[Federal Register: January 7, 1999 (Volume 64, Number 4)]
[Proposed Rules]
[Page 996-1003]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr07ja99-10]

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Proposed Rules
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.

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[[Page 996]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 216

[Docket No. 98N-0182]


List of Bulk Drug Substances That May Be Used in Pharmacy
Compounding

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing a new
regulation which will identify the bulk drug substances that may be
used in pharmacy compounding under the exemptions provided by the
Federal Food, Drug, and Cosmetic Act (the act) even though such
substances are neither the subject of a current United States
Pharmacopeia (USP) or National Formulary (NF) monograph nor a component
of an FDA-approved drug. FDA's development and publication of this bulk
drugs list is statutorily required by the Food and Drug Administration
Modernization Act of 1997 (the Modernization Act).

DATES: Submit written comments on or before March 23, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Robert J. Tonelli, Center for Drug
Evaluation and Research (HFD-332), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-827-7295.

SUPPLEMENTARY INFORMATION:

I. Background

    President Clinton signed the Modernization Act (Pub. L. 105-115)
into law on November 21, 1997. Section 127 of the Modernization Act,
which added section 503A to the act (21 U.S.C. 353a), clarifies the
status of pharmacy compounding under Federal law. Under section 503A of
the act, drug products that are compounded by a pharmacist or physician
on a customized basis for an individual patient may be entitled to
exemptions from three key provisions of the act: (1) The adulteration
provision of section 501(a)(2)(B) (21 U.S.C. 351 (a)(2)(B)) (concerning
the good manufacturing practice requirements); (2) the misbranding
provision of section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the
labeling of drugs with adequate directions for use); and (3) the new
drug provision of section 505 (21 U.S.C. 355) (concerning the approval
of drugs under new drug or abbreviated new drug applications).
    To qualify for these statutory exemptions, a compounded drug
product must satisfy several requirements. One of these requirements,
found in section 503A(b)(1)(A) of the act, restricts the universe of
bulk drug substances that a compounder may use. Section 503A(b)(1)(A)
provides, in relevant part, that every bulk drug substance used in
compounding: (1) Must comply with an applicable and current USP or NF
monograph, if one exists, as well as the current USP chapter on
pharmacy compounding; (2) if such a monograph does not exist, the bulk
drug substance must be a component of an FDA-approved drug;\1\ or (3)
if a monograph does not exist and the bulk drug substance is not a
component of an FDA-approved drug, it must appear on a list of bulk
drug substances that may be used in compounding (i.e., the bulk drugs
list being proposed in this rulemaking). The term ``bulk drug
substance'' is defined in FDA regulations at 21 CFR 207.3(a)(4) to mean
``any substance that is represented for use in a drug and that, when
used in the manufacturing, processing, or packaging of a drug, becomes
an active ingredient or finished dosage form of the drug, but the term
does not include intermediates used in the synthesis of such
substances'' (see section 503A(b)(1)(A) of the act).
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    \1\ To identify such FDA-approved drugs, compounders can consult
the publication entitled ``Approved Drug Products with Therapeutic
Equivalence Evaluation,'' commonly referred to as the ``Orange
Book.''
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II. Criteria for Bulk Drug Substances

    According to section 503A(d)(2) of the act, the criteria for
determining which substances should appear on the bulk drugs list
``shall include historical use, reports in peer reviewed medical
literature, or other criteria the Secretary of Health and Human
Services may identify.'' The FDA, after consulting with the USP and the
Pharmacy Compounding Advisory Committee, is proposing to use the
following four criteria: (1) The chemical characterization of the
substance; (2) the safety of the substance; (3) the historical use of
the substance in pharmacy compounding; and (4) the available evidence
of the substance's effectiveness or lack of effectiveness, if any such
evidence exists.
    In evaluating candidates for the bulk drugs list under these
criteria, the agency proposes to use a balancing test. No single one of
these criteria will be considered to be dispositive. Rather, the agency
will consider each criterion in the context of the others and balance
them, on a substance-by-substance basis, in deciding whether a
particular substance is appropriate for inclusion on the list.
    Under the first criterion, the chemical characterization of the
substance, FDA will consider each substance's purity, identity, and
quality. Based on attributes such as the substance's chemical formula,
melting point, appearance, and solubilities, FDA will determine whether
the substance can be identified consistently based on its chemical
characteristics. If a substance cannot be well characterized
chemically, this criterion will weigh against its inclusion on the
proposed bulk drugs list because there can be no assurance that its
properties and toxicities when used in compounding would be the same as
the properties and toxicities reported in the literature and considered
by the agency.
    Under the second criterion, FDA will consider the safety issues
raised by the use of each substance in general pharmacy compounding.
Based on FDA's review of the substances nominated to date, it is
unlikely that candidates for the bulk drugs list will have been
thoroughly investigated in well-controlled animal toxicology studies,
or that there will be well-controlled clinical studies to substantiate
their safe use in humans.

[[Page 997]]

 Thus, in evaluating list candidates, the agency is likely to have at
its disposal either none or very little of the type or quality of
information that is ordinarily required and evaluated as part of the
drug approval process.
    To evaluate the safety of the substances, then, the agency will
rely on information about each substance's acute toxicity, repeat dose
toxicity, and other reported toxicities, including mutagenicity,
teratogenicity, and carcinogenicity. The agency will also rely on
reports and abstracts in the literature about adverse reactions the
substances have caused in humans. In applying the toxicity criterion,
FDA may also consider the availability of alternative approved
therapies when the toxicity of a particular substance appears to be
significant. The existence of alternative approved therapies is likely
to weigh against inclusion on the proposed list because the risks of
using a substance with significant toxicities is more likely to
outweigh the benefits when approved alternative therapies are
available.
    Under the third criterion, the historical use of the substance in
pharmacy compounding, FDA will consider the length of time the
substance has been used in pharmacy compounding, the medical conditions
it has been used to treat, and how widespread its use has been. This
criterion will weigh in favor of list inclusion for nominated
substances that have enjoyed longstanding and widespread use in
pharmacy compounding for a particular indication. Evidence of both
widespread and longstanding use will be viewed by the agency as
indicative of the substance's perceived usefulness and acceptance in
the medical community. Fraudulent or ``quack'' remedies, on the other
hand, will be less likely to be included on the list as a result of
this criterion because the practice of compounding such drugs is not
expected to be sufficiently prevalent and longstanding.
    Under the fourth criterion, FDA will consider the available
evidence of the substance's effectiveness or lack of effectiveness for
a particular use, if any such evidence exists. When drugs go through
the new drug approval process, they are required to demonstrate
effectiveness under the substantial evidence standard described in
section 505(d) of the act. FDA recognizes that few, if any, of the
candidates for the bulk drugs list will have been studied in adequate
and well-controlled investigations sufficient to satisfy this standard.
Thus, in its balancing of the relevant criteria, the agency will take
into account whatever relevant evidence concerning effectiveness is
available.
    For example, for substances that have been widely used for a long
period of time, the literature may include anecdotal reports of
effectiveness for a particular use, or reports of one or more trials
demonstrating effectiveness. Conversely, the literature may contain
anecdotal or clinical evidence that a particular bulk drug substance
was shown not to be effective for a particular use (negative
effectiveness data).
    When evaluating a bulk drug substance used to treat a less serious
illness, FDA will generally be more concerned about the safety of the
substance than about its effectiveness. Thus, the absence of
effectiveness data, or the existence of mere anecdotal reports, will be
less likely to preclude inclusion of the substance on the list.
However, for a bulk drug substance used to treat a more serious or
life-threatening disease, there may be more serious consequences
associated with ineffective therapy, particularly when there are
alternative approved therapies. In those cases, the absence of
effectiveness data, or the presence of negative effectiveness data,
will weigh more heavily in FDA's balancing of the relevant criteria.

III. FDA Development of a Bulk Drugs List

A. Methodology

    Although the Modernization Act directs FDA to develop a list of
bulk drug substances for use in pharmacy compounding, it does not
specify how candidates for the list should be identified. In a notice
published in the Federal Register of April 7, 1998 (63 FR 17011), FDA
invited all interested persons to nominate bulk drug substances for
inclusion on the list. In response to this request, FDA received
nominations for 41 different drug substances. The nominations came from
Abbott Laboratories, the American Academy of Dermatology, the Texas
Pharmacy Association, the North Carolina Board of Pharmacy, Moss
Pharmacy and Nutrition Center, the University of Texas MD Anderson
Cancer Center, the International Academy of Compounding Pharmacists,
Baxter Healthcare Corp., Scottsdale Skin & Cancer Center Ltd.,
Dermatology Associates, and Neil Brody, M.D.
    Ten of the nominated substances (clotrimazole, fluocinonide,
hydrocortisone, hydroquinone, mechlorethamine, pramoxine, quinacrine
hydrochloride, salicylic acid, tretinoin, and triamcinolone) are the
subject of a USP or NF monograph or are components of FDA-approved
drugs. As such, they already qualify for use in pharmacy compounding
under section 503A(b)(1)(A)(i) of the act (assuming they satisfy all
other applicable requirements of the act). Therefore, FDA dismissed
these substances as list candidates and will not address them further
in this proposed rulemaking. An additional substance (sulfadimethoxine)
was eliminated as a list candidate after being withdrawn by its sponsor
at the inaugural meeting of the Pharmacy Compounding Advisory
Committee. It too will not be addressed further in this proposed
rulemaking.
    The remaining 30 nominations were appropriate list candidates and
were evaluated based on a balancing of the four criteria identified in
section II of this document: (1) The chemical characterization of the
substance; (2) the safety of the substance; (3) the historical use of
the substance in pharmacy compounding; and (4) the available evidence
of the substance's effectiveness or lack of effectiveness, if any such
evidence exists.\2\
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    \2\ In making its evaluations, the agency did not consider
whether any of the nominated substances are manufactured by an
establishment registered under section 510 of the act (see 21 U.S.C.
353a(b)(1)(A)(ii)). This registration requirement is one of a number
of other conditions that must be satisfied to qualify for the
applicable compounding exemptions.
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    The information that FDA assessed under each of the evaluation
criteria was obtained from journal reports and abstracts from reliable
medical sources, including peer reviewed medical literature. This
information is available for viewing at the Dockets Management Branch
(address above) under Docket No. 98N-0182. Some of this information was
submitted in support of the nominations. The remainder FDA gathered
through independent searches of medical and pharmaceutical data bases.
FDA did not review any raw data.
    The nature, quantity, and quality of the information assessed by
FDA varied considerably from substance to substance. In some cases
there was very little data. For example, the agency found only two
relevant journal articles concerning thymol iodide. For other
substances, such as taurine and sodium butyrate, reports in the
literature were more plentiful and sometimes comprised hundreds of
articles. In those cases, the agency reviewed a limited sample of the
available literature sources.
    Because FDA's assessment of the nominated substances was far less
rigorous and far less extensive than the agency's ordinary evaluation
of drugs as part of the new drug approval process,

[[Page 998]]

the inclusion of a drug substance on the proposed bulk drugs list
should not, in any way, be equated with an approval, endorsement, or
recommendation of the substance by FDA. Nor should it be assumed that
substances on the proposed list have been proven to be safe and
effective under the standards normally required to receive agency
approval. In fact, any person who represents that a compounded drug
made with a bulk drug substance that appears on this list is FDA-
approved, or otherwise endorsed by FDA generally or for a particular
indication, will cause such drug to be misbranded under section 502(a)
of the act.
    On October 14 and 15, 1998, FDA consulted with the Pharmacy
Compounding Advisory Committee, created under section 503A(d)(1) of the
act about the contents of this proposed rule (see 63 FR 47301,
September 4, 1998). The discussion included the criteria FDA proposes
to use to evaluate candidates for the bulk drugs list and the
nominations that FDA has already received.\3\ In general, the advisory
committee agreed with the approach taken by the agency in evaluating
the nominated bulk drug substances and the agency's tentative
conclusions regarding whether these substances should be included on
the bulk drugs list. The agency has taken into consideration all of the
advisory committee's recommendations in developing this proposed rule,
and the agency intends to continue to consult with the Pharmacy
Compounding Advisory Committee in evaluating future candidates for the
bulk drugs list.
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    \3\ A transcript of the advisory committee meeting may be found
at the Dockets Management Branch (address above) under Docket No.
98N-0182.
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    After evaluating the comments on this proposed rule, FDA is
proposing to issue the bulk drugs list as a final rule which will be
codified in the Code of Federal Regulations (CFR). The final version of
the rule may include all, or only some, of the substances proposed for
inclusion on the list in this proposal, depending on the comments
received. Individuals and organizations will be able to petition FDA to
amend the list (to add or delete bulk drug substances) at any time
after the final rule is published. Amendments to the list will be
proposed through rulemaking.
    With regard to nominated substances discussed in this proposed
rulemaking (substances proposed for inclusion on the proposed list and
substances that have been nominated but are still under consideration
by the agency), FDA intends to exercise its enforcement discretion
regarding regulatory action during the pendency of this proposed
rulemaking. For further information on this subject, see the guidance
for industry entitled ``Enforcement Policy During Implementation of
Section 503A of the Federal Food, Drug, and Cosmetic Act'' (see 63 FR
64723, November 23, 1998).

B. Nominated Drug Substances Being Proposed for Inclusion on the Bulk
Drugs List

    Under section 503A(d)(2) of the act, FDA is proposing that the
following 20 drug substances, which are neither the subject of a
current USP or NF monograph nor components of FDA-approved drugs, be
included in the list of bulk drug substances that may be used in
compounding under the exemptions provided in section 503A of the act
(sections 501(a)(2)(B), 502(f)(1), and 505). When a salt or ester of an
active moiety is listed, e.g., diloxanide furoate, only that particular
salt or ester may be used. Neither the base compound nor other salts or
esters of the same active moiety qualify for section 503A of the act's
compounding exemptions, unless separately listed.
    The following bulk drugs list is being proposed in Sec. 216.23 of
title 21 of the CFR. (Section 216.23 will be included in new part 216,
which is currently intended to include all FDA regulations whose
primary purpose is implementation of the pharmacy compounding
provisions found in section 503A of the act):
    Bismuth citrate. Bismuth citrate is well characterized chemically.
It has been used extensively in compounded products for short-term
treatment of several gastrointestinal disorders, including Helicobacter
pylori-associated ulcers. At doses reported in the literature for these
indications, bismuth citrate appears to be relatively nontoxic, and
serious adverse reactions associated with its use have not been
commonly reported. Limited anecdotal evidence of bismuth citrate's
effectiveness for these indications is also reported in the literature.
    Caffeine citrate. Caffeine citrate is well characterized
chemically. As a central nervous system stimulant, caffeine citrate has
been used extensively and for many years in compounded products to
treat apnea in premature infants. At doses reported in the literature
for this indication, caffeine citrate appears to be relatively
nontoxic, and serious adverse reactions associated with its use have
not been commonly reported. Limited anecdotal evidence of caffeine
citrate's effectiveness for this indication is also reported in the
literature.
    Cantharidin. Cantharidin, which is well characterized chemically,
is a substance obtained from the Chinese blister beetle, among other
beetle species, that has been used topically in the treatment of warts
and molluscum contagiosum, often in patients with compromised immune
systems. Limited anecdotal evidence of cantharidin's effectiveness for
these indications is reported in the literature. Although cantharidin
is an extremely toxic substance, it is apparently used only in the
professional office setting and not dispensed for home use. Because of
cantharidin's toxicity, FDA is proposing to include it on the bulk
drugs list for topical use in the professional office setting only.
    Choline bitartrate. Choline bitartrate is well characterized
chemically. It has been used to treat Alzheimer's-type dementia. It has
also been used to treat infantile colic. At doses reported in the
literature for these indications, choline bitartrate appears to be
relatively nontoxic, and serious adverse reactions associated with its
use have not been commonly reported. Limited anecdotal evidence of
choline bitartrate's effectiveness for these indications is also
reported in the literature. Additionally, FDA has previously
established that choline bitartrate is generally recognized as safe, as
a dietary supplement, when used in accordance with good manufacturing
practices (see 21 CFR 182.8250 (45 FR 58837, September 5, 1980)).
    Diloxanide furoate. Diloxanide furoate is well characterized
chemically. It has been used to treat parasitic diseases such as
intestinal amoebiasis. At doses reported in the literature for these
indications, diloxanide furoate appears to be relatively nontoxic, and
serious adverse reactions associated with its use have not been
commonly reported. Limited anecdotal evidence of diloxanide furoate's
effectiveness for these indications is also reported in the literature.
    Dimercapto-1-propanesulfonic acid. Dimercapto-1-propanesulfonic
acid (DMPS), a chelating agent, is well characterized chemically. DMPS
has been used to treat heavy metal poisoning. At doses reported in the
literature for this indication, DMPS appears to be relatively nontoxic,
and serious adverse reactions associated with its use have not been
commonly reported. Limited anecdotal evidence of DMPS's effectiveness
for this indication is also reported in the literature.

[[Page 999]]

    Ferric subsulfate.\4\ Ferric subsulfate is well characterized
chemically. It has been used as a topical hemostatic agent to control
bleeding associated with minor surgical procedures, biopsies, and minor
gynecological surgery involving the cervix. At doses reported in the
literature for this indication, ferric subsulfate appears to be
relatively nontoxic, and serious adverse reactions associated with its
use have not been commonly reported. Limited anecdotal evidence of
ferric subsulfate's effectiveness for this indication is also reported
in the literature. However, because the literature is limited to
topical use of this substance, FDA is proposing to include it on the
bulk drugs list for topical use only.
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    \4\ Both ferric subsulfate solution and ferric subsulfate powder
were nominated for inclusion on the bulk drugs list. FDA combined
them under one entry for ferric subsulfate.
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    Ferric sulfate hydrate. Ferric sulfate hydrate is well
characterized chemically. It has been used topically as a hemostatic
agent to control bleeding from dermatological and dental procedures. At
doses reported in the literature for these indications, ferric sulfate
hydrate appears to be relatively nontoxic, and serious adverse
reactions associated with its use have not been commonly reported.
Limited anecdotal evidence of ferric sulfate hydrate's effectiveness
for this indication is also reported in the literature. However,
because the literature is limited to topical use of this substance, FDA
is proposing to include it on the bulk drugs list for topical use only.
    Glutamine. Glutamine, the most abundant free amino acid found in
the human body, is well characterized chemically. Glutamine is involved
in a wide variety of metabolic processes, including regulation of the
body's acid-base balance. For years, glutamine has been used in
compounding as a supplement in parenteral nutrition regimens in adults.
At doses reported in the literature for this use, glutamine appears to
be relatively nontoxic, and serious adverse reactions associated with
its use have not been commonly reported. Limited anecdotal evidence of
glutamine's effectiveness for this indication is also reported in the
literature.
    Guaiacol. Guaiacol is well characterized chemically. It has been
used for decades in compounded products as an expectorant. At doses
reported in the literature for this indication, guaiacol appears to be
relatively nontoxic, and serious adverse reactions associated with its
use have not been commonly reported. Limited anecdotal evidence of
guaiacol's effectiveness for this indication is also reported in the
literature.
    Iodoform. Iodoform is well characterized chemically. It has been
used for the control of acute epistaxis (nosebleeds) and as a paste for
dental root fillings. Iodoform has tested positive in in vitro
mutagenicity assays and in an in vitro transformational assay in
mammalian cells. However, in 2-year bioassays conducted by the National
Toxicology Program, iodoform was found to be noncarcinogenic in rats
and mice. At doses reported in the literature for these indications,
iodoform appears to be relatively nontoxic, and serious adverse
reactions associated with its use have not been commonly reported.
Limited anecdotal evidence of iodoform's effectiveness for these
indications is also reported in the literature. However, because the
literature is limited to the topical and intradental use of this
substance, FDA is proposing to include it on the bulk drugs list for
topical and intradental use only.
    Metronidazole benzoate. Metronidazole benzoate, which is well
characterized chemically, has been used to treat parasitic diseases
such as amoebiasis and giardiasis. The base of this substance
(metronidazole) is an FDA-approved drug which has a bitter taste. The
benzoate salt apparently renders metronidazole tasteless, however, so
metronidazole benzoate is sometimes prescribed instead of the
metronidazole base to increase patient compliance, especially in
children. Serious adverse reactions associated with the use of
metronidazole benzoate have not been commonly reported, and limited
anecdotal evidence of its effectiveness is reported in the literature.
Although the agency is proposing to include metronidazole benzoate on
the bulk drugs list, it is specifically seeking public comment on
metronidazole benzoate's solubility and appropriate dosing, as
questions about these issues have been raised in the literature.
    Myrrh gum tincture. Myrrh is a gum resin obtained from the stem of
Commiphora molmol and other species of camphora. Myrrh is a mixture of
many substances and has not been well characterized chemically. Myrrh
has been used in its natural form and as a tincture to treat
inflammatory disorders of the mouth and pharynx. The preparation
reviewed by FDA is the tincture, which, at doses reported in the
literature for those indications, appears to be relatively nontoxic.
Serious adverse reactions associated with the use of myrrh gum tincture
have not been commonly reported. Limited anecdotal evidence of myrrh
gum tincture's effectiveness for those indications is also reported in
the literature. Because the literature is limited to the topical use of
this substance, FDA is proposing to include it on the bulk drugs list
for topical use only.
    Phenindamine tartrate. Phenindamine tartrate is well characterized
chemically. It is an antihistamine that has been used to treat
hypersensitivity reactions including urticaria (hives) and rhinitis
(nasal inflammation). At doses reported in the literature for this
indication, phenindamine tartrate appears to be relatively nontoxic,
and serious adverse reactions associated with its use have not been
commonly reported. Additionally, in developing the over-the-counter
monograph for antihistamine drug products, FDA previously established
that phenindamine tartrate, under the conditions established in the
monograph (including particular labeling and dosage limits), is
generally recognized as safe and effective for over-the-counter
antihistamine use (see 21 CFR 341.12; 57 FR 58356, December 9, 1992).
Limited anecdotal evidence of phenindamine tartrate's effectiveness as
an antihistamine is reported in the literature.
    Phenyltoloxamine dihydrogen citrate. Phenyltoloxamine dihydrogen
citrate, a structural isomer of diphenhydramine, is well characterized
chemically. It has been used as an antihistamine. At doses reported in
the literature for this indication, phenyltoloxamine dihydrogen citrate
appears to be relatively nontoxic, and serious adverse reactions
associated with its use have not been commonly reported. Limited
anecdotal evidence of phenyltoloxamine dihydrogen citrate's
effectiveness as an antihistamine is reported in the literature.
    Piracetam. Piracetam, a derivative of the amino acid gamma-amino
butyric acid, is well characterized chemically. Piracetam is believed
by some to enhance certain cognitive skills, and has been used to treat
Down's syndrome, dyslexia, and Alzheimer's disease, among other
cognitive disorders. At doses reported in the literature for these
indications, piracetam appears to be relatively nontoxic, and serious
adverse reactions associated with its use have not been commonly
reported. Limited anecdotal evidence of piracetam's effectiveness for
these indications is reported in the literature.
    Sodium butyrate. Sodium butyrate is a short chain fatty acid that
is well characterized chemically. It has been

[[Page 1000]]

used rectally in an enema formulation to treat several inflammatory
bowel conditions, including ulcerative colitis and diversion colitis.
At doses reported in the literature for these indications, sodium
butyrate appears to be relatively nontoxic, and serious adverse
reactions associated with its use have not been commonly reported.
Limited anecdotal evidence of sodium butyrate's effectiveness for these
indications is also reported in the literature. However, because the
literature is limited to the use of sodium butyrate rectally in an
enema formulation, FDA is proposing to include it on the bulk drugs
list for use in this dosage form and route of administration only.
    Taurine. Taurine, an amino acid with several important
physiological functions, including a role in bile acid conjugation, is
well characterized chemically. It has been used for years in
compounding as a component in parenteral nutrition solutions for
infants and adult patients. At doses reported in the literature for
this use, taurine appears to be relatively nontoxic, and serious
adverse reactions associated with its use have not been commonly
reported. Limited anecdotal evidence of taurine's effectiveness for
this indication is also reported in the literature.
    Thymol iodide. Thymol iodide is well characterize chemically. It
has been used as a topical agent for its absorbent, protective, and
antimicrobial properties. At doses reported in the literature for these
indications, thymol iodide appears to be relatively nontoxic, and
serious adverse reactions associated with its use have not been
commonly reported. Limited anecdotal evidence of thymol iodide's
effectiveness for these indications is also reported in the literature.
FDA notes, however, that it was able to identify only two relevant
articles concerning this substance. Because the literature is limited
to the topical use of thymol iodide, FDA is proposing to include it on
the bulk drugs list for topical use only.
    Tinidazole. Tinidazole is a chemically well-characterized
derivative of 5-nitromidazole. It has been used, often in conjunction
with diloxanide furoate, which also appears on this proposed list, to
treat parasitic diseases such as amoebiasis and giardiasis. At doses
reported in the literature for these indications, tinidazole appears to
be relatively nontoxic, and serious adverse reactions associated with
its use have not been commonly reported. Limited anecdotal evidence of
tinidazole's effectiveness for these indications is also reported in
the literature.

C. Nominated Drug Substances Still Under Consideration for the Bulk
Drugs List

    The following 10 drug substances were nominated for inclusion on
the proposed bulk drugs list. However, for the reasons described in
section III.C of this document, they are still under review by the
agency:
    4-Aminopyridine. The drug substance 4-Aminopyridine (4-AP), which
is well characterized chemically, is a potassium channel blocker that
may enhance the release of acetylcholine from nerve terminals. It has
been used to treat several neurological disorders, including Lambert-
Eaton myasthenic syndrome, multiple sclerosis, and Alzheimer's disease.
It also has been used to reverse the effects of nondepolarizing muscle
relaxants. At doses reported in the literature, the side effects of 4-
AP for most patients do not appear to be serious. However, there have
been some reports of seizures associated with the use of 4-AP. FDA
would like more information about the historical use, safety, and
effectiveness of 4-AP before deciding whether to propose it for
inclusion on the bulk drugs list. The Pharmacy Compounding Advisory
Committee similarly expressed a desire for more information about 4-AP
before making a recommendation about its status to the agency. FDA is
soliciting public input on these and any other issues that are relevant
to the agency's consideration of this substance for the bulk drugs
list.
    Betahistine dihydrochloride. Betahistine dihydrochloride is a
chemically well characterized histamine analog. Formerly marketed as
Serc tablets, betahistine dihydrochloride was approved by FDA to treat
the symptoms of vertigo in patients with Meniere's disease. In 1970,
however, FDA withdrew approval of the new drug application for Serc
tablets because they were found to lack substantial evidence of
effectiveness for this approved indication (see 35 FR 17563, November
14, 1970). FDA will consult with the Pharmacy Compounding Advisory
Committee at a future meeting about whether to include betahistine
dihydrochloride on the bulk drugs list and will address the effect of
its withdrawal from the market at that time.
    Cyclandelate. Cyclandelate, which is well characterized chemically,
is a vasodilator that was formerly approved by FDA for two indications:
(1) Treatment for intermittent claudication caused by arteriosclerosis
obliterans, and (2) as a treatment for cognitive dysfunction in
patients suffering from senile dementia of the multi-infarct or
Alzheimer's type. Cyclandelate was formerly marketed in Cyclospasmol
capsules and tablets, which were removed from the market for lack of
effectiveness for these approved indications (see 61 FR 64099, December
3, 1996). FDA will consult with the Pharmacy Compounding Advisory
Committee at a future meeting about whether to include cyclandelate on
the bulk drugs list and will address the effect of its withdrawal from
the market at that time.
    3,4-Diaminopyridine. The drug substance 3,4-Diaminopyridine (DAP),
which is well characterized chemically, is a potassium channel blocker
that may enhance the release of acetylcholine from nerve terminals. DAP
has been used in the treatment of several neuromuscular disorders,
including Lambert-Eaton myasthenic syndrome, myasthenia gravis,
amyotrophic lateral sclerosis, and multiple sclerosis. At doses
reported in the literature, DAP appears to be well tolerated and its
toxicity appears to be dose related. There have been reports of
seizures with its use, however, and DAP is contraindicated in patients
with epilepsy. FDA would like more information about the historical
use, safety, and effectiveness of DAP before deciding whether to
propose it for inclusion on the bulk drugs list. The Pharmacy
Compounding Advisory Committee similarly expressed a desire for more
information about DAP before making a recommendation about its status
to the agency. FDA is soliciting public input on these and any other
issues that are relevant to the agency's consideration of this
substance for the bulk drugs list.
    Dinitrochlorobenzene. Dinitrochlorobenzene (DNCB), which is well
characterized chemically, has been used in the treatment of recurrent
melanoma and as a skin sensitizer to estimate immune system competency.
It also has been used topically in the treatment of warts. Limited
anecdotal evidence of DNCB's effectiveness for these indications is
reported in the literature. DNCB is a highly toxic substance that may
be fatal if inhaled, swallowed, or absorbed through skin. High
concentrations of DNCB are also extremely destructive to tissues of the
mucous membranes and upper respiratory tract, eyes, and skin. At the
inaugural meeting of the Pharmacy Compounding Advisory Committee, the
nominator of this substance withdrew it as a list candidate, but
several members of the committee recommended that it still be
considered. The Pharmacy Compounding Advisory Committee then voiced
concerns about the safety of the

[[Page 1001]]

substance and expressed a desire for more information about it before
making a recommendation to the agency. FDA agrees and, therefore, is
requesting public input about the historical use, safety, and
effectiveness of DNCB, as well as any other information that would be
relevant to the agency's consideration of DNCB for the bulk drugs list.
    Diphenylcyclopropenone. Diphenylcyclopropenone, which is well
characterized chemically, has been used for the topical treatment of
extensive alopecia areata. The nomination of this substance was not
received by FDA in time to permit a full discussion of it at the
October 1998 meeting of the Pharmacy Compounding Advisory Committee. A
decision about this substance is therefore being deferred until after
FDA has had an opportunity to consult the Pharmacy Compounding Advisory
Committee about it at a future meeting.
    Hydrazine sulfate. Hydrazine sulfate is well characterized
chemically and has been used to treat cachexia in cancer patients. The
substance, however, is extremely toxic. Multiple exposures to hydrazine
sulfate have caused liver and kidney damage, gastrointestinal damage,
convulsions, and coma, among other conditions. Hydrazine sulfate is
also considered by the International Agency for Research on Cancer to
be a potential carcinogen to humans. In at least two clinical studies,
hydrazine sulfate was shown to have no effect, or even a negative
effect, on patients who received it. FDA would like more information
about the historical use, safety, and effectiveness of hydrazine
sulfate before deciding whether to propose it for inclusion on the bulk
drugs list. The Pharmacy Compounding Advisory Committee similarly
expressed a desire for more information about hydrazine sulfate before
making a recommendation about its status to the agency. FDA is
soliciting public input on these and any other issues that are relevant
to the agency's consideration of this substance for the bulk drugs
list.
    Pentylenetetrazole. Pentylenetetrazole, which is well characterized
chemically, was approved by FDA for use in the treatment of senile
confusion, depression, psychosis, fatigue, and debilitation, as well as
for the relief of dizzy spells, mild behaviorial disorders,
irritability, and functional memory disorders in elderly patients.
Pentylenetetrazole was formerly marketed in numerous drug products, all
of which were removed from the market for lack of effectiveness for
these approved indications (see 47 FR 19208, May 4, 1982). FDA will
consult with the Pharmacy Compounding Advisory Committee at a future
meeting about whether to include pentylenetetrazole on the bulk drugs
list and will address the effect of its withdrawal from the market at
that time.
    Silver protein mild. Mild silver protein is well characterized
chemically. It has been used to treat conjunctivitis and by
ophthalmologists as a preoperative chemical preparation of the eye. At
doses reported in the literature for these indications, mild silver
protein appears to be relatively nontoxic, and serious adverse
reactions associated with its use have not been commonly reported. When
mild silver protein is administered internally, however, it can cause
serious untoward side effects, including argyria, a permanent ashen-
gray discoloration of the skin, conjunctiva, and internal organs (see
61 FR 53685, October 15, 1996). At this time, FDA is deferring a
decision on this substance because questions were raised at the
inaugural meeting of the Pharmacy Compounding Advisory Committee about
its efficacy. FDA is soliciting public input on this issue and any
other issues that are relevant to the agency's consideration of mild
silver protein for the bulk drugs list.
    Squaric acid dibutyl ester. Squaric acid dibutyl ester, which is
well characterized chemically, is a contact sensitizer that has been
used as a topical treatment for alopecia areata and warts. The
nomination of this substance was not received by FDA in time to permit
a full discussion of it at the October 1998 meeting of the Pharmacy
Compounding Advisory Committee. A decision about this substance is
therefore being deferred until after FDA has had an opportunity to
consult the Pharmacy Compounding Advisory Committee about it at a
future meeting.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

V. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Order
12866 directs agencies to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The Regulatory
Flexibility Act requires agencies to examine regulatory alternatives
for small entities if the proposed rule is expected to have a
significant economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act requires agencies to prepare an
assessment of anticipated costs and benefits before enacting any rule
that may result in an expenditure in any 1 year by State, local and
tribal governments, in the aggregate, or by the private sector, of $100
million (adjusted annually for inflation).
    The agency has reviewed this proposed rule and has determined that
it is consistent with the regulatory philosophy and principles
identified in the Executive Order and these two statutes. The proposed
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order. As
discussed below, the agency certifies that this proposed rule will not
have a significant economic impact on a substantial number of small
entities. Also, because the rule is not expected to result in any
annual expenditures, FDA is not required to prepare a cost/benefit
analysis under the Unfunded Mandates Reform Act.
    FDA is proposing to amend its regulations to include a list of bulk
drugs that may be used in pharmacy compounding under certain conditions
even though such substances are neither the subject of a USP or NF
monograph nor components of FDA-approved drugs. FDA has requested and
received nominations for bulk drugs to be included on this list. Twenty
of the nominated substances are being proposed for inclusion, which
means they would be eligible for use in pharmacy compounding under the
exemptions provided by section 503A of the act. As a result, there
would be no loss of any sales, or other economic impact, for compounded
drug products containing these 20 substances.
    FDA has proposed to include some of these substances on the list
with a restriction on their route of administration or a requirement
that the resulting compounded drug product be for professional office
use only. As FDA is unaware that any of these drug substances are
currently used in compounding outside of the proposed restrictions, the
agency does not expect these restrictions to result in decreased sales
of any compounded drug product.

[[Page 1002]]

 Further, this regulation is not anticipated to impose any other
compliance costs on bulk drug manufacturers or compounding pharmacies.
    Ten additional nominated substances, while not being proposed for
inclusion on the bulk drugs list, are still under review by the agency.
As explained more fully in the guidance for industry entitled
``Enforcement Policy During Implementation of section 503A of the
Federal Food, Drug, and Cosmetic Act'' (see notice of availability, 63
FR 64723, November 23, 1998), FDA intends to exercise its enforcement
discretion regarding these 10 substances. In short, FDA does not intend
to take regulatory action against a drug product that has been
compounded with one of these substances while the substance is being
evaluated during the pendency of this rulemaking proceeding, as long as
the compounding complies with the other effective requirements in
section 503A of the act and does not appear to present a significant
safety risk.
    Although usage or sales data for the nominated drug substances is
limited, the agency further concludes that even if any of the 10
deferred drug substances were, in the future, to be excluded as
candidates for the bulk drugs list, the economic impact would not be
significant, particularly not for any substantial number of pharmacies
or other small entities. The quantity demanded of these 10 drugs
appears to be relatively small, especially when compared to the total
number of prescription drugs dispensed annually in the United States.
In addition, if any of the 10 substances were ultimately excluded from
the list, sales of alternatives to the excluded drugs would be expected
to reduce the economic impact of such exclusion.
    At the October 1998 meeting of the Pharmacy Compounding Advisory
Committee, a representative of the International Academy of Compounding
Pharmacists (IACP) presented usage and sales data for four of the
deferred substances: 3,4-DAP, 4-AP, hydrazine sulfate, and mild silver
protein. According to the IACP representative, the drug substances 3,4-
DAP and 4-AP are currently being used in compounding to treat patient
populations estimated at 1,000 and 10,000 patients, respectively;
hydrazine sulfate is currently being used to treat between 5,000 and
10,000 patients annually; and the annual production of mild silver
protein is approximately 9 kilograms. FDA does not have a firm estimate
of the number of patients being treated with mild silver protein, but
estimates it to be several thousand. Similarly, FDA does not have usage
or sales data for the six other deferred drug substances, but estimates
that their usage is also relatively low. The agency invites comments
and data on any projected loss of sales or other compliance costs
directly attributable to this proposal.
    If a rule is expected to have a significant economic impact on a
substantial number of small entities, the Regulatory Flexibility Act
requires agencies to analyze regulatory options to minimize these
impacts. Section 503A of the act specifically directs FDA to develop a
list of bulk drug substances that may be used in pharmacy compounding.
The agency received nominations from the public for 41 bulk drugs to be
included on this list. All the nominations are either proposed for
inclusion on the list or are still under review. The agency therefore
certifies that this proposal will not have a significant economic
impact on a substantial number of small entities. The agency invites
public comment and data on these issues, specifically the number and
size of the bulk drug manufacturers and compounding pharmacies that
sell any of the deferred substances, or drug products containing them,
and any sales data on these compounded drug products.
    The Unfunded Mandates Reform Act requires (in section 202) that
agencies prepare an assessment of anticipated costs and benefits before
proposing any expenditure by State, local, and tribal governments, in
the aggregate, or by the private sector of $100 million (adjusted
annually for inflation) in any 1 year. The publication of FDA's list of
bulk drug substances for use in pharmacy compounding is not expected to
result in any expenditure of funds by State, local and tribal
governments or the private sector. Because the proposed rule is not
expected to result in any mandated expenditures, FDA is not required to
perform a cost/benefit analysis according to the Unfunded Mandates
Reform Act.

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no
collections of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.

VII. Request for Comments

    Interested persons may, on or before March 23, 1999, submit to the
Dockets Management Branch (address above) written comments regarding
this proposal. Two copies of any comments are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with docket number found in brackets in the heading of this document.
Received comments may be seen in the office above between 9 a.m. and 4
p.m., Monday through Friday.

List of Subjects in 21 CFR Part 216

    Drugs, Pharmacy compounding, Prescription drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 216 be added as follows:
    1. Part 216 is added to read as follows:

PART 216--PHARMACY COMPOUNDING

Subpart A--General Provisions [Reserved]

Subpart B--Compounded Drug Products

Sec.
216.23  Bulk drug substances for use in pharmacy compounding.
216.24  [Reserved]
    Authority: 21 U.S.C. 351, 352, 353a, 355, 371.

Subpart A--General Provisions [Reserved]

Subpart B--Compounded Drug Products

Sec. 216.23  Bulk drug substances for use in pharmacy compounding.

    (a) The following bulk drug substances, which are neither the
subject of a current United States Pharmacopeia or National Formulary
monograph nor components of the Food and Drug Administration approved
drugs, may be used in compounding under section 503A(b)(1)(A)(i)(III)
of the Federal Food, Drug, and Cosmetic Act.
    Bismuth citrate.
    Caffeine citrate.
    Cantharidin (for topical use in the professional office setting
only).
    Choline bitartrate.
    Diloxanide furoate.
    Dimercapto-1-propanesulfonic acid.
    Ferric subsulfate (for topical use only).
    Ferric sulfate hydrate (for topical use only).
    Glutamine.
    Guaiacol.
    Iodoform (for topical and intradental use only).
    Metronidazole benzoate.
    Myrrh gum tincture (for topical use only).
    Phenindamine tartrate.
    Phenyltoloxamine dihydrogen citrate.
    Piracetam.
    Sodium butyrate (for rectal enema use only).

[[Page 1003]]

    Taurine.
    Thymol iodide (for topical use only).
    Tinidazole.
    (b) FDA balances the following criteria in evaluating substances
considered for inclusion on the list set forth in paragraph (a) of this
section: The chemical characterization of the substance; the safety of
the substance; the historical use of the substance in pharmacy
compounding; and the available evidence of the substance's
effectiveness or lack of effectiveness, if any such evidence exists.
    (c) Based on evidence currently available there are inadequate data
to establish substantial evidence or general recognition of the safety
or effectiveness of any of the drug substances set forth in paragraph
(a) of this section, for any indication.

Sec. 216.24  [Reserved]

    Dated: December 29, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 99-277 Filed 1-6-99; 8:45 am]
BILLING CODE 4160-01-F