaning of section 502(f) (1) and (2) drug should be discontinued. Children: 250 to 500 milligrams per dose, shall bear the first of these warning and () of the Federal Food, Drug, and statements. Such a warning statement when labeled or advertised repeated in 3 to 4 hours If necessary. Use Cosmetic Act of the drug should be as brief as possible. is required for compliance with section for routine use as antipyretics or anal- 502(f) (2) of the Federal Food, Drug, and gesics. (4) A new-drug application for such Cosmetic Act and is intended to guard (2) Regulatory proceedings may be a preparation should include a commit- against accidental poisonings. Safety initiated with regard to the continued ment that all advertising for the drug closures that prevent access to the drug marketing of any such preparations with will bear the information required by by young children are also recommended labeling or advertising offering such paragraph (d) (3) () of this section, to guard against accidental poisonings. drugs for routine use as antipyretics or and that any advertisement that pro- (b) Effervescent preparations and analgesics. vides any information regarding indi- preparations containing para-aminosal- cations or dosage recommendations will Icylate as the only rallcvlate ingredient (3) Such preparations may be ap- to ap- proved as safe and effective for market- include the information required are exempted from this labeling require- pear in the package labeling by para- ment. Ing on the basis of new-drug applications (c) Aspirin containing labeling to the following graph (d) (3) (ii) of this section and tablets sold as such and effect, which labeling differs substantially will not xecommend or suggest use of the containing no other active ingredients, from the labeling that has been com- drug under any other conditions. except tablets which cannot be readily monly employed for many years in the (5) A new-drug application will be subdivided into a child's dose because of marketing of such drugs: regarded as approable if It contains their coating or size, should always bear

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dosage directions for each age group (g) (1) The label of any drug con- eral Food, Drug, and Cosmetic Ac, unless - down to 3 years of age, with a statement taining more than 5 percent methyl sail- the labeling: such as "For children under 3 years of cylate (wintergreen oil) should bear a -(1) (1) Limits directions for.use for ate, consult your physician." It is rec- conspicuous warning such as: "Warning: denture repair kits to emergency repair- ommended that: Do not use otherwise than as directed. Ing pending unavoidable delay In ob- (1) Aspirin tablets especially made Keep out of the reach of children to taining professional reconstruction of for pediatric use be produced only in avoid accidental poisoning." the denture; 1y4-grain size to reduce the hazard of (2) If the preparation is a counter- (11) Limits directions for use for den- errors in dosage; irritant or rubefacient, it should also ture reliners, pads, and cushions to tem- (2) By June 1, 1967, manufacturers bear a caution such as, ""Caution: Dis- porary refitting pending unavoidable de- and distributors of I 4-grain size aspirin continue use if excessive Irritation of the lay in obtaining professional reconstruc- ,tablets discontinue the distribution of skin develops. Avoid getting nto the tion of the denture; such tablets in retail containers con- eyes or on mucous membranes." (See (2) Contains in a conspicuous manner taining more than 36 tablets, to reduce also § 201.303.) the word "emergency" preceding and the hazard of accidental posoning; (Sec. 502,52 Stat. 1051; 21 U.S.C. 352) modifying each ndication-for-use state- (3) The flavoring of 5-grain aspirin ment for denture repair kits and the tablets or other "adult aspirin tablets" be § 201.315 Over-the-counter drugs for word "temporary" preceding and modify- discontinued; and n e minor sore throats; suggested warn. Ing each ndlcation-for-use statement (4) Labeling giving undue emphasis Lng. for relIners, pads, and cushions; and to the pleasant flavor of flavored aspirin The Food and Drug Administration (3) Includes a conspicuous warning tablets be discontinued. has studied the problem of the labeling statement to the effect: (d) Salicylate preparations other than of lozenges or troches containing a local (I) For denture repair kits: "Warn- -" aspirin tablets sold as such may, at the anesthetic, chewing gum containing as- -g-Foremergency repairsonly. Long- option of the distributor, be labeled for pirin, various mouth washes and gargles term use of home-repaired dentures may use by adults only. If their labeling and and other articles sold over the counter cause faster bone loss, continuing irrita- advertising clearly offer them for ad- - for the relief of minor irritations of the tion, sores, and tumors. This kit for ministration to adults only. mouth or throat. It will not object to emergency use only. See Dentisf Without (e)(1) It is the obligation of the dis- the labeling of suitable articles of this Delay." tributor who labels a salicylate prepark- type "For the temporary relief of minor (11) For denture reliners, pads, and tion for administration to children to sore throats", provided this is immedi- cushions: "Warning-Fortemporary sa make certain that the article is suitable ately followed n the labeling with a only. Long-term use of this product may for such-use and labeled with adequate warning statement In prominent type lead to faster bone loss, continuing Irri- directions for use in the age group for essentially as follows: "Warning-Severe tation, sores, and tumors. For Use Only which it is offered, but in no case should or bersistent sore throat or sore throat Until a Dentist Can Be Seen." such an article bear directions for use accompanied by high fever, headache, (c) Adequate directions for use re- .inchildren under 3 years of age. If the nausea, and vomiting may be serious. quire full information of the temporary directions provide for administration to Consult physician promptly. Do not use and emergency use recommended in children as young as 3 years of age, the more than 2 days or administer to chil- order for the layman to understand the label should bear the statement, "For dren under 3 years of age unless directed limitations of usefulness, the reasons children under 3 years of age consult by physician." therefor, and the importance of adher- your physician." Howeyer, If the direc- (Sec. 502,52 Stat. 1051; 21 U.S.C. 352) Ing to the warnings. Accordingly, the tions provide for administration to chl1- labeling should contain substantially the dr.en only of an age greater than 3 years Subpart H-Special Requirements for following information: (for example, the dosage instructions Specific Devices (1) For denture repair kits: Special provide for administration of the article § 201.405 Labeling of articles intended training and tools are needed to repair to children only down to age 6), the label for lay use in the repairing drid/or dentures to fit properly. Home-repaired should bear a statement such as, :'For refitting of dentures. dentures may cause irritation to the younger children consult your physl- gums and -discomfort and tiredness cianw" (a) The American Dental Association while eating. Long-term use may lead to (2) A statement such-as, "For children and leading dental authorities have ad- more troubles, even permanent changes under 3 years of age consult your physi- vised the Food and Drug Administra- in bones, teeth, and gums, which may cian" or "For younger children consult tion of their concern regarding the safety make it impossible to wear dentures in your physician" is not required on the of denture rellners, repair kits, pads, the future. For these reasons, dentures label of an article clearly offered for ad- cushions, and other articles marketed repared with this kit should be used only. ministration to adults only. and labeled for lay use In the repair- in an emergency until a dentist can be (f) If the labeling or advertising of a ing, refitting, or cushioning of ill-fitting, seen. Dentures that don't fit properly __salicylate preparation offers it for use broken, or irritating dentures. It Is the cause Irritation and injury to the gums in arthritis or rheumatism, the label and opinion of dental authorities and the and faster bone loss, which is permanent. labeling should clearly state that the Food and Drug Administration that to Dentures that don't fit properly cause beneficial effects claimed are limited to: properly repair and properly refit den- gum changes that may require surgery 'Torthe temporary relief of miffor aches tures a person must have professional for correction. Continuing irritation and and pains of arthritis and rheumatism." knowledge and specialized -technical injury may lead. to cancer in the mouth. The qualifying phrase "for the temporary skill. Layman cannot be expected to You must see your dentist as soon as relief of minor aches and pains" should maintain the original vertical dimension possible. appear with the same degree of promi- of occlusion and the centric relation es- (2) For denture rellners, pads, and nence and conspicuousness as the phrase sential in the proper repairing or refit- cushions: Use of these preparations or "arthritis and-rheumatism". The label ting of dentures. The continued wearing devices may temporarily decrease the and labeling should bear In juxtaposition of improperly repaired or refitted den- discomfort; however, their use will not with such directions for use conspicu- tures may cause acceleration of bone re- make the denture fit properly. Special ous warning statements to the effect: sorption, soft tissue hyperplasia, and training and tools are needed to repair "Caution: If pain-persistg for more than other irreparable damage to the oral a denture to fit properly. Dentures that 10 days, or redness is present, or in con- cavity. Such articles designed for lay use do not fit properly cause irritation and ditions affecting children under 12 years should be limited to emergency or tem- injury to the gums and faster bone loss, of age, consult a physician Immediately." porary situations pending the services of which is permanent and may require a The saliylate dosage should not exceed a licensed dentist. a completely new denture. Changes in 60 grains in a 24-hour period or 10 grains . (b) The Food and Drug Administra- In a 4-hour period. If the article con- the gurbs caused by dentures that do not tains other analgesics, the salicylate dos- tion therefore regards such articles as fit properly may require surgery for cor- age should be appropriately reduced. unsafe and misbranded under the Fed- rection. Continuing irritation and injury

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may lead to cancer in the mouth. Y6u plate. The total weight of the base plate quest at all reasonable hours by any offi- must see your dentist as soon as possible. and its rigidly attached fixtures shall be cer or employee acting on behalf of the (3) If the denture relining or repair- not less than 27 pounds. For lenses of Secretary of Health, Education, and Wel- ing material forms a permanent bond small minimum diameter, a support tube fare and shall permit such officer or em- with the denture, a warning statement having an outside diameter of less than ployee to inspect and copy such records, to the following effect should be In- 1Y4 inches may be used. The support to make such Inventories of stock as he cluded: "This reliner becomes fixed to tube shall be made of rigid acrylic plas- deems necessary, and otherwise to check the denture and a completely new den- tic, steel or other suitable substance and the correctness of such inventories. ture may be required because of its use." shall have securely bonded on the top (g) For the purpose of this section, the (d) Labeling claims exaggerating the edge a Y- by %-Inch neoprene gasket term "manufacturer" Include3 an im- usefulness or the safety of the material having a hardness of 40±5, as deter- porter for resale. Such importer may or failing to disclose all facts relevant to mined by ASTM Method D 1415; a min- have the tests required by paragraph the claims of usefulness will be regarded inum tensile strength of 1,200 pounds, (d) of this section conducted in the coun- as false and misleading under sections as determined by ASTM Method D 412; try of origin but must make the results 201(n) and 502(a) of the Federal Food, and a minimum ultimate elongation of thereof available, upon request, to the Drug, and Cosmetic Act. 400 percent, as determined by ASTM Food and Drug Administration, as soon (e) Regulatory action may be Initi- Method D 412. The diameter and/or as practicable. ated with respect to any article found contour of the lens support may be mod- (h) The transition to Impact-resistant within the jurisdiction of the act con- ified as necessary so that the %- by Y/- lenses must be completed as promptly trary to the provisions of this policy inch neoprene gasket supports the lens as possible; however, to provide for the statement after 90 days following the at its periphery. Each finished impact- development of an adequate supply of date of publication of this section in the resistant glass lens for prescription use Impact-resistant lenses and to facilitate FEDERAL REGISTER. shall be subjected to the impact test pre- an orderly changeover to these lenses, § 201.410 Use of impact-resistant lenses scribed by this paragraph. Raised ledge all lenses manufactured after January 31, in eyeglasses and sunglasses. multifocal lenses must be impact-resis- 1972, must be Impact-resistant, except tant but need not be tested beyond initial when the physician or optometrist finds (a) Eiamilnation of data available on design testing. To demonstrate that all that impact-resistant lenses will not ful- the frequency of eye injuries resulting other types of impact-resistant lenses fill the visual requirements of a partcu- from the shattering of ordinary crown (including impact-resistant laminated ldr patient. glass lenses indicate that the use of such glass lenses) are capable of withstanding (I) This statement of policy does not lenses constitutes an avoidable hazard this impact test, the manufacturer of apply to contact lenses. to the eye of the wearer. such lenses shall subject to the impact (Sees. 602(j), 62 Stat. 1051; 21 U.S.o. 362(j)) (b) The consensus of the ophthalmic test a statistically significant sampling of community is that the number of eye lenses from each production batch, and injuries would be substantially reduced the-lenses so tested shall be representa- PART 202-PRESCRIPTION DRUG by the use in eyeglasses and sunglasses tive of the finished forms as worn by the ADVERTISING of either plastic lenses, heat-treated wearer (including finished forms that Sec. crown glass lenses, or lenses made are of minimal lens thickness and have 202.1 PrescrIption-drug advertisementa, impact-resistant by other methods. been subjected to any treatment used to Axvuoarr: Secs. 201 (n), 502, 605, 607, 701, (c) To protect the public more ade- impart impact resistance). Plastic pre- 52 Stat. 1041, 1050-1053 as amended, 1055-. quately from potential eye Injury, eye- scription and all nonprescription lenses, 1056 as amended by 70 Stat. 919 and 72 Stat, glasses and sunglasses must be fitted 948, 59 Stat. 463 as amended (21 U.SO. tested on the basis of statistical signif- 321 (n), 352, 355, 367, 701). with Impact-resistant lenses, except In icance, may be tested in uncut finished those cases where the physician or op- or semifinished form at the point of orig- § 202.1 Prescription drug advertise. tometrist finds that such lenses will not inal manufacture. This statement of ments. fulfill the visual requirements of the par- policy, will be appropriately amended to ticular patient, directs in writing the use (a) (1) The ingredient information provide for use of alternate methods of required by section 502(n) of the Federal of other lenses and gives written testing the impact resistance of lenses if notification thereof to the patient. Food, Drug, and Cosmetic Act shall ap- it can be shown that the alternate pear together, without any intervening (d) The physician or optometrist shall method is equal to or superior to the have the option of ordering heat-treated written, printed, or graphic matter, ex- method prescribed in this paragraph. cept the proprietary names of ingredi- glass lenses, plastic lenses, laminated (e) Copies of invoice(s), shipping glass lenses, or glass lenses made Impact ents, which may be included with the document(s), and records of sale or dis- listing of established names. resistant by other methods; however, all tribution of all impact resistant lenses such lenses must be capable of with- (2) The order of listing of ingredients standing (including finished eyeglasses and sun- in the advertisement shall be the same an impact test in which a %- glasses) shall be kept and maintained inch steel ball weighing approximately as the order of listing of ingredients on for a period of 3 years; however, the the label of the product, and the 0.56 ounces is dr9pped from a height of names and addresses of individuals Infor- 50 pur- mation presented in the advertisement Inches upon the horizontal upper sur- chasing nonprescription eyeglasses and face of the lens. The ball shall strike concerning the quantity of each such in- sunglasses at the retail level need not be gredient shall be the same within a %-inch diameter circle located kept and as the corro- maintained by the retailer. The spending information on the label of the at the geometric center of the lens. The records kept in compliance with this ball may be guided, but not restricted, product. paragraph shall be made available upon (3) The advertisement shall not em- in its fall by being dropped through a request at all reasonable hours by any tube extending to within approximately ploy a fanciful proprietary name for the officer or employee of the Food and Drug drug or any ingredient in such a manner 4 inches of the lens. In order to pass the Administration or by any other officer or test, the lens must not fracture (for the as to imply that the drug or ingredient employee acting on behalf of the Secre- has some unique effectiveness or com- purpose of this section, a lens will be tary of Health, Education, and Welfare considered to have fractured if it cracks position, when, In fact, the drug or In- and such officer or emnloyee shall be gredient Is a common substance, the lim- through its entire thickness, including a permitted to inspect and copy such rec- laminar layer, If any, and across a com- itations of which are readily recognized ords, to make such inventories of stock. when the drug or ingredient Is listed by plete diameter into two or more separate as he deems necessary, and otherwise to pieces or if any lens material visable to Its established name. check the correctness of such inventories. (4) The advertisement the naked eye becomes detached from (f) In addition, shall not fea- those persons conduct- ture inert or Inactive ingredlents In a the ocular surface). The test shall be con- ing impact tests* in accordance with ducted with the lens supported by a tube manner that creates an impression of paragraph (d). of this section, shall keep value greater than their true 1-inch inside diameter, 1 -inch outside and maintain the functional diameter, results thereof for a role in the formulation. and approximately 1-nch period of 3 years. Such records and re- high) affixed to a rigid iron or steel base (5) The advertisement shall not desig- sults shall be made available, upon re- nate a drug or ingredient by a proprle-

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tary name that, because of similarity In (c) In the case of a prescription drug tion and unless adequate provision is spelling or pronunciation, may be con- containing two or more active Ingredi- made for dissemination of the approved fused with the proprietary name or the ents, if the advertisement bears a pro- or permitted package labeling in con- established "name of a different drug'or prietary name or designation for such nection with the broadcast'presentation Ingredient. mixture and there is no established nnme shall contain a brief summary of all nec- (b) (1) If an advertisement for a pre- corresponding to such proprietary name essary Information related to side effects scription drug bears a proprietary name or designation, the quantitative Ingredi- and contraindications. or designation for the drug or any in- ent information required in the adver- (2) Exempt advertisements. Tha fol- gredient thereof, the established name. tisement by section 502(n) of the act lowing advertisements are exempt from if such there be, corresponding to such shall be placed in direct conjunction with the requirements of paragraph (e) (I) of proprietary name or designation shall ac- the most prominent display of the pro- this section under the conditions speci- company such proprietary name or des- prietary name or designation. The fied: Ignation each time it is featured in the prominence of the quantitative ingredi- (i) Reminder advertisements. Re- advertisement for the drug; but, except ent information shall bear a reasonable minder advertisements if they contain as provided below In this subparagraph, relationship to the prominence of*the only the properletary or trade name of the established name need not be used proprietary name.' a drug (which necessitates declaring the with the proprietary name or designation (d) (1) If theadvertlsement employs established name, if any, and furnishing in the running text of the advertisement. one proprietary name or designation to the formula showing quantitatively each On any page of an advertisement in refer to a combination Qf active Ingredi- ingredient of the drug to the extent re- .which the proprietary name or designa-o ents present in more than one prepara- quired for labels) and, optionally, infor- tion is not featured but is used in the run- tion (the individual preparations differ- mation relating to dosage form, quantity ning text, the established name shall be Ing from each other as to quantities of of package contents, price, the name and 'used at least once in the running text In active Ingredients and/or the form of the address of the manufacturer, packer, or association with such proprietary name finished preparation) and there Is no distributor or other written, printed, or or designation and in the same type size established name corresponding to such graphic matter containing no repre- used in the running text: Provided, how- proprietary name or designation, a list- sentation or suggestion relating to the ever, That if the proprietary name or ing showing the established names of the advertised drug: Provided,however, That designation is used inthe running text in active ingredients shall be placed in di- if the Comminsoner finds that there is larger size type, the established 'name rect conjunction with the most promi- evidence of significant incidence of fa- shall be used at least once in association nent display of such proprietary name talities or serious damage associated with with, and in type at least half as large as or designation. The prominence of this the use of a particular prescription drug, the type used for, the most prominent listing of active Ingredients shall bear he may notify the manufacturer, packer, presentation of the proprietary name or a reasonable relationship to the promi- or distributor of the drug by mail that designation in such running text. If any nence of the proprietary name and the this exemption does not apply to such advertisement'includes a column with relationship between such proprietary drug by reason of such finding: And pro- running text containing detailed infor- name or designation, and the listing of vided, however, That reminder adver- mation as to composition, prescribing, active Ingredients shall be made clear tisements are not permitted for a drug side effects, or contraindications and the by use of such phrase as "brand of", pre- for which an announcement has been proprietary name or designation, is used ceding the listing of active ingredient, published pursuant to a review of the in such column but is not featured above (2) The advertisement shall promi- labeling claims for the drug by the Na- or below the column, the established nently display the name of at least one tional Academy of Sciences-National name shall be used at least once in such specific dosage form and shall have the Research Council, Drug Efficacy Study column of running text in association quantitative ingredient information re- Group, and for which no claim has been 'with such proprietary name or designa- quired by section 502(n) of the act in evaluated as higher than "possibly ef- tion and in the same type size used in direct conjunction with such display. If fective." If the Commissioner finds the such column of running text: Provided, other dosage forms are listed in the ad- circumstances are such that a reminder however, That if the proprietary name vertisement, the quantitative ingredl- advertisement may be misleading to pre- or designation is used in such column of ent information for such dosage forms scribers of drugs subject td NAS-NRC running text in larger size type, the es- shall appear in direct conjunction and evaluation such advertisements will not tablished name shall be used at least once in equal prominence with the most prom- be allowed and the manufacturer, In association with, and in type at least inent listing of the names of such dosage packer, or distributor will be notified half as large -as the type used for, the forms. either in the publication of the conclu- most prominent presentation of the pro- (e) True statement of information in slons on the effectiveness of the drug or prietary name or designation in such brief summary relating to side effects, byletter. column of running text. Where the es- contraindications, and effectiveness: (f1) Advertisements of bulIk-saZe tablished name is required to accompany (1) When required.All advertisements drugs.Advertisements of bulk-sale drugs or to be used In association with the pro- for any prescription drug ("prescription that promote sale of the drug in bulk prietary name or designation, the estab- drug" as used in this section means drugs packages in accordance with the practice lished name shall be placed in direct defined in section 503(b) (1) of the act of the trade solely to be processed, manu- conjunction- with the proprietary name and § 201.105, applicable to drugs for factured, labeled, or repackaged In sub- or designation, and the relationship be- use by man and veterinary drugs, re- stantial quantities and that contain no tween the proprietary name or designa- spectively), except advertisements de- claims for the therapeutic safety or tion and the established name shall be *cribed in paragraph (e) (2) of this sec- effectiveness of the drug. made clear by use of a phrase such as tion, shall present a true statement of (iII) Advertisements of Prescription- "brand of" preceding the established information in brief summary relating compounding drugs. Advertisements of name, by brackets surrounding the es- to side effects, contraindlcations (when prescription-compounding drugs that tablished name, or by other suitable used in this section "side effects, con- promote sale of a drug for use as a pre- means. traindicatons" include side effects, warn- scription chemical or other compound (2) The established name shall be ings, precautions, and contraindicatlons for use by registered pharmacists in printed In letters that are at least half and include any such Information under compounding prescriptions If the drug as large as the letters comprising the such headings as cautions, special con-. otherwise complies with the conditions proprietary name or designation with siderations, important notes, etc.) and for the labeling exemption contained in which it is Joined, and the established effectiveness. Advertisements broadcast § 201.120 and the advertisement contains name shall have a prominence commen- through media such as radio, television, no claims for the therapeutic safety or surate with the prominence with which or telephone communications systems effectiveness of the drug. such proprietary name or designation shall include information relating to the (3) Scope of information to be z- appears, taking into account all perti- major side effects and contraindlcations cluded,; applicability to the entire ad- nent factors, including typography, lay- of the advertised drugs in the audio or vertisement. () The requirement of a out, contrast, and other printing features. audio and visual parts of the presenta- true statement of information relating

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCfl 27, 1975

HeinOnline -- 40 Fed. Reg. 14017 1975 14018 RULES AND REGULATIONS to side effects, contraindications, and after August 1, 1969. or any approved (a) For which the drug Is generally effectiveness applies to the entire ad- supplement thereto, shall not recommend recognized as safe and effective among vertisement. Untrue or misleading in- or suggest any use that is not in the label- experts qualified by scientific training formation n any part of the advertise- ing accepted in such approved new-drag and experience to evaluate the safety and ment will not be corrected by the In- application or supplement. The adver- effectiveness of such drugs; or clusion in another distinct part of the tisement shall present information from (b) For which there exists substantial advertisement of a brief statement con- labeling-required, approved, or permitted evidence of safety and effectiveness, taining true information relating to side in a new-drug application relating to consisting of adequate and well-con- effects, contraindicatlons, and effective- each specific side effect and contraindica- trolled investigations, including clinical ness of the drug. If any part or theme of- tion in such labeling that relates to the investigations (as used in this secotion the advertisement would make the ad- uses of the advertised drug dosage "clinical investigations," "clinical ex- vertisement false or misleading by rea- form(s) or shall otherwise conform to perience," and "clinical significance" son of the omission of appropriate the provisions of paragraph' (e) (3) (iii) mean In the case of drugs intended f9r qualification or pertinent information, of this section. administration to man, investigations, that part or. theme shall include the (b) If'a prescription drug was covered experience, or significance in humans, appropriate qualification or pertinent by a new-drug application or a supple- and in the case of drugs Intended for information, which may be concise If It ment thereto that became effective prior administration to other animals, investi- Is supplemented by a prominent refer- to October 10, 1962, an advertisement gations, experience, or significance in the ence on each page to the presence and may recommend- or suggest: specie or species for which the drug In location elsewhere in the advertisement (1) Uses contained in the labeling ac- advertised), by experts qualified by of a more complete discussion of such cepted in such new-drug application and scientific training and experience to qualification or information. any effective, approved, or permitted evaluate the safety and effectiveness of (i) The information relating to effec- supplement thereto. the drug involved, on the basis of which tiveness is not required to nclude'infor- (2) Additional uses contained in label- it can fairly and responsibly be concluded mation relating to all purposes for which ing in commercial use on October 9, by such experts that the drug Is safe the drug Is intended but may optionally 1962, to the extent that such uses did not uses; or be limited to a true statement and effective for such of the ef- cause the drug to be an unapproved "new Jc) For which there exists substan- fectiveness of the drug for the selected drug" as "new drug" was defined in sec- tial clinical experience (as used in this purpose(s) for which the drug is recom- ion 201(p) of the act as then in force, section this means substantial clinical mended or suggested in the advertise- and to the extent that such uses would experience adequately documented in ment. The information relating to effec- be permitted were the drug subject to medical literature or by other data (to tiveness shall include specific indications paragraph (e) (4) (iii) of this section. be supplied to the Food and Drug Ad- for use of the drug for purposes claimed (3) Additional uses contained in la- ministration, If requested)), on the in the advertisement; for example, when beling in current commercial use to the basis of which It can fairly and respon- an advertisement contains a broad claim extent that such uses that do not cause the sibly be concluded by qualified experts a drug is an antibacterial agent, the drug to be an unapproved "new drug" that the drug is safe and effective for advertisement shall name a type or types as defined in- section 201(p) of the act such of infections and microorganisms for uses; or which as amended or a "new animal drug" as (M) For which safety Is supported un- the drug is effective clinically as defined in section 201(w) of the act as der any of the preceding clauses In para- specifically as required, approved, or per- amended. (c) mitted in the drug package labeling. - graph (e) (4) (l) (a), (b), and of (Il) The information this section and effectiveness Is sup- relating to side The advertisement shall present infor- ported under any other of such clauses. effects and contraindications shall dis- mation from labeling required, approved, close each specific side effect and contra- or permitted in a new-drug application The advertisement shall present In- indication (which include side effects, relating to each specific side effect and formation relating to each specific side warnings, precautions, and contraindi- contraindication in such labeling that effect and contraindication that Is re- cations and include any such information relates to the uses of the advertised drug quired, approved, or permitted In the under such headings as cautions, special dosage form(s) or shall otherwise con- package labeling by §§ 201.100 or 201,105 considerations, important notes, etc.; see form to the provisions of paragraph of this chapter of the drug dosage paragraph (e) (1) of this section) con- (e) (3) (iii) of this section. form(s) or shall otherwise conform to tafled in required, approved, or per- (i) An advertisement for a prescrip- the provisions of paragraph (e) (3) (iD mitted labeling for the advertised drug tion drug subject to certification under of this section. dosage form(s): Provided, however, section 507 or 512 of the act shall not rec- (5) "True statement" of information. (a) The side effects and contraindica- ommend or suggest any use that is not in An advertisement does not satisfy the re- tions disclosed may be limited to those the labeling covered by the certification quirement that It present a "true state- pertinent to the indications for which the or the applicable certification regula- ment" of information in brief summary drug is recommended or suggested in the tions or regulations providing for exemp- relating to side effects, contraindications, advertisement to the extent that such tion from certification. The advertise- and effectiveness If: limited disclosure has previously been ap- ment shall present information from (I) It Is false or misleading with re- proved or permitted in drug labeling con- such labeling covered by the certification spect to side effects, contraindicatlons, or forming to the provisions of §§ 201.100 or or the applicable certification regulations effectiveness; or 201.105; and or regulations providing for exemption (i) It fails to present a fair balance (b) The use of a single term for a from certification, relating to each spe- between information relating to side ef- group of side effects and contraindica- cific side effect and contraindication in fects and contraindicatlons and infor- tions (for example, "blood dyseraslas" such labeling and such regulations for mation relating to effectiveness of the for disclosure of "leukopena'," "agranu- the advertised drug dosage form(s) or drug in that the Information relating locytosis," and "neutropenla") is per- shall otherwise cdnform to the pro- to effectiveness is presented in greater mitted only to the extent that the use of visions of paragraph (e) (3) (iii) of this scope, depth, or detail than Is required such a single term in place of disclosure section. by section 502(n) of the act and this of each specific side effect and contrain- (Ili) In the case of an advertisement information Is not fairly balanced by a dication has been previously approved or for a prescription drug other than a drug presentation of a summary of true Infor- permitted In drug labeling conforming the labeling of which causes It to be an mation relating to side effects and con- to the provisions of §§ 201.100 or 201.105. unapproved "new drug" and other than traindications of tho drug; ProvidCed, (4) Substance o1 information to be in- drugs covered by paragraph (e) (4) (i) however, That no advertisement shall be cluded in brief summary. (I) (a) An ad- vertisement for a prescription drug cov- and (ii) of this section, an advertise- considered to be in violation of this sec- ered by a new-drug application approved ment may recommend and suggest the tion if the presentation of true Informa- pursuant to section 505 of the act after drug only for those uses contained in the tion relating to side effects and contrain- October 10, 1962 or section 512 of the act labeling thereof: dicatlons is comparable in depth and de-

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14018 1975 RULES AND REGULATIONS 14019 tall with the claims for, effectiveness or not required unless the advertisement with dosages different from those au- safety. promotes the drug for use by man). thorized, if the results in such patients (I It fails to reveal facts material (vii) Contains favorable data or con- are not used. In the light of its representations or ma- clusions from nonclinical studies of a (xvii) Uses headline, subheadline, or terial with respect to consequences that drug, such as In laboratory animals or in pictorial or other graphic matter in away 'may result from the use of- the drug as vitro, in a way that suggests they have that Is misleading. recommended or -suggested in the clinical significance when in fact no (xix) Represents or suggests that drug advertisement. such -clinical significance has been dosages properly recommended for use (6) Advertisements that are false, demonstrated. in the treatment of certain classes of lacking in fair balance, or otherwise mis- (viii) Uses a statement by a recog- patients or disease conditions are safe leading. An advertisement for a prescrip- nized authority that is apparently favor- and effective for the treatment of other tion drug is false, lacking in fair balance, able about a drug but falls to refer to classes of patients or disease conditions or otherwise misleading, or otherwise concurrent or more recent unfavorable when such Is not the case. violative of section 502(n) of the act. data or statements from the same au- (mO Presents required information among other reasons, if it: thority on the same subject or subjects. relating to side effects or contraindica- (I) Contains a representation or sug- (Ux) Uses a quote or paraphrase out tions by means of a general term for a gestion, not approved or permitted for of context to convey a false or misleading group in place of disclosing each specific use in the labeling, that a drug is better, Idea. side effect and contraindication (for ex- more effective, useful in a broader range Cx) Uses literature quotations or refer- ample employs the term "blood dys- of conditions or patients (as used In this ences that purport to support an ad- craslas" instead of "leukopenia," "agran- section "patients" means humans and vertising claim but in fact do not support ulocytosis," "neutropenla." etc.) unless n the case of veterinary drugs, other an- the claim or have relevance to the claim. the use of such general term conforms to imals), safer, has fewer, or less inci- (xi) Uses literature, quotations, or the provisions of paragraph (e) (3) (ii) dence of, or less serious side effects or references for the purpose of recom- of this section. contraindications than has been demon- mending or suggesting conditions of drug Provided, however, That any provision of strated by substantial evidence or sub- use that are not approved or permitted this paragraph shall be waived with re- stantial clinical experience (as described In the drug package labeling. spect to a specified advertisement as set in paragraph (e) (4) (i11) (b) and (c) (xil) Offers a combination of drugs forth In a written communication from of this section) whether or not such for the treatment of patients suffering the Food and Drug Administration on a representations are made by comparison from a condition amenable to treatment petition for such a waiver from a person with other drugs or treatments, and by any of the components rather than who would be adversely affected by the whether or not such a representation or limiting the indications for use to enforcement of such provision on the suggestion is made directly or through patients for whom concomitant therapy basis of a showing that the advertisement use of published or unpublished litera- as Provided by the fixed combination Is not false, lacking in fair balance, or ture, quotations, orother references. drug is indicated, unless such condition otherwise misleading, or otherwise viola- 0i Contains a drug comparison that is included in the uses permitted under tive of section 502(n) of the act. A peti- represents or suggests that a drug is safer paragraph (e) (4) of this section. tion for such a waiver shall set forth or more effective than another drug in- (xlii) Uses a study on normal In- clearly and concisely the petitioner's in- some paricular when It has not been dividuals without disclosing that the terest in the adv-Utsement, the specific demonstrated to be safer or more effec- subjects were normal, unless the drug provision of this paragraph from which tive in such particular by substantial evi- is intended for use on normal Individuals. a waiver is sought, a complete copy of dence or substantial clinical experience. (xiv) Uses "statistics" on numbers of the advertisement, and a showing that (ii) Contains favorable information patients, or counts of favorable results or the advertisement is not false, lacking in or opinions about a drug previously re- side effects, derived from pooling data fair balance, or otherwise misleading, or garded as valid but which have been ren- from various insignificant or dissimilar otherwise violative of section 502(n) of dered invalid by contrary and more cred- studies in a way that suggests either that the act. ible recent information, or contains lit- such "statistics" are valid if they are not (7) Advertisements that may be false. erature references or quotations that are or that they are derived from large or lacking in fair balance, or otherwise mfg- significantly more favorable to the drug significant studies supporting favorable leading. An advertisement may be false, than has been demonstrated by stibstan- conclusions when such Is not the case. lacking in fair balance, or otherwise mis- ta evidence or substantial clinical (xv) Uses erroneously a statistical leading or otherwise violative of section experience.- finding of "no significant difference" to 502(n) of the act if it: (iv) Contains a representation or sug- claim clinical equivalence or to deny or (I) Contains favorable information or gestion that a drug is safer than It has conceal -the potential existence of a real conclusions from a study that is inade- been demonstrated to be by substantial clinical difference. quate In design, scope, or conduct; to fur- evidence or substantial clinical experi- (xvi) Uses statements or representa- nish significant support for such infor- *ence, by selective presentation of in- tions that a drug differs from or doesnot mation or conclusions. formation from published articles -or contain a named drug or category of (i) Uses the concept of "statistical other -references that report no side drugs, or that It has a greater potency significance" to support a claim that has effects or minimal side effects with the per unit of weight. in a way that suggests not been demonstrqted to have clinical drug or otherwise selects information falsely or misleadingly or without sub- evidence or substantial clinical significance or validity, or fails to reveal from any source in a way that makes a stantial the range of variations around the drug appear to be safer than has been experience that the advertised drug Is safer or more effective than such other quoted average results. demonstrated. (Ill) Uses statistical analyses and (v)Presents information from a study drug or drugs. (xvii) Uses 'data favorable to a drug techniques on a retrospective basis to in a way that implies that the study discover and cite findings not soundly represents larger-or more general experi- derived from patients treated with dos- ages different from those recommended supported by the study, or to suggest ence with the.drug than it actually does. scientific validity and rigor for data from (vi) Contains references to literature in approved or permitted labeling if the or studies that misrepresent the effec- drug advertised is subject to section 505. studies the design or protocol of which tiveness of a drug by failure to disclose 507, or 512 of the act, or, in the case of are not amenable to formal statistical that claimed results may be due to con- other drugs, if the dosages employed were evaluations. comitant therapy, or by'failure to dis- different from those recommended In the (iv) Uses tables or graphs to distort close the credible information available labeling and generally recognized as safe or misrepresent the relationships, trends, concerning the extent to which claimed and- effective. This provision is'not in- differences, or changes among the varia-- results may be due to placebo effect (In- tended to prevent citation of reports of bles or products studied; for example, formation concerning placebo effect is studies that include some patients treated by falling to label abscissa and ordinate

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14019 1975 14020 RULES AND REGULATIONS to sec- so that the graph creates a misleading seminated without prior approval by the (1) (1) Advertisements subject impression. Food and Drug Administration if: tion 502(n) of the act Include advertise- (v) Uses reports or statements rep- (I) The sponsor or the Food and Drug ments in published journals, magazines, to be statistical analyses, in- Administration has received information other periodicals, and newspapers, and resented media terpretations, or evaluations that are in- that has not been widely publicized in advertlsemuts broadcast through consistent with or violate the established medical literature that the use of the such as radio, television, and telephone theory, methodol- drug may cause fatalities or serious communication systems. principles of statistical booklets, mailing ogy, applied practice, and inference, or damage; (2) Brochures, the (i) The Commissioner (or',in his ab- pieces, detailing pieces, file cards, bulle- that are derived from clinical studies Usts, catalogs, house design, data, or conduct of which sub- sence the officer acting as Commis- tins, calendars, price stantially invalidate'the application of sioner), after evaluating the reliability organs, letters, motion picture films, film such information, has notified the strips, lantern sllder, sound recordings, statistical analyses, interpretations, or of sim- evaluations. sponsor that the information must be a exhibits, literature, and reprints and (vi) Contains claims concerning the part of.the advertisements for the drug; liar pieces of printed, audio, or visual mechanism or site of drug action that and matter descriptive of a drug and refer- are not generally regarded as established (III) The sponsor has failed within a ences published (for xaample, the "Physi- by scientific evidence by experts quali- reasonable time as specified In such cians Desk Reference") for use by medi- fied by scientific training and experience notification to present to the Food and cal practitioners, pharmacists, or nurses, without disclosing- that the claims are Drug Administration a program, ade- containing drug Information supplied by not established and the limitations of quate in light of the nature of the In- the manufacturer, paicker, or distributor the supporting evidence. formation, for assuring that such in- of the drug and which are disseminated (vii) Fails to provide sufficient em- formation will be publicized promptly by or on behalf of its manufacturer, phasis for the information relating to and adequately to the medical profes- packer, or distributor are hereby deter- sion In subsequent advertisements. mined to be labeling as defined In sec- side effects and contraindications, when tion 201 (m) of the act. such information is contained in a dis- If the Commissioner finds that the pro- tinct part of an advertisement, because gram presented Is not being followed, he of repetition or other emphasis in that will notify the sponsor that prior ap- PART 207-REGISTRATION OF PRODUC- part of the advertisement of claims for proval of all advertisements for the par- ERS OF DRUGS AND LISTING OF DRUGS effectiveness or safety of the drug. ticular drug will be required. Nothing IN COMMERCIAL DISTRIBUTION (viii) Fails to present information in this paragraph is to be construed as Subpart A-Definitlons relating to side effects and contraindica- limiting the Commissioner's or the Sec- Sec. tions with a prominence and readability retary's rights, as authorized by law, 207.3 Definitions. reasonably comparable with the presen- to issue publicity, to suspend any new- Subpart --Procedure for Domestic Drug tation of information relating to effec- drug application, to decertify any anti- Establishments tiveness of the drug, taking into account biotic, or to recomend any regulatory 207.20 Who must regiEter and submit a drug all implementing factors such as typog-_ action. list. riphy, layout, contrast, headlines, para- (2) Within a reasonable time after in- 207.21 Times for re,istration and drug graphing, white space, and any other formation concerning the possibility that listing. apt to achieve emphasis. 207.22 How and where to register and list techniques a drug may cause fatalities or serious drugs. (ix) Fails to provide adequate em- damage has been widely publicized in 207.25 Information required in registration phasis (for example, by the use of color medical literature, the Food and Drug and drug listing, scheme, borders, headlines, or copy that Administration shall notify the sponsor 207.26 Amendments to registration. extends across the gutter) for the fact of the drug by mall that prior approval 207.30 Updating drug listing information. that two facing pages are part of the of advertisements for the drug Is no 207.31 Additional drug listing information. same advertisement when one page con- longer necessary. 207.35 Notification of registrant; drug estab- relating to side effects lishment registration number and tains information (3) Dissemination of an advertisement drug listing number. and contraindications. not in compliance with this paragraph 207.37 Inspection of registrations and drug (x) In an advertisement promoting shall be deemed to be an act that causes listings. use of the drug in a selected class of pa- the drug to be misbranded under section 207.39 Misbranding by reference to registra- tients (for example, geriatric patients or 502(n) of the act. tion or to regi3tration number. depressed patients), falls to present with (4) Any advertisement may be sub- Subpart C-Procedures for Foreign Drug adequate emphasis the significant side mitted to the Food and Drug Adminis- Establishments effects and contraindications or the sig- tration prior to publication for comment. 207.40 Drug listing requirements for for- nificant dosage considerations, when If the advertiser is notified that the eign dAig establishments. dosage recommendations are -included submitted advertisement Is not in viola- Subpart D-Exemptions in an advertisement, especially appli- tion and. at some subsequent time, the cable to that selected class of patients. Food and Drug Administration changes 207.65 Exemptions for domestic establish- (xi) Fails to present on a page facing its opinion, the advertiser will be so ments. another page (or on another full page) notified and will be given a reasonable A onrry: Sees. 201, 502, 605, 506, 507, 510, of an advertisement on more than one 512, 701(a), '04; 52 Stat. 1040-1042 as time for correction before any regulatory amended, 1050-1053 as amended. 1056, 1057 page, information relating to side ef- action is taken under this section. Noti- as amended; 21 U.S.C. 321, 352, 355, 350, 351, fects and contraindications when such fication to the advertiser that a proposed 360, 360b, 371(a). 374; sec. 351, 68 Stat. 7'02 information is in a distinct part of the advertisement is or Is not considered to as amended; 42 U.S.C. 262; the Drug Listing advertisement. be in violation shall be in written form. Act of 1972, Pub. L, 92-387; 86 Stat. 659-462 (xil) Fails to include on each page or (k) An advertisement issued or caused (21 U.S.C. 360 note) unless otherwise noted, spread of an advertisement the informa- to be issued by the manufacturer, packer. tion relating to side effects and contra- or distributor of the drug promoted by Subpart A-Deflnitions indications or a prominent reference to the advertisement and which is not in § 207.3 Definitions. Its presence and location when it is of the (a) The term "act" means the Federal presented as a distinct part of an compliance with section 502(n) act and the applicable regulations there- Food, Drug, and Cosmetic Act approved advertisement. 1938 (52 Stat. 1040 et seq., as uhder shall cause stocks of such drug in June 25, (xiii) Contains information from pub- 21 U.S.C. 301-392). lished or unpublished reports or opin- possession of the person responsible for amended, (b) "Establishment" means a place of Ions falsely or misleadingly represented issuing or causing the issuance of the one or suggested to be authentic or authori- business under one management at advertisement, and stocks of the drug general physical location. The term in- tative. by such person and still in (f) through (i) [Reserved] distributed cludes, among others, independent labo- (j) (1) No advertisement concerning a the channels of commerce, to be mis- ratories that engage In control activitles particular prescription drug may be dis- branded under section 502(n) of the act. for registered drug establishment (e.g.,

FEDERAL REGISTER, VOL. 40, NO. 60--THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14020 1975 RULES AND REGULATIONS 14021

"consulting"i laboratories), manufactur- (i) "Advertising" and 'labeling" 'In- under § 207.30 shall so certify to the reg- ers of medicated feeds and of vitamin clude the promotional material described istered establishment that such submis- products that are "drugs" within the in § 202.1() (1) and (2) of this chapter sion has been made by providing a signed meaning of section. 201(g) of the act, respectively. copy of Form FD-2656 (Registration of human blood donor centers, and animal (i) The definitions and interpretations Drug Establishment) to the registered facilities used for the production or con- contained in sections 201 and 510 of the establishment which manufactures, pre- trol testing of licensed biologicals. act shall be applicable to such terms pares, propagates, compounds, or proc- (c)'Manufacture, preparation, propa- when used in this Part 207. esses the drug. The original of Form PD- 2656 (Registration of Drug Establish- gation, compounding, or processing of a Subpart B-Procedures for Domestic drug or drugs means the making by ment) showing such certification shall chemical, physical, biological, or other , Drug Establishments be submitted to the Food and Drug Ad- procedures of any articles -which meet §.207.20 Who must register and submit ministration. Such certification shall be the definition of drugs as defined in sec- a drug list. accompanied by a list showing the Na- tional Drug Code number assigned to -tion 201(g) of the act; and including drug manipulation, sampling, testing, or con- (a) Owners or operators of all each drug product by the distributor. establishments, not exempt under sec- to engaging in the trol procedures applied to the final prod- tion 510(g) of the act or Subpart D of c) Preparatory uct or to any part of the'process. The this Part 207, that engage in the manu- manufacture, preparation, propagation, term includes repackaging or otherwise facture, preparation, propagation, com- compounding, or processing of a drug, changing the container, wrapper, or pounding, or processing of a drug or ovners or operators of establishments labeling of any drug package in further- drugs are required to register and to sub- who are submitting new drug "ap- ance of the distribution of the drug from list of every drug in commercial plications, new animal drug applications, - the original place of manufacture to the m it a Form FD-1800 (Medicated Feed Appli- delivery or sale distribution (except that listing Infor- person who makes final mation may be submitted by the parent, cation), antibiotic Forms 5 and 6, or an to the ultimate consumer. establishment license application in (d) "Commercial distribution" -means subsidiary, and/or affiliate company for order to manufacture biological prod- all establishments when operations are to register before the any distribution of a human drug except conducted at more than one establish- ucts are required pursuant to the investigational use pro- exists joint ownership new drug application, new animal drug visions of § 312.1 of this chapter, and ment and there application, Form FD-1800, antibiotic and control among all the establish- 5 or 6, or establishment license any distribution of an animal drug or ments). Such owners or operators are Form an animal feed bearing or containing an required to register and to submit a list application is approved. animal drug for noninvestigational uses d) No registration fee is required- internal or inter- of every drug in commercial distribution but does not include (except that listing information may be Registration and listing do not constitute plant transfer of a bulk drug substance an admission or agreement or determi- between registered domestic establish- submitted by the parent, subsidiary, and/ or affiliate company for all establish- nation that a product is a "drug" within ments within the same parent, subsidi- ments when operations are conducted at the meaning of section 201(g) of the ary, and/or affiliate company. establishment and there act. (e) 'Representative sampling of ad- more than one exists Joint ownership and control among §207.21 Times for registration and vertisements" means typical advertising whether or not material (excluding labeling as de- all the establishments), drug listing. termined in § 202.1(1) (2) of this chap- the output of such establishment or any The owner or operator of an establish- ter) which gives a balanced picture of the particular drug so listed enters interstate ment entering into an operation defined promotional claims being used for the commerce, except that drug listing is not in § 207.3 Cc) shall register such estab- drug (e.g., if more than one medical required at this time for the manufac- lishment within 5 days after the begin- journal advertisement is used but their turing, preparation, propagation, com- ning of such operation and submit a list promotional content is essentially identi- pounding, or processing of an animal feed of every drug In commercial distribution cal, only one need be submitted). (including a feed concentrate, a feed at that time. If the owner or operator of (f) "Representative sampling of any supplement, and a complete animal the establishment defined in § 207.1(c) other labeling" as used In this part means feed) bearing or containing an animal has not previously entered into such op- typical labeling material (excluding drug. eration, registration shall follow within labels and package inserts) which gives (b) Distributors which are not other- 5 days after the submission of a new drug a balanced picture -of the promotional wise required to register under section application, new animal drug applica- claims being used for the drug (e.g.. if 510 of the act, may submit drug listing tion, Form FD-1800, antibiotic Form 5 or more than one brochure is used but their information directly to the Food and 6, or an establishment license application promotional content is essentially identi- Drug Administration for those drugs in order to manufacture biological prod- cal, only one need be submitted). which they distribute under their own ucts. Owners or operators of all estab- (g) "Any material change" includes label or trade name but which are manu- lishment so engaged shall register an- but is not limited, to any change in the factured, prepared, propagated, com- nually between November 15 and name of the drug, in the quantity or pounded, or processed by a registered es- December 31 and shall update their drug Identity of the active ingredient(s) or tablishment. Where drug listing infor- listing Information every June and in the quantity or identity of the in- mation is submitted by a distributor, the December. active ingredient(s) where quantitative registration number of the drug estab- lishment which manufactured, prepared, § 207.22 How and where to register and listing of all ingredients i required pur- list drugs. suant to § 207.31(a) (2), any significant propagated, compounded, or processed change in the labeling -of a prescription the drug shall be included for each drug (a) The first registration of an drug, and any significant change in the listed. If a distributor does not elect to establishment shall be oA Form PD- label or package insert of an over-the- obtain a "Labeler Code" the registered 2656 (Registration of Drug Establish- counter dug. Changes that are not sig- establishment shall submit the drug list- ment) obtainable on request from the nificant include changes in arrangement ing information. Such submissions and Department of Health. Education, and or printing or changes of an editorial requests for Labeler Codes shall be made Welfare, Food and Drug Administration, nature. on Form FD-2658 (Registered Establish- Bureau of Drugs, Registration Section, (h) '"ulk drug substance" means any ments' Report of Private Label Distribu- 5600 Fisheri Lane, Rockvlle, MD 20852, substance that is represented for use in tors). All distributors submitting drug or from Food dnd Drug Administration a drug and when used in the manufactur- listing information to the Food and Drug- district offices. Subsequent annual reg- ing, processing, or packaging of a drug Administration assume full responsibil- istration shall also be accomplished on becomes an active ingredient or a fin- ity for compliance with all of the require- Form FD-2656 (Registration of -Drug ished dosage form of such drug, but does ments of this part. Each distributor at Establishment), which will be furnished not include intermediates used in the the time of each submission of drug list- by the Food and Drug Administrationbe- synthesis of such substances. ing information or updating as required fore November 15 of each year to estab-

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 197i

HeinOnline -- 40 Fed. Reg. 14021 1975 14022 RULES AND REGULATIONS lishments whose drug registration for (4) For each human drug so listed § 207.30 Updating drug listing informa- that year was validated pursuant to which is subject to section 503(b) (1) of tion. § 207.35. The completed form shall be the act and regarded by the registrant as (a) After submision of the Initial mailed .to the above address before not subject to section 505, 506, or 507 of drug listing Information, every person December 31 of that year. the act or 351 of the Public Health Serv- who is required to list drugs pursuant to (b) The first list of .drugs and sub- ice Act, and which is not manufactured § 207.20 shall submit on Form FD-2657 sequent June and December updatings by a registered blood bank, a copy of all (Drug Product Listing) during each sub- shall be on Form FD-2657 (Drug Product current labeling except that only one rep- sequent June and December, or at the Listing), obtainable upon request as resentative container or carton label discretion of the registrant at the time described in paragraph (a) of this sec- need be submitted where differences the change occurs, the following tion. In lieu of Form FD-2657 (Drug exist only in the quantity of contents Information: Product Listing), tapes for computer in- statement and a representative sampling (1) A list of each drug Introduced by puts may be submitted if, equivalent in of advertisements. the registrant for commercial distribU- all elements of information as specified (5) For each human over-the-counter tion which has not been included In any in Form FD-2657 (Drug' Product List- drug or each animal drug so listed which list previously submitted. All of the In- ing). All formats proposed for such use is regarded by the registrant as not sub- formation required by § 207.25(b) shall will require initial review and approval ject to section 505, 506, 507, or 512 of the be provided for each such drug, by the Food and Drug Administration. act, or 351 of the Public Health Service (2) A list of each drug formerly listed § 207.25 Information required in regis- Act, a copy of the label except that only pursuant to § 207.25(b) for which com- tration and drug listing. one representative container or carton mercial distribution has been discon- label need be submitted where differ- tinued, including for each drug so listed (a) Form FD-2656 (Registration of ences exist only in the quantity of con- Drug Establishment) requires the NDC number, the Identity by estab- furnishing tents statement, package insert, and a lished name and proprietary name, and or confirming infdrmation required by representative sampling of any other the act. This information includes the date of discontinuance. It s requested labeling. but not required that the reason for dis- name and street address of the drug (6) For each prescription or over-the- continuance of distribution be included establishment,. including post office ZIP counter drug so listed which is regarded code; all trade names with this information. used by the estab- by the registrant as not subject to sec- (3) A list of each drug for which a lishment; the kind of ownership or op- tion 505, 506, 507, or 512 of the act, or 351 eration (that is, individually owned notice of discontinuance was submitted part- of the Public Health Service Act, and pursuant to paragraph (a)(2) of this nership, or corporation); and the name which is not manufactured by a regis- of the owner or operator section and for which commercial dis- of such estab- tered blood bank, quantitative listing of tribution has been resumed, including lishment. The term "name of the owner the active ingredient(s). If the drug is or operator" shall include in the case for each drug so listed the NDC number, of in unit dosage form the statements of the the identity by established name as de- a partnership the name of each partner, quantity'of ingredient shall express the and In the case of a corporation the name fined in section 502(e) of the act and by amount, not the percent, of such ingre- any proprietary name, the date of re- and title of each corporate officer and dient in each such unit, unless the quan- director and the name sumption, and any other information of the State of titative listing is expressed as a percent- required by § 207.25(b) not previously incorporation. The information required age in the official compendium. If the shall be given separately for each estab- submitted. drug is not in unit dosage form, the state- (4) Any material change In any in- lishment, as defined in § 207.3 (b). ment of the quantity of an ingredient (b) Form FD-2657 (Drug Product formation previously submitted. shall express the amount, not the per- (b) When no changes have occurred Listing) requires furnishing information cent, of such Ingredient in a specific unit required by the act as follows: since the previously submitted list, no of weight or measure of the drug unless report is required. (1) Alist of drugs, including bulk drug the quantitative listing is expressed as a substances and drug premixes for use percentage in the official compendium, § 207.31 Additional drug listing infor- in the. manufacture of animal feeds as except that for drug premixes for use in mation. I well as finished dosage forms, by estab- the manufacture of animal feeds such in- (a) In addition to the Information lished name as defined in section 502(e) gredient which is not an antibiotic may routinely required by §§ 207.25 and 207.30, of the act and by proprietary name, be expressed in terms of percent. If a the Commissioner may require submis- which are being manufactured, prepared, drug premix has been assigned a Product sion of the following information by let- propagated, compounded, or processed Code as provided for in § 207.35(b) (2) ter or by FEDERAL REISTERa notice: for commercial distribution and which (Ili), the quantitative listing of ingredi- (1) For a particular drug so listed have not been included in any list pre- ents may be limited to each variation of which is subject to section 503(b) (1) of viously submitted on Form FD-2657 level of active drug ingredient. the act and regarded by the registrant (Drug Product Listing) or in conjunc- (7) For each drug listed, the registra- as not subject to section 505, 506, or 507 tion with the Food and Drug Administra- tion number of every drug establishment of the act, upon request made by the tion voluntary inventory on Form FD- within the parent company at which it is Commissioner for good cause, a copy of 2422 (Survey Report of Marketed Drugs), manufactured, prepared, propagated, all advertisements. or Form FD-2250 (National Drug Code compounded, or processed. (2) For a particular drug product so Directory Input). (8) For each drug so listed, the Na- listed which is regarded by the registrant (2) For each drug so listed which is tional Drug Code (NDC) number. If no as not subject to section 505, 500, 607, regarded by the registrant as subject to NDC Labeler Code number has been as- or 512 of the act, upon a finding by the section 505, 506, 507, or 512 of the act, signed, the Product Code and Package Commissioner that it is necessary to the new drug application number, abbre- Code will be included and a Labeler Code carry out the Purposes of the act, a viated new drug application number, new will be assigned as described jn § 207.35 quantitative listing of all Ingredients. animal drug application number, or Form (b) (2) (1). (3) For a particular drug product 5 or Form 6 number, and, a copy of all § 207.26 Amendments to registration. upon requesk by the Commissioner, a current labeling, except that only one brief statement of the basis upon which representative container or carton label Changes in individual ownership, cor- the registrant has determined that the need be submitted where differences exist porate or partnership structure location drug product Is not subject to section only in the quantity of contents state- or drug-handling activity, shall be sub- 505, 506, 507, or 512 of the act. ment. emitted by Form FD-2656 (Registration (4) For each registrant, upon a find- (3) For each drug so listed which is of Drug Establishment) as amendment ing by the Commissioner that it Is neces- regarded by the registrant as subject to, to registration within 5 days* of such sary to carry out the ptirposes of the section 351 of the Public Health Service changes. Changes in the names of offi- act, a'list of each listed drug product cers and directors of the corporations do- Act, the license number of the manufac-' containing a particular ingredient. not require such amendment but must (b) It is requested but not required turer. be shown at time of annual registration. that information concerning the quantity

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14022 1975 RULES AND REGULATIONS 14023

of drug-distributed be submitted In con- tration of Drug Establishment). Any not require the submission of a supple- junction with the annual registration registered firm that does not have an mental new drug application, supple- in the-format prescribed in a section of assigned "Labeler Code" will be assigned mental new animal drug application, or Form FD-2656A (Optional Distribution one when registration and listing in- supplemental antibiotic Form 5 or 6. Data), for each drug currently listed. formation is submitted. (4) If any material change occurs In (c) It is requested but not required (ii) The last five numeric characters product characteristics (including but that a qualitative listing of the inactive of the 10-character code identify the not limited to a change In dosage form, ingredients be submitted for all listed drug and the 'trade package size alf active ingredient(s) or active ingredi- drugs in the format prescribed in Form type. The segment which Identifies the ent(s) strength or concentration, route D--2657 (Drug Product Listing). drug formulation is known as the Pxoduct of administration, or product name, etc.) d) It is requested but not required Code and the segment which Identifies a new NDC number shall be assigned by that a quantitative listing of the active the trade package size and type is known the registrant to the new product ver- ingredients be submitted for all drugs as the Package Code. The Product Code sion and the Information submitted to listed which are subject to section 505, and the Package Code shall be assigned the Food and Drug Administration. If a 506. 507, or 512 of the -act or section 351 by the manufacturer or distributor prior change In packaging only Is Involved of the Public Health Service Act. to drug listing and included in Form the trade package code can be revised § 207,35 Notification of registrant; drug FD--2657 (Drug Product Listing). Either without the necessity of assigning a new estabnlishment registration number of two methods may be used by the man- product code segment, but the Food and and drug listing number. ufacturer or distributor In assigning the Drug Administration shall be informed Product and Package Codes; a 3-2 Prod- about the new trade package code and (a)- The Commissioner will provide to uct-Package Code configuration (i.e., characteristics. the registrant a validated copy of Form 542-12) or a 4-1 Product-Package Code (c) Although registration and drug -FD-2656 (Registration of Drug Estab- configuration (i.e., 5421-2). Only one listing are required to engage In the lishment) as evidence of registration. such Product-Package Code configura- drug activities described in § 207.20, This validated copy will be sent only to tion may be used by a manufacturer or validation of registration and the as- the location shown for the registering distributor with a given Labeler Code signment of a drug listing number do establishment. A permanent registration and this same configuration shall be used not, In themselves, establish that the -number will be assigned to each drug in assigning the Product-Package Codes holddr of the registration is legally establishment registered in accordance for all drugs included In the drug listing. -'qualified to deal in such drugs. with these regulations. The manufacturer or distributor shall Nore: The provisions or § 207.35(b) (3) (b) A drug listing number will be as- report to the Food and DrugAdmlnlstra- rubll not be eirecti e until printing plates signed, using the National Drug Code tion the Product-Package Code configu- arm revisled or until July 1, 1975 (38 R numbering system, to each drug or class ration he used in assigning these codes. 27593). of drugs listed as follows: Once a Product Code has been assigned (1)If a drug is already listed In the to a specific drug, this same code may § 207.37 Inspection of registrations and National Drug Code System or in the never again be used for any other drug ,druglistings. National Health Related Items Code regardless whether the drug has been (a) A copy of the Form FD-2656 System, the number will be the same as discontinued. (Registration of Drug- Establishment) that assigned pursuant to those codes. A (Il) If the drug formulation is a cus- filed by the registrant will be available lead zero will be added by the Food and tom premix intended for use in the man- for Inspection pursuant to section 510(f) Drug -Administration to the first three ufacture of an animal feed, a separate of the act, at the Department of Health, characters of the code, which Identifies Product Code s required only for each Education, and Welfare, Food and Drug the manufacturer or distributor, to ex- variation of level of active drug In- Administration, Bureau of Drugs, Reg- pand the "Labeler Code" segment to four gredient. istration Section, 5600 Fishers Lane, characters. The National Drug Code, (3) The NDC number is requested but Rockville, MD 20852. In addition, there Product Code and Package Code con- not required to appear on all drug labels will be available for inspection at each figurations used to'describe such drugs, and in all drug labeling, including the of the Food and Drug Administration or any new drugs added to the product label of any prescription drug container distrizt offices the same information for line, will remain thi same (Me., a four- furnished to a consumer. If the NDC firms within the geographical area of character Product Code and a two- number is shown on a drug label it shall such district office. Upon request and character Package Code). Alphanumeric be placed -as follows: receipt of a self-addressed stamped en- characters where already used In thd (I) The NDC number shall be placed velope, vertification of registrationnum- Product Code and Package Code seg- prominently in the top third of thd center ber, or location of a registered concern ments of -the National Drug Code may be panel of the label of the immediate con- will be provided. retained, however, these alphanumeric tainer and of the outside container or (1) The following information submit- characters may be converted to all nu- wrapper if such there be. ted pursuant to the drug listing require- meric digits. The manufacturer or dis- (It) The NDC number shall be pre- ments is illustrative of the type of infor- tributor shall inform the Food and Drug ceded by the initials NDC, in a different mation that will be available for public Adnlstra~tibn of such changes. color or different type style (font) than disclosure when It is compiled: (2) If a registered establishment or that used to print the number If the (i) A list of all drug-products. distributor has not previously partici- label is printed rather than typewritten, (it) A list of all drug products broken pated In the National Drug Code system, whenever it is used on a label or in down by labeled indications or pharma- or in the National Health Related Items labeling. qological category. Code system,- the -National Drug Code (ill) A list of all drag products, broken numbering system will be used in assign- (Wil)The Product-Package Code con- down by manufacturer. ing a number, as follows (only numerics figuration shall be indicated and the seg- (1v) A list of a drug product's active will be used): ments of the number shall be separated Ingredients. (I) The first five numeric characters by a dash (Me.,NDC 15643-542-12 or NDC V) A list of drug products newly mar- of the' 10-character code identify the 15643-5421-2). keted or where marketing is resumed. manufacturer or distributor and are (iv) All 10 characters shall appear and (vi) A list of drug products discon- known as the Labeler Code. The Food the leading zeros in any segment of the tinued. and Drug Administration will expand the NDC number shall be shown: Provided, (vii) Alilabellng. Labeler Code from five to six numeric however, That when the NDC number is (vil) All advertising. characters when the available five-char- used for product Identification by direct (x) All data or information that has acter code combinations are exhausted. imprinting on dosage forms, leading zeros already become a matter of public These code numbers are assigned by the may be dropped from the Product Code knowledge. Food and Drug Administration and pro- segment of the NDC number. (2) The following information sub- - vided to the registrant along with the v) The placing of the assigned NDC mitted pursuant to the drug listing re- validated copy of Form FD-2656 (Regis- number on a label or in labeling does quirement is illustrative of the-type of

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14023 1975 14024 RULES AND REGULATIONS information that will not be available for the Commissioner has found, under sec- intended for use In in vitro diagnostlo public disclosure: tion 510(g) (4), that such registration is procedures in the diagnosis of disease (i) Any data or information submitted not necessary for the protection of the or in the determination of the state of as the basis upon which it has been de- public health. health in order to cure, mitigate, treat, termined that a particular drug product (a) Pharmacies that are operating or prevent disease or Its sequelne, Is not subject to section 505, 506, 507, or under applicable local laws regulating 512 of the act. dispensing of prescription drugs and that PART 210-CURRENT GOOD MANUFAC. (i) A list of a drug product's inactive dQ not manufacture, prepare, propagate, TURING PRACTICES IN MANUFACTUR. ingredients. compound, or process drugs for sale other ING, PROCESSING, PACKING, OR HOLD. (iiI) A list of drugs containing a par- than in the regular course of the practice ING OF DRUGS: GENERAL ticular ingredient. of the profession of pharmacy including Sec, (iv) Provided, That any of the above the business of dispensing and selling information will be available for public 210.3 Definitions. drugs at retail. The supplying by such 52 disclosure if it has already become a pharmacies of prescription drugs to a AvrHonrrY: Secs. 501, 701, Stat. 1049- matter of public knowledge or if the 1050 as amended, 1055-1056 as amended (21 practitioner licensed to adminste such U.S.C. 351, 371). I Commissioner finds that confidentiality drugs for his use in the course of his would be inconsistent with protection of professional practice or to other pharma- § 210.3 Definition3. the public health. cies to meet temporary inventory short- (a) As used in this part, "act" means (b) Requests for information about such registrations and drug listings should ages are not acts which require the Federal Food, Drug, and Cosmetic Health, pharmacies to register. Act, sections 201-902, 52 Stat. 1052 (21 be directed to the Department of public with all the amendments Education, and Welfare, Food and Drug (b) Hospitals, clinics, and U.S.C. 321-392) Administration, Bureau of Drugs, Regis- health agencies which maintain estab- thereto. lishments in conformance with any ap- (b) The definitions and interpreta- tration Section, 5600 Fishers Lane, Rock- plicable local laws regulating the prac- tions contained in section" 201 of the act ville, MD 20852. tices of pharmacy ana medicine and shall be applicable to such terms when § 207.39 Misbranding by reference to which 'are regularly engaged in dispens- used in the regulations in this part. registration or to registration number. ing prescription drugs, other than hu- (c) As used in this part: Registration of a drug establishment man blood or blood products, upon (1) The term "medicated feed" means or drug wholesaler or assignment of a prescription of practitioners licensed any "complete feed," "feed additive sup- registration number or assignment of a by law to administer such drug for pa- plement," or "feed additive concentrate," NDC number does not in any way denote tients under the care of such practi- as defined in § 121.200 of this chapter, approval of the firm or its products. Any tioners in the course of their professional which feed contains one or more drugs representation that creates an impres- practice. as defined in section 201(g) of the sion of official approval because of regis- (a) Practitioners who are licensed by act'. Medicated feeds are subject to tration or possession of registration num- law to prescribe or administer drugs and §§ 225.1 through 225.115 of this chapter, ber or NDC number is misleading and who manufacture, prepare, propagate, inclusive. constitutes misbranding. compound, or process drugs solely for (2) The term "medicated premix" use in the course of their professional means a substance that meets the dofi- Subpart C-Procedures for Foreign practice. nition in § 121.200 of this chapter for Drug Establishments (d) Persons who manufacture, pre- a "feed additive premix," except that § 207.40 Drug listing requirements for pare, propagate, compound, or process It contains one or more drugs as defined foreign drug establishments. drugs solely for use in research, teach- in section 201(g) of the act and is in- ing, or chemical analysis and not for sale. tended for manufacturing use in the (a) Every foreign drug establishment (e) Manufacturers of harmless inac- production of a medicated feed. Medi- shall comply with the drug listing re- tive ingredients which are excipients, cated premixes are subject to 0§ 220.1 quirements contained in Subpart B of colorings, flavorings, emulsifiers, lubri- through 226.115 of this chapter, inclu- this part, unless exempt under Subpart cants, preservatives, or solvents that be- sive. D of this part, whether or not it is also come components of drugs, and who (d) As used in §§ 211.1 through 211.115 registered. otherwise would not be required to regis- of this chapter, inclusive: (b) No drug may be imported from a ter under the provisions of this Part 207. (1) The term "component" means any foreign drug establishment into the (f) Any person who uses drugs to pre- ingredient intended for use in the man- United States except a drug imported or pare feed for his own animals: Provided, ufacture of drugs In dosage form, in- offered for import pursuant to the in- That under the act and its regulations cluding those that may not appear in vestigational use provisions of § 312.1 of such person would not be required* to the finished product. this chapter, unless it is first the subject hold an approved new animal drug ap- (2) The term "batch" means a spe- of a drug listing as required in Subpart B plication (or supplement thereto) or a cific quantity of a drug that has uniform of this part. The drug listing information Form FD-1800 in order to possess and character and quality, within specified shall be in the English language. ,use the drug. limits, and is produced according to a (c) Foreign drug establishments shall (g) Any manufacturer of a virus, single manufacturing order during the submit as part of 'the drug listing, the serum, toxin, or analogous product in- same cycle of manufacture. name and address of the establishment tended-for treatment of domestic ani- (3) The term "lot" means a batch or and the name of the individual respdn- mals, who holds an unsuspended and un- any portion of a batch of a drug or, in sible for submitting drug lsting infor- revoked license issued by the Secretary the case of a drug produced by a con- mation. Any changes in this information of Agriculture under the animal virus- tinuous process, an amount of drug pro- shall be reported to the Food and Drug serum-toxin law of March 4, 1913 (37 duced in a unit of time or quantity in Administration at the intervals specified Stat. 832; 21 U.S.C. 151 et seq.) : Provided, a manner that assures Its uniformity, in That such exemption from registration and in either case which is Identified by for updating drug listing information shall apply only with respect to the § 207.30(a). a distinctive lot number and has uniform manufacture of such animal virus, serum, character and quality within specified Subpart D-Exemptions toxin, or analogous product. limits. (h) Carriers, by reason of their receipt, (4) The terms "lot number" or "con- § 207.65 Exemptions for domestic estab- holding, or delivery of drugs in lishments. carriage, trol number" mean any distinctive com- the usual course of business as carriers. bination of letters or numbers, or both, The following classes of persons are (I) Persons who are engaged, solely in from which the complete history of the exempt from registration and drug list- the manufacture, preparation, propaga- manufacture, control, packaging, and this Part 207 ing in accordance with tion, compounding, or processing of a of a batch or lot of drug under the provisions of section 510(g), general purpose laboratory reagent (as distribution (1), (2), and (3) of the act, or because described in § 328.10(d) of this chapter) can be determined.

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14024 1975 RULES AND REGULATIONS 1402-5

(5) The term "active ingredient" that a drug meets the requirements of (6) Any packaging or-labeling opera- means any component which is intend ,d the act as to safety and has the Identity tions. to furnish pharmacological activity ior and strength and meets the quality and (7) Storage of finished products. other direct effect in the-diagnosis, cutre,purity characteristics which it purports (8) Control and production-labora- mitigation, treatment, or prevention, of or is represented to possess as required tory operations. disease, or to affect the structure or ariy by section 501(a) (2) 03) of the act. (b) Provide adequate lighting, venti- function of the body of man or other (b) The regulations In this part per- lation, and screeninc and, when neces- animals. The term shall include those mit the use of precision automatic, me- sary for the intended production or components which may undergo cheml- chanical-or electronic equipment In the control purposes, provide facilities for cal change in the manufacture of tIie production and control of drugs when adequate air-pressure, microbiological, drug and bepresent in the finished dn ig adequate Inspection and checking pro- dust, humidity, and temperature controls product in a modified form intended 1to cedures are used to assure proper to: furnish the specified activity or effect 1. performance. (1) Mnimilze contamination of prod- * (6) The term "Inactive ingredenlitP § 211.10 Pcrsonncl. ucts by extraneous adulterants, includ- means any component other than a ing cross-contamination of) one prod- "active ingredient" present in a drug. (a) The personnel responsible for uct by dust or particles of ingredients (7) The term "materials approv al directing. the manufacture and control arising from the manufacture, storage, unit" means any organizational elemeiit of the drug shall be adequate in number or handling of another product havingthe authority and responsibililty and background of education, training, (2) "MInlinize dissemination of micro- to approve or reject components, irt- and experience, or combination thereof, brganlsms from one area to another. process materials, packaging comp(3- to assure that the drug has the safety, (3) Provide suitable storage conditions nents, and final products. Identity, strength, quality, and purity for drug components, in-process mate- (8) The term "streigth" means: that It purports to possess. All personnel rials, and finished drugs in conformance (I) The concentration of the drug shall have capabilities commensurate with stability Information as derived substance (for example, w/w, w/v, or unit with their assignedfunctions, a thorough under § 211.60. dose/volume basis) and/or understanding of the manufacturing or (c) Provide adequate locker facilities (ii) The potency, thatis, the therapet t- control operations they perform, the and hot and cold water washing facili- tic activity of the drug substance as ind1- -necessary training or experience, and ties, including soap or detergent. air-drier cated by appropriate laboratory tests cor adequate information concerning the or single service towels, and clean toilet 'by- adequately developed and controlled reason for application of pertinent pro- facilities near working areas. clinical data (expressed, for example, In visions of this part to their respective (W) Provide an adequate supply of terms of units by reference to a functions. potable water (§ 1250.82 of this chapter) standard). (b) Any person shown at any time under continuous positive pressure in a (either by medical examination or super- plumbing system. free of defects that visory observation) to have an apparent could cause or contribute to contamina- PART 211-CURRENT GOOD MANUFAI illness or open lesions that may adversely TURING PRACTICE FOR FINISHED affect tion of any drug. Drains shall be of ade- PHARMACEUTICALS the safety or quality of drugs shall quate size and, where connected directly be excluded from direct Subpart contact with to a sewer, shall be equipped with traps A--General Plfdlslons drug products until the condition Is cor- to preventback-siphonage.. Sec. rected. All employees shall be instructed (e) Provide suitable housing and space 2.11.1 :Finished pharmaceuticals; maniu- to report to supervisory personnel any faturing practicie. for the care of all laboratory animals. 211.10 Personnel. conditions that may have such an ad- (f) Provide for safe and sanitary dis- verse effect on drug products. posal of sewage, trash, and other refuse Subpart B--Constructlori and Maintenance i Facilities and Equipment f Subpart B--Construction and Maintenance within and from the buildings and im- 21120 -Buildings. of Facilities and Equipment mediate premises. 211.30 Equipment. § 211.20 Buildings. § 211.30 Equipment. Subpart C-Product Quality Control Buildings shall be maintaindd in a Equipment used for the manufacture, 211.40 Production and control -procedures. clean and orderly manner and shall be processing, packing, labeling, holding, 211.42 Components. testing, or control of drugs shall be main- 211.55 Product containers of suitable size, construction, and loca- and their cor L- tion to facilitate adequate tained in a clean and orderly manner ponents. cleaning, 211.58 Laboratory controls. maintenance, and proper operations in and shall be of suitable design, size, con- 211.60 Stability. the manufacturing, processing, packing, struction, and location to facilitate 211.62 Expiration dating. labeling, or holding of a drug. The build, cleaning, maintenance, and operation Ings shall: for Its intended purpose. The equipment Subpart D--Packaging and Labeling shall: 211.80 Packaging and labeling. (a) Provide adequate space for: (1) Orderly placement of equipment (a) Be so constructed that all surfaces Subpart E-Records and Reports and materials to minimize any risk of that come Into contact with a drug prod- 211.101 Master production and control rec mixups between different drugs, drug uct shall not be reactive, additive, or ab- ords; sorptive so as to alter the safety, Identity, batch production and con - components, in-process materials, pack- trol records. aging materials, or labeling, and to mini- strength, quality, or purity- of the drug 211.110 Distribution records. mize the or Its components beyond the offelal or 211.115 Complaint fies. possibility of contamination. other established requirements. A'uTo~rr: Sees. 501, 701. 52 Stat. 1049 (2) The receipt, storage, and with- (b) Be so constructed that any sub- 1050 asnmended, 1055-1056 as amended (2 holding from use of components pending stances required for operation of the U.S.C. 351,371). I sampling, Identification, and testing equipment. such as lubricants or cool- prior to release by the materials Subpart A--General Provisions approval ants, do not contact drug products so as unit for manufacturing or packaging. to alter the safety, Identity, strength, § 211.1 Finished pharmaceuticals; man . (3) The holding of rejbcted compo- quality, or purity of the drug or its com- ufacturing practice. nents prior to disposition to preclude the ponents beyond the offclal or other (a) The criteria in §§ 211.20-211.115 possibility of their use in manufachlring established requirements. inclusive, .shall apply in determinint or packaging procedures for which they (c)Be constructed and installed to whether the methods used in, or th( are unsuitable. facilitate adjustment disassembly clean- facilities or controls used for, the manu-. (4) The storage of components. ing and maintenance to assure the reli- facture, processing, packing, or holdinE containers, l5ackagng materials, and ability of control procedures uniformity of a'drug conform to or are operated o r labeling. of production and exclusion from the administered in conformity with curreni6 '_(5) Any manufacturing and process- drugs of contaminants from'previous good manufacturing practice to assure Ing operations performed. and current operations that mlght

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14025 1975 14026 RULES AND REGULATIONS affect the safety, identity, strength, qual- specifications for the product before drug product or component. Use of an ity, or purity of the drug or its com- distribution. asbestos-containing filter with or with- ponents beyond the official or other (h) Procedurds shall be instituted out subsequent use of a specific non- established requirements. whereby review and approval of all pro- fiber-releasing filter is permissible only (d) Be of suitable type, size, and duction and control records, including upon submission of proof to the appro- accuracy for any testing, measuring, mix- packaging and labeling, shall be made priate bureau of the Food and Drug Ad- ing, weighing, or other processing or prior to the release or distribution of a ministration that use of a non-fiber-re- storage operations. batch. A thorough investigation of any leasing filter will, or is likely to, Subpart C-Product Quality Control unexplained discrepancy or the failure compromise the safety or effectiveness of of a batch to meet any of Its specifica- the drug. § 211.40 Production and control proce- tions shall be undertaken whether or (3) Substitution for a fiber-releasing dures. not the batch has already been distrib- filter shall be achieved on or before Sep- Production and control procedures uted. This investigation shall be under- tember 14, 1976. If such substitution is shall include all reasonable precautions, taken by a competent and responsible not achieved on or before March 14, including the following, to assure that individual and shall extend to other 1976, the manufacturer of the drug prod- the drugs produced have the safety, batches of the same drug and other uct for pafenteral injection who requires identity, strength, quality, and purity drugs that may have been associated the additional 6 months to develop new they purport to possess: with the specific failure. A written record manufacturing procedures so as to uti- (a) Each significant step in the proc- of the investigation shall be made lize non-fiber-releasing filters in place of ess, such as the selection, weighing, and and shall include the conclusions and fiber-releasing filters shall submit measuring of components, the addition followup. monthly reports to the appropriate bu- of ingredients during the process, weigh- (i) Returned goods shall be identified reau of the Food and Drug Administra- ing and measuring during various stages as such and held. If the conditions under tion indicating progress in substituting of the processing, and the determination which returned goods have been held, the new filters. Such a substitution shall of the finished yield, shall be performed stored, or shipped prior to or during be shown to have been effected without by a competent and responsible individ- their return, or the condition of the loss of the safety or effectiveness of the ual and checked by a second competent product, its container, carton, or label- drug. and responsible individual; or if such ing as a result of storage or shipping, Paragraph Wi)is effective April 14, 1975. steps in the processing are controlled cast doubt on the safety, identity, by precision automatic, mechanical, or" strength, quality, ot purity of the drug, § 211.42 Components. electronic equipment, their proper per- the returned goods shall be destroyed All components and other materials formance is adequately checked by one or subjected to adequate examination or used in the manufacture, processing, and or more competent and responsible indi- testing to assure that the material meets packaging of drug products, and mate- viduals. The written record of the sig- all appropriate standards or specifica- rials necessary for building and equip- nificant steps in the process shall be tions before being returned to stock for ment maintenance, upo4 receipt shall be identified by the individual performing warehouse distribution or repacking. If stored and handled In a safe, sanitary, these tests and by the individual charged the product is neither destroyed nor re- and orderly manner. Adequate measures with checking these steps. Such identi- turned to stock, it may be reprocessed shall be taken to prevent mixups and flcations shall be recorded immediately provided the final product meets all its cross-contanination affecting drugs and following the completion of such steps. standards and specifications. Records of drugproducts. Components shall be with- (b) All containers, lines, and equip- returned goods shall be maintained and held from use until they have been Iden- ment used during the production of a shall indicate the quantity returned, tified, sampled, and tested for conform- batch of a drug shall be properly Iden- date, and actual disposition of the prod- ance with established specifications and tified at all times to accurately and com- uct. If the reason for returned goods are released by a materials approval pletely indicate their contents and, when implicates associated batches, an appro- unit. Control of components shall include necessary, the stage of processing of the -priate investigation shall be made In ac- the following: batch. cordance with the requirements of para- (a) Each container of component shall (c) To minimize contamination and graph (h) of this section. be examined visually for damage or con- prevent mixups, equipment, utensils, and (j) Use of asbestos-containing or other tamination prior to use, Including exami- containers shall be thoroughly and ap- fiber-releasing filters: (1) Filters used nation for breakage of seals when in- propriately cleaned and properly stored in the manufacture, processing or pack- dicated. and have previous batch Identification aging of components of drug products (b) An adequate number of samples removed or obliterated between batches for parenteral injection in humans shall shall be taken from a representative or at suitable intervals in continuous not release fibers into such products. No number of component containers from production operations. asbestos-containing or other fiber-re- each lot and shall be subjected to one or (d) Appropriate precautions shall be leasing fiter may be used in the manu- more tests to establish the specific taken to minimize microbiological and facture, processing or packaging of such identity. other contamination -in the production. products unless it is not possible to man- (c) Representative samples of com- of drugs purporting to be sterile or ufacture that drug product or component ponents liable to contamination with which by virtue of their intended use without the use of such a filter. Filtra- filth, insect infestation, or other extra- should be free from objectionable micro- tion, as needed, shall be through a non- neous contaminants shall be appropri- organisms. fiber-releasing filter. For the purposes ately examined. (e) Appropriate procedures shall be of this regulation a non-fiber-releasing (d) Representative samples of all com- established to minimize the hazard of filter is defined as a nonasbestos, non- ponents intended for use as active ingre- cross-contamination of any drugs while glass fiber filter which, after any appro- dients shall be tested to determine their being manufactured or stored. priate pretreatment such as washing or strength in order to assure conformance (f) To assure the uniformity and In- flushing, will not continue to release with appropriate specifications. tegrity of products, there shall be ade- fibers into the drug product or compo- (e) Representative samples of com- quate In-process controls, such as check- nent which is being filtered. A fiber is de- ponents liable to microbiological con- ing the weights and disintegration times fined as any particle with length at least tamination shall be subjected to micro- of tablets, the adequacy of mixing, the three times greater than its width. biological tests prior to use. Such homogeneity of suspensions, and the (2) If use of a fiber-releasing filter is components shall not contain micro- clarity of solutions. In-process sampling required, an additional non-fiber-releas- organisms that are objectionable in view shall be done at appropriate intervals ing filter of maximum pore size of 0.22 of their intended use. using suitable equipment. microns (0.45 microns if the manufac- f) Approved components shall be (g) Representative samples of all dos- turing conditions so dictate) shall sub- appropriately Identified and retested as age form drugs shall be tested to sequently be used to reduce the content necessary to assure that they conform determine their conformance witfi the of any asbestos-form particles in the to appropriate specifications of Identity,

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'strength, quality, and purity at time of tion of the sampling and testing proce- tion of other drugs by penicillin, shall use. This requires the following: dures used for them. Said samples shall test such nonpenicillin products to de- (1) Approved components shall be be representative and adequately Identi- termine whether any have become cross- handled and stored to guard against con- fied. Such records shall also provide for contaminated by penicillin. Such prod- taminating or being contaminated by appropriate retesting of drug compo- ucts shall not be marketed if intended other drugs or components. nents, product containers, and their com- for use in man and the product is con- (2) Approved components shall be ro- ponents subject to deterioration. taminated with an amount of penicillin tated in such a manner that the oldest (b) A reserve sample of all active equivalent to 0.05 unit or more of peni- stock is used first. ingredients as required by § 211.42 (h). cillin G per maximum single dose rec- (3) Rejected components shall be (c) The establishment of master ommended in the labeling of a drug in- identified and held to preclude their records, when needed. containing speci- tended for parenteral administration, or use in manufacturing or processing pro- fications and a description of sampling, an amount of penicillin equivalent to 0.5 cedures for which they are unsuitable. and testing procedures for in-process unit or more of penicillin G per maxi- (g). Appropriate records shall be drug preparations. Such samples shall be mum single dose recommended in the maintained, including the following: adequately representative and properly labeling of a drug intended for oral use. (1) The identity and quantity of the Identified. §211.60 Stability. component, the name of the supplier, the Cd) The establishment of master supplier's -lot number, and the -date of records containing a description of sam- There shall be assurance of the stabil- receipt. ping procedures and appropriate speci- Ity of finished drug products. This sta- (2) Examinations and tests performed fications for finished drug products. Such bility shall be: and rejected components and their samples shall be adequateyrepreseta- Ca) Determined by reliable, meaning- disposition. tive and properly Identified. ful, and specific test mdthods. (3) An individual inventory and rec- (e) Adequate provisions for checking (b) Determined on product- in the ord for each component used in each the Identity and strength of drug prod- same container-closure systems in batch of drug manufactured or processed. ucts for all active ingredients and for which they are marketed. (i) An appropriately identified re- assuring: (c) Determined on any dry drugprod- serve sample of all active ingredients . (1) Sterility of drugs purported to be uct that is to be reconstituted at the time consisting of at least twice the quantity sterile and freedom from objectionable of dispensing (as directed in its labeling), necessary for all required tests, except microorganisms for those drugs which as well as on the reconstituted product. those for sterility and determination of should be so by virtue of their Intended d) Recorded and maintained in such * the presence of pyrogens, shall be re- use. manner that the stability data may be tained for at least 2 years after distribu- (2)" The absence of pyrogens for those utilized in establishing product expira- * tion of the last drug lot incorporating drugs purporting to be pyrogen-free. tion dates. the component has been completed or 1 (3) MInimal contamination of oph- §211.62 Expiration dating. year after the expiration date of this last thalmic ointments by foreign particles drug lot, whichever is longer. and harsh or abrasive substances. To assure that drug products liable to § 211.55 Product containers and their (4) That the drug release pattern of deterioration meet appropriate standards components. sustained release products Is tested by of Identity, strength, quality, and purity laboratory methods to assure conform- at the time of use, the label of all such Suitable specifications, test methods, ance to the release specifications. drugs shall have suitable expiration cleaning procedures, and when indicated, Cf) Adequate provision for auditing dates which relate to stability tests per- sterilization procedures shall be used to the reliability, accuracy, precision, and formed on the product. assure that containers, closures, and performance of laboratory test proce- (a) Expiration dates appearing on the other component parts of drug packages dures and laboratory instruments used. drug labeling shall be justified by readily are suitable for their intended use. Con- (g) A properly identified reserve available data from stability studies such tainers for parenteral drugs, drug prod- sample of the finished product (stored In as described in § 211.60. ucts or drug components shall be the same immediate container-closure (b) Expiration dates shall be related cleansed with water which has been il- system in which the drug Is marketed) to appropriate storage conditions stated teredthrougha non-fiber-releasing filter consisting of at least twice the quantity on the labeling wherever the expiration equivalent to that indicated in § 211.40() necessary to perform all the required date appears. (2Y- Product containers and their com- tests, except those for sterility and de- Cc) When the drug is marketed in the ponents hal not be reactive, additive, termination of the absence of pyrogens, dry state for use. in preparing a liquid or absorptive so as to alter the safety, and stored under conditions consistent product, the labeling shall bear expira- identity, strength, quality, or plrity of with product labeling shall be retained tion Information for the reconstituted the -drug or -its components beyond the for at least 2 years after the drug dIs- product as well as an expiration date for official or established requirements and tribution has been completed or at least the dry product. shall provide adequate protection against 1 year gfter'the drug's expiration date, external factors that can cause deterio- whichever is longer. Subpart D-Packaging and Labeling ration or contamination, of the drug. Ch) Provision for retaining complete § 211.80 Packaging and labeling. Effective date. This section effective records of all laboratory data relating to Packaging and labeling operations April 14, 1975. each batch or lot of drug to which they apply. Such records shall be retained for shall be adequately controlled: To as- (Se'cs. 501, 502, 701, 52 Stat. 1049-1051, 1055- at*least 2 years after distribution has sure that only those drug products that 1056, as amended; (21 U.S.C. 351, 352, 371)) have met the standards and specifica- been completed or 1 year after the drug's tions established in their master pro- § 211.58- Laboratorycontrols. expiration date, whichever Is longer. duction and control records shall be Laboratory controls shall include the () Provision that annmals shall be distributed; to prevent mixups between establishment of scientifically sound and maintained and controlled In a manner dru&s during filling, packaging, and appropriate specifications,' standards, that assures suitability for their intended labeling operations; to assure that cor- and test procedures to assure that com- use. They shall be Identified and appro- rect labels and labeling are employed ponents, in-processed drugs, and finished priate records maintained to determine for the drug; and to identify the finished products conform to appropriate stand- the history of use. product with a lot or control nmnber that ards of identity, strength, quality, and () Provision that firms which manu- permits determination of the history of purity. Laboratory controls shall include: facture nonpenicillin products (includ- the manufacture and control of the (a) The establishment.of master rec- ing certifiable antibiotic products) on batch. An hour, day, or shift code is ords containing appropriate specifica- the same premises or use the same equip- appropriate as a lot or control number tions for the acceptance of each lot of ment as that used for manufacturing for drug products manufactured or proc- drug components, product -containers, penicillin products, or that operate under essed in continuous production equip- and their components used in drug pro- any circumstances that may reasonably ment. Packaging and labeling operations duction and packaging and a descrip- be regarded as conducive to contamina- shall:

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(a) Be separated (physically or spa- Subpart E-Records and Reports (2) A record of each significant step tially) from operations on other drugs In § 211.101 Master production and con- in the manufacturing, processing, pack- a manner adequate to avoid-mixups and trol records; batch production and aging, labeling, testing, and controlling minimize cross-contamination. Two or control records. of the batch, including: Dates: individual more packaging or labeling operations major equipment and lines employed: having drugs, containers, or labeling sim- (a) To assure uniformity from batch specific identification of each batch of ilar in appearance shall not be in process to batch, a master production and con- components used; weights and measure3 simultaneously on adjacent or nearby trol record for each drug product and of components and products used In the lines unless these operations are sepa- each batch size of drug product shall be course of processing; in-process and lab- rated either physically or spatially. prepared, dated, and signed or initialed oratory control results; and Identifica- (b) Provide for an inspection of the by a competent and responsible indi- tions of the individual(s) actively per- facilities prior to use to assure that all vidual and shall be independently forming and the individual(s) directly drugs and previously used packaging and checked, reconciled, dated, and signed or supervising or checking each significant labeling materials have been removed. initialed by a second competent and re- step in the operation. (c) Include the following labeling 'sponsible individual. The master produc- (3) A batch number that Identifles controls: tion and control record shall include: all the production and control docu- (1) The holding of labels and package (1) The name of the product, descrip- ments relating to the history of the batch labeling upon receipt pending review and tion of the dosage form, and a specimen and all lot or control numbers associated proofing against an approved final copy or copy of each label and all other label- with the batch. by a competent and responsible indi- ing associated with the retail or bulk (4) A record og any investigation vidual to assure that they are accurate unit, including copies of such labeling made according to § 211.40 (h). signed or initialed and dated by the per- regarding Identity, content, and con- § 211.110 Distribution records. formity with the approved copy before son or persons responsible for approval release to.inventory. of such labeling. (a) inished goods warehouse con- (2) The .maintenance and storage of (2) The name and weight or measure trol and distribution procedures shall In- each type of label and package labeling of each active ingredient per dosage unit clude a system by which the distribution representing different products,-strength, or per unit of weight or measure of the of each lot of drug can be readily deter- dosage forms, or quantity of contents in finished drug, and a statement of the mined to facilitate Its recall If necessary. such a manner as to prdvent mixups and total weight or measure of any dosage Records within the system shall contain provide proper Identification. unit. the name and address of the consignee, (3) A suitable system for assuring that (3) A complete list of ingredients date and quantity shipped, and lot or only current labels and package labeling designated by names or codes sufficiently control number of the drug. Recordl are retained and that stocks of obsolete specific to indicate any special quality shall be retained for at least 2 years after labels and package labeling are characteristic; an accurate statement of the distribution of the drug has been destroyed. the weight or measure of each ingredient completed or 1 year after the expiration (4) Restriction of access to labels and regardless of whether it appears in the date of the drug, whichever Is longer. package labeling to authorized personnel. finished product, except that reasonable (b) To assure the quality of the (5) Avoidance of gang printing of cut variations may be permitted in the product, finished goods warehouse con- labels, cartons, or inserts when the amount of components necessary in the trol shall also include a system whereby labels, cartons, or inserts are for differ- preparation in dosage form provided the oldest approved stock Is distributed ent products or different strengths of that provisions for such variations are first whenever possible. (See 21 CFR 1304- the same products or are of the same size included in the master production and for regulations relating to manufactur- and have identical or similar format control record; an appropriate statement ing and distribution records of drugs and/or color schemes. If gang printing concerning any calculated excess of an subject to the Drug Abuse Control is employed, packaging and labeling op- ingredient; an appropriate statement of theoretical weight or measure at various Amendments of 1965; Public Law 89- erations shall provide for added control 74.) procedures. These added controls should stages of processing; and a statement of consider sheet layout, stacking, cutting, the theoretical yield. § 211.115 Complaint files. and handling during and after printing. (4) A description of the containers, Records shall be maintained of all (d) Provide strict control of the pack- closures, and packaging and finishing materials. written and oral complaints regarding age labeling Issued for use with the drug. each product. An Investigation of each Such issue shall be carefully checked by (5) Manufacturing and control in- a competent and responsible person for structions, procedures, specifications, complaint shall be made in accordance Identity and conformity to the labeling special notations, and precautions to be with § 211.40(h). The record of each in- followed. vestigation shall be maintained for at specified in the batch production record. (b) The batch production and control Said record shall Identify the labeling record shall be prepared for each batch least 2 years after distribution of the and the quantities Issued and used and drug has been completed or 1 year after shall reasonably reconcile any dis- of drug produced and shall include com- crepancy between the quantity of drug plete information relating to the produc- the expiration date of the drug, which- finished and the quantities of labeling is- tion and control of each batch. These ever is longer. records shall be retained for at least 2 sued. All excess package labeling bear- years after the batch distribution Is ing lot or control numbers shall be PART 225-CURRENT GOOD MANUFAC. destroyed. In event of any significant un- complete or at least 1 year after the TURING PRACTICE FOR MEDICATED explained discrepancy, an investigation batch expiration date, whichever is FEEDS longer. These records shall Identify the should be carried out according to Subpart A-General Provisions §211.40(h). specific labeling and lot or control num- bers used on the batch and shall be Sec. (e) Provide for adequate examination readily available during such retention 225.1 Current good manufacturing prac- or laboratory testing of representative period. The batch record shall include: tice. samples of finished products after pack- 225.10 Personnel. aging and labeling to safeguard against (1) An accurate reproduction of the appropriate master formula record Subpart B-Construction and Malntenance of any errors in the finishing operations and checked, dated, and signed or initialed Facilities and Equipment to prevent distribution of any batch until by a competent and responsible Indi- 225.20 Buildings. all specified tests have been met. vidual. 225.30 Equipment.

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Subpart C-Produqt Quality Control (4) Storage of containers, packaging integrity of the final product.'If such' See. - materials, labeling, and finishing prod- steps in the processing are controlled by 225.40 Production and control procedures. ucts. precision, automatic, mechanical, or elec- 225.42 Components. (b) Provide adequate lighting and tronic equipment, provision shall be made 225.58 Laboratory controls. other physical facilities necessary to pre- to adequately check its performance. Subpart D-Packaging and Labeling vent unsafe contamination of raw ma- (b) All containers to be used for undi- 225.80 Packaging and-labeling. - terials and finished products before, dur- luted drugs, drug components, Inter- Ing, and after production. mediate mixtures, and finished feeds Subpart E-Records and Reports (c) Provide for -adequate washing. shall be received, adequately Identified. 225.102 Formula and production records. cleaning, toilet, and locker facilities. and properly stored and handled in a 225.110 DistrLbution records. manner adequate to prevent mixups or 225.115. Conplaint files. Work areas and equipment used far the production of medicated feeds or for the contamination. A=onrros: Sees. 501, 7014 52- Stat. 1049- c) Equipment, including dust-con- 1050 as amended, 1055-1056 as amended (21 storage of the components of medicated trol and other equipment, such as that U.S.C. 351,371). feeds shall not be used for the production, mixing, or storage of finished or un- used for holding and returning recovered Subpart -- General Provisions or flush-out materials back into produc- finished Insecticides, fungicides, or ro- tion, shall be maintained and operated In § 225.1 Current good manufacturing denticides or their components. such a manner as to prevent unsafe con- practice. § 225.30 Equipment. tamination of the medicated feed. The criteria in §.225.10 through 225.- Equipment used for the manufacture, d) The steps used to prevent unsafe 115, inclusive, shall apply in determining processing, packaging, bulk shipment, contamination of medicated feed include whether the methods used in, or the labeling, holding or control of medicated one or more of the following, or other facilities and controls used for, the feeds or their components shall be main- equally effective procedures: manufacture, 'processing, packing, or tained in a reasonably clean and orderly (1)Cleaning of those parts of storage, holding of a medicated feed conform to manner and shall be of suitable design, mixing, conveying, and any other equip- or are operated or administered in con- size, construction, and location in rela- ment coming In contact with the drug formity with current good manufactur- tion to surroundings to facilitate main- component of the medicated feed for the ing practice to assure that a medicated tenance and operation for its intended purpose of cleaning out of the equipment feed meets the requirements of the act as purpose. The equipment shall: any drug, drug component, or medicated to safety, and has the identity and (a) Be so constructed that any sur- feed prior to the use of the same equip- strength, and meets -the quality and faces that come into contact with medi- ment for the production of-a different purity characteristics which it purports cated feeds are suitable, in that they are medicated feed. -or is represented to possess, as required not reactive, additive, or absorptive to (2)The cleaning of the equipment as by section 501(a) (2) (B) of the act. The an"extent that significantly affects the required in paragraph (d)(1) of this regulations in this Part 225 permit the Identity, strength, quality, or purity of section, may be achieved by flushing use of Precision, automatic, mechanical, the medicated feed or its components. all feed-contacting surfaces of such or electronic equipment in the production (b) Be so constructed that any sub- equipment used in the production of a of 'a medicated feed when adequate in- stance required for the operation of the medicated feed with a quantity of an spection and checking procedures are equipment, such as lubricants, coolants, appropriate drug-free feedstuff that has usedto assure proper-performance. etc., may be eniployed without hazard of been found suffielent to remove any sig- § 225.10 Personnel. becoming an unsafe additive to the med- nificant quantity of a drug component icated feed. or an intermediate mix or complete medi- 'The key employees and/or consultants cated feed prior to the production of a responsible for the formulation, manu- Cc) Be constructed to facilitate adjust- ment, cleaning, and maintenance, and to different medicated feed. The yield .facture, and control of the medicated assure from any such flushing operation may be feed shall have a background of educa- uniformity of production and re- liability of control procedures and to incorporated In appropriate amounts in tion or experience or a combination the subsequent productionof a medi- thereof that is adequate to assure assure the exclusion from medicated proper feeds of unsafe contamination, including cated feed intended to contain the same composition and labeling of the medi- drug component (or components) to pro- cated cross-examination from manufactur- feeds. ing operations. duce a complete medicated feed con- Subpart B--Construction and Maintenance (d) Be suitably grounded electrically forming to its composition and labeling of Facilities and Equipment to prevent lack of uniform mixing due specifications. (e) § 225.20 Buildings. to electrically charged particles. If there Is sequential production (e) Be of suitable size and accuracy of batches of a medicated feed containing. Buildings in which medicated feeds are for use in any intended measuring, mix- the same drug component (or compo- manufactured, processed, packaged, la- ing or weighing operations. nents) at the same or lower levels, there beled, or held shall be maintained in a shall be suficlent safeguards to avoid any reasonably clean and orderly manner Subpart C-Product Quality Control -buildup above the specified levels of the and shall be of suitable size, construc- § 225.40 Production and control pro- drug components in any of the batches tion, and location in relation to sur- cedures. of the complete feed. roundings to facilitate maintenance and Wf)A sampling and -assay schedule on operation for their intended purpose. The Production and control procedures the finished medicated feed, or a sched- buildings shall: shall include all reasonable precautions, ule at least as reliable, for checking on (a) Provide adequate space for the including the following, to assure that the composition of the finished article orderly placement of equipment andma- the medicated feeds produced are of shall be applied as follows: " terils used in any of the following opera- proper composition and labeling: (1)In the case of a medicated feed tions for which they are employed, to (a) Each critical step In the process, that requires an approved Form FD:-1800 minimize anyr risk of mixups between such as the selection, weighing, and for its manufacture and marketing, the dlfferent.medicated feeds, their compo- measuring of components; the addition schedule of assays established in such nentp, packaging, or labeling: of drugs or components during the proc- application shall be used. (1)The receipt, control, and storage -ess; the control of mixing times; the ad- (2) In the case of a medicated feed of components. justment of the equipment involved In that does not require an approved Form (2)Any ianufacturing and process- continuous production processes; and FD-1800 for Its marketing, three appro- ing operations performed the determination of the finished yield, priately drawn samples from each 400 on the medi- shall be performed cated feed. in a manner that has tons of such medicated feeds produced been determined by appropriate methods, shall be taken at appropriately spaced (3) -Any packaging and labeling opera- including laboratory testing of the med- tions. Intervals over the productionperiod, and, icated feed, to be adequate to assure the in any event, not less than three such

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HeinOnline -- 40 Fed. Reg. 14029 1975 14030 RULES AND REGULATIONS samples of each particular medicated centrate or supplement label or labeling (b) The establishment of finished- feed during any 1 year shall be collected information and directions for use in the product specifications for medicated and analyzed. For the purposes of. this manufacturing of the medicated feed,- feeds and a description of any necessary subparagraph, the term "each particular or laboratory test procedures to check medicated feed" shall be construed to in- (v) The medicated feed contains only them, including methods of assay for the clude all feeds containing the same drug drug components as provided by and in active drug Ingredient. components) at different levels. The col- accordance with the regulations in Part (c) A determination that the drug ponent (or the same mixture of com- 558 of this chapter and was manu- components remain uniformly dispersed ponents) at different levels. The col- factured from a feed additive supple- and stable in the medicated feed under lection and analysis of samples shall be ment, a low level growth-promotion ordinary conditions of shipment, stor- from the medicated feed containing the antibiotic premix, a low level growth- age, and use; this may consist of a sup- highest level of the drug component (or promotion antibiotic concentrate, a feed plier's or consultant's determination mixture of components). additive concentrate, or a combination made on a feed of substantially the same (3) A medicated feed covered by para- of any two of these used in accordance formula. graph (f) (2) of this section shall be with the conditions det forth in para- (d) Adequate provision to check the exempt from the prescribed sampling graph (f) (3) (ii), (iii), and (iv) of this reliability, accuracy, and precision of any and analytical schedule under the fol- section. laboratory test procedure used; the lowing conditions: (g) Production and control procedures official Methods of Analysis of the Asso- (I) The manufacturing practices used shall include provision for discontinuing ciation of Official Agricultural Chem- in the production of the medicated feed distribution of any medicated feed found ists, methods described in an official were consistent with the regulations of by the assay procedures, or any other compendium, and any method, submitted this part; and controls preformed, to fail to conform as a part of a food additive petition or (ii) The manufacturer of the medi- to appropriate specifications. Distribu- new-drug application, which has been cated feed has produced at least 3 batches tion of subsequent production shall not accepted by the Food and Drug Admin- of such feed conforming to composition begin until it has been determined that istration shall be regarded as meeting and labeling specifications during the proper control produres have been this provision. 1-year period immediately preceding the established. date of manufacture of the feed and (e) Provision for the maintenance of during § 225.42 Components. the results of any assays, Including dates that period has not been notified and endorsement of analysts. Such rec- by the Food and Drug Administration or (a) Drug components, including un- ords, together with records of analyses any State regulatory official that his diluted drugs and any intermediate mixes reported by any State feed control of- manufacturing practices were in conflict containing drugs used in the manufac- ficial shall be retained in the possession with section 501(a) (2) (B) of the act ture and processing of medicated feeds. of the manufacturer or in the possession or the regulations of this part and has shall be received, stored, handled. 'and of a consulting laboratory operating in not distributed a medicated feed during otherwise controlled in a manner to that period which his behalf. Such records shall be main- has been proceeded .maintain the integrity and identification tained for a period of at least 1 year after against under the act because of failure of such articles. Appropriate receipt of such feed to comply with Its composi- distribution of the medicated feed has and inventory records shall be main- been completed. tion or labeling requirements or which tained for 1. year and such records shall has been analyzed by any State official show the origin of any drug components. .Subpart D-Packaging and Labeling and found to be deflclent;.and the batches in which they were used, and § 225.80 Packaging and labeling. (liI) The medicated feed contains the results of any testing of them by or only, as the drug component (or com- on behalf of the medicated-feed manu- Packaging and labeling operations ponents), a low-level growth-proqiotion facturer. shall be adequately performed and con- antibiotic (or antibiotics) as provided (b) Nondrug components shall be trolled to assure that only those medi- by and in accordance with the regula- stored and otherwise handled in a man- cated feeds made In compliance with tions in Part 558 of this chqpter; it was ner to avoid unsafe contamination, in- established formula records and manu- manufactured from a feed additive cluding cross-contamination from man- facturing and control directions shall be premix, feed additive concentrate, or ufacturing operations. distributed; to prevent milxups between feed additive supplement that, at the (c) Statements relating to the identi- the medicated feeds during the packag- time of receipt by the medicated-feed fication-and the quantitative composition ing and labeling operations; and to as- manufacturer, bore a label, or was ac- appearing on the labels of undiluted sure that correct labeling is employed for companied by labeling, containing a drugs or other drug components received" the medicated feed. In the case of quantitative composition statement of by, the medicated-feed manufacturer medicated feeds distributed in bulk, com- its antibiotic content together with di- from other suppliers may be relied upon plete labeling shall accompany the ship- rections for its use in the manufactur- by the medicated-feed manufacturer as ment and be supplied to the consignee at ing of a legal medicated feed; and the acceptable evidence of the identity and the time of delivery. Such labeling may medicated-feed manufacturer, in good composition'of the drug or drug com- consist of an invoice or placard Identi- faith, relied upon and followed the feed ponents in lieu of actual testing of each fying the medicated feed and bearing additive premix, concentrate, or supple- such drug or drug component if such re- adequate information for the safe and ment label or labeling information and liance is made in good faith. effective use of the medicated feed, directions for use in the manufacturing Labels and labeling shall be received, of the medicated feed; or § 225.58 Laboratory controls. handled, and stored In a manner that (iv) The medicated feed contains Laboratory controls shall include the avoids labeling mixups, Previously used only, as the drug component (or com- establishment of adequate specifications containers shall be adequately cleaned ponents), a drug (or drugs) as provided and test procedures to assure that the and labeled before reuse to avoid adult- by and in accordance with the regula- drug components and the finished medi- oration or misbranding. tions in Part 558 of this chapter; it was cated- feeds conform to appropriate Subpart E-Records and Reports manufactured from a feed-additive con- standards 6f Identity, strength, quality, centrate or feed additive supplement and purity. Laboratory controls shall § 225.102 Formula and production rec- that, at the time of receipt by the medi- include: ords. cated-feed manufacturer, bore a label, (a) The establishment of master rec- (a) For each medicated feed, a master or was accompanied by labeling, con- ords containing appropriate specifica- formula record or card shall be prepared, taining the quantitative composition of tions and a description of the test pro- checked, and maintained by a responsible Its drug content together with directions cedures used to check them for each key employee and retained for Its use in the manufacturing of a kind of drug used in the manufacture of for at least legal medicated feed; and the medicated- medicated feeds; this may consist of the 1 year after production of the last batch. feed manufacturer, in good faith, relied manufacturer's or supplier's statement The formula record or card shall include upon and followed the feed additive con- of specifications. at least the following:

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14030 1975 RULES AND REGULATIONS 14031 Subpart B-Construction and Maintenance (1) The name of the medicated feed, feed that is manufactured or distrib- of Facilities and Equipment together with any other information nec- uted by him and, where indicated, make essary for the correct identification of the such further investigations or take such § 226.20 Buildings. feed. appropriate action as appears to be war- Buildings In which medicated pre- (2) The weight or measure of each in- ranted in the circumstances. A record mixes are manufactured, processed, gredient, adequately identified,- to be of complaints and the action taken by packaged, labeled, or held shall be main- used in manufacturing a stated weight the feed manufacturer shall be main- tained in a clear and orderly manner of the medicated feed. tained for a period of 2 years. If the and shall be of suitable size, construc- (3) A copy, description, or nbtation medicated feed is the subject of an ap- tion and location in relation to sur- adequately identifying the label, labeling, proved new-drug application held by the roundings to facilitate maintenance and or placard necessary to be used on or feed manufacturer, he shall make such operation for their Intended purpose. The feed. reports as are required by § 510.301 of with the complete medicated this chapter. building sball: (4) Manufacturing instructions for (a) Provide adequate space for the each medicated feed produced on a batch orderly placement of equipment and or continuous operation basis, including PART 226-CURRENT GOOD MANUFAC- materials used in any of the following mixing steps, mixing times, and batch. TURING PRACTICE FOR MEDICATED PREMIXES operations for which they are employed formulas,that have been determined to to minimize risk of mixups between dif- yield an adequately mixed medicated Subpart A-General Provisions ferent medicated premixes, their com- -feed; and in the case of medicated feeds Sec. ponents, packaging, or labeling: produced by continuous production run, 226.1 Current good manufacturing prac- (1) The recept, sampling, control, and any additional manufacturing directions tice. storage of components. including, when indicated, the settings 226.10 Personnel. (2) Manufacturing and procesqing -of equipment.that have been determined Subpart B--Construction and Maintenance of operations performed on the medicated to yield an adequately mixed medicated Facilities and Equipment premix. feed of the specified formula. 226.20 Buildings. (3) Packaging and labeling opera- (5) Appropriate control directions, in- 226.30 Zquipment. tions. cluding the manner and frequency with Subpart c-Product Quality Control (4) Storage of containers, packaging which any necessary samples of the med- 226A0 Production and control procedure3. materials, labeling, and finished prod- icated feed are to be taken for specified 2 6.42 Components. ucts. laboratory, tests, the criteria for using 226.58 Laboratory controls. (5) Control laboratory operations. laboratory test results -to change formu- Subpart D-Packaglng and Labeling (b) Provide adequate lighting and lations or manufacturing procedures, and ventilation, and when necessary for the the procedures to be observed to avoid 226.80 Packaging and labeling. • intended production or control purposes, Unsafe contamination of the medicated Subpart E-Records and Reports adequate screening, dust and tempera- feed with other medicated feeds or drug 226.102 ZAaster-formula and batch-produc- ture controls, to avoid contamination of components. ' tion records. medicated premixes, and to avoid other (b) A production record shall be pre- 226.110 Distrlbution records. conditions unfavorable to the safety, pared for each batch or run of medicated 226.115 Complaint files. Identity, strength, quality, end purity of feed produced, and shall be retained for Avrrzonrry: Secs. 501, 701, 52 Stat. 1049-" the raw materials and medicated pre- at least 1 year; The production record 1050 as amended; 1055-1056 as amended (21 mixes before, during, and gfter produc- shall include: U.S.C. 351, 371). tion. (1) Product identification, date of Subpart A-General Provisions (c) Provide for adequate washing, production, and endorsement by a re- cleaning, toilet, and locker facilities. sponsible individual. § 226.1 Current 'good manufacturing (2) A. record of the quantity of drug practice. Work aieas and equipment used for the components used. The criteria in §§ 226.10 through 226.- production of medicated premIxes or for (3) A record of the quantity of medi- 115, inclusive, shall apply in determining the stoiage of the components of medi- cated feed produced. whether the methods used in. or the fa- cated premixes shall not be used for the (c) In the case of a customer-fdrmula clitie&and controls used for the manu- production, mixing or storage of finished - feed made to the specifications of a cus- facture, processing, packing, or holding or unfinished insecticides, fungicides, tomer, the formula and production rec. of a medicated premix conform to or are rodenticides, or other pesticides or their ords required by this section may con- operated or administered in conformity components unless such materials are sist of copies of customers' purchase with .current good manufacturing pmc- recognized as approved drugs intended ,orders and sellers' invoices bearing the tice to assure that a medicated premix for usen animal feeds. information required by this section. meets the requirements of the act as to § 226.30 Equipment. safety, and has the identity and strength, § 225.110 Distribution records. and meets the quality and purity charac- Equipment used for the manufachire, Complete records shall be maintained teristics which It purports or Is repre- processing, packaging, bulk shipment, for each shipment of medicated feeds sented to possess, as required by section labeling, holding, or control of medicated in a manner that will facilitate the re- 501(a) (2) (B) of the act. The regulations premixes or their components shall be call, diversion, or destruction of themed- in this Part 226 permit the use of preci- maintained in a clean and orderly man- icated feed, if necessary. Such records sion, automatic, mechanical, or elec- ner and shall be of suitable design, size, retained for at least 6 months construction, and lqcation to facilitate shall be tronic equipment in the production of a maintenance and operation for its in- after the date of the shipment, and shall medicated premix when adequate inspec- include the name and address-of the tion and checking procedures or other tended purpose. The equipment shall. consignee, the date and quantity shipped, quality control procedures are used to as- (a) Be so constructed that any sur- and the manufacturing dates, control sure proper performance. faces that come into contact with medi- marks identifying the medi- cated premlxes are suitable, in that they numbers, or 226.10 Personnel. cated feed shipped. If the medicated § are not reactive, additive,-or absorptive feed is held under control of the manu- The key personnel and any consult- to an extent that significantly affects facturer for further shipment at estab- ants involved in the manufacture and .the Identity, strength, quality, or purity lishments other than where produced, control of the medicated premix shall of the medicated premix or its compo- records as outlined in this section shall have a background of appropriate edu- nents. be maintained at these establishments. cation or appropriate experience or com- (b) Be so constructed that any sub- bination thereof for assuming responsi- stance required for the operation of the § 225.115 Complaint files. bility to assure that the medicated pre- equipment, such as lubricants, coolants, The medicated-feed manufacturer mix has the proper labeling and the etc.. may be employed without hazard of shall evaluate by responsible key person- safety, Identity, strength, quality, and becoming an unsafe additive to the nel each complaint received by him on a purity that it purports to possess. medicated premix.

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14031 1975 14032 RULES AND REGULATIONS (c) Be constructed to facilitate adjust- distribution of any medicated premix shipment, storage, and use. This may ment, cleaning, and maintenance, and found by the assay procedures, or other consist of a determination on a medicated to assure uniformity of prodabtion and controls performed to fail to conform premix of substantially the same formula reliability of control procedures and to to appropriate specifications. Distribu- and characteristics. Suitable expiration assure the exclusion from medicated pre- tion- of subsequent production of such dates shall appear on the labels of the mixes of contamination, including cross- medicated premix shall not begin until it medicated premixes when needed to as- contamination from manufacturing has been determined that proper control sure that the articles meet the appropri- operations. procedures have been established. ate standards of Identity, strength, qual- (d) Be suitably grounded electrically § 226.42 Components. ity, and purity at the time of use. to prevent lack of uniform mixing due (e) Adequate provision to check the to electrically charged particles. (a) Drug components, including undi- reliability, accuracy, and precision of any (e) Be of suitable size and accuracy luted drugs and any intermediate mixes laboratory test procedure used. The of- for use in any intended measuring, mix- containing drugs used in the manufac- ficial methods in "Methods of Analysis ing, or weighing operations. ture and processing of medicated pre- of the Association of Official Analytical mixes, shall be received, examined, or Subpart C-Product Quality Control Chemists," I methods described In -n of- tested, stored, handled, and otherwise ficial compendium, and any method sub- § 226.40 Production and control pro- controlled in a manner to maintain the mitted as a part of a food additive cedures. integrity and identification of such ar- petition or new-drug application that has Production and control procedures ticles. Appropriate receipt and inventory been accepted by the Food and Drug Ad- shall include all reasonable precautions, records shall be maintained'for 2 years, ministrton shall be regarded as meeting including the following, to assure that and such records shall show the origin this provision. the medicated premixes produced have of any drug c6mponents, the manufaC- (f) Provisions for the maintenance of, the Identity, strength, quality, and purity turer's control number Olf any), the the results of any assays, Including dates, they purport to possess: dates and batches in which they were and endorsement og analysts. Such rec- (a) Each critical step in the process, used, and the results of any testing of ords shall be retained In the possession such as the selection, weighing, and them. of the manufacturer and shall be main- measuring of components; the addition (b) Nondrug components shall be tained for a period of at least 2 years of drug components during the process; stored and otherwise handled in a man- after distribution by the manufacturer weighing and measuring during various ner to avoid contamination, including of the medicated premix has been stages of the processing; and the deter- cross-contamination from manufactur- completed. mination of the finished yield, shall be ing operations. Subpart D-Packaglng and Labeling performed by one or more competent, re- § 226.58 Laboratory controls. § 226.80 Packaging and labeling. sponsible individuals. If such steps In the Laboratory controls shall include the processing are controlled by precision, establishment of adequate specifications (a) Packaging and labeling operatons automatic, mechanical, or electronic and test procedures to assure that the shall be adequately controlled: equipment, their proper performance (1) To assure that only those medi- drug components and the medicated pre- cated shall be adequately checked by one or mixes conform to appropriate standards premixes that have met the speci- more competent, responsible individuals. of identity, strength, quality, and purity. fications established in the master-for- (b) All containers to be used for un- Laboratory controls shall include: mula records shall be distrlbuted. diluted drugs, drug components, inter- (a) The establishment of master rec- (2) To prevent mixups during the mediate mixtures thereof, and medicated ords containing appropriate specifica- packaging and labeling operations. premixes shall be received, adequately tions and a description of the test pro- (3) To assure that correct Iabeling is identified, and properly stored and han- cedures used to check them for each kind employed for each medicated premix. died in, a maner adequate to avoid mix- of drug component used in the manu- (4) To Identify medicated premixes ups and contamination. facture of medicated premixes. This may with lot or control numbers that permit (c) Equipment, including dust-control consist of the manufacturer's or sup- determination of the history of the man- and other equipment, such as that used plier's statement of specifications and ufacture and control of the batch of for holding and returning recovered or methods of analyses. medicated premix. flush-out materials back into production, (b) Thq establishment of specifica- (b) Packaging and labeling operations shall be maintained and operated in a tions for medicated premixes and a shall provide: manner to avoid contamination of the description of necessary laboratory test (1) For storage of labeling In a man- medicated premixes and to insure the procedures to check such specifications. ner to avoid mixups. integrity of the finished product. (c) Assays which shall be made of (2) For careful checking of labeling (d) Competent and responsible per- representative samples of finished medi- for identity and conformity to the label- sonnel shall check actual against theo- cated premixes in accordance with the ing specified in the batch-production -retical yield of a batch of medicated following schedule: records. premix, and, in the event of any signifi- (1) Each batch of a medicated premix (3) For adequate control of the quan- cant discrepancies, key personnel shall manufactured from an undiluted drug tities of labeling issued for use with the prevent distribution of the batch in shall be assayed for its drug compo- medicated premix. question and other associated batches of nent(s), (c)Medicated premixes shall be dis- medicated premixes that may have been (2) In the case of medicated premixes tributed in suitable containers to insure involved in a mixup with it. which are manufactured by dilution of the safety, Identity, strength, and quality (e) Adequate procedures for cleaning medicated premix(es) assayed in accord- of the finished product. of those parts of storage, mixing convey- ance with paragraph (c) (1) of this Subpart E-Records and Reports ing and other equipment coming in con- section, each batch shall be assayed tact with the drug component of the for its drug component(s) with the first § 226.102 Master-formula and balti. medicated premix shall be used to avoid five consecutive batches assaying within production records. contamination of medicated premixes. the limitations, followed thereafter by (a) For each medicated premix, (f) If there is sequential production of assay of representative samples of not master-formula records shall be pro- batches of a medicated premix contain- less than 5 percent of all batches pro- pared, endorsed, and dated by a compe- Ing the same drug component (or com- duced. When any batch does not assay tent and responsible individual and shall ponents) at the same or lower levels. within limitations, each batch should be independently checked, reconciled, en- there shall be sufficient safeguards to again be assayed until five consecutive dorsed, and datcd by a second competent avoid any buildup above the specified batches are within limitations. levels of the drug components in any of (d) A determination establishing that may the batches of the medicated premix. 'Copies be obtained from: Assocla- the drug components remain uniformly tion of Oflcial Analytical Chomistg, P.O. Box (g) Production and control procedures dispersed and stable in the medicated 540; Ben Franklin Station, Washington, DO shall include provision for discontinuing premix under ordinary conditions of 20044.

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14032 1975 RULES AND REGULATIONS 14033 and responsible individual. The record quantity shipped, and the manufacturing Sec. shall include: dates, control numbers, or marks Identi- 250.102 Drug -preparations Intended for (1) The name of the medicated pre- fying the medicated prenx shipped. human uca containing certain mix and a specimen copy "coronary vasodllators." of its label. § 226.115 Complaint files. 250.103 Thorium dioxide for drug use. , (2) The weight or measure of each In- 250.104 Status of salt substitutes under the gredient, adequately identified, to be Records shall be maintained for a pe- Federal Food, Drug, and Cosmetic used in manufacturing a stated weight riod of 2 years of all written or verbal Act. of the medicated premix. complaints concerning the safety or ef- 250.105 Gelsralum-containing preparations (3) A complete formula for each batch -ficacy of each medicated premlx. Com- regarded as prescription drugs. size, or of appropriate size in the case plaints shall be evaluated by competent 250.106 Cobalt preparations intended for of continuous systems to be produced and responsible personnel and, where use by man. from indicated, appropriate action shall be 250.107 Dimetsylaulfoxide (DMSO) prep- the master-formula record, includ- arations; clinical testing and in- ing a complete list of ingredients desig- taken. The record shall indicate the vestlgational use. nated'by names or codes sufficiently evaluation and the action. 250103 Potassium permanganate prepara- specific to indicate any special quality tons as 'prezerption drugs. 250.102 Vitamin A preparations characteristics; an accurate statement of PART 229-CURRENT GOOD MANUFAC- for oral use the weight or measure of each ingredient, as drugs. TURING PRACTICE FOR CERTAIN 250.110 Vitamin D preparations for oral use except that reasonable variations may be OTHER DRUG PRODUCTS as drugs. permitted in the amount of ingredients I necessary in the preparation of the medi- Sec. Subpart C--Requirements for Drugs and Foods 229.25 W'hole blood (hunan). red blood cated premix, provided that the varia- cells (human), and allergenio 250.201 Preparations for the treatment of tions are stated in the master formula; products. ,pernicious anemia. drugs Gubject to licens- 250.203 8tatus of fluoridated an appropriate statement concerning any Ing by the Food and ]Drug Ad- water and foods prepared with fluoridated calculated excess of an ingredient; and ministraton. water. a statement of the theoretical yield. (4) Manufacturing 'instructions for Anoanrr: Secs. 501. 701. 52 Stat. 1049- Subpart D--Requlrements for Drugs and 1050 as amended, 1055-1056 as amengied (21 Cosmetics each type of medicated premix produced U.S.C. 351,371). on a batch or continuous operation basis, 250.250 Hexachlorophene; as a component including mixing steps and mixing times § 229.25 Whole blood (human), red of drug and cosmetic products. that have been determined to yield an blood cells (human), and allergenic Subpart E-Special Packaging Requirements adequately -mixed medicated premix; products; drugs subject to licsing by the Food and Drug Administra- 250.300 Nitroglycerin for human use; pack- and in the case of medicated premixes tion. aging and warnings. produced by continuous production run, Aunsonnr: Se 701. 52 Stat. 1055-1056 (21 any additional manufacturing directions (a) The methods used in, or the facil- U.S.C. 371) unlezz otherwise noted. including, when indicated, the settings of ities or controls used for, the manufac- equipment that have been determined to, ture, processing, packing, or holding of Subpart A-Drugs Regarded as Misbranded yield an adequately mixed medicated the drugs whole blood (human), red § 250.10 Oral prenatal drugs containing premix of the specified formula. blood cells (human), and allergenic fluorides intended for human use. (5) Control instructions, procedures, products do not conform to, or are not specifications, special notations, and pre- operated or administered in conformity (a) The Food and Drug Administra- cautions to be followed. with, current good manufacturing prac- tion finds that there Is neither substan- (b) A separate batch-production and tice to assure that any such drug meets tial evidence of effectiveness nor a gen- control record shall be prepared for each the requirements of the act as to safety eral recognition by qualified expertsthat batch or run of medicated premix pro- and 'has the identity and strength and prenatal drug preparations containing duced and shall be retained for at least meets the quality and purity character- 2 years after distribution by the manu- istics, which it purports or Is represented fluorides promote tooth development in facturer has been completed, The batch-, to possess, unless the manufacture, pro- the fetus, prevent dental caries In the production and control record shall cessing, packing, and holding of such offspring, or prevent dental caries in include: drugs conform to the licensing and other pregnant women. (1) Product identification, date of pro- requirements as to such- drugs and (b) Any such drug preparation that is the practices and standards of manu- duction, and endorsement by a compe- so labeled, represented, or advertised will tent and responsible individual. facture, processing, packing, and hold- (2) Records of each step in the manu- ing-applicable to such drugs set forth in be retarded as misbranded and subject facturing, packaging, labeling, and con- Part 640 of this chapter. Applications for to regulatory proceedings unless such trolling of the batch, including dates, licensing shall be submitted to the Di- recommendations are covered by a new- specific identification of drug compo- rector, Bureau of Biologics, Food and drug application, Including substantial nents used, weights or measures of all Drug Administration, Bldg. 29A, 9000 evidence of effectiveness, Rockvllle approved pur- components, laboratory-control results. Pike, Bethesda, MD 20014. suant mixing times, and the endorsements of to section 505 of the Federal Food the individual actively performing or the Drug, and Cosmetic Act. Any such drug individual actively PART 250-SPECIAL REQUIREMENTS FOR preparation that is labeled, represented, supervising or check- SPECIFIC HUMAN DRUGS ing each step in the operation. or advertised as containing fluorides as Subpart A-Drugs (3) A batch number that permits de- Regarded as Misbranded an active Ingredient of the drug for pre- termination of all laboratory-control Sec. natal use will similarly be regarded as procedures and results on the batch and 250.10 Oral prenatal drugs containing all lot or control numbers appearing on fluorides intended for human use. misbranded and subject to regulatory the labels of the medicated premix. 250.11 Thyroid-containing drug prepara- proceedings. tions Intended for treatment of § 226.110 Distribution records. obesity In humans. (c) A completed and signed "Notice of 250.12 Stramonlum preparations labeled Claimed Investigational Exception for Complete records shall be maintained with directions for uso in self- a New Drug." Form FD-1571 set forth in for each shipment of medicatedpremixes medication regarded as mls- in a manner that will facilitate the re- branded. § 312.1 of this chapter, must be sub- call, diversion, or destruction of the med- Subpart B-New Drug or Prescription Status of mitted to cover clinical investigations icated premix, if necessary. Such records Specific Drugs designed to obtain evidence that such shall be retained for gt least 2 years after 250.100 Amyl nitrite inbalapt as a prescrlp- .preparations are effective for such uses. the date of the shipment by the manu- tlon drug for human use. tao Regulatory proceedings may be facturer and shall include the name and 250.101 Amphetamine and methampheta- mine Inhalers regarded as pre- .nltlated with respect to drug prepara- address of the consignee, the date and scription drugs. tions shipped within the jurisdiction of

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14033 1975 14034 RULES AND REGULATIONS the act that are contrary to provisions of (b) Labeling these products with a ter, and Its label bears the legend "Cau- this statement after 30 days from the warning that they are not for oral inges- tion: Federal law prohibits dispensing tioh has not been effective in protecting without prescription." date of publication of this statement in be the FEDERAL REGLsrE the public. Misuse of stramonium prep- (c) Regulatory proceedings may arations can cause serious toxic effects initiated with regard to the interstate (Seca. 502 (a). (r). 505, 52 Stat. 1060. 1051. shipment of amyl nitrite Inhalant that Is 1052, as amended; 21 U.S.C. 352 (a). (U},355) including toxic delirium, visual disturb- ances, fever, and coma. A number of seri- labeled, advertised, or dispensed con- § 250.11 Thyroid-containing drug prep- ous reactions have already occurred from trary to this statement of policy If such arations intended for treatment of the oral ingestion of such products. act occurs after July 1, 1969. obesity in humans. (c) On the basis of this information, (Sec. 503(b), 52 Stat. 1052, as amended: 21 (a) Investigation by the Food and the Commissioner of Food and Drugs has U.S.C. 353(b)) Drug Administration has revealed that concluded that such articles have a po- § 250.101 Amphetamine and methant. a large number of drug preparations tentiality for harmful effect through safe for use except phetamino inhlters regardcd as pre. containing thyroid or thyrogenic sub- misuse and are not scription drugs. stances in combination with central under the supervision of a physician. In nervous system stimulants, with or with- the interest of public health protection, (a) Recurring reports of abuse and out one or more additional drug sub- therefore, the Food and Drug Adminis- misuse of methamphetamine (also stances such as barbiturates or laxatives, tration adopts the following policy: - known as desoxyephedrine) Inhalers are being marketed for or as adjuncts to (1) Preparations containing stramo- show that they have a potentiality for the treatment, control, or management nium supplied from the leaves, seeds, or harmful effect and that they should not of obesity in humans. The Commissioner any other part of the plant in the form of be freely available to the public through of Food and Drugs finds that the admin- a powder, pipe mixture, cigarette, or any over-the-counter sale. From com- istration of such combinations for said other form, with or without admixture plaints by law-enforcement officials, purposes is without medical rationale of othier ingredients, will be regarded as health officials, individual physicians, except possibly in those relatively un- misbranded if they are labeled with parents, and others as well as from Food common instances where the condition directions for use in self-medication. and Drug Administration investigations, is directly related to hypothyroidism and (2) The Food and Drug'Admlnlstra- It is evident that the wicks from these there exists a concurrent need for appe- tion will, on request, furnish comment inhalers are being removed and the tite control (in such instances the safety on proposed labeling limiting any such methamphetamIne they contain Is being and effectiveness of such combinations preparation to prescription sale. used as a substitute for amphetamine are not generally recognized). In partic- (d) The labeling or dispcung of tablets. Amphetamine tablets and am- ular, the Commissioner of Food and stramonium preparations contrary to phetamine Inhalers have been restricted Drugs finds that neither the consensus this statement after 60 days following to prescription sale because of their po- of informed medical opinion nor clinical the date of its publication In the FEDERAL tentiality for harm to the user. experience Justifies any representation REGISTER may be made the subject of (b) It Is the considered opinion of the regulatory proceedings. Food and Drug Administration that, in that such combinations are safe and order to adequately protect the public effective in connection with the treat- (Secs. 502 (a), (f), 503(b); 62 Stat. 1050-51. methamphet- ment, control, or management of obesity 1052. as amended; 21 U.S.O. 352 (a). (f). health, inhalers containing 353(b)) amine or methamphetamine salts (d- in patients having normal thyroid func- desoxyephedrine, or dl-desoxyephedrne, tion. Subpart B-New Drug or Prescription or their salts), as well as amphetamine (b) Combinations of thyroid or other Status of Specific Drugs Inhalers should-be restricted to prescrip- thyrogenic drugs with central nervous tion sale and should be labeled with the system stimulants with or without other § 250.100 Amyl nitrite inhalant as a pre- scription drug for human use., legend "Caution: Federal law prohibits drug substances when offered for or as dispensing without prescription." adjuncts to the treatment, control, or (a) Amyl nitrite inhlialant has been management of obesity not related to available over-the-counter for emer- (Secs. 503(b) (1) (B), r2 Stat. 1052 as amend- hypothyroldism are regarded as mis- gency use by the patient in the manage- ed; 21 U.S.C. 353(b) (1) (B)) branded. Such combinations when of- ment of angina pectoris for a number § 250.102 Drug preparations intended fered for obesity in humans directly of years. As a result of a proposed policy for human use containing certain attributable to established hypothy- statement published August 25, 1967 "coronary vasolilators." roidism are regarded as new drugs within (32 FR 12404), the Commissioner of (a) (1) The Food and Drug Adminis- the meaning of section 201(p) of the Food and Drugs received reports of the tration finds that the following "coro- Federal Food, Drug, and Cosmetic Act. abuse of this drug by those who do not nary vasodilators" are extensively re- (Ses. 201(p). 502, 52 Stat. 1041-42, 1050, as require it for medical purposes. Addi- garded by physicians as safe and useful amended; 21 U.S.C. 321(p), 352). tionally, comment included a great deal as employed under medical supervision of concern expressed by individual physi- § 250.12 Stramonium preparations la- for the management of angina pctofis cians, medical associations, pharma- in some patients: beled with directions for use in self- associations, manufacturers, and medication regarded as misbranded. ceutical Amyl nitrite. State and local health authorities. Based E-ybthrityl tetranitrate. (a) Stramonium products for inhala- on the information available, it is the Mannltol hexanitrate. tion have been offered for use in the opinion of the Commissioner of Food and Nitroglycerin. therapy of the acute attacks of bronchial Drugs, concurred in by the Food and Potassium nitrite. asthma for many years although their Drud Administration Medical Advisory Sodium nitrite. reliability and effectiveness are question- Board, that amyl nitrite inhalant Is a able. Recently, a significantly increased drug with a potentiality for harmful (2) Additionally, new-drug applica- number of reports have come to the at- effect and that It should be removed tions have been approved for products tention of the Food and Drug Adminis- from over-the-counter status and re- containing: tration showing that such products have stricted to sale on the prescription of Inositol hexanitrate. been subject to abuse and misuse on a a practitioner licensed by law to ad- Isosorbide dinitrato. Octyl nitrite. fairly large scale, mostly by young minister such drug. Pentaerythritol tetranitrato. people, through oral ingestion for the (b) Therefore, amyl nitrite inhalant -Tretbanolamine trinitrate biphosphato (trol- purposb of producing hallucinations. Re- will be regarded as misbranded unless nitrate phosphate). ports of such use have been received the labeling on or within the package from physicians and police and other from which the drug is to be dispensed (b) The Food and Drug Administra- law enforcement authorities. Reports bears adequate- information for its safe tion also finds that there is neither sub- have also appeared in the public press and effective use by physicians, in ac- stantial evidence of effectiveness nor a and in medical Journals. . cordance with § 201.100(c) of this chap- general recognition by qualified experts

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that such drugs are effective for any of marketing on the basis of new-drug ap- §-250.105 Gelsemiumncontaining prep- the other purposes for which some such plications containing -labeling bearing, arations regarded as prescription drugs are Dromoted to the medical pro- in. addition to other requirements, infor- drugs. fesslon in labeling and advertising. In mation to the following effect, which It Is the consensus of Informed medical particular, neither clinical Investigations differs substantially from the labeling opinion that the margin of safety be- nor clinical experience justify any repre- that has been employed In the past in tween the therapeutic and toxic concen- sentations that such drugs are effective the marketing of such drugs: tration of gelsemium is narrow and it is In the management of hypertension: in (1) Warning. For use only when this difficult to predict the point at which the management of coronary insuffi- drug has a unique clinical usefulness and the dose will be toxic. Very small doses ciency or coronary artery disease, except- there s. substantial evidence of limited may cause toxic symptoms. It is there- for their anginal manifestations; or In life expectancy by reason of disease or fore the view of the Food and Drug Ad- the management of the post coronary advanced age. Not for administration ministration that gelsemlum is not a state, except angina pectoris present to food-producing animals. proper ingredient In any product that after coronary occlusion and myocardial (2) Precautions. Special precautions Is to be sold without prescripton. Ac- infarction. should be taken to prevent soft tissue cordingly, any drug containing gelsemi- (c) Any preparation containing such extravasation of the injected material. ua will be regarded as misbranded under drugs thatis labeled or advertised for any Precautions should be taken to prevent eection 503(b)(4) of the Federal Food, use other than management of angina - Injection of thorium dioxide into the sub- Drug, and Cosmetic Act If its label falls pectoris, or that Is represented to be arachnold space. to bear In a prominent and conspicuous efficacious for any other purpose by (3) Ind cations for use. For demon- fashion the statement "Caution: Federal reason of its containing such drug,- will stration of primary or secondary tumors law prohibits dispensing without pre- be regarded by the Food and Drug Ad- In the liver; for the delineation of the scription." ministration as misbranded and subject wall of a cystic mali a=t brain tumor to regulatory proceedings, unless such when such delineation Is deemed advan- § 250.106 Cobalt preparations intended recommendations are covered by the ap- tageous for purposes of progressive mon- for use by man. proval of a new-drug application based itoring in the course of therapy. (a) On January 17, 1967 (21 CFR on a showing of safety and effectiveness. (4) Dosage. Minimum amount neces- 3.48; 32 FR 449), the -Commissioner of (d) Any such drug in long-acting dos- sary for adequate visualization should Food and Drugs Issued a revised state- age form is regarded as a new drug that be utilized. ment of policy with respect to the status requires an approved new-drug appli- (d) A new-drug application will be of cobalt-containing drup preparations cation before marketing. regarded as approvable If It contains intended for use by man, which revision (e) Any of the drugs listed in para- appropriate labeling conforming to the was to be modified as needed following graph (a) (2) of this section is regarded provisions of paragraph (c) of this sec- consideration of such drugs by a panel as a new drug that requires an approved tion and satisfactory information of the of hematlogists. A panel consisting of new-drug application. Articles for kinds required by Items 2, 3, 4, 6, 7, and authorities in the field of hematology which new-drug approvals are now in 9 of the new-drug application form con- met on March 8, 1967, with representa- effect should be covered by supplemental tained in § 314.1(c) of this chapter. tives of the Medical Advisory Board for new-drug applications as necessary .to (Secs. 502(f), 62 Stat. 1050 an amened: 21 the Food and Drug Administration to provide for labeling revisions consistent U.S.C. 352 (f); Ses. 402, 400, 62 Stat. 104, as' consider the status of cobalt-containing with this policy statement. amended, 1049, as amended; 21 U.S.C. 342. drugs and the following findings and fSecs. 502(f), 505; 62 Stat. 1051, 1052, 21 346) recommendations were made: U.S.C. 352(fl, 355) §250.104 Status of salt substitukc (1) Cobalt salts are not suitable for § 250.103 Thorium dioxide for drug use. under the Federal Food, Drug, and over-the-counter sale to the public for Cosmetic Act the treatment of Iron-deficiency anemia (a) Thorium dioxide is a source of They are as-ociated with toxic effects naturally occurring radioactivity that (a) As a result of reported poison- and offer no advantneu over Iron'aIone has been used over a period of years as tugs from salt substitutes containing (2) Potential toxic effects of these a radiopaque medium. When thorium lithium chloride, under date of March 8. alts Includes liver danmae. claudatin. dioxide is injected, it Is permanently" 1949, the Food and Drug Administration myocardial d .ran thyroldbyperplasla. storedin the body. Because of Its radio- announced that It would regard each hypothyrolLm, detmtit1S, naumn.- and activity, this storage causes scarring and salt substitute as a new drug within the anorezia. carcinogenesis in the area of storage. meaning-of section 201 (p) of theFcderal (3) Cobalt sal- are not; generally rec- There are reports in the medical litera- Food,. Drug, and Cosmetic Act and that ozgned cs .mfeor effective therapy for ture of malignancy and deaths resulting Interstate distribution of each salt sub- any diseae condition- from the injection of thorium dioxide. stitute should be discontinued until a (b) On the badis of the avullable ev1- Therefore, the use In man of drugs con- new-drug application had been filed and dence and the findlngs and recommen- taining thorium dioxide is justified only become effective. Substantial nforma- dations of the representatives of the -when this drug has a-unique clinical use- tion concerning the safety of many of the Medical Advisory Board, the Commis- fulness and there is substantial evidence igredients used in salt substitutes has sioner of Food and Drugs finds and de- of limited life expectancy by reason of been developed and published since the termines with respect to cobalt-contaiu- disease or advanced age. The adminis- announcement was made. It Is now pos- Ing drug preparations intended for use tration of the drug to food-producing sible to evaluate the safety of many in- by man, except radioactive forms of animals cannot be justified since it may dividual salt substitutes and to determine cobalt and Its salts and cobalamin and result in residues of the drug in food. whether they are new drugs requiring ef- Its derivatives, that: (b) Drugs containing thorium dioxide fective applications prior to distribution (1)Such articles, because of their are unsafe and are regarded as mis- potential for causing toxic effects, are branded within the meaning of sectibn in interstate commerce. not suitable for over-the-counter use In 502 (f) (1), (2), and (j) of the Federal (b) The Food and Drug Administra- Iron-deficiency anemia; any such article Food, Drug, and Cosmetic Act when la- tion no longer regards all salt substitutes that is labeled, represented, or adver- beled or advertised for administration as new drugs. Upon request, the Ad- tised for over-the-counter use in the pre- to man except when they have a unique rtlnlstration will express Its opinion vention or treatment of Iron-deficiency clinical usefulness and there is substan- anemia will be regarded as subject to tial evidence of limited life expectancy whether a new-drug application Is neces. regulatory proceedings. by reason of disease or advanced age. sary for any particular product If com- (2) Such articles are not generally (c) Drug preparations containing tho- plete information concerning its compo- recognized by qualified experts as safe rium dioxide may be approved for sition and proposed labeling is submitted. or effectivq therapeutic agents for Iron-

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HeinOnline -- 40 Fed. Reg. 14035 1975 14036 RULES AND REGULATIONS deficiency anemia or for any condition tions was discontinued for a time and posed studies shall provide for pretreat- whether for over-the-counter sale or for later resumed under restricted conditions. ment liver function studies and k com- prescription dispensing; any such article (2) An adequate, controlled human plete blood count (CBC), to be repeated labeled, represented, or advertised for toxicity study (Phase I) involving short- within 7 days after commencing treat- any condition will be regarded as subject term cutaneous application of 1 gram of ment and at the conclusion of the study. to regulatory proceedings unless such dimethylsulfoxide (DMSO). per kilogram Routine monitoring of effects upon the recommendations are covered by a new- of body weight daily for 14 consecutive eye is not required. drug application approved pursuant to days has recently been completed. Data (3) All proposals must show that section- 505 of the Federal Food, Drug, obtained, not previously available, show patient consent requirements will be and,Cosmetic Act and based on a show- that when dimethylsulfoxide (DMSO) carefully observed and shall Include a ing of safety and effectiveness. was applied topically to the skin of commitment that patients will be fully (3) Cobalt salts added to drugs in healthy volunteers, it did not produce ad- informed of: The effects of dimethylsul- small amounts are not effective for any verse effects upon the eyes of the sub- toxide (DMSO) in animals, the possi- purpose and should be removed. Jects. Mild, apparently reversible, changes bility that these may occur in humans, (c)A completed and signed "Notice'of were seen suggesting that the drug may and the known possible effects of the Claimed Investigational Exemption for have som& effect upon the liver and upon drug In humans. a New Drug," Form FD-1571 set forth In the hemopoietic system in some subjects. d) Dimethylsulfoxide (DMSO) prep- § 312.1 of this chapter, must be submitted (b) A comprehensive evaluation of arations may be shipped within the Juris- to cover clinical investigations to obtain all available data on dimethylsulfoxide diction of the act. evidence that such preparations are safe (DMSO) preparations justifies further (1) For tests in vitro and in laboratory and effective for aby purpose. clinical investigation of the drug in research animals, in-accord with § 312.9 (d) (1) For such preparations for treating certain serious conditions. Al- (a) and § 511.1(a) of this chapter. which new-drug approvals are in effect, though reports concerning the use of (2) For clinical investigations in ani- supplemental new-drug applications may dimethylsulfoxide (DMSO) in relatively mals in accord with § 511.1(b) of thl. be submitted if changes consistent with benign conditions are equivocal regard- chapter. this policy statement can be effected ing Its efficacy, short-term clinical use (Sees. 505, 812, 52 Stat. 1052, 1053, as thereby. If the composition and labeling has been established as reasonably safe amended; 82 Stat. 843-251; 21 U.. 055, of an article are such that the cobalt is by adequate Phase I studies. Under ap- 360b) not significant in relation to the labeling propriate protocols, further short-term claims, It will be permissible for the ap- clinical investigations in the treatment § 250.108 Potassium permanganate plicant to rerhove the cobalt salt from of such benign conditions can be Justi- preparations as prescription drugs. the formulation, delete all references to. fled. (a) There have been a number of re- It-in the labeling and resume marketing (c) No person may ship dimethylsul- ports in the medical literature of serious the reformulated drug, provided that a foxide (DMSO) within the Jurisdiction injuries to women resulting from the supplement is submitted within 30 days of the Federal Food, Drug, and Cosmetic misuse of potassium permanganate in an from the date of publication of this policy Act for clinical testing in man until a effort to induce abortion. Reports from statement in the FEDERAL REGISTER fur- "Notice of Claimed Investigational Ex- physicians who have treated such case nishing full information regarding such emption for a New Drug," pursuant to show that the Injuries are commonly changes, including the date on which § 312.1 of this chapter, is on file with caused by introducing tablets or crystals such changes are being effected. the Food and Drug Admintitration and of potassium parmanganate Into the (2) Applicants holding other approved all the following conditions are met: vagina. Experience with these cases new-drug applications for such prepara- (1) Proposed long-term clinical studies shows that such use of potassium per- tions should submit, within 30 days, a (Phase I) are restricted to the use of manganate is not effective In producing written statement waiving opportunity DMSO to cutaneous application in seri- abortion, but that instead the drug pro- for a hearing preliminary to withdrawing ous conditions, such as the incapacitat- duces serious and painful Injury to the approval of the application unless the ing arthropathies, scleroderma, derma- walls of the vagina, causing ulcers, mas- applicant wishes to avail himself of the tomyositis, and intractible pain due to sive hemorrhage, and Infection. Such opportunity for a hearing. malignancy, are to be conducted in dangerous and useless employment of (e)Regulatory proceedings may be medical centers having adequate facili- potassium permanganate is apparently initiated with respect to any drug within ties and well-trained, experienced medi- encouraged among the misinformed by the jurisdiction of the act that Is con- cal personnel, and are to include the the mistaken Idea that the vaginal bleed- trary to the Provisions of: following essential conditions in the .Ing caused by the corrosive action of the (1) Paragraph (b) of this section and study protocol. All subjects will receive a drug indicates a termination of preg- shipped after the date of publication of full examination including: nancy, which It does not. this policy statement in the FzaxAT. (i) An eye evaluation by an ophthal- (b) Potassium permanganate Is a REGISTER. mologist to include actual refractive er- strong oxidizing agent, a highly caustic, (2) Paragraphs (c) and (d) of this ror measurements and slt-larIp findings tissue-destroying chemical, and a poi- section and shipped after 30 days from as well as other parameters of the ocular son. There are no circumstances under the date of publication of this policy examination prior to receiving the drug, which crystals and tablets of potassium statement in the FEDERAL RGrsTtmL at intervals not exceeding 3 months dur- permanganate constitute safe dosage (Sees. 502 (a), (f), (J). 505. 52 Stat. 1050- ing'the study and 3 months after dis- forms for use in self-medication. It is 1053. as amended; 21 U.S.C. 352 (a). (f), (), continuing the drug. the consensus of Informed medical 355) (ii) Liver function tests and a com- opinion that the only dosage forms of plete blood count (CBC) prior to receiv- potassium permanganate known to bo § 250.107 Dimethylsulfoxide (DMSO) Ing the drug, at intervals not exceeding safe for use in self-medication are preparations; clinical testing and in- 4 weeks during the study and 4 weeks vestigational use. aqueous solutions containing not more after discontinuing the drug. than 0.04 percent potassium permanga- (a) (1) Chronic-toxicity studies with (2) Proposed short-term studies nate. Such solutions are safe for use dimethylsulfoxide (DMSO) in animals, (Phase ID restrict the use of dimethyl- in self-medication only by external ap. including dogs, rabbits, and swine, re- qufoxde (DMSO) to cutaneous applica- ,plicatlon to the skin. ported by a consulting laboratory in Eng- tion for not more than 14 days in closer (c) In view of the very real poten- land and by a number of laboratories in monitored investigations with appropri- tiality for harmful effect, and the actual the United States show that the admin- ate control groups, that may include injuries caused by the misuse of potas- istration of dimethylsulfoxide (DMSO) studies of use in such conditions as adute sium permanganate, the Food and Drug causes changes in the refractive index of musculoskeletal conditions (acute arthri- Administration believes that in order the lens of the eyes of such animals. On tis. per arthritis. capsulitis. bursitis, ten- adequately to protect the public hbalth: the basis of these reports, clinical testing donltis. synovitis. .and .post-traumatic (1) Potassium permanganate and po- of dimethylsulfoxide (DMSO) prepara- lesions) and soft tissue injuries. The pro- tassium permanganate tablets Intended

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for humani use are drugs subject to sec- (seca.502(f) (1). (2). (J).03(b)(1).705(b). .(2) The labeling bears full disclosure tion 503(b) (1) of the Federal Food, 52 Stat. 1050, 1051. 1052. as amended. 1057; information as required by § 201.100(c) .21 U.S.C. 852(f) (1). (2). (1). 253(b) (1). (D and especially appro- Drug, and Cosmetic Act and should be 375 (b)) of this chapter, restricted to prescription sale.- Such priate warnings regarding vitamin D drugs ill be regarded'as misbranded if §250.109 Vitamin A preparations for toxicity. at any time prior to dispensing the label oral use as drugs. (c)Preparations containing 400 or less falls to bear the legend, "Caution: Fed- (a)Vitamin A is an essental nutrient IU of vitamin D per dosage unit will be eral law pf0hibits dispensing without for humans. It Is widely recognized that regarded as misbranded if their recom- prescription." large amounts of vitamin A can cause mended daily intake exceeds 400 1U. (2) Potassium permanganate labeled adverse effects, some of which are serious. (d) Foods which are represented for for use as a prescription component in The U.S. Recommended Daily Allowance use solely'under medical supervision to human drugs under the exemption pro- (U.S. RDA) for vitamin A Is 1500 Inter- meet nutritional requirements of persons vided in § 20L120 of this chapter or national :Units, (IU) for Infants. 2500 IU with poor vitamin D absorption may con- labeled for manufacturing use-under the for children under 4 years of age, 5000 tain vitamin D not in excess of 1000 IU exemption -provided in § 201.122 of this IU for adults and children 4 or more years per dosage unit or recommended daily chapter will be regarded as misbranded of age, and 000 IU for pregnant or lac- intake. .unless the label bears the statement, tating women. (SecW. 502(a). (f), and (j), 503(b), 'O10(a), 52 "Caution: Federal law prohibits dispens- (b) In view of the toxicity of excessive Stat. 1050-1052, az amended, 1055; 21 U.S.C. ing without prescription." consumption of vitamin A. the Food and b52(a). (f). and (j), 353(b). 371(a)) (3) These drugs will be regarded as Drug Administration finds that, In order Subpart C-Requlrements for Dugs and misbranded when intended for veteri- to protect the public health, oral prep- Foods nary use unless the label bears the leg- arations containing vitamin A In excess of 10,000 IU per dosage unit or recom- §250.201 Preparations for the treat- end, "Caution, Federal law restricts ment of pernicious anemia. this drug to sale by or on the order of a mended daily intake are drugs sub- (a) licensed veterinarian"; Provided, how- ject to section 503(b) (1) of the Federal The ninth announcement of the ever, That this shall not apply to a drag Food, Drug, and Cosmetic Act and shall Anti-anemia Preparations Advisory labeled and marketed for veterinary use be restricted to prescription sale. Such Board of the United States Pharmao- If such drug contains not more than 50 products will be regarded as misbranded pela is concerned with the status of the percent of pbtassium permanganate and if at any time prior to dispensing the treatment of pernicious anemia. It ,following conditions are not met: clearly presents the following facts: Includes other ingredients which make It (1) The label bears the unsuitable for human use and unlikely legend, "Cau- (1) The Sixteenth Revision of the that the article would be used in an at- tion: Federal law prohibits dispensing Pharmacopela of. the United States. tempt to induce abortion. without a prescription"; and which became official on October 1, 1960, does not include preparations intended (4) Any preparation of potassium per- (2) The labeling bears full disclosure manganate Intended for over-the-coun- information as required by § 201.100(c) for the treatment of pernicious anemia (1) of this chapter, and especially appro- by oral administration, ter sale for human use Internally or by (2) The U.S.P. unit for anti-anemia application to any mucous membranes or priate warnings regarding vitamin A toxicity. preparations no longer has any signifi- for use in the vagina will be regarded (c)Preparations containing 10,000 or cance. 'as misbranded under the provisions of less IU of vitamin A per dosage unit will (3) The U.S.P. Anti-anemia Prepara- section 502(f) (1) and (2) and section be regarded as misbranded if their recom- tLions Advisory Board was disbanded. 502(j) of the act. mended daily intake exceeds 10,000 117. (b) On the basis of the scientific evi- (5) Any other preparation of potas- (Ses. 502(a), (f), and (j). 503(b). '701(a). 52 dence and conclusions summarized inthe sium permanganate intexided for over- Stat. 1050-1052, as amended, 1055: 21 U.S.C. statement of the U.S.P. Anti-anemtia the-counter sale for human use will- be 352(a), (f), and (j). 353(b), 371(a)) Preparations Advisory Board as well regarded as misbranded under section as pertinent Information from other 502(f) (1) and (2) and section 502(J) of § 250.110 Vitamin D preparations for sources, the Commissioner of Food and the act unless, among other things, all oral use as drugs. Drugs finds It is the consensus of well of the following conditions are met: (a) Vitamin D is an essential nutrient Informed medical opinion that: (1) It is an aqueous solution contain- for humans. It is widely recognized that (1)The parenteral administration of ing not more than 0.04 percent potas- vitamin D, when ingested daily in large cyanocobalamin or vitamin _3% is gen- sium permanganate. amounts, is toxic. The U.S.Recommended erally recognized as a fully effective (Cl)The label and labeling bear, in Daily Allowance (US. RDA) for vitamin treatment of pernicious anemia. Paren- Juxtaposition with" adequate directions D is 400 International Units (IU). teral cyanocobalamin preparations have for use, clear warning statements des- (b) In view of the toxicity of the exces- not been and are not authorized for use ignated as "Warning," and to the effect: sive consumption of vitamin D. the Food except by or on the prescription of a -Warning-For'external use on the skin and Drug Administration finds that, in duly licensed medical practitioner. only. Severe" Injury may result from -order to protect the public health, oral (2) Some patients aficted with per- use Internally or as a douche. Avoid preparations containing vitamin D In ex- niclous anemia do not respond to orally contact with- mucous membranes." cess of 400 IU per dosage unit or recom- ingested products. There is no known mended daily intake are drugs subject to (d) The labeling or dispensing of any way to predict which patients will fall potassium permanganate preparations section 503(b)'(1) of the Federal Food, to respond or will cease to respond to intended for drug use within the Juris- Drug, and Cosmetic Act and shall be re- the treatment of pernicious anemia with diction of the Federal Food,-Drug, and stricted to prescription sale. Such prod- orally ingested preparations. Cosmetic Act ucts will be regarded as misbranded if at (3) The substitution of a possibly in- contrary to this statement any time prior to dispensing the following after 60 days from the date of Its pub- adequate treatment, such as thengestion lication id the FEDERAL REGISR conditions are not met: of oral preparations of vitamin Ba with may be (1) The label bears the legend, made the subject of regulatory proceed- "Cau- intrinsic factor concentrate, In place of tion: Federal law prohibits dispensing parenteral vitamin B, products for a dis- insg without a prescription"; and ease condition as serious as pernicious

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Reg. 14037 1975 1403& RULES AND REGULATIONS anemia cannot be regarded as safe in all (e) Any drug for oral ingestion in- the status of such water under the provi- cases. tended, represented, or advertised for sions of the act and the status, in (4) The development of the classical the prevention or treatment of perni- Interstate commerce, of commercially symptoms of pernicious anemia that cipus anemia or which purports to con- prepared foods In which fluoridated would cause a person to seek medical tain any substance or mixture of sub- water has been used. attention may In some cases be delayed ,stances described in paragraph (d) of (c) The Department of Health, Edu- by oral ingestion of Intrinsic factor. this section (other than diagnostic cation, and Welfare will regard water Pernicious anemia is a disease that Is drugs containing radioactive cyanocobal- supplies containing fluorine, within the associated, among other things, with a amin) will be regarded as misbranded limitations recommended by the Public higher than normal incidence of cancer. under sections 502 (f) (2) and (J) of the Health Service, as not actionable under of the stomach and that for the safety act unless Its labeling bears a statement the Federal Food, Drug, and Cosmetic of the patient, requires continuous expert to the effect that some patients afflicted Act. Similarly, commercially prepared medical supervision. with pernicious anemia may not respond foods within the Jurisdiction of the act, (5) With Inadequate treatment there to the orally ingested product and that in which a fluoridated water supply has may be markedly deleterious effects on there is no known way to predict which been used in the processing operation, the nervous system. It is well estab- patients will respond or which patients will not be regarded as actionable under lished that whereas the development of may cease to respofid to thte orally in- the Federal law because of the flourine anemia Is completely reversible with gested products. The labeling shall also content of the water sq used, unless the adequate treatment, the involvement of bear a statement that periodic exam- process Involves a significant concentra- the nervous system may not be com- inations and laboratory studies of per- tion of fluorine from the water. In the pletely reversible and thus may result in niclous-anemia patients are essential latter instance the facts with respect to pdrmanent damage. and recommended. the particular case will be controlling. (6) Some hematologists prescribe oral (f) Under section 409 of the Federal Subpart -- Requrements for Drugs and preparations of vitamin B12 in the treat- Food, Drug, and Cosmetic Act, intrinsic Cosmetics ment of pernicious-anemira patients. factor and intrinsic factor concentrate (7) Intrinsic factor and intrinsic fac- are regarded as-food additives. No food § 250.250 Hexachloroplicne, as a com- tor concentrate serve no known useful additive regulation nor existing exten- ponent of drug and cosmetic prod. therapeutic or nutrltite purpose except sion of the effective date of section 409 ucts. to the extent that they do increase the of the act authorizes these additives In (a) Antibacterial component. , The gastrointestinal absorption of vitamin foods, including foods for special dtetaryO use of hexachlorophene as an antibac- B12 in patients with a deficiency or ab- uses. Any food containing added in- terial component In drug and cosmeto sence of intrinsic fadtor, which may trinsic factor or intrinsic factor con- products has expanded widely In recent eventually lead to pernicious anemia. centrate will be regarded as adulter- years. It is used in such products because This conclusion does not apply to diag- ated within -the meaning of section of its bacteriostatic action against gram- nostic. procedures using- radioactive 402(a) (2) (C) of the act. positive organisms, especially against cyanocobalamin. (g) Regulatory action may be ini- strains of staphylococcus; however, (8) Medical expertise is required.for tiated witkf respect to any article shipped hexachlorophene offers no protection the diagnosis as well as the management within the jurisdiction of the act con- against gram-negative infections. In ad- of pernicious anemia. trary to the provisions of this policy dition the antibacterial activity depends (c) The Eleventh Edition of The statement after the 180th day following largely on repeated use. A notice pub- National Formulary and its first Interim lished In the FEDErAL REOXTrR of April 4, Revision publication of this statement In the Include monographs for oral FEDmnL RsTEn. 1972 (37 FR 6775), Invited data on OTC preparations of vitamin Bu with Intrinsic antimicrobial ingredients, including factor concentrate, establish a unit of (Sec. 402, 602. 503, 52 Stat. 1051. 1602 aa hexachlorophene, for review by an OTC vitamin B12 with intrinsic factor con- amended: 65 Stat. 648, 72 Stat. 1784: 21 Drug Advisory Review Panel to ba con- centrate, and provide for a National U.S.C. 342, 352, 353) vened under the procelures set forth in Formulary Anti-anemia Preparations § 250.203 Status of fluoridated water the FDmu RECisTER of May 11, 1072 Advisory Board to assign the potency of and foods prepared with fluoridated (37 FR 9464). This statement of policy such preparations. This provides for the water. will remain In effect unless and untl1 availability of such oral preparations. (a) The program for fluoridation of replaced by a monograph rezulting from standardized within the meaning of the public water supplies recommended by the OTC Drug Advisory Review Panel. broad limits characteristic-of the evalu- the Department of Health, Education, (b) Adverse effecti. Though considered ation of such preparations. and Welfare, through the Public Health safe for many yca=s, recent Information (d) Any drug that is offered for or Service, contemplates the controlled ad- has become available arsoclatinmg hoa- purports to contain intrinsic factor or dition of fluorine at a level optimum for chlorophene with toxic effects, including intrinsic factor concentrate will be the prevention of dental caries. deaths. Studies have shown that toric regarded as misbranded within the (b) Public water supplies do not ordi- amounts of hexachlorophene can be ab- meaning of section 503(b) of the Fed- -narily come under the provisions of the sorbed through the skin of humans, es- eral Food, Drug, and Cosmetic Act unless pecialy the skin of premature babies it Is labeled with the legend "Caution- Federal Food, Drug, and Cosmetic Act. or Federal law prohibits dispensing without Nevertheless, a substantial number of damaged skin. Human toxicity reporta prescription." inquiries have been received concerning include data on symptomatology, blood

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14038 1975 RULES AND REGULATIONS 14039

and tissue levels of-hexachlorophene, and tions and decerebrate rigidity following proved new drug application. Use of descriptions of neuropathologic lesions. application of a 6 percent hexnbloropbena hexachlorophene as a preservative at a powder. E-mnqtIon of branstems of those Recent infant deaths due to use of baby Infants revealed vacuoulztion like that which level higher than 0.1 percent is regarded powder accidentally contaminated with can be produced in newborn experimdntal as a new drug use requiring an approved 6 percent hexachlorophene have- oc- animals following repeated topical applica- new drug application, which must be curred. The accumulated evidence of tion of 3 percent hexachlorophene. Moreover submitted within the time set out'in toxicity is sufficient to require that con- a study of histologic zectlous of premature paragraph (c)(4) of this-section. tinned marketing of hexachlorophene infants who died of unrelated causs ba (e)Cosmetics. Hexachlorophene may containing products be carefully defined shown a positive correlation between he=- be used as a preservative in cosmetic in order-to protect consumers. chlorophene baths and lesions In white mat- products other than those which in (c) Prescriptiondrugs. (1) Because of ter of brains normal use may be applied to muclus their potential for harmful effect, drugs (I) On the Immediate container label membranes or which are intended to be containing hexachlorophene, other'than prominently displayed and In bold print: used on mucous membranes, at a level as a preservative as described below, are "Special Warning: This compound may be that is no higher than necessary to ,not considered to have been shown to be toxic if used other than as directed. Rinse achieve the intended preservative func- safe and effective, are regarded as new thoroughly after use. Monitor patients clozely tion, and in no event higher than 0:1 drugs-requiring approved new drug ap- for toxicity symptoms." percent. Such use of hexachlorophene plications, and would be misbranded for (4) Marketing of products for the in- shall'be limited to situations where an - over-the-counter distribution. In the In- dications listed in paragraph (c)(3) of alternative preservative has not yet been terest of public health protection; hexa- this section may be continued If all the shown -o be as effective or where ade- chlorophene containing drugs will be re- following conditions are met after the quate integrity and stability data for the garded as. misbranded and subject to effectve date of this section (9-27-72): reformulated product are not yet avail- regulatory proceedings unless the label (i) The product is labeled with the able. The component of a preservative bears the legend "Caution: Federal prescription legend and adequate infor- system, whether hexachlorophene or, law prohibits dispensing without a pre- mation for safe and effective use as set other antimicrobial agent, should be scription," and the labeling on or within forth in paragraph (c)(3) of this sec- selected on the basis of the effect on the the package from which the drug is to tion. total microbial ecology of the product, be dispensed bears adequate Information (it) Within 30 days, or by (10-27-72) not merely on gram-positive bacteria. for its safe and effective use by prac- the holder of an approved new drug ap- (1) Adequate safety data do not pres- titioners, in accord with § 201.100(c) of plcation submits a supplement to pro- ently exist to Tustify wider use of hexa- this chapter. vide for the revised label and full dis- chiorophene in cosmetics. (2) The Food and Drug Administra- closure labeling. As the label and labeling (2) Antibacterial ingredients used as tion recognizes that hexachIlorophene is will have been put into use, the supple- substitutes for hexachlorophene in cos- useful as a bacteriostatIc skin cleanser. ment should be submitted under the pro- metic products, and. finished cosmetic It further concludes that the margin of vision of § 314.8(d) of this chapter. products containing such ingredients, safety is such that products containing (ii)Within 30 days, or by (10-27-72) shall be adequately tested for safety hexachlorophene may appropriately be the holder of an approved new drug ap- prior to marketing. Any such ingredient used within clearly delineated conditions plication submits a supplement to pro- or product whose safety is not adequately of use. vide for a revised formulation where substantiated prior to marketing may be (3) In order for such drugs to bear appropriate to comply-with this order. adulterated and will in any event be adequate information for safe and ef- .(iv) Within 90 days, or by (12-26-72) deemed misbranded unless it contains a fective use the following statements are the holder of an approved new drug ap- conspicuous front panel statement that representativeof the type of labeling for plcation submits a supplement contain- the product has not been adequately products shown to be effective bacterio- ing blood level data obtained from use tested for safety and may be hazardous. static skin cleansers. -Labeling for prod- of the drug as recommended, unless such -(f)Content statement. All reference ucts other than bacteriostatic skin information is a part of the new drug to hexachlorophene limit In this order cleansers will be determined through the" application file. Is on a welght-n-weight (wlw) basis. new drug procedures based on the avail- (v) Quantitative declaration of hexachloro- Within 90 days, or by (12-26-72), phene content able data.- the manufacturer or distributor of such on the labeling of the (D In the labeling other than on the a drug for which a new drug approval is products, where required, shall .be on a immediate container label. not in effect submits a w/w basis. new drug appli- (g) Shipments of products.Shipments IDMATIONs cation in accord with § 314.1 of the new drug regulations CFR of products falling within the scope of 1. Bacterlostatlc skin cleanser for surgical (21 314.1), includ- (e) ing blood level data obtained from use paragraph (c), (d), or of this section scrubbing or handwashing as part of patient of which are not in compliance with.the care. the drug as recommended. guidelines stated herein shall be the 2. For topical application to control' an (5) Prescription drug products may outbreak of gram-positive Infection where contain hexachlorophene as part of an subject of regulatory'proceedings after other infection control procedures have been effective preservative system only under -the effective date of the final order. unsuccessful Use only as long as necessary the conditions and limitations provided (h) Priornotices. This order preempts for Infection control for under paragraph (d)of this section. any conditions for marketing products CoNwR&UMncAxo~s (d) Over-the-counter (OTC) drugs.- set forth in the following prior notices. 1. Not for use on burned or denuded skin Over-the-counter drug products, other 1.DI No. 4749 (34 FR 15389, October 2, or on mucous membranes. - than those which in normal use may be 1969). "Certain OTC Drugs for Topical Use." 2. Not for routine prophylactic total body applied to mucous membranes or which 2-. DESI No. 2855 (35 M 12423, August 4, bathing. 1970), "Certain Mouthwash and Gargle Prep- are intended to be used on mucous mem- arations"' - WARNecs branes, may contain hexachlorophene 3. DESI No. 8940 (36 PR. 14510, August 6, Rins thoroughly after use. Patients only as part of an effective preservative 1971), "Topical Cream Containing Pyrila- should be closely monitored and use should system, at a level that is no higher than mine Maleate, Benzocaine, Hexachlorophene, be immediately discontinued at the first necessary to achieve the intended pre- and Cetrimonium Bromide." sign of any of the symptoms described below. servative function, and in no event 4. DESI No. 6615 (36 FR 18022, Septem- Hexaclorophene is rapidly absorbed and ber 8.1971). "Deodorant/AntiperspIrant." may produce toxic blood levels when applied higher than 0.1 percent. Such use or hexachlorophene shall be limited 5.DESI No. 6270 (36 PR -23330,Decem- to skin lesions such as ichthyosls congenita to situ- ber 8,1971). "Certain Preparations Contain- or the dermatitis of Letterer-Siwe's syn- ations where an alternative preservative ing Hexachlorophene". drome or other generauzed dermatologic con- has not yet been shown to be as effective ditions. Application to burns has -also pro- or where adequate integrity and stability (Sees.201(n), 502"(a), (f), (J), 503(b), 505, duced neurtoxicity and death. 601(a). 602 (a), (c). 701(a). 52 Stat. 1041. data for the reformulated product are 1050-55 as Infants have developed dermatitis, irri- not yet available. This use of hexachloro- amended; 21 U.S.C. 321(n), 352 tabulity, generalized clonic muscular contrac- (a). (f), (J). 353(b). 355, 361(a), 382 (a), phene will not, by itself, require an ap- (a). 371(a))

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14039 1975 14040 RULES AND REGULATIONS

Subpart E-Special Packaging chapteir to provide for use of glass con- § 290.5, promulgated under section Requirements tainers and labeling as described in this 503(b) of the Federal Food, Drug, and § 250.300 Nitroglycerin for human use; section or submit data or reference to Cosmetic Act, requires the following packaging and warnings. data adequate to show that such changes warning on the label of certain druga are not necessary. The labeling and when dispensed to or for a patient: (a) Nitroglycerin preparations have packaging requirements of this section "Caution: Federal law prohibits the long been used under medical supervisi6n must be met unless an approved supple- transfer of this drug to any person other for the management of angina pectoris. ment to a new-drug application provides than the patlent for whom It was pro- The volatility of nitroglycerin has been for alternate packaging methods. scribed." The Spanish version of this Is: recognized for many years, and conse- (e) For containers other than glass, "Precauclon: La ley Federal prohlbe el quently packaging requirements for approval must be obtained from the Food transferir de esta droga a otra persona preparations containing this drug pro- and Drug Administration on the basis of que no sea el paclente para quen fuo vide for 'storage in tight containers. data submitted by interested persons recetada." When glass containers were used al- establishing its suitability for packaging (Seca. 502. 503: 53 Stat. 864, 05 Stat. 648; most exclusively this limited packaging of nitroglycerin. Upon review and ap- 21 U.S.C. 352, 353) requirement was probably adequate, even proval of alternate packaging this sec- though no provisions were made to in- tion will be amended to provide for such § 290.10 Definition of emergency situa- form the user that his filled prescription packaging. The data should be submitted tion. should be kept in a tight container. The to the Division of Cardiopulmonary For the purposes of authorizing an recent trend toward packaging contain- Renal Drug Products (BD-110), Bureau oral prescription of a controlled sub- ers made of materials other than glass of Drugs, Food and Drug Administration, stance listed in schedule II of the Fed- presents new problems because of the 5600 Fishers Lane, Rockville, MID 20852. eral Controlled Substances Act, the term different properties of such materials. Such data should be accompanied with "emergency situation" means those sit- Recent information, including labora- a request that an exemption be made as uations in which the prescribing prac- tory data, available to the Food and Drug provided for in this paragraph. Until ap- titioner determines: Administration indicates that improper proval for containers other than glass is (a) That immediate administration of packaging of the drug either before or given by the Food and Drug Adminis- the controlled substance is necessary, for after dispensing to the patient will likely tration, such alternate containers are proper treatment of the intended ulti- result in a substantial loss of nitroglyc- not considered suitable for the packag- mate user; and erin. The Food and Drug Administra- ing of nitroglycerin preparations. (b) That no appropriate alternativo tion's studies indicate that commonly (f) Any nitroglycerin drug prepara- treatment is available, including admin- used plastic containers and certain kinds tion which is shipped or dispensed within istration of a drug which is not a con- of strip packaging allow appreciable the, jurisdiction of the act and contrary trolled substance under schedule II of evaporation of nitroglycerin from nitro- to the provisions of this section after its the Act; and glycerin tablets. '% effective date will be the subject of regu- (c)That it is not reas6nably possible (b) The Commissioner views these latory proceedings. for the prescribing practitioner to pro- findings as raising serlou questions con- (Secs. 501, 502, 505, 52 Stat. 1049-53 as vide a written prescription to be pre- cerning the packaging practices for amended, 1056 as amended by 70 Stat. 919 sented to the person dispensing the nitroglycerin preparations and their re- and 72 Stat. 948; 21 U.S.C. 351, 352, 355) substance, prior to the dispensing. lationship to.the potency characteristics of the drug at the time of dispensing and Subpart B--[Reserved] use by the patient. Stability studies with PART 290-CONTROLLED DRUGS Subpart C-Requirements for Specific containers other than glass are needed Subpart A-General Provisions Controlled Drugs before reasonable assurance can be made Sec. that packaging and storage in these con- 290.5 Drugs; statement of required § 290.35 Metladone in the maintenance tainers does not contribute to the loss warning. treatment of narcotic addicts. of nitroglycerin in any dosage form. 290.6 Spanish-language veirslon of required (a) The Food and Drug Administra- '(c) The following packaging and warning. tion and the Drug Enforcement Ad- labeling is required for preparations con- 29D.10 Definition of emergency situation. ministration recognize that the In- taining nitroglycerin: Subpart B [Reserved] vestigational use of methadone requiring (1) Preparations containing nitro- Subpart C-Requirements for Specific Controlled the prolonged maintenance of narcotic glycerin shall be packaged in tight (as Drugs dependence as part'of a total treatment defined in the United States Pharmaco- 290.35 lethadone in the maintenance treat- effort has shown promise in the miinage- peia) glass containers with tightly fitting ment of narcotic addicts. ment and rehabilitation of selected nar- metal screw caps or in containers of AuTHosrry: Sec. 701, 52 Stat. 1055-1056 as cotic addicts. It is also recognized that a materials approved by the Food and amended; 21 U.S.C. 371, unless otherwise number of dangers and possible abuses Drug Administration. No more than 100 noted. may arise from such efforts If profes- dosage units shall be packaged in any Subpart A-General Provisions sional services and controls are inade- such container. quately applied. It is further felt that (2) In addition to other required § 290.5 Drugs; statement of required additional research Is urgently needed labeling Information, the following shall warning. so that data may be accumulated which be displayed on the container in a The label of any drug listed as a "con- will permit sound determinations of prominent and conspicious manner: trolled substance" in schedule II, III, safety, efficacy, and necessary procedural (I) A statement directed to the or IV of the Federal Controlled Sub- safeguards. pharmacist that the drug should be stances Act shall, when dispensed to or (b) Therefore, the Commissioner of stored at controlled room temperitture for a patient, contain the following Food and Drugs and the Director of the (as defined in the United States Phar- warning: "Caution: Federal law pro- Drug Enforcement Administration, De- macopela) and dispensed only in the hibits the transfer of this drug to any partment of Justice agree that interested original, unopened container. person other than the patient for whom professionals, municipalities, and organi- (ii) A warning statement to the pa- it was prescribed." This statement is not zatioLns should be allowed to conduct fur- tient as follows: "Warning. To prevent required to appear on the label of a ther research in this area within a frame- loss of potency, keep these tablets in the controlled substance dispensed for use work of adequate controls designed to original container. Close tightly immedi- in clinical investigations which are protect the Individual patients and the ately after each use." "blind." community. To facilitate this purpose, (d) The holder of an approved new § 290.6 Spanish.language version of re- the Food and Drug Administration and drug application for a nitroglycerin quired warning. the Drug Enforcement Administration, preparation should either submit a sup- Department of Justice have Jointly plement to his new-drug application By direction of section 305(c) of agreed upon acceptable criteria and under the provisions of § 314.8(d) of this the Federal Controlled Substances Act, guidelines which are set forth in pro-

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14040 1975 RULES AND REGULATIONS 14041 N posed 21 CER 1319.505. In addition such American Pharmaceutical Association, or otherwise will not commit the Food other provisions of the Federal narcotic and has been engaged In the asslgnment and Drug Administration to adopting laws and regulations as are applicable of names to drugs since January 1964. such terminology as official. must also be observed. The Council negotiates with manufac- (Sees. 502(e). 503.52 Stat. 1050, as amended. (Sec.-505. 52 Stat. 1052-53, as amended; 21 turing firms In the selection of nonpro- 16 Stat. 789, 790, 21 U.S.C. 352(e), 358) U.S.C. 355) prietary names for drugs. (d) The Food and Drug Administra- § 299.5 Drugs; compendial name. PART 299-DIUGS; OFFICIAL NAMES tIon cooperates with add is represented (a) The name by which a drug is des- AND ESTABLISHED NAMES on the USAN Council. In addition, the ignated shall be clearly distinguishing Subpart A--General Provisions Food and Drug Administration Is In and differentiating from any name rec- agreement with the "Guiding Principles ognized in an official compendium dness Sec. for Coining U.S. Adopted Names for 299.3 Definitions and interpretations. such drug complies in identity with the 299.4 Established names for drugs. Drugs," published in New Drugs Evalu- Identity prescribed in an official com- 299.5 Drugs; compendial name. ated by A.M.A. Council on Drugs, 1967 pendium under such recognized name. edition, pages 556-561, and In U.S. (b) The term "drug defined in an 'Subpart B-Designated Names Adopted Names (USAN), Cumulative official compendium" means a drug hav- 299.20 Drugs; official names. List, number 5,1961-1966, -pages100-105.2 ing the Identity prescribed for a drug in AuTonir: Sees. 508, 701(a), 52 Stat. 1055, All applicants for new-drug applications an official compendium. 76 Stat. 1789; 21 US.C. 358. 371(a), unless and sponsors for "Notice of Claimed In- c) A statement that a drug defined otherwise noted. vestigational Exemption for a New in an official compendium differs in Subpart A--General Provisions Drug" (IND's) are encouraged to con- strength, quality, or purity from the tact the USAN Council for assistance In standard of strength, quality, or purity § 299.3 Definitions and interpretations. selection of a simple and useful name set forth for such drug in an official (a) As used in this Part 299, "act" for a new chemical entity. Approval of compendium shall show all the respects means the Federal Food, Drug, and Cos- a new-drug application providing for the in which such drug so differs, and the metic Act, sections 201-902, 52 Stat. 1040 use of a new drug substance or a new extent of each such difference. (21 U.S.C. 321-3R2), with all amend- antibiotic drug may be delayed if a simple (Sec. 501, 52 Stat. 1050, as amended; 21 ments thereto. and useful nonproprIetary name does U.S.O. 351) (b) The definitions and intei'preta- not exist for the substance and if one tions contained in section 201 of the act is not proposed In the application that Subpart B-Designated Names shall be applicable to such terms when meets the above-cited guidelines. Prior § 299.20 Drugs;oficilnam-es. used in this Part 299. use of a name In the medical literature (c)The term "official name" means, The following are designated official with respect to a drug or ingredient 2 Copies may be obtained from: U.S. Phar- under section 508 of the act and are thereof- the name designlated in this Part macopetal Convention. Inc, 12601 Twinbrook "established" names within the meaning 299 junder section 508 of the act as the Parkway, Itockville, MD 20852. of section 502(e) of the act: official xiame. § 299.4 Established names for drugs. Offi i name Chemial nme er.dezzptlon MoLbdu ofrzmus (a) SectIon 508 of the Federal Food, Acecdne...... 3.Quiuc d~nol ctata (c-ter); 3-ncc titylndidim.... Ci.iiNO,S Drug, and Cosmetic Act (added by the 4'4"' -Slonylbl steetaniide] ...... CiEN0S Kefauver-Harris Drug Amendments of, ,'-ActY'i-L mtelao ...... Acdals-n-...... 9-Am,- da, " ,wth4.h i .ey.". ".--...... ' CsHnNOaCn.H:3N', Cu. ,O 1962; Public Law 87-781) authorizes the Acronine...... 3,L..Dlbydro . hboey.'3..2. rtm yi.7 ...... cr.dl- Commissioner of Food and Drugs to Adenosine...... Cn~t'Ns designate an official name for any drug G6Amn o~ndeuneyiBprn...... CounNOl Adiphune.------....;tI ~Lm~ 0 y tliphenylacwl ...... if he determines that such action is nec- or CnUnNiO Akiorlde...... ;. /10'O"dfr D. .J "=O...... CTHIClNs0z essary or desirable in the interest of An antiblotl substace dervcd fro Trrcdern= '. Pen. usefulness and simplicity. Section 502(e) Alcaranum...... Alwroluxa_ ...... MnDllyinartazlednn; dhlyf hlled...n..... of the act (as amended by said Drug Al d-ne ...... Amendments) prescribes that the label- 5,5l.1-D1[enhgynt Itlylbarblturicaddd. cnl(-.e...... - ...... ----.... Cn..Oe ing of a drug must bear its established AIlnr ot...... l-PyrWoI,4.djpyr1:nldLn-1o; 4-bydrypyrzoo (34)-pyrm name, if there is one, to the exclusion of dine. any -other nonproprietary name (except AlprenoloL...... 14o-Al .3. p)rppymlno)-2.pronol..... CUUUNOs Ambuphylline ..... Theoph Une. compoundylib 2-.ro-2-mvrl-l-p o oL...... ICTHNOZ.CHIINO the applicable systematic chemical name Ambuside ...... Sya- do;(-h T2-bntyldnen)aml-no-.benz(I..l- or the chemical formula) and, if the UCnHuCINioss b u te neyl d e )nne ieilne. drug is fabricated from two or more in- Amiloride ...... N-AmtdanoU Ln o#c-lo pyraznzccaboxamIl...... gredients, the established name of each Amqulnnet-...... - G-Ainlnoomdd e...... ldo) active ingredient. Axnaporayin...... -D-Mlnoep:. nya -3.3-dl...... 7.o.o-.- l SCuH,,NzsCnutiNaot Ampl in ...... A substnc Pod ce y qni= niincocanzus. (b) The term "established name" is ctsruNtOl5 defined in section 502(e) (2) of the act Apqulnte...... [CL'= 'O2 Asotropn ...... CaHaNO: as (1) an official name designated pur- Apzone ...... suant to section 508 of the act; (2) If no Aprotila...... Arg-P.o-Asp (tentatve).Phs.-HC tLeu.Giu (tntatlveo.ro-Pro- such official name has been designated 'I'yr-Thr. Gly.PmICy,.Ly.A.r.1hu.len.Arg.Tyr.phe. for the drug- and the drug is an article Tlsr-A Py-Qiay-Ljs-.Aia.AOLyzz-Ar.G -N.T. -pbe.Vya.er recognized in an official compendium, 3lIu -,sp%1-II Cys l-- .'-hr-HCys-G If. Gy-AL. then the official title theretof in such Aranotl ...... 6,I13a-T.1hn.de - ydrwy.sU, 4H3.d II.Ta. ,e Pldthb0- 7Hi 5-b p 91,tpoZ3.44,5 . ipyrazine.75.. compendium; and (3) if neither para- SC,H', Oz graph (b) (1) nor (2) of this section Arglnine.------. applies, then the common or usual name Artoraft...... Arterial gaft compoced of a sctioni of bovino carltd artery thbua -as been subje--ti to enymat a ditcon w-th fide =n tanned of the drug. with dialdcbyda starch. (c)The Food and Drug Administra- Atolide ...... tion recognizes the skill and experience Azaperono...... -- 4'lao '4(-pedy),Pcranylbutrophen=aa1i3.flnaro-c enzoy) .prOpIl (Z-pyrddyl)p4pczalle. of the US. Adopted Names Council Azariblne...... 2.8.D-RIbefarnan .a i I -wy ( -"I ),3"5-trtaceate;n2E4/ (USAN) in deriving names for drugs. CazHnFNO Seina d1-azcetato (etr)...... CI4 H,,N:0, The U.S. Adopted Names Council Is a Nletbyli-tro:nldzol.,-y) tho purn...... private drganization sponsored by the Benazohine ...... 2WWutyAbnl0n)mehyIjP hydox nlbhoLfyl ...... C=H2aN2OS (-,M. inzobtben-3.yl)ctbl.2.ldazollne;2-ntby.3- American Medical Association, the -('r al l3ntbyl)ben , oM n. CisaNW.20 United States Pharmacopeia, and the Bendarna ......

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, M,'ARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14041 1975 14042 RULES AND REGULATIONS

Official name Chemical name or description I Molecular formula

Be alan ...... 3,-DIbromo-N-(p-bromobenzyl) sallcylamide ...... CufHil3rNO3 Benzetimide d.. .. 2-(1-Benzyl-4-plperidyl)-2-phenylglutarimide ...... --- .... Benzoctamino ------...N-Methyl-9 10-ethanoanthracene-9(IOH)-methylamino ...... ------CislInN BenzoxiquineBaetahistine ...... 8-Quinolinol benzeate (ester); 8-benzoyl-oxyquinoline ...... CzoHnNO2 2-12-5.51-Diallyl-a,o'-bis(diethylamino)-in.7n-hitolyl-4,4'-dHIe (Methylamlno)thyl]pyridlne ...... -...... ------CsHt:N2 BlalamicoL .... ------1,11-Tetramethylencbis[1,2,3,4-t CuHzoN20i Bisobrin r----...... etmhydro-6,7-dimethoxyis(o- qulnline]. CnHSNiO4 Blisoxatin ...... 2,2-Bis(p-hydroxyphenyl)-2?-1,4-benzoxaztn-3(41)-one ...... C:)HjsNO4 Boldenouo...... 17P-Hydroxyandrosta-1,4-dieu-3-ono ...... Bolenol.. 19-Nor-17a-pregn-5-en-17-ol; 17-a-cthyl-5-estren-17-ol ...... Ci9Hz F:NO Blexidin e . 7-Bromo-1,3-dihydro-5-(2-pyridlyl)1-2-[[4'-(Trlfluoromethyl)-4-blphenylyloxy]ethyl]pyrrolldino -2ff-1,4-benzodiazepii-2-ono ------Bromazepm ...... CI4HIoBrNsO Bromelains .. s..... A concentrate of proteolytic enzymes derived from the pineapple plant. Bromhoxine ...... 3,5-Dlbremo--N'c-cyloheyl-Na-methyltoluen e-a,2-dIamine ...... CitHnBr2N2 Bucllzin ...... n 1-(p-rt-Butylbenzyl)4-(p-chloro-a-phonylbenzyl)-piperazne ...... CtUsH3CIN Bucrylat ...... t Isohutyl 2-cyaneacrylate ------C&HInNO: 2 B u n l ----o .....-----(-)-5-3-(tert-Butylamino)-2-hydroxypropoxy]-3,4-dihydro-1(2H)o C112NOs naphthalenone. CuHisN2Oa Butalbital b. ta...... r-Allyl-5-isobutylbarbituric acid ...... B u t a p e r az in e ...... 1-[10-3-(4-ethyl-l-pperazinyl)propyl]pbenotliazino2-yl]-l- C24HUNOS butanene. Buthlazdde ...... 6-Chloro-3,4-dihydro-3-Laobutyl-2H-1,2,4-benzothadazine-7 CnHiaCIN:O S2 sulfonamide 1,1-dioxide. 4 Calcltonln ... n...... Hormone from the thyroid gland, a polypeptide of molecular weight less than 10,000. Calcium cbasph-in.. Calcium salicylato diacetate compound with urea ...... CinathCaOs.CH4NaO Candicidin .... ------An antibiotic substance derived from Streptomyces orluus Waksman and Henricl. Canrenon ...... e 17-Hydroxy-3-oxo-17a-pregna-4,6-dlene-21-carboxylic acid gamma- CnH23OS lactone; 17c-(2-carbezyethyl)-170-hydrozy and rosta-4,6-dien-3-one lactone. • I C a pr eom y ci n .. .i . . . . . An antibiotic substance derived from Streptaoyces capreolus. .-.....-...... C ap t a m ----- iin ..... 2-(Dimethylamino)ethanethio; N-(2-mercaptoetbyl) dimethylamlne. Carbaddx ...... l\ethyl-3-(2-quinoxalnylmethylne)carbazato.NN-dixio-de...... CuHONiOI C arb am az epin e ...... 5H-Dibenz[b,J]-azepine-5-carboxamido ------CislliN20sS Carbeniclllin ------Carbory-3,3-dimethyl-7-oxo-4-thia-l-azableyclo 3.2.0]-hept-6- y )-2-phenylmalonamic acid; 6-(2-catboxy-2-pboenylacetamido)- 3,3-dimethyl-7-oxo-4-tbla-l-azabicycle[3.2.0]beptane-2-crhboxylic acid. Carboclral -- ...... Ethyl (2,2,2-trichloro-l-hydroxyethyl)carbamate ...... CJH8CINOs Carbemer ...... A polymer of acrylic acid crosusinked with allyl sucrose ...... - ...... Carphenazine ------1-[1-(3-4-(2-Hydroxyethyl)-l-piperazinyl]propyl)phenothiazin-2- yl]-1-propanone. Casanthranol ...... A carapurified sorada. mixture of the anthranol glycosides derived from Cas-

Cellaburate ...... ,,,/ AUAUU t t * kt UIJtt,VJlN Lt ...... Cellulase ------A cocetraten of cellulose-sing enzym- iesjW deivedfro WAserit. hta niger and other sources. Cephalexin ------D-7-(2-Amino-2-phenyacetamido)-3-mthyl--oxo-5-thia-l-azablcyclo 4.2.0]et-2-one-2-carboxylc acid. Cephaloglyctn...... 7-v-2-Amino-2-phenylactamldo)-3-(hydrxymethyl)--oxo-5- Ci#HniNzOiS3 thia-l-azabicyce[4.2.0olct-2-ene-2-crboxylic acid, acetate. Cephaleridine ...... 1-12-Carboxy-8-oxo-7-2-2-thinyl)acetamido]-5-thia-l-aabicyco- CisHipW0aS2 [4.2.0]oect-2-en-3-yl]metbyl]pyridlnlum hydroxide, inner salt. Cephalothin...... f(Hydrozymethl)-8-oxo-7-[2-(2-thienyl)acetamidol-5-thia-1- Cn=HuN=OS azablcyco[4.2.0Joct-2-ene-2-carboxyllc acid, acetate. Cotalkonium .....---.--Benzylhexadecyldimethylammonium ion ...... Cetophenleol ...... D-threo-N-[p-Acetyl-P-hydroxy-a-(hydroxymethyl)phenthyl].2,2 CI2HIJ&CI2NOI dichloroacetamide. Chlophedlanol ...... 2-Chloro-u-[2-(dimetbylamino)ethyl]benzhydroL ...... CisTHCINO Chlordantoin ----... 5-(1-Ethylpentyl)-3-[(trichloromethyl)thlolhydrantoin ...... CuHuCIINiOiS Chlorhexidine ...... 1,1'-Hexamethylenebis[5-(-chlorophenyl)blguau.de] ---...... CnUH:Cl2Nio Chlorindanol ...... 7-Chloro-4-indanoL ....------COHOCIOCnHnCO~t Chlormadinone ------6-Chloro-17-hydroxypregna-4,6-diene-3,20-dione; 17a-hyrozypregesterone. 6-chloro-d-dehydro- C21H2CIO3 -1 -kj-WVLVjJU-Y)-A Chorpienter.-... C oHnCIN Chlorprothixone ..... 2-Chlro-',INV-clhnetbylthlexanth ene Al-rpropylamin ...... CisHuCINS Chlorthalldone ...... 2-Chloro-5-(l-hydroxy-3-oxo-l-isoindolinyl) benzenesulonamide-..... CuHOICINS04S Cingestol ------19-Nor-17a-pregn-5-en-20-yn-17-ol; 17a-etbynyl-5-stren-7-o ...... Cinnamedrine ...... a-[1-(Cinnamy=ethylamino)-ethl]benzylmethy amino) ol-pnenylpropanel. alcohol; 2-(N-cinnamyl- Ci91HNO Clunarizine ...... 1-Cinnamyl-t-dlphenylmethylpperazlne ...... Cinoxate ...... 2-Etboxyethyl p-methoxycinnamate ...... CnHn Oa Cinperene ...... 2-(,-Cinnarmyl-4-plperidyl)-2-phenylglutarimide; l-cinnamyl-4-(2,6- CuHuN2O2 dtxo-3-phenyl-3-piperidyl)plperidine.

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

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Offlcal name Chemical name oredcpUon I looaafm1fo i

Cnt azone-----...... 2-Pentyl--pbenyl-IH-pyzolol,2o] cUao4,3(2n)-ldno ...... Croleycln-..--...... An antiblotc substance derived from Eiuyeanyou bfus var. var. . o.a..,rokrps C:eHnCiO0 C is lo m lph e n ..a .. . . MrIbezoj d1c4ycleapteac Irboxam d e..o...... Cit de ---.----- C2I~nCIN0 Clemastine . -... (-)2-P-C ro-methyl-a-phnylbcnl)oxylethylj-l4.m tbyl- pyrrolldtne. Clindarycln. ....-... Mdethyl 7( ).hboro-0,7-trfldcoxyft"a*-(I.methyl-propyl-L-- CzniHClN'OS ; 7(,m)pyrrolidlnecarboxamldo)ch 11ro-7.deoxylinmmycin. -l-th eo-L-fo-cytan"toced Clioxanido ...... 4'C cyan"doatate; arsro-3,5-dilo Zamto4'bqro-3,5- dilodobeaznl=lde. C.u tCILNO ndazololna. CHsEMCIN10 Clodazon...... 3-p-hloro=Uilno)-l~iprobphenyl):&1Chlor--13-(dmethylamno)propyll3.b -d;ydro- eny -*bo (L~opropyll- Clofazimln ...... mino)pbenne. CuHnCI41O Clofibrate ...... 4,4¥-DIEthylr-(p-oropheoxy)-metylprpontte cro.3 -(Wflumetby)carb~nIdo ...... C lo lu c arb ..an .n ..... CntH.,CIO CnHnClIN Clogestone_..n...... CnH:2CI0s Clomacran ...... 2-Chlaro- 3-(dimethylamlao)-propyJl awdn ...... n...... Clomegestone --...... 6-C-loro-l7hydroxy-hnmcty preana4,rEedlmal-3 ...... CIomiphene ...... 24iND2-Cbioro-1,24dpeyralphnzltll CnH=CI0NOCucIN2O Clonau pam-._ .... 5-(o-Chloropbeny)1..dm ydr.7aitro.2H.-bli4ndL pla.2.Ono-.... Clondine..; ....-... I ~ Ctm~aCINaOS ClonixerL ...... 2-{3-C horo-o-tl diao] nlotllo ad...... Clonlin ...... -...X 3o,-D lchloro-9-6-dimetbyl4-pyrdlL ...... - Clopidol ...... C:HICINO Chlorazeplo acld-....- 7-Chloro-2,3-dhydro-.db ydroxy-5-phenyl--l,4zodLo- CtllnClNiO plaecarboxyllc acid. Corexolone .. .-...... 6-Chloro-2cyclobezyl3-aozo-.5otndolne oulf anamde; 5.-blo-1- cycloh exy.l-l-=4-syllwiadolUne, C31111CIN1B C l o r te r mnne : -...... o-Chloro-a,-dmethylphentbylamle ...... CunCIN. Closram Ine- ..-..... 8-Chloro.1142-(dimethylnmno) cthyl].6,11-dydro-tnal.b[e],- cyclobe pt1,-] pyr dlne. Clomacilozn ....--..... 6-13-o-C hlo rophenyl) -methylozz cc boam do-3.3dl- methyl-7-oo-tha-l.-azbicyclol0 be n --caro U acid. Clozappne -----...... 8-Chloro-ll-(4-methyl-l-piperainyI)4lL.dlbea ,[14 ] dLazeplaa.. CziUuCINI ColestipoL ...... Tetraethylenepentnmle polymer with l-chi.ro. poxprOpso._ Cosyntrop ...... p "-ser-Tyr-Ser-Met-Olu-EL-Phe-ArT-Gly-LTs-Pro- - ly- LYs-Lys-Ar-Arr-l'ro-Val-Lys-V- -l O. 5,5'-[(2-Hydrozytrlmethylene)dlo lbL[.-ozo .- i. pY=*n- Cn~Utoz Cromolyn ...... 2-carbozylate]; 143-bis(2.caboz cbroman.,-$a).-ydrzy- Crufom ...... tte '.2ut-2-ihloropenymeth lpethylpbwpormdato ..... Citz,,Cl!NOt oo o) -'%3-dh ethy l-7. o.o44hI3-l- Cyclacilin...... 6-( -Amlnocyclobeynne=r acbIcyclol3.. O]heptano-2-cazboxylle acdd. Cu'UhC1Ns Cyloguanfl ...... 4.6-Damlno-l-(p-cblorophenyl)-l.2.dlbydro- dnetbyI-jtuael.. Cyclophenazne .- 1043-(4-Cyclopropyl-l-plperztlnyl) propyl-2-{tlflurombethyl) phenothlazIe: 1043-(4-cyclopropylppem.o)-propyll-2- trlfluoromethylphenothlnzte. CaaUhnNSS Cyclopenthlazide ...... 6-Chloro-4-(cyclopentylmethy) -34.dIbydro-2UilA4-beazotblas diazlne-7-sulfoaamlde l1dioxide. 6.Chloro-3,4-dlhydro-3-,-rboe n-2.yl)-2-I,%4-benotbbdLino- C:4U11ClN1Otsz Cyclothazde ...... 7-sufon.alde 1,l.dioxide. CuH uCaOSs Cyprouinate ..-..... Ethyl 6,7-bs(cyclapropylmethozi)-bydmy--3-qulnoSnea- Cyproximdde ...... Cytarabin. --- ...... R Actlnoycln.orpeyj-...... _..p ca ...... Dactiomycln...... Danazol...... 17a-.Prega-2.4-dle.0-yno!2,0 BLoz1-17.l0 I-ethynyl23,b4. 5,10,1%lo,.lb, 11,12, lvdecahydro-lft,12-dlmetbyl .H.yc - pen7].phanth3,24yra1.1.-ol Decoqui ate..... o .. Ethyl 6-(decyloxy)-7-.etoxy4ydroy-3-qut nau bzlate--... CnHzaNgOC.tlN.ae0 Defemialne ...... AN[l3e-A.l.pentyl)hldHE4&-,Lhydro xyacetamld o)p-tyll ycarbtmoyilpplanamldo1tyl- -b 3-my~f pmp~o nony o, z a~cid. CuHamNs Desipramne . n...... 10.U.Dthydro-(3-(mcth ylmlno)propy .3i-dlbenz bjlzcp n...... Dexivaelne ...... (-)-..ethyl-,6-h.ip olozylldlde; (+)-l-N.metbyplpcoIjz acid 2.-.dlmetb yLanlllld. Dexp3nthenaoL .. .. D(+)-2,4-Dhydra-.g-3 ydroyr opy-3,dlmt dO.othylbutY Dextran 4 ...... A polysacchadde vhavng a s t avcr molecuolmr t o CsiafaNsO 40.000; produced by the action of Leucom=Ix =caurrcdf an sacrose. Dlamocaine ...... 1-(2Anlllnothy).4420dletb ylemino)thoyj-(-pb-y]ploper .. DIapamIde ...... 4-Chloro-N-methyl--(methulamoyl) bem ldo...... CIUSICIN20Os: 3,5.Di1detaald o-, 4,6-trlodobeazole add ...... cuuhCINsO - Dlstrizol acd..--.... *7.Chaoro-1,3dlh ydro-l-methy1-.ph fnyl.2&-l,4-bflOdpfno. Ci.HuI"O Dilue am ......

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27,.1975

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Official name Chemical name or description I Molecular formula

Dibromsalan -- . . 4 .D romosla- ...... CnHn7Cls~hO Dtcloxscillln ------(,3-2Il-chiorophenyl).5miethyl-4-isoxazolcarboyamido]-3,3- Culruora acid.ethyl-7-oxo-4-thal-azabicyclo[3.2.oheptane-2-carboxylo Dflusanne ...... 1-(2-Anilinotbyl)-4-[4,4-bis(p-fluorophnyl)butyl]piprazne; 1:[4,4- di(4-fluorophanyl) butyl]-4-(2-anllinoethyl)piprazino. CntnFlOf Difluortolone..--...... 6a,9-Difluoro-1lP,21-hydroxy-Ca-mthylpregna-l,4-diene-3,-Alone. " - Dflumldone. .--...... 3-Benzoyl-1,l-difluoromethanesulfonanllide ...... CssHuFOiCI4I1FNO:S Difluprednatt...-..... 6cr9-Difluoro-llT17,21-trihydroxypregna-1,4-dlenc-3,20-dione 21-ace- Late 17-butyrate. 2-[-[242-(Dimethylamino) cthyl]inden-3-yl]ethyl]pyrdino ...... Dimothinden- ...... e 1701-ydrory-methyl-17-(1-Propynyl) androst-4-an-ne ------Dimethisterono ------2,2'-Dihydroxy.--methoxyb ---...... - Dioxybenzona ... enzophonone CaHnOi Dlphenidol .. o ...... a,¢rDlpenyl-l-piperidinebutnol ------CnHnNO Dipyridamole ------2,2',2",2"'-[(4,0 -- lipiperldinopyrimido5,4-d]pyrimidine-2,6- diy) dinitilo]tetraetbanol. o ZHuiaNaO4S.ifO Dipyron ---o e-...... Sodium (antipyrinyhuethylamino)methanesulfonate hydrate ...... Domlphee------...... Dodeycldimethyl(2-phenozyethyl)ammoniunm ...... Dopamine ------4-(2-Aminoethy )pyrocatthol...... Doxaprrm - ...... 1-Ethyl-4-(2-morpholinoethyl)-3,3-dphenyl-2-pyrroldinono .---- CnH4nNO Doxopln...... LVA-Dimethyldbenz[b,e]oxepinl(sa,.7-propylamine ...------Doxycycline.... - 4- hy3droxy-6-methyi-IDimethylamino)-1,4,4a,5 ,11l-dloxo-2-n a,1 ,2a-octahydro-3,5,10,12,12a-penta-pa eoecr..aid.r l-[-3-(p-Fuorobenzoyl)propyl-.12,3,6-tetrahyro-pyridyl-2- Droperldol .... ------benzimidazolinone. Cio~aNO 0 Ow-Pregna-4,6-dioe -3,20-dtono ------Dydrogesterone ...... ------.CnHnO Epim ...... sttrol fthoxTestra-l,3,5,(lO)-trienO-6a,lTa-dIo Estrazinol----...... DL-tran-3-Methory--az-l9-nor-17a-prcgna-1,3,5-trln-2D-yn-17-ol.... Ethacrynic acid ...... [2 3-Dichloro-4-(2-methylenebutyryl)pbonoxylacetic acid ...... EthambutoL ...... C-)-2,2"-(Ethylenedflmino) -ll -butanol) ------CzHnNO2 Ethml ivan...... -- -b is-lthylvan am do ------alla CIOHUoN2O Ethlonamide ...... 2-Ethylthiolsonicotinamide ------CnHuNsO Ethonan. ------Ethyl--l, 2,34-tetrahydro-l-naphthyl) imidazole-5-carboxylate; 1-(1,Z3,4-terahydro-l-naphtby]) -5-ethozycabony) Imidazolo. Ethosuximido -.-----2-Ethyl-2-methylsuccinimide ------Ethoxazene ------4-[(p-Ethoxypheny)azol-m-phenylenediamine ...... CaH23N02 Ethynodiol ...... 19-Nor-17c-pregn.4-en-20-yn-3P, 17-dioL ...... CiiH:#N%02CtOH.N2O Ethylestrendl .------19-Nor-17a-pregn-4-en-17#-ol... _ ...... -...... CaHuINOCjsHnO Etidroaio Acid-. (1-Hydroxyethylidene)dphosphonc(-- acid ------...... Etoxadrol ...... (2-Etbyl-2-phenyl-1,3-dioxolan-4-yl piperidine CisHnNO, Euprocin...... 0-6-Isopentylhydrocupreine ------Famotin ...... 14(p-Chlorophenoxy)methyl-3,4-dlhydrolsoquinollne ...... CIE1CINO Fantridone ------(3-(Dimethylamino) propyl]1-(5H)-phenanthridne ...... C,in O Fenalamide...... Ethyl-..V2-(diethylamino)ethy-2-ethyl-2-phenylmaonamate; phenylethylmnlonic acid monethylester diethyl minothylamilde. C,H, sOINOz Fenclonine ...... DL-3-(p-Chlorophenyl)alanine ------Fonestrel ...... 5-Ethyl-6-methyl-4-phenyl-3-cyclohexene-l-csrboxylic acid; 2-methyl- 3-ethyl-4-phenyl-4-cyclohexenecarboxylic acid. Fentanyl ...... 2,-- 2-Thlobls[4;chloropc1-Phcnethyl-4-plperidyl o] ? proplonantlide...... ---- ...... CnHnN2O Fontlolor...... CIM&5C12O±S Farris fructose ...... Fructose iron complex, compoumd with potassium (2:1) ...... 'aN OeY.C/ Fetoxylato...... 2-Phenozyetbyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipec- 9 otate. FillI -...... 3,6,7,9, 1,13 15 25,27-Nonabydroxy-2-(l-hydroxyhexyl)-l6-methyl- 1d,18 20,22,24-octacosapentaenoO acid 1.27-lactono. Flavoxate ...... 2-Pipeidinoetbyl 3-mathyl-4-ozo-2-phenyl-4H-l-benzopyran-8- Cu sNOi carboxylate. Floxuridine...... 2'-Deoxy-5-fluorouridine ...... CgHIIFN30& Flucrylato...... 2 22-Trlfuoro-l-methylethyl 2-cyanoacrylate ...... CiHiFsNO3 Flucytosino------Fluorocytosine ...... C4H4FNSO FIudorex ...... P-MethoZy--mnethyl-m-(trifluoromethyl) phenethylamine ...... CnHuF:O FlufensaL ...... 4'-Fluoro-4-hydroxy-3-biphenylcarboxyic acid acetate ...... Flumethasone .... Ocr,9-Difluoro-l1P,17,21-trihydrory-16c-methylpregna-l,4-dieno-3,20- ione. Flunidazolo ------2-f -Fluorophnyl)-5-nitromldazole-l-ethano...... Fluocinolone ------6a,9-Dlfluoro-15.6a,7 21-tetrahydroxypregna-,4-dien-3,20- CnSHIF04 dione; Ocrga-difluoro-l6c-bydroxyprednlsolone. Cn~HFsOr Flhocinonldo ------6c,9-Difluoro-lIP, 16c, 17,21-tetrahydroxyprgna-,4-dlene-3,20- dione, cyclic 16,17-acetal with acetone, 21-acetate. - Ca~haIPNaO Fluprednsolone ..... 6c-Fluoro-l5V, 17a,21-trihydroxypregna-1,4-diene-3,20-dione Ca- fluoroprednIsolone. o Flurazepa-r ...... 7-Chloro-1-[2-(diethylamino)etbyl]-5-(o-fluorophenyl)-l,3-dihydro 2H-1,4-benzodiazepin-2-one. Flurothyl ------Bis(2,2,2-trffluorothyl)ether ...... CiHnFsO Fluroxene ...... 2,2.2-Trifluoroethyl vinyl ether ------Flutlazin ------8-(Trifluoromethyl)phenotbiazine--carboxylic acid ...... CzThFsNOjS Fonazino ...... 10-2-(Dimethylamino)propyl]-N,N-dlmethylphenotiazin-2-tSulon- Ci#112NMOS: amlde. Fospirate...... Dimethyl 3,5,6-trichloro-2-pyridyl phphate ...... FuroGeamido. 4-Chloro-N-furfury-5-sulamoylathraniic acid ------CuHnCINOS Fuesi-...... 3,6-Dibromo-N-(tetrahydrofnrluryl)saloylamide; 3,5-dibromosalioyl- CuHnBnrNOs X-tetrahydrofurfurylamide. Gontamicin .... An antibiotic substance derived from Micromonosora purPura, nonspecific.

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27. 1975

HeinOnline -- 40 Fed. Reg. 14044 1975 RULES AND REGULATIONS 14045

Official name Chemical name or description IMoeJulrp nula

Gloxazone ...... 3-Ethamy2oxoburldobydehis(thltarfbao); a-cihloxy. cathaNgOS2 ethyiglYoxal dioslcarasone.pyraaosp...... Glucosmne...... 2-Amino-2-deoxy-*--glu COTSUNOs l fon y yeo - Glyburldeei ...... I -nyldr=;-(. hloro- Ar.. -(8*1CthWwdo)ethyl] henareo~ o)-ctiyl) bcnzo- CnunCluOaS sulfonyl-N-cyclobexylure. *Glycopyrrolate -.... 3-Eydoxy1.-dlmetbYlPyrrolldialum braoido a-cyclopentyl. CisThelrNO -3,6-Dlhydro4-mehyl,1 (2H')-pyridyl) ethylluanidine...._-,. Gnae.llna ..-...... 14-iotxapirol[4. dwo-ylmcthyl) unndino ...... Guanadrel- 4 chlorphyl)4hydspldno]4'fluoouyro- Ha1loperidol ...... ---- C'nlinClFN0 phenone. Halquinolis ------5,7-Dlehloro--qulnolno, 5-chloro-S-qulnoln oand 7 chloro-&- CiUsCl.W end quinoUnollrnportions resulting naturaly from chlozlnatian ot C,IaChNO- Hetaclln .... .n - 642. Imoth--oxo4-phenyl.l--mdzolldlny!).3,3-dlmelhyl.7.o-ro- CuUn0 S 44hia-l-nzylcyclo!3±0]bcptane-2-ccrboxllareld. Hexafluorenlum .. Hexmothylenebf[9uMao nyldlmethyiam tmluIon ...... Hou I...... zl 2 .... 2-Hydroxy-2-bIt4nylpopyl 4-(,7-dicthby4-qulnzo=nyl)-- CuHnN',Oa plperazlnecmrboxylute. Hydroxcobalamln.. -- Cobfnm do hydroxide phosphate, 31.estcr -with 5,04dlmclhyl-l-a- D-ribofumnosylendmildaol ner l Cu.lleCsOs P Hydroxyure .es ...... Hydroxyurea ...... r.st...... Tuprofen .. e...... p-Isobutylhydmtroplo acd; 2(p-l obutylphnyl)propIonI*dc... ctasol so...... The sodium salt of asulonted delvutveof bItum iss o ... Idoxuridin n e-...... V'-D eay-,54odou idino...... add ...... Indomethain ...... NJ.1-p-Chlorobenoyl)-Dlethy l.l-p -,eaylde..cthylm .ethoxy.M2-mthyllnd! o3-cctln...... C.sllChNO ludriline...... CuliuncOn Inositol niaG;iate.. inypo-lao:sital hexanco~te Cu~uCINOs Iocetal acd.... -Acetyl--43-n o-2,4,-tlp -mthyl-L ...... Iodamide-...... a,5-1|l ,tamido-2,4,G4diod o-tn- le add ...... Iomethn I 125...... 4-13-(DImethylamino)propyl] naol-7.4odo-ml.qu lnau ...... n. CuuhslN3 (tnwhlCh the iWdinn atom Is ml). IomethinI 13L.... 4-3-(Dlmethylomlno)propyl mlno)7-4odo- J3uloll...... Czj UInW (In whlc zS3).the Iodine atom Is lopydol ------. 1-2.3Dlhyd rpopyl-3,5.dllodo (L).pyyddo ...... C Ie-zNOz Iopydone ...... 3,5-DIIod- .yldoneod o-iA'-m ...... thyllsopht CeHsI0NO Iothalanme add...... 5-Acetaceldo-,2v haamle c~d...... ------...... cang 1of Ironorte..ro Asell ofolda ton of a compe of trlvalcat Iron, =rbltol, and dtic asld, st bil idwith dextrin and rarbitl. Isoetharnae...... CnIhN0z - 3.4-Dlhydro1x -(Isopropy ftropylbentyl alcohol ....l. Isomylamnn ..... 2-(Dlethynino)ethyl 1.sopentyly lobeaecaboxylate-...... "Iaafunglla ...... -An ntiblotlsub tance derived from Srupjn-gc toar=Anufs strain. kala. Ketoami...... (- -)-2-(o-Chlorophenyl)-24-methyl.mlno)cycloxon e...... CIU LICINO 3-Ethoy-Ildlhydroxy-2-butanono ...... ClanOt Ca1MNIO Ketlpramla ...... n 543-(Dlmethylxn-lno)propyll]5l-dlhydro-4.dnlaz[&,j.o pln- 10-one. Kitasamyc lh------An ntlbiotic substance obtained from culture of &.rtc=y kliascztoensis. L vam.eiae... 4) -a-Methyl phenothyLamne ...... Levodop ....p ...... )-3-(3,4-D lbymxyphenyl)aynnhn ...... l ...... CsHuNO. Llcomyclt...- An ntibioto substance derived from S rep fowv W.lzw methyl &1._deoxy.-.(.mthyLrons-ipropyl-.I2-pyrorlldia - carboznmldo)-thlo-D-erthiD.gAlaioocopynnosde. Mei ------..A mizture of. Sodium liothyronino (sodium .--3, trodothyro- CtsUTjNNaO, sad nine) and sodium levothyroine (rodium L-3,"5,V-tetrnlodo CuOeNNaO. -thyronIno). Lithium carbonate.... Lithium c ...... rrbobota LbaCO3 Lomofungnn --.------. An antiblotiosubstace derived from &rtezVycero. ndtWr var. tomondmuis. Lorazepam ...... 7-Chloro-5o-cblorophnyl).3-lb dro-3-hydromx.2 L.4-b.odi. ue pln-2-one. Lucanthone....-...... -[[2-(Dlethytano)etyll lnoel4-methylthl ioxat-cngo ...... LypressnLydimycln ------...... An antibioticva.opre substance in------derived from ------rel o ' Icfteu...... ------Mafenld d e...... A nl no o ...... CXHO lagaldrato ...... Tetrakis(ydro n lum) decahydroxydlaumlatodihydmte.. AisHiillgOzr2h Mebutmt- yl-I or .-methyl-2- 2..e.o..utyi..metscbt1l3-prop~nool ropanedlol dlca,-bamote. dIcab-te; Mecrylate_ ...... -- --- Mehl2-yn rylato...... Moedae psm ...... -- -hl hy's-dro-l-et hyl- ,-phen y l.I-. 4-et- tplano 6=;methyl pre -Pcuo-3, -ddono...... MedrysoneMefenmoc ...... d.___ X...2,-y nIath9ll adcd ...... CasIuCD4 Mefenorea...... de... ropI)-a-meth hcthylnlno ...... Mefoxamido ...... ---- o)2WetaWil t*llr-{pmetho.z'-ph ory)a.ctaal do ...... CuHuNSO Melltrace-...... NA0.10-Tetamethyl-A (10 ,-r-nthneepropynalao; 9- Cn~heN dimethylanilpropyidlno)-0,0-dlmtbyl-, 0-dLhydro=-

Melphalan...... v-3PI s(2-clorocthyl)amlnopheUnyll n ...... CunzcI5 s'.z0

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14045 1975 A 14046 RULES AND REGULATIONS

omficial name Chemical name or description IMolecular formula

Memotine ...... 3,4-Dihy&o-l-[(P-methoxyphenoxy)methyllisoquinoline ------...C17HIIN02 Menoctone ...... 6-(8-Cyclohoxyloctyl)-3-hydroxy-l,4-naphthoqunone ...... Mephenytoin ...... S-ethy-3-methyl-5-phenyhydantoin ----- ..------CuluN02 Mepredrdsono...... 17,21-Dthydroxy-10f-mothylprefn-i n - . Mequidox ...... 3-ietbyl-2-quinoxalnemethanoi 1,4-dioxide ...... CioaiN:OsCnH2303 Mesoridazino ...... 10-2(1-Mthyl-2-piperidyl)thyll-2-(methylsulfiny1)prnothiazin.-.. Mestranol ...... 3-Methoxy-19-nor-17apregna-1,3,5(10)-txien-20-yn-17-o ------CnHnNiO52 Mesuprino ...... 2'-Hydroxy-5;-[l-hy.&oxy-2-[(P-methoxyphenothyl) anino]propyl] methanesulfonanilldo. Metabromasalan... 3;-Dlbromosalicyla d..ido.------CtUHBrsNO eietalol...... 4 -[l-Hydroxy-2-(methylamino)propyl]methanesullonanil de ...... CuisN203S2 Metaxalono. ------543 5-Xylyoxy)methyil-2-oxazolidinone ...... CllisNOs Metformin ...... 1,1-bimethybI-g-ndo...... CWtuNs MethacycIlno ...... 4-(Dimothylamaino) -1,4,4a,5,6a,6,ll,12a-octahydrc-3,5,10,12,12a-ponta- hydroxy-5-methnylne-1,l-dox-2-naphthacenecarboxamide; CvnllNaOs oeoxy-6-demothyl-6-methyleno -oxytetracyclino. Methalliburo ...... I-Methyl-6-(l-methylalyl)-25-djtliobiura ...... CntuNXOCrHuN4 S, Mothaqualone .------2-Methyl-3-o-tolyl-4(3H)-qulnazolnono ------:.---- CnnNNS Methlxene ...... l-Methyl-3-(thioxanthen-9-yimothyl)pipeddline ...... Methoxyflurane ...... 2,2-Dicllro-,-dffluoroethyl methyl ether ...... Methyldopa ...... 1-3-(3,4-DI hydroxyphenyl)-2-mothylalanine ------Metlapino ...... 2-Mthyl-U-(4-methyl-l-piperaxinyl)dibcnzoi.flI,4]tliazepno ...... Metizolino ..--- --.- 2-[(2-Methylbenzo[b]thlen-3-yI)methyll-2-1midazoUne ------Cu0HC1I~N2S Nz0, Metolazono ------7-Chloro-,2,3,4-ttrabydro-2-methyl-4-oxo-3-o-tolyl.quinzoline- C2HaOlN20C13ISUNS sulfonamide. Motoserpate. M.thyl ll,l7a,18a-trmethoxy-3V, -yohmbaa-ic-carboylato .... MetronIdaole...... 2-e thyl-5-nltroinidazole-l-etbano ------C24113iNs0sC&HtNaOs Mianserin...... 1,2,3,4,10,14b-Hexahydro-2-metbydibcnzolc,f]pyrazino[1,2.a] azopino. Cu~sNaaCullN '0 Midaflur ...... 4-Amino-2,2,5,5-tetrais(trflaoromethyl)-3-inidazoline ...... 'Mlipertine ...... 5,6-Dimethozy-3-[2-[4-(o-mctboxyphenyl) -1-plperazinyl] etbyl]-2- CnCsihfuN3 HnNa methylindole. Minocyclino ...... 4,7-Bs(dlmethylamino)-l,4,4a,5 Sa,6,11,12a-cctahydro-3,10,12,12a tetrahydro-1,11doxo-2-naphthacencarboxamid. Mitbramycin ...... From Sireptompces argillaceus nsp.and zireptomyces tanas isw-....Czs~uN,0, Mltocromin...... An antibiotic substance produced by Strepomyrccs rirfidochromogenes. Mitomalcin...... An antibiotic substance produced by Streptemyces mnalayils ...... MItotano...... 1,1-Dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)etbano ...... Molindono...... 2-3-Ethyl-6 -Ethyltetrahydlro-5-[tetrahydro-3-methyl-5-[tc 7-dibydro-2-methyl-5-(morpholinomethyl)Indol-4(5H)-on. trahydro.G. CjsHlsNi02 Monensin...... nydroxy-6-Phydrozymethyl) -3,5-dimothylpyrn-2-,yl]-2-furyl]-2- furyi]-9-hydroxy-P-methoxy-a,, 4,5j dccanc-7-butyric acid. 2,8-tetramethyl-1,6-dioxmspiro Morantel ...... (A) -1,4,5,-Tetrabydro-l-methyl-2-[2-(3-metbyl-2-thlenyl)vinyl] pyrimidine. Nadide ...... 3-CarbamoyI-l- -D-ribofuranosylpyridinium hydroxide, 5'-ester with Cn~HviOiiPz adenosine-5'-pyrophospbato, inner salt; codehydrogenaso I. 1'afci n...... -- 6-(2-Ethoxy-l-naphthamdo)-3,3-dimetyl-7-oxo-4.tha-l-zxbl- CnHnNiOS cyclo[3.2.0]-hoptanc-2-earboxyliciicid; 6-(2-ethoxy-l-naph- thamido) ponleillanic acid. Nafronyl ...... 2-(DIethylamlno)ethyl tetrahydro-a.(l-naphthylmetbyl)-2-fumnpro- Plonate. CnhUN0t Nalbuphine ------1-E17-(Cyclobutlmethyl)-4,569poxymorphnan-3,6a,14-trioI thyl-l,4-dihydro-7-metbyl-4-oxo-l,8-naphthyrdlne-3-carboxylic ------Nalidixic acid ...... acid. CziHUaN0a Nalmexono ...... 7,7a,8,9-Ttrahydro-3,7a-dhydroxy-12-(3-methyl-2-butnyl)-6H-S,ec- imlno-ethanophenanthro[4,-bed faran-5(4H).-one; .N-3,3'- dimethylallynoroxymorpbone. - CnHinNOt Noloxon . e ...-. (-)-17-AIyi-4,5 aoxy-3,14-dibydroxymorphina .-6-one ...... Nandrolono ...... 0-11ydroxyester-en-3-on ---- -...... ------...... Naranol ...... 8,9,10,11,l1a.12-Heiahydro-8,10-dmethyl-7aH-nphbol[,,.,:5,1 pymnoI3,2-c]pyridin-7a-oL. Nebramycln ...... An antibiotic substance derived from 'treqmyc=? tcnetrariw ... Nequinato...... 3-Acetoxy-6-butyl-7-benzyory4oxoquinoinoi. . -..--- Nifuraidezono-..... C,N,0OsCt2UNOt Nifurimido -----.- )-4-Metbyl-l-(-nitrofufurylidc~o)amin]2 doldnon--- Nifnrsol...... - 3,6-Dinitrozalicylic acid (-nitrofudlyHdcn3)bydrazido....-... CfON40tiC2uII4CO Ninzone ... L..... 3-(P-ChIorophnyl)-4-mino-2-oxo-l-m dzoldin c eitonitrIle...... NIrldaolo ...... 1-(5-Nitro-2-thLzolyl)-2-imidnzolIdinon . NIsabamte. _ Isopropylarbamia acid ester with 2-(hydroxymc1.hyI)-2,3-d1meth- yipentyl carbasnabs Nonoxynol 4- - NonylphenoxypolyethyleneoxyethanoL ...... CISUuO(CHO). 4n=approximately Nonoxynol 9 -- -. o...... - - --... cu IuO0(C,h0O),, (n=approzimaely N onoxynol 15 ------do...... CzISH0(COud0), (n=pproxlmntely 15) Nonoxynol 20 ...... ------(n=approximately 30) NorothIndrono ------17-Hydroxy-19nor-17-pregn-4-en-D-yn-3-ono ...... C ul' O NoretbynodreL ...... 17-Hydroxy-19-nor.-17a-pregn-5(10)-en-20-yn-3-ono; 17-ethynyl.17- hydroxy-6(10)-estren-3-one.

FEDERAL REGISTER, VOL. 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14046 1975 RULES AND REGULATIONS 14047

OflllaeChema nor dczrptloa Moulr fmuk,

Noreiurane ...... l ,-l,2-Tetr-luorebe ...... C,,I=O, Norestrel...... (h)-I-Ethyll 7-hydrory-18.19dL r-7Ia pr.l n.20-yn..o o... Norrptyllne Ih N.methyl-5tfdbco~odlo.cptr.A,. ]C:..F4 a. . , Orylto_ ...... Ucryc u-cyanacryine...... ICrillnOtP urnNO Oetlclzer...... 2-Ethyihexyl diphenyl phcphato...... Octodrlne ...... C11111,; OplpraioL ..... 443-(61t-dibeazjbt~xpln.@ roy.Gppmneeln . . 0rgoteln ...... A pure, water-soluble, hlghy compact pr lcn of Likly law mrec- ular weight (about 34,000with a pedomInantly lph.hclcal confguraUon; the molecule is eh.ated ith from tro (2) to four (4) atoms of dlyalcut xaetals, for example, Mg,Zn. and Cu, and Ormetoprin ...... It is presently produced from bovine Ilver In a multistep pr-z. Ozandrolone ..... 4-Dlinorncthylvetrl)pyrimldn --...... Oxarepasn...... 170-Hydroxy-7-methyl-ama drotan-3-o--n-o- Cu11:3Oi Ozethazalne ...... 7-Chloro-dlhydroydmsy4 bc yl-21-1,4-cmodLc pln-2-one. CuIuCIN:O2 2,2'-methylaeaadHydroxyetvl)mieHL?! '-lm- cthylphccthy-).NV- Oxisuaran..... (Methyrsulflnyl)methyl C-pyrldyl ketne...... CzsHsON30C i~iNO2 S Oxogestone...... 20H-Ilydrory-19-norpregn-t-cn--one;p-hydxy.l-nor-- CtUlfNOs Oxprenlol...... Cirilu0a l-i-ylxy)phenoy].6(sopopmnno).propnal.----9 ._ 4 Oxyhlorosen e---.... The hypochlorous add complex of a mlxturo of tha phenyl vulfanate iCrellNOg Sderivatives of allphlUq hydrocarbon. CuaIgn..s Oxycodone -----.---- I Dlhdrohydrozy on ...... cruUnNol Oxymetzollne-.- Oxymetholone ..... 17-Hydroxy-2-(hydroymet 5,-Dmethoxy-2mcthl-3-I2(4-pheny1.l-l5,0 ]D.metha ylene)-17a-mthyl-Ecandrotan-3.-ae. ra y)cthl]-di.. CnlI=O Oxypertlne .. CMUC,.,NhOt Pancrelipe ...... A concentrate ofpanreatri enzymes tandsrdu frlipa mcontcaLt Pancuronium .----1,1-{Sc, 17P-DIhydroxy-.5a-androstan-2, IC;.ylcne)hbi5.methyl- CnUh2N10, plprldilalum Ion diacetate. PanthenaL ...... _. (+)2,4-Dihydroxy-Ar(3-hydroxypropyl)-3,dldmcthylbutymlde; pantothenyl alcohoL Paramethasone ...... Ga.Fluoro-lp,17,2-hihydro xy-l1c-methylprc .1,4-lcn--3-O. Cr.UnFOs dione. Parbendazole ...... N-:Methlyl-NMethylk-butyl-24aelnldazolc..baatc...... 2-propyaylbczylaraie ...... Pargyline_ -.....-. CuHuNaXOX Pemollne ...... Pencllamlne__..... Al-Mercaptovaline.-...... o-5Carb-moyphenethylln 42l34..rboxyamm...... CsIIUNOiS Pentagastrln. -..... 34ndol-3.ylpropioannmldoj-(mcthylthlo)hutyraml 9o1cdnamlo add N- a tylest. N-f lr-butyl rbonyli-lnyl.etrypto- phyl-L-methonyl-s.partyl.L-pltnyly lne asWde. Pentazo e ...... (-&)1,2.,3,4,5,.6-Uexhydr.cd-6,1I-dlmethyl3-(3mchyl.O0butenyl)o 2-(2,2Dcycloexylethyl)plpedine...... 2,6-methano-3-benzazod.-oL Perhexilene...... CizUz:AN Perlapine...... -(4-Methyl-l.p praxlnyl)zmorph nthrdi.ne...... Phentermine --. -. a,a-Dimethylph nthylamln ...... Cn~H~nz PhenyramidoL ...... a-(2-Pyridy afno) methyllbcnylalho ...... Phthalofyne ...... Mono(I-cthyl-I methyl-2-propynyl) phthaato...... Pimozide ...... 1-l,4-B-fl uaropheyl) buty Ipp .tdyl.l mhlmdzoI maone; l-l4,4-bs(v-fluorpheayl)butylI+(-oxo4.h~cnlmdazoUny)plpcr idine. SCa=ha OaS Pipazethate...... 242-Pperldlnoethoxy)etbyl IOf-pyddo3,2]-&l[i,4bct,zo .ne. Calux~~ Pperacetazine ...... 1043-[4-(2.-Hdrozyethyl)plpcldlno] ppyliphenothbazdn.2.yl methyl ketone. Plprozolln ...... Ethyl 3-ethyl-olo-s-pcridlno-Al-thtalodinint e ..... Cti1Er.'O0S PIquiL-...... Isobutyl 4(.-dlimethzy4-qulnazol yl) .&pnvlanecx bylnto... Polacrilln ...... A synthetle oa-chnn resin prepaed through the polymcrlr- tlon of methacryito add and divlnylbeaznoe and uppUd In the ----. o...... hydrogen orfreeadd farm. PolarerlIn potassium.. The potassium salt of a synthetic Ion.exchange redin derived through the copolymerlzatlon of methacryllo cdd and dlrlnyl. benzene. .--- Poldine - 2Hydroxymethyl).,l-dlmcthylpyoldlnlam bcn.ali--e. .... ,"..... - C NO Pollgeeaan ...... --3,6nh-ydro 4O3-.Palactopyrsyl-a D Aliopynom2 4!.bI LCuHuMzOu.%]. (pot.sstumsodlum sulfate (l-.poly de.c waher-aMNa of K Poloxalene ...... uld nonloalsurfactant polymer of uthpolyoyppylne paly-. ozyethylene type*, having an average moleul cbt, of uXO. Polyg ycoll acid. - Poly oycarbonylmethylene) ...... (CIoMOO. Polymacon ...... Polybydrayethyl metlaryLte ...... - (Ca.nO7). Polyte.-...... ol(tetafluoroethylene) ...... (CWF&) PolythazIde .. .. 6-Cloro,4-dlhydxb--methyl-3-12E-10 -bnzothadazn-7-sulf t(.I%22-sfloaroethyln-mlo l,l-dWWea. Ulo]-mehyll-I CHunCIF3NaOiSs Poncuroniam ------l,1.(3a. I7.Dlhydrozne drt.Z,Cyne)bsl-metbyl CuutusTiOe piperldiniamldlncetate. Pordane...... Polyvo...pyrroltdne ...... + ...... Pralidoxime ...... -ormyl-methylpyrldlnlumlme...... [C O Prednival ...... 1721-Trihyd pro nn-ldn,o2Dl=on 17.veliemto...... l=EnO& Pregnaenlone -..... : 3 dyen-n-on...... CailnOs Prlocalne ...... 2-(PropylIno)-o-proploaptolUldlde ...... CuHZ-qO Procarbazlne-- ..... rpyl-a.mthylhydx, .tolunmld...... C lN Profladol...... - y(thY3-p1pyI3-pyrroldlnyl)p he-ol...... CzHnNO

FEDERAL REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14047 1975 14048 RULES AND REGULATIONS

Official name Chemical name or description Molecular formula

Proplolactone ------2-Oxetanone; P-propiolactone C3110 2 Propranolol ------l-Qsopropylamlno)-3-(-naphthyloxy)-2-propanoi ...... CifnNOs Protriptyllne ------N-Methyl-5H-dlbenzoia,d]cycloheptene-5-propylamina ...... Pyrante ------(E)-l,4,5,6-Tetrahydro-l-methy-2.f2-(2-thIenyl)vinyl]pyrlmidlne.. Cn2HSINI Pyrithlone zinc ------Bls[lI-hydroxy-2(IH)-pyridinethlonatolzinc ...... CiollsiNOC,3 lsN:03S2Zn Pyrrocalne ------il-Pyrroldineaceto-21,6'-xylldide ...... PyrrolIntrin------3-Chloro-4-(3-chloro-2-nitrophenyl)pyrrole ...... C,)H60l3Ns0i Quazodine ------4-Ethyl-6,7-dlmathozyquinazollne; ,7-dimethoxy-t-ethylqulnazoline C,,UInN,0, Quinaldine blue-.---'- 1-Ethyl-2-[3-(l-ethyl-2(1l) qulnoylldene)propcnyl] quinolinium C01ninOC2sHsCIN B chloride. Quingestanol ------3-(Cyclopentyloy)-9-nor-17,-prgna-3-dilen-2.)-yn-17-o .------C23f, 102 Quint ol .ne------8-Hydroxy--.(isoropylamino)methyl--uinolinemethsuol... Racephenicol ..-... (-)-threo-2,2-Dichloro-N4--hydroxy-a-(hydroxymethyl)-p- (mathylsulfonyl)phenethy] - a . Ranmycin ------An antibiotic substance derived from Strepomyces lnconensts-.. Ribaminol ------Rlibonuclelc acid compohnd with 2-(diethylamino)ethanol; 2- . hydroxytriathyan ibonucleate. lboprine ------N-(3-Mat hyl-2-butenyl)adenosine; 6-N-(3-methyl-2-butenyl- Cos,O. amlno(-9-*-n-ribofuranosyl-purino. CseHgOIN0 Rffampin ------5,6,9,17,19,21-Hexahydroxy-23-methoxy-2,4,12,16,18,20,22-hepta-inethyl-8-[N-(4-mcthyl-l-plperazinyl) formimldoyl]-2,7-(opoxy- C12HeIsCNOSCanUsitOis pentadecall,11,13]trienlmino)naphtho[2,1-b]furan-l,11(2)-dione CaunCItNO 21-acetate; 3-(4-methylplperazinyllminomethyl) rifamycin SV. CirlrN03 Rtodrine ------Erytro-p-hydroxy-a.-[(p-hydroxyphenethyl)amino]ethyl]benzylalcohol. Ronidazole ----- (1-Methyl-5-nitroimidazol-2-yl)methylearbamate ...... Co~sN4O4 Rotoxamlne------. 1-2-lp-Chloro-a-[2-(dimethyi mno)-ethoxy] benzyllpyridine ...... Roxarsone .------4-Hydroxy-3-nitrobnzenax~enic acid ...... Salothamide ------N-12-(Dlethylamino)ethyl]saUcylamlde ...... SBperidol ------4-[4-(4-chloro-a,a,a-trifluoro-m-tolyl)-4-hydroxy-plperldinoi-4'- CnHnCIFtN0s fluorobutyrophenone; 1-[3-4-fluorobenzoyl)-propyl]-4-hydroxy- CuHnuNO 4-(3-trlfluoromethyl-l-chiorophenyl)-pipcrdlne. Silandrone ....-...... 17P-(Trimethylsloy)androst-4-n-3-one ------CnilsO=st Simethteone ------A mixture of dimethyl polysiloxanes and silica gel ------Botalol ------4'-f1-Hydroxy-2-(lsopropylamino)-ethyl]-methanesulfonanlido ...... Soterenol ------2'-H-- ydroxy---ydroy-2-(lsopropyla iao)ethyllmthano- sulfonanllde...... CisfHuOI ..o Stanozolol ------17-Methyl-Se-androstano3,2-c]pyrazol-17P-oL. ------Steffimycin ------An antibiotic substance derived from Streftomes steffisbzrgenSts CutHnN0O 3 var. atefisburgeasissp.n. Sulfadoxine ------NV-(5,6-Dimethozy-4-pyrlmldlnyl)sulfanlamld --...... CtsWN0 48 Sulfameter ------N 5-Methoxy-2-pyrlmldlnvl)ulfanflamlde ...... CsHuNOs Sulfamoxole ..-...... ID-(4,5-Dlmcthyl-2-oxazolyli)sulfananlde ....------CasH13Ns, Sulfanitran. .------4'[(P-Nitrophenyl)sulfamoyl]acetanilde-- ...... CsHuNaOsS Sulfazamet ------NL(3-Methyl-1-phenylpyrazol-5-yl)sulfanilamlde ------Sullsobenzone ..---- -Benzoyl-4-hydrory-2-methoxybenzenesl fonlc acid ...... CIIH11o69 Sulpirde ------N-[(1-Ethyl-2-pyrrolldlnyl)mcthyl]-5-sulfamoyl-o- nlsamide ...... Surgibone ------Bone and cartilage obtained from bovine embryos and young calves. CIOU2103S Terazepam- ...-.... 7-Ohloro-1,3-dlhydro-3-hydroxy-l-methyl-5-phanyl-2H-, 4-benzo- CuthsOlNs0z diazepin-2-one. Testolactone ------13-Hydroxy-3-oxo-13,17-seceandrosta-l.4-dlen-17lc acid 3-lactone ...... CnB'it0s Tetrydamine ------4,5,6,7-Ttmhydro-2-metbyl-3-(mothyliamno)-2H-indazole; 2- CPHuNs methyl-3-mathylamino-4,6 6 7-tetrabydroindazolo. --F -t ro,2Dlelo o-.N'[-ydroxy-a- (ydr oxymet hyl) -p- ThiaraphenicolThimpsuel...... ------(methylsul)he onyl)-phenethy)]acetamide. CasaCssuN,SCISNrOB Thioguanine ------2-Aminopurine-6-thlol,homlhydmte ...... Thioridazine ------i-2-(1-Methyl-2-plperdyl)thyl]-2-(mthylthlo)pbenothiazine ..... Thiosalan ------3,4 ,5-Tribromo-2-mercaptobenzanlllde; 3,4',S-tribromothiosallyl- GaflaNsS,3CuHsBrNOS anilde. Thlothixene ------,N-Dlmethyl-9-[ -(4-methyl-l-piperazinyl)propyidene]tblo- zanthen-2-sulfonamide. Thiphenaml ------812-(DIethyIamino)ethylj dlphenylthloacetate ...... Thira -.. ..------las(dlmethylthlocarbamoyl) disulfide ...... Thonzonium...... -.... Hexadeeyl[2-[(p-methozybenzyl)-2-pyrimdinylamino]ethyl]- dimethylammonlnm Ion. Tibolone ...... ------17-Hydrory-7-methyl-19-nor-17a-pren-5(0)-en-20-yn-3-one ...... Tibrofan ..------.. ,4,5-Tribromo-2-thlophenerboxanlde; 4,5-dlbromothlophne-2- CsHaBrsNOB carboxyl-4-bromanlllde. Tigestol ------1Nor-17a-pregn-(1O)-en-20-yn-17-ol; 17a-othynyl-5(10)-estrn-17- CaU2NOS Tlletamine ...- 2-(Ethylamlno)-2-(2-thienyl)cyclohexanoneoL ...... Tilidine ------Ethyl 2-(dlmethylamino)-1-phenyl-3-cyclobezene-l-carboxylate ...... Tinldazole ...------1-2-(Ethylsulfonyl)ethyl]-2-methyl-5-nitromidazole ...... CI[IHO.CItNOa TocamphyL------1-(p a-Dlimethylbenzyl) camphorate 1:1 salt with 2,2'-lxlnodl- ethanol. or Cu=[aNO, Tofenacin ------N-Methyl-2-(o-methyl-a-pbenylbenzyl) -oxy]cthyla-ne...... CTH,,NO Tolazamide ..- 1-(Hxahydro-lH-azepin--yl)-3-(p-tolylsul onylur -...... CHUNOSCufHuNs0=s Tolnaftate ...------0-2-NaphtbyliN-dimethylthlocarbanlate ------Tramadol ------(.)-trans-2-[(Dmthylamlno)mthyl]--(s-mt hoxyphenyl)cyclo- CnHuaN,Cn'H N hexanol. CuHCIN0O Transclomipbone ---- 2-[p-(2-Chloro-trans-l,2-dphenylvinyl)phenoxy]-triethylamlno -... CouflnrNO Triamtorene ...-..... 2,4,7-Trlamino-6 phenylpteridine ...... Tribromsalan ...... 3,4 5-Tribromoaallcylanllde ------CuHsBrsN0jMss~aCIasO Trllocarban ...... 3,4,4'-Triclcorocarbanlllde -...... ------...-. CnHoGhNiO

FEDERAL REGISTER, VOL. 40, NO..60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14048 1975 RULES AND REGULATIONS 140-49

Officlal name . Chenlea namo ordescdptlon Mo!_-aart-rmnaI

Tilofos ------2,12,-Trlchloroethylilihydro.e n~ Clath~Oj Trflocin -...... ---- . CahsFzNO± Trfllmldate...... Ethylm-beazoyl-N4(trfluorometbyl)1onlJ ...... CanHF OlS TrifluperldoL_- ...... 4'-F ouro-44-hydro'-4-{aaA-tdI u- .- yl} pipefinol C=U=F#NOJ3 butyrophenone. Trtmlpramine ...... 5-3-(Dlmethylmno)--methylppyl.1-dlhydo-SHilben - Czlu:u,;2 Ib..jazeplae. Trloxisalen --...... 6-Hydroxy-.2,7,-rimethyl-5benluraa= c ad, -blcn ...... C:zutnOz Tromethnmine ------2-Amino.-Y hydrOXyMethyl).1,3-prop~edloL ...... CsHtuN0z Troplcamide. ---- .. -E thyl-2-pheayl-(4-pyridylm eth y)-bydrryamldo...... CuiaNoOs Tybamate------2-Methyl-2-propyltrime yleno butylcrbamate cbamote; or 2- Csua-ioOd (hydroxymethyl)-l-methylpentyl butyleazbiato carhbmatc. Tyloxapol.- ...... - p-{l,3,3-Tetra nethylbuty)phenol polymcr with famaldebyde, eter with pol yethy lene &Icol. VerapamiL ------,[(3,4-Dimethotyphenextyl)mothyhmlno].2.(3,4-dlmethaoyo Cv.]3'1) 4 VlablasttneVinbistin..------pheny1)-2-1sopgyvalcxan~trifeClUo. -----...... (v Ceukolatine) extractdfrom / ric : ...... CalmuvTOs Vincristine ------Alkaloid from Vtnca rosea. Lion ...... C'Hsun'KOa Volazoclne ..-...... 3-(Cyclopropylmethyl)-.2,3,4.5,0-heoydro-ts-ll.d/metbhyl.,- CuluN meth no-3-benzazoetne. Zolamlne ------2-[(2-Dlmethyamlno)ethyl](p-mc.oxyubnyl)amlno]tbhb.o:. CijnXIOS

No .--Incorporation by reference materials approved by the Director. Offtce of the FzDPaAL REGS March 20. 1973 and March 25. 1975. [F& Doc.75-7952 Filed 3-26-75;8:45 am]

FEDERAL .REGISTER, VOL 40, NO. 60-THURSDAY, MARCH 27, 1975

HeinOnline -- 40 Fed. Reg. 14049 1975