[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]
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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