[Federal Register Volume 63, Number 54 (Friday, March 20, 1998)]
[Rules and Regulations]
[Pages 13526-13529]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-7186]


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

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.

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

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