[Federal Register Volume 63, Number 195 (Thursday, October 8, 1998)]
[Proposed Rules]
[Pages 54082-54089]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-26923]


=======================================================================
-----------------------------------------------------------------------

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List of Drug Products That Have Been Withdrawn or Removed From 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.

-----------------------------------------------------------------------

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had their approval withdrawn or were removed from the market because 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