List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness

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List of Drug Products That Have Been Withdrawn or Removed From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their approval withdrawn or were removed from the market because the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products that have been withdrawn or removed from the market because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that the list of drug products that have been withdrawn or removed from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

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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

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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