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

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

§ 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 § 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
Federal Register / Vol. 60, No. 75 / Wednesday, April 19, 1995 / Proposed Rules 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

§ 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 chloroquineresistant 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
19652 Federal Register / Vol. 60, No. 75 / Wednesday, April 19, 1995 / Proposed Rules

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, lifethreatening, 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
Federal Register / Vol. 60, No. 75 / Wednesday, April 19, 1995 / Proposed Rules 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, pseudoallergic 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-yearold 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, Westward 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 drugresistant 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.
19654 Federal Register / Vol. 60, No. 75 / Wednesday, April 19, 1995 / Proposed Rules

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 § 310.547 is added to subpart

E to read as follows:
Federal Register / Vol. 60, No. 75 / Wednesday, April 19, 1995 / Proposed Rules 19655

§ 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