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

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