Drug Products Containing Quinine for the Treatment and/or Prevention of Malaria for Over-the-Counter Human Use

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 94N-0355]

Drug Products Containing Quinine for the Treatment and/or

Prevention of Malaria for Over-the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule

establishing that over-the-counter (OTC) drug products containing

quinine for the treatment and/or prevention of malaria are not

generally recognized as safe and are misbranded. FDA is issuing this

final rule after considering public comment on the agency's notice of

proposed rulemaking and all data and information that have come to the

agency's attention on the safety of quinine.

EFFECTIVE DATE: April 20, 1998.

FOR FURTHER INFORMATION CONTACT: John D. Lipnicki, Center for Drug

Evaluation and Research (HFD-560), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

The agency's proposed rule for OTC drug products for the treatment

and/or prevention of malaria was published in the Federal Register of

April 19, 1995 (60 FR 19650). In that proposed rule, the agency

summarized the history of quinine in the OTC drug review for use as an

analgesic, antipyretic, and muscle relaxant (for the treatment and/or

prevention of nocturnal leg muscle cramps). The agency also recognized

that quinine has been marketed for decades, on both an OTC and a

prescription basis, as an anti-infective agent for the treatment and/or

prevention of malaria, a serious and potentially life-threatening

disease that at one time was endemic in this country. However, data and

information reviewed by the agency during the rulemaking for OTC drug

products for the treatment and/or prevention of nocturnal leg muscle

cramps raised serious safety concerns about the continued OTC

availability of quinine for the treatment and/or prevention of malaria.

The agency also discussed serious safety and efficacy concerns about

the continued OTC availability of quinine for the self-treatment of

malaria without the care and supervision of a doctor. Interested

persons were invited to file comments by July 3, 1995.

For reasons discussed in this document, FDA is classifying OTC drug

products containing quinine or any quinine salt (e.g., quinine sulfate)

and labeled for the treatment and/or prevention of malaria as not

generally recognized as safe, as misbranded, and as a new drug within

the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic

Act (the act) (21 U.S.C. 321(p)), for which an application or

abbreviated application (hereinafter called application) approved under

section 505 of the act (21 U.S.C. 355) and 21 CFR part 314 is required

for marketing. In the absence of an approved application, these

products are considered misbranded under section 502 of the act (21

U.S.C. 352). The final rule is being incorporated into 21 CFR part 310,

Subpart E--Requirements for Specific New Drugs or Devices, by adding

new Sec. 310.547.

As discussed in the preamble to the proposed rule for OTC drug

products containing quinine for the treatment and/or prevention of

malaria, the conditions under which the drug products that are subject

to this rule are not generally recognized as safe and effective and are

misbranded would be effective 30 days after the date of publication of

the final rule in the Federal Register. On or after April 20, 1998, no

OTC drug product that is subject to the final rule may be initially

introduced or initially delivered for introduction into interstate

commerce unless it is the subject of an approved application. Further,

any OTC drug product subject to the final rule that is repackaged or

relabeled after the effective date of the final rule must be in

compliance with the final rule regardless of the date the product was

initially introduced or initially delivered for introduction into

interstate commerce.

In response to the proposed rule, one comment from a drug

distributor was submitted. The comment (Ref. 1) is on public display in

the Dockets Management Branch (HFA-305), Food and Drug Administration,

12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.

Reference

(1) Comment No. C1, Docket No. 94N-0355, Dockets Management

Branch.

II. The Agency's Conclusion on the Comment

The comment contended that the agency had failed to distinguish

between the safety of quinine used for malaria and quinine used for leg

cramps. The comment contended that the agency appeared to commingle its

safety concerns about quinine for these two uses. The comment noted the

agency's discussion of adverse reaction reports on file for quinine:

110 reports over 22 years from 1969 through 1990. The comment noted

that this was an average of only five cases per year. The comment added

that only 26 of the 110 reports were identified as cases where it can

be reasonably concluded that quinine was the causative agent and that

only 5 of the 26 reports involved quinine products used for the

treatment of malaria. The comment concluded that this is an extremely

low incidence of adverse reaction reports for quinine used for malaria:

On average, 0.25 reports per year from 1969 through 1990. The comment

further noted an agency statement in the Federal Register of August 22,

1994 (59 FR 43234 at 43252), that approximately ``two-thirds of these

quinine-containing products are marketed for antimalarial use (with

approximately one-third for the treatment and/or prevention of

nocturnal leg muscle cramps).'' The comment concluded that OTC quinine

products are safe and effective for the treatment of malaria due to the

very low incidence of reports of adverse reactions for quinine products

used for the treatment of malaria and the two-thirds marketing of

quinine products for malaria. The comment argued that these facts

demonstrate a lack of scientific support for this proposed rule.

The agency does not agree with the comment. The Center for Disease

Control and Prevention stated that approximately 1,000 cases of malaria

are reported each year in the United States (60 FR 19650 at 19651). It

is not known how many of these people might have used quinine as part

of their treatment. As discussed in section III of this document,

quinine is not the drug of choice for malaria. Although many quinine

products are marketed for the treatment of malaria, many of these

products may have been used to treat leg muscle cramps. In 1987, a U.S.

manufacturer of quinine estimated (based on sales figures) that there

are well over 1 million users of quinine for leg muscle cramps in the

United States (Ref. 1). Based on the large number of people using

quinine for leg muscle cramps, a larger number of adverse drug

experiences would be expected to occur

[[Page 13527]]

in this population when compared with the much smaller number of people

using the drug for malaria. However, the daily dosage of quinine for

treating malaria (see below) is greater than the dosage used for leg

muscle cramps. Therefore, one would expect a higher rate of adverse

reactions in the population using the drug for malaria.

In addition, the agency believes that underreporting of adverse

reactions for OTC drug products is substantial. In the Federal Register

of August 22, 1994 (59 FR 43234 at 43241 and 43242), the agency stated:

Underreporting of such reactions into the agency's spontaneous

reporting system is believed to be very substantial for OTC drug

products. This may be due to physicians (the principal reporters to

the spontaneous reporting system) not becoming aware of reactions to

OTC drugs, and because manufacturers and distributors are not

generally required to transmit reports of serious adverse reactions

involving OTC drugs to FDA.

The agency reviewed labeling from eight randomly selected OTC

quinine drug products for malaria and found that the dosage

recommendations ranged from 200 milligrams (mg) to 975 mg three times a

day (for 6 to 12 days) (60 FR 19650 at 19653). The adverse event

characteristics of quinine toxicity have been observed in clinical

efficacy studies using typical doses for nocturnal leg cramps of 260 mg

and 325 mg daily (59 FR 43234 at 43237). Given the much higher dosage

recommended for malaria, it is reasonable to assume that these types of

dose-related adverse reactions may increase with the malaria dosage.

Finally, the agency is greatly concerned that if quinine remains

available on an OTC basis labeled for the treatment and/or prevention

of malaria, an extensive amount of such products would be sold OTC and

used to treat and/or prevent leg muscle cramps, resulting in continued

possible serious adverse reactions to OTC users of these products.

Quinine was removed from the market for this use because of the lack of

substantial evidence of effectiveness of quinine in this condition,

along with evidence of quinine toxicity at the OTC doses employed for

leg cramps in a proportion of the target population, and the potential

for serious, life threatening, and fatal hypersensitivity reactions to

quinine (59 FR 43234 at 43251).

Reference

(1) Levy, N. W., ``Overview: Efficacy and Safety of Quinine

Sulfate in the Treatment and/or Prevention of Nocturnal Leg

Cramps,'' unpublished report in SUP00033, Docket No. 77N-0094,

Dockets Management Branch.

III. The Agency's Final Conclusions on OTC Quinine Drug Products

for the Treatment and/or Prevention of Malaria

Malaria is rare in the United States, but is a serious and

potentially deadly disease. Diagnosis and treatment of malaria depend

on such factors as the specie(s) of parasite involved, the density of

parasites in the blood, the potential for possible exposure to drug-

resistant parasites that are associated with malaria in humans, e.g.,

Plasmodium falciparum or P. vivax, and concomitant medical conditions.

Malaria requires a medical diagnosis, both to confirm the disease and

to determine the treatment of choice. Prompt and proper diagnosis,

treatment, and monitoring of the therapeutic efficacy of the treatment

used require laboratory analyses of blood samples and clinical

assessments. Continuous physician monitoring is then necessary to

determine if the selected drug therapy is effective and if the malarial

parasites have been eradicated. Section 503(b)(1)(B) of the act (21

U.S.C. 353(b)(1)(B)) requires that a drug intended for use by man

which, ``* * * because of its toxicity or other potentiality for

harmful effect, * * * or the collateral measures necessary to its use,

is not safe for use except under the supervision of a practitioner

licensed by law to administer such drug * * *,'' be limited to

prescription use only. Quinine used for malaria has considerable

potential for toxic or harmful effects, and its use requires

substantial collateral measures to ensure safe and effective treatment.

There are serious safety concerns about the continued availability

of quinine sulfate for OTC use, even at dosages much lower than those

used for the treatment of malaria. Adverse events characteristic of

quinine toxicity have been observed in healthy individuals at doses of

260 and 325 mg daily. These events included visual, auditory, and

gastrointestinal symptoms, and fever. Studies of auditory, vestibular,

and visual function in subjects given quinine confirm sensory

disturbances at these and lower doses (59 FR 43234 at 43239). Altered

pharmacokinetics with age result in a longer half-life of quinine in

older people, which suggests that the frequency and severity of adverse

effects could be greater in the elderly.

Adverse events associated with quinine toxicity are possible at the

therapeutic doses of quinine used in the treatment of malaria (i.e.,

600 to 650 mg three times daily for 3 to 7 days). A fatal dose of

quinine for an adult is approximately 2,000 to 8,000 mg. Thus, in the

treatment of malaria, a narrow margin of safety exists between a

therapeutic dose and a toxic dose of quinine.

In addition to toxic effects, serious and unpredictable

hypersensitivity reactions to quinine drug products can occur. Symptoms

are often dramatic, leading people to seek medical treatment.

Hospitalization may be required, and fatalities have been reported.

Quinine is the only drug available OTC that has such a high association

with thrombocytopenia, a serious adverse event. Because there are no

known factors that predispose people to the development of

hypersensitivity to quinine, which may occur after 1 week of exposure

or after months or years of use, label warnings cannot be expected to

protect consumers from idiosyncratic hypersensitivity reactions to

quinine drug products.

In addition, unsupervised quinine therapy (allowing for incomplete

or interrupted treatments due to poor compliance with dosing

instructions) is a practice believed to promote proliferation of

malarial parasites less sensitive to quinine. Furthermore, interrupted

quinine therapy in persons with falciparum malaria may also predispose

them to the serious complications of blackwater fever, including

anemia, red blood cell destruction, and renal failure.

Current public health recommendations do not include the use of

oral quinine in the prevention of malaria and limit its use in the

treatment of the disease (primarily to uncomplicated, low-density,

chloroquine-resistant falciparum malaria). Current treatments for

malaria include the use of quinine only in combination therapies with

prescription drugs or as part of an intensive therapy involving blood

transfusions and parenteral drugs during hospitalization. Thus, any

patient properly using quinine for malaria should be under the care and

supervision of a doctor.

Based upon quinine's demonstrated toxic effects and potential for

harm and the extensive collateral measures necessary to ensure a

successful outcome for quinine therapy, the agency has determined that

consumers cannot safely and effectively self-treat malaria.

Accordingly, the agency concludes that quinine is not safe and

effective for OTC use in the treatment of malaria.

This final rule requires that any OTC quinine drug product for the

treatment and/or prevention of malaria have an approved application for

continued marketing.

[[Page 13528]]

IV. Analysis of Impacts

An analysis of the costs and benefits of this regulation, conducted

under Executive Order 12866, was discussed in the proposed rule for OTC

quinine drug products for the treatment and/or prevention of malaria

(60 FR 19650 at 19654). No comments were received in response to the

agency's request for specific comment on the economic impact of this

rulemaking.

FDA has examined the impacts of the final rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).

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). Under the Regulatory

Flexibility Act, if a rule has a significant impact on a substantial

number of small entities, an agency must analyze regulatory options

that would minimize any significant impact of the rule on small

entities.

Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et

seq.) requires that agencies prepare a written statement and economic

analysis before proposing any rule that may result in an expenditure in

any one year by State, local, and tribal governments, in the aggregate,

or by the private sector, of $100 million (adjusted annually for

inflation). The proposed rule that has led to the development of this

final rule was already well into the publication cycle at the time the

Unfunded Mandates Reform Act was enacted, publishing approximately 1

month later on April 19, 1995. The agency explains in this final rule

that the final rule will not result in an expenditure in any one year

by State, local, and tribal governments, in the aggregate, or by the

private sector, of $100 million.

The agency believes that this final rule is consistent with the

principles set out in the Executive Order and in these two statutes.

The purpose of this final rule is to establish that OTC quinine drug

products for the treatment and/or prevention of malaria are not

generally recognized as safe and are misbranded. Quinine formulations

for the treatment of malaria are currently marketed as both OTC and

prescription drug products. There are a limited number of quinine

products marketed at this time. The agency's Drug Listing System

identifies approximately 22 products containing quinine sulfate in

dosage unit strengths of 200 mg to 325 mg. These products are marketed

by 14 different manufacturers, most of which are considered to be small

entities, using the U.S. Small Business Administration designations for

this industry (750 employees). The agency believes that any other

unidentified manufacturer of these products is also likely to be a

small entity.

Manufacturers will no longer be able to market OTC quinine drug

products for the treatment and/or prevention of malaria after the

effective date of this final rule. While the manufacturers will incur a

loss of revenue from the sale of these products, the agency believes

the economic impact will be minimal for several reasons. First, it

appears that current use in the United States of oral OTC quinine for

the treatment of malaria is minimal. Approximately 1,000 cases of

malaria are reported each year in the United States (60 FR 19650 at

19651). However, current public health recommendations do not include

the use of oral quinine in the prevention of malaria and limit its use

in the treatment of the disease. The agency does not believe that any

of the affected manufacturers have any considerable amount of sales of

OTC quinine drug products that are used for the treatment of malaria.

Second, when quinine is needed for treatment of malaria, this final

rule does not affect the availability of quinine products by a doctor's

prescription.

Manufacturers have known since April 1995 that if adequate data

were not submitted to establish general recognition of the safety of

quinine drug products for OTC use in the treatment and/or prevention of

malaria, cessation of marketing of the current OTC drug products would

be required when the final rule published. No data have been received.

Further, the agency is concerned that if quinine remains available on

an OTC basis labeled for the treatment and/or prevention of malaria, an

extensive amount of such products would be sold and used to treat and/

or prevent leg muscle cramps, resulting in continued possible adverse

reactions to users of these products. Due to the safety concerns

discussed in this document, manufacturers are required to comply with

the provisions of this final rule 30 days after its date of publication

in the Federal Register.

The agency considered but rejected several alternatives: (1) To

allow continued marketing of OTC quinine drug products for the

treatment of malaria, and (2) to allow a longer implementation period.

FDA does not consider either of these approaches acceptable because the

agency does not consider quinine to be safe for OTC drug use and

because no new data concerning the safety of OTC quinine are

forthcoming.

The analysis shows that this final rule is not economically

significant under Executive Order 12866 and that the agency has

considered the burden to small entities. The agency certifies that this

final rule will not have a significant economic impact on a substantial

number of small entities. Finally, this analysis shows that the

Unfunded Mandates Act does not apply to the final rule because it would

not result in an expenditure in any one year by State, local, and

tribal governments, in the aggregate, or by the private sector, of $100

million.

V. 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.

List of Subjects in 21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, 21 CFR part

310 is amended as follows:

PART 310--NEW DRUGS

1. The authority citation for 21 CFR part 310 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

360b-360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241,

242(a), 262, 263b-263n.

2. Section 310.547 is added to subpart E to read as follows:

Sec. 310.547 Drug products containing quinine offered over-the-counter

(OTC) for the treatment and/or prevention of malaria.

(a) Quinine and quinine salts have been used OTC for the treatment

and/or prevention of malaria, a serious and potentially life-

threatening disease. Quinine is no longer the drug of choice for the

treatment and/or prevention of most types of malaria. In addition,

there are serious and complicating aspects of the disease itself and

some potentially serious and life-threatening risks associated with the

use of quinine at doses employed for the treatment of malaria. There is

a lack of adequate data to establish general recognition of the safety

of quinine drug products for OTC

[[Page 13529]]

use in the treatment and/or prevention of malaria. Therefore, quinine

or quinine salts cannot be safely and effectively used for the

treatment and/or prevention of malaria except under the care and

supervision of a doctor.

(b) Any OTC drug product containing quinine or quinine salts that

is labeled, represented, or promoted for the treatment and/or

prevention of malaria is regarded as a new drug within the meaning of

section 201(p) of the act, for which an approved application or

abbreviated application under section 505 of the act and part 314 of

this chapter is required for marketing. In the absence of an approved

new drug application or abbreviated new drug application, such product

is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any

drug product labeled, represented, or promoted for OTC use for the

treatment and/or prevention of malaria is safe and effective for the

purpose intended must comply with the requirements and procedures

governing the use of investigational new drugs set forth in part 312 of

this chapter.

(d) After April 20, 1998, any such OTC drug product initially

introduced or initially delivered for introduction into interstate

commerce that is not in compliance with this section is subject to

regulatory action.

Dated: March 9, 1998.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 98-7186 Filed 3-19-98; 8:45 am]

BILLING CODE 4160-01-F