The Code of Federal Regulations of the United States of America

§ 3.43 Phenindione; labeling of drug preparations intended for use by

man.

(a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that phenindione, a synthetic anticoagulant drug, has caused a number of cases of agranulocytosis (with two fatalities). There are also reports implicating the drug in cases of hepatitis and hypersensitivity reactions. In view of the potentially serious effects found to be associated with preparations of this drug intended for use by man, the Commissioner of Food and Drugs will regard such preparations as misbranded within the meaning of section 502(f) (1) and (2) of the Federal Food, Drug, and Cosmetic Act, unless the label and labeling on or within the package from which the drug is to be dispensed, and any other labeling furnishing or purporting to furnish information for use of the drug, bear a conspicuous warning statement to the following effect: "Warning: Agranulocytosis and hepatitis have been associated with the use of phenindione. Patients should be instructed to report promptly prodromal symptoms such as marked fatigue, chill, fever, and sore throat. Periodic blood studies and liver function tests should be performed. Use of the drug should be discontinued if leukopenia occurs or if evidence of hypersensitivity, such as dermatitis or fever, appears."

(b) Regulatory action may be initiated with respect to preparations of phenindione intended for use by man found within the jurisdiction of the act on or after November 25, 1961, unless such preparations are labeled in accordance with paragraph (a) of this section.

(Secs. 502(1), 52 Stat. 1051, 21 U.S.C. 352(f)) [26 F.R. 9041, Sept. 26, 1961; 26 F.R. 9131, Sept. 28, 1961]

§ 3.44 Aminopyrine or dipyrone drug preparations for human use; directions and warnings.

(a) Because of the increasing number of reports of fatal agranulocytosis associated with the use of aminopyrine (4dimethylamino-2,3-dimethyl-1-phenyl3-pyrazolin-5-one) and dipyrone (1phenyl-2,3-dimethyl-5-pyrazolone-4

methylaminomethanesulfonate sodium), the Commissioner of Food and Drugs convened an ad hoc Committee on Aminopyrine and Dipyrone. The members

of the committee consisted of authorities in the fields of hematology, internal medicine, neurology, pediatrics, and pharmacology. This committee considered the questions of safety and effectiveness of aminopyrine and dipyrone and reported its findings and recommendations to the Commissioner of Food and Drugs. Copies of the committee's report and recommendations are available upon request, directed to the Office of Public Information, Food and Drug Administration, Washington, D.C., 20204. The committee found:

(1) Aminopyrine and dipyrone, a derivative of aminopyrine, are capable of causing and have caused fatal agranulocytosis.

(2) Relatively small amounts of these drugs given intermittently over a period of time, as well as regular and continued administration, can precipitate the reaction of agranulocytosis.

(3) In most instances, other antipyretics and analgesics that are much safer should be used in preference to aminopyrine or dipyrone.

(4) The only conditions in which aminopyrine or dipyrone are known to be possibly indicated are febrile convulsions in children, where a parenteral antipyretic may be needed, and in rare instances of Hodgkin's disease and similar malignant diseases in which the fever cannot be controlled by any other means. (b) The committee summarized its recommendations as follows:

1. It is recommended that aminopyrine and dipyrone for the present be retained on the market, but that the following statements be included in the labeling of the drugs:

All brochures, mailing pieces, detail pieces, advertising, and other labeling should contain the following paragraphs, in this order: Warning-THIS DRUG MAY CAUSE FATAL AGRANULOCYTOSIS. (This should immediately follow the name of the drug.)

Caution-This drug should be used only in those conditions in which it is specifically indicated and in which other less toxic drugs have proved ineffective or are not tolerated. The potential benefit accruing from the use use of this drug must be weighed against the possibility of fatal agranulocytosis.

Indications for use. Aminopyrine and aminopyrine derivates (dipyrone preparations) should be restricted for use in serious or lifethreatening situations where salicylates or similar drugs are known to be ineffective or are contraindicated or not tolerated.

Duration of administration. Fatal agranulocytosis has been reported after short-term use, intermittent use, and after long-term administration. Therefore, the use of these agents should be as brief as possible.

Precautions. Frequent white blood cell and differential counts should be carried out. However, it is emphasized that agranulocytosis may occur precipitously without prior warning. The drug should be discontinued at the first evidence of any alteration of the blood count or sign of agranulocytosis, and the patient should be instructed to discontinue use of the drug at the first indication of sore throat or sign of other infection in the mouth or throat (pain, swelling, tenderness, ulceration).

Dosage. Adults: The usual antipyretic dose should not exceed 2 to 1 gram per dose, nor should more than 3 grams total daily dosage be used. If the desired effect is not achieved within a very few days, use of the drug should be discontinued.

Children: 250 to 500 milligrams per dose, repeated in 3 to 4 hours if necessary. Use of the drug should be as brief as possible.

2. It is recommended that every effort be made through educational media to emphasize the identical nature of aminopyrine and dipyrone insofar as toxicity is concerned.

3. It is further recommended that the official name of dipyrone be changed to aminopyrinesulfonate sodium, if possible. The purpose of this is to achieve the objective of Item 2 above.

4. The committee suggests that the panel be recalled by the Commissioner of the Food and Drug Administration within approximately one year after these recommendations have been fully implemented. The purpose of such a meeting would be to ascertain whether the use of dipyrone and aminopyrine and the cases of fatal agranulocytosis associated with the use of these drugs had been noticeably reduced by the method proposed. If the recommended labeling changes do not have the desired effect, other recommendations would need to be considered at that time.

(c) The committee also decided that a letter should be sent to all physicians to remind them of the close similarity and toxicity of aminopyrine and dipyrone.

(d) On the basis of the available evidence, including the findings and recommendations of the committee, the Commissioner of Food and Drugs finds and determines with respect to any drug preparation intended for administration to man that contains aminopyrine or dipyrone:

(1) Such drugs are unsafe and are regarded as misbranded within the meaning of section 502(f) (1) and (2) and section 502(j) of the Federal Food. Drug, and Cosmetic Act when labeled or advertised for routine use as antipyretics or analgesics.

(2) Regulatory proceedings may be initiated with regard to the continued marketing of any such preparations with

labeling or advertising offering such drugs for routine use as antipyretics or analgesics.

(3) Such preparations may be approved as safe and effective for marketing on the basis of new-drug applications containing labeling to the following effect, which labeling differs substantially from the labeling that has been commonly employed for many years in the marketing of such drugs:

(i) The label and labeling of the drug contains prominently and conspicuously, immediately following the trade name of the drug, without any intervening written, printed or graphic matter, the following:

(a) A quantitative declaration of the aminopyrine content; or

(b) A quantitative declaration of the dipyrone content with the name "dipyrone" followed immediately and conspicuously in parentheses by the declaration "aminopyrine derivative"; and

(c) The statement "Warning:-This drug may cause fatal agranulocytosis.” (ii) Labeling on or within the package from which the drug is to be dispensed and any other labeling for the drug that furnishes or purports to furnish information for use, or which prescribes, recommends, or suggests a dosage for the use of the drug, bears, in addition to the information required in this subparagraph, information to the following effect:

WARNING THIS DRUG MAY CAUSE FATAL AGRANULOCYTOSIS.

CAUTION: This drug should be used only in those conditions in which it is specifically indicated and in which other less toxic drugs have proved ineffective or are not tolerated. The potential benefit accruing from the use of this drug must be weighed against the possibility of fatal agranulocytosis.

Indications for use. Aminopyrine and aminopyrine derivatives (dipyrone preparations) should be restricted to use for their antipyretic effect in serious or lifethreatening situations where salicylates or similar drugs are known to be ineffective or are contraindicated or not tolerated.

Duration of administration. Fatal agranulocytosis has been reported after shortterm use, intermittent use, and after longterm administration. Therefore, the use of these agents should be as brief as possible.

the patient should be instructed to discontinue use of the drug at the first indication of sore throat or sign of other infection in the mouth or throat (pain, swelling, tenderness, ulceration).

Children: 250 to 500 milligrams per dose, repeated in 3 to 4 hours if necessary. Use of the drug should be as brief as possible.

(4) A new-drug application for such a preparation should include a commitment that all advertising for the drug will bear the information required by subparagraph (3) (i) of this paragraph, and that any advertisement that provides any information regarding indications or dosage recommendations will include the information required to appear in the package labeling by subparagraph (3) (ii) of this paragraph and will not recommend or suggest use of the drug under any other conditions.

(5) A new-drug application will be regarded as approvable if it contains satisfactory information of the kinds required by items 2, 3, 4, 6, 7 and 9 of the new-drug application form contained in § 130.4 (c) of this chapter.

(6) Regulatory proceedings may be initiated with regard to the interstate shipment of any such preparations labeled or advertised contrary to this statement of policy.

(7) No regulatory proceedings will be initiated with regard to the continued marketing of preparations of aminopyrine or dipyrone under labeling and advertising complying with this section; Provided, That within 90 days from the date of publication of this statement of policy in the FEDERAL REGISTER:

(i) The manufacturer, packer, or distributor of the drug submits a satisfactory new-drug application covering the marketing of the article in accord with this section; and

(ii) The applicant, starting from the thirtieth day after publication of this statement in the FEDERAL REGISTER, maintains records and submits reports in compliance with the provisions of § 130.13 of this chapter, including reports within intervals of 3 months during the first year; 6 months during the second year; and at yearly intervals thereafter. (Sec. 502 (f), (j); 52 Stat. 1051; 21 U.S.C. 352 (f), (j)) [29 F.R. 15364, Nov. 17, 1964]

§ 3.45 Sterilization of drugs by irradiation.

There is a current interest in the utilization of newly developed sources of radiation for the sterilization of drugs. Prior to the marketing of a drug sterilized by such means, it is necessary in the interest of protecting the public health to establish by adequate investigations that the irradiation treatment does not cause the drug to become unsafe or otherwise unsuitable for use. Accordingly, all drug products, including injections, ophthalmic solutions, surgical sutures, and surgical dressings sterilized by means of irradiation are regarded as new drugs within the meaning of section 201 (p) of the Federal Food, Drug, and Cosmetic Act. An effective new-drug application pursuant to section 505 of the act is therefore a prerequisite to interstate shipment of such articles, except as provided by section 505 (i).

(Secs. 201, 505, 52 Stat. 1040, as amended, 1052, as amended; 21 U.S.C. 321, 355) [20 F.R. 9554, Dec. 20, 1955]

§ 3.46 Interpretations of orders relating to dietary supplements; vitamin and mineral-fortified foods; foods for special dietary use.

In the FEDERAL REGISTER of June 18, 1966 (31 F.R. 8521), the Commissioner of Food and Drugs issued regulations in Part 5, Part 80, and Part 125 of this chapter. Following publication, the Commissioner received requests for clarification of certain of these regulations. As a guide to those who may be making determinations as to whether or not objections should be filed to these particular regulations under section 701(e) of the Federal Food, Drug, and Cosmetic Act, the Commissioner issues the interpretations hereinafter set forth. In announcing the confirmation of the effective date of the subject regulations, it will be the purpose of the Commissioner to make editorial changes in the sections involved consistent with this policy statement.

(a) The fact that certain standardized foods, such as enriched flour, enriched bread, etc., do not appear in § 80.2(c) of the order of June 18, 1966 (31 F.R. 8525), is of no significance. Standards already promulgated for such foods are controlling. Section 80.2(g) is not applicable to standards issued earlier, such as that for enriched bread. The standard in § 80.2 (c) for alimentary pastes does not apply to those products covered by §§ 16.9 to

16.12, inclusive, and § 16.14 of this chapter.

(b) In § 80.2 (c), representations have been made that the size portions of fruit juices should be changed from 4 fluid ounces to 6 fluid ounces. Decision on this point will be reserved until additional information is received. All who have data in this area are invited to submit it to the Hearing Clerk, Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue SW., Washington, D.C. 20201.

(c) Under § 80.2(c), a point has been raised that the 8-ounce serving for processed cereals is unrealistic. This specification "8 ounces" is in error and should be "1 ounce."

(d) Under § 80.2(c), representations have been made that infant cereals should be permitted to be fortified to levels above those allowed for whole grain. Consideration will be given to any data received on this point.

(e) It is represented that, in addition to the foods listed in current standards of identity as "enriched" and the foods set forth in § 80.2(c), other foods should be authorized for carrying added vitamins and/or minerals. The Commissioner will consider proposals in this area consistent with the policy outlined in § 80.2(a) if accompanied by reasonable grounds.

(f) In the statement of authority for the issuance of Part 80, section 403(j) (52 Stat. 1048; 21 U.S.C. 343(j)) was inadvertently omitted. That section of the Federal Food, Drug, and Cosmetic Act, together with the prohibition against false and misleading claims and the general authority to issue regulations for the efficient enforcement of the act, are relied upon to support some provisions of Part 80.

(g) With respect to § 125.4(b) of the order of June 18, 1966 (31 F.R. 8521), the term "such food" relates to § 125.4(a). It does not apply to a food which is merely prepared in a form suitable for use by infants, such as pureed spinach, where the product does not otherwise purport to be and is not represented for special dietary use for infants.

(h) Section 125.5(b) applies also to foods that have been standardized (under section 401 of the act) containing artificial sweeteners, such as artificially sweetened canned peaches.

(i) In § 125.5(b) (4), the comparison to be made may be with a comparable item customarily made and sold; for ex

canned

ample, artificially sweetened peaches may be compared with the same kind of peaches in heavy or extra heavy sirup. The regulations do not authorize the marketing of artificially sweetened condiments, such as steak sauce.

(j) Foods subject to §125.5 (e) and (f) shall also bear the label statements required by § 125.5(a).

(k) The comparison

required by

§ 125.5(e) is a comparison with a comparable product that the food is to replace; for example, canned peaches with artificially sweetened canned peaches, not canned peaches with lettuce. Water-packed products may be offered as "packed in water" and labeled "lower in calories" when a 50-percent reduction in caloric value is effected by the water pack.

(1) In making a determination of the application of the "lower in calories" provision of § 125.5(e), the comparison need not necessarily be made with a product of the same manufacturer. (See the comment on § 125.5(b) (4) in paragraph (d) of this section.) The restrictions of § 125.5 (b) (4) shall apply in considering the application of § 125.5(e).

(m) With reference to § 125.5, questions have been asked about the use of alternative or replacement terms, such as "reduced in calories" instead of "lower in calories" and "low calorie." The Food and Drug Administration will consider any data submitted in support of such proposals.

(Secs. 401, 403 (j), 52 Stat. 1046, as amended, 1048; 21 U.S.C. 341, 343 (j)) [31 F.R. 9215, July 6, 1966]

§ 3.47 DMT, LSD, mescaline and its salts, psilocybin, and psilocyn; conditions for investigational use.

(a) No person may sell, deliver, or otherwise dispose of DMT (dimethyltryptamine), LSD (LSD-25, d-lysergic acid diethylamide), mescaline and its salts, psilocybin (psilocibin), and psilocyn (psilocin):

(1) For clinical testing in man until a proposal for such studies has had advance approval by the Commissioner of Food and Drugs on the basis of a Notice of Claimed Investigational Exemption for a New Drug (form FD 1571) justifying such studies.

(2) For tests in vitro or in laboratory research animals until a proposal for such studies has had advance approval by the Commissioner on the basis of the

§ 3.48

Cobalt preparations intended for use by man.

The present state of scientific knowledge concerning the use of cobalt salts as hemopoietic agents is limited, in that the mechanism of their action is not known and the possible deleterious effects of prolonged administration have not been fully determined. Serious toxic effects have been reported to be associated with such use of cobalt preparations, but there is a difference of opinion whether the cobalt preparations were causative agents in these injuries. In view of the limitations of the current state of scientific knowledge regarding cobalt and in the interest of public health protection, the Food and Drug Administration is adopting the following policies concerning cobalt preparations intended for use by man.

(a) Preparations containing per dosage unit more than 10 milligrams of cobalt chloride, or more than 2.5 milligrams of cobalt in the form of any cobalt salts are not safe for use except under the supervision of a practitioner licensed by law to administer the drug.

(1) Such preparations should be labeled with the statement "Caution: Federal law prohibits dispensing without prescription."

(2) Such preparations are regarded as new drugs within the meaning of section 201 (p) of the Federal Food, Drug, and Cosmetic Act if their labeling or advertising sponsored by or on behalf of their distributor prescribes, recommends, or suggests the administration of more than 15 milligrams of cobalt in the form

of any of its salts; for example, more than 60 milligrams of cobalt chloride per 24-hour period.

(3) The labeling of such preparations should bear adequate information for their use by physicians including, among other things, the following:

(i) A statement that substantial quantities of iron salts should usually be administered simultaneously with the administration of cobalt, to obtain the maximum hemopoietic effect.

(ii) A forthright disclosure of the toxic and adverse effects reported to be associated, with the use of cobalt, including those effects in which the role of cobalt may be controversial.

(iii) Disclosure of the fact that the possible deleterious effects of prolonged administration of cobalt are not fully known.

(b) Articles containing per dosage unit more than 2 milligrams but not more than 10 milligrams of cobalt chloride, or more than 0.5 milligram but not more than 2.5 milligrams of cobalt in the form of any cobalt salts may be labeled with adequate directions for use in the selfmedication of simple iron-deficiency anemia only; but such articles will be regarded as misbranded under the provisions of section 502 (f) (1) and/or section 502 (f) (2) and/or section 502 (j), and may be regarded as new drugs within the meaning of section 201 (p) of the act, unless all the following conditions are met:

(1) The dosages prescribed, recommended, or suggested in the labeling do not exceed 40 milligrams of cobalt chloride or 10 milligrams of cobalt in the form of any cobalt salts per 24-hour period.

(2) When used as directed in the labeling, the preparations supply not less than 100 milligrams of iron (Fe) in the form of ferrous sulfate or other assimilable salts of iron per 24-hour period.

(3) The labeling bears, in juxtaposition with the directions for use, clear warning statements, so designated, against:

(i) Exceeding the recommended dosage.

(ii) Administration to children under 12 years of age unless directed by a physician.

(iii) Use for more than 2 months unless directed by a physician.

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