[Federal Register: October 8, 1998 (Volume 63, Number 195)]
[Proposed Rules]
[Page 54082-54089]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08oc98-22]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 216

 [Docket No. 98N-0655]


List of Drug Products That Have Been Withdrawn or Removed From
the Market for Reasons of Safety or Effectiveness

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations to include a list of drug products that may not be used
for pharmacy compounding pursuant to the exemptions under section 503A
of the Federal Food, Drug, and Cosmetic Act (the act) because they have
had their approval withdrawn or were removed from the market because
the drug product or its components have been found to be unsafe or not
effective. The list has been compiled under the new statutory
requirements of the Food and Drug Administration Modernization Act of
1997 (Modernization Act).

DATES: Comments must be received on or before November 23, 1998.

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: Wayne H. Mitchell, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    President Clinton signed the Modernization Act (Pub. L. 105-115)
into law on November 21, 1997. One of the issues addressed in this new
legislation is the applicability of the act to the practice of pharmacy
compounding. Compounding involves a process whereby a pharmacist or
physician combines, mixes, or alters ingredients to create a customized
medication for an individual patient. Section 127 of the Modernization
Act, which adds section 503A to the act (21 U.S.C. 353a), describes the
circumstances under which compounded drugs qualify for exemptions from
certain adulteration, misbranding, and new drug provisions of the act
(i.e., 501(a)(2)(B), 502(f)(1), and 505 of the act (21 U.S.C.
351(a)(2)(B), 352(f)(1), and 355)). Section 127(b) of the Modernization
Act provides that section 503A of the act will become effective on
November 21, 1998, 1 year from the date of the Modernization Act's
enactment.
    Section 503A of the act contains several conditions that must be
satisfied for pharmacy compounding to qualify for the exemptions under
section 503A. One of the conditions is that the licensed pharmacist or
licensed physician does not ``compound a drug product that appears on a
list published by the Secretary in the Federal Register of drug
products that have been withdrawn or removed from the market because
such drug products or components of such drug products have been found
to be unsafe or not effective.''

II. Rulemaking to Establish the List

    In accordance with section 503A of the act, FDA has developed a
list of drug products that have been withdrawn or removed from the
market because they have been found to be unsafe or not effective. Many
of the drug products on the list were withdrawn from the market through
official proceedings, including publication of a notice in the Federal
Register. For these drug products, this preamble to the proposed rule
includes the reason for the withdrawal and the citation to the official
notice of withdrawal. Other products, both approved and unapproved,
were removed from the market voluntarily by the manufacturer or
application holder, and FDA has information indicating that the reason
for the removal was because the product was unsafe or not effective. In
such cases, the reason for the removal is provided, and additional
sources of information on the drug can be found in the docket
identified by the number found in brackets in the heading of this
document.
    This proposed rule is the first of a series of rulemaking
proceedings to establish the list of withdrawn or removed drug
products, as the development and issuance of this list will be an
ongoing process. The primary focus of this proposed rule is drug
products that have been removed or withdrawn for safety reasons. FDA
intends that future rulemaking

[[Page 54083]]

proceedings will focus on drug products that were withdrawn for reasons
of effectiveness, on drug products that are identified as having been
withdrawn for reasons of safety or effectiveness after the preparation
of this proposed rule, and on additional drug products that will be
proposed for inclusion on the list either during the comment period or
subsequently.
    FDA is specifically seeking comment on whether additional drug
products should be added to the list and whether products now on the
list should remain on the list. Persons submitting comments
recommending that a drug product be added to the list should include
appropriate documentation, including any notices published in the
Federal Register. In addition, individuals and organizations may
petition FDA to amend the list at any time through the regular citizen
petition process described in 21 CFR 10.30.
    After evaluating the comments on this proposed rule and consulting
an advisory committee on compounding, as required by section 503A(d)(1)
of the act, FDA will issue the list as a final rule which will be
codified in the Code of Federal Regulations. The initial list published
as a final rule may include all or some of the products proposed for
inclusion on the list in this proposal, depending upon the comments
received. Additional products will be added to the list through the
rulemaking process after the data on the products are evaluated, and
after consultation with the advisory committee on compounding.

III. Description of the Proposed Rule

    FDA is proposing that the drug products described in this section
be included in the list of drug products that have been withdrawn or
removed from the market because such drug products or components of
such drug products have been found to be unsafe or not effective.
Compounding a drug product that appears on this list is not covered by
the exemption provided in section 503A(a) of the act, and may be
subject to enforcement action under sections 501(a)(2)(B), 502(f)(1),
and 505 (among other applicable provisions) of the act.
    The listings are arranged alphabetically by the established name of
the active ingredient contained in the drug product. For many of the
drugs, the proprietary or trade name of some or all of the drug
products which contained the active ingredient are also given in the
preamble paragraphs describing the withdrawn or removed drug products.
Some of the drugs listed were withdrawn or removed from the market
based on problems relating only to one dosage form or route of
administration. In such cases, the listing for that drug product
reflects that fact, e.g., ``Neomycin Sulfate: Parenteral drug products
containing neomycin sulfate.'' In other cases, the problem is
associated with the active ingredient, or appears to relate to other
dosage forms or routes of administration, and the listing reflects that
fact, e.g., ``Adrenal Cortex: All drug products containing adrenal
cortex.'' In several instances, a particular formulation, dosage form,
or route of administration is explicitly excluded from an entry on the
list because there is an approved drug (that has not been withdrawn or
removed from the market) that contains the same active ingredient(s) as
the drug product that has been withdrawn or removed from the market. In
these instances, the listing includes the appropriate qualification,
e.g., ``Suprofen: All drug products containing suprofen (except
ophthalmic solutions).''
    In several cases, the withdrawn drug products are identified
according to the established name of the active ingredient, listed as a
particular salt or ester of the active moiety, e.g., ``Dexfenfluramine
hydrochloride: All drug products containing dexfenfluramine
hydrochloride.'' Although the specific listing may be limited to a
particular salt or ester, other salts or esters of the active moiety
will not qualify for the compounding exemptions in section 503A of the
act unless (among other requirements) the particular salt or ester is
the subject of a United States Pharmacopeia or National Formulary
monograph; is a component of an FDA approved drug; or appears on the
FDA list of bulk drug substances that may be used for compounding. (See
section 503A(b)(1)(A)(i) of the act).
    The list is being proposed as Sec. 216.24 of Title 21 of the Code
of Federal Regulations. This new section will be included in a new
part, 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.
    The following drug products are proposed for inclusion in proposed
Sec. 216.24. The supporting documentation for each listed drug product
may be found in the docket identified by the number found in brackets
in the heading of this document. The supporting documentation will be
arranged alphabetically according to the established name of the active
ingredient of the drug products.
    Adenosine phosphate: All drug products containing adenosine
phosphate. Adenosine phosphate, formerly marketed as a component of
Adeno for injection, Adco for injection, and other drug products, was
determined to be neither safe nor effective for its intended uses as a
vasodilator and an anti-inflammatory. FDA directed the removal of these
drug products from the market in 1973.
    Adrenal cortex: All drug products containing adrenal cortex. The
low level of corticosteroids found in adrenal cortex injection and
adrenal cortex extract were determined to present a substantial risk of
undertreatment of serious conditions, such as adrenal cortical
insufficiency, burns, and hypoglycemia. FDA determined that adrenal
cortex for injection and adrenal cortex extract presented a significant
potential hazard and directed the removal of these drug products from
the market in January 1978.
    Azaribine: All drug products containing azaribine. The use of
azaribine, formerly marketed as Triazure tablets, was associated with
very serious thromboembolic events. Approval of the new drug
application (NDA) for Triazure tablets was withdrawn June 10, 1977 (see
the Federal Register of June 10, 1977 (42 FR 29998)).
    Benoxaprofen: All drug products containing benoxaprofen. The use of
benoxaprofen, formerly marketed as Oraflex tablets, was associated with
fatal cholestatic jaundice among other serious adverse reactions. The
holder of the approved application voluntarily withdrew Oraflex tablets
from the market on August 5, 1982.
    Bithionol: All drug products containing bithionol. Bithionol,
formerly marketed as an active ingredient in various topical drug
products, was shown to be a potent photosensitizer with the potential
to cause serious skin disorders. Approvals of the NDA's for bithionol
drug products were withdrawn on October 24, 1967 (see the Federal
Register of October 31, 1967 (32 FR 15046)).
    Bromfenac sodium: All drug products containing bromfenac sodium.
The use of bromfenac sodium, formerly marketed as Duract capsules, was
associated with fatal hepatic failure. Duract capsules were voluntarily
withdrawn from the market by their manufacturer on June 22, 1998.
    Butamben: All parenteral drug products containing butamben. The use
of a parenteral drug product containing butamben, formerly marketed as
Efocaine, was associated with severe adverse reactions, such as severe
tissue slough and transverse myelitis.

[[Page 54084]]

 Approval of the NDA for Efocaine was withdrawn on August 7, 1964 (see
the Federal Register of August 14, 1964 (29 FR 11656)).
    Camphorated oil: All drug products containing camphorated oil.
Products containing camphorated oil were associated with poisoning in
infants and young children due to accidental ingestion. FDA directed
the removal from the market of drug products containing camphorated oil
in 1982 (see 21 CFR 310.526 (1997)).
    Carbetapentane citrate: All oral gel drug products containing
carbetapentane citrate. Carbetapentane citrate gel, formerly marketed
as Candette Cough Jel, was determined not to be safe because the
inexact methods of measuring the gel by consumers were potentially
dangerous. Approval of the NDA for Candette Cough Jel was withdrawn on
November 29, 1972 (see the Federal Register of November 29, 1972 (37 FR
25249)).
    Casein, iodinated: All drug products containing iodinated casein.
Iodinated casein, formerly marketed as a component of Neo-Barine, was
associated with thyrotoxic side effects. Approval of the NDA for Neo-
Barine was withdrawn October 22, 1964 (see the Federal Register of
October 28, 1964 (29 FR 14676)).
    Chlorhexidine gluconate: All tinctures of chlorhexidine gluconate
formulated for use as a patient preoperative skin preparation.
Chlorhexidine gluconate topical tincture 0.5%, formerly marketed as
Hibitane, was associated with chemical and thermal burns when used as a
patient preoperative skin preparation. The drug product was voluntarily
removed from the market in early 1984. FDA determined that
chlorhexidine gluconate topical tincture 0.5% was removed from the
market for reasons of safety (see the Federal Register of October 6,
1997 (62 FR 52137)).
    Chlormadinone acetate: All drug products containing chlormadinone
acetate. Chlormadinone acetate, formerly marketed as a component of the
combination drug products Estalor-21 and C-Quens tablets, was
associated with the development of mammary tumors in dogs. The
manufacturer ceased marketing the drug in 1970 and approvals of the
NDA's for Estalor-21 and C-Quens tablets were withdrawn by FDA on March
16, 1972 (see the Federal Register of March 16, 1972 (37 FR 5516)).
    Chloroform: All drug products containing chloroform. National
Cancer Institute studies demonstrated that chloroform is carcinogenic
in animals. FDA directed the removal from the market of drug products
containing chloroform in 1976 (see 21 CFR 310.513 (1997)).
    Cobalt: All drug products containing cobalt salts (except
radioactive forms of cobalt and its salts and cobalamin and its
derivatives). FDA found that cobalt salts were not safe or effective
for treatment of iron-deficiency anemia. The toxic effects of cobalt
salts include liver damage, claudication, and myocardial damage. FDA
directed the removal from the market of drug products containing cobalt
salts in 1967 (see 21 CFR 250.106 (1997)).
    Dexfenfluramine hydrochloride: All drug products containing
dexfenfluramine hydrochloride. Dexfenfluramine hydrochloride, formerly
marketed as Redux capsules, was associated with valvular heart disease.
The manufacturer of dexfenfluramine hydrochloride capsules voluntarily
withdrew the drug from the market in September 1997.
    Diamthazole dihydrochloride: All drug products containing
diamthazole dihydrochloride. Diamthazole dihydrochloride, formerly
marketed as Asterol ointment, powder, and tincture, was associated with
neurotoxicity. Approvals of the NDA's for Asterol ointment, powder, and
tincture were withdrawn on July 19, 1977 (see the Federal Register of
July 19, 1977 (42 FR 37057)).
    Dibromsalan: All drug products containing dibromsalan. Dibromsalan,
formerly marketed in a number of drug products, largely antibacterial
soaps, as an antimicrobial, preservative, or for other purposes, was,
with other halogenated salicylanilides listed in this proposal, found
to be a potent photosensitizer capable of causing disabling skin
disorders. FDA directed the removal from the market of drug products
containing dibromsalan in 1975 (see Sec. 310.508 (21 CFR 310.508)
(1997)).
    Diethylstilbestrol: All oral and parenteral drug products
containing 25 milligrams (mg) or more of diethylstilbestrol per unit
dose. Diethylstilbestrol, marketed in various tablet and parenteral
drug products, was associated with adenocarcinoma of the vagina in the
offspring of the patient when used in early pregnancy. Approvals of the
NDA's for these diethylstilbestrol drug products were withdrawn on
February 18, 1975 (see the Federal Register of February 5, 1975 (40 FR
5384)).
    Dihydrostreptomycin sulfate: All drug products containing
dihydrostreptomycin sulfate. Dihydrostreptomycin sulfate, formerly
marketed in several parenteral drug products, was associated with
ototoxicity. Approvals of the NDA's for dihydrostreptomycin sulfate
drug products were withdrawn on July 20, 1970 (see the Federal Register
of September 3, 1970 (35 FR 13988)).
    Dipyrone: All drug products containing dipyrone. Dipyrone, formerly
marketed as Dimethone tablets and injection, Protemp oral liquid, and
other drug products, was associated with potentially fatal
agranulocytosis. Approvals of the NDA's for dipyrone drug products were
withdrawn on June 27, 1977 (see the Federal Register of June 17, 1977
(42 FR 30893)).
    Encainide hydrochloride: All drug products containing encainide
hydrochloride. Encainide hydrochloride, formerly marketed as Enkaid
capsules, was associated with increased death rates in patients who had
asymptomatic heart rhythm abnormalities after a recent heart attack.
The manufacturer of Enkaid capsules voluntarily withdrew the product
from the market on December 16, 1991.
    Fenfluramine hydrochloride: All drug products containing
fenfluramine hydrochloride. Fenfluramine hydrochloride tablets,
formerly marketed as Pondimin tablets, were associated with valvular
heart disease. The manufacturer of fenfluramine hydrochloride tablets
voluntarily withdrew the drug from the market in September 1997.
    Flosequinan: All drug products containing flosequinan. Flosequinan,
formerly marketed as Manoplax tablets, was the subject of a study that
indicated the drug had adverse effects on survival, and that beneficial
effects on the symptoms of heart failure did not last beyond the first
3 months of therapy. After the first 3 months of therapy, patients on
the drug had a higher rate of hospitalization than patients taking a
placebo. The manufacturer of Manoplax tablets voluntarily withdrew the
drug from the market in July 1993.
    Gelatin: All intravenous drug products containing gelatin. Gelatin
for intravenous use, formerly marketed as Knox Special Gelatine
Solution Intravenous-6 percent, was found not to be suitable as a
plasma expander because the drug caused increased blood viscosity,
reduced blood clotting, and prolonged bleeding time. Approval of the
NDA for Knox Special Gelatine Solution Intravenous-6 percent was
withdrawn on April 19, 1978 (see the Federal Register of April 7, 1978
(43 FR 14743)).
    Glycerol, iodinated: All drug products containing iodinated
glycerol. Iodinated glycerol, formerly marketed as Iodur Elixir and
other drug products, was

[[Page 54085]]

found to have carcinogenic potential. FDA directed the removal from the
market of drug products containing iodinated glycerol in April 1993.
    Gonadotropin, chorionic: All drug products containing chorionic
gonadotropins of animal origin. Chorionic gonadotropins of animal
origins, formerly marketed as Synapoidin Steri-Vial, were shown to
produce allergic reactions. Approval of the NDA for Synapoidin Steri-
Vial was withdrawn on July 6, 1972 (see the Federal Register of July 6,
1972 (37 FR 13284)).
    Mepazine: All drug products containing mepazine hydrochloride or
mepazine acetate. Mepazine hydrochloride, formerly marketed as Pacatal
tablets, and mepazine acetate, formerly marketed as Pacatal for
injection, were associated with granulocytopenia, granulocytosis,
paralytic ileus, urinary retention, seizures, hypotension, and
jaundice. Approval of the NDA for Pacatal tablets and Pacatal for
injection was withdrawn on May 28, 1970 (see the Federal Register of
May 28, 1970 (35 FR 8405)).
    Metabromsalan: All drug products containing metabromsalan.
Metabromsalan, formerly marketed in a number of drug products, largely
antibacterial soaps, as an antimicrobial, preservative, or for other
purposes, was, with other halogenated salicylanilides listed in this
proposal, found to be a potent photosensitizer capable of causing
disabling skin disorders. FDA directed the removal from the market of
drug products containing metabromsalan in 1975 (see Sec. 310.508
(1997)).
    Methamphetamine hydrochloride: All parenteral drug products
containing methamphetamine hydrochloride. Parenteral methamphetamine
hydrochloride, formerly marketed as Methedrine injection and Drinalfa
injection and used as an adjunct treatment for weight reduction, was
found to have a history of serious abuse and a severe risk of
dependence. Approvals of the NDA's for Methedrine injection and
Drinalfa injection were withdrawn on March 30, 1973 (see 21 CFR 310.504
(1997)).
    Methapyrilene: All drug products containing methapyrilene.
Methapyrilene, formerly marketed in many drug products, was shown to be
a potent carcinogen. Manufacturers voluntarily withdrew methapyriline
drug products from the market in May and June 1979.
    Methopholine: All drug products containing methopholine.
Methopholine, formerly marketed as Versidyne tablets, was associated
with ophthalmic changes and corneal opacities in dogs. Approval of the
NDA for Versidyne tablets was withdrawn on March 22, 1965 (see the
Federal Register of March 27, 1965 (30 FR 4083)).
    Mibefradil dihydrochloride: All drug products containing mibefradil
dihydrochloride. Mibefradil dihydrochloride, formerly marketed as
Posicor tablets, was associated with potentially harmful interactions
with other drugs. Mibefradil dihydrochloride reduced the activity of
certain liver enzymes that are important in helping the body eliminate
many other drugs. Inhibiting these enzymes can cause some of these
drugs to accumulate to dangerous levels in the body. The manufacturer
voluntarily removed Posicor tablets from the market on June 8, 1998.
    Neomycin sulfate: All parenteral drug products containing neomycin
sulfate. Parenteral neomycin sulfate was found to present toxicity
problems when used to irrigate wounds and was found not to be
acceptable for the treatment of urinary tract infections due to the
availability of newer, safer antibiotics that were as effective as, or
more effective than, parenteral neomycin sulfate. Approvals of the
marketing applications for parenteral neomycin sulfate were withdrawn
on January 5, 1989 (see the Federal Register of December 6, 1988 (53 FR
49232)).
    Nitrofurazone: All drug products containing nitrofurazone (except
topical drug products formulated for dermatalogic application).
Nitrofurazone, formerly marketed in nasal drops, otic drops, and
vaginal suppositories, was associated with mammary neoplasia in rats.
Approvals of the NDA's for the nitrofurazone drug products were
withdrawn on December 4, 1974, and June 10, 1975 (see the Federal
Register of December 4, 1974 (39 FR 42018), and May 30, 1975 (40 FR
23502)).
    Nomifensine maleate: All drug products containing nomifensine
maleate. Nomifensine maleate, formerly marketed as Merital capsules,
was associated with an increased incidence of hemolytic anemia. The
approved application holder removed Merital capsules from the market on
January 23, 1986. FDA published a notice of its determination that
Merital capsules were removed from the market for safety reasons (see
the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the
NDA for Merital capsules was withdrawn on March 20, 1992 (see the
Federal Register of March 20, 1992 (57 FR 9729)).
    Oxyphenisatin: All drug products containing oxyphenisatin.
Oxyphenisatin, formerly marketed in Lavema Compound Solution and Lavema
Enema Powder, was associated with hepatitis and jaundice. The approvals
of the NDA's for Lavema Compound Solution and Lavema Enema Powder were
withdrawn on March 9, 1973 (see the Federal Register of March 9, 1973
(38 FR 6419)).
    Oxyphenisatin acetate: All drug products containing oxyphenisatin
acetate. Oxyphenisatin acetate, formerly marketed in Dialose Plus
capsules, Noloc capsules, and other drug products, was associated with
hepatitis and jaundice. Approvals of the NDA's for the oxyphenisatin
acetate drug products were withdrawn on February 1, 1972 (see the
Federal Register of February 1, 1972 (37 FR 2460)).
    Phenacetin: All drug products containing phenacetin. Phenacetin,
formerly marketed in A.P.C. with Butalbital tablets and capsules and
other drug products, was associated with a high potential for harm to
the kidneys and the possibility of hemolytic anemia and
methemoglobinemia resulting from abuse. The approvals of the NDA's for
the phenacetin drug products were withdrawn on November 4, 1983 (see
the Federal Register of October 5, 1983 (48 FR 45466)).
    Phenformin hydrochloride: All drug products containing phenformin
hydrochloride. Phenformin hydrochloride, formerly marketed as D.B.I.
tablets, Meltrol-50 capsules, and other drug products, was associated
with lactic acidosis. Approvals of the NDA's for the phenformin
hydrochloride drug products were withdrawn on November 15, 1978 (see
the Federal Register of April 6, 1979 (44 FR 20967)).
    Pipamazine: All drug products containing pipamazine. Pipamazine,
formerly marketed as Mornidine tablets and injection, was associated
with hepatic lesions. Approval of the NDA for Mornidine tablets and
injection was withdrawn on July 17, 1969 (see the Federal Register of
July 17, 1969 (34 FR 12051)).
    Potassium arsenite: All drug products containing potassium
arsenite. Potassium arsenite, formerly marketed as Fowler's Solution
(oral), was toxic and highly carcinogenic. FDA determined Fowler's
Solution was a new drug in April 1980, and the manufacturers removed
the drug product from the market.
    Potassium chloride: All solid oral dosage form drug products
containing potassium chloride that supply 100 mg or more of potassium
per dosage unit

[[Page 54086]]

(except for controlled-release dosage forms and those products
formulated for preparation of solution prior to ingestion).
Concentrated solid oral dosage forms of potassium salt were associated
with small bowel lesions. Approvals of NDA's for all solid oral dosage
form drug products containing potassium chloride that supply 100 mg or
more of potassium per dosage unit (except for controlled-release dosage
forms and those products formulated for preparation of solution prior
to ingestion) were withdrawn on July 29, 1977, and April 29, 1992 (see
the Federal Register of July 29, 1977 (42 FR 38644), and April 29, 1992
(57 FR 18157)).
    Povidone: All intravenous drug products containing povidone.
Povidone, marketed as Polyvinylpyrrolidone in Normal Saline, was found
to be unsafe for use as a plasma expander in the emergency treatment of
shock because povidone accumulates in the body and may cause storage
disease with the formation of granulomas. Povidone also interferes with
blood coagulation, hemostasis, and blood typing and cross matching.
Approval of the NDA for Polyvinylpyrrolidone in Normal Saline was
withdrawn on April 19, 1978 (see the Federal Register of April 7, 1978
(43 FR 14743)).
    Reserpine: All oral dosage form drug products containing more than
1 mg of reserpine. Reserpine, marketed as Reserpoid tablets, Rau-Sed
tablets, and other drug products for the treatment of hypertension and
psychiatric disorders, was associated with a greater frequency and
severity of adverse effects in strengths greater than 1 mg. Approvals
of NDA's, or those portions of NDA's, for solid oral dosage form drug
products containing more than 1 mg of reserpine were withdrawn on May
9, 1977 (see the Federal Register of April 29, 1977 (42 FR 21844)).
    Sparteine sulfate: All drug products containing sparteine sulfate.
Sparteine sulfate, formerly marketed as Spartocin injection and
Tocosamine sterile solution, was found to have unpredicatable effects
and was associated with tetanic uterine contractions and obstetrical
complications. Approvals of the NDA's for Spartocin injection and
Tocosamine sterile solution were withdrawn on August 17, 1979 (see the
Federal Register of August 7, 1979 (44 FR 46316)).
    Sulfadimethoxine: All drug products containing sulfadimethoxine.
Sulfadimethoxine, formerly marketed in Madricidin capsules, was
associated with Stevens-Johnson syndrome and fatalities. Approval of
the NDA for Madricidin capsules was withdrawn on March 11, 1966 (see
the Federal Register of March 19, 1966 (31 FR 4747)).
    Sulfathiazole: All drug products containing sulfathiazole (except
those formulated for vaginal use). Sulfathiazole, formerly marketed in
Tresamide tablets and several other brands of tablets, was associated
with renal complications, rash, fever, blood dyscrasias, and liver
damage. Approvals of the NDA's for sulfathiazole tablets were withdrawn
on September 28, 1970 (see the Federal Register of October 15, 1970 (35
FR 16190)).
    Suprofen: All drug products containing suprofen (except ophthalmic
solutions). Suprofen, formerly marketed as Suprol capsules, was
associated with flank pain syndrome. The manufacturer voluntarily
removed Suprol capsules from the market in May 1987.
    Sweet spirits of nitre: All drug products containing sweet spirits
of nitre. Sweet spirits of nitre, also known as spirit of nitre, spirit
of nitrous ether, and ethyl nitrite spirit, was associated with
methemoglobinemia in infants. FDA directed the removal from the market
of drug products containing sweet spirits of nitre in 1980 (see 21 CFR
310.525 (1997)).
    Temafloxacin hydrochloride: All drug products containing
temafloxacin hydrochloride. Temafloxacin hydrochloride, formerly
marketed as Omniflox tablets, was associated with hypoglycemia in
elderly patients, as well as a constellation of multisystem organ
involvement characterized by hemolytic anemia, frequently associated
with renal failure, markedly abnormal liver tests, and coagulopathy.
The approved application holder voluntarily removed Omniflox tablets
from the market in Spring 1992. Approval of the NDA for Omniflox
tablets was withdrawn on September 25, 1997 (see the Federal Register
of September 25, 1997 (62 FR 50387)).
    Terfenadine: All drug products containing terfenadine. Terfenadine,
formerly marketed in Seldane and Seldane-D tablets, was associated with
serious heart problems when used concurrently with certain drugs,
including certain antibiotics and antifungals. Seldane and Seldane-D
tablets were voluntarily removed from the market by their manufacturer
in February 1998.
    3,3',4',5-tetrachlorosalicylanilide: All drug products containing
3,3',4',5-tetrachlorosalicylanilide. The halogenated salicylanilide
3,3',4',5-tetrachlorosalicylanilide, formerly marketed in a number of
drug products, largely antibacterial soaps, as an antimicrobial,
preservative, or for other purposes, was, with other halogenated
salicylanilides listed in this proposal, found to be a potent
photosensitizer capable of causing disabling skin disorders. FDA
directed the removal from the market of drug products containing
3,3',4',5-tetrachlorosalicylanilide in 1975 (see Sec. 310.508 (1997)).
    Tetracycline: All liquid oral drug products formulated for
pediatric use containing tetracycline in a concentration greater than
25 mg/milliliter (mL). Concentrated tetracycline was associated with
temporary inhibition of bone growth, permanent staining of the teeth,
and enamel hypoplasia in children. FDA amended the antibiotic drug
regulations so that drug products containing tetracycline formulated
for pediatric use in a concentration greater than 25 mg/mL would not be
certified (see the Federal Register of October 31, 1978 (43 FR 50676)).
    Ticrynafen: All drug products containing ticrynafen. Ticrynafen,
formerly marketed as Selacryn tablets, was associated with liver
toxicity. Selacryn tablets were voluntarily withdrawn from the market
by their manufacturer on January 16, 1980. Approval of the NDA for
Selacryn tablets was withdrawn on May 20, 1996 (see the Federal
Register of May 20, 1996 (61 FR 25228)).
    Tribromsalan: All drug products containing tribromsalan.
Tribromsalan, formerly marketed in a number of drug products, largely
antibacterial soaps, as an antimicrobial, preservative, or for other
purposes, was, with other halogenated salicylanilides listed in this
proposal, found to be a potent photosensitizer capable of causing
disabling skin disorders. FDA directed the removal from the market of
drug products containing tribromsalan in 1975 (see Sec. 310.508
(1997)).
    Trichloroethane: All aerosol drug products intended for inhalation
containing trichloroethane. Trichloroethane is potentially toxic to the
cardiovascular system and was associated with deaths from misuse or
abuse. FDA directed the removal from the market of aerosal drug
products intended for inhalation containing trichloroethane in 1977
(see 21 CFR 310.507 (1997)).
    Urethane: All drug products containing urethane. Urethane (also
known as urethan and ethyl carbamate), formerly marketed as an inactive
ingredient in Profenil injection, was determined to be carcinogenic.
Approval of the NDA for Profenil

[[Page 54087]]

injection was withdrawn on March 28, 1977 (see the Federal Register of
March 18, 1977 (42 FR 15138)).
    Vinyl chloride: All aerosol drug products containing vinyl
chloride. The inhalation of vinyl chloride is associated with acute
toxicity manifested by dizziness, headache, disorientation, and
unconsciousness. FDA directed the removal from the market of aerosol
drug products containing vinyl chloride in 1974 (see 21 CFR 310.506
(1997)).
    Zirconium: All aerosol drug products containing zirconium.
Zirconium, formerly used in several aerosol drug products as an
antiperspirant, was associated with human skin granulomas and toxic
effects in the lungs and other internal organs of test animals. FDA
directed the removal from the market of aerosol drug products
containing zirconium in 1977 (see 21 CFR 310.510 (1997)).
    Zomepirac sodium: All drug products containing zomepirac sodium.
Zomepirac sodium, formerly marketed as Zomax tablets, was associated
with fatal and near-fatal anaphylactoid reactions. The manufacturer
voluntarily removed Zomax tablets from the market in March 1983.

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 the 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). Executive Order 12866
classifies a rule as significant if it meets any one of a number of
specified conditions, including having an annual effect on the economy
of $100 million or adversely affecting in a material way a sector of
the economy, competition, or jobs, or if it raises novel legal or
policy issues. As discussed in the following paragraphs, the agency
believes that this proposed rule is consistent with the regulatory
philosophy and principles identified in the Executive Order. In
addition, 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.
    The agency has not estimated any compliance costs or loss of sales
due to this proposal because it prohibits pharmacy compounding of only
those drug products that have already been withdrawn or removed from
the market. Although the agency is not aware of any routine use of
these drug products in pharmacy compounding, the agency invites the
submission of comments on this issue and solicits current compounding
usage data for these drug products.
    Unless an agency certifies that a rule will not have a significant
economic impact on a substantial number of small entities, the
Regulatory Flexibility Act requires agencies to analyze regulatory
options to minimize any significant economic impact of a regulation on
small entities. The agency is taking this action in order to comply
with Section 503A of the act. This provision specifically directs FDA
to develop a list of drug products that have been withdrawn or removed
from the market because such products or components have been found to
be unsafe or not effective. Any drug product on this list will not
qualify for the pharmacy compounding exemptions under section 503A of
the act. The drug products on this list were manufactured by many
different pharmaceutical firms, some of which may have qualified under
the Small Business Administration (SBA) regulations (those with less
than 750 employees) as small businesses. However, since the list only
includes those drug products that have already been withdrawn or
removed from the market for safety or efficacy concerns, this proposal
will not negatively impact these small businesses. Moreover, no
compliance costs are estimated for any of these small pharmaceutical
firms because they are not the subject of this rule and are not
expected to realize any further loss of sales due to this proposal.
Further, the SBA guidelines limit the definition of small drug stores
or pharmacies to those that have less than $5.0 million in sales.
Again, the pharmacies that qualify as small businesses are not expected
to incur any compliance costs or loss of sales due to this regulation
because the products have already been withdrawn or removed from the
market, and the agency believes that these drugs would be compounded
only very rarely, if ever. Therefore, FDA certifies that this rule will
not have a significant economic impact on a substantial number of small
entities.
    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 the list of
products withdrawn or removed from the market because they were found
to be unsafe or ineffective will not result in expenditures of funds by
State, local, and tribal governments or the private sector in excess of
$100 million annually. Because the agency does not estimate any annual
expenditures due to the proposed rule, 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 (Pub.
L. 104-13) is not required.

VII. Request for Comments

    Interested persons may, on or before November 23, 1998, 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 the 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.
    The agency notes that the comment period in this document is
shorter than the 75-day period that is customarily provided by FDA for
proposed rules of a technical nature. Likewise, this comment period is
less than the 60 days ordinarily provided, as set out in FDA's
procedural regulations, Sec. 10.40(b)(2) (21 CFR 10.40(b)(2)). As
discussed in the following paragraphs, FDA believes that a 45-day
comment period is appropriate in this instance. Executive Order 12889
(58 FR 69681, December 30, 1993), which implemented the North American
Free Trade Agreement, states that any agency subject to the
Administrative Procedure Act should provide a 75-day comment period for
any proposed Federal technical regulation or any Federal sanitary or
phytosanitary measure of general application. However, Executive Order
12889 provides an exception to the 75-

[[Page 54088]]

day period where the United States considers the measure necessary to
address an urgent problem related to the protection of human, plant, or
animal health. Similarly, FDA regulations establish a 60-day comment
period as ordinary agency practice, but provide that the 60-day period
may be shortened if the Commissioner of Food and Drugs finds good cause
for doing so.
    As discussed in this document, section 503A(a) of the act exempts
certain compounded drug products from some specific misbranding and
adulteration provisions, as well as the new drug provision, of the act.
Section 503A(b)(1)(C) of the act excludes from the exemption drugs that
FDA has found were removed from the market or had marketing
applications withdrawn because the drug product or some component of
the drug product was unsafe or ineffective. Compounding versions of
many of these drug products presents a serious risk to human health,
either indirectly, because a patient is being provided an ineffective
drug product when effective drug products may be available, or
directly, due to the toxicity of the drug product. Indeed, many of the
drug products listed in this proposed rule have been associated with
human fatalities.
    Section 127(b) of the Modernization Act provides that section 503A
of the act will go into effect on November 21, 1998. If a final
regulation issuing the list of drug products that have been withdrawn
or removed is not published before November 21, 1998, these drug
products may be compounded, exempt from various legal requirements,
contrary to the expressed intent of Congress and at a risk to human
health. Accordingly, the agency intends to solicit public comment on
this proposal, consider the comments submitted, and prepare and publish
a final implementing regulation by November 21, 1998. FDA has concluded
that the urgency of this matter is sufficient justification for
shortening the comment period for this proposal to 45 days, consistent
with Executive Order 12889. Similarly, this urgency constitutes good
cause within the meaning of Sec. 10.40(b), which justifies shortening
the period to 45 days.

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 to read 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   [Reserved]
216.24   Drug products withdrawn or removed from the market for
reasons of safety or effectiveness.
    Authority: 21 U.S.C. 351, 352, 353a, 355, and 371.

Subpart A--General Provisions    [Reserved]

Subpart B--Compounded Drug Products

Sec.  216.23  [Reserved]

Sec. 216.24  Drug products withdrawn or removed from the market for
reasons of safety or effectiveness.

    The following drug products were withdrawn or removed from the
market because such drug products or components of such drug products
were found to be unsafe or not effective. The following drug products
may not be compounded under the exemptions provided by section 503A(a)
of the Federal Food, Drug, and Cosmetic Act:
    Adenosine phosphate: All drug products containing adenosine
phosphate.
    Adrenal cortex: All drug products containing adrenal cortex.
    Azaribine: All drug products containing azaribine.
    Benoxaprofen: All drug products containing benoxaprofen.
    Bithionol: All drug products containing bithionol.
    Bromfenac sodium: All drug products containing bromfenac sodium.
    Butamben: All parenteral drug products containing butamben.
    Camphorated oil: All drug products containing camphorated oil.
    Carbetapentane citrate: All oral gel drug products containing
carbetapentane citrate.
    Casein, iodinated: All drug products containing iodinated
casein.
    Chlorhexidine gluconate: All tinctures of chlorhexidine
gluconate formulated for use as a patient preoperative skin
preparation.
    Chlormadinone acetate: All drug products containing
chlormadinone acetate.
    Chloroform: All drug products containing chloroform.
    Cobalt: All drug products containing cobalt salts (except
radioactive forms of cobalt and its salts and cobalamin and its
derivatives).
    Dexfenfluramine hydrochloride: All drug products containing
dexfenfluramine hydrochloride.
    Diamthazole dihydrochloride: All drug products containing
diamthazole dihydrochloride.
    Dibromsalan: All drug products containing dibromsalan.
    Diethylstilbestrol: All oral and parenteral drug products
containing 25 milligrams or more of diethylstilbestrol per unit
dose.
    Dihydrostreptomycin sulfate: All drug products containing
dihydrostreptomycin sulfate.
    Dipyrone: All drug products containing dipyrone.
    Encainide hydrochloride: All drug products containing encainide
hydrochloride.
    Fenfluramine hydrochloride: All drug products containing
fenfluramine hydrochloride.
    Flosequinan: All drug products containing flosequinan.
    Gelatin: All intravenous drug products containing gelatin.
    Glycerol, iodinated: All drug products containing iodinated
glycerol.
    Gonadotropin, chorionic: All drug products containing chorionic
gonadotropins of animal origin.
    Mepazine: All drug products containing mepazine hydrochloride or
mepazine acetate.
    Metabromsalan: All drug products containing metabromsalan.
    Methamphetamine hydrochloride: All parenteral drug products
containing methamphetamine hydrochloride.
    Methapyrilene: All drug products containing methapyrilene.
    Methopholine: All drug products containing methopholine.
    Mibefradil dihydrochloride: All drug products containing
mibefradil dihydrochloride.
    Neomycin sulfate: All parenteral drug products containing
neomycin sulfate.
    Nitrofurazone: All drug products containing nitrofurazone
(except topical drug products formulated for dermatalogic
application).
    Nomifensine maleate: All drug products containing nomifensine
maleate.
    Oxyphenisatin: All drug products containing oxyphenisatin.
    Oxyphenisatin acetate: All drug products containing
oxyphenisatin acetate.
    Phenacetin: All drug products containing phenacetin.
    Phenformin hydrochloride: All drug products containing
phenformin hydrochloride.
    Pipamazine: All drug products containing pipamazine.
    Potassium arsenite: All drug products containing potassium
arsenite.
    Potassium chloride: All solid oral dosage form drug products
containing potassium chloride that supply 100 milligrams or more of
potassium per dosage unit (except for controlled-release dosage
forms and those products formulated for preparation of solution
prior to ingestion).
    Povidone: All intravenous drug products containing povidone.
    Reserpine: All oral dosage form drug products containing more
than 1 milligram of reserpine.
    Sparteine sulfate: All drug products containing sparteine
sulfate.
    Sulfadimethoxine: All drug products containing sulfadimethoxine.
    Sulfathiazole: All drug products containing sulfathiazole
(except those formulated for vaginal use).

[[Page 54089]]

    Suprofen: All drug products containing suprofen (except
ophthalmic solutions).
    Sweet spirits of nitre: All drug products containing sweet
spirits of nitre.
    Temafloxacin hydrochloride: All drug products containing
temafloxacin hydrochloride.
    Terfenadine: All drug products containing terfenadine.
    3,3',4',5-tetrachlorosalicylanilide: All drug products
containing 3,3',4',5-tetrachlorosalicylanilide.
    Tetracycline: All liquid oral drug products formulated for
pediatric use containing tetracycline in a concentration greater
than 25 milligrams/milliliter.
    Ticrynafen: All drug products containing ticrynafen.
    Tribromsalan: All drug products containing tribromsalan.
    Trichloroethane: All aerosol drug products intended for
inhalation containing trichloroethane.
    Urethane: All drug products containing urethane.
    Vinyl chloride: All aerosol drug products containing vinyl
chloride.
    Zirconium: All aerosol drug products containing zirconium.
    Zomepirac sodium: All drug products containing zomepirac sodium.

    Dated: October 1, 1998.
 William B. Schultz,
 Deputy Commissioner for Policy.
[FR Doc. 98-26923 Filed 10-2-98; 4:25 pm]
BILLING CODE 4160-01-F