[Federal Register Volume 60, Number 75 (Wednesday, April 19, 1995)]
[Proposed Rules]
[Pages 19650-19655]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-9701]




[[Page 19649]]

_______________________________________________________________________

Part IV





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 310



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

Federal Register / Vol. 60, No. 75 / Wednesday, April 19, 1995 / 
Proposed Rules 
[[Page 19650]] 

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: Notice of proposed rulemaking.

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

SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of 
proposed rulemaking that would establish 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 notice of proposed rulemaking after considering data and 
information on the safety of quinine.

DATES: Written comments by July 3, 1995. Written comments on the 
agency's economic impact determination by July 3, 1995. The agency is 
proposing that any final rule that may issue based on this proposal 
become effective 30 days after its date of publication in the Federal 
Register.

ADDRESSES: Written comments to the Dockets Management Branch (HFA-305), 
Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, 
MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-810), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION: In the Federal Register of July 8, 1977 (42 
FR 35346), FDA published an advance notice of proposed rulemaking to 
amend Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), and to establish a 
monograph for OTC internal analgesic, antipyretic, and antirheumatic 
drug products, together with the recommendations of the Advisory Review 
Panel on OTC Internal Analgesic and Antirheumatic Drug Products 
(Internal Analgesic Panel), which was the advisory review panel 
responsible for evaluating data on the active ingredients in this drug 
class. Although the Internal Analgesic Panel did not review the use of 
quinine as an antimalarial (other than to note its use in lowering the 
fever of malarial patients), it did review the safety of quinine used 
OTC as an analgesic, antipyretic, and muscle relaxant. The Internal 
Analgesic Panel concluded that ``Until controlled studies show that a 
dose of not more than 325 milligrams (mg) daily is safe and useful for 
relief of nocturnal leg cramps the drug should not be available for OTC 
use for treatment of nocturnal leg cramps.'' (See 42 FR 35346 at 
35434.)
    The agency's proposed regulation, in the form of a tentative final 
monograph, for OTC internal analgesic, antipyretic, and antirheumatic 
drug products was published in the Federal Register of November 16, 
1988 (53 FR 46204). In the proposed rule (53 FR 46204 at 46243), the 
agency agreed with the Internal Analgesic Panel's conclusions 
concerning the safety of quinine and proposed that quinine be Category 
II (not generally recognized as safe and effective, and misbranded) 
when labeled for any OTC antipyretic or internal analgesic use other 
than the treatment and/or prevention of nocturnal leg muscle cramps.
    In the Federal Register of May 10, 1993 (58 FR 27636), the agency 
issued a final rule for certain Category II and III (more data needed) 
active ingredients for which no significant comments or new data to 
upgrade the status of these ingredients had been submitted. In that 
final rule (58 FR 27636 at 27639), the agency determined that quinine 
(among other ingredients) is not generally recognized as safe and 
effective and is misbranded when present in OTC internal analgesic, 
antipyretic, and antirheumatic drug products.
    In the Federal Register of October 1, 1982 (47 FR 43562), FDA 
published an advance notice of proposed rulemaking to amend 
Sec. 330.10(a)(6) and to reopen the rulemaking for OTC internal 
analgesic, antipyretic, and antirheumatic drug products to consider the 
OTC use of quinine for the treatment of nocturnal leg muscle cramps. 
The document reflected the recommendations of the Advisory Review Panel 
on OTC Miscellaneous Internal Drug Products (Miscellaneous Internal 
Panel), which was the advisory review panel responsible for evaluating 
data on the active ingredients in this drug class. Although the 
Miscellaneous Internal Panel stated that quinine ``* * * appears to be 
reasonably safe * * * in generally recommended doses of 200 to 325 mg 
daily'' (47 FR 43562 at 43564), the Miscellaneous Internal Panel 
recommended that quinine be placed in Category III for use in the 
treatment of nocturnal leg muscle cramps because of the need for more 
information about both safety and efficacy (47 FR 43564).
    The agency's proposed regulation for OTC drug products for the 
treatment and/or prevention of nocturnal leg muscle cramps was 
published in the Federal Register of November 8, 1985 (50 FR 46588). 
The agency concurred with both the Internal Analgesic and Miscellaneous 
Internal Panels that no active ingredient (including quinine) in OTC 
drug products for the treatment and/or prevention of nocturnal leg 
muscle cramps had been found to be generally recognized as safe and 
effective and not misbranded. Although the agency acknowledged the OTC 
availability of quinine for the treatment of malaria (50 FR 46588 at 
46592), only its use in the treatment and/or prevention of leg muscle 
cramps was covered by the proposed rule.
    Subsequently, a citizen petition (Ref. 1) requested, among other 
things, a ban on the OTC sale of all quinine sulfate drug products. 
Upon review of the citizen petition and other data and information, in 
the Federal Register of August 22, 1994 (59 FR 43234), the agency 
issued a final rule establishing that any OTC drug product for the 
treatment and/or prevention of nocturnal leg muscle cramps is not 
generally recognized as safe and effective and is misbranded. The 
agency concluded, among other things, that quinine is not safe for OTC 
use in the treatment and/or prevention of nocturnal leg muscle cramps 
(59 FR 43234 at 43239). In that final rule, the agency also stated that 
OTC quinine drug products for antimalarial use would be discussed in 
future issues of the Federal Register.
    The agency recognizes that quinine has been marketed for decades, 
on both an OTC and 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 
(Ref. 2). However, data and information (discussed elsewhere in this 
document) reviewed by the agency during the rulemaking for OTC drug 
products for the treatment and/or prevention of nocturnal leg muscle 
cramps have raised serious safety concerns about the continued OTC 
availability of quinine for the treatment and/or prevention of malaria.
    For reasons discussed in this document, FDA is proposing to 
classify OTC drug products containing quinine or any quinine salt 
(e.g., quinine sulfate) labeled for the treatment and/or prevention of 
malaria as not generally recognized as safe, as misbranded, and a new 
drug within the meaning of section 201(p) of the Federal Food, Drug, 
and Cosmetic Act (the act) (21 [[Page 19651]] 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, the proposed rule would also declare these 
products misbranded under section 502 of the act (21 U.S.C. 352). The 
rule will be incorporated into 21 CFR part 310, subpart E--Requirements 
for Specific New Drugs or Devices, by adding new Sec. 310.547.
    If this proposal is adopted as a final rule, the agency advises 
that the conditions under which the drug products that are subject to 
this rule are not generally recognized as safe and effective and are 
misbranded will be effective 30 days after the date of publication of 
the final rule in the Federal Register. On or after that date, no OTC 
drug product that is subject to the 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.

References

    (1) Comment No. CP0006, Docket No. 77N-0094, Dockets Management 
Branch.
    (2) Russell, P. F., ``The United States and Malaria: Debits and 
Credits,'' Bulletin of the New York Academy of Medicine, 44(6):623-
653, 1968.

I. Quinine Use In The Treatment and/or Prevention of Malaria

    Malaria is an infectious and potentially fatal disease caused by 
microscopic parasites (known as protozoa) of the genus Plasmodium 
(Refs. 1 and 2). Of the four species of Plasmodium typically associated 
with malaria in humans (P. falciparum, P. vivax, P. ovale, and P. 
malariae), malaria caused by P. falciparum (i.e., falciparum malaria) 
is the form of the disease usually associated with severe symptoms and 
death (if not promptly and properly treated). Malaria is most commonly 
transmitted to humans through the bite of an infected Anopheles 
mosquito (Refs. 1 and 2).
    Malaria is initially characterized by nonspecific symptoms similar 
to those in viral illnesses. Symptoms include fever, lack of well-
being, headache, fatigue, and muscle aches (Refs. 1 and 2). Laboratory 
analysis of blood samples from persons suspected of having malaria in 
conjunction with medical assessment and monitoring are necessary to: 
(1) Confirm a diagnosis of malaria; (2) determine the species of 
parasite(s) involved; (3) determine the density of parasites in the 
blood; (4) monitor therapeutic efficacy of treatment; (5) determine the 
potential for possible exposure to drug-resistant P. falciparum and (6) 
assess coexistent medical complications (all of which influence 
treatment decisions) (Refs. 1, 2, and 3).
    Malaria was a major infectious disease in the United States in the 
19th century and through the first third of the 20th century (Ref. 4). 
Through a combination of control programs, drug development, and 
education, malaria has since been virtually eradicated from North 
America (Refs. 1 through 4). Although, approximately 1,000 cases of 
malaria are reported to the Centers for Disease Control and Prevention 
(CDC) each year, all but a few cases are associated with travel to or 
from malaria-endemic areas in other parts of the world (Ref. 3). In 
those areas, however, malaria remains a major infectious disease and 
cause of death (Ref. 3).
    Preparations made from the bark of one or more species of tree of 
the genus Cinchona have been used for centuries in the treatment and 
prevention of malaria (Ref. 5). Although Cinchona bark contains varying 
amounts of several drugs with antimalarial action, collectively known 
as quinoline alkaloids, quinine is the chief member of this group. Use 
of the term ``quinine'' in this document includes both the purified 
alkaloid and its derivatives. Oral quinine for the treatment of malaria 
is most commonly available as the salt quinine sulfate (Refs. 5 and 6).
    In discussing the period in which malaria was endemic in the United 
States, Russell (Ref. 4) states that quinine ``* * * in large bottles 
stood on the clock shelf in thousands of homes'' in the 19th century 
and was extensively used as a mass prophylactic in malaria control 
programs in the first quarter of the 20th century. Russell notes that 
the use of less toxic and more effective synthetic antimalarial drugs 
(especially chloroquine) replaced quinine as the drug of choice by the 
1930's. However, quinine has again become therapeutically important in 
the management of malaria due to the increasing resistance of P. 
falciparum (and more recently P. vivax) to chloroquine (Refs. 3 and 7).
    Current treatment of malaria includes the use of oral quinine (in 
combination with other prescription antimalarial drugs) in medically 
uncomplicated cases when the disease is diagnosed or suspected of 
having been caused by P. falciparum contracted in areas where the 
parasite has become resistant to treatment with chloroquine, and the 
person is able to tolerate oral medications (Refs. 1, 2, and 3). 
Quinine is also used for the treatment of malaria following therapies 
involving exchange blood transfusions and/or intravenous drug therapy 
during hospitalization for complicated or high density falciparum 
malaria (a medical emergency), or when the species/drug sensitivity of 
the parasite is unknown (Refs. 2 and 3).
    Falciparum malaria contracted in some areas has demonstrated a 
reduced susceptibility to standard quinine therapy (Refs. 3 and 7). 
Increasing resistance to quinine in such endemic areas may in part be 
due to its extensive use in unsupervised therapy (Ref. 7). Unsupervised 
therapy (with a drug known to commonly cause unpleasant adverse effects 
(see section II)) allows for incomplete treatments due to poor 
compliance with dosing instructions, a practice that may promote 
proliferation of malarial parasites less sensitive to quinine (Ref. 7). 
During the treatment of falciparum malaria with quinine, it is 
recommended that therapeutic efficacy be monitored by the daily 
examination of blood samples for the presence of malarial parasites 
until the samples are negative (Ref. 2). Failure to show parasite 
reduction may indicate drug resistance and necessitate a change in 
therapy. It is believed that the use of combinations of drugs (e.g., 
quinine plus either sulfadoxine/pyrimethamine or tetracycline) in the 
treatment of malaria may help prevent the development of drug-resistant 
strains of malarial parasites (Refs. 7, 8, and 9). Furthermore, it is 
believed that such interrupted or irregular quinine therapy during the 
treatment of falciparum malaria may predispose persons to the serious 
complications of blackwater fever, including anemia, red blood cell 
destruction, and renal failure (Refs. 10 and 11).
    The continued spread of chloroquine-resistant P. falciparum has 
reduced the number of effective drugs for malaria prevention. CDC 
recommendations for the prevention of malaria in travelers take into 
account ``* * * the risk of exposure to malaria, the effectiveness and 
safety of antimalarial drugs, and the use of personal protective 
measures.'' Quinine is not included in the list of drugs currently 
recommended by CDC for the prevention of malaria (Ref. 12).
    In summary, malaria is an infectious disease that has been 
virtually eradicated from North America. Quinine, once the major 
therapeutic [[Page 19652]] agent for the treatment of malaria, was 
replaced in the 1930's with less toxic and more effective drugs. 
Current public health recommendations do not include the use of quinine 
in the prevention of malaria and limit its use in the treatment of the 
disease. Current recommendations for the treatment of malaria only 
include the use of quinine in combination therapies with other 
prescription drugs or as part of an intensive therapy involving blood 
transfusions and parenteral drugs during hospitalization. Clinical and 
laboratory assessments are necessary for prompt and proper diagnosis 
and treatment, including clinical monitoring during drug therapy to 
determine therapeutic efficacy and confirm the successful treatment of 
this serious and potentially fatal disease.

References

    (1) Wyler, D. J., ``Plasmodium Species (Malaria),'' in 
Principles and Practice of Infectious Diseases, 3d ed., edited by G. 
L. Mandell, R. G. Douglas, Jr., and J. E. Bennett, Churchill 
Livingstone, New York, pp. 2056-2066, 1990.
    (2) White, N. J., and J. G. Breman, ``Malaria,'' in Harrison's 
Principles of Internal Medicine, 13th ed., edited by K. J. 
Isselbacher et al., McGraw-Hill, New York, pp. 887-895, 1994.
    (3) McCarthy, A. E., and J. S. Keystone, ``Malaria,'' in Conn's 
Current Therapy, 1994, edited by R. E. Rakel, W. B. Saunders Co., 
Philadelphia, pp. 94-100, 1993.
    (4) Russell, P. F., ``The United States and Malaria: Debits and 
Credits,'' Bulletin of the New York Academy of Medicine, 44(6): 623-
653, 1968.
    (5) Webster, Jr., L. T., ``Drugs Used in the Chemotherapy of 
Protozoal Infections,'' in The Pharmacological Basis of 
Therapeutics, 8th ed., edited by A. G. Gilman et al., Pergamon 
Press, New York, pp. 978-998, 1990.
    (6) McEvoy, G. K., editor, AHFS Drug Information, American 
Society of Hospital Pharmacists, Bethesda, MD, pp. 437-440, 1993.
    (7) Weinke, T. et al., ``Malaria Therapy in 452 Patients with 
Special Reference to the Use of Quinine,'' Journal of Infection, 
25(2): 173-180, 1992.
    (8) Smit, E. H. D., ``Quinine Is Not What It Used To Be,'' Acta 
Leidensia, 55:21-27, 1987.
    (9) Gramiccia, G., ``Quinine: Should the Past Be Taken as a 
Guidance for the Future,'' Acta Leidensia, 55:15-20, 1987.
    (10) Bateman, D. N., and E. H. Dyson, ``Quinine Toxicity,'' 
Adverse Drug Reactions and Acute Poisoning Reviews, 4:215-233, 1986.
    (11) USPDI, Drug Information for the Health Care Professional, 
The U. S. Pharmacopeial Convention, Inc., Rockville, MD, vol. I, 
14th ed., pp. 2379-2382, 1994.
    (12) ``Recommendations for the Prevention of Malaria Among 
Travelers,'' Morbidity and Mortality Weekly Report, Public Health 
Service, Centers for Disease Control, 39(RR-3):1-10, 1990.

II. Safety Considerations

    Quinine taken orally is currently used as part of a combination 
drug treatment of uncomplicated, low-density, chloroquine-resistant 
falciparum malaria. The adult dosage of quinine sulfate used for 
treatment of this condition is 600 to 650 mg three times daily for 3 to 
7 days (Refs. 1 through 5).
    In the final rule for OTC drug products for the treatment and/or 
prevention of nocturnal leg muscle cramps (59 FR 43234), the agency 
discussed a number of safety concerns related to the OTC availability 
of quinine for this use. The agency noted that adverse reaction reports 
(59 FR 43234 at 43239) suggested that quinine doses of 260 to 325 mg/
day (which are much lower than the dosage used for the treatment of 
malaria) in healthy, middle-aged adults can produce symptoms of quinine 
toxicity, including auditory, visual, and gastrointestinal effects. The 
agency also noted that vestibular, auditory, visual, and vascular 
effects of quinine can occur in healthy young adults at doses in and 
below the range commonly employed for the treatment and/or prevention 
of nocturnal leg muscle cramps (59 FR 43234 at 43239).
    Symptoms of side effects associated with quinine (collectively 
referred to as ``cinchonism'') include tinnitus (a ringing or buzzing 
in the ear), nausea, vomiting, visual changes, auditory deficits, and 
cardiovascular abnormalities (Ref. 1). These symptoms are of varying 
severity depending upon the amount of quinine used. Some people will 
experience these side effects even at quinine doses of 260 to 325 mg/
day (59 FR at 43239). These side effects occur more frequently at the 
higher dosages generally used in the treatment of malaria (Ref. 1).
    A more severe problem is that people taking quinine remain at risk 
of developing hypersensitivity to the drug and experiencing a serious, 
life-threatening, or fatal reaction as a consequence. Reports of 
adverse reactions to quinine products listed in the agency's 
spontaneous reporting system show that, from 1969 through June 1992, 
FDA received 157 reports in which quinine was listed as a suspect drug. 
(See 59 FR 43234 at 43236.) There were 84 serious reactions: 23 deaths, 
5 cases in which the person was disabled, and 56 hospitalizations not 
involving death or disablement. A trend of increasing numbers of 
reports per year since 1986 was also observed as the marketing of OTC 
drug products containing quinine for the treatment and/or prevention of 
nocturnal leg muscle cramps expanded after 1986.
    A detailed review of 110 reports on file from 1969 through 1990 (59 
FR 43236 to 43237) showed 69 (approximately 63 percent) of these 
reports involved hypersensitivity reactions ranging from rash and fever 
to angioneurotic edema, thrombocytopenia, or generalized anaphylaxis. 
Of these 69 reports, 57 (approximately 83 percent) involved quinine 
products and/or quinine dosages used in the treatment and/or prevention 
of nocturnal leg muscle cramps. An attempt was made to identify only 
those reports in which the relationship between quinine and the 
reported event was strong and reasonably unrelated to other factors. 
Factors considered included the temporal relationship between quinine 
administration and the event, absence of concomitant medications (or 
abatement of the adverse event after quinine was discontinued), absence 
of confounding medical conditions, a positive test for quinine mediated 
antibodies, or history of a similar reaction associated with previous 
quinine exposure. Using these factors, 26 of the 110 reports were 
identified as cases where it can be reasonably concluded that quinine 
was the causative agent. These included 6 moderately severe to severe 
skin reactions, 2 of which were erythema multiforme-like reactions; 13 
hematologic events, with 2 resulting in death; 2 cases of hepatitis or 
elevated liver enzymes; 2 renal reactions, one leading to renal failure 
requiring dialysis, the other leading to death; 2 cases of a 
hypersensitivity syndrome with symptoms that included chills, nausea, 
vomiting, and diarrhea; and 1 report of anaphylaxis complicated by 
seizures and hypoxia following a single dose of quinine. None of these 
cases reported an overdose of the drug, and 21 of the 26 reports 
(approximately 81 percent) involved quinine products and/or quinine 
dosages used in the treatment and/or prevention of nocturnal leg muscle 
cramps.
    Quinine-induced thrombocytopenia may occur after 1 week of exposure 
or after months or years of quinine administration, and there may be no 
characteristic that would predict an adverse event in the person using 
the product (59 FR 43234 at 43243). The agency believes that a 
physician could help people using this drug appreciate the nature and 
frequency of the risk and advise about the signs of thrombocytopenia, 
such as petechiae (pinpoint, nonraised, round, purplish red spots) and 
purpura (small [[Page 19653]] hemorrhage), perhaps allowing 
identification of this condition before a significant hemorrhage 
occurred. A number of the adverse reaction reports note the occurrence 
of a similar prior event related to previous ingestion of quinine in 
which neither the user nor the physician recognized the relationship of 
the illness to quinine ingestion. Use of quinine under a physician's 
prescription, with appropriate emphasis on warning signs, may make 
timely recognition easier.
    Although drug-induced immunologic thrombocytopenia may be the best 
studied idiosyncratic reaction caused by quinine, quinine has also been 
reported to have been associated with a number of other 
hypersensitivity reactions and pharmacologic effects (59 FR 43234 at 
43243). These include the possibility of decreased digoxin clearance, 
increased half-life of quinine when given concurrently with cimetidine, 
pseudo-allergic reactions in aspirin-sensitive patients, drug fever, 
nonspecific granulomatous hepatitis, asthma, hemolytic anemia, 
inhibition of tolbutamide metabolism, hypoprothrombinemia, and 
hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient 
patients (59 FR 43234 at 43243). Furthermore, the possible 
pharmacologic effects may have particular significance for the elderly, 
who may be taking concomitant medications that adversely interact with 
quinine. Blackbourn and Bajrovic (Ref. 6) mention that 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 may be greater in the elderly.
    The agency is aware of reports asserting that the labeling of OTC 
quinine products for malaria may not be consistent with current medical 
recommendations and/or may be associated with excessive or inadequate 
dosages (Refs. 7 and 8). Houlihan (Ref. 7) reported a case involving a 
63-year-old man with a history of malaria who thought he was having a 
recurrence and began self-treatment with 975 mg of quinine sulfate 
three times a day in accordance with the product's labeling. After 2 
days of self-treatment, the man was hospitalized for blindness (that 
resolved after 10 days) and exhibited electrocardiographic 
abnormalities (that resolved after 2 days). However, blood tests after 
hospitalization showed no indication of the existence of malarial 
parasites. The agency randomly reviewed labels from eight OTC quinine 
products labeled for use in malaria (Ref. 9) and noted dosage 
recommendations as low as 200 mg three times a day (for 6 to 12 days) 
and as high as 975 mg three times a day (for 6 to 12 days). A fatal 
dose of quinine for an adult is approximately 2,000 to 8,000 mg (Refs. 
3, 10, and 11).
    Thus, in the treatment of malaria, a narrow margin of safety exists 
between a therapeutic dose and a toxic dose of quinine. The agency 
believes this risk requires that a prescribing physician participate in 
the decision to use the drug, by assuring the diagnosis, considering 
the species and possible drug resistance of the infecting parasite, 
evaluating concurrent medical problems and medications, counseling 
patients concerning common and potentially severe adverse reactions, 
and monitoring patient safety and treatment effectiveness.

References

    (1) White, N. J., and J. G. Breman, ``Malaria,'' in Harrison's 
Principles of Internal Medicine, 13th ed., edited by K. J. 
Isselbacher et al., McGraw-Hill, New York, pp. 887-895, 1994.
    (2) McCarthy, A. E., and J. S. Keystone, ``Malaria,'' in Conn's 
Current Therapy, 1994, edited by R. E. Rakel, W. B. Saunders Co., 
Philadelphia, pp. 94-100, 1993.
    (3) Webster, Jr., L. T., ``Drugs Used in the Chemotherapy of 
Protozoal Infections,'' in The Pharmacological Basis of 
Therapeutics, 8th ed., edited by A. G. Gilman et al., Pergamon 
Press, New York, pp. 978-998, 1990.
    (4) USPDI, Drug Information for the Health Care Professional, 
The U. S. Pharmacopeial Convention, Inc., Rockville, MD, vol. I, 
14th ed., pp. 2379-2382, 1994.
    (5) Heppner, Jr., D. G. et al., ``Infectious Diseases in 
Somalia,'' New England Journal of Medicine, 329(12): 889-890, 1993.
    (6) Blackbourn, J., and D. Bajrovic, ``Quinine--Forever and 
Ever?,'' Hospital Pharmacy, 23:732, 735, 1988.
    (7) Houlihan, G. M., ``Labeling of Nonprescription Quinine Needs 
Revision,'' American Journal of Hospital Pharmacy, 48(9):1892, 1991.
    (8) Letter from H. Most, New York University Medical Center, to 
E. J. Martin, FDA, copy in OTC Vol. 260001, Docket No. 94N-0355, 
Dockets Management Branch.
    (9) Copies of labeling for Genetco Quinine Sulfate 5 grain 
Capsules, Major Quinine Sulfate 325 mg Capsules, Royce Quinine 
Sulfate 325 mg Capsules, Rugby Quinine Sulfate 325 mg Captabs and 
Capsules, West-ward Quinine Sulfate 200 mg and 325 mg Capsules, and 
Zenith Quinine Sulfate 200 mg Capsules, copy in OTC Vol. 260001, 
Docket No. 94N-0355, Dockets Management Branch.
    (10) Drug Facts and Comparisons, Facts and Comparisons, Inc., 
St. Louis, pp. 366-368, January 1993.
    (11) McEvoy, G. K., editor, AHFS Drug Information, American 
Society of Hospital Pharmacists, Bethesda, MD, pp. 437-440, 1993.

III. The Agency's Tentative Conclusions on OTC Quinine Drug 
Products for the Treatment and/or Prevention of Malaria

    Malaria is a rare (in the United States) but serious and 
potentially deadly disease that exhibits several biologic patterns. 
Diagnosis and treatment of the disease depend on such factors as the 
species of parasite(s) involved, the density of parasites in the blood, 
the potential for possible exposure to drug-resistant P. falciparum or 
P. vivax, and the existence of coexistent medical complications. 
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 therapeutic efficacy 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 to determine if the malarial parasites 
have been eradicated. Accordingly, the agency concludes that consumers 
cannot safely and effectively self-treat malaria. Except for quinine 
products, no other antimalarial drug is available OTC.
    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 should be under the care and supervision 
of a doctor.
    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.
    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. [[Page 19654]] Studies of 
auditory, vestibular, and visual function in subjects given quinine 
confirm sensory disturbances at even lower doses. 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 may be greater in the elderly.
    Adverse events associated with quinine toxicity are common 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. Based upon quinine's 
demonstrated toxic effects and potential for harm if used in an 
unsupervised manner, the agency has determined that quinine should be 
available for the treatment of malaria only under the supervision of a 
doctor.
    In addition to toxic effects, serious and unpredictable 
hypersensitivity reactions to quinine 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 hematologic sensitivity. 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 hypersensitivity reactions to quinine products.
    Quinine is an important drug in the treatment of drug-resistant 
forms of malaria. However, it is no longer the primary drug of choice 
for initial treatment 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. For these 
reasons, the agency tentatively concludes that quinine is not safe for 
OTC use in the treatment of malaria.
    The agency is aware that quinine for the treatment of malaria has 
been marketed both OTC and by prescription, in all cases without 
approved new drug applications. This proposal would require that any 
OTC quinine drug products for the treatment and/or prevention of 
malaria be required to have an approved application for continued 
marketing. Prescription quinine drug products will be addressed in a 
future issue of the Federal Register.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
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). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
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 Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Quinine formulations for the treatment of malaria 
are currently marketed as both OTC and prescription products. None have 
an approved application. The final rule would stop the initial 
introduction or initial delivery for introduction into interstate 
commerce of all OTC quinine products that are labeled for the treatment 
and/or prevention of malaria, until such time as an approved 
application is obtained. The final rule would not affect the continued 
marketing and availability of quinine products by a doctor's 
prescription. The agency will address this form of marketing in a 
future issue of the Federal Register. The final rule may impose a 
direct one-time cost associated with changing product labels to conform 
with prescription labeling requirements. Due to the safety concerns 
discussed elsewhere in this document, manufacturers would be required 
to comply with the provisions of the final rule, if implemented, 30 
days after its date of publication. Manufacturers are therefore urged 
to comply voluntarily with this proposed rule and to cease OTC 
marketing at the earliest possible date. Accordingly, the agency 
certifies that the proposed rule will not have a significant economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on OTC 
quinine drug products for the treatment and/or prevention of malaria. 
Types of impact may include, but are not limited to, costs associated 
with relabeling, repackaging, or reformulating. Comments regarding the 
impact of this rulemaking on OTC quinine drug products for the 
treatment and/or prevention of malaria should be accompanied by 
appropriate documentation. The agency will evaluate any comments and 
supporting data that are received and will reassess the economic impact 
of this rulemaking in the preamble to the final rule.
    The agency has determined under 21 CFR 25.24(c)(6) 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.
    Interested persons may, on or before July 3, 1995, submit written 
comments to the Dockets Management Branch (address above). Written 
comments on the agency's economic impact determination may be submitted 
on or before July 3, 1995. Three copies of all comments are to be 
submitted, except that individuals may submit one copy. Comments are to 
be identified with the docket number found in brackets in the heading 
of this document and may be accompanied by a supporting memorandum or 
brief. Comments may be seen in the office above between 9 a.m. and 4 
p.m., Monday through Friday.

List of Subjects

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, it is 
proposed that 21 CFR part 310 be amended as follows:

PART 310--NEW DRUGS

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

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301, 
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C. 
216, 241, 242(a), 262, 263b-263n).
    2. New Sec. 310.547 is added to subpart E to read as follows: 
[[Page 19655]] 


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 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 May 19, 1995, 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: April 12, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-9701 Filed 4-18-95; 8:45 am]
BILLING CODE 4160-01-F