[Federal Register Volume 64, Number 44 (Monday, March 8, 1999)]
[Rules and Regulations]
[Pages 10944-10947]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-5517]


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List of Drug Products That Have Been Withdrawn or Removed From 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

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations to include a list of drug products that may not be used for 
pharmacy compounding under 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their approval withdrawn or were removed from the market because the 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: This rule is effective on April 7, 1999.

FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers

[[Page 10945]]

Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

     Section 127 of the Modernization Act (Pub. L. 105-115), which 
added 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 503A of the act contains several conditions that must be 
satisfied for pharmacy compounding to qualify for the exemptions. 
Section 503A(b)(1)(C) of the act provides 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products that have been withdrawn or removed from the market because 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.'' Section 503A(d)(1) of the act requires 
that the list of drug products that have been withdrawn or removed from 
the market because they were unsafe or not effective be issued as a 
regulation and that an advisory committee be consulted in the 
rulemaking process.
     In the Federal Register of October 8, 1998 (63 FR 54082), FDA 
proposed a rule to establish the list of drug products that have been 
withdrawn or removed from the market because they were unsafe or not 
effective. The primary focus of that initial proposed rule and this 
final rule is on drug products that have been withdrawn or removed from 
the market because they were found to be unsafe. FDA may initiate 
rulemaking to add other drug products to the list that have been 
withdrawn or removed from the market because they were found to be not 
effective or to update the list as new information becomes available to 
the agency regarding products that were removed from the market because 
they were unsafe. The proposed rule was presented to the Pharmacy 
Compounding Advisory Committee at a meeting held on October 14 and 15, 
1998 (see the Federal Register of September 4, 1998 (63 FR 47301)). The 
committee did not have any adverse comments on the proposed rule and 
did not suggest any changes.

II. Comments on the Proposed Rule

     FDA received comments from consumers, pharmacists, a medical 
doctor, a pharmaceutical manufacturer, a pharmaceutical manufacturers' 
organization, and a committee representing the plaintiffs in a drug 
product liability class action suit.
     1. Two comments questioned FDA's shortening the comment period 
from 75 to 45 days.
     As FDA stated in the preamble to the proposed rule (63 FR 54082 at 
54087 to 54088), the agency believes that a shorter comment period was 
warranted to expedite this rulemaking proceeding because the 
compounding of many of the drug products on the list would present a 
serious threat to the public health. Many of the drug products have 
caused death or life-threatening conditions. Some of the drugs on the 
list are believed to cause cancer, while others were shown to be toxic 
to the liver and other organs.
     2. One comment objected to the wording of the first sentence of 
proposed Sec. 216.24, which says ``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 comment expressed concerns that the finding that a 
drug was withdrawn from the market by the manufacturer because it was 
not safe or effective might be used in a product liability lawsuit 
against the manufacturer who voluntarily withdrew the drug product from 
the market. The comment also expressed concerns that fear of having the 
finding used against them might discourage manufacturers from 
voluntarily withdrawing drug products when concerns about the drug 
product's safety and effectiveness have developed.
     The agency does not believe it is necessary to change the wording 
of Sec. 216.24 in response to this comment. Compounding pharmacists and 
physicians are the intended audience for this rule. The purpose of 
Sec. 216.24 is to provide these compounders a list of drugs that they 
may not compound under section 503A of the act. This list is not 
intended to be used as evidence in a product liability suit, and the 
addition of language designed to minimize the potential effect of the 
list in litigation is unnecessary to fulfill its intended purpose.
     For the purposes of this rule, FDA has determined that it is not 
necessary to deviate from the statutory language found in section 
503A(b)(1)(C) of the act, which prohibits compounders from compounding 
``a drug product that appears on a list published by [FDA] 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 ineffective.''
     The agency wishes to emphasize that the inclusion of a drug 
product on the list does not mean that the drug product was marketed 
negligently, was defective, or was marketed in breach of any warranty. 
Even after exhaustive clinical studies, safety problems may not become 
apparent until a drug product has been in commercial distribution for a 
significant amount of time, so the fact that a drug was removed or 
withdrawn from the market does not mean that the drug was improperly 
placed in commercial distribution.
     3. A large number of comments objected to drug products containing 
adrenal cortex being placed on the list. One of the comments included a 
photocopy of an article from the November issue of the magazine 
Nutrition & Healing. This article apparently is the source of much of 
the content of many of the comments. None of the comments provided any 
information about the removal of adrenal cortex extract from the 
market, other than the unsupported statements that the removal of 
adrenal cortex extract was economically motivated. These comments 
included unsupported statements that adrenal cortex extract has never 
been associated with a death or serious adverse event (except for a 
series of adverse events in 1996 and 1997 associated with contaminated 
adrenal cortex extract) and that adrenal cortex extract is safer and 
more effective than the synthetic adrenocortical steroids that have 
replaced it in medical use. The comments also asserted, without 
presenting any scientific data or historical information to support the 
assertion, that FDA acted improperly in directing the removal of drugs 
containing adrenal cortex from the market because the low levels of 
corticosteroids found in the drugs presented a substantial risk of 
undertreatment of serious conditions.
     FDA's concerns about the safety of adrenal cortex extract have 
grown stronger since the drug product was removed from the market in 
1978. Adrenal cortex extract is derived from the cortex adrenal glands 
of domestic food animals, including cattle. In 1986 the disease bovine 
spongiform encephalopathy (BSE) was identified in cattle. BSE has been 
found to be epidemic in Great Britain and present in Western Europe and 
Oman. Hundreds of thousands of cattle have either died or been 
destroyed as a result of BSE infection. Since that time strong evidence 
has been developed associating ingestion of tissues from

[[Page 10946]]

BSE-infected cattle with the development of new variant Creutzfeldt-
Jakob disease (nvCJD) in humans. A patient taking a drug derived from 
the adrenal cortex of a BSE-infected cow would be running an 
unacceptable risk of contracting nvCJD. Due to the destruction of BSE-
infected cattle and other controls (see the Federal Register of August 
29, 1994 (59 FR 44591)), the chances of a patient getting nvCJD from 
adrenal cortex extract are low. However, there is still a risk involved 
in taking adrenal cortex extract, and that risk must be taken very 
seriously in light of the fact that nvCJD appears to always be fatal.
     Concerning the comments that FDA acted improperly in removing 
drugs containing adrenal cortex from the market because of a 
substantial risk of undertreatment of serious conditions, FDA's action 
was investigated by the General Accounting Office and found to be 
proper (see ``By the Comptroller General, Report to the Honorable Barry 
M. Goldwater, Jr., House of Representatives of the United States: 
Adrenal Cortical Extract Taken Off Drug Market'' (HRD-81-61, 1981)).
     For the reasons stated previously, FDA is keeping drug products 
containing adrenal cortex on the list of drugs that may not be 
compounded under section 503A of the act.
     4. One comment strongly supported the inclusion of drug products 
containing dexfenfluramine hydrochloride and fenfluramine hydrochloride 
on the list.
     5. One comment pointed out that there is a hearing request pending 
before the agency regarding the withdrawal of approval of the 
applications for neomycin sulfate in sterile vials for injection (see 
the Federal Register of December 6, 1988 (53 FR 49232)) and another 
pending request for a hearing regarding the withdrawal of approval of 
the applications for neomycin sulfate for prescription compounding (see 
the Federal Register of December 6, 1988 (53 FR 49231)). A petition for 
stay of action regarding the two actions mentioned above and regarding 
a labeling guideline for neomycin sulfate for prescription compounding 
(see the Federal Register of April 15, 1988 (53 FR 12662)) is also 
pending before the agency.
     Because of the complex administrative record on neomycin sulfate 
currently before the agency and because of the public health need to 
expedite implementation of this rule, FDA is postponing final action on 
listing all parenteral drug products containing neomycin sulfate. 
Parenteral drug products containing neomycin sulfate may be added to 
the list at a later date.

III. 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.

IV. Analysis of Impacts

     FDA has examined the impacts of the final 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 paragraphs below, the agency 
believes that this rule is consistent with the regulatory philosophy 
and principles identified in the Executive Order. In addition, the 
final 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 final rule because it prohibits pharmacy compounding of 
only those drug products that have already been withdrawn or removed 
from the market. The agency is not aware of any routine use of these 
drug products in pharmacy compounding and received no significant data 
in response to the request in the preamble to the proposed rule for the 
submission of comments on this issue and current compounding usage data 
for these drug products. Additionally, FDA did not receive any comments 
on compliance costs and loss of sales due to this rule or current 
compounding usage data for the drug products listed in this rule at the 
Pharmacy Compounding Advisory Committee meeting held on October 14 and 
15, 1998.
     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 the 
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 final 
rule 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 loss of sales due to this rule. 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.
     Section 202 of the Unfunded Mandates Reform Act requires that 
agencies prepare an assessment of anticipated costs and benefits before 
it finalizes any rule requiring 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 final rule, 
FDA is not required to

[[Page 10947]]

perform a cost/benefit analysis according to the Unfunded Mandates 
Reform Act.

V. Paperwork Reduction Act of 1995

     This final rule contains no collection of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

 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, 21 CFR 
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.
    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).
    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.
    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: March 1, 1999.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 99-5517 Filed 3-5-99; 8:45 am]
BILLING CODE 4160-01-F