Where has Dr. Atkinson-Barr been?!
Lance Baum
with flagyl? Did he ever get his website up? I was anxious to hear good
more news about flagyl treatment. Anybody know anything?
Spiroflex
time of the year when CPAs work an 18-hour day and 7 days per week. I'm
sure MAB will be back online later in the year, but right now he is probably
buried in work.
The last thing I heard from MAB was that he knew of a case of someone
having taken Tinidazole for 7 months and then went off all abx and had
enjoyed 3 months of total remission. Maybe some other abx was used along
with the Tinidazole, I don't know. --- Spiroflex
"Lance Baum" <lan...@sgi.net> wrote in message
news:oS0w4.365$s7.8...@news.sgi.net...
Martin Atkinson-Barr
Spiroflex wrote:
Hello, I'm just going through the newsgroup today. We also had to upgrade our
computers to Windows 98. Ugh - what a mess! Took me about a week to get things
straight and working. Its kind of serious when the accounting business doesn't
have a fax.
I'm waiting for a decision on an NIH grant to test metronidazole gel to prevent
onset of Lyme after tick bite. Also I have a contact with a philanthropic
organization - I'm hoping to go to the UK later this spring to set up a double
blind of tinidazole in late stage Lyme (tinidazole is licensed here so it makes
the matter much easier).
The news is that the patients here treated with tinidazole have not relapsed
after 1 1/2 years and 7 months respectively and continue to improve without any
therapy (the little girl treated with Flagyl has been symptom free for > 2years
and is now an A student). No signs of symptoms esp. night sweats, joint pain or
neurologicals. I'm very hopeful. I'm waiting for the culture lab in Palo Alto to
be tested and functional to put in some more proposals for research programs.
Good luck to everyone.
MAB
Kathleen N
Kathleen
Martin Atkinson-Barr <mc...@worldnet.att.net> wrote in message
news:38D7B1F2...@worldnet.att.net...
Martin Atkinson-Barr
Kathleen N wrote:
> What is tinidazole?
>
> Kathleen
>
> Martin Atkinson-Barr <mc...@worldnet.att.net> wrote in message
> news:38D7B1F2...@worldnet.att.net...
Similar to metronidazole (i.e a nitroimidazole) made by Pfizer and sold all
round the world, except in the US for marketing reasons, as Fasigyn.
Anton
about your research on tinidazole. I was infected while living
in the UK over 10 years ago and was only recently diagnosed.
I may be moving back to the UK next year and was wondering if
you might be able to provide me with any contact info. for LLD's
there. Also do you know if tinidazole is available privately in
the US and what the cost is?
Any info would be much appreciated.
* Sent from RemarQ http://www.remarq.com The Internet's Discussion Network *
The fastest and easiest way to search and participate in Usenet - Free!
Martin Atkinson-Barr
Anton wrote:
Tinidazole is freely available on prescription in the UK as Fasigyn. Dr. Sue
O'Connell runs the Lyme Unit at Southampton General Hospital. Tinidazole is
available in the US through compounding pharmacies. It costs about $1/capsule
there. Its cheaper in countries where it is fully approved for Rx. In Mexico it
costs 25c/tablet (500mg)
Drl2040
Hi MAB,
Someone recently posted your views regarding tinidazole vs. Flagyl, stating
that you felt there was evidence that the former may be more effective than the
latter. Is there any significant difference in their side-effect profiles or
carcinogenicity? Regarding the latter, how significant a cancer-promoter do
you think Flagyl is? I've heard concerns about it but am not sure how serious
they are. Regards, Dorian
Anton
that a couple of patients treated with tinidazoloe in the UK are
symptom free after 1 1/2 years and 7 months respectively. Would
you happen to know if they were treated with tinidazole
exclusively and what the dosages and duration was?
Martin Atkinson-Barr
Anton wrote:
Thy were initially treated with metronidazole and a range of classic
antibiotics. When it became clear that short (1-2month) treatments with Flagyl
were insufficient thay switched to long term tinidazole. Remarkably they
continue to improve, with no treatment, for months after treatment ends, in
terms of energy and well-being. This may be a transition from a person who views
the world as a "sick person" and one who feels healthy.
Dosage of tiidazole was somewhat arbitrary but around 14mg/lb body weight. Taken
for 2 months after all obvious symptoms disappeared.
BTW I've had a lot of e-mails and phone calls from people who confirm these
results. usually they say something like "at first I didn't feel this would
work, then my physician put me on it - and it works!"
Anton
encouraging. Will your double blind studies be conducted for
tinidazone? When do you expect to have the results? My last
question is do you know if it is legal to import tinidazole from
Mexico or must one travel there?
Sorry for all the questions, but as you know there are so few
avenues of hope for the chronic in this disease.
Drl2040
Mexico or must one travel there>>
I'm quite sure that it is legal to import tinidazole from Mexico, but finding a
pharmacy that carries it might be a problem. Pharmacies in Mexico (at least
the ones I've seen) aren't as well stocked as in the US. If anyone knows of a
pharmacy in Mexico that does mail service to the US and that either carries or
can obtain tinidazone would you post their address, email or phone number here?
By the way, is tinidazole usually prescribed in the same dosages as
metronidizole? Dorian
mike...@my-deja.com
You cross the border and go to a drug store. There is usually a booth
or counter out front, where for $10 bucks the MD's perscription will be
converted to a Mexican perscription. The drug store will then fill the
perscription. The drug will be from an American mfg, and be the same
that you would buy here.
Mike
Sent via Deja.com http://www.deja.com/
Before you buy.
ktcm
pharmacy can make up capsules for
you. If they need the formula-they can get source from
Hopewells. The below is the regulatiuon
from FDA.
Approval Compounding Tinidazole
[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]
========================================================================
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.
========================================================================
[[Page 996]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
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.
-----------------------------------------------------------------------
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).
---------------------------------------------------------------------------
\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.''
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\3\ A transcript of the advisory committee meeting may be
found
at the Dockets Management Branch (address above) under Docket No.
98N-0182.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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