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Code of Federal Regulations
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[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.3]
[Page 6-7]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart A--General Provisions
Sec. 310.3 Definitions and interpretations.
As used in this part:
(a) The term act means the Federal Food, Drug, and Cosmetic Act, as
amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C.
321-392).
(b) Department means the Department of Health and Human Services.
(c) Secretary means the Secretary of Health and Human Services.
(d) Commissioner means the Commissioner of Food and Drugs.
(e) The term person includes individuals, partnerships,
corporations, and associations.
(f) The definitions and interpretations of terms contained in
section 201 of the act shall be applicable to such terms when used in
the regulations in this part.
[[Page 7]]
(g) New drug substance means any substance that when used in the
manufacture, processing, or packing of a drug, causes that drug to be a
new drug, but does not include intermediates used in the synthesis of
such substance.
(h) The newness of a drug may arise by reason (among other reasons)
of:
(1) The newness for drug use of any substance which composes such
drug, in whole or in part, whether it be an active substance or a
menstruum, excipient, carrier, coating, or other component.
(2) The newness for a drug use of a combination of two or more
substances, none of which is a new drug.
(3) The newness for drug use of the proportion of a substance in a
combination, even though such combination containing such substance in
other proportion is not a new drug.
(4) The newness of use of such drug in diagnosing, curing,
mitigating, treating, or preventing a disease, or to affect a structure
or function of the body, even though such drug is not a new drug when
used in another disease or to affect another structure or function of
the body.
(5) The newness of a dosage, or method or duration of administration
or application, or other condition of use prescribed, recommended, or
suggested in the labeling of such drug, even though such drug when used
in other dosage, or other method or duration of administration or
application, or different condition, is not a new drug.
(i) [Reserved]
(j) The term sponsor means the person or agency who assumes
responsibility for an investigation of a new drug, including
responsibility for compliance with applicable provisions of the act and
regulations. The ``sponsor'' may be an individual, partnership,
corporation, or Government agency and may be a manufacturer, scientific
institution, or an investigator regularly and lawfully engaged in the
investigation of new drugs.
(k) The phrase related drug(s) includes other brands, potencies,
dosage forms, salts, and esters of the same drug moiety, including
articles prepared or manufactured by other manufacturers: and any other
drug containing a component so related by chemical structure or known
pharmacological properties that, in the opinion of experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, it is prudent to assume or ascertain the
liability of similar side effects and contraindications.
(l) Special packaging as defined in section 2(4) of the Poison
Prevention Packaging Act of 1970 means packaging that is designed or
constructed to be significantly difficult for children under 5 years of
age to open or obtain a toxic or harmful amount of the substance
contained therein within a reasonable time and not difficult for normal
adults to use properly, but does not mean packaging which all such
children cannot open or obtain a toxic or harmful amount within a
reasonable time.
(m) [Reserved]
(n) The term radioactive drug means any substance defined as a drug
in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act which
exhibits spontaneous disintegration of unstable nuclei with the emission
of nuclear particles or photons and includes any nonradioactive reagent
kit ornuclide generator which is intended to be used in the preparation
of any such substance but does not include drugs such as carbon-
containing compounds or potassium-containing salts which contain trace
quantities of naturally occurring radionuclides. The term ``radioactive
drug'' includes a ``radioactive biological product'' as defined in
Sec. 600.3(ee) of this chapter.
[39 FR 11680, Mar. 29, 1974, as amended at 39 FR 20484, June 11, 1974;
40 FR 31307, July 25, 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb.
22, 1985]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.4]
[Page 7-8]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart A--General Provisions
Sec. 310.4 Biologics; products subject to license control.
(a) If a drug has an approved license under section 351 of the
Public Health Service Act (42 U.S.C. 262 et seq.) or under the animal
virus, serum, and toxin law of March 4, 1913 (21 U.S.C. 151 et seq.), it
is not required to have an approved application under section 505 of the
act.
(b) To obtain marketing approval for radioactive biological products
for human use, as defined in Sec. 600.3(ee) of
[[Page 8]]
this chapter, manufacturers must comply with the provisions of 601.2(b)
of this chapter.
[64 FR 56448, Oct. 20, 1999]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.6]
[Page 8-9]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart A--General Provisions
Sec. 310.6 Applicability of ``new drug'' or safety or effectiveness findings in drug efficacy study implementation notices and notices of opportunity for hearing to identical, related, and similar drug products.
(a) The Food and Drug Administration's conclusions on the
effectiveness of drugs are currently being published in the Federal
Register as Drug Efficacy Study Implementation (DESI) Notices and as
Notices of Opportunity for Hearing. The specific products listed in
these notices include only those that were introduced into the market
through the new drug procedures from 1938-62 and were submitted for
review by the National Academy of Sciences-National Research Council
(NAS-NRC), Drug Efficacy Study Group. Many products which are identical
to, related to, or similar to the products listed in these notices have
been marketed under different names or by different firms during this
same period or since 1962 without going through the new drug procedures
or the Academy review. Even though these products are not listed in the
notices, they are covered by the new drug applications reviewed and thus
are subject to these notices. All persons with an interest in a product
that is identical, related, or similar to a drug listed in a drug
efficacy notice or a notice of opportunity for a hearing will be given
the same opportunity as the applicant to submit data and information, to
request a hearing, and to participate in any hearing. It is not feasible
for the Food and Drug Administration to list all products which are
covered by an NDA and thus subject to each notice. However, it is
essential that the findings and conclusions that a drug product is a
``new drug'' or that there is a lack of evidence to show that a drug
product is safe or effective be applied to all identical, related, and
similar drug products to which they are reasonably applicable. Any
product not in compliance with an applicable drug efficacy notice is in
violation of section 505 (new drugs) and/or section 502 (misbranding) of
the act.
(b)(1) An identical, related, or similar drug includes other brands,
potencies, dosage forms, salts, and esters of the same drug moiety as
well as of any drug moiety related in chemical structure or known
pharmacological properties.
(2) Where experts qualified by scientific training and experience to
evaluate the safety and effectiveness of drugs would conclude that the
findings and conclusions, stated in a drug efficacy notice or notice of
opportunity for hearing, that a drug product is a ``new drug'' or that
there is a lack of evidence to show that a drug product is safe or
effective are applicable to an identical, related, or similar drug
product, such product is affected by the notice. A combination drug
product containing a drug that is identical, related, or similar to a
drug named in a notice may also be subject to the findings and
conclusions in a notice that a drug product is a ``new drug'' or that
there is a lack of evidence to show that a drug product is safe or
effective.
(3) Any person may request an opinion on the applicability of such a
notice to a specific product by writing to the Food and Drug
Administration at the address shown in paragraph (e) of this section.
(c) Manufacturers and distributors of drugs should review their
products as drug efficacy notices are published and assure that
identical, related, or similar products comply with all applicable
provisions of the notices.
(d) The published notices and summary lists of the conclusions are
of particular interest to drug purchasing agents. These agents should
take particular care to assure that the same purchasing policy applies
to drug products that are identical, related, or similar to those named
in the drug efficacy notices. The Food and Drug Administration applies
the same regulatory policy to all such products. In many instances a
determination can readily be made as to the applicability of a drug
efficacy notice by an individual who is knowledgeable about drugs and
their indications for use.
[[Page 9]]
Where the relationships are more subtle and not readily recognized, the
purchasing agent may request an opinion by writing to the Food and Drug
Administration at the address shown in paragraph (e) of this section.
(e) Interested parties may submit to the Food and Drug
Administration, Center for Drug Evaluation and Research, Office of
Compliance, HFD-300, 5600 Fishers Lane, Rockville, MD 20857, the names
of drug products, and of their manufacturers or distributors, that
should be the subject of the same purchasing and regulatory policies as
those reviewed by the Drug Efficacy Study Group. Appropriate action,
including referral to purchasing officials of various government
agencies, will be taken.
(f) This regulation does not apply to OTC drugs identical, similar,
or related to a drug in the Drug Efficacy Study unless there has been or
is notification in the Federal Register that a drug will not be subject
to an OTC panel review pursuant to Secs. 330.10, 330.11, and 330.5 of
this chapter.
[39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983; 50
FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.100]
[Page 9]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart B--Specific Administrative Rulings and Decisions
Sec. 310.100 New drug status opinions; statement of policy.
(a) Over the years since 1938 the Food and Drug Administration has
given informal advice to inquirers as to the new drug status of
preparations. These drugs have sometimes been identified only by general
statements of composition. Generally, such informal opinions were
incorporated in letters that did not explicitly relate all of the
necessary conditions and qualifications such as the quantitative formula
for the drug and the conditions under which it was prescribed,
recommended, or suggested. This has contributed to misunderstanding and
misinterpretation of such opinions.
(b) These informal opinions that an article is ``not a new drug'' or
``no longer a new drug'' require reexamination under the Kefauver-Harris
Act (Public Law 87-781; 76 Stat. 788-89). In particular, when approval
of a new drug application is withdrawn under provisions of section
505(e) of the Federal Food, Drug, and Cosmetic Act, a drug generally
recognized as safe may become a ``new drug'' within the meaning of
section 201(p) of said act as amended by the Kefauver-Harris Act on
October 10, 1962. This is of special importance by reason of proposed
actions to withdraw approval of new drug applications for lack of
substantial evidence of effectiveness as a result of reports of the
National Academy of Sciences--National Research Council on its review of
drug effectiveness; for example, see the notice published in the Federal
Register of January 23, 1968 (33 FR 818), regarding rutin, quercetin, et
al.
(c) Any marketed drug is a ``new drug'' if any labeling change made
after October 9, 1962, recommends or suggests new conditions of use
under which the drug is not generally recognized as safe and effective
by qualified experts. Undisclosed or unreported side effects as well as
the emergence of new knowledge presenting questions with respect to the
safety or effectiveness of a drug may result in its becoming a ``new
drug'' even though it was previously considered ``not a new drug.'' Any
previously given informal advice that an article is ``not a new drug''
does not apply to such an article if it has been changed in formulation,
manufacture control, or labeling in a way that may significantly affect
the safety of the drug.
(d) For these reasons, all opinions previously given by the Food and
Drug Administration to the effect that an article is ``not a new drug''
or is ``no longer a new drug'' are hereby revoked. This does not mean
that all articles that were the subjects of such prior opinions will be
regarded as new drugs. The prior opinions will be replaced by opinions
of the Food and Drug Administration that are qualified and current on
when an article is ``not a new drug,'' as set forth in this subchapter.
[39 FR 11680, Mar. 29, 1974]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.103]
[Page 9-10]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart B--Specific Administrative Rulings and Decisions
Sec. 310.103 New drug substances intended for hypersensitivity testing.
(a) The Food and Drug Administration is aware of the need in the
practice of medicine for the ingredients of
[[Page 10]]
a new drug to be available for tests of hypersensitivity to such
ingredients and therefore will not object to the shipment of a new drug
substance, as defined in Sec. 310.3(g), for such purpose if all of the
following conditions are met:
(1) The shipment is made as a result of a specific request made to
the manufacturer or distributor by a practitioner licensed by law to
administer such drugs, and the use of such drugs for patch testing is
not promoted by the manufacturer or distributor.
(2) The new drug substance requested is an ingredient in a marketed
new drug and is not one that is an ingredient solely in a new drug that
is legally available only under the investigational drug provisions of
this part.
(3) The label bears the following prominently placed statements in
lieu of adequate directions for use and in addition to complying with
the other labeling provisions of the act:
(i) ``Caution: Federal law prohibits dispensing without a
prescription''; and
(ii) ``For use only in patch testing''.
(4) The quantity shipped is limited to an amount reasonable for the
purpose of patch testing in the normal course of the practice of
medicine and is used solely for such patch testing.
(5) The new drug substance is manufactured by the same procedures
and meets the same specifications as the component used in the finished
dosage form.
(6) The manufacturer or distributor maintains records of all
shipments for this purpose for a period of 2 years after shipment and
will make them available to the Food and Drug Administration on request.
(b) When the requested new drug substance is intended for
investigational use in humans or the substance is legally available only
under the investigational drug provisions of part 312 of this chapter,
the submission of an ``Investigational New Drug Application'' (IND) is
required. The Food and Drug Administration will offer assistance to any
practitioner wishing to submit an Investigational New Drug Application.
(c) This section does not apply to drugs or their components that
are subject to the licensing requirements of the Public Health Service
Act of 1944, as amended. (See subchapter F--Biologics, of this chapter.)
[39 FR 11680, Mar. 29, 1974, as amended at 55 FR 11578, Mar. 29, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.200]
[Page 10-11]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart C--New Drugs Exempted From Prescription-Dispensing Requirements
Sec. 310.200 Prescription-exemption procedure.
(a) Duration of prescription requirement. Any drug limited to
prescription use under section 503(b)(1)(C) of the act remains so
limited until it is exempted as provided in paragraph (b) or (e) of this
section.
(b) Prescription-exemption procedure for drugs limited by a new drug
application. Any drug limited to prescription use under section
503(b)(1)(C) of the act shall be exempted from prescription-dispensing
requirements when the Commissioner finds such requirements are not
necessary for the protection of the public health by reason of the
drug's toxicity or other potentiality for harmful effect, or the method
of its use, or the collateral measures necessary to its use, and he
finds that the drug is safe and effective for use in self-medication as
directed in proposed labeling. A proposal to exempt a drug from the
prescription-dispensing requirements of section 503(b)(1)(C) of the act
may be initiated by the Commissioner or by any interested person. Any
interested person may file a petition seeking such exemption, which
petition may be pursuant to part 10 of this chapter, or in the form of a
supplement to an approved new drug application.
(c) New drug status of drugs exempted from the prescription
requirement. A drug exempted from the prescription requirement under the
provisions of paragraph (b) of this section is a ``new drug'' within the
meaning of section 201(p) of the act until it has been used to a
material extent and for a material time under such conditions except as
provided in paragraph (e) of this section.
(d) Prescription legend not allowed on exempted drugs. The use of
the prescription caution statement quoted in section 503(b) (4) of the
act, in the labeling
[[Page 11]]
of a drug exempted under the provisions of this section, constitutes
misbranding. Any other statement or suggestion in the labeling of a drug
exempted under this section, that such drug is limited to prescription
use, may constitute misbranding.
(e) Prescription-exemption procedure of OTC drug review. A drug
limited to prescription use under section 503(b)(1)(C) of the act may
also be exempted from prescription-dispensing requirements by the
procedure set forth in Sec. 330.13 of this chapter.
[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42
FR 4714, Jan. 25, 1977; 42 FR 15674, Mar. 22, 1977]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.201]
[Page 11-18]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart C--New Drugs Exempted From Prescription-Dispensing Requirements
Sec. 310.201 Exemption for certain drugs limited by new-drug applications to prescription sale.
(a) The prescription-dispensing requirements of section 503(b)(1)(C)
of the Federal Food, Drug, and Cosmetic Act are not necessary for the
protection of the public health with respect to the following drugs
subject to new drug applications:
(1) N-Acetyl-p-aminophenol (acetaminophen, p-hydroxy-acetanilid)
preparations meeting all the following conditions:
(i) The N-acetyl-p-aminophenol is prepared, with or without other
drugs, in tablet or other dosage form suitable for oral use in self-
medication, and containing no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The N-acetyl-p-aminophenol and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505 (b) of the act is approved for it.
(iv) The preparation contains not more than 0.325 gram (5 grains) of
N-acetyl-p-aminophenol per dosage unit, or if it is in liquid form not
more than 100 milligrams of N-acetyl-p-aminophenol per milliliter.
(v) The preparation is labeled with adequate directions for use in
minor conditions as a simple analgesic.
(vi) The dosages of N-acetyl-p-aminophenol recommended or suggested
in the labeling do not exceed: For adults, 0.65 gram (10 grains) per
dose or 2.6 grams (40 grains) per 24-hour period: for children 6 to 12
years of age, one-half of the maximum adult dose or dosage; for children
3 to 6 years of age, one-fifth of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations, a clear warning statement against administration of the
drug to children under 3 years of age and against use of the drug for
more than 10 days, unless such uses are directed by a physician.
(viii) If the article is offered for use in arthritis or rheumatism,
the labeling prominently bears a statement that the beneficial effects
claimed are limited to the temporary relief of minor aches and pains of
arthritis and rheumatism and, in juxtaposition with directions for use
in such conditions, a conspicuous warning statement, such as ``Caution:
If pain persists for more than 10 days, or redness is present, or in
conditions affecting children under 12 years of age, consult a physician
immediately''.
(2) Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations
meeting all the following conditions:
(i) The sodium gentisate is prepared, with or without other drugs,
in tablet or other dosage form suitable for oral use in self-medication,
and containing no drug limited to prescription sale under the provisions
of section 503(b)(1) of the act.
(ii) The sodium gentisate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 0.5 gram (7.7 grains) of
anhydrous sodium gentisate per dosage unit.
(v) The preparation is labeled with adequate directions for use in
minor conditions as a simple analgesic.
(vi) The dosages of sodium gentisate recommended or suggested in the
labeling do not exceed: For adults, 0.5 gram (7.7 grains) per dose of
2.0 grams (31 grains) per 24-hour period; for children 6 to 12 years of
age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations,
[[Page 12]]
a clear warning statement against administration of the drug to children
under 6 years of age and against use of the drug for a prolonged period,
except as such uses may be directed by a physician.
(3) Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-
N'-2-thiazolyl-N'-p-methoxybenzyl-ethyl- enediamine hydrochloride)
preparations meeting all the following conditions:
(i) The isoamylhydrocupreine and zolamine hydrochloride are prepared
in dosage form suitable for self-medication as rectal suppositories or
as an ointment and containing no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The isoamylhydrocupreine, zola-amine hydrochloride, and all
other components of the preparation meet their professed standards of
identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 0.25 percent of
isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride.
(v) If the preparation is in suppository form, it contains not more
than 5.0 milligrams of isoamylhydrocupreine and not more than 20.0
milligrams of zolamine hydrochloride per suppository.
(vi) The preparation is labeled with adequate directions for use in
the temporary relief of local pain and itching associated with
hemorrhoids.
(vii) The directions provide for the use of not more than two
suppositories or two applications of ointment in a 24-hour period.
(viii) The labeling bears, in juxtaposition with the dosage
recommendations, a clear warning statement against use of the
preparation in case of rectal bleeding, as this may indicate serious
disease.
(4) Phenyltoloxamine dihydrogen citrate (N,N-dimethyl-(a-phenyl-O-
toloxy) ethylamine dihydrogen citrate), preparations meeting all the
following conditions:
(i) The phenyltoloxamine dihydrogen citrate is prepared, with or
without other drugs, in tablet or other dosage form suitable for oral
use in self-medication, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The phenyltoloxamine dihydrogen citrate and all other
components of the preparation meet their professed standards of
identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 88 milligrams of
phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of
phenyltoloxamine) per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of hay fever and/or the symptoms of
other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 88 milligrams of phenyltoloxamine dihydrogen citrate
(equivalent to 50 milligrams of phenyltoloxamine) per dose or 264
milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 150
milligrams of phenyltoloxamine) per 24-hour period; for children 6 to 12
years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age, except as directed by a physician, and
against driving a car or operating machinery while using the drug, since
it may cause drowsiness.
(b) If the article is offered for temporary relief of the symptoms
of colds, a statement that continued administration for such use should
not exceed 3 days, except as directed by a physician.
(5)-(7) [Reserved]
(8) Dicyclomine hydrochloride (1-cyclohexylhexahydrobenzoic acid.
<greek-b>-diethylaminoethyl ester hydrochloride; diethylaminocarbethoxy-
bicyclohexyl hydrochloride) preparations meeting all the following
conditions:
(i) The dicyclomine hydrochloride is prepared with suitable antacid
and other components, in tablet or other
[[Page 13]]
dosage form for oral use in self-medication, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The dicyclomine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 milligrams of
dicyclomine hydrochloride per dosage unit, or if it is in liquid form
not more than 0.5 milligram of dicyclomine hydrochloride per milliliter.
(v) The preparation is labeled with adequate directions for use only
by adults and children over 12 years of age, in the temporary relief of
gastric hyperacidity.
(vi) The dosages recommended or suggested in the directions for use
do not exceed 10 milligrams of dicyclomine hydrochloride per dose or 30
milligrams in a 24-hour period.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations, clear warning statements against:
(a) Exceeding the recommended dosage.
(b) Prolonged use, except as directed by a physician, since
persistent or recurring symptoms may indicate a serious disease
requiring medical attention.
(c) Administration to children under 12 years of age except as
directed by a physician.
(9)-(10) [Reserved]
(11) Hexadenol (a mixture of tetracosanes and their oxidation
products) preparations meeting all the following conditions:
(i) The hexadenol is prepared and packaged, with or without other
drugs, solvents, and propellants, in a form suitable for self-medication
by external application to the skin as a spray, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The hexadenol and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 percent by weight of
hexadenol.
(v) The preparation is labeled with adequate directions for use by
external application in the treatment of minor burns and minor skin
irritations.
(vi) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Use on serious burns or skin conditions or prolonged use, except
as directed by a physician.
(b) Spraying the preparation in the vicinity of eyes, mouth, nose,
or ears.
(12) Sulfur dioxide preparations meeting all the following
conditions:
(i) The sulfur dioxide is prepared with or without other drugs, in
an aqueous solution packaged in a hermetic container suitable for use in
self-medication by external application to the skin, and containing no
drug limited to prescription sale under the provisions of section
503(b)(1) of the act.
(ii) The sulfur dioxide and all other components of the preparation
meet their professed standards of identity, strength, quality, and
purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 grams of sulfur
dioxide per 100 milliliters of solution.
(v) The preparation is labeled with adequate directions for use by
external application to the smooth skin in the prevention or treatment
of minor conditions in which it is indicated.
(vi) The directions for use recommend or suggest not more than two
applications a day for not more than 1 week, except as directed by a
physician.
(13)-(15) [Reserved]
(16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations
meeting all the following conditions:
(i) The tuaminoheptane sulfate is prepared, with or without other
drugs, in an aqueous vehicle suitable for administration in self-
medication as nose drops, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
[[Page 14]]
(ii) The preparation is packaged with a style of container or
assembly suited to self-medication by the recommended route of
administration, and delivering not more than 0.1 milliliter of the
preparation per drop.
(iii) The tuaminoheptane sulfate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iv) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(v) The tuaminoheptane sulfate content of the preparation does not
exceed 10 milligrams per milliliter.
(vi) The preparation is labeled with adequate directions for use in
the temporary relief of nasal congestion.
(vii) The dosages recommended or suggested in the directions for use
do not exceed the equivalent: For adults, 5 drops of a 1 percent
solution per nostril per dose, and 5 doses in a 24-hour period; for
children 1 to 6 years of age, 3 drops of a 1 percent solution per
nostril per dose, and 5 doses in a 24-hour period; for infants under 1
year of age, 2 drops of a 1 percent solution per nostril per dose, and 5
doses in a 24-hour period.
(viii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against use of more than 5 doses daily,
and against use longer than 4 days unless directed by a physician.
(b) A clear warning statement to the effect that frequent use may
cause nervousness or sleeplessness, and that individuals with high blood
pressure, heart disease, diabetes, or thyroid disease should not use the
preparation unless directed by a physician.
(17) [Reserved]
(18) Vibesate (a mixture of copolymers of hydroxy-vinyl
chlorideacetate, sebacic acid, and modified maleic rosin ester)
preparations meeting all the following conditions.
(i) The vibesate is prepared and packaged, with or without other
drugs, solvents, and propellants, in a form suitable for self-medication
by external application to the skin as a spray, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The vibesate and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 13 percent by weight of
vibesate.
(v) The preparation is labeled with adequate directions for use by
external application as a dressing for minor burns, minor cuts, or other
minor skin irritations.
(vi) The labeling bears in juxtaposition with the directions for use
clear warning statements against:
(a) Use on serious burns and on infected, deep, and puncture wounds
unless directed by a physician.
(b) Spraying the preparation near the eyes or other mucous
membranes.
(c) Inhaling the preparation.
(d) Use near open flames.
(e) Puncturing the container or throwing the container into fire.
(19) Pramoxine hydrochloride (4-N-butoxyphenyl <greek-g>-
morpholinopropyl ether hydrochloride) preparations meeting all the
following conditions:
(i) The pramoxine hydrochloride is prepared, with or without other
drugs, in a dosage form suitable for use in self-medication by external
application to the skin, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The pramoxine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1.0 percent of pramoxine
hydrochloride.
(v) The preparation is labeled with adequate directions for use by
external application to the skin for the temporary relief of pain or
itching due to minor burns and sunburn, nonpoisonous insect bites, and
minor skin irritations.
(vi) The directions for use recommend or suggest not more than four
[[Page 15]]
applications of the preparation per day, unless directed by a physician.
(vii) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Prolonged use.
(b) Application to large areas of the body.
(c) Continued use if redness, irritation, swelling, or pain persists
or increases, unless directed by a physician.
(d) Use in the eyes or nose.
(20) Carbetapentane citrate (2-(2-diethylaminoethoxy)-ethyl-1-
phenyl- cyclopentyl-1-carboxylate citrate) preparations meeting all the
following conditions:
(i) The carbetanentane citrate is prepared, with or without other
drugs, in tablet or other dosage form suitable for oral use in self-
medication, and containing no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The carbetapentane citrate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, and application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of
carbetapentane citrate per dosage unit; or if it is in liquid form, not
more than 1.5 milligrams of carbetapentane citrate per milliliter.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of cough due to minor conditions in which it is
indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 30 milligrams of carbetapentane citrate per dose or
120 milligrams of carbetapentane citrate per 24-hour period; for
children 4 to 12 years of age, 7.5 milligrams per dose or 30 milligrams
per 24-hour period; for children 2 to 4 years of age, 4.0 milligrams per
dose or 16.0 milligrams per 24-hour period.
(vii) The label bears a conspicuous warning to keep the drug out of
the reach of children, and the labeling bears, in juxtaposition with the
dosage recommendations:
(a) A clear warning statement against administration of the drug to
children under 2 years of age, unless directed by a physician.
(b) Clear warning statements against use of the drug in the presence
of high fever or if cough persists, since persistent cough as well as
high fever may indicate the presence of a serious condition.
(21) Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate)
preparations meeting all the following conditions:
(i) The pamabrom is prepared with appropriate amounts of a suitable
analgesic and with or without other drugs, in tablet or other dosage
form suitable for oral use in self-medication, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The pamabrom and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 50 milligrams of
pamabrom per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the minor pains and discomforts that may occur a
few days before and during the menstrual period.
(vi) The dosages recommended or suggested in the labeling do not
exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour
period.
(22) Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-
piperidinium methylsulfate) preparations meeting all the following
conditions:
(i) The diphemanil methylsulfate is prepared, with or without other
drugs, in a dosage form suitable for use in self-medication by external
application to the skin, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The diphemanil methylsulfate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
[[Page 16]]
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 2.0 percent of
diphemanil methylsulfate.
(v) The preparation is labeled with adequate directions for use by
external application to the skin for the relief of symptoms of mild
poison ivy, oak, and sumac and other minor irritations and itching of
the skin.
(vi) The directions for use recommend or suggest not more than four
applications of the preparation per day, unless directed by a physician.
(vii) The labeling bears, in juxtaposition with the directions for
use, a clear warning statement, such as: ``Caution: If redness,
irritation, swelling, or pain persists or increases, discontinue use and
consult physician.''
(23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone
hydrochloride; 4-n-butoxy-<greek-b>-piperidonopropiophenone
hydrochloride) preparations meeting all the following conditions:
(i) The dyclonine hydrochloride is prepared, with or without other
drugs, in a dosage form suitable for use as a cream or ointment in self-
medication by external application to the skin, or rectally, and
contains no drug limited to prescription sale under the provisions of
section 503(b)(1) of the act.
(ii) The dyclonine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1.0 percent of dyclonine
hydrochloride.
(v) The preparation is labeled with adequate directions for use:
(a) By external application to the skin for the temporary relief of
pain and itching in sunburn, nonpoisonous insect bites, minor burns,
cuts, abrasions, and other minor skin irritations.
(b) [Reserved]
(c) In the prevention or treatment of other minor conditions in
which it is indicated.
(vi) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Continued use if redness, irritation, swelling, or pain persists
or increases, unless directed by a physician.
(b) Use in case of rectal bleeding, as this may indicate serious
disease.
(c) Use in the eyes.
(d) Prolonged use.
(e) Application to large areas of the body.
(f) Use for deep or puncture wounds or serious burns.
(24) Chlorothen citrate (chloromethapyrilene citrate; N,N-dimethyl-
N'-(2-pyridyl)-N'-(5-chloro-2-thenyl) ethylenediamine citrate)
preparations meeting all the following conditions:
(i) The chlorothen citrate is prepared, with or without other drugs,
in tablet or other dosage form suitable for oral use in self-medication,
and containing no drug limited to prescription sale under the provisions
of section 503(b)(1) of the act.
(ii) The chlorothen citrate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of
chlorothen citrate per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of hay fever and/or the symptoms of
other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 25 milligrams of chlorothen citrate per dose or 150
milligrams of chlorothen citrate per 24-hour period; for children 6 to
12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age or exceeding the recommended dosage,
unless directed by a physician, and against driving a car or operating
machinery while using
[[Page 17]]
the drug, since it may cause drowsiness.
(b) If the article is offered for the temporary relief of symptoms
of colds, a statement that continued administration for such use should
not exceed 3 days, unless directed by a physician.
(25) [Reserved]
(26) Methoxyphenamine hydrochloride (<greek-b>-(o-methoxyphenyl)-
isopropyl-methylamine hydrochloride; 1-(o-methoxyphenyl)- 2-methylamino-
propane hydrochloride) preparations meeting all the following
conditions:
(i) The methoxyphenamine hydrochloride is prepared with appropriate
amounts of a suitable antitussive, with or without other drugs, in a
dosage form suitable for oral use in self-medication, and containing no
drug limited to prescription sale under the provisions of section
503(b)(1) of the act.
(ii) The methoxyphenamine hydrochloride and all other components of
the preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 3.5 milligrams of
methoxyphenamine hydrochloride per milliliter.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of cough due to minor conditions in which it is
indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 35 milligrams of methoxyphenamine hydrochloride per
dose or 140 milligrams of methoxyphenamine hydrochloride per 24-hour
period; for children 6 to 12 years of age, one-half of the maximum adult
dose or dosage.
(vii) The label bears a conspicuous warning to keep the drug out of
the reach of children, and the labeling bears, in juxtaposition with the
dosage recommendations:
(a) A clear warning statement against administration of the drug to
children under 6 years of age, unless directed by a physician.
(b) A clear warning statement to the effect that frequent or
prolonged use may cause nervousness, restlessness, or drowsiness, and
that individuals with high blood pressure, heart disease, diabetes, or
thyroid disease should not use the preparation unless directed by a
physician.
(c) A clear warning statement against use of the drug in the
presence of high fever or if cough persists, since persistent cough as
well as high fever may indicate the presence of a serious condition.
(27) Biphenamine hydrochloride (<greek-b>-diethylaminoethyl- 3-
phenyl-2-hydroxybenzoate hydrochloride) preparations meeting all the
following conditions:
(i) The biphenamine hydrochloride is prepared in a form suitable for
use as a shampoo and contains no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The biphenamine hydrochloride meets its professed standards of
identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1 percent of biphenamine
hydrochloride.
(v) The preparation is labeled with adequate directions for use for
the temporary relief of itching and scaling due to dandruff.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children.
(28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium
chloride ophthalmic preparations meeting all the following conditions:
(i) The tyloxapol and benzalkonium chloride are prepared, with other
appropriate ingredients which are not drugs limited to prescription sale
under the provisions of section 503(b)(1) of the act, as a sterile,
isotonic aqueous solution suitable for use in self-medication on eye
prostheses.
(ii) The preparation is so packaged as to volume and type of
container as to afford adequate protection and be suitable for self-
medication with a minimum risk of contamination of the solution during
use. Any dispensing unit is sterile and so packaged as to maintain
sterility until the package is opened.
(iii) The tyloxapol, benzalkonium chloride, and other ingredients
used to
[[Page 18]]
prepare the isotonic aqueous solution meet their professed standards of
identity, strength, quality, and purity.
(iv) An application pursuant to section 505(b) of the act is
approved for the drug.
(v) The preparation contains 0.25 percent of tyloxapol and 0.02
percent of benzalkonium chloride.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children and the labeling bears, in juxtaposition with the
dosage recommendations, a clear warning that if irritation occurs,
persists, or increases, use of the drug should be discontinued and a
physician consulted. The labeling includes a statement that the dropper
or other dispensing tip should not touch any surface, since this may
contaminate the solution.
(29) [Reserved]
(b) [Reserved]
[39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977;
52 FR 15892, Apr. 30, 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779,
Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR 49898, Sept. 23, 1993; 59
FR 4218, Jan. 28, 1994; 60 FR 52507, Oct. 6, 1995]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.303]
[Page 18]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart D--Records and Reports
Sec. 310.303 Continuation of long-term studies, records, and reports on certain drugs for which new drug applications have been approved.
(a) A new drug may not be approved for marketing unless it has been
shown to be safe and effective for its intended use(s). After approval,
the applicant is required to establish and maintain records and make
reports related to clinical experience or other data or information
necessary to make or facilitate a determination of whether there are or
may be grounds under section 505(e) of the act for suspending or
withdrawing approval of the application. Some drugs, because of the
nature of the condition for which they are intended, must be used for
long periods of time--even a lifetime. To acquire necessary data for
determining the safety and effectiveness of long-term use of such drugs,
extensive animal and clinical tests are required as a condition of
approval. Nonetheless, the therapeutic or prophylactic usefulness of
such drugs may make it inadvisable in the public interest to delay the
availability of the drugs for widespread clinical use pending completion
of such long-term studies. In such cases, the Food and Drug
Administration may approve the new drug application on condition that
the necessary long-term studies will be conducted and the results
recorded and reported in an organized fashion. The procedures required
by paragraph (b) of this section will be followed in order to list such
a drug in Sec. 310.304.
(b) A proposal to require additional or continued studies with a
drug for which a new drug application has been approved may be made by
the Commissioner on his own initiative or on the petition of any
interested person, pursuant to part 10 of this chapter. Prior to
issuance of such a proposal, the applicant will be provided an
opportunity for a conference with representatives of the Food and Drug
Administration. When appropriate, investigators or other individuals may
be invited to participate in the conference. All requirements for
special studies, records, and reports will be published in Sec. 310.304.
[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42
FR 15674, Mar. 22, 1977]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.305]
[Page 18-21]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart D--Records and Reports
Sec. 310.305 Records and reports concerning adverse drug experiences on marketed prescription drugs for human use without approved new drug applications.
(a) Scope. FDA is requiring manufacturers, packers, and distributors
of marketed prescription drug products that are not the subject of an
approved new drug or abbreviated new drug application to establish and
maintain records and make reports to FDA of all serious, unexpected
adversedrug experiences associated with the use of their drug products.
Any person subject to the reporting requirements of paragraph (c) of
this section shall also develop written procedures for the surveillance,
receipt, evaluation, and reporting of postmarketing adverse drug
experiences to FDA.
(b) Definitions. The following definitions of terms apply to this
section:-
Adverse drug experience. Any adverse event associated with the use
of a drug
[[Page 19]]
in humans, whether or not considered drug related, including the
following: An adverse event occurring in the course of the use of a drug
product in professional practice; an adverse event occurring from drug
overdose whether accidental or intentional; an adverse event occurring
from drug abuse; an adverse event occurring from drug withdrawal; and
any failure of expected pharmacological action.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Life-threatening adverse drug experience. Any adverse drug
experience that places the patient, in the view of the initial reporter,
at immediate risk of death from the adverse drug experience as it
occurred, i.e., it does not include an adverse drug experience that, had
it occurred in a more severe form, might have caused death.
Serious adverse drug experience. Any adverse drug experience
occurring at any dose that results in any of the following outcomes:
Death, a life-threatening adverse drug experience, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result in
death, be life-threatening, or require hospitalization may be considered
a serious adverse drug experience when, based upon appropriate medical
judgment, they may jeopardize the patient or subject and may require
medical or surgical intervention to prevent one of the outcomes listed
in this definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency or drug abuse.
Unexpected adverse drug experience. Any adverse drug experience that
is not listed in the current labeling for the drug product. This
includes events that may be symptomatically and pathophysiologically
related to an event listed in the labeling, but differ from the event
because of greater severity or specificity. For example, under this
definition, hepatic necrosis would be unexpected (by virtue of greater
severity) if the labeling only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater specificity) if the labeling
only listed cerebral vascular accidents. ``Unexpected,'' as used in this
definition, refers to an adverse drug experience that has not been
previously observed (i.e., included in the labeling) rather than from
the perspective of such experience not being anticipated from the
pharmacological properties of the pharmaceutical product.
(c) Reporting requirements. Each person identified in paragraph
(c)(1)(i) of this section shall report to FDA adverse drug experience
information as described in this section and shall submit one copy of
each report to the Division of Pharmacovigilance and Epidemiology (HFD-
730), Center for Drug Evaluation and Research, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857.
(1) Postmarketing 15-day ``Alert reports''. (i) Any person whose
name appears on the label of a marketed prescription drug product as its
manufacturer, packer, or distributor shall report to FDA each adverse
drug experience received or otherwise obtained that is both serious and
unexpected as soon as possible, but in no case later than 15 calendar
days of initial receipt of the information by the person whose name
appears on the label. Each report shall be accompanied by a copy of the
current labeling for the drug product.
(ii) A person identified in paragraph (c)(1)(i) of this section is
not required to submit a 15-day ``Alert report'' for an adverse drug
experience obtained from a postmarketing study (whether or not conducted
under an investigational new drug application) unless the applicant
concludes that there is a reasonable possibility that the drug caused
the adverse experience.
(2) Postmarketing 15-day ``Alert reports''--followup. Each person
identified in paragraph (c)(1)(i) of this section shall promptly
investigate all serious, unexpected adverse drug experiences that are
the subject of these postmarketing 15-day Alert reports and shall submit
followup reports within 15
[[Page 20]]
calendar days of receipt of new information or as requested by FDA. If
additional information is not obtainable, records should be maintained
of the unsuccessful steps taken to seek additional information.
Postmarketing 15-day Alert reports and followups to them shall be
submitted under separate cover.
(3) Submission of reports. To avoid unnecessary duplication in the
submission of, and followup to, reports required in this section, a
packer's or distributor's obligations may be met by submission of all
reports of serious adverse drug experiences to the manufacturer of the
drug product. If a packer or distributor elects to submit these adverse
drug experience reports to the manufacturer rather than to FDA, it shall
submit each report to the manufacturer within 5 calendar days of its
receipt by the packer or distributor, and the manufacturer shall then
comply with the requirements of this section even if its name does not
appear on the label of the drug product. Under this circumstance, the
packer or distributor shall maintain a record of this action which shall
include:
(i) A copy of each adverse drug experience report;
(ii) The date the report was received by the packer or distributor;
(iii) The date the report was submitted to the manufacturer; and
(iv) The name and address of the manufacturer.
(4) Each report submitted to FDA under this section shall bear
prominent identification as to its contents, i.e., ``15-day Alert
report,'' or ``15-day Alert report-followup.''
(5) A person identified in paragraph (c)(1)(i) of this section is
not required to resubmit to FDA adverse drug experience reports
forwarded to that person by FDA; however, the person must submit all
followup information on such reports to FDA.
(d) Reporting form. (1) Except as provided in paragraph (d)(3) of
this section, each person identified in paragraph (c)(1)(i) of this
section shall submit each report of a serious and unexpected adverse
drug experience on an FDA Form 3500A (foreign events may be submitted
either on an FDA Form 3500A or, if preferred, on a CIOMS I form).
(2) Each completed FDA Form 3500A should pertain only to an
individual patient.
(3) Instead of using Form FDA Form 3500A, a manufacturer, packer, or
distributor may use a computer-generated FDA Form 3500A or other
alternative format (e.g., a computer-generated tape or tabular listing)
provided that:
(i) The content of the alternative format is equivalent in all
elements of information to those specified in FDA Form 3500A, and
(ii) The format is agreed to in advance by MedWatch: The FDA Medical
Products Reporting Program.
(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the
instructions for completing the form may be obtained from the Division
of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857. More than 10 copies of the form may be
obtained by writing to the Consolidated Forms and Publications
Distribution Center, Washington Commerce Center, 3222 Hubbard Rd.,
Landover, MD 20785.
(e) Patient privacy. Manufacturers, packers, and distributors should
not include in reports under this section the names and addresses of
individual patients; instead, the manufacturer, packer, and distributor
should assign a unique code number to each report, preferably not more
than eight characters in length. The manufacturer, packer, and
distributor should include the name of the reporter from whom the
information was received. Names of patients, individual reporters,
health care professionals, hospitals, and geographical identifiers in
adverse drug experience reports are not releasable to the public under
FDA's public information regulations in part 20 of this chapter.
(f) Recordkeeping. (1) Each manufacturer, packer, and distributor
shall maintain for a period of 10 years records of all adverse drug
experiences required under this section to be reported, including raw
data and any correspondence relating to the adverse
[[Page 21]]
drug experiences, and the records required to be maintained under
paragraph (c)(4) of this section.
(2) Manufacturers and packers may retain the records required in
paragraph (f)(1) of this section as part of its complaint files
maintained under Sec. 211.198 of this chapter.
(3) Manufacturers, packers, and distributors shall permit any
authorized FDA employee, at all reasonable times, to have access to and
copy and verify the records established and maintained under this
section.
(g) Disclaimer. A report or information submitted by a manufacturer,
packer, or distributor under this section (and any release by FDA of
that report or information) does not necessarily reflect a conclusion by
the manufacturer, packer, or distributor, or by FDA, that the report or
information constitutes an admission that the drug caused or contributed
to an adverse effect. The manufacturer, packer, or distributor need not
admit, and may deny, that the report or information submitted under this
section constitutes an admission that the drug caused or contributed to
an adverse effect.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0210)
[51 FR 24479, July 3, 1986, as amended at 52 FR 37936, Oct. 13, 1987; 55
FR 11578, Mar. 29, 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, June
25, 1997; 62 FR 52249, Oct. 7, 1997]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.500]
[Page 21-29]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.500 Digoxin products for oral use; conditions for marketing.
(a) Studies have shown evidence of clinically significant
differences in bio-availability in different batches of certain marketed
digoxin products for oral use from single manufacturers as well as in
batches of these products produced by different manufacturers. These
differences were observed despite the fact that the products met
compendial specifications. Other studies have shown that there is a
sufficient correlation between bioavailability in vivo and the
dissolution rate of digoxin tablets in vitro to make the dissolution
test an important addition to the compendial standards. Because of the
potential for serious risk to cardiac patients using digoxin products
which may vary in bioavailability, the Commissioner of Food and Drugs
has determined that immediate action must be taken to assure the
uniformity of all digoxin products for oral use. The Commissioner is of
the opinion that digoxin products for oral use are new drugs within the
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act
for which approved new drug applications are required. The Commissioner
has determined that, because of questions raised regarding the
bioavailability of digoxin products for oral use, there is sufficient
evidence to invoke the authority under section 505(j) of the act to
fully investigate this question and to facilitate a determination of
whether there is a ground for withdrawal of approval of the drug product
under section 505(e) of the act. Marketing of these products may be
continued only under the following conditions:
(1) Digoxin products for oral use, other than tablets: Any person
marketing digoxin products for oral use, other than tablets, shall
submit to the Food and Drug Administration on or before February 21,
1974, an abbreviated new drug application for these products. Any such
drug product then on the market which is not the subject of an
application submitted for the drug product shall be subject to
regulatory procedures under section 505 of the act. In addition to the
information specified in Sec. 314.50 of this chapter, the application
shall contain:
(i) A full list of the articles used as components of the digoxin
product, specifications for components, detailed identification and
analytical procedures used to assure that the components meet
established specifications of identity, strength, quality, and purity
and a complete description of the manufacturing process.
(ii) The source of the digoxin used in the formulation including the
name and address of the supplier.
(iii) A statement that stability studies will be conducted to
establish a suitable expiration date for the digoxin product in the form
in which it is distributed.
[[Page 22]]
(iv) A statement that the product label will contain a suitable
expiration date. In the absence of any stability test data, this
expiration date shall be no longer than one year after the batch is
manufactured. If the expiration date is greater than one year,
supporting stability data shall be included in the application.
(v) Labeling that is in compliance with all requirements of the act
and regulations promulgated thereunder, the pertinent parts of which are
as indicated in paragraph (e) of this section.
(vi) A statement that the applicant will initiate recall of all
stocks of the drug product outstanding when so requested by the Food and
Drug Administration.
(vii) A statement that the applicant intends to conduct in vivo
bioavailability tests and that the applicant, under the records and
reports provisions of section 505(k) of the act, will:
(a) Within 30 days after the submission of the application, submit
to the Food and Drug Administration the protocol which the applicant
proposes to follow in conducting these in vivo bioavailability tests.
The protocol shall contain all of the essential elements set forth in
paragraph (d) of this section. The tests shall not be initiated prior to
receiving notification from the Food and Drug Administration that the
bioavailability protocol has been reviewed and either approved or its
deficiencies delineated.
(b) Within 180 days after receiving notification from the Food and
Drug Administration that the bioavailability protocol has been reviewed,
submit to the Food and Drug Administration the results of the in vivo
bioavailability tests.
(2) Digoxin tablets: Any person marketing digoxin tablets, in
addition to complying with all of the requirements of paragraph (a)(1)
of this section, shall include in their abbreviated new drug
application:
(i) A statement that the applicant will establish procedures to test
each lot of digoxin tablets prior to releasing the batch for
distribution to assure that the batch meets all of The United States
Pharmacopeia (USP XVIII) requirements for digoxin tablets including, but
not limited to, potency, content uniformity, and dissolution and either
(a) that the quantity of digoxin dissolved at one hour is not more than
95 percent of the assayed amount of digoxin or (b) that the quantity of
digoxin dissolved at 15 minutes is not more than 90 percent of the
assayed amount of digoxin.
(ii) A statement that finished product specifications shall be
established to include provisions to assure that the range of average
one-hour dissolution values among batches of digoxin tablets does not
exceed 20 percent.
(3) Before releasing for distribution any batch of digoxin tablets
manufactured after January 22, 1974, the manufacturer shall:
(i) Test a sample of the batch to assure that the batch meets all of
the requirements of The United States Pharmacopeia (USP XVIII) including
but not limited to, potency, content uniformity, and dissolution and
either (a) that the quantity of digoxin dissolved at one hour is not
more than 95 percent of the assayed amount of digoxin or (b) that the
quantity of digoxin dissolved at 15 minutes is not more than 90 percent
of the assayed amount of digoxin.
(ii) Submit a sample of the batch to the Food and Drug
Administration according to the procedures set forth in paragraph (g) of
this section. Results of tests conducted on the batch by or for the
manufacturer and the batch production record shall accompany the sample.
(iii) Withhold the batch from distribution until he is notified by
the Food and Drug Administration that the sample was tested and found to
meet all of the requirements in The United States Pharmacopeia (USP
XVIII) for potency, content uniformity, and dissolution and either (a)
that the quantity of digoxin dissolved at one hour is not more than 95
percent of the assayed amount of digoxin or (b) that the quantity of
digoxin dissolved at 15 minutes is not more than 90 percent of the
assayed amount of digoxin.
(iv) Submit a sample of each batch of digoxin tablets as provided
for in paragraph (a)(3)(ii) of this section until he is notified by the
Food and Drug Administration that he is released from
[[Page 23]]
the certification program. This notification will be made on the basis
of sample test results, inspectional findings regarding compliance with
current good manufacturing practice, and compliance with all other
requirements of this section and any other directives issued by the Food
and Drug Administration as a condition for release from the
certification program.
(4) Any manufacturer who has distributed any batch of digoxin
tablets which does not meet the compendial requirement for dissolution,
when tested by the method in The United States Pharmacopeia (USP XVIII),
shall initiate recall of the subject batch when so requested by the Food
and Drug Administration.
(b) Failure of an applicant to submit the protocol and/or the
results of the in vivo bioavailability tests showing adequate evidence
of the product's bioavailability within the times specified in paragraph
(a)(1)(vii) of this section and/or to comply with all of the
certification requirements of paragraph (a)(3) of this section shall be
justification for withdrawal of approval of the application under
section 505(e) of the act.
(c) Any product reformulation or change in manufacturing process
will require the submission of a supplement to the approved abbreviated
new drug application containing adequate data to demonstrate the
bioavailability of the reformulated product. Food and Drug
Administration approval of the supplement is required before the
reformulated product is marketed. The Food and Drug Administration
recommends that, where digoxin tablets are reformulated, manufacturers
reformulate their product to achieve dissolution of 70 to 90 percent at
one hour when tested by all three methods (i.e., the USP method, and the
``paddle-water'' and ``paddle-acid'' methods) described in paragraph (h)
of this section.
(d) The protocol for the in vivo bioavailability tests required in
paragraphs (a) and (c) of this section shall employ a three-way
crossover design using the digoxin test product; a reference digoxin
tablet supplied, on request, by the Food and Drug Administration; and
bulk digoxin USP in an oral solution. Appropriate venous blood and
urinary samples are to be collected and analyzed. The method shall be
capable of detecting the difference between the reference tablet and the
reference oral solution. Bioavailability of the test product shall be
demonstrated if a mean absorption of at least 75 percent of the combined
mean of the two reference standards is observed. Assistance in
developing a protocol for a particular dosage formulation may be
obtained by contacting the Food and Drug Administration, Center for Drug
Evaluation and Research (HFD-420), 5600 Fishers Lane, Rockville, MD
20857.
(e) Parts of the digoxin product labeling indicated below shall be
as follows:
Digoxin Labeling Guidance
(adult and pediatric)
description
Digoxin is one of the cardiac (or digitalis) glycosides, a closely
related group of drugs having in common specific and powerful effects on
the myocardium. These drugs are found in a number of plants. The term
``digitalis'' is used to designate the whole group. Typically, the
glycosides are composed of three portions: a steroid nucleus, a lactone
ring, and a sugar (hence ``glycosides'').
(This section should include a chemical and physical description of
digoxin and the same quantitative ingredient information as that
required on the label.)
Action
The digitalis glycosides have qualitatively the same therapeutic
effects on the heart. They (1) increase the force of myocardial
contraction, (2) increase the refractory period of the atrioventricular
(A-V) node, and (3) to a lesser degree, affect the sinoatrial (S-A) node
and conduction system via the parasympathetic and sympathetic nervous
systems.
Gastrointestinal absorption of digoxin is a passive process. About
50-75 percent of digoxin in tablet form is absorbed. Digoxin is only 20-
25 percent bound to plasma proteins and is predominantly excreted by the
kidneys unmetabolized unless there is significant renal failure. Renal
excretion of digoxin is proportional to glomerular filtration rate and
is largely independent of urine flow. Digoxin is not effectively removed
from the body by dialysis, exchange transfusion, or during
cardiopulmonary bypass, presumably because of tissue binding. In
subjects with normal renal function, digoxin is excreted exponentially
with an average half-life of 36 hours, resulting in the loss of 35-40
percent of the body stores daily.
Serum levels and pharmacokinetics are essentially unchanged by
massive weight loss,
[[Page 24]]
suggesting that lean body mass should be used in dosage calculations.
The peak blood level from oral dosing with tablets occurs 1-3 hours
after administration. The onset of therapeutic action of digoxin after
oral tablets is 1-2 hours, with the peak therapeutic effect occurring 6-
8 hours after dosing.
indications
1. Congestive heart failure, all degrees, is the primary indication.
The increased cardiac output due to digoxin results in diuresis and
general amelioration of the disturbances characteristic of right (venous
congestion, edema) and left (dyspnea, orthopnea, cardiac asthma) heart
failure.
Digoxin, generally, is most effective in ``low output'' failure and
less effective in ``high output'' (bronchopulmonary insufficiency,
infection, hyperthyroidism) heart failure.
Digoxin should be continued after heart failure is abolished unless
some known precipitating factor is corrected.
2. Atrial fibrillation, especially when the ventricular rate is
elevated. Digoxin rapidly reduces ventricular rates and eliminates the
pulse deficit. Palpitation, precordial distress or weakness are relieved
and any concomitant congestive failure ameliorated.
Digoxin should be continued in doses necessary to maintain the
desired ventricular rate and other clinical effects.
3. Atrial flutter. Digoxin slows the heart and regular sinus rhythm
may appear. Frequently the flutter is converted to atrial fibrillation
with a slow ventricular rate. Stopping digoxin at this point may be
followed by restoration of sinus rhythm, especially if the flutter was
of the paroxysmal type. It is preferable, however, to continue digoxin
if failure ensues or if atrial flutter is a frequent occurrence.
4. Paroxysmal atrial tachycardia. Oral digoxin may be used,
especially if the condition is resistant to lesser measures. Depending
on the urgency, a more rapid acting parenteral preparation may be
preferable to initiate digitalization, although if heart failure has
ensued or paroxysms recur frequently, digoxin should be maintained by
oral administration.
Digoxin is not indicated in sinus tachycardia unless due to heart
failure.
5. Cardiogenic shock. The drug is often employed, especially when
the condition is accompanied by pulmonary edema. Digoxin seems to affect
adversely shock due to septicemia from gram negative bacteria.
contraindications
The presence of toxic effects (See ADVERSE REACTIONS section)
induced by any digitalis preparation is a contraindication to all of the
gylcosides.
Allergy, though rare, does occur. It may not extend to all
preparations, and another may be tried.
Ventricular fibrillation.
Warnings
Digitalis alone or with other drugs has been promoted for use in the
treatment of obesity. This use of digoxin or other digitalis glycosides
is unwarranted. Moreover, since they may cause potentially fatal
arrhythmias or other adverse effects, the use of these drugs in the
treatment of obesity is dangerous.
Many of the arrhythmias for which digoxin is advised closely
resemble those reflecting digoxin intoxication. If the possibility of
digoxin intoxication cannot be excluded, cardiac glycosides should be
temporarily withheld if permitted by the clinical situation.
The patient with congestive heart failure may complain of nausea and
vomiting. These symptoms may also be indications on digoxin
intoxication. A clinical determination of the cause of these symptoms
must be attempted before further drug administration.
Patients with renal insufficiency require smaller than usual doses
of digoxin. See ACTION section for mechanism.
precautions
Atrial arrhythmias associated with hypermetabolic states are
particularly resistant to digoxin treatment. Care must be taken to avoid
digoxin toxicity if digoxin is used to help the arrhythmia.
Digoxin is not indicated for the treatment of ventricular
tachycardia unless congestive heart failure supervenes after a
protracted episode not itself due to digoxin.
Potassium depletion sensitizes the myocardium to digoxin, and
toxicity may develop even with the usual dosage. Hypokalemia may also
alter the rate of onset and intensity of the positive inotropic effect
of digoxin. Therefore, it is desirable to maintain normal serum
potassium levels in patients being treated with digoxin.
Potassium wastage may result from diuretic or corticosteriod
therapy, hemodialysis, and from suction of gastrointestinal secretions.
It may accompany malnutrition, diarrhea, prolonged vomiting, old age,
and long-standing congestive heart failure. In general, rapid changes in
serum potassium or other electrolytes are to be avoided, and intravenous
treatment with potassium should be reserved only for special
circumstances as described below (see TREATMENT OF ARRHYTHMIAS PRODUCED
BY OVERDOSAGES section).
Patients with acute myocardial infarction, severe pulmonary disease,
or far advanced heart failure may be more sensitive to digoxin and more
prone to disturbances of rhythm.
[[Page 25]]
Calcium affects contractility and excitability of the heart in a
manner similar to that of digoxin. Calcium may produce serious
arrhythmias in digitalized patients.
In myxedema the digoxin requirements are less because excretion rate
is decreased and blood levels are significantly higher.
In incomplete A-V block, especially in patients subject to Stokes-
Adams attacks, advanced or complete heart block may develop if digoxin
is given. Heart failure in these patients can usually be controlled by
other measures and by increasing the heart rate.
Patients with chronic constructive pericarditis may respond
unfavorably to digoxin.
Patients with idiopathic hypertrophic subaortic stenosis must be
managed extremely carefully. Unless cardiac failure is severe, it is
doubtful whether digoxin should be employed.
Renal insufficiency delays the excretion of digoxin, and dosage must
be adjusted accordingly in patients with renal disease. Note: This
applies also to potassium administration should it become necessary.
Electrical conversion of arrhythmias may require reduction of
digoxin dosage.
adverse reactions
Gynecomastia, uncommon.
Overdosage or toxic effects.
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea are the most
common early symptoms of overdosages in the adult (but rarely
conspicuous in infants). Uncontrolled heart failure may also produce
such symptoms.
Central nervous system: Visual disturbances (blurred vision, yellow
vision), headache, weakness, apathy.
Cardiac disturbances (arrhythmias): Ventricular premature beats are
the most common, except in infants and young children. Paroxysmal and
nonparoxysmal nodal rhythms, atrioventricular (interference)
disassociation and paroxysmal atrial tachycardia (PAT) with block are
also common arrhythmias due to digoxin overdosage. Conduction
disturbances: Excessive slowing of the pulse is a clinical sign of
digoxin overdosage. Atrioventricular block of increasing degree may
proceed to complete heart block. Note: The electrocardiogram is
fundamental in determining the presence and nature of these cardiac
toxic disturbances. Digoxin may also induce other changes (as of the ST
segment), but these provide no measure of the degree of digitalization.
treatment of arrhythmias produced by overdosages
Digoxin should be discontinued until all signs of toxicity are
abolished. Discontinuation may be all that is necessary if toxic
manifestations are not severe and appear after the time for peak effect
of the drug.
Potassium salts are commonly used. Potassium chloride in divided
oral doses totaling 4-6 grams for adults (see PEDIATRIC INFORMATION
section for pediatric dosage) may be given provided renal function is
adequate.
When correction of the arrhythmia is urgent and the serum potassium
level is low or normal, potassium should be administered intravenously
in a solution of 5 percent dextrose in water. A total of 40-100
milliequivalents (30 milliequivalents per 500 milliliters) is given at
the rate of 20 milliequivalents per hour unless limited by pain due to
local irritation.
Additional amounts may be given if the arrhythmia is uncontrolled
and the potassium well tolerated.
Continuous electrocardiographic monitoring should be performed to
watch for any evidence of potassium toxicity, e.g., peaking of T waves,
and to observe the effect on the arrhythmia so that the infusion may be
promptly stopped when the desired effect is achieved.
Caution: Potassium should not be used and may be dangerous for
severe or complete heart block due to digoxin and not related to any
tachycardia.
Other agents that have been approved for the treatment of digoxin
intoxication include procainamide, lidocaine, and propranolol.
dosage and administration
Oral digoxin is administered slowly or rapidly as required until the
desired therapeutic effect is obtained without symptoms of overdosage.
The amount can be predicted approximately from the lean body mass of the
patient with allowances made for excretion during the time taken to
induce digitalization.
Subsequent maintenance dosage is also determined tentatively by the
amount necessary to sustain the desired therapeutic effect.
Recommended dosages are practical average figures that may require
considerable modification as dictated by individual sensitivity or
associated conditions. Diminished renal function is the most important
factor requiring modification of recommended or average doses. (See
WARNINGS and PRECAUTIONS sections.)
The average amount of digoxin that patients must accumulate to be
digitalized with digoxin tablets is 1.0-1.5 milligrams. Digitalization
may be accomplished by any of several approaches that vary in dosage and
frequency of administration, but reach the same endpoint in terms of
total amount accumulated.
In previously undigitalized patients, a single loading dose of 0.5-
0.75 milligram orally usually produces a detectable effect in 1-2 hours
that becomes maximal in 6-8 hours.
[[Page 26]]
Additional doses of 0.25-0.5 milligram may be given cautiously at 6-8
hour intervals to full digitalization.
In previously undigitalized patients, institution of daily
maintenance therapy (0.125-0.5 milligram, see next paragraph) without a
loading dose results in development of a steady-state plateau
concentrations in about 7 days in patients with normal renal function.
The average daily oral maintenance dose is 0.125-0.5 milligram,
usually 0.25 milligram. In the elderly patient, 0.125-0.25 milligram
should be considered the average maintenance dose.
In patients with renal impairment, digoxin excretion is impaired and
serum half-life is prolonged (see ACTION section). Digitalizing and
maintenance doses are lower than those recommended for patients with
normal renal functions. Signs of digoxin toxicity develop sooner in
patients with renal impairment, and it takes longer for toxic signs and
symptoms to disappear. Because of the prolonged half-life, a longer
period of time is required to achieve an initial or new steady-state
plateau in patients with renal impairment than in patients with normal
renal function.
It cannot be overemphasized that the values given are averages and
substantial individual variation can be expected.
(If pediatric dosage is available, the labeling sections above
should be expanded to include the following information.)
pediatric information
warnings
Newborn infants display considerable variability in their tolerance
to digoxin, depending on their degree of maturity.
Premature and immature infants are particularly sensitive, and
dosage must be reduced and digitalization should be even more
individualized and cautiously approached than in more mature infants.
Impaired renal function must also be carefully taken into consideration.
Congestive heart failure accompanying acute glomerulonephritis
requires extreme care in digitalization. A relatively low total dose
administered in divided doses and concomitant use of antihypertensive
drugs has been recommended. ECG monitoring is essential. Digoxin should
be discontinued as soon as possible.
Patients with idiopathic hypertrophic subaortic stenosis must be
managed extremely carefully. Unless cardiac failure is severe, it is
doubtful whether digoxin should be employed.
Patients with rheumatic carditis, especially when severe, are
unusually sensitive to digoxin and prone to disturbances of rhythm. If
heart failure develops, digitalization may be initiated with relatively
low doses; then it can be cautiously increased until a beneficial effect
is obtained. If a therapeutic trial does not result in improvement, the
drug should be considered ineffective and be discontinued.
Note: Digitalis glycosides are an important cause of accidental
poisoning in children.
precautions
Dosage must be carefully titrated and differences in the
bioavailability of parenteral preparations, elixirs, and tablets should
be taken into account when switching patients from one preparation to
another.
Electrocardiographic monitoring may be necessary to avoid
intoxication.
Premonitory signs of toxicity in the newborn are undue slowing of
the sinus rate, sinoatrial arrest, and prolongation of PR interval.
adverse reactions
Toxic signs differ from the adult in a number of respects. Cardiac
arrhythmias are the more reliable and frequent signs of toxicity.
Vomiting and diarrhea, neurologic and visual disturbances are rare
as initial signs.
Premature ventricular systoles are rarely seen; nodal and atrial
systoles are more frequent.
Atrial arrhythmias, atrial ectopic rhythms, and paroxysmal atrial
tachycardia with A-V block particularly are more common manifestations
of toxicity in children. Ventricular arrhythmias are rare.
treatment of arrhythmias produced by overdosages
(See adult section for other recommendations for the treatment of
arrhythmias produced by overdosages and for additional recommendations
and cautions regarding the use of potassium.) Potassium preparations may
be given orally in divided doses totaling 1-1.5 milliequivalents/
kilogram (1 gram K contains 13.4 milliequivalents). When correction of
the arrhythmia is urgent, approximately 0.5 milliequivalents/kilogram of
potassium per hour may be given, with careful electrocardiographic
monitoring, as a solution of 20 milliequivalents or less per 500
milliliters in 5 percent dextrose in water. The total dose should
generally not exceed 2 milliequivalents of potassium/kilogram.
dosage and administration
Digitalization must be individualized. Generally, premature and
immature infants are particularly sensitive, requiring reduced dosage
that must be determined by careful titration.
Oral Dosage. Beyond the immediate newborn period, children require
proportionally greater doses than adults on the basis of
[[Page 27]]
body weight or surface area. The recommended oral digitalizing dosages
in children with normal renal function are:
Newborn infants (normal), up to 1 month, require 40-60 micrograms/
kilogram.
Infants, 1 month to 2 years, require approximately 60-80 micrograms/
kilogram.
Children 2 years to 10 years, require 40-60 micrograms/kilogram.
Children, over 10 years of age, require adult dosages in proportion
to their body weight.
Maintenance therapy is 20-30 percent of the digitalizing dose
administered each day.
Long term use of digoxin is indicated in almost all infants who have
been digitalized for acute congestive heart failure unless the cause is
transient. Many favor maintaining digoxin until at least 2 years of age
in all infants with paroxysmal atrial tachycardia or in those who show
either definite or latent failure.
Many children with severe inoperable congenital defects need digoxin
throughout childhood and often for life.
(f) Abbreviated new drug applications shall be submitted to the Food
and Drug Administration, Center for Drug Evaluation and Research, Office
of Generic Drugs, 5600 Fishers Lane, Rockville, MD 20857.
(g) All samples of digoxin tablets required by paragraph (a)(3) of
this section to be submitted to the Food and Drug Administration shall
be handled as follows:
(1) The sample shall consist of 6 subsamples of 1000 tablets each
collected at random from throughout the manufacturing run. Each of the 6
subsamples shall be identified with the name of the product, the labeled
potency, the date of manufacture, the batch number, and the name and
address of the manufacturer.
(2) The sample together with the batch production record and results
of all tests conducted by or for the manufacturer to determine the
product's identity, strength, quality, and purity, content uniformity
and dissolution shall be submitted to the Department of Health and Human
Services, Public Health Service, FDA National Center for Drug Analysis,
1114 Market St., St. Louis, MO 63101. The outer wrapper shall be
identified ``SAMPLE--DIGOXIN CERTIFICATION.''
(h) The Food and Drug Administration is aware of data with two in
vitro methods, in addition to that described in The United States
Pharmacopeia (USP XVIII), developed to measure digoxin tablets
dissolution. These two methods, the so-called ``paddle-water'' and
``paddle-acid'' methods, are described below and are identical with the
exception of the nature of the dissolution medium used in the procedures
(i.e., distilled or deionized water vs. dilute hydrochloric acid (0.6
percent volume/volume)). The dissolution apparatus used in these two
methods differs significantly from the apparatus described in the method
in the compendium. The Food and Drug Administration is aware that the
three methods (i.e., USP, ``paddle-water,'' and ``paddle-acid'') show
significant differences in dissolution in comparative tests on some
formulations. Definitive bioavailability data to compare the relative
value of each of these methods to predict bioavailability of the few
formulations where the methods show significant differences in
dissolution rate are not now available. Manufacturers who conduct
research utilizing the ``paddle-water'' and ``paddle-acid'' methods,
particularly in comparison with the method in The United States
Pharmacopeia, shall submit any data obtained using these methods to the
Food and Drug Administration pursuant to section 505(k) of the act.
(1) Dissolution apparatus.
(Note: Throughout this procedure use scrupulously clean glassware,
which previously has been rinsed with dilute hydrochloric acid,
distilled or deionized water, then with alcohol, and carefully dried.
Take precautions to prevent contamination from airborne, fluorescent
particles and from metal and rubber surfaces.) The apparatus consists of
a suitable water bath, a 1000 milliliter glass vessel (Kimble Glass No.
26220 or equivalent), a motor, and a polytetrafluoroethylene stirring
blade (Sargent S-76637, Size B, 3 inch length; or equivalent) on a glass
stirring shaft (Sargent 5-76636, 14.5 inch length; or equivalent). The
water bath may be of any convenient size that permits keeping the water
temperature uniformly at 37 deg. C. <SUP>plus-minus</SUP>0.5 deg. C.
throughout the test. The vessel is spherical, and is provided with three
ports at the top, one of which is centered. The lower half of the vessel
is 65 millimeters in inside radius and the vessel's nominal capacity is
1000 milliliters. The glass stirring shaft from the motor is placed in
the center port, and one of the outer ports may be used for insertion of
a thermometer. Samples may be removed for analysis through the other
port. The motor is fitted with a speed-regulating
[[Page 28]]
device that allows the motor speed to be held at 50 rpm
<SUP>plus-minus</SUP>2 rpm. The motor is suspended above the vessel in
such a way that it may be raised or lowered to position the stirring
blade. The glass stirring shaft is 10 millimeters in diameter and about
37 centimeters in length. It must run true on the motor axis without
perceptible wobble. The polytetrafluoroethylene stirring blade is 4
millimeters thick and forms a section of a circle, whose diameter is 83
millimeters and which is subtended by parallel chords of 42 and 77
millimeters. The blade is positioned horizontally, with the 42-
millimeter edge down, 2.5 centimeters <SUP>plus-minus</SUP>0.2
centimeter above the lowest inner surface of the vessel.
(2) Reagents--(i) Dissolution medium. For ``paddle-water,'' use
distilled or deionized water. For ``paddle-acid,'' use dilute
hydrochloric acid (0.6 percent volume/volume). Use the same batch of
dissolution medium throughout the test.
(ii) Standard solutions. Accurately weigh approximately 25
milligrams of The United States Pharmacopeia Digoxin Reference Standard,
dissolve in a minimum amount of 95 percent ethanol in a 500 milliliter
volumetric flask and add 95 percent ethanol to volume and mix. Dilute
10.0 milliliters of this first solution to 100.0 milliliters with 95
percent ethanol and mix for the second solution. Just prior to use,
individually dilute 1.0, 2.0, 3.0, 4.0, and 5.0 milliliter aliquots of
the second solution with dissolution medium to 50.0 milliliters. These
solutions are equivalent to 20, 40, 60, 80, and 100 percent of
dissolution, respectively, for a 0.25 milligram digoxin tablet.
(iii) Extraction solvent. Prepare a solvent containing 6 volumes of
chloroform, analytical reagent grade, with 1 volume of n-propyl alcohol,
analytical reagent grade.
(iv) Ascorbic acid-methanol solution. Prepare a solution containing
2 milligrams of ascorbic acid, analytical reagent grade, per 1
milliliter of methanol, absolute, analytical reagent grade.
(v) Hydrochloric acid, concentrated reagent grade.
(vi) Hydrogen peroxide-methanol solution. On the day of use, dilute
2.0 milliliters of recently assayed 30 percent hydrogen peroxide,
reagent grade, with methanol, absolute, analytical reagent grade to
100.0 milliliters. Store in a refrigerator. Just prior to use, dilute
2.0 milliliters of this solution with methanol to 100.0 milliliters.
(3) Procedure--(i) Dissolution. Place 500 milliliters of dissolution
medium in the vessel, immerse it in the constant-temperature bath set at
37 deg.C.<SUP>plus-minus</SUP>0.5 deg.C., and allow the dissolution
medium to assume the temperature of the bath. Position the shaft so that
there is a distance of 2.5 centimeters <SUP>plus-minus</SUP>0.2
centimeter between the midpoint of the bottom of the blade and the
bottom of the vessel. With the stirrer operating at a speed of 50
rpm<SUP>plus-minus</SUP>2 rpm, place 1 tablet into the flask. After 60
minutes, accurately timed, withdraw 25 milliliters, using a glass
syringe connected to a glass sampling tube, of solution from a point
midway between the stirring shaft and the wall of the vessel, and
approximately midway in depth. Filter the solution promptly after
withdrawal, using a suitable membrane filter of not greater than 0.8
micron porosity (Millipore AAWP 025 00, or equivalent), mounted in a
suitable holder (Millipore Swinnex SX00 025 00, or equivalent),
discarding the first 100 milliliters of filtrate. This is the test
solution. Repeat the dissolution procedure on 5 additional tablets.
(ii) Extraction. Transfer 10.0 milliliters of each of the six
filtrates, 10.0 milliliters of each of the five standard solutions, and
10.0 milliliters of dissolution medium, to provide a blank, in separate
60-milliliter separators. Extract each solution with two 10-milliliter
portions of extraction solvent. Combine the extracts of each solution in
separate, glass-stoppered, 50-milliliter conical flasks, and evaporate
on a steam bath with the aid of a stream of nitrogen to dryness, rinsing
the sides of the flasks with extraction solvent. Take care to ensure
that all traces of solvent are removed, but avoid prolonged heating. For
convenience the residues may be stored in a vacuum desiccator overnight.
(iii) Measurement of fluorescence. Begin with the standard
solutions, and keep all flasks in the same sequence throughout, so that
the elapsed time from addition of reagents to reading of fluorescence is
the same for each.
[[Page 29]]
Carry the test solutions, standard solutions, and the blank through the
determination in one group. Add the following three reagents in as rapid
a sequence as possible, swirling after each addition, treating 1 flask
at a time, in the order named: 1.0 milliliter of ascorbic acid-methanol
solution, 3.0 milliliters of concentrated hydrochloric acid, and 1.0
milliliter of hydrogen peroxide-methanol solution. Insert the stoppers
in the flasks, and after 2 hours, measure the fluorescence at about 485
millimicrons, using excitation at about 372 millimicrons. In order to
provide a check on the stability of the fluorometer, reread one or more
standard solutions. Correct each reading for the blank and plot a
standard curve of fluorescence versus precentage dissolution. Determine
the percentage dissolution of digoxin in the test solutions by reading
from the standard graph.
(iv) Digoxin tablets formulated so that the quantity of digoxin
dissolved at one hour, when tested by the method in The United States
Pharmacopeia (USP XVIII), is greater than 95 percent of the assayed
amount of digoxin and so that the quantity of digoxin dissolved at 15
minutes is greater than 90 percent of the assayed amount of digoxin are
new drugs which may be marketed only with an approved full new drug
application as provided for in Sec. 314.50 of this chapter. The
application shall include, but not be limited to, clinical studies
establishing significantly greater bioavailability than digoxin tablets
meeting compendial requirements and dosage recommendations based on
clinical studies establishing the safe and effective use of the
bioavailable digoxin product. Marketing of these digoxin products will
be allowed only under a proprietary or trade name, established name, and
labeling which differs from that used for digoxin tablets that meet all
of the requirements in The United States Pharmacopeia (USP XVIII) and
that are formulated so that either (a) the quantity of digoxin dissolved
at one hour is not more than 95 percent of the assayed amount of digoxin
or (b) the quantity of digoxin dissolved at 15 minutes is not more than
90 percent of the assayed amount of digoxin. New drug applications for
these digoxin products shall be submitted to the Food and Drug
Administration, Center for Drug Evaluation and Research, Office of Drug
Evaluation I (HFD-100), 5600 Fishers Lane, Rockville, MD 20857.
[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 43137, Sept. 30, 1976;
41 FR 49482, Nov. 3, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar.
29, 1990; 65 FR 56479, Sept. 19, 2000]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.501]
[Page 29-30]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.501 Patient package inserts for oral contraceptives.
(a) Requirement for a patient package insert. The safe and effective
use of oral contraceptive drug products requires that patients be fully
informed of the benefits and the risks involved in their use. An oral
contraceptive drug product that does not comply with the requirements of
this section is misbranded under section 502 of the Federal Food, Drug,
and Cosmetic Act. Each dispenser of an oral contraceptive drug product
shall provide a patient package insert to each patient (or to an agent
of the patient) to whom the product is dispensed, except that the
dispenser may provide the insert to the parent or legal guardian of a
legally incompetent patient (or to the agent of either). The patient
package insert is required to be placed in or accompany each package
dispensed to the patient.
(b) Distribution requirements. (1) For oral contraceptive drug
products, the manufacturer and distributor shall provide a patient
package insert in or with each package of the drug product that the
manufacturer or distributor intends to be dispensed to a patient.
(2) Patient package inserts for oral contraceptives dispensed in
acute-care hospitals or long-term care facilities will be considered to
have been provided in accordance with this section if provided to the
patient before administration of the first oral contraceptive and every
30 days thereafter, as long as the therapy continues.
(c) Contents of patient package insert. A patient package insert for
an oral contraceptive drug product is required to contain the following:
(1) The name of the drug.
(2) A summary including a statement concerning the effectiveness of
oral contraceptives in preventing pregnancy, the contraindications to
the
[[Page 30]]
drug's use, and a statement of the risks and benefits associated with
the drug's use.
(3) A statement comparing the effectiveness of oral contraceptives
to other methods of contraception.
(4) A boxed warning concerning the increased risks associated with
cigarette smoking and oral contraceptive use.
(5) A discussion of the contraindications to use, including
information that the patient should provide to the prescriber before
taking the drug.
(6) A statement of medical conditions that are not contraindications
to use but deserve special consideration in connection with oral
contraceptive use and about which the patient should inform the
prescriber.
(7) A warning regarding the most serious side effects of oral
contraceptives.
(8) A statement of other serious adverse reactions and potential
safety hazards that may result from the use of oral contraceptives.
(9) A statement concerning common, but less serious side effects
which may help the patient evaluate the benefits and risks from the use
of oral contraceptives.
(10) Information on precautions the patients should observe while
taking oral contraceptives, including the following:
(i) A statement of risks to the mother and unborn child from the use
of oral contraceptives before or during early pregnancy;
(ii) A statement concerning excretion of the drug in human milk and
associated risks to the nursing infant;
(iii) A statement about laboratory tests which may be affected by
oral contraceptives; and
(iv) A statement that identifies activities and drugs, foods, or
other substances the patient should avoid because of their interactions
with oral contraceptives.
(11) Information about how to take oral contraceptives properly,
including information about what to do if the patient forgets to take
the product, information about becoming pregnant after discontinuing use
of the drug, a statement that the drug product has been prescribed for
the use of the patient and should not be used for other conditions or
given to others, and a statement that the patient's pharmacist or
practitioner has a more technical leaflet about the drug product that
the patient may ask to review.
(12) A statement of the possible benefits associated with oral
contraceptive use.
(13) The following information about the drug product and the
patient package insert:
(i) The name and place of business of the manufacturer, packer, or
distributor, or the name and place of business of the dispenser of the
product.
(ii) The date, identified as such, of the most recent revision of
the patient package insert placed prominently immediately after the last
section of the labeling.
(d) Other indications. The patient package insert may identify
indications in addition to contraception that are identified in the
professional labeling for the drug product.
(e) Labeling guidance texts. The Food and Drug Administration issues
informal labeling guidance texts under Sec. 10.90(b)(9) of this chapter
to provide assistance in meeting the requirements of this section. A
request for a copy of the guidance texts should be directed to the
Center for Drug Evaluation and Research, Division of Metabolism and
Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857.
(f) Requirement to supplement approved application. Holders of
approved applications for oral contraceptive drug products that are
subject to the requirements of this section are required to submit
supplements under Sec. 314.70(c) of this chapter to provide for the
labeling required by this section. Such labeling may be put into use
without advance approval by the Food and Drug Administration.
[54 FR 22587, May 25, 1989]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.502]
[Page 30-31]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.502 Certain drugs accorded new drug status through rulemaking procedures.
(a) The drugs listed in this paragraph have been determined by
rulemaking procedures to be new drugs within the meaning of section
201(p) of the act. An approved new drug application under
[[Page 31]]
section 505 of the act and part 314 of this chapter is required for
marketing the following drugs:
(1) Aerosol drug products for human use containing 1,1,1-
trichloroethane.
(2) Aerosol drug products containing zirconium.
(3) Amphetamines (amphetamine, dextroamphetamine, and their salts,
and levamfetamine and its salts) for human use.
(4) Camphorated oil drug products.
(5) Certain halogenated salicylanilides (tribromsalan (TBS, 3,4',5-
tribromosalicylanilide), dibromsalan (DBS, 4', 5-dibromosalicylanilide),
metabromsalan (MBS, 3, 5-dibromosalicylanilide), and 3,3', 4,5'-
tetrachlorosalicylanilide (TC-SA)) as an ingredient in drug products.
(6) Chloroform used as an ingredient (active or inactive) in drug
products.
(7) Cobalt preparations intended for use by man.
(8) Intrauterine devices for human use for the purpose of
contraception that incorporate heavy metals, drugs, or other active
substances.
(9) Oral prenatal drugs containing fluorides intended for human use.
(10) Parenteral drug products in plastic containers.
(11) Sterilization of drugs by irradiation.
(12) Sweet spirits of nitre drug products.
(13) Thorium dioxide for drug use.
(14) Timed release dosage forms.
(15) Vinyl chloride as an ingredient, including propellant, in
aerosol drug products.
(b) [Reserved]
[62 FR 12084, Mar. 14, 1997, as amended at 64 FR 401, Jan. 5, 1999]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.503]
[Page 31-34]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.503 Requirements regarding certain radioactive drugs.
(a) On January 8, 1963 (28 FR 183), the Commissioner of Food and
Drugs exempted investigational radioactive new drugs from part 312 of
this chapter provided they were shipped in complete conformity with the
regulations issued by the Nuclear Regulatory Commission. This exemption
also applied to investigational radioactive biologics.
(b) It is the opinion of the Nuclear Regulatory Commission, and the
Food and Drug Administration that this exemption should not apply for
certain specific drugs and that these drugs should be appropriately
labeled for uses for which safety and effectiveness can be demonstrated
by new drug applications or through licensing under the Public Health
Service Act (42 U.S.C. 262 et seq.) in the case of biologics. Continued
distribution under the investigational exemption when the drugs are
intended for established uses will not be permitted.
(c) Based on its experience in regulating investigational
radioactive pharmaceuticals, the Nuclear Regulatory Commission has
compiled a list of reactor-produced isotopes for which it considers that
applicants may reasonably be expected to submit adequate evidence of
safety and effectiveness for use as recommended in appropriate labeling.
Such use may include, among others, the uses in this tabulation:
------------------------------------------------------------------------
Isotope Chemical form Use
------------------------------------------------------------------------
Chromium 51........... Chromate............... Spleen scans.
Do................ ......do............... Placenta localization.
Do................ ......do............... Red blood cell labeling
and survival studies.
Do................ Labeled human serum Gastrointestinal
albumin. protein loss studies.
Do................ ......do............... Placenta localization.
Do................ Labeled red blood cells Do.
Cobalt 58 or Cobalt 60 Labeled cyanocobalamin. Intestinal absorption
studies.
Gold 198.............. Colloidal.............. Liver scans.
Do................ ......do............... Intracavitary treatment
of pleural effusions
and/or ascites.
Do................ ......do............... Interstitial treatment
of cancer.
Iodine 131............ Iodide................. Diagnosis of thyroid
functions.
Do................ ......do............... Thyroid scans.
Do................ ......do............... Treatment of
hyperthyroidism and/or
cardiac dysfunction.
Do................ ......do............... Treatment of thyroid
carcinoma.
Do................ Iodinated human serum Blood volume
albumin. determinations.
Do................ ......do............... Cisternography.
Do................ ......do............... Brain tumor
localization.
Do................ ......do............... Placenta localization.
Do................ ......do............... Cardiac scans for
determination of
pericardial effusions.
[[Page 32]]
Do................ Rose Bengal............ Liver function studies.
Do................ ......do............... Liver scans.
Do................ Iodopyracet, sodium Kidney function studies
iodohippurate, sodium and kidney scans.
diatrizoate,
diatrizoate
methylglucamine,
sodium diprotrizoate,
sodium acetrizoate, or
sodium iothalamate.
Do................ Labeled fats and/or Fat absorption studies.
fatty acids.
Do................ Cholografin............ Cardiac scans for
determination of
pericardial effusions.
Do................ Macroaggregated Lung scans.
iodinated human serum
albumin.
Do................ Colloidal Liver scans.
microaggregated human
serum albumin.
Iodine 125............ Iodide................. Diagnosis of thyroid
function.
Do................ Iodinated human serum Blood volume
albumin. determinations.
Do................ Rose Bengal............ Liver function studies.
Do................ Iodopyracet, sodium Kidney function
iodohippurate, sodium studies.
diatrizoate,
diatrizoate methyl-
glucamine, sodium
diprotrizoate, sodium
acetrizoate, or sodium
iothalamate.
Do................ Labeled fats and/or Fat absorption studies.
fatty acids.
Iron 59............... Chloride, citrate and/ Iron turnover studies.
or sulfate.
Krypton 85............ Gas.................... Diagnosis of cardiac
abnormalities.
Mercury 197........... Chlormerodrin.......... Kidney scans.
Do................ ......do............... Brain scans.
Mercury 203 \1\....... ......do............... Kidney scans.
Do................ ......do............... Brain scans.
Phosphorus 32......... Soluble phosphate...... Treatment of
polycythemia vera.
Do................ ......do............... Treatment of leukemia
and bone metastasis.
Do................ Colloidal chromic Intracavitary treatment
phosphate. of pleural effusions
and/or ascites.
Do................ ......do............... Interstitial treatment
of cancer.
Potassium 42.......... Chloride............... Potassium space
studies.
Selenium 75........... Labeled methionine..... Pancreas scans.
Strontium 85.......... Nitrate or chloride.... Bone scans on patients
with diagnosed cancer.
Technetium 99m........ Pertechnetate.......... Brain scans.
Do................ ......do............... Thyroid scans.
Do................ Sulfur colloid......... Liver and spleen scans.
Do................ Pertechnetate.......... Placenta localization.
Do................ ......do............... Blood pool scans.
Do................ ......do............... Salivary gland scans.
Do................ Diethylenetri-amine Kidney scans.
pentaacetic acid
(DTPA).
Xenon 133............. Gas.................... Diagnosis of cardia
abnormalities.
Cerebral bloodflow
studies. Pulmonary
function studies.
Muscle bloodflow
studies.
------------------------------------------------------------------------
\1\ This item has been removed from the AEC list for kidney scans but is
included as the requirements of this order are applicable.Starttime
Tuesday, April 20, 1999 16:55:11
(d)(1) In view of the extent of experience with the isotopes listed
in paragraph (c) of this section, the Nuclear Regulatory Commission and
the Food and Drug Administration conclude that such isotopes should not
be distributed under investigational-use labeling when they are actually
intended for use in medical practice.
(2) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (c) of this section, in the ``chemical form'' and intended for
the uses stated, is terminated on March 3, 1972, except as provided in
paragraph (d)(3) of this section.
(3) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (c) of this section, in the ``chemical form'' and intended for
the uses stated, for which drug a new drug application or a
``Investigational New Drug Application'' was submitted prior to March 3,
1972, or for which biologic an application for product license or
``Investigational New Drug Application'' was submitted prior to March 3,
1972, is terminated on August 20, 1976, unless an approvable notice was
issued on or before August 20, 1976, in which case the exemption is
terminated either upon the subsequent issuance of a nonapprovable notice
for the new drug application or on November 20, 1976, whichever occurs
first.
(e) No exemption from section 505 of the act or from part 312 of
this chapter
[[Page 33]]
is in effect or has been in effect for radioactive drugs prepared from
accelerator-produced radioisotopes, naturally occurring isotopes, or
nonradioactive substances used in conjunction with isotopes.
(f)(1) Based on its experience in regulating investigational
radioactive pharmaceuticals, the Nuclear Regulatory Commission has
compiled a list of reactor-produced isotopes for which it considers that
applicants may reasonably be expected to submit adequate evidence of
safety and effectiveness for use as recommended in appropriate labeling;
such use may include, among others, the uses in this tabulation:
------------------------------------------------------------------------
Isotope Chemical form Use
------------------------------------------------------------------------
Fluorine 18........... Fluoride............... Bone imaging.
Indium-113m........... Diethylenetriamine Brain imaging; kidney
pentaacetic acid imaging.
(DTPA).
Do................ Chloride............... Placenta imaging; blood
pool imaging.
Technetium 99m........ Human serum albumin Lung imaging.
microspheres.
Do................ Diethylenetriamine Kidney imaging; kidney
pentaacetic acid (Sn). function studies.
Do................ ......do............... Brain imaging.
Do................ Polyphosphates......... Bone imaging.
Do................ Technetated aggregated Lung imaging.
albumin (human).
Do................ Disodium etidronate.... Bone imaging.
------------------------------------------------------------------------
(2) In view of the extent of experience with the isotopes listed in
paragraph (f)(1) of this section, the Nuclear Regulatory Commission and
the Food and Drug Administration conclude that they should not be
distributed under investigational-use labeling when they are actually
intended for use in medical practice.
(3) Any manufacturer or distributor interested in continuing to ship
in interstate commerce drugs containing the isotopes listed in paragraph
(f)(1) of this section for any of the indications listed, shall submit,
on or before August 25, 1975 to the Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, a new drug application or a ``Investigational New Drug
Application'' for each such drug for which the manufacturer or
distributor does not have an approved new drug application pursuant to
section 505(b) of the act. If the drug is a biologic, a
``Investigational New Drug Application'' or an application for a license
under section 351 of the Public Health Service Act shall be submitted to
the Center for Biologics Evaluation and Research, Food and Drug
Administration, 8800 Rockville Pike, Bethesda, MD 20014, in lieu of any
submission to the Center for Drug Evaluation and Research.
(4) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (f)(1) of this section, in the ``chemical form'' and intended
for the uses stated, is terminated on August 26, 1975 except as provided
in paragraph (f)(5) of this section.
(5)(i) Except as provided in paragraph (f)(5)(ii) of this section,
the exemption referred to in paragraph (a) of this section, as applied
to any drug containing any of the isotopes listed in paragraph (f)(1) of
this section, in the ``chemical form'' and intended for the uses stated,
for which drug a new drug application or ``Investigational New Drug
Application'' was submitted to the Center for Drug Evaluation and
Research on or before August 25, 1975 is terminated on August 20, 1976,
unless an approvable notice was issued on or before August 20, 1976, in
which case the exemption is terminated either upon the subsequent
issuance of a nonapprovable notice for the new drug application or on
November 20, 1976, whichever occurs first.
(ii) The exemption referred to in paragraph (a) of this section, as
applied to any biologic containing any of the isotopes listed in
paragraph (f)(1) of this section in the ``chemical form'' and intended
for the uses stated, for which biologic an application for product
license or ``Investigational New Drug Application'' was submitted to the
Center for Biologics Evaluation and Research on or before August 25,
1975 is terminated on October 20, 1976, unless an approvable notice was
issued on or before October 20, 1976, in which case the exemption is
terminated either upon the subsequent issuance of a nonapprovable notice
for the new drug application or on January 20, 1977, whichever occurs
first.
[[Page 34]]
(g) The exemption referred to in paragraph (a) of this section, as
applied to any drug intended solely for investigational use as part of a
research project, which use had been approved on or before July 25, 1975
in accordance with 10 CFR 35.11 (or equivalent regulation of an
Agreement State) is terminated on February 20, 1976 if the manufacturer
of such drug or the sponsor of the investigation of such drug submits on
or before August 25, 1975 to the Food and Drug Administration, Bureau of
Drugs, HFD-150, 5600 Fishers Lane, Rockville, MD 20857, the following
information:
(1) The research project title;
(2) A brief description of the purpose of the project;
(3) The name of the investigator responsible;
(4) The name and license number of the institution holding the
specific license under 10 CFR 35.11 (or equivalent regulation of an
Agreement State);
(5) The name and maximum amount per subject of the radionuclide
used;
(6) The number of subjects involved; and
(7) The date on which the administration of the radioactive drugs is
expected to be completed.
(h) The exemption referred to in paragraph (a) of this section, as
applied to any drug not referred to in paragraphs (d), (f), and (g) of
this section, is terminated on August 26, 1975.
[39 FR 11680, Mar. 29, 1974, as amended at 40 FR 31307, July 25, 1975;
40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947,
Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990; 64
FR 56449, Oct. 20, 1999]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.509]
[Page 34]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.509 Parenteral drug products in plastic containers.
(a) Any parenteral drug product packaged in a plastic immediate
container is not generally recognized as safe and effective, is a new
drug within the meaning of section 201(p) of the act, and requires an
approved new drug application as a condition for marketing. An
``Investigational New Drug Application'' set forth in part 312 of this
chapter is required for clinical investigations designed to obtain
evidence of safety and effectiveness.
(b) As used in this section, the term ``large volume parenteral drug
product'' means a terminally sterilized aqueous drug product packaged in
a single-dose container with a capacity of 100 milliliters or more and
intended to be administered or used intravenously in a human.
(c) Until the results of compatibility studies are evaluated, a
large volume parenteral drug product for intravenous use in humans that
is packaged in a plastic immediate container on or after April 16, 1979,
is misbranded unless its labeling contains a warning that includes the
following information:
(1) A statement that additives may be incompatible.
(2) A statement that, if additive drugs are introduced into the
parenteral system, aseptic techniques should be used and the solution
should be thoroughly mixed.
(3) A statement that a solution containing an additive drug should
not be stored.
(d) This section does not apply to a biological product licensed
under the Public Health Service Act of July 1, 1944 (42 U.S.C. 201).
[62 FR 12084, Mar. 14, 1997]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.515]
[Page 34-35]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.515 Patient package inserts for estrogens.
(a) Requirement for a patient package insert. FDA concludes that the
safe and effective use of drug products containing estrogens requires
that patients be fully informed of the benefits and risks involved in
the use of these drugs. Accordingly, except as provided in paragraph (e)
of this section, each estrogen drug product restricted to prescription
distribution, including products containing estrogens in fixed
combinations with other drugs, shall be dispensed to patients with a
patient package insert containing information concerning the drug's
benefits and risks. An estrogen drug product that does not comply with
the requirements of this section is misbranded under section 502(a) of
the Federal Food, Drug, and Cosmetic Act.
(b) Distribution requirements. (1) For estrogen drug products, the
manufacturer and distributor shall provide a patient package insert in
or with each package of the drug product that the
[[Page 35]]
manufacturer or distributor intends to be dispensed to a patient.
(2) In the case of estrogen drug products in bulk packages intended
for multiple dispensing, and in the case of injectables in multiple-dose
vials, a sufficient number of patient labeling pieces shall be included
in or with each package to assure that one piece can be included with
each package or dose dispensed or administered to every patient. Each
bulk package shall be labeled with instructions to the dispensor to
include one patient labeling piece with each package dispensed or, in
the case of injectables, with each dose administered to the patient.
This section does not preclude the manufacturer or labeler from
distributing additional patient labeling pieces to the dispensor.
(3) Patient package inserts for estrogens dispensed in acute-care
hospitals or long-term care facilities will be considered to have been
provided in accordance with this section if provided to the patient
before administration of the first estrogen and every 30 days
thereafter, as long as the therapy continues.
(c) Patient package insert contents. A patient package insert for an
estrogen drug product is required to contain the following information:
(1) The name of the drug.
(2) The name and place of business of the manufacturer, packer, or
distributor.
(3) A statement regarding the benefits and proper uses of estrogens.
(4) The contraindications to use, i.e., when estrogens should not be
used.
(5) A description of the most serious risks associated with the use
of estrogens.
(6) A brief summary of other side effects of estrogens.
(7) Instructions on how a patient may reduce the risks of estrogen
use.
(8) The date, identified as such, of the most recent revision of the
patient package insert.
(d) Guidance language. The Food and Drug Administration issues
informal labeling guidance texts under Sec. 10.90(b)(9) of this chapter
to provide assistance in meeting the requirements of paragraph (c) of
this section. Requests for a copy of the guidance text should be
directed to the Center for Drug Evaluation and Research, Division of
Metabolism and Endocrine Drug Products (HFD-510), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857.
(e) Exemptions. This section does not apply to estrogen-progestogen
oral contraceptives. Labeling requirements for these products are set
forth in Sec. 310.501.
(f) Requirement to supplement approved application. Holders of
approved applications for estrogen drug products that are subject to the
requirements of this section must submit supplements under
Sec. 314.70(c) of this chapter to provide for the labeling required by
paragraph (a) of this section. Such labeling may be put into use without
advance approval by the Food and Drug Administration.
[55 FR 18723, May 4, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.517]
[Page 35-36]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea class.
(a) The University Group Diabetes Program clinical trial has
reported an association between the administration of tolbutamide and
increased cardiovascular mortality. The Food and Drug Administration has
concluded that this reported association provides adequate basis for a
warning in the labeling. In view of the similarities in chemical
structure and mode of action, the Food and Drug Administration also
believes it is prudent from a safety standpoint to consider that the
possible increased risk of cardiovascular mortality from tolbutamide
applies to all other sulfonylurea drugs as well. Therefore, the labeling
for oral hypoglycemic drugs of the sulfonylurea class shall include a
warning concerning the possible increased risk of cardiovascular
mortality associated with such use, as set forth in paragraph (b) of
this section.
(b) Labeling for oral hypoglycemic drugs of the sulfonylurea class
shall include in boldface type at the beginning of the ``Warnings''
section of the labeling the following statement:
Special Warning on Increased Risk of Cardiovascular Mortality
The administration of oral hypoglycemic drugs has been reported to
be associated
[[Page 36]]
with increased cardiovascular mortality as compared to treatment with
diet alone or diet plus insulin. This warning is based on the study
conducted by the University Group Diabetes Program (UGDP), a long-term
prospective clinical trial designed to evaluate the effectiveness of
glucose-lowering drugs in preventing or delaying vascular complications
in patients with non-insulin-dependent diabetes. The study involved 823
patients who were randomly assigned to one of four treatment groups
(Diabetes, 19 (supp. 2): 747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus
a fixed dose of tolbutamide (1.5 grams per day) had a rate of
cardiovascular mortality approximately 2\1/2\ times that of patients
treated with diet alone. A significant increase in total mortality was
not observed, but the use of tolbutamide was discontinued based on the
increase in cardiovascular mortality, thus limiting the opportunity for
the study to show an increase in overall mortality. Despite controversy
regarding the interpretation of these results, the findings of the UGDP
study provide an adequate basis for this warning. The patient should be
informed of the potential risks and advantages of (name of drug) and of
alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was
included in this study, it is prudent from a safety standpoint to
consider that this warning may also apply to other oral hypoglycemic
drugs in this class, in view of their close similarities in mode of
action and chemical structure.
[49 FR 14331, Apr. 11, 1984]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.518]
[Page 36-37]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.518 Drug products containing iron or iron salts.
Drug products containing elemental iron or iron salts as an active
ingredient in solid oral dosage form, e.g., tablets or capsules shall
meet the following requirements:
(a) Packaging. If the product contains 30 milligrams or more of iron
per dosage unit, it shall be packaged in unit-dose packaging. ``Unit-
dose packaging'' means a method of packaging a product into a
nonreusable container designed to hold a single dosage unit intended for
administration directly from that container, irrespective of whether the
recommended dose is one or more than one of these units. The term
``dosage unit'' means the individual physical unit of the product, e.g.,
tablet or capsule. Iron-containing drugs that are subject to this
regulation are also subject to child-resistant special packaging
requirements in 16 CFR parts 1700, 1701, and 1702.
(b) Temporary exemption. (1) Drug products offered in solid oral
dosage form (e.g., tablets or capsules), and containing 30 milligrams or
more of iron per dosage unit, are exempt from the provisions of
paragraph (a) of this section until January 15, 1998, if the sole source
of iron in the drug product is carbonyl iron that meets the
specifications of Sec. 184.1375 of this chapter.
(2) If this temporary exemption is not extended or made permanent,
such drug products shall be in compliance with the provisions of
paragraph (a) of this section on or before July 15, 1998.
(c) Labeling. (1) The label of any drug in solid oral dosage form
(e.g., tablets or capsules) that contains iron or iron salts for use as
an iron source shall bear the following statement:
WARNING: Accidental overdose of iron-containing products is a
leading cause of fatal poisoning in children under 6. Keep this product
out of reach of children. In case of accidental overdose, call a doctor
or poison control center immediately.
(2)(i) The warning statement required by paragraph (c)(1) of this
section shall appear prominently and conspicuously on the information
panel of the immediate container label.
(ii) If a drug product is packaged in unit-dose packaging, and if
the immediate container bears labeling but not a label, the warning
statement required by paragraph (c)(1) of this section shall appear
prominently and conspicuously on the immediate container labeling in a
way that maximizes the likelihood that the warning is intact until all
of the dosage units to which it applies are used.
(3) Where the immediate container is not the retail package, the
warning statement required by paragraph (c)(1) of this section shall
also appear prominently and conspicuously on the information panel of
the retail package label.
(4) The warning statement shall appear on any labeling that contains
warnings.
(5) The warning statement required by paragraph (c)(1) of this
section shall be set off in a box by use of hairlines.
[[Page 37]]
(d) The iron-containing inert tablets supplied in monthly packages
of oral contraceptives are categorically exempt from the requirements of
paragraphs (a) and (c) of this section.
[62 FR 2250, Jan. 15, 1997; 62 FR 15111, Mar. 31, 1997]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.519]
[Page 37]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.519 Drug products marketed as over-the-counter (OTC) daytime sedatives.
(a) Antihistamines, bromides, and scopolamine compounds, either
singly or in combinations, have been marketed as ingredients in over-
the-counter (OTC) drug products for use as daytime sedatives. The
following claims have been made for daytime sedative products:
``occasional simple nervous tension,'' ``nervous irritability,''
``nervous tension headache,'' ``simple nervousness due to common every
day overwork and fatigue,'' ``a relaxed feeling,'' ``calming down and
relaxing,'' ``gently soothe away the tension,'' ``calmative,''
``resolving that irritability that ruins your day,'' ``helps you
relax,'' ``restlessness,'' ``when you're under occasional stress . . .
helps you work relaxed.'' Based on evidence presently available, there
are no ingredients that can be generally recognized as safe and
effective for use as OTC daytime sedatives.
(b) Any OTC drug product that is labeled, represented, or promoted
as an OTC daytime sedative (or any similar or related indication) is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act for which an approved new drug
application under section 505 of the act and part 314 of this chapter is
required for marketing.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted as an OTC daytime
sedative (or any similar or related indication) is safe and effective
for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) Any OTC daytime sedative drug product introduced into interstate
commerce after December 24, 1979, that is not in compliance with this
section is subject to regulatory action.
[44 FR 36380, June 22, 1979; 45 FR 47422, July 15, 1980, as amended at
55 FR 11579, Mar. 29, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.527]
[Page 37-38]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.527 Drug products containing active ingredients offered over-the-counter (OTC) for external use as hair growers or for hair loss prevention.
(a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid,
biotin and all other B-vitamins, dexpanthenol, estradiol and other
topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20,
polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction
of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat
germ oil have been marketed as ingredients in OTC drug products for
external use as hair growers or for hair loss prevention. There is a
lack of adequate data to establish general recognition of the safety and
effectiveness of these or any other ingredients intended for OTC
external use as a hair grower or for hair loss prevention. Based on
evidence currently available, all labeling claims for OTC hair grower
and hair loss prevention drug products for external use are either
false, misleading, or unsupported by scientific data. Therefore, any OTC
drug product for external use containing an ingredient offered for use
as a hair grower or for hair loss prevention cannot be considered
generally recognized as safe and effective for its intended use.
(b) Any OTC drug product that is labeled, represented, or promoted
for external use as a hair grower or for hair loss prevention is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
new drug application under section 505 of the act and part 314 of this
chapter is required for marketing. In the absence of an approved new
drug application, such product is also misbranded under section 502 of
the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC external use as a
hair grower or for hair loss prevention is safe and effective for the
purpose intended must
[[Page 38]]
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After January 8, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[54 FR 28777, July 7, 1989]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.528]
[Page 38]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.528 Drug products containing active ingredients offered over-the-counter (OTC) for use as an aphrodisiac.
(a) Any product that bears labeling claims that it will arouse or
increase sexual desire, or that it will improve sexual performance, is
an aphrodisiac drug product. Anise, cantharides, don qual, estrogens,
fennel, ginseng, golden seal, gotu kola, Korean ginseng, licorice,
mandrake, methyltestosterone, minerals, nux vomica, Pega Palo,
sarsaparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine
hydrochloride, and yohimbinum have been present as ingredients in such
drug products. Androgens (e.g., testosterone and methyltestosterone) and
estrogens are powerful hormones when administered internally and are not
safe for use except under the supervision of a physician. There is a
lack of adequate data to establish general recognition of the safety and
effectiveness of any of these ingredients, or any other ingredient, for
OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use
are either false, misleading, or unsupported by scientific data. The
following claims are examples of some that have been made for
aphrodisiac drug products for OTC use: ``acts as an aphrodisiac;''
``arouses or increases sexual desire and improves sexual performance;''
``helps restore sexual vigor, potency, and performance;'' ``improves
performance, staying power, and sexual potency;'' and ``builds virility
and sexual potency.'' Based on evidence currently available, any OTC
drug product containing ingredients for use as an aphrodisiac cannot be
generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or prompted
for use as an aphrodisiac is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the
act), for which an approved new drug application under section 505 of
the act and part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as an
aphrodisiac is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After January 8, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[54 FR 28786, July 7, 1989]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.529]
[Page 38-39]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.529 Drug products containing active ingredients offered over-the-counter (OTC) for oral use as insect repellents.
(a) Thiamine hydrochloride (vitamin B-1) has been marketed as an
ingredient in over-the-counter (OTC) drug products for oral use as an
insect repellent (an orally administered drug product intended to keep
insects away). There is a lack of adequate data to establish the
effectiveness of this, or any other ingredient for OTC oral use as an
insect repellent. Labeling claims for OTC orally administered insect
repellent drug products are either false, misleading, or unsupported by
scientific data. The following claims are examples of some that have
been made for orally administered OTC insect repellent drug products:
``Oral mosquito repellent,'' ``mosquitos avoid you,'' ``bugs stay
away,'' ``keep mosquitos away for 12 to 24 hours,'' and ``the newest way
to fight mosquitos.'' Therefore, any drug product containing ingredients
offered for oral use as an insect repellent cannot be generally
recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for oral use as an insect repellent is regarded as
[[Page 39]]
a new drug within the meaning of section 201(p) of the Federal Food,
Drug and Cosmetic Act for which an approved new drug application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application, such
product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted OTC for oral use as an
insect repellent is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any such drug product in interstate commerce after December 17,
1985, that is not in compliance with this section is subject to
regulatory action.
[40 FR 25171, June 17, 1985, as amended at 55 FR 11579, Mar. 29, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.530]
[Page 39]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.530 Topically applied hormone-containing drug products for over-the-counter (OTC) human use.
(a) The term ``hormone'' is used broadly to describe a chemical
substance formed in some organ of the body, such as the adrenal glands
or the pituitary, and carried to another organ or tissue, where it has a
specific effect. Hormones include, for example, estrogens, progestins,
androgens, anabolic steroids, and adrenal corticosteroids, and synthetic
analogs. Estrogens, progesterone, pregnenolone, and pregnenolone acetate
have been present as ingredients in OTC drug products marketed for
topical use as hormone creams. However, there is a lack of adequate data
to establish effectiveness for any OTC drug use of these ingredients.
Therefore, with the exception of those hormones identified in paragraph
(e) of this section, any OTC drug product containing an ingredient
offered for use as a topically applied hormone cannot be considered
generally recognized as safe and effective for its intended use. The
intended use of the product may be inferred from the product's labeling,
promotional material, advertising, and any other relevant factor. The
use of the word ``hormone'' in the text of the labeling or in the
ingredient statement is an implied drug claim. The claim implied by the
use of this term is that the product will have a therapeutic or some
other physiological effect on the body. Therefore, reference to a
product as a ``hormone cream'' or any statement in the labeling
indicating that ``hormones'' are present in the product, or any
statement that features or emphasizes the presence of a hormone
ingredient in the product, will be considered to be a therapeutic claim
for the product, or a claim that the product will affect the structure
or function of the body, and will consequently cause the product to be a
drug.
(b) Any OTC drug product that is labeled, represented, or promoted
as a topically applied hormone-containing product for drug use, with the
exception of those hormones identified in paragraph (e) of this section,
is regarded as a new drug within the meaning of section 201(p) of the
act, for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as a
topically applied hormone-containing drug product is safe and effective
for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) After March 9, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(e) This section does not apply to hydrocortisone and hydrocortisone
acetate labeled, represented, or promoted for OTC topical use in
accordance with part 348 of this chapter.
[58 FR 47610, Sept. 9, 1993]
[[Page 40]]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.531]
[Page 40]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.531 Drug products containing active ingredients offered over-the-counter (OTC) for the treatment of boils.
(a) Aminacrine hydrochloride, benzocaine, bismuth subnitrate,
calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene,
ichthammol, isobutamben, juniper tar (oil of cade), lanolin, magnesium
sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum,
phenol, pine tar, rosin, rosin cerate, sassafras oil, sulfur, thymol,
triclosan, and zinc oxide have been present in OTC boil treatment drug
products. There is a lack of adequate data to establish general
recognition of the safety and effectiveness of these or any other
ingredient for OTC use for the treatment of boils. Treatment is defined
as reducing the size of a boil or reducing an infection related to a
boil. Treatment has involved the use of ``drawing salves'' for these
purposes. These ``drawing salves'' contained various ingredients. Based
on evidence currently available, any OTC drug product offered for the
treatment of boils cannot be considered generally recognized as safe and
effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for the treatment of boils is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act),
for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any OTC
boil treatment drug product is safe and effective for the purpose
intended must comply with the requirements and procedures governing the
use of investigational new drugs set forth in part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product that contains
aminacrine hydrochloride, bismuth subnitrate, calomel, camphor,
cholesterol, ergot fluid extract, hexachlorophene, isobutamben, juniper
tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl
salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin,
rosin cerate, sassafras oil, thymol, or zinc oxide initially introduced
or initially delivered for introduction into interstate commerce that is
not in compliance with this section is subject to regulatory action.
(e) After May 16, 1994, any such OTC drug product that contains
benzocaine, ichthammol, sulfur, or triclosan initially introduced or
initially delivered for introduction into interstate commerce that is
not in compliance with this section is subject to regulatory action.
(f) This section does not apply to drug products that contain
benzocaine labeled, represented, or promoted for OTC topical use in
accordance with part 348 of this chapter.
[58 FR 60336, Nov. 15, 1993]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.532]
[Page 40-41]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.532 Drug products containing active ingredients offered over-the-counter (OTC) to relieve the symptoms of benign prostatic hypertrophy.
(a) The amino acids glycine, alanine, and glutamic acid (alone or in
combination) and the ingredient sabal have been present in over-the-
counter (OTC) drug products to relieve the symptoms of benign prostatic
hypertrophy, e.g., urinary urgency and frequency, excessive urinating at
night, and delayed urination. There is a lack of adequate data to
establish general recognition of the safety and effectiveness of these
or any other ingredients for OTC use in relieving the symptoms of benign
prostatic hypertrophy. In addition, there is no definitive evidence that
any drug product offered for the relief of the symptoms of benign
prostatic hypertrophy would alter the obstructive or inflammatory signs
and symptoms of this condition. Therefore, self-medication with OTC drug
products might unnecessarily delay diagnosis and treatment of
progressive obstruction and secondary infections. Based on evidence
currently available, any OTC drug product containing ingredients offered
for use in relieving the symptoms of benign prostatic hypertrophy cannot
be generally recognized as safe and effective.
[[Page 41]]
(b) Any OTC drug product that is labeled, represented, or promoted
to relieve the symptoms of benign prostatic hypertrophy is regarded as a
new drug within the meaning of section 201(p) of the Federal Food, Drug,
and Cosmetic Act (the act), for which an approved application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved application, such product is
also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use to relieve
the symptoms of benign prostatic hypertrophy is safe and effective for
the purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After August 27, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[55 FR 6930, Feb. 27, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.533]
[Page 41]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.533 Drug products containing active ingredients offered over-the-counter (OTC) for human use as an anticholinergic in cough-cold drug products.
(a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids
as contained in Atropa belladonna and Datura stramonium have been
present as ingredients in cough-cold drug products for use as an
anticholinergic. Anticholinergic drugs have been marketed OTC in cough-
cold drug products to relieve excessive secretions of the nose and eyes,
symptoms that are commonly associated with hay fever, allergy, rhinitis,
and the common cold. Atropine sulfate for oral use as an anticholinergic
is probably safe at dosages that have been used in marketed cough-cold
products (0.2 to 0.3 milligram); however, there are inadequate data to
establish general recognition of the effectiveness of this ingredient.
The belladonna alkaloids, which contain atropine (d, dl hyoscyamine) and
scopolamine (l- hyoscine), are probably safe for oral use at dosages
that have been used in marketed cough-cold products (0.2 milligram) but
there are inadequate data to establish general recognition of the
effectiveness of these ingredients as an anticholinergic for cough-cold
use. Belladonna alkaloids for inhalation use, as contained in Atropa
belladonna and Datura stramonium, are neither safe nor effective as an
OTC anticholinergic. There are inadequate safety and effectiveness data
to establish general recognition of the safety and/or effectiveness or
any of these ingredients, or any other ingredient, for OTC use as an
anticholinergic in cough-cold drug products.
(b) Any OTC cough-cold drug product that is labeled, represented, or
promoted for use as an anticholinergic is regarded as a new drug within
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic
Act, for which an approved new drug application under section 505 of the
act and part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
cough-cold drug product labeled, represented, or promoted for OTC use as
an anticholinergic is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC
cough-cold drug product that is labeled, represented, or promoted for
use as an anticholinergic may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application.
[50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.534]
[Page 41-42]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.534 Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents.
(a) Allantoin, carbamide peroxide in anhydrous glycerin, water
soluble chlorophyllins, and hydrogen peroxide in aqueous solution have
been present in oral mucosal injury drug products
[[Page 42]]
for use as oral wound healing agents. Oral wound healing agents have
been marketed as aids in the healing of minor oral wounds by means other
than cleansing and irrigating, or by serving as a protectant. Allantoin,
carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins,
and hydrogen peroxide in aqueous solution are safe for use as oral wound
healing agents, but there are inadequate data to establish general
recognition of the effectiveness of these ingredients as oral wound
healing agents.
(b) Any OTC drug product that is labeled, represented, or promoted
for use as an oral wound healing agent is regarded as a new drug within
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic
Act, for which an approved new drug application under section 505 of the
act and part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as an oral
wound healing agent is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any OTC drug
product that is labeled, represented, or promoted for use as an oral
wound healing agent may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application.
[51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.536]
[Page 42]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.536 Drug products containing active ingredients offered over-the-counter (OTC) for use as a nailbiting or thumbsucking deterrent.
(a) Denatonium benzoate and sucrose octaacetate have been present in
OTC nailbiting and thumbsucking deterrent drug products. There is a lack
of adequate data to establish general recognition of the safety and
effectiveness of these and any other ingredients (e.g., cayenne pepper)
for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence
currently available, any OTC drug product containing ingredients offered
for use as a nailbiting or thumbsucking deterrent cannot be generally
recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, and promoted
as a nailbiting or thumbsucking deterrent is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act) for which an approved application or abbreviated
application under section 505 of the act and part 314 of this chapter is
required for marketing. In the absence of an approved new drug
application or abbreviated new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as a
nailbiting or thumbsucking deterrent is safe and effective for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After March 2, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[58 FR 46754, Sept. 2, 1993]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.537]
[Page 42-43]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.537 Drug products containing active ingredients offered over-the-counter (OTC) for oral administration for the treatment of fever blisters and cold sores.
(a) l-lysine (lysine, lysine hydrochloride), Lactobacillus
acidophilus, and Lactobacillus bulgaricus have been present in orally
administered OTC drug products to treat fever blisters and cold sores.
There is a lack of adequate data to establish general recognition of the
safety and effectiveness of these or any other orally administered
ingredients for OTC use to treat or relieve the symptoms or discomfort
of fever blisters and cold sores. Based on evidence currently available,
any
[[Page 43]]
OTC drug product for oral administration containing ingredients offered
for use in treating or relieving the symptoms or discomfort of fever
blisters and cold sores cannot be generally recognized as safe and
effective.
(b) Any OTC drug product for oral administration that is labeled,
represented, or promoted to treat or relieve the symptoms or discomfort
of fever blisters and cold sores is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act
(the act), for which an approved application under section 505 of the
act and part 314 of this chapter is required for marketing. In the
absence of an approved application, such product is also misbranded
under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product for oral administration labeled, represented, or promoted
for OTC use to treat or relieve the symptoms or discomfort of fever
blisters and cold sores is safe and effective for the purpose intended
must comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After December 30, 1992, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[57 FR 29173, June 30, 1992]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.538]
[Page 43]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.538 Drug products containing active ingredients offered over-the-counter (OTC) for use for ingrown toenail relief.
(a) Any product that bears labeling claims such as for ``temporary
relief of discomfort from ingrown toenails,'' or ``ingrown toenail
relief product,'' or ``ingrown toenail reliever,'' or similar claims is
considered an ingrown toenail relief drug product. Benzocaine,
chlorobutanol, chloroxylenol, dibucaine, sodium sulfide, tannic acid,
and urea have been present as ingredients in such products. There is
lack of adequate data to establish general recognition of the safety and
effectiveness of these or any other ingredients for OTC use for ingrown
toenail relief. Based on evidence currently available, any OTC drug
product containing ingredients offered for use for ingrown toenail
relief cannot be generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for ingrown toenail relief is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act),
for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use for ingrown
toenail relief is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After March 9, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[58 FR 47605, Sept. 9, 1993]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.540]
[Page 43-44]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.540 Drug products containing active ingredients offered over-the-counter (OTC) for use as stomach acidifiers.
(a) Betaine hydrochloride, glutamic acid hydrochloride, diluted
hydrochloric acid, and pepsin have been present as ingredients in over-
the-counter (OTC) drug products for use as stomach acidifiers. Because
of the lack of adequate data to establish the effectiveness of these or
any other ingredients for use in treating achlorhydria and
hypochlorhydria, and because such conditions are asymptomatic, any OTC
drug product containing ingredients offered for use as a stomach
acidifier cannot be considered generally recognized as safe and
effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for use as a stomach acidifier is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug, and
[[Page 44]]
Cosmetic Act, for which an approved new drug application under section
505 of the act and part 314 of this chapter is required for marketing.
In the absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted as a stomach acidifier
for OTC use is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC
drug product initially introduced or initially delivered for
introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
[53 FR 31271, Aug. 17, 1988]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.541]
[Page 44]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.541 Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hypophosphatemia.
(a) Hypophosphatemia is a condition in which an abnormally low
plasma level of phosphate occurs in the blood. This condition is not
amenable to self-diagnosis or self-treatment. Treatment of this
condition should be restricted to the supervision of a physician. For
this reason, any drug product containing ingredients offered for OTC use
in the treatment of hypophosphatemia cannot be considered generally
recognized as safe and effective.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of hypophosphatemia is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act), for which an approved application under section
505 of the act and part 314 of this chapter is required for marketing.
In the absence of an approved application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use in the
treatment of hypophosphatemia is safe and effective for the purpose
intended must comply with the requirements and procedures governing the
use of investigational new drugs set forth in part 312 of his chapter.
(d) After November 12, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[55 FR 19858, May 11, 1990]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.542]
[Page 44]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.542 Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hyperphosphatemia.
(a) Hyperphosphatemia is a condition in which an abnormally high
plasma level of phosphate occurs in the blood. This condition in not
amenable to self-diagnosis or self-treatment. Treatment of this
condition should be restricted to the supervision of a physician. For
this reason, any drug product containing ingredients offered for OTC use
in the treatment of hyperphosphatemia cannot be considered generally
recognized as safe and effective.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of hyperphosphatemia is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act), for which an approved application under section
505 of the act and part 314 of this chapter is required for marketing.
In the absence of an approved application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for use in the treatment
of hyperphosphatemia is safe and effective for the purpose intended must
comply with the requirements and procedures governing use of
investigational new drugs set forth in part 312 of this chapter.
(d) After November 12, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[55 FR 19858, May 11, 1990]
[[Page 45]]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.543]
[Page 45]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.543 Drug products containing active ingredients offered over-the-counter (OTC) for human use in exocrine pancreatic insufficiency.
(a) Hemicellulase, pancreatin, and pancrelipase have been present as
ingredients in exocrine pancreatic insufficiency drug products.
Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin
(protease), and lipase. Significant differences have been shown in the
bioavailability of marketed exocrine pancreatic insufficiency drug
products produced by different manufacturers. These differences raise a
potential for serious risk to patients using these drug products. The
bioavailability of pancreatic enzymes is dependent on the process used
to manufacture the drug products. Information on this process is not
included in an OTC drug monograph. Therefore, the safe and effective use
of these enzymes for treating exocrine pancreatic insufficiency cannot
be regulated adequately by an OTC drug monograph. Information on the
product's formulation, manufacture, quality control procedures, and
final formulation effectiveness testing are necessary in an approved
application to ensure that a company has the ability to manufacture a
proper bioactive formulation. In addition, continuous physician
monitoring of patients who take these drug products is a collateral
measure necessary to the safe and effective use of these enzymes,
causing such products to be available by prescription only.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of exocrine pancreatic insufficiency is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
application under section 505 of the act and part 314 of this chapter is
required for marketing. In the absence of an approved application, such
product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use in the
treatment of exocrine pancreatic insufficiency is safe and effective for
the purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After May 7, 1991, any such OTC drug product that contains
hemicellulase initially introduced or initially delivered for
introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
(e) After October 24, 1995, any such OTC drug product that contains
pancreatin or pancrelipase initially introduced or initially delivered
for introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
[60 FR 20165, Apr. 24, 1995]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.544]
[Page 45-46]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.544 Drug products containing active ingredients offered over-the-counter (OTC) for use as a smoking deterrent.
(a) Any product that bears labeling claims that it ``helps stop or
reduce the cigarette urge,'' ``helps break the cigarette habit,''
``helps stop or reduce smoking,'' or similar claims is a smoking
deterrent drug product. Cloves, coriander, eucalyptus oil, ginger
(Jamaica), lemon oil (terpeneless), licorice root extract, lobeline (in
the form of lobeline sulfate or natural lobelia alkaloids or Lobelia
inflata herb), menthol, methyl salicylate, povidone-silver nitrate,
quinine ascorbate, silver acetate, silver nitrate, and thymol have been
present as ingredients in such drug products. There is a lack of
adequate data to establish general recognition of the safety and
effectiveness of these or any other ingredients for OTC use as a smoking
deterrent. Based on evidence currently available, any OTC drug product
containing ingredients offered for use as a smoking deterrent cannot be
generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
as a smoking deterrent is regarded as a new drug within the meaning of
section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act),
for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required
[[Page 46]]
for marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as a smoking
deterrent is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product containing cloves,
coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless),
licorice root extract, menthol, methyl salicylate, quinine ascorbate,
silver nitrate, and/or thymol initially introduced or initially
delivered for introduction into interstate commerce that is not in
compliance with this section is subject to regulatory action. After
December 1, 1993, any such OTC drug product containing lobeline (in the
form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata
herb), povidone-silver nitrate, silver acetate, or any other ingredients
initially introduced or initially delivered for introduction into
interstate commerce that is not in compliance with this section is
subject to regulatory action.
[58 FR 31241, June 1, 1993]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.545]
[Page 46-56]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.545 Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses.
(a) A number of active ingredients have been present in OTC drug
products for various uses, as described below. However, based on
evidence currently available, there are inadequate data to establish
general recognition of the safety and effectiveness of these ingredients
for the specified uses:
(1) Topical acne drug products.
Alcloxa
Alkyl isoquinolinium bromide
Aluminum chlorohydrex
Aluminum hydroxide
Benzocaine
Benzoic acid
Boric acid
Calcium polysulfide
Calcium thiosulfate
Camphor
Chloroxylenol
Cloxyquin
Coal tar
Dibenzothiophene
Estrone
Magnesium aluminum silicate
Magnesium sulfate
Phenol
Phenolate sodium
Phenyl salicylate
Povidone-iodine
Pyrilamine maleate
Resorcinol (as single ingredient)
Resorcinol monoacetate (as single ingredient)
Salicylic acid (over 2 up to 5 percent)
Sodium borate
Sodium thiosulfate
Tetracaine hydrochloride
Thymol
Vitamin E
Zinc oxide
Zinc stearate
Zinc sulfide
(2) Anticaries drug products--(i) Approved as of May 7, 1991.
Hydrogen fluoride
Sodium carbonate
Sodium monofluorophosphate (6 percent rinse)
Sodium phosphate
(ii) Approved as of October 7, 1996.
Calcium sucrose phosphate
Dicalcium phosphate dihydrate
Disodium hydrogen phosphate\1---------------------------------------------------------------------------
\1\ These ingredients are nonmonograph except when used to prepare
acidulated phosphate fluoride treatment rinses identified in
Sec. 355.10(a)(3) of this chapter.
---------------------------------------------------------------------------
Phosphoric acid<SUP>1</SUP>
Sodium dihydrogen phosphate
Sodium dihydrogen phosphate monohydrate
Sodium phosphate, dibasic anhydrous reagent<SUP>1</SUP>
(3) Antidiarrheal drug products.
Aluminum hydroxide
Atropine sulfate
Calcium carbonate
Carboxymethylcellulose sodium
Glycine
Homatropine methylbromide
Hyoscyamine sulfate
Lactobacillus acidophilus
Lactobacillus bulgaricus
Opium, powdered
Opium tincture
Paregoric
Phenyl salicylate
Scopolamine hydrobromide
Zinc phenolsulfonate
(4) Antiperspirant drug products.
[[Page 47]]
Alum, potassium
Aluminum bromohydrate
Aluminum chloride (alcoholic solutions)
Aluminum chloride (aqueous solution) (aerosol only)
Aluminum sulfate
Aluminum sulfate, buffered (aerosol only)
Sodium aluminum chlorohydroxy lactate
(5) [Reserved]
(6) Cold, cough, allergy, bronchodilator, and antiasthmatic drug
products--(i) Antihistamine drug products--(A) Ingredients.
Methapyrilene hydrochloride
Methapyrilene fumarate
Thenyldiamine hydrochloride
(B) Ingredients.
Phenyltoloxamine dihydrogen citrate
Methapyrilene hydrochloride
Methapyrilene fumarate
Thenyldiamine hydrochloride
(ii) Nasal decongestant drug products--(A) Approved as of May 7,
1991.
Allyl isothiocyanate
Camphor (lozenge)
Creosote, beechwood (oral)
Eucalyptol (lozenge)
Eucalyptol (mouthwash)
Eucalyptus oil (lozenge)
Eucalyptus oil (mouthwash)
Menthol (mouthwash)
Peppermint oil (mouthwash)
Thenyldiamine hydrochloride
Thymol
Thymol (lozenge)
Thymol (mouthwash)
Turpentine oil
(B) Approved as of August 23, 1995.
Bornyl acetate (topical)
Cedar leaf oil (topical)
Creosote, beechwood (topical)
Ephedrine (oral)
Ephedrine hydrochloride (oral)
Ephedrine sulfate (oral)
Racephedrine hydrochloride (oral/topical)
(iii) Expectorant drug products.
Ammonium chloride
Antimony potassium tartrate
Beechwood creosote
Benzoin preparations (compound tincture of benzoin, tincture of benzoin)
Camphor
Chloroform
Eucalyptol/eucalyptus oil
Horehound
Iodides (calcium iodide anyhydrous, hydroidic acid syrup, iodized lime,
potassium iodide)
Ipecac
Ipecac fluidextract
Ipecac syrup
Menthol/peppermint oil
Pine tar preparations (extract white pine compound, pine tar, syrup of
pine tar, compound white pine syrup, white pine)
Potassium guaiacolsulfonate
Sodium citrate
Squill preparations (squill, squill extract)
Terpin hydrate preparations (terpin hydrate, terpin hydrate elixir)
Tolu preparations (tolu, tolu balsam, tolu balsam tincture)
Turpentine oil (spirits of turpentine)
(iv) Bronchodilator drug products--(A) Approved as of October 2,
1987.
Aminophylline
Belladonna alkaloids
Euphorbia pilulifera
Metaproterenol sulfate
Methoxyphenamine hydrochloride
Pseudoephedrine hydrochloride
Pseudoephedrine sulfate
Theophylline, anhydrous
Theophylline calcium salicylate
Theophylline sodium glycinate
(B) Approved as of January 29, 1996. Any combination drug product
containing theophylline (e.g., theophylline and ephedrine, or
theophylline and ephedrine and phenobarbital).
(C) Approved as of June 19, 1996. Any ingredient(s) in a pressurized
metered-dose inhaler container.
(7) Dandruff/seborrheic dermatitis/psoriasis drug products.
Alkyl isoquinolinium bromide
Allantoin
Benzalkonium chloride
Benzethonium chloride
Boric acid
Calcium undecylenate
Captan
Chloroxylenol
Colloidal oatmeal
Cresol, saponated
Ethohexadiol
Eucalyptol
Juniper tar
Lauryl isoquinolinium bromide
Menthol
Mercury oleate
Methylbenzethonium chloride
Methyl salicylate
Phenol
Phenolate sodium
Pine tar
Povidone-iodine
Resorcinol
Sodium borate
Sodium salicylate
Thymol
Undecylenic acid
[[Page 48]]
(8) Digestive aid drug products--(i) Approved as of May 7, 1991.
Bismuth sodium tartrate
Calcium carbonate
Cellulase
Dehydrocholic acid
Dihydroxyaluminum sodium carbonate
Duodenal substance
Garlic, dehydrated
Glutamic acid hydrochloride
Hemicellulase
Homatropine methylbromide
Magnesium hydroxide
Magnesium trisilicate
Ox bile extract
Pancreatin
Pancrelipase
Papain
Peppermint oil
Pepsin
Sodium bicarbonate
Sodium citrate
Sorbitol
(ii) Approved as of November 10, 1993.
Alcohol
Aluminum hydroxide
Amylase
Anise seed
Aromatic powder
Asafetida
Aspergillus oryza enzymes (except lactase enzyme derived from
Aspergillus oryzae)
Bacillus acidophilus
Bean
Belladonna alkaloids
Belladonna leaves, powdered extract
Betaine hydrochloride
Bismuth subcarbonate
Bismuth subgallate
Black radish powder
Blessed thistle (cnicus benedictus)
Buckthorn
Calcium gluconate
Capsicum
Capsicum, fluid extract of
Carbon
Cascara sagrada extract
Catechu, tincture
Catnip
Chamomile flowers
Charcoal, wood
Chloroform
Cinnamon oil
Cinnamon tincture
Citrus pectin
Diastase
Diastase malt
Dog grass
Elecampane
Ether
Fennel acid
Galega
Ginger
Glycine
Hydrastis canadensis (golden seal)
Hectorite
Horsetail
Huckleberry
Hydrastis fluid extract
Hydrochloric acid
Iodine
Iron ox bile
Johnswort
Juniper
Kaolin, colloidal
Knotgrass
Lactic acid
Lactose
Lavender compound, tincture of
Linden
Lipase
Lysine hydrochloride
Mannitol
Mycozyme
Myrrh, fluid extract of
Nettle
Nickel-pectin
Nux vomica extract
Orthophosphoric acid
Papaya, natural
Pectin
Peppermint
Peppermint spirit
Phenacetin
Potassium bicarbonate
Potassium carbonate
Protease
Prolase
Rhubarb fluid extract
Senna
Sodium chloride
Sodium salicylate
Stem bromelain
Strawberry
Strychnine
Tannic acid
Trillium
Woodruff
(iii) Charcoal, activated
(9) [Reserved]
(10) External analgesic drug products--(i) Analgesic and anesthetic
drug products.
Aspirin
Chloral hydrate
Chlorobutanol
Cyclomethycaine sulfate
Eugenol
Hexylresorcinol
Methapyrilene hydrochloride
Salicylamide
Thymol
(ii) Counterirritant drug products.
Chloral hydrate
Eucalyptus oil
(iii) Male genital desensitizer drug products.
Benzyl alcohol
[[Page 49]]
Camphorated metacresol
Ephedrine hydrochloride
(iv) Diaper rash drug products.
Any ingredient(s) labeled with claims or directions for use in the
treatment and/or prevention of diaper rash.
(v) Fever blister and cold sore treatment drug products.
Allyl isothiocyanate
Aspirin
Bismuth sodium tartrate
Camphor (exceeding 3 percent)
Capsaicin
Capsicum
Capsicum oleoresin
Chloral hydrate
Chlorobutanol
Cyclomethycaine sulfate
Eucalyptus oil
Eugenol
Glycol salicylate
Hexylresorcinol
Histamine dihydrochloride
Menthol (exceeding 1 percent)
Methapyrilene hydrochloride
Methyl nicotinate
Methyl salicylate
Pectin
Salicylamide
Strong ammonia solution
Tannic acid
Thymol
Tripelennamine hydrochloride
Trolamine salicylate
Turpentine oil
Zinc sulfate
(vi) Insect bite and sting drug products.
Alcohol
Alcohol, ethoxylated alkyl
Benzalkonium chloride
Calamine
Ergot fluidextract
Ferric chloride
Panthenol
Peppermint oil
Pyrilamine maleate
Sodium borate
Trolamine salicylate
Turpentine oil
Zinc oxide
Zirconium oxide
(vii) Poison ivy, poison oak, and poison sumac drug products.
Alcohol
Aspirin
Benzethonium chloride
Benzocaine (0.5 to 1.25 percent)
Bithionol
Calamine
Cetalkonium chloride
Chloral hydrate
Chlorobutanol
Chlorpheniramine maleate
Creosote, beechwood
Cyclomethycaine sulfate
Dexpanthenol
Diperodon hydrochloride
Eucalyptus oil
Eugenol
Glycerin
Glycol salicylate
Hectorite
Hexylresorcinol
Hydrogen peroxide
Impatiens biflora tincture
Iron oxide
Isopropyl alcohol
Lanolin
Lead acetate
Merbromin
Mercuric chloride
Methapyrilene hydrochloride
Panthenol
Parethoxycaine hydrochloride
Phenyltoloxamine dihydrogen citrate
Povidone-vinylacetate copolymers
Pyrilamine maleate
Salicylamide
Salicylic acid
Simethicone
Sulfur
Tannic acid
Thymol
Trolamine salicylate
Turpentine oil
Zirconium oxide
Zyloxin
(11) [Reserved]
(12) Laxative drug products--(i) Bulk laxatives.
Agar
Carrageenan (degraded)
Carrageenan (native)
Guar gun
(ii) Saline laxative.
Tartaric acid
(iii) Stool softener.
Poloxamer 188
(iv)(A) Stimulant laxatives--Approved as of May 7, 1991.
Aloin
Bile salts/acids
Calcium pantothenate
Calomel
Colocynth
Elaterin resin
Frangula
Gamboge
Ipomea
Jalap
Ox bile
Podophyllum resin
Prune concentrate dehydrate
[[Page 50]]
Prune powder
Rhubarb, Chinese
Sodium Oleate
(iv)(B) Stimulant laxatives--Approved as of January 29, 1999.
Danthron
Phenolphthalein
(13) [Reserved]
(14) Oral health care drug products (nonantimicrobial).
Antipyrine
Camphor
Cresol
Dibucaine
Dibucaine hydrochloride
Eucalyptol
Lidocaine
Lidocaine hydrochloride
Methly salicylate
Myrrh tincture
Pyrilamine maleate
Sorbitol
Sugars
Tetracaine
Tetracaine hydrochloride
Thymol
(15) Topical otic drug products for the prevention of swimmer's ear
and for the drying of water-clogged ears--(i) Approved as of May 7,
1991.
Acetic acid
(ii) Approved as of August 15, 1995.
Glycerin and anhydrous glycerin
Isopropyl alcohol
(16) Poison treatment drug products.
Ipecac fluidextract
Ipecac tincture
Zinc sulfate
(17) Skin bleaching drug products.
Mercury, ammoniated
(18) Skin protectant drug products. (i) Ingredients.
Allantoin (wound healing claims only)
Sulfur
Tannic acid
Zinc acetate (wound healing claims only)
(ii) Astringent drug products.
Acetone
Alcohol
Alum, ammonium
Alum, potassium
Aluminum chlorhydroxy complex
Aromatics
Benzalkonium chloride
Benzethonium chloride
Benzocaine
Benzoic acid
Boric acid
Calcium acetate
Camphor gum
Clove oil
Colloidal oatmeal
Cresol
Cupric sulfate
Eucalyptus oil
Eugenol
Ferric subsulfate (Monsel's Solution)
Honey
Isopropyl alcohol
Menthol
Methyl salicylate
Oxyquinoline sulfate
P-t-butyl-m-cresol
Peppermint oil
Phenol
Polyoxeythylene laurate
Potassium ferrocyanide
Sage oil
Silver nitrate
Sodium borate
Sodium diacetate
Talc
Tannic acid glycerite
Thymol
Topical starch
Zinc chloride
Zinc oxide
Zinc phenolsulfonate
Zinc stearate
Zinc sulfate
(iii) Diaper rash drug products.
Aluminum hydroxide
Cocoa butter
Cysteine hydrochloride
Glycerin
Protein hydrolysate
Racemethionine
Sulfur
Tannic acid
Zinc acetate
Zinc carbonate
(iv) Fever blister and cold sore treatment drug products.
Bismuth subnitrate
Boric acid
Pyridoxine hydrochloride
Sulfur
Tannic acid
Topical starch
Trolamine
Zinc sulfate
(v) Insect bite and sting drug products.
Alcohol
Alcohol, ethoxylated alkyl
Ammonia solution, strong
Ammonium hydroxide
Benzalkonium chloride
Camphor
Ergot fluidextract
[[Page 51]]
Ferric chloride
Menthol
Peppermint oil
Phenol
Pyrilamine maleate
Sodium borate
Trolamine
Turpentine oil
Zirconium oxide
(vi) Poison ivy, poison oak, and poison sumac drug products.
Alcohol
Anion and cation exchange resins buffered
Benzethonium chloride
Benzocaine
Benzyl alcohol
Bismuth subnitrate
Bithionol
Boric acid
Camphor
Cetalkonium chloride
Chloral hydrate
Chlorpheniramine maleate
Creosote
Diperodon hydrochloride
Diphenhydramine hydrochloride
Eucalyptus oil
Ferric chloride
Glycerin
Hectorite
Hydrogen peroxide
Impatiens biflora tincture
Iron oxide
Isopropyl alcohol
Lanolin
Lead acetate
Lidocaine
Menthol
Merbromin
Mercuric chloride
Panthenol
Parethoxycaine hydrochloride
Phenol
Phenyltoloxamine dihydrogen citrate
Povidone-vinylacetate copolymers
Salicylic acid
Simethicone
Tannic acid
Topical starch
Trolamine
Turpentine oil
Zirconium oxide
Zyloxin
(19) [Reserved]
(20) Weight control drug products.
Alcohol
Alfalfa
Alginic acid
Anise oil
Arginine
Ascorbic acid
Bearberry
Biotin
Bone marrow, red
Buchu
Buchu, potassium extract
Caffeine
Caffeine citrate
Calcium
Calcium carbonate
Calcium caseinate
Calcium lactate
Calcium pantothenate
Carboxymethylcellulose sodium
Carrageenan
Cholecalcierol
Choline
Chondrus
Citric acid
Cnicus benedictus
Copper
Copper gluconate
Corn oil
Corn syrup
Corn silk, potassium extract
Cupric sulfate
Cyanocobalamin (vitamin B<INF>12</INF>)
Cystine
Dextrose
Docusate sodium
Ergocalciferol
Ferric ammonium citrate
Ferric pyrophosphate
Ferrous fumarate
Ferrous gluconate
Ferrous sulfate (iron)
Flax seed
Folic acid
Fructose
Guar gum
Histidine
Hydrastis canadensis
Inositol
Iodine
Isoleucine
Juniper, potassium extract
Karaya gum
Kelp
Lactose
Lecithin
Leucine
Liver concentrate
Lysine
Lysine hydrochloride
Magnesium
Magnesium oxide
Malt
Maltodextrin
Manganese citrate
Mannitol
Methionine
Methylcellulose
Mono- and di-glycerides
Niacinamide
Organic vegetables
Pancreatin
Pantothenic acid
Papain
Papaya enzymes
Pepsin
Phenacetin
[[Page 52]]
Phenylalanine
Phosphorus
Phytolacca
Pineapple enzymes
Plantago seed
Potassium citrate
Pyridoxine hydrochloride (vitamin B<INF>6</INF>)
Riboflavin
Rice polishings
Saccharin
Sea minerals
Sesame seed
Sodium
Sodium bicarbonate
Sodium caseinate
Sodium chloride (salt)
Soybean protein
Soy meal
Sucrose
Thiamine hydrochloride (vitamin B<INF>1</INF>)
Thiamine mononitrate (vitamin B<INF>1</INF> mononitrate)
Threonine
Tricalcium phosphate
Tryptophan
Tyrosine
Uva ursi, potassium extract
Valine
Vegetable
Vitamin A
Vitamin A acetate
Vitamin A palmitate
Vitamin E
Wheat germ
Xanthan gum
Yeast
(21) Ophthalmic drug products.
(i) Ophthalmic anesthetic drug products.
Antipyrine
Piperocaine hydrochloride
(ii) Ophthalmic anti-infective drug products.
Boric acid
Mild silver protein
Yellow mercuric oxide
(iii) Ophthalmic astringent drug products.
Infusion of rose petals
(iv) Ophthalmic demulcent drug products.
Polyethylene glycol 6000
(v) Ophthalmic vasoconstrictor drug products.
Phenylephrine hydrochloride (less than 0.08 percent)
(22) Topical antifungal drug products.
(i) Diaper rash drug products. Any ingredient(s) labeled with claims
or directions for use in the treatment and/or prevention of diaper rash.
(ii) Ingredients.
Alcloxa
Alum, potassium
Aluminum sulfate
Amyltricresols, secondary
Basic fuchsin
Benzethonium chloride
Benzoic acid
Benzoxiquine
Boric acid
Camphor
Candicidin
Chlorothymol
Coal tar
Dichlorophen
Menthol
Methylparaben
Oxyquinoline
Oxyquinoline sulfate
Phenol
Phenolate sodium
Phenyl salicylate
Propionic acid
Propylparaben
Resorcinol
Salicylic acid
Sodium borate
Sodium caprylate
Sodium propionate
Sulfur
Tannic acid
Thymol
Tolindate
Triacetin
Zinc caprylate
Zinc propionate
(iii) Any ingredient(s) labeled with claims or directions for use on
the scalp or on the nails.
(iv) Ingredients.
Camphorated metacresol
Chloroxylenol
m-cresol
Nystatin
(23) Internal analgesic drug products. (i) Approved as of November
10, 1993.
Aminobenzoic acid
Antipyrine
Aspirin, aluminum
Calcium salicylate
Codeine
Codeine phosphate
Codeine sulfate
Iodoantipyrine
Lysine aspirin
Methapyrilene fumarate
Phenacetin
Pheniramine maleate
Pyrilamine maleate
Quinine
Salsalate
[[Page 53]]
Sodium aminobenzoate
(ii) Approved as of February 22, 1999.
Any atropine ingredient
Any ephedrine ingredient
(24) Orally administered menstrual drug products. (i) Approved as of
November 10, 1993.
Alcohol
Alfalfa leaves
Aloes
Asclepias tuberosa
Asparagus
Barosma
Bearberry (extract of uva ursi)
Bearberry fluidextract (extract of bearberry)
Blessed thistle (cnicus benedictus)
Buchu powdered extract (extract of buchu)
Calcium lactate
Calcium pantothenate
Capsicum oleoresin
Cascara fluidextract, aromatic (extract of cascara)
Chlorprophenpyridamine maleate
Cimicifuga racemosa
Codeine
Collinsonia (extract stone root)
Corn silk
Couch grass
Dog grass extract
Ethyl nitrite
Ferric chloride
Ferrous sulfate
Gentiana lutea (gentian)
Glycyrrhiza (licorice)
Homatropine methylbromide
Hydrangea, powdered extract (extract of hydrangea)
Hydrastis canadensis (golden seal)
Hyoscyamine sulfate
Juniper oil (oil of juniper)
Magnesium sulfate
Methapyrilene hydrochloride
Methenamine
Methylene blue
Natural estrogenic hormone
Niacinamide
Nutmeg oil (oil of nutmeg)
Oil of erigeron
Parsley
Peppermint spirit
Pepsin, essence
Phenacetin
Phenindamine tartrate
Phenyl salicylate
Piscidia erythrina
Pipsissewa
Potassium acetate
Potassium nitrate
Riboflavin
Saw palmetto
Senecio aureus
Sodium benzoate
Sodium nitrate
Sucrose
Sulferated oils of turpentine
Taraxacum officinale
Theobromine sodium salicylate
Theophylline
Thiamine hydrochloride
Triticum
Turpentine, venice (venice turpertine)
Urea
(ii) Approved as of February 22, 1999.
Any atropine ingredient
Any ephedrine ingredient
(25) Pediculicide drug products--(i) Approved as of November 10,
1993.
Benzocaine
Benzyl alcohol
Benzyl benzoate
Chlorophenothane (dichlorodiphenyl trichloroethane)
Coconut oil soap, aqueous
Copper oleate
Docusate sodium
Formic acid
Isobornyl thiocyanoacetate
Picrotoxin
Propylene glycol
Sabadilla alkaloids
Sulfur, sublimed
Thiocyanoacetate
(ii) Approved as of June 14, 1994. The combination of pyrethrum
extract (formerly named pyrethrins) and piperonyl butoxide in an aerosol
dosage formulation.
(26) Anorectal druq products--(i) Anticholinergic drug products.
Atropine
Belladonna extract
(ii) Antiseptic drug products.
Boric acid
Boroglycerin
Hydrastis
Phenol
Resorcinol
Sodium salicylic acid phenolate
(iii) Astringent drug products.
Tannic acid
(iv) Counterirritant drug products.
Camphor (greater than 3 to 11 percent)
Hydrastis
Menthol (1.25 to 16 percent)
Turpentine oil (rectified) (6 to 50 percent)
(v) Keratolytic drug products.
Precipitated sulfur
Sublimed sulfur
(vi) Local anesthetic drug products.
Diperodon
[[Page 54]]
Phenacaine hydrochloride
(vii) Other druq products.
Collinsonia extract
Escherichia coli vaccines
Lappa extract
Leptandra extract
Live yeast cell derivative
Mullein
(viii) Protectant druq products.
Bismuth oxide
Bismuth subcarbonate
Bismuth subgallate
Bismuth subnitrate
Lanolin alcohols
(ix) Vasoconstrictor druq products.
Epinephrine undecylenate
(x) Wound healinq druq products.
Cholecalciferol
Cod liver oil
Live yeast cell derivative
Peruvian balsam
Shark liver oil
Vitamin A
(27) Topical antimicrobial drug products--(i) First aid antiseptic
drug products.
Ammoniated mercury
Calomel (mercurous chloride)
Merbromin (mercurochrome)
Mercufenol chloride (ortho-chloromercuriphenol, ortho-
hydroxyphenylmercuric chloride)
Mercuric chloride (bichloride of mercury, mercury chloride)
Mercuric oxide, yellow
Mercuric salicylate
Mercuric sulfide, red
Mercury
Mercury oleate
Mercury sulfide
Nitromersol
Para-chloromercuriphenol
Phenylmercuric nitrate
Thimerosal
Vitromersol
Zyloxin
(ii) Diaper rash drug products.
Para-chloromercuriphenol
Any other ingredient containing mercury
(28) Vaginal contraceptive drug products.
Dodecaethylene glycol monolaurate (polyethylene glycol 600 monolaurate)
Laureth 10S
Methoxypolyoxyethyleneglycol 550 laurate
Phenylmercuric acetate
Phenylmercuric nitrate
Any other ingredient containing mercury
(29) Sunscreen drug products.
Diethanolamine methoxycinnamate
Digalloyl trioleate
Ethyl 4-[bis(hydroxypropyl)] aminobenzoate
Glyceryl aminobenzoate
Lawsone with dihydroxyacetone
Red petrolatum
(b) Any OTC drug product that is labeled, represented, or promoted
for the uses specified and containing any active ingredient(s) as
specified in paragraph (a) of this section is regarded as a new drug
within the meaning of section 210(p) of the Federal Food, Drug, and
Cosmetic Act (the Act), for which an approved new drug application under
section 505 of the Act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application, such
product is also misbranded under section 502 of the Act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for the OTC uses and
containing any active ingredient(s) as specified in paragraph (a) of
this section is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any OTC drug product that is not in compliance with this section
is subject to regulatory action if initially introduced or initially
delivered for introduction into interstate commerce after the dates
specified in paragraphs (d)(1) through (d)(31) of this section.
(1) May 7, 1991, for products subject to paragraphs (a)(1) through
(a)(2)(i), (a)(3) through (a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7)
(except as covered by paragraph (d)(3) of this section), (a)(8)(i),
(a)(10)(i) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv)(A),
(a)(14) through (a)(15)(i), and (a)(16) through (a)(18) of this section.
(2) February 10, 1992, for products subject to paragraph (a)(20) of
this section.
(3) December 4, 1992, for products subject to paragraph (a)(7) of
this section that contain menthol as an antipruritic in combination with
the antidandruff ingredient coal tar identified in Sec. 358.710(a)(1) of
this chapter.
[[Page 55]]
(4) February 28, 1990, for products subject to paragraph (a)(6)(iii)
of this section, except those that contain ipecac.
(5) September 14, 1993, for products subject to paragraph
(a)(6)(iii) of this section that contain ipecac.
(6) December 9, 1993, for products subject to paragraph (a)(6)(i)(B)
of this section.
(7) March 6, 1989, for products subject to paragraph (a)(21) of this
section, except those that contain ophthalmic anti-infective ingredients
listed in paragraph (a)(21)(ii).
(8) June 18, 1993, for products subject to paragraph (a)(21) of this
section that contain ophthalmic anti-infective ingredients.
(9) June 18, 1993, for products subject to paragraph (a)(10)(iv) of
this section.
(10) June 18, 1993, for products subject to paragraph (a)(22)(i) of
this section.
(11) November 10, 1993, for products subject to paragraphs
(a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except
products that contain ferric subsulfate) through (a)(18)(vi),
(a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) of this section.
(12) March 2, 1994, for products subject to paragraph (a)(22)(iii)
of this section.
(13) August 5, 1991, for products subject to paragraphs (a)(26) of
this section, except for those that contain live yeast cell derivative.
(14) September 2, 1994, for products subject to paragraph
(a)(26)(vii) and (a)(26)(x) of this section that contain live yeast cell
derivative.
(15) September 23, 1994, for products subject to paragraph
(a)(22)(iv) of this section.
(16) June 14, 1994, for products subject to paragraph (a)(25)(ii) of
this section.
(17) [Reserved]
(18) August 15, 1995, for products subject to paragraph (a)(15)(ii)
of this section.
(19) October 2, 1987, for products subject to paragraph
(a)(6)(iv)(A) of this section.
(20) January 29, 1996, for products subject to paragraph
(a)(6)(iv)(B) of this section.
(21) April 21, 1994, for products subject to paragraph (a)(8)(iii)
of this section.
(22) April 21, 1993, for products subject to paragraph (a)(18)(ii)
of this section that contain ferric subsulfate.
(23) August 23, 1995, for products subject to paragraph
(a)(6)(ii)(B) of this section.
(24) October 7, 1996, for products subject to paragraph (a)(2)(ii)
of this section.
(25) June 19, 1996, for products subject to paragraph (a)(6)(iv)(C)
of this section.
(26) February 22, 1999, for products subject to paragraphs
(a)(23)(ii) and (a)(24)(ii) of this section.
(27) [Reserved]
(28) October 22, 1998, for products subject to paragraphs (a)(27)
and (a)(28) of this section.
(29) January 29, 1999, for products subject to paragraph
(a)(12)(iv)(B) of this section.
(30) [Reserved]
(31) May 21, 2001 for products subject to paragraph (a)(29) of this
section.-
[55 FR 46919, Nov. 7, 1990]
Editorial Note: For Federal Register citations affecting
Sec. 310.545, see the List of CFR Sections Affected, which appears in
the Finding Aids section of the printed volume and on GPO Access.
Effective Date Notes: 1. At 61 FR 9571, Mar. 8, 1996, in
Sec. 310.545 in paragraph (a)(6)(ii)(B), the entry for ``l-
desoxyephedrine (topical)'' was stayed until further notice.
1a. The stay of Sec. 310.545(a)(15)(ii), published at 60 FR 42436,
Aug. 16, 1995, and effective June 22, 1995, is lifted at 65 FR 48902,
Aug. 10, 2000, effective Sept. 11, 2000.
2. At 64 FR 27687, May 21, 1999, in Sec. 310.545 paragraph (a)(29)
was added, (d) introductory text was revised, paragraph (d)(30) was
added and reserved, and paragraph (d)(31) was added, effective May 21,
2001. At 65 FR 36319, 36324, June 8, 2000, the effective date was
delayed through Dec. 31, 2002, and paragraph (d)(31) was revised. For
the convenience of the user, the revised text is set forth as follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
* * * * *
(d) Any OTC drug product that is not in compliance with this
section is subject to regulatory action if initially introduced or
initially delivered for introduction into
[[Page 56]]
interstate commerce after the dates specified in paragraphs (d)(1)
through (d)(29) of this section.
* * * * *
(31) December 31, 2002, for products subject to paragraph (a)(29) of
this section.
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.546]
[Page 56]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.546 Drug products containing active ingredients offered over-the-counter (OTC) for the treatment and/or prevention of nocturnal leg muscle cramps.
(a) Quinine sulfate alone or in combination with vitamin E has been
present in over-the-counter (OTC) drug products for the treatment and/or
prevention of nocturnal leg muscle cramps, i.e., a condition of
localized pain in the lower extremities usually occurring in middle life
and beyond with no regular pattern concerning time or severity. There is
a lack of adequate data to establish general recognition of the safety
and effectiveness of quinine sulfate, vitamin E, or any other
ingredients for OTC use in the treatment and/or prevention of nocturnal
leg muscle cramps. In the doses used to treat or prevent this condition,
quinine sulfate has caused adverse events such as transient visual and
auditory disturbances, dizziness, fever, nausea, vomiting, and diarrhea.
Quinine sulfate may cause unpredictable serious and life-threatening
hypersensitivity reactions requiring medical intervention and
hospitalization; fatalities have been reported. The risk associated with
use of quinine sulfate, in the absence of evidence of its effectiveness,
outweighs any potential benefit in treating and/or preventing this
benign, self-limiting condition. Based upon the adverse benefit-to-risk
ratio, any drug product containing quinine or quinine sulfate cannot be
considered generally recognized as safe for the treatment and/or
prevention of nocturnal leg muscle cramps.
(b) Any OTC drug product that is labeled, represented, or promoted
for the treatment and/or prevention of nocturnal leg muscle cramps is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
application or abbreviated application under section 505 of the act and
part 314 of this chapter is required for marketing. In the absence of an
approved new drug application or abbreviated new drug application, such
product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use for the
treatment and/or prevention of nocturnal leg muscle cramps is safe and
effective for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) After February 22, 1995, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[59 FR 43252, Aug. 22, 1994]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.547]
[Page 56-57]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.547 Drug products containing quinine offered over-the-counter (OTC) for the treatment and/or prevention of malaria.
(a) Quinine and quinine salts have been used OTC for the treatment
and/or prevention of malaria, a serious and potentially life-threatening
disease. Quinine is no longer the drug of choice for the treatment and/
or prevention of most types of malaria. In addition, there are serious
and complicating aspects of the disease itself and some potentially
serious and life-threatening risks associated with the use of quinine at
doses employed for the treatment of malaria. There is a lack of adequate
data to establish general recognition of the safety of quinine drug
products for OTC use in the treatment and/or prevention of malaria.
Therefore, quinine or quinine salts cannot be safely and effectively
used for the treatment and/or prevention of malaria except under the
care and supervision of a doctor.
(b) Any OTC drug product containing quinine or quinine salts that is
labeled, represented, or promoted for the treatment and/or prevention of
malaria is regarded as a new drug within the meaning of section 201(p)
of the act, for which an approved application or abbreviated application
under section 505 of the act and part 314 of this chapter
[[Page 57]]
is required for marketing. In the absence of an approved new drug
application or abbreviated new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use for the
treatment and/or prevention of malaria is safe and effective for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After April 20, 1998, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[63 FR 13528, Mar. 20, 1998]
[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR310.548]
[Page 57]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 310--NEW DRUGS--Table of Contents
Subpart E--Requirements for Specific New Drugs or Devices
Sec. 310.548 Drug products containing colloidal silver ingredients or silver salts offered over-the-counter (OTC) for the treatment and/or prevention of disease.
(a) Colloidal silver ingredients and silver salts have been marketed
in over-the-counter (OTC) drug products for the treatment and prevention
of numerous disease conditions. There are serious and complicating
aspects to many of the diseases these silver ingredients purport to
treat or prevent. Further, there is a lack of adequate data to establish
general recognition of the safety and effectiveness of colloidal silver
ingredients or silver salts for OTC use in the treatment or prevention
of any disease. These ingredients and salts include, but are not limited
to, silver proteins, mild silver protein, strong silver protein, silver,
silver ion, silver chloride, silver cyanide, silver iodide, silver
oxide, and silver phosphate.
(b) Any OTC drug product containing colloidal silver ingredients or
silver salts that is labeled, represented, or promoted for the treatment
and/or prevention of any disease is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act
(the act) for which an approved application or abbreviated application
under section 505 of the act and part 314 of this chapter is required
for marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product containing colloidal silver or silver salts labeled,
represented, or promoted for any OTC drug use is safe and effective for
the purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs as set forth in part 312
of this chapter.
(d) After September 16, 1999, any such OTC drug product containing
colloidal silver or silver salts initially introduced or initially
delivered for introduction into interstate commerce that is not in
compliance with this section is subject to regulatory action.
[64 FR 44658, Aug. 17, 1999]
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