Drug Products for the Treatment and/or Prevention of Nocturnal Leg Muscle Cramps for Over-the-Counter Human Use; Final Rule DEPARTMENT OF HEALTH AND HUMAN SERVICES

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

rule establishing that any over-the-counter (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. FDA is

issuing this final rule after considering public comments on the

agency's proposed regulation, which was issued in the form of a

tentative final monograph, and all new data and information on drug

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

cramps that have come to the agency's attention. This final rule is

part of the ongoing review of OTC drug products conducted by FDA.

EFFECTIVE DATE: February 22, 1995.

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 October 1, 1982

(47 FR 43562), FDA published, under Sec. 330.10(a)(6) (21 CFR

330.10(a)(6)), an advance notice of proposed rulemaking 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, together with 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. Interested persons were invited to submit comments by December

30, 1982. Reply comments in response to comments filed in the initial

comment period could be submitted by January 31, 1983.

In accordance with Sec. 330.10(a)(10), the data and information

considered by the Panel were put on display in the Dockets Management

Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420

Parklawn Dr., Rockville, MD 20857, after deletion of a small amount of

trade secret information.

The agency's proposed regulation, in the form of a tentative final

monograph, 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). Interested persons were invited to file

by January 7, 1986, written comments, objections, or requests for oral

hearing before the Commissioner of Food and Drugs regarding the

proposal. Interested persons were invited to file comments on the

agency's economic impact determination by March 10, 1986. New data

could have been submitted until November 10, 1986, and comments on the

new data could have been submitted until January 8, 1987. Final agency

action occurs with the publication of this final rule on OTC drug

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

cramps.

In the preamble to the agency's proposed rule on OTC drug products

for the treatment and/or prevention of nocturnal leg muscle cramps (50

FR 46588), the agency stated that no active ingredient in drug products

used OTC 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, but that Category I labeling was being proposed in

that document in the event that data were submitted that resulted in

the upgrading of any ingredients to monograph status in the final rule.

In this final rule, no ingredient in OTC drug products for the

treatment and/or prevention of nocturnal leg muscle cramps has been

determined to be generally recognized as safe and effective. Therefore,

proposed part 343 (21 CFR 343), subpart E for OTC drug products for the

treatment and/or prevention of nocturnal leg muscle cramps is not being

issued as a final regulation.

This final rule declares OTC drug products containing active

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

cramps to be new drugs under 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,

products containing drugs for this use also would be misbranded under

section 502 of the act (21 U.S.C. 352). In appropriate circumstances, a

citizen petition to establish a monograph may be submitted under 21 CFR

10.30 in lieu of an application.

This final rule amends 21 CFR part 310 to include drug products

containing active ingredients for the treatment and/or prevention of

nocturnal leg muscle cramps by adding new Sec. 310.546 (21 CFR 310.546)

to subpart E. The inclusion of OTC drug products for the treatment and/

or prevention of nocturnal leg muscle cramps in part 310 is consistent

with FDA's established policy for regulations in which there are no

monograph conditions. (See, e.g., Secs. 310.510, 310.519, 310.525,

310.526, 310.532, 310.533, and 310.534.) If, in the future, any

ingredient is determined to be generally recognized as safe and

effective for use in an OTC drug product for the treatment and/or

prevention of nocturnal leg muscle cramps, the agency will promulgate

an appropriate regulation at that time.

The OTC drug procedural regulations (21 CFR 330.10) provide that

any testing necessary to resolve the safety or effectiveness issues

that formerly resulted in a Category III classification, and submission

to FDA of the results of that testing or any other data, must be done

during the OTC drug rulemaking process before the establishment of a

final monograph. Accordingly, FDA does not use the terms ``Category I''

(generally recognized as safe and effective and not misbranded),

``Category II'' (not generally recognized as safe and effective or

misbranded), and ``Category III'' (available data are insufficient to

classify as safe and effective, and further testing is required) at the

final monograph stage. In place of Category I, the term ``monograph

conditions'' is used; in place of Categories II or III, the term

``nonmonograph conditions'' is used.

In the proposed rule for OTC drug products for the treatment and/or

prevention of nocturnal leg muscle cramps (50 FR 46588), the agency

advised that it would provide a period of 12 months after the date of

publication of the final monograph in the Federal Register for

relabeling and reformulation of drug products for the treatment and/or

prevention of nocturnal leg muscle cramps to be in compliance with the

monograph. Although several manufacturers submitted data and

information in response to the proposed rule, the data and information

were not sufficient to support monograph conditions, and no monograph

is being established at this time. Therefore, drug products for the

treatment and/or prevention of nocturnal leg muscle cramps that are

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

and are misbranded (nonmonograph conditions). The agency also stated

that if a safety problem is identified for a particular nonmonograph

condition, a shorter deadline may be set for removal of that condition

from OTC drug products. As stated below, a safety problem has been

identified for OTC drug products containing quinine sulfate for the

treatment and/or prevention of nocturnal leg muscle cramps. Therefore,

the agency has determined that initial introduction or initial delivery

for introduction into interstate commerce of quinine sulfate for the

treatment and/or prevention of nocturnal leg muscle cramps must cease

effective February 22, 1995. After that date, no OTC drug products that

are subject to this final rule may be initially introduced or initially

delivered for introduction into interstate commerce unless they are the

subject of an approved application. The agency is unaware of any

quinine sulfate drug product for this indication that is the subject of

an approved application. Any such drug product in interstate commerce

after the effective date of this final rule that is not in compliance

with the regulation is subject to regulatory action.

In response to the proposed rule on OTC drug products for the

treatment and/or prevention of nocturnal leg muscle cramps, three drug

manufacturers and a nutrition information service submitted comments.

One comment included a request for an oral hearing before the

Commissioner of Food and Drugs.

After the administrative record closed, a citizen petition was

submitted on December 1, 1988. In response to this petition, nine

additional comments were submitted. The Commissioner found that the

petition and subsequent comments raised safety and effectiveness issues

that warranted consideration before the final rule issued. Accordingly,

under Sec. 330.10(a)(7)(v), the Commissioner determined that good cause

was shown to warrant consideration of the petition and the additional

comments before the final rule issued. Copies of the comments received

and the petition are on public display in the Dockets Management Branch

(address above). Additional information that has come to the agency's

attention since publication of the proposed rule is also on public

display in the Dockets Management Branch.

I. The Agency's Conclusions on the Comments

A. General Comments

1. One comment disagreed with the agency's determination that

adequate clinical data did not exist to support the Category I status

of quinine for both safety and effectiveness for OTC use in the

treatment and/or prevention of nocturnal leg muscle cramps (50 FR 46588

at 46590). The comment expressed the belief that sufficient evidence

already exists for this use of quinine. In support of its position, the

comment referred to information it had submitted on December 27, 1982,

in response to the advance notice of proposed rulemaking for this class

of drug products.

The agency discussed this information in the tentative final

monograph (50 FR 46588 at 46589) and concluded that it did not provide

sufficient evidence to establish that quinine is generally recognized

as safe and effective for OTC use for the treatment and/or prevention

of nocturnal leg muscle cramps. The agency identified the issues to be

addressed in studies before quinine could be reclassified from Category

III to Category I (50 FR 46590 and 46591). The comment did not provide

any new information to address these issues. New data and information

submitted by other interested persons are discussed in section I.B.,

comments 4 through 9 of this document.

B. Comments on the Safety of Nocturnal Leg Muscle Cramp Ingredients

2. Two comments contended that FDA accepted the safe OTC use of

quinine sulfate for nocturnal leg cramps when it published, and did not

dissent from, the Miscellaneous Internal Panel's conclusions and

recommendations that ``* * * quinine appears to be reasonably safe over

prolonged periods of time in generally recommended doses of 200 to 325

mg daily'' (47 FR 43562 at 43564).

Contrary to the comments' contention, the record makes it clear

that neither the agency nor the advisory panels accepted the safety of

OTC use of quinine for nocturnal leg muscle cramps. The July 8, 1977

report of the Advisory Review Panel on OTC Internal Analgesic and

Antirheumatic Drug Products (42 FR 35346 at 35434) summarized the

safety of quinine and stated ``Although quinine has demonstrated

analgesic, antipyretic and muscle relaxant actions, its numerous toxic

effects give it an unfavorable benefit to risk ratio for these

purposes.'' The Panel concluded that ``Until controlled studies show

that a dose of not more than 325 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.'' While the Miscellaneous

Internal Panel's report stated that quinine ``* * * appears to be

reasonably safe * * *'' (47 FR 43564), the Panel did not conclude that

quinine was safe in doses used for the treatment of nocturnal leg

muscle cramps. The Panel's recommendation that quinine should be placed

in Category III for use in the treatment of nocturnal leg muscle cramps

cited the need for more information about both safety and efficacy in

its concluding statement (47 FR 43564).

In the tentative final monograph for OTC drug products for the

treatment and/or prevention of nocturnal leg muscle cramps, the agency

concurred with: (1) The Miscellaneous Internal Panel's classification

of quinine sulfate as Category III, and (2) the Internal Analgesic

Panel's conclusion that the drug should not be generally recognized as

safe and effective (Category II) for this use until its safety and

efficacy are demonstrated in controlled clinical trials (50 FR 46588 at

46592). It is clear, therefore, that neither the agency nor its

advisory panels have determined that quinine may be safely used for

this indication.

3. Three comments stated that quinine has been safely used by

millions of consumers for a variety of conditions, including leg

cramps, for more than 50 years, and that this long history of usage

demonstrates the safety of quinine.

General reference to the history of use of quinine cannot be

accepted as evidence of its safety. Historically, there has been no

clear location for the organized collection and analysis of adverse

drug experience reports on OTC drug products. Adverse events associated

with OTC drug products are still vastly underreported for a number of

reasons. First, for most OTC drugs there is no requirement that

manufacturers and distributors report adverse events to the FDA, even

those that are serious or life threatening. Second, physicians, who are

the principal reporters to the United States spontaneous reporting

system, may not become aware of reactions to OTC drugs. Patients often

do not mention OTC drugs in giving medication histories. If they do, it

is often not clear to physicians to which manufacturer the adverse

event should be reported.

4. Two comments in support of keeping quinine available OTC

discussed the adverse event reports on file for quinine in FDA's

spontaneous reporting system. Lavy (Ref. 1) stated that there were 52

reports suggestive of hypersensitivity reactions, including 8 deaths,

among the reports on file from 1969 to 1988. Lavy concentrated on

reports of thrombocytopenia (a decrease in the number of blood

platelets) and stated that bleeding secondary to thrombocytopenia may

have been related to four of the eight deaths reported in this 20-year

period. The comment stated that only one case provided sufficient

information to fulfill all diagnostic criteria for drug-induced

immunologic thrombocytopenia (consistent clinical history, exclusion of

other causes, positive in vitro test and, theoretically, the

demonstration of recurrent thrombocytopenia after rechallenge). Lavy

pointed out that adverse event reports should reflect a significant

prevalence of severe quinine-associated purpura (if occurring) because

this reaction is readily identifiable by the patient, physician, and

hospital. Using industry quinine sales figures and data from the FDA

spontaneous reporting system, Lavy concluded that the number of

reported quinine-related hypersensitivity reactions is quite low, even

if greatly underreported.

Aster (Ref. 2) reviewed adverse drug reactions reported to FDA from

1969 through December 1989 and estimated that approximately 1,000

reactions in 313 individuals were reported for quinine. Aster's

estimate was not limited to hypersensitivity reactions, but included

all reported reactions (including multiple reactions per individual).

Aster did not report the specific search criteria used to obtain the

adverse drug reaction reports other than to state that the ``FDA

materials provide a cumulative listing of all adverse drug reactions

(ADR) reported in connection with quinine since 1969.'' After

eliminating reactions considered highly unlikely to bear a cause-and-

effect relationship to quinine, Aster identified 254 reactions that he

considered ``significant.'' There were 83 hematologic reactions and 46

additional reactions possibly associated with hypersensitivity. Of 63

possible cases of thrombocytopenia, 36 included information verifying

low platelet levels. Aster identified 50 fatalities (15 from

hematologic complications, 3 from hypersensitivity, and 32 from other

causes). Overall, Aster classified 51 percent of the adverse reactions

as idiosyncratic and eight percent as the result of overdose. The

remaining 41 percent were of indeterminate etiology and consisted of

liver and kidney dysfunction, neurologic disorders, and various

hemorrhagic manifestations. Of the reports in which inadequate

information was provided for full evaluation, Aster noted the

possibility that some of the six cerebrovascular accidents reported may

have been associated with thrombocytopenia induced by quinine. Aster

concluded that: (1) No information is available that would enable the

identification of people at risk to sensitivity reactions to quinine;

(2) the rarity of sensitivity reactions and the rapidity with which

they occur make early detection of such reactions impossible and, (3)

the dramatic symptomatology of such reactions, when they occur, leads

people to seek prompt medical attention. Aster concluded, therefore,

that serious adverse reactions would neither be prevented nor reduced

in incidence by restricting quinine availability to prescription

status.

The agency has reviewed the comments and the reports of adverse

reactions to quinine products (listed in the agency's spontaneous

reporting system under quinine, quinine sulfate, and three brand name

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

muscle cramps). From 1969 through June 1992, FDA received 157 adverse

reaction reports in which quinine was listed as a suspect drug. There

were 84 serious reactions: 23 deaths, 5 cases in which the person was

disabled, and 56 hospitalizations not involving death or disablement.

Of the 157 adverse reaction reports, 52 (approximately 33 percent) did

not contain dosage and/or product name information, or reported daily

dosages in excess of those typically recommended for the treatment and/

or prevention of nocturnal leg muscle cramps. The remaining 105 reports

listed the names of quinine products labeled for use in the treatment

and/or prevention of nocturnal leg muscle cramps and/or daily dosages

recommended by these products, and included 60 serious reactions

involving 16 deaths, 4 cases of disablement, and 40 hospitalizations

not involving death or disablement. More importantly, 56 of the 105

reports (approximately 53 percent) have been received since 1988, and

there is an alarming trend of increasing numbers of reports per year

since 1986 as the market for OTC drug products containing quinine for

the treatment and/or prevention of nocturnal leg muscle cramps has

expanded during that period. Approximately 70 percent (42 of 60) of all

reports of serious reactions, 44 percent (7 of 16) of all reported

deaths, and 78 percent (31 of 40) of all reported hospitalizations on

file since 1969 were reported in the 4 1/2-year period between January

1988 and July 1992. There were 20 cases (19 percent of reports on file)

reported in 1991 alone: 3 were disabling, 11 required hospitalization,

and 1 resulted in death.

Nocturnal leg muscle cramps are a common condition in the elderly

(Ref. 3). Presumably, with an increasing average age in the American

population, the market for OTC drug products containing quinine for the

treatment and/or prevention of nocturnal leg muscle cramps also

increased during this period. The number of adverse reaction reports

for people 60 years of age or older, involving quinine products and/or

quinine dosages used in the treatment and/or prevention of nocturnal

leg muscle cramps, has increased by a factor of five (from 2 to 10)

during the period between January 1988 and December 1991.

The agency conducted a detailed review of 110 reports on file from

1969 through 1990; 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, of the 110 reports 26 were

identified in which 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.

Even using strict criteria to identify cases in which a causal

relationship of quinine to adverse event is likely, FDA finds that

quinine is associated with serious adverse events. There is no

compelling reason to restrict evaluation of the safety of quinine to

reported cases of thrombocytopenia, as Lavy did. The other adverse

effects are also serious and must be considered in weighing the

benefits and risks of products containing quinine. The agency agrees

with Aster that there is currently no way in advance to identify people

at risk of hypersensitivity reactions and, therefore, no effective way

to warn against use by such individuals (see section I.B., comment 10).

It does not agree, however, that physician monitoring might not

minimize serious reactions. Thrombocytopenia, for example, can lead to

bruising and other evidence of cutaneous bleeding. A physician could

warn patients to report such signs and stop the drug, perhaps

preventing a significant hemorrhagic event.

References

(1) Lavy, 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.

(2) Aster, R. H., ``Q-Vel: Could Serious Adverse Reactions be

Prevented by Having the Drug Available Only on Prescription,''

unpublished report in Comment No. C176, Docket No. 77N-0094, Dockets

Management Branch.

(3) Jones, K., and C. M. Castleden, ``A Double-Blind Comparison

of Quinine Sulphate and Placebo in Muscle Cramps,'' Age and Ageing,

12(2):155-158, 1983.

5. Several comments contended that the true incidence of quinine-

induced thrombocytopenia is many times smaller than that suggested by

estimates based on events reported from exposure to quinine-containing

drug products alone. The comments contended that such estimates fail to

account for the much larger exposure to quinine through beverages. Lavy

estimated exposure to quinine in beverages to be about 10 times greater

than exposure to quinine in drug products (Ref. 1). An agency search of

the medical literature identified only 10 cases of hypersensitivity

reactions attributed to quinine in beverages (Refs. 2 through 9). One

of these reactions occurred following ingestion of a drug product

containing quinine by a person presumed to have been previously

sensitized by exposure to beverages (Ref. 5). None of these events was

fatal.

The agency finds that the available information supports the safe

use of quinine in beverages such as tonic water and bitter lemon. Given

the level of consumption of quinine beverages, there is a scarcity of

reported hypersensitivity reactions, even assuming that reactions to

food products are vastly underreported.

Despite these safety data from beverage use, the agency does not

consider pooling total consumption and adverse reaction data on quinine

from food and drug products to be a legitimate basis to judge the

safety of drug products containing quinine. First, there are

differences in the quinine exposure levels because quinine is present

in much greater amounts in drug products. Second, there is a great

disparity in the incidence of reports of hypersensitivity reactions to

beverage and drug products.

The agency considers the appropriate basis on which to estimate the

incidence of hypersensitivity to quinine-containing drug products in

leg cramp sufferers is to evaluate reports of reactions in the people

who take such products at the dose, frequency, and for the duration

recommended in product labeling. Adjusting the reported incidence of

reactions to drug products by pooling data on beverages erroneously

exaggerates the risk of reaction to quinine in beverages, vastly

underestimates the risk of reaction to quinine-containing drug

products, and contradicts the raw data on these products. Both the

number and the severity of reported hypersensitivity reactions to drug

products containing quinine raise safety concerns about these products

(see section I.B., comment 4).

The agency considers the virtual absence of reports of reactions to

beverages containing small amounts of quinine (i.e., not more than 83

parts per million) as support for the safety of such use. Thus, the use

of quinine salts in food in accord with conditions described in 21 CFR

172.575 is not affected by this final rule on drug products for the

treatment and/or prevention of nocturnal leg muscle cramps.

References

(1) Lavy, 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.

(2) Belkin, G. A., ``Cocktail Purpura. An Unusual Case of

Quinine Sensitivity,'' Annals of Internal Medicine, 66(3):583-586,

1967.

(3) Korbitz, B. C., and E. Eisner, ``Cocktail Purpura. Quinine-

dependent Thrombocytopenia,'' Rocky Mountain Medical Journal,

70(10):38-41, 1973.

(4) Siroty, R. R., ``Purpura on the Rocks - With a Twist,''

Journal of the American Medical Association, 235(23):2521-2522,

1976.

(5) Elliott, H. L., and D. B. Trash, ``Intravenous Coagulation

Induced by Quinine,''Scottish Medical Journal, 24(3):244-245, 1979.

(6) Murray, J. A. et al., ``Bitter Lemon Purpura,'' British

Medical Journal, 2(6204): 1551-1552, 1979.

(7) Calnan, C. D., and G. A. Caron, ``Quinine Sensitivity,''

British Medical Journal, 2:1750-1752, 1961.

(8) Cundall, R. D., ``Idiosyncrasy to Quinine in Bitter Lemon,''

British Medical Journal, 1:1638, 1964.

(9) Callaway, J. L., and W. E. Tate, ``Toxic Epidermal

Necrolysis Caused by `Gin and Tonic','' Archives of Dermatology,

109:909, 1974.

6. Four comments submitted five reports (Refs. 1 through 5) of

controlled clinical studies of quinine alone or in combination with

vitamin E. The agency has reviewed these studies for evidence

pertaining to the safety of quinine used to treat and/or prevent

nocturnal leg muscle cramps.

The first study (Ref. 1) was a 10-week, crossover study of 69

subjects randomized to either 260 milligrams (mg) quinine sulfate or

placebo. Subjects were 26 to 77 years of age, with a mean age of 51.

Five adverse reactions to quinine (a 7 percent incidence) were

reported. One subject was unable to tolerate the quinine because

tinnitus (ringing in the ears) in both ears occurred while taking the

study drug. Two additional subjects experienced tinnitus while taking

quinine, but continued the medication and completed the study (although

the protocol called for discontinuation of the study drug if ringing in

the ears occurred). One additional subject experienced disorientation

and another reported dizziness while taking quinine. No adverse events

to placebo were reported.

The second study (Ref. 2) was a 10-week, double-blind, randomized,

crossover study of 62 subjects receiving daily doses of either 325 mg

quinine sulfate or placebo. Subjects were 21 to 76 years of age, with a

mean age of 47. Three subjects on quinine and three subjects on placebo

reported adverse events. The quinine reactions included tinnitus (which

quickly resolved when the drug was discontinued), blurred vision, and

headache, which occurred on 3 days during drug administration. One of

the subjects dropped out of the study because of dizziness and

drowsiness. Another subject discontinued quinine for the last two days

of the treatment period because of tinnitus. In the placebo group, one

subject reported chest pains and heartburn; another subject experienced

fever and nausea; and one subject reported constipation and dropped out

of the study. An additional eight subjects dropped out of the study for

reasons described in the report as not related to the drug products,

but no details were provided.

The third study (Ref. 3) was a 5-week randomized, crossover study

involving 205 subjects randomly assigned to quinine sulfate 260 mg/day,

vitamin E 1,600 international units (I.U.)/day, a combination of

quinine and vitamin E in the above doses, or placebo. Subjects were 18

to 80 years of age, with a mean age of 44. Twenty-seven adverse

reactions were reported: 9 (4.4 percent) in subjects receiving the

combination of quinine and vitamin E, 8 (3.9 percent) in subjects on

quinine alone, 6 (2.9 percent) in subjects on vitamin E alone, and 4 (2

percent) in subjects receiving placebo. There was an almost twofold

difference in overall adverse experiences when subjects were taking

either of the test drugs containing quinine. Adverse events in subjects

receiving quinine alone included stomach cramps, headache, nausea,

diarrhea, swollen hands, and slight muscle twitching. Adverse events in

subjects receiving the quinine and vitamin E combination included upset

stomach, headache, diarrhea, tiredness, constipation, and pain in the

legs. Adverse effects in subjects receiving vitamin E included

abdominal cramps, vomiting, loose bowels, headache, and intensified

menstrual cramps. Adverse events in the placebo group included nausea,

stomach cramps, and tingly fingers. Gastrointestinal disturbances were

reported by twice as many subjects when they were taking quinine alone

or in combination than when assigned to vitamin E alone or placebo.

Most of the adverse experiences in this study, irrespective of

treatment group, were described by investigators as not related or

probably not related to the study medication. Reported events, however,

were consistent with those classically associated with quinine

toxicity, which includes gastrointestinal symptoms (nausea, vomiting,

abdominal pain, and diarrhea), vasodilation, sweating, headache,

tinnitus, vertigo, and visual disturbances (Ref. 6).

The fourth study (Ref. 4) was a 5-week, crossover study involving

24 subjects 51 to 64 years of age (with a mean age of 57). All subjects

received placebo in weeks 1, 3, and 5; half of the subjects were

assigned to quinine sulfate (260 mg per (/) day) and half to the

combination of quinine sulfate and vitamin E during week 2. In week 4,

those subjects on the combination in week 2 were assigned to quinine

alone and vice versa. Nausea was reported by 3 subjects (12.5 percent)

who received quinine sulfate during week 2. No details of the reported

reactions were provided. No other adverse events were reported.

The fifth and largest study was a multicenter, block-randomized,

parallel design involving 559 subjects 18 to 84 years of age (Ref. 5).

A 1-week, single-blind, placebo phase was followed by a 2-week, double-

blind, randomized, treatment phase. Subjects who had at least one leg

cramp per night for a minimum of 3 nights during the single-blind

placebo week and met other selection criteria were randomized to one of

four double-blind treatment groups: Quinine sulfate 259.2 mg (subject

ages ranged from 19 to 79 years with a mean age of 46), vitamin E,

1,600 I.U. (subject ages ranged from 18 to 76 years with a mean age of

42), a combination of quinine and vitamin E in the above doses (subject

ages ranged from 18 to 83 years with a mean age of 46), and placebo

(subject ages ranged from 21 to 84 years with a mean age of 45).

Besides meeting the criteria for frequency of nocturnal leg cramps,

subjects admitted to the study were generally in good health, were

predominantly female, and had a mean age of less than 50 years. The

study report stated that no unexpected or idiosyncratic adverse events

were seen ``* * * among patients taking an effective course of therapy

* * * nor was there a higher than usual incidence of recognized adverse

drug reactions associated with ingestion of quinine.''

One subject randomized to the combination product was reported to

have experienced a reaction consisting of fever, headache, nausea,

vomiting, and diffuse muscle pain after 5 days. The episode was

sufficiently severe to warrant medical intervention in which the test

drug (quinine/vitamin E) was stopped and the subject was treated with

analgesic/antipyretic therapy and a prescription antiemetic. Symptoms

subsided over 3 days. When the study medication was resumed, the

subject again experienced nausea, vomiting, abdominal pain, severe

headache, diffuse myalgia with severe pain in the legs, and fever. The

subject required hospitalization. Therefore, the study drug was

stopped. When the subject was discharged 5 days later, the physician

advised her to consider herself sensitive to quinine. Given the

temporal relationship between the onset of symptoms and administration

of the study drug as well as the positive rechallenge, this case

appears to be a well-documented hypersensitivity reaction.

In addition, another subject on quinine experienced itching,

nausea, and vomiting and discontinued the drug. Two other subjects

experienced moderately severe wheezing on the 8th and 12th days of

quinine treatment, but neither subject discontinued the medication.

The overall incidence of adverse events reported in the fifth study

(Ref. 5) was high and approximately equal in all groups (quinine

sulfate, 43.3 percent; vitamin E, 37.2 percent; the combination of

quinine sulfate and vitamin E, 39.3 percent; and placebo, 41.3

percent). Headache accounted for the greatest number of reported events

in each group (quinine sulfate, 19.1 percent; vitamin E, 16.8 percent;

combination of quinine sulfate and vitamin E, 19.1 percent; and

placebo, 21 percent), but did not appear to be treatment related.

Differences in the side- effect profile of the treatments emerge when

only events with an incidence of 1 percent or more are considered, and

both headache and events considered by the investigators as not related

to the study drug are excluded. This analysis shows an adverse event

rate of 12.8 percent with quinine sulfate (nausea, vomiting, diarrhea,

dizziness, tinnitus, pruritus, and urticaria); 3.6 percent with vitamin

E (nausea and myalgia); and 12 percent with the combination product

(nausea, vomiting, diarrhea, tinnitus, and fever). None of the events

reported by subjects on placebo, which the investigators considered

potentially related to the study drug, had an incidence of 1 percent or

more. Similarly, events reported to be severe or moderately severe

(excluding headache and events with an incidence less than 1 percent)

were more frequent in subjects taking quinine sulfate (6.4 percent) or

the combination product (7.1 percent) than vitamin E alone (3.6

percent) or placebo (2.2 percent).

The potential for symptoms of quinine toxicity from the low doses

generally recommended for the OTC treatment and/or prevention of

nocturnal leg muscle cramps has been confirmed in several other studies

(Refs. 7, 8, and 9). A recent study of the relationship between plasma

quinine levels and hearing impairment (Ref. 7) found that quinine, even

at low doses, produced auditory changes. In this study, single oral

doses of quinine of 5 milligrams/kilogram (mg/kg), 10 mg/kg, and 15 mg/

kg were administered to six healthy females 24 to 39 years of age. The

study did not specify subject weights. If subject weights of 50 to 60

kg were assumed, these doses would correspond to single quinine doses

of 250 to 300 mg, 500 to 600 mg, and 750 to 900 mg, respectively. Even

at the lowest dose (which is equivalent to the dose used in OTC drug

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

cramps), a drug effect on hearing impairment was detected in half of

the subjects. When plasma concentrations exceeded 15 micromoles/liter

(mmol/L), subjective hearing loss or tinnitus was observed in all

subjects. No symptoms were detectable at levels below 5 mmol/L. The

shift in hearing threshold was equal over the frequency range studied.

The effect over time was consistent with the level of the dose given.

The investigators concluded that a consistent effect-concentration

relationship for hearing impairment caused by quinine can be defined by

audiometry.

Zajtchuk (Ref. 8) compared the effect on vestibular and auditory

function of 0, 52.5 mg, and 105 mg quinine administered in the form of

commercial tonic water (containing 52.5 mg of quinine per 822

milliliter (mL) bottle) in 17 active duty military personnel. The study

was initiated following findings of low levels of quinine in post-

mortem tissues from military pilot fatalities. Tonic water was

administered over a 3-hour period daily for 14 days. While control

subjects and subjects given the low dose had normal function throughout

the test, three of the four subjects given 105 mg/day developed

transient vestibular abnormalities (manifested by rapid, involuntary,

rhythmic movements of the eyeball associated with certain positions of

the head or body) on positional testing.

Worden, Shephard, and Frape (Ref. 9) conducted two similar studies.

In one study, 6 men and 14 women (18 to 39 years of age) were given 100

mg quinine hydrochloride daily in the form of tonic water for 14 days.

In the second study, 4 men and 6 women (18 to 53 years of age) were

divided into 2 groups. One group received 120 mg in a fortified tonic

water, while the other drank a carbonated drink without quinine. No

audiometric changes were found in any of the subjects in either study.

However, 12 subjects (60 percent) in the first study complained of

visual disturbances, 14 (70 percent) reported dizziness, and 14 (70

percent) experienced headache.

The potential for adverse effects from quinine may be greater in

the elderly. A survey at one hospital (Ref. 10) of 201 inpatients 70

years of age or older found that 23 (11 percent) were taking quinine

for cramps. Sixty percent were taking 300 mg nightly; 40 percent were

taking twice that amount (600 mg nightly). Approximately one-third of

these subjects had been taking the drug continuously and chronically

for 2 years or more. The authors noted that the mean elimination half-

life of quinine in elderly patients has been reported to be 19 hours

compared with 8.5 hours in younger adults. The authors also stated that

``Chronic therapy is likely to result in accumulation of quinine,

putting elderly patients at greater risk of adverse effects. Possible

adverse effects include symptoms of cinchonism (tinnitus, headache,

nausea, rash, visual disturbance and temporary blindness), allergic

reactions, and thrombocytopenia and haemolytic anaemia.''

Wanwimolruk et al. (Ref. 11) found the elimination half-life of

quinine to be 18.4 plus-minuss> 5.7 hours in 8 healthy elderly

subjects 65 to 78 years old compared with 10.5 plus-minuss> 1.6

hours in 12 subjects 20 to 35 years old. Furthermore, a significantly

greater amount of quinine was excreted unchanged in the elderly

subjects, suggesting that quinine metabolism is reduced in elderly

people. Overall, there was a 26-percent reduction in clearance of

quinine in the older group. The authors concluded that accumulation of

quinine may occur in elderly people, thus placing them at a greater

risk of adverse events.

These studies indicate that serious safety concerns exist with

regard to the OTC availability of quinine sulfate for the treatment

and/or prevention of nocturnal leg muscle cramps. Subjects in all

studies submitted were generally in good health, with a mean age of 44

to 57 years in the various groups. However, the adverse reactions

reported in these studies suggest that quinine doses of 260 to 325 mg/

day in healthy, middle-aged adults can produce symptoms of quinine

toxicity, including auditory, visual, and gastrointestinal effects.

Some studies (Refs. 7, 8, and 9) suggest that the 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. Altered

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

in older people. This longer half-life increases the frequency and

severity of adverse effects in the elderly (Ref. 11), a group in which

leg cramps are a common condition (Refs. 12 and 13). Therefore, the

agency concludes that quinine is not safe for OTC use in the treatment

and/or prevention of nocturnal leg muscle cramps.

References

(1) Bottner, M., ``Clinical Trial of the Efficacy of Quinine

Sulfate in the Treatment of Nocturnal Leg Muscle Cramps, Protocol

84-46,'' draft of an unpublished paper in Comment No. C123, Docket

No. 77N-0094, Dockets Management Branch.

(2) Hays, R., and J. J. Goodman,``Clinical Trial of the Efficacy

of Quinine Sulfate in the Treatment of Nocturnal Leg Muscle Cramps,

Protocol 86-48,'' draft of an unpublished paper in Comment No. C126,

Docket No. 77N-0094, Dockets Management Branch.

(3) Leo Winter Associates, Inc., ``FinalMedical Report and Data

Summary Analysis and Final Statistical Report on Double Blind

Randomized Crossover Study of Q-VELR Versus Quinine Sulfate Versus

Vitamin E Versus Placebo in the Treatment of Nocturnal Leg Muscle

Cramps (No. 1285-5082),'' draft of an unpublished paper in Comment

No. SUP00031, Docket No. 77N-0094, Dockets Management Branch.

(4)Biodesign GmbH, ``Clinical Evaluationof Q-VELR in Patients

with Nocturnal Leg Muscle Cramps,'' draft of an unpublished paper in

Comment No. SUP00031, Docket No. 77N-0094, Dockets Management

Branch.

(5) Draft of an unpublished study entitled: ``A Short-Term,

Randomized, Double-Blind, Parallel Study of Q-Vel vs. Quinine

Sulfate vs. Vitamin E vs. Placebo in the Prevention and Treatment of

Nocturnal Leg Cramps,'' Comment No. SUP00033, Docket No. 77N-0094,

Dockets Management Branch.

(6) Bateman, D. N., and E. H. Dyson, ``Quinine Toxicity,''

Adverse Drug Reactions and Acute Poisoning Reviews, 4:215-233, 1986

(7) Alvan, G. et al., ``Hearing Impairment related to Plasma

Quinine Concentration in Healthy Volunteers,``British Journal of

Clinical Pharmacology, 31:409-412, 1991.

(8) Zajtchuk, J. T. et al., ''Electronystagmographic findings

in Long-term Low-Dose Quinine Ingestion,`` Archives of

Otolaryngology, 110:788-791, 1984.

(9) Worden, A. N., N. W. Shephard, and D. L. Frape, ``Report on

the Daily Consumption for 14 Days by Normal Subjects of Tonic Water

Containing Quinine Hydrochloride,'' unpublished report, copy in OTC

Vol. 03AFM, Docket No. 77N-0094, Dockets Management Branch.

(10) Blackbourn, J., and D. Bajrovic, ``Quinine--Forever and

Ever?,'' Hospital Pharmacy, 23:732, 735, 1988.

(11) Wanwimolruk, S. et al., ``Pharmaco-kinetics of Quinine in

Young and Elderly Subjects,'' Transactions of the Royal Society of

Tropical Medicine and Hygiene, 85(6):714-717, 1991.

(12) Griggs, R. C., ``Pain, Spasm, and Cramps of Muscle,'' in

``Harrison's Principles of Internal Medicine,'' 12th ed., edited by

J. D. Wilson et al., McGraw-Hill, Inc., New York, pp. 173-176, 1991.

(13) Jones, K., and C. M. Castleden, ``A Double-Blind Comparison

of Quinine Sulphate and Placebo in Muscle Cramps,'' Age and Ageing,

12(2):155-158, 1983.

7. One comment (Ref. 1) requested a ban on the OTC marketing of any

quinine sulfate products used in the treatment of nocturnal recumbency

leg cramps. The comment based this request, in part, on adverse

reactions reported to the FDA, including eight deaths it described as

closely linked to quinine products. The comment contended that serious

and fatal adverse reactions to quinine sulfate purchased OTC for this

use continue to be reported. The comment mentioned that these reactions

can occur in several ways: (1) In persons hypersensitive to quinine,

(2) from the innate toxicity of quinine, or (3) as a result of

interactions with other drugs, including digoxin, anticoagulants, and

antiarrhythmics. The comment concluded that the risks associated with

quinine used for leg cramps are unacceptable in light of its lack of

efficacy for this use.

The agency agrees that quinine has the potential to elicit serious

hypersensitivity reactions at doses employed in OTC drug products used

for the treatment and/or prevention of nocturnal leg muscle cramps. The

agency's spontaneous adverse reaction reporting system includes

reasonably unconfounded reports of thrombocytopenia, hemolytic anemia,

leukopenia, granulocytopenia, anaphylaxis, hypersensitivity syndrome,

severe skin reactions (including urticaria, angioedema, and erythema

multiforme), liver abnormalities, renal failure, and death (see section

I.B., comment 4). Reports in the literature have identified quinine

sulfate (in doses typically recommended for the treatment and/or

prevention of nocturnal leg muscle cramps) as the causative agent in

cases of photosensitive dermatitis (Refs. 2, 3, and 4), psychosis (Ref.

5), disseminated intravascular coagulation (Ref. 6), and hemolytic

uremic syndrome (Ref. 7).

The agency agrees that quinine may interact with several other

drugs (Refs. 8, 9, and 10), including those mentioned by the comment.

This information could be included in the labeling of OTC quinine drug

products. However, the agency does not need to make a decision on such

drug interaction precautions because no ingredients for treating and/or

preventing nocturnal leg muscle cramps are currently generally

recognized as safe and effective for inclusion in an OTC drug

monograph.

Cinchonism is a cluster of symptoms of varying severity that

includes: Tinnitus, dizziness, disorientation, nausea, visual changes,

auditory deficits, and (at higher doses) cardiac arrhythmias.

Cinchonism is dose related. The clinical studies discussed in section

I.B., comment 6 demonstrate that adverse events typical of quinine

toxicity (in some cases, sufficiently severe to lead to discontinuation

of the drug) occur in some people at doses generally recommended for

the treatment and/or prevention of nocturnal leg muscle cramps. These

studies indicate that some people who self-medicate with quinine to

treat and/or prevent nocturnal leg muscle cramps at doses recommended

in product labeling will experience these quinine-related adverse

events. In addition, people taking quinine remain at risk of developing

hypersensitivity to the drug and experiencing a serious, life

threatening, or fatal reaction as a consequence. Even if quinine were

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

cramps, this risk would require that a prescribing physician

participate in the decision to use the drug, by assuring the diagnosis,

considering alternative treatment options, evaluating concurrent

medical problems and medications, and monitoring patient safety

throughout treatment.

References

(1) Comment No. CP0006, Docket No. 77N-0094, Dockets Management

Branch.

(2) Diffey, B. L. et al., ``The Action Spectrum in Quinine

Photosensitivity,'' British Journal of Dermatology, 118:679-685,

1988.

(3) Ferguson, J. et al., ``Quinine Induced Photosensitivity:

Clinical and Experimental Studies,'' British Journal of Dermatology,

117:631-40, 1987.

(4) Ljunggren, B., and P. Sjovall, ``Systemic Quinine

Photosensitivity,'' Archives of Dermatology , 122:909-911, 1986.

(5) Verghese, C., ``Quinine Psychosis,'' British Journal of

Psychiatry, 153:575-576, 1988.

(6) Spearing, R. L. et al., ``Quinine-induced Disseminated

Intravascular Coagulation,'' Lancet, 336:1535-1537, 1990.

(7) Gottschall, J. L. et al., ``Quinine-Induced Immune

Thrombocytopenia Associated with Hemolytic Uremic Syndrome: A New

Clinical Entity,'' Blood, 77(2):306-310, 1991.

(8) Lavy, 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.

(9) USPDI, ``Drug Information for the Health Care

Professional,'' The U. S. Pharmacopeial Convention, Inc., Rockville,

MD, vol. I, 14th ed., pp. 2379-2382, 1994.

(10) ``Drug Evaluations Subscription,'' American Medical

Association, Chicago, 1 (4):10-11, 1993.

8. Several comments downplayed the potential for hypersensitivity

reactions to quinine, particularly quinine- induced immunologic

thrombocytopenia, arguing that the continued OTC marketing of quinine

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

should not be stopped because of this potential consequence of its use.

One comment (Ref. 1) submitted an expert review of drug-induced

immunologic thrombocytopenia (DIITP), which stated that DIITP has been

reported with over 100 drugs. Gold salts, heparin, and the cinchona

alkaloids are the drugs most commonly associated with this condition.

According to the expert review supplied by the comment, there is no

known information about the dose of quinine required to induce DIITP

sensitivity. DIITP occurs more frequently in people over 50 years old,

possibly because of their greater exposure to drugs. It typically is

characterized by a warm sensation, followed by a chill. Bleeding

episodes, manifested by petechiae (pinpoint red spots, caused by

intradermal or submucosal hemorrhage), purpura (purplish or brownish

red discolorations visible through the skin, caused by hemorrhage into

the tissues), hemorrhagic lesions of the oral mucosa, and occasionally

hemorrhage of the gastrointestinal and urinary tracts may occur 6 to 12

hours after drug exposure in individuals who develop severe

thrombocytopenia. Intracerebral hemorrhage and lethal intrapulmonary

hemorrhage have been reported. Primary treatment is to discontinue the

offending drug; bleeding usually subsides in 3 to 4 days. Other

interventions (including glucocorticoid therapy and platelet

transfusions) have not been shown to be beneficial.

Another comment argued that many drugs and additives to foods have

the propensity to induce a variety of adverse reactions (Ref. 2). The

comment stated that the prevalence of hypersensitivity to tartrazine

(FD&C Yellow No. 5), a widely used dye, has been estimated to be about

1 in 10,000 in the general population. The comment pointed out that

when tartrazine is used in OTC drug products, a labeling statement is

required to inform consumers that the product contains tartrazine and

that it may cause allergic-type reactions. The comment stated that this

was ``a clear precedent for the OTC drug use of products that have

potential for rare hypersensitivity.'' The comment also described

aspirin sensitivity as widespread and emphasized that a brief warning

statement in labeling regarding use by people with asthma or aspirin

sensitivity is deemed adequate to ensure safe OTC use.

The agency finds that the information in the first comment

indicates that quinine is one of the drugs most frequently associated

with DIITP. While other drugs (e.g., gold salts and heparin) cause

DIITP, quinine is the only drug highly associated with DIITP that is

available OTC.

In March 1985, the Department of Health and Human Services

established an Ad Hoc Advisory Committee on Hypersensitivity to Food

Constituents (the Committee) to evaluate data relevant to allergic-type

reactions in humans that were associated with food constituents. The

Committee concluded that tartrazine may cause mild cases of urticaria

(hives) in a small subset of the population (usually not requiring

medical intervention). The Committee found no evidence that the color

additive constitutes a hazard to the general public when used in food

at its current levels. Prior to the Committee's findings, the agency

had decided that labeling provides an adequate safeguard for those

sensitive to tartrazine. (See the Federal Register of February 4, 1977

(42 FR 6835) and June 26, 1979 (44 FR 37212).) The agency requires the

label of OTC and prescription drug products containing tartrazine

intended for oral, nasal, rectal, or vaginal use to specifically

declare the presence of tartrazine by listing the color additive using

the names ``FD&C Yellow No. 5'' and ``tartrazine.'' (See 21 CFR

74.1705(c)(2).) In addition to this label statement, prescription drug

products for these uses must also include in their labeling the warning

statement ``This product contains FD&C Yellow No. 5 (tartrazine) which

may cause allergic-type reactions (including bronchial asthma) in

certain susceptible persons. Although the overall incidence of FD&C

Yellow No. 5 (tartrazine) sensitivity in the general population is low,

it is frequently seen in patients who also have aspirin

hypersensitivity.''

There are a number of differences between hypersensitivity

reactions to tartrazine and aspirin and hypersensitivity reactions to

quinine. In a review of allergic reactions to drug additives (Ref. 3),

Simon stated that reactions to tartrazine ``if they occur at all, are

indeed quite rare for the asthmatic population, even for the aspirin-

sensitive subpopulation.'' Simon further reported that no positive

responses were found after 125 double-blind, placebo-controlled

tartrazine challenges (with at least 25 mg) in an aspirin-sensitive

asthmatic population. Simon also reviewed adverse reactions to food

additives (Ref. 4) and stated that, although tartrazine is the food

additive most frequently associated with hypersensitivity reactions,

``tartrazine has been confirmed to be at best only occasionally

associated with flares of urticaria or asthma.'' Reports of these

relatively mild tartrazine reactions, however, are in contrast to the

serious reports for quinine, which involve life threatening and fatal

hypersensitivity reactions.

Virchow et al. (Ref. 5) evaluated sensitivity to tartrazine in 156

Europeans with confirmed aspirin-induced asthma. Oral challenges were

performed with increasing doses. All positive challenges were repeated

under double-blind conditions. Only four subjects had positive

reactions; none were serious. The incidence of tartrazine cross

sensitivity to aspirin in this European population was 2.6 percent. In

a similar study, Morales et al. (Ref. 6) conducted 141 challenge tests

on 47 subjects with asthma associated with intolerance to analgesics,

using tartrazine doses of 5, 25, 50, 100, and 200 mg and a placebo.

Only five tests were positive in four of the subjects; repeat tests

were negative in three of the four subjects. The authors stated that

clinical instability in these subjects may be the cause of some

respiratory symptoms attributed to tartrazine and that the practice of

recommending color free diets should be reserved for cases in which a

positive challenge test has been obtained on at least two occasions.

This experience suggests that: (1) The incidence of tartrazine

sensitivity may be overestimated, and (2) the nature of reactions to

tartrazine is sufficiently benign to permit multiple rechallenges to

confirm intolerance. Rechallenge of quinine-sensitive individuals, in

contrast, is contraindicated because the reactions are serious, life

threatening, or fatal, even under controlled conditions.

Safford (Ref. 7) was unable to detect antibody formation with

tartrazine and its metabolites in animal studies, suggesting that an

immunologic response is not involved in tartrazine sensitivity.

Hypersensitivity to quinine, in contrast, is mediated by an immunologic

mechanism.

Aspirin sensitivity is relatively common compared to quinine

sensitivity, but is more manageable and usually predictable. In a

review of aspirin sensitivity, Settipane (Ref. 8) described a number of

factors that are predictive of subjects in whom intolerance is most

likely to occur. Sensitivity is seen in 23 to 28 percent of people with

chronic urticaria, 14 to 23 percent of people with nasal polyps, and up

to 19 percent of people with asthma. These people are likely to be

under a doctor's care and to have been told to avoid aspirin products.

Genton et al. (Ref. 9) studied the usefulness of oral provocation tests

to aspirin and food additives in 34 subjects with asthma or chronic

urticaria, concluding that such investigations are safe and useful in

managing such subjects by identifying intolerance to various compounds.

As with tartrazine, hypersensitivity to aspirin does not appear to be

mediated by an immunologic response (Ref. 8). In contrast to aspirin,

there are no predictive factors for quinine hypersensitivity and, as

noted above, in vivo rechallenge is contraindicated.

Sensitivity to aspirin (Ref. 8) and tartrazine (Ref. 10) is a

problem that is manageable. The sensitivity generally results in

urticarial or bronchospastic symptoms that are responsive to medical

treatment. Anaphylaxis has been reported with aspirin, but is extremely

rare given the extensive use of products containing aspirin. In a

retrospective study of anaphylaxis occurring outside of hospitals in a

hospital catchment area in Denmark over a 13-year period, the rate of

anaphylaxis caused by aspirin was 0.48 cases per 100,000 inhabitants

(Ref. 11). Sensitivity to quinine, in contrast to aspirin or

tartrazine, affects a number of body systems and may be serious,

manifested as urticaria/angioedema, hepatic injury, renal failure,

serious dermatologic conditions, serious hematologic events, and death

(Ref. 12) (also see section I.B., comment 6). Three sources estimate

the incidence of quinine-induced immunologic thrombocytopenia to be in

the range of about 1:1,000 to 1:3,000 (see section I.B., comment 9).

FDA's spontaneous reporting system contains 110 case reports

involving quinine for the period from 1969 through 1990. Sixty-nine

(approximately 63 percent) of these reports represent possible

hypersensitivity reactions, including 22 reports of thrombocytopenia

(57 of these cases [approximately 83 percent] involved quinine products

and/or quinine dosages typically used in the treatment and/or

prevention of nocturnal leg muscle cramps). Of the eight deaths that

occurred among the reported hypersensitivity reactions, medical records

and autopsy findings were sufficiently complete in two of these cases

(both involving OTC quinine products indicated for the treatment of leg

muscle cramps) to implicate quinine-induced thrombocytopenia as

precipitating fatal hemorrhages in each case. 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 concludes that the severity of quinine hypersensitivity

reactions, even in their first occurrence, and the inability to

identify predisposing factors to this occurrence create a risk clearly

different from that presented by tartrazine or aspirin. The agency does

not consider it likely that a warning statement in quinine product

labeling would be of significant value because it is impossible to

prospectively identify the groups at risk (see section I.B., comment

10).

References

(1) Aster, R. H., ``Thrombocytopenia Induced by Quinine and

Other Drugs'', unpublished report in Comment No. C143, Docket No.

77N-0094, Dockets Management Branch.

(2) Lavy, 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.

(3) Simon, R. A., ``Adverse Reactions to Drug Additives,''

Journal of Allergy and Clinical Immunology, 74(4 Pt 2):623-630,

1984.

(4) Simon, R. A., ``Adverse Reactions to Food Additives,'' New

England and Regional Allergy Proceedings, 7(6):533-542, 1986.

(5) Virchow, C. et al., ``Intolerance to Tartrazine in Aspirin-

Induced Asthma: Results of a Multicenter Study,'' Respiration,

53(1):20-23, 1988.

(6) Morales, M. C. et al., ``Challenge Tests with Tartrazine in

Patients with Asthma Associated with Intolerance to Analgesics (ASA-

Triad): A Comparative Study with Placebo,`` Clinical Allergy,

15(1):55-59, 1985.

(7) Safford, R. J., and B. F. Goodwin, ''Immunological Studies

on Tartrazine and its Metabolites. I. Animal Studies.''

International Archives of Allergy and Applied Immunology, 77(3):331-

336, 1985.

(8) Settipane, G. A., ``Aspirin and Allergic Diseases: A

Review,''American Journal of Medicine, 74(6A):102-109, 1983.

(9) Genton, C., P. C. Frei, and A. Pecoud, ``Value of Oral

Provocation Tests to Aspirin and Food Additives in the Routine

Investigation of Asthma and Chronic Urticaria,`` Journal of Allergy

and Clinical Immunology, 76(1):40-45, 1985.

(10) Dipalma, J. R., ''Tartrazine Sensitivity,'' American Family

Physician, 42(5):1347-1350, 1990.

(11) Sorensen, H. T., B. Nielsen, and J.Ostergaard-Nielsen,

``Anaphylactic Shock Occurring Outside Hospitals,'' Allergy,

44(4):288-290, 1989.

(12) Bateman, D. N., and E. H. Dyson,``Quinine Toxicity,''

Adverse Drug Reactions and Acute Poisoning Reviews, 4:215-233, 1986.

9. Two comments provided estimates of the incidence of quinine-

induced immunologic thrombocytopenia (QIITP). Lavy (Ref. 1) presented

several estimates, each based on different assumptions and information.

For one estimate, Lavy noted that four of six hypersensitivity

reactions reported to FDA in 1987 were cases of thrombocytopenia. Lavy

converted the total sales of quinine drug products for 1987 by dosage

unit to ``total number of days of therapy sold'' by dividing the number

of tablets and capsules sold by the dose per day described in product

labeling. Lavy assumed that quinine was taken for leg cramps

approximately one quarter of the year by each subject. By dividing the

``total days of therapy purchased'' by the ``total days used per

person,'' Lavy estimated the size of the population exposed to drug

products containing quinine in 1987 to be 1.66 x 106, and calculated

the incidence of QIITP to be 1 case per 415,000 people, based upon 4

cases reported to FDA that year. Lavy did not try to correct for

underreporting.

Using another approach, Lavy reported that quinine has been

estimated to be the causative agent in approximately 10 percent of all

drug-induced immunologic thrombocytopenia reports. He noted that

secondary thrombocytopenia was the principal diagnosis in approximately

4,000 discharges in the 1987 National Hospital Discharge Survey.

Assuming that 10 percent of these thrombocytopenia cases were drug-

induced and 10 percent of drug-induced immunologic thrombocytopenia

cases are related to quinine, 40 cases could be attributed to quinine.

Assuming the population exposed to drug products containing quinine in

1987 was 1.66 x 106 (as calculated above), Lavy calculated the

incidence of QIITP to be 1:41,500. Lavy cited a third estimate of the

incidence of QIITP based on information from Danielsen's report on

drug-induced blood disorders among admissions at the Group Health

Cooperative of Puget Sound (Ref. 2). In this retrospective study, 6

cases of thrombocytopenia related to quinine or quinidine among 5,089

subjects were reported for an apparent incidence of 1 case per 848

subjects taking 1 or the other of the 2 drugs.

Another comment (Ref. 3) estimated the incidence of QIITP from

ingestion of drug products to be 1:3,300 per year. The comment based

its calculations on the number of cases of documented quinine-induced

thrombocytopenia at the Blood Center of Southeastern Wisconsin over a

10-year period. In making this estimate, it was assumed that at least

half of all cases occurring in this population would have been referred

to the laboratory for confirmation of diagnosis.

The agency notes that the estimates of the incidence of

thrombocytopenic reactions to drug products containing quinine range

from more than 1 in 1,000 (for quinine and quinidine considered

together) to less than 1 in 400,000. This wide range suggests that a

precise estimate will be hard to obtain. It is difficult to conclude,

however, that the first estimate proposed by Lavy is correct. The

number of events used by Lavy is the number reported to FDA in 1987.

While no one knows the extent of underreporting, it is believed to be

very substantial. For example, if even a 1 percent rate is assumed,

this would translate, using Lavy's other figures, to about 1 in 4,000

people. The exposure estimate could also be considerably in error. Lavy

assumed the drug was used for one-quarter of the year by each person.

If, in fact, it was used for one half of the year, the number of

exposed people would be half that proposed and the rate of drug-induced

immunologic thrombocytopenia would be double that calculated.

The incidence calculated based on the National Hospital Discharge

Survey (Ref. 1) employed the estimate of population discussed above and

assumed 1 percent of the diagnoses of secondary thrombocytopenia were

attributable to quinine. There is no way to know the accuracy of this

estimate; if it were higher, even by a factor of 5, the estimated rate

would be above 1 in 10,000, a substantial rate.

Probably the most credible of Lavy's estimates is the Puget Sound-

based estimate (Ref. 2), because it is based on hospital diagnoses and

well-documented exposure. The estimate of the incidence of QIITP based

on the number of documented cases occurring in the population served by

the Blood Center of Southeastern Wisconsin over a 10-year period (Ref.

3) also is based on relatively few assumptions and appears reliable.

The only assumption in this calculation was that twice as many events

occurred as were reported to the laboratory. The estimates from these

two sources, 1:848 (Puget Sound) and 1:3,300 (Southeastern Wisconsin)

are similar to the estimate of 1:1,000 cited by Mitchell (Ref. 4).

These three sources provide a reasonably small range for the incidence

of QIITP that can be expected, about 1:1,000 to 1:3,000.

Therefore, while the agency believes that a precise estimate of the

incidence of QIITP will be difficult to obtain, credible estimates from

three sources (Refs. 2, 3, and 4) do not support the assertion that

QIITP is a rare event.

References

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

Sulfate in the Treat ment and/or Prevention of Nocturnal Leg

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

Dockets Management Branch.

(2) Danielson, D. A. et al., ``Drug-induced blood disorders,''

Journal of the American Medical Association, 252(23):3257-3260,

1984.

(3) Aster, R. H., ``Thrombocytopenia Induced by Quinine and

Other Drugs,'' unpub-lished report in Comment No. C143, Docket No.

77N-0094, Dockets Management Branch.

(4) Mitchell, T. R., and J. D. Morrow, ``Quinine Purpura,''

Journal of the Tennessee Medical Association, 81(9):578, 1988.

10. Three comments contended that warnings in product labeling

could adequately inform and protect consumers from the well-known side

effects of quinine, including idiosyncratic reactions. One comment

stated that warnings recommended by the Miscellaneous Internal Panel

(47 FR 43562 at 43564), including those concerning idiosyncratic

reactions, have been incorporated into the labeling of currently

marketed products. Another comment stated that careful warning language

in its product labeling helps to further protect consumers by informing

them of the possibility of untoward, idiosyncratic reactions. This

labeling states: ``Discontinue use and consult your doctor immediately

if swelling, bruising, skin rash, skin discoloration or bleeding

occurs. These symptoms may indicate a serious condition. Discontinue

use if ringing in the ears, deafness, diarrhea, nausea or visual

disturbances occur * * * Do not take if * * * allergic or sensitive to

quinine or under 12 years of age.'' A third comment, citing a report by

Lavy (Ref. 1), stated that serious adverse effects occur at a frequency

probably less than 1 in 40,000 people (see section I.A., comment 9),

the clinical course is only rarely complicated, and that labeling can

clearly and concisely warn ``* * * regarding the more common yet low

frequency side effects, which are generally treated simply by

discontinuing use.''

In the tentative final monograph (50 FR 46588 at 46592) the agency

proposed the following warning in Sec. 343.150(c) for OTC drug products

containing quinine: ``Discontinue use if ringing in the ears, deafness,

skin rash, or visual disturbances occur. Do not take if pregnant,

sensitive to quinine, or under 12 years of age.'' The agency proposed

this labeling in the event that data were submitted that resulted in

the inclusion of quinine in a monograph in the final rule. While

proposed, this labeling was not required at that time.

The agency has reviewed the warning information currently appearing

on OTC quinine products marketed for the treatment and/or prevention of

leg muscle cramps. The language varies slightly between products, but

the information provided is similar. In general, labeling warns

patients to discontinue taking the drug should any of a number of

listed events occur. However, the labeling differs in the events listed

and in recommending when a physician should be contacted.

There are several factors that argue against the sufficiency of

label warnings to protect consumers from serious adverse events related

to quinine. The frequency of these reactions is probably greater than

assumed by the comments (see section I.B., comment 9). Many of the

adverse advents are unpredictable. For example, thrombocytopenia may

occur after 1 week of exposure or after months or years of quinine

administration. Further, there may be no characteristic that would

predict an adverse event in the person using the product. The agency

believes that a physician could help people using this drug appreciate

the nature and frequency of the risk and help in the consideration

whether that risk is acceptable. The physician could also advise about

the signs of thrombocytopenia, such as petechiae (pinpoint, nonraised,

round, purplish red spots) and purpura (small 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 (Ref. 2), quinine has

also been reported to have been associated with a number of other

hypersensitivity reactions and pharmacologic effects. Lavy (Ref. 1)

notes that 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,

hemolytic anemia in glucose-6-phosphate dehydrogenase (G-6-PD)

deficient patients, etc.'' Cooper and Bunn (Ref. 3) reported that G-6-

PD-deficient individuals (i.e., those variants susceptible to hemolytic

anemia from quinine) are relatively common among eastern Mediterranean

and Chinese people. Quinine may also interact with several other drugs

(see section I.B., comment 7). Furthermore, the possible pharmacologic

effects may have particular significance for the elderly who may be

taking concomitant medications that either provoke muscle cramps or

adversely interact with quinine. Altered pharmacokinetics with age also

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 (Ref. 4) (also see section I.B., comment 6). The foregoing

possible additional adverse reactions, including those related to

ethnicity, age, and concurrent drug therapy, are not addressed by the

labeling of the comment's product and would generally be difficult to

address in OTC drug product labeling.

It should also be noted that the number of reports of serious

adverse reactions submitted to FDA's spontaneous reporting system,

including those resulting in hospitalization and death, has been

increasing over the past several years in spite of the industry's

revision of labeling to incorporate the warnings suggested by the

Miscellaneous Internal Panel in 1982. There has been an increasing

number of reports per year since 1986, and 56 of 105 reports

(approximately 53 percent) have been received by FDA since 1988. (See

section I.B., comment 4.)

The agency concludes there is insufficient evidence that warnings

in product labeling could adequately inform and protect consumers from

the well-known side effects of quinine, including idiosyncratic

reactions. This conclusion is based primarily on the severity of

hypersensitivity reactions to drug products that contain quinine and

the inability to identify predisposing factors to these reactions, the

frequency of such reactions, and the relationship of quinine-related

adverse events to factors such as ethnicity, age, and concurrent drug

therapy.

References

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

Sulfate in the Treat-ment and/or Prevention of Nocturnal Leg

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

Dockets Management Branch.

(2) Aster, R. H., ``Q-Vel: Could Serious Adverse Reactions be

Prevented by Having the Drug Available Only on Prescription,''

unpublished report in Comment No. C176, Docket No. 77N-0094, Dockets

Management Branch.

(3) Cooper, R. A., and H. F. Bunn, ``Hemolytic Anemias,'' in

``Harrison's Principles of Internal Medicine,'' 12th ed., edited by

J. D. Wilson et al., McGraw-Hill, New York, pp. 1531-1543, 1991.

(4) Blackbourn, J., and D. Bajrovic, ``Quinine--Forever and

Ever?,'' Hospital Pharmacy, 23:732, 735, 1988.

11. Two comments objected to the agency's discussion on the safety

of vitamin E (50 FR 46588 at 46591), contending that a considerable

body of data demonstrating safety in humans had been excluded from the

agency's evaluation. The comments primarily objected to the agency's

emphasis on the observations of one physician as an expert on vitamin E

because they considered the data referred to by this individual to be

anecdotal, uncontrolled, and largely subjective. The comments provided

a literature review and other data (Refs. 1, 2, and 3) to support the

safe use of vitamin E in humans.

Another comment disagreed with the agency's Category III

classification of vitamin E both individually and in combination with

quinine sulfate for the treatment and prevention of nocturnal leg

muscle cramps, contending that adequate information already existed to

support the safety of these ingredients (alone or in combination). The

comment included the results of two new clinical studies (Refs. 4 and

5) comparing vitamin E, quinine sulfate, a combination product

containing vitamin E and quinine sulfate, and placebo to support the

safe use of the individual ingredients as well as the combination of

these ingredients for this indication. In both studies, subjects

received a daily dose of 1,600 I.U. of vitamin E, either alone or in

combination with quinine sulfate.

One additional comment included the results of a third new clinical

study comparing vitamin E, quinine sulfate, a combination product

containing vitamin E and quinine sulfate, and placebo (Ref. 6). Some

safety information on vitamin E can be derived from this study.

In the tentative final monograph, the agency classified vitamin E

in Category III for the treatment and prevention of nocturnal leg

muscle cramps, stating that a safe and effective OTC dosage had not

been established for this use (50 FR 46588 at 46591). The agency

evaluated all of the data that had been submitted to this rulemaking

proceeding but acknowledges that these data were not the total body of

information that has been published on vitamin E. The agency did point

out that the paper by Roberts (Ref. 7) raised some questions about a

safe dose of OTC vitamin E.

The agency has reviewed the additional data and information that

have been submitted and determined that sufficient evidence has been

presented to support the safety of vitamin E for the treatment and/or

prevention of nocturnal leg muscle cramps. However, the evidence is

inadequate to support the effectiveness of vitamin E for this use (see

section I.C., comment 13).

Farrell and Bieri (Ref. 2) evaluated potential toxic and/or

beneficial effects of vitamin E intake. Twenty-eight adults who had

been self-administering 100 to 800 I.U. of vitamin E daily for an

average of 3 years were studied. A review of the subjects' past medical

histories did not reveal any apparent gross evidence of toxicity from

vitamin E intake. The highest plasma alpha-tocopherol concentrations in

the vitamin E subjects were two times the upper limit of normal, as

determined in control subjects. A broad range of laboratory tests were

performed to assess toxic effects on various organ systems. No

disturbance in liver, kidney, muscle, thyroid gland, erythrocytes,

leukocytes, coagulation parameters, or blood glucose was found.

Salkeld (Ref. 1) reviewed over 9,000 cases in which daily doses of

up to 3,000 I.U. of vitamin E were taken for up to 11 years (and 55,000

I.U. daily for 5 months in a few subjects). In 1,014 cases with vitamin

E intake from 200 I.U. up to 3,000 I.U. daily for up to 11 years, it

was stated that no side effects were observed. In another 8,241 cases

with similar intake and duration, there was no mention of side effects.

In other trials, 82 of 813 subjects complained of one or more side

effects. The reported effects included dermatitis, pruritus ani, acne,

cheilosis, fatigue and weakness, gastrointestinal symptoms, prostatic

obstruction, tachycardia, and vasodilation. Thus, in a total of 10,068

cases, Salkeld found a 0.8 percent overall incidence of side effects.

The Advisory Review Panel on OTC Vitamin, Mineral, and Hematinic Drug

Products relied in part on this same literature review by Salkeld in

stating its conclusion ``that vitamin E is safe'' (March 16, 1979, 44

FR 16126 at 16172). The Advisory Review Panel on OTC Antimicrobial (II)

Drug Products, in the advance notice of proposed rulemaking for OTC

topical acne drug products (March 23, 1982, 47 FR 12430), mentioned

that there are no notable pharmacological or toxicological effects of

oral vitamin E and that numerous experiments indicate that high dietary

intakes of vitamin E (up to 800 I.U. daily for up to 3 years) are

apparently without toxic side effects (47 FR 12462).

One of the new clinical studies submitted includes the results of

laboratory tests performed in 24 patients to evaluate the effect of the

product on various organ systems (Ref. 4). Tests were performed at

baseline and at the end of each 1-week treatment period. No abnormal

results in liver, kidney, leukocytes, erythrocytes, platelets,

electrolytes, or blood glucose were found in any of the patients at any

time. In this study vitamin E was used only in a combination product,

and each subject had a daily intake of 1,600 I.U. of vitamin E.

However, the combination product was only taken during 1 week of the

study. Therefore, the laboratory data do not provide any useful

information on the long-term effects of vitamin E.

The second new clinical study (Ref. 5) was a four-period crossover

study in which each subject received 1,600 I.U. of vitamin E daily

(either singly or in a combination product) for 5 days during two of

the four treatment periods of the study. Although no laboratory tests

were performed, the subjects were asked to report any adverse reactions

at the end of each treatment period. Twenty-seven adverse reactions

were reported by 19 subjects out of 205 individuals completing all

phases of the study. Six of these adverse reactions were from subjects

who received vitamin E singly. Complaints included: Abdominal cramps,

nausea, loose bowels, and headache. The most commonly occurring

complaint was gastrointestinal disturbance (nausea, flatulence, or

diarrhea) of a transient nature. These reactions are consistent with

those previously reported in other studies; however, the investigators

considered the reactions as not related or probably not related to the

study drug.

In the third new clinical study (Ref. 6), vitamin E (1,600 I.U.

daily for 2 weeks) was compared with placebo, quinine sulfate, and a

combination of quinine sulfate and vitamin E for the treatment and/or

prevention of nocturnal leg muscle cramps. Details of this multicenter,

parallel-design study are described in section I.C., comment 12.

Vitamin E alone was administered to 137 subjects. Headache was the most

frequently reported adverse event, occurring in 23 subjects (16.8

percent). However, a similar rate of headache (21 percent) was reported

in subjects taking placebo. The investigators described only six of

these events as possibly related to the study medication. Other adverse

events described by the investigators as possibly related to vitamin E

included three of four reports of nausea, two of three reports of

myalgia, and one of three reports of local edema. Thus, daily doses of

1,600 I.U. of vitamin E were well tolerated in this study.

Bendich and Machlin (Ref. 8) reviewed six double-blind studies

involving vitamin E at doses as high as 3,200 I.U. daily for up to 6

months. Very few adverse effects were noted, and no specific side

effect was consistently observed in all the studies. In one study, 202

college students received 600 I.U. of vitamin E or placebo daily for 28

days in a randomized, double-blind trial (Ref. 9). No effects on

prothrombin time, total blood leukocyte count, or serum creatine

phosphokinase activity were evident. In a randomized, double-blind,

placebo-controlled study, 30 healthy adults were given 800 I.U. of

vitamin E or placebo daily for 16 weeks. There were no significant

differences in effects on plasma lipids between the vitamin E and

placebo groups (Ref. 10). No side effects were observed in a double-

blind, crossover study of 48 subjects who received 1,600 I.U. of

vitamin E or placebo daily for a period of 6 months (Ref. 11). There

were no reports of significant side effects, weakness, fatigue, or

thrombophlebitis in a double-blind, crossover study in which 2,000 I.U.

of vitamin E or placebo was given daily to 25 adult onset-diabetic

subjects for a period of 6 weeks (Ref. 12). Thyroid hormone levels were

found to be identical for both the treatment and placebo periods. Hale

et al. (Ref. 13) examined the incidence of various clinical disorders

and measured a number of laboratory variables in 369 subjects who used

vitamin E supplements and 1,861 subjects who did not. All subjects were

over age 65. Use of vitamin E appeared to have little influence on

clinical disorders or hematologic or biochemical parameters. Only the

serum glutamic oxaloacetic transaminase was higher in vitamin E users.

However, the values were still within the accepted normal range. There

were no significant differences between users and nonusers in the

prevalence of hypertension, vaginal bleeding, frequent headache,

dizziness, recurrent diarrhea, diabetus mellitus, lightheaded-ness, or

thyroid disorders.

Roberts (Ref. 7) raised concerns about an increased incidence of

thrombophlebitis associated with excessive vitamin E intake. In over 10

years of practice, Roberts encountered more than 80 patients with

problems that he attributed to self-medication with high doses of

vitamin E (greater than 800 I.U. daily). He suggested that vitamin E

may encourage thrombosis in patients with a predisposing condition.

Symptoms of thrombophlebitis were said to have abated upon cessation of

vitamin E therapy. Conventional treatment for thrombophlebitis (e.g.,

bed rest, local heat) was administered along with the discontinuation

of vitamin E therapy. Thus, it is difficult to assess which action was

responsible for the improvement. In addition, no controlled studies or

concurrent references were included in support of his conclusions.

Fitzgerald and Brash (Ref. 14) stated that vitamin E at 1,600 I.U.

a day in humans decreases platelet thromboxane production which could

consequently reduce the potential for thrombosis formation. In

addition, they noted that associations between thrombophlebitis and

vitamin E use have not been reported by other authors.

Several authors (Refs. 2, 9, and 15) have reported that oral intake

of high doses of vitamin E has not produced blood coagulation

abnormalities in normal humans. However, in individuals deficient in

vitamin K (caused by malabsorption, diet, or anticoagulant therapy),

large doses of vitamin E can exacerbate coagulation defects. Therefore,

high levels of supplemental vitamin E may be contraindicated in such

conditions (Ref. 8).

Based on the discussion above, the agency concludes that sufficient

evidence exists to support the safety of vitamin E at the daily doses

that have been commonly used for the treatment and/or prevention of

nocturnal leg muscle cramps.

References

(1) Salkeld, R. M., ``Safety and Tolerance of High-Dose Vitamin

E Administration in Man: A Review of the Literature,'' draft of

unpublished data in Comment No. C124, Docket No. 77N-0094, Dockets

Management Branch.

(2) Farrell, P. M., and J. G. Bieri, ``Megavitamin E

Supplementation in Man,'' The American Journal of Clinical

Nutrition, 28:1381-1386, 1975.

(3) Hathcock, J., ``Vitamin Safety: A Current Appraisal,'' in

``Vitamin Issues,'' Vol. V, No. 1, published by Vitamin Nutrition

Information Service, in Comment No. C122, Docket No. 77N-0094,

Dockets Management Branch.

(4) Biodesign GmbH, ``Clinical Evaluation of Q-VELR in Patients

with Nocturnal Leg Muscle Cramps,'' draft of an unpublished paper in

Comment No. SUP00031, Docket No. 77N-0094, Dockets Management

Branch.

(5) Leo Winter Associates, Inc., ``Final Medical Report and Data

Summary Analysis and Final Statistical Report on Double-Blind

Randomized Crossover Study of Q-VELR Versus Quinine Sulfate Versus

Vitamin E Versus Placebo in the Treatment of Nocturnal Leg Muscle

Cramps (No. 1285-5082),'' draft of an unpublished paper in Comment

No. SUP00031, Docket No. 77N-0094, Dockets Management Branch.

(6) Draft of an unpublished study entitled ``A Short-Term,

Randomized, Double-Blind, Parallel Study of Q-Vel vs. Quinine

Sulfate vs. Vitamin E vs. Placebo in the Prevention and Treatment of

Nocturnal Leg Cramps,'' Comment No. SUP00033, Docket No. 77N-0094,

Dockets Management Branch.

(7) Roberts, H. J., ``Perspective On Vitamin E as Therapy,''

Journal of the American Medical Association, 246(2):129-131, 1981.

(8) Bendich, A., and L. J. Machlin, ``Safety of Oral Intake of

Vitamin E,'' The American Journal of Clinical Nutrition, 48:612-619,

1988.

(9) Tsai, A. C. et al., ``Study on the Effect of Megavitamin E

Supplementation in Man, ''The American Journal of Clinical

Nutrition, 31(5):831-837, 1978.

(10) Stampfer, M. J. et al., ``Effect of Vitamin E on Lipids,''

American Journal of Clinical Pathology, 79(6):714-716, 1983.

(11) Gillilan, R. E., B. Mondell, and J. R. Warbasse,

``Quantitative Evaluation of Vitamin E in the Treatment of Angina

Pectoris,''American Heart Journal, 93(4):444-449, 1977.

(12) Bierenbaum, M. L. et al., ``The Effect of Supplemental

Vitamin E on Serum Parameters in Diabetics, Post Coronary and Normal

Subjects,'' Nutrition Report International, 31(6):1171-1180, 1985.

(13) Hale, W. E. et al., ``Vitamin E Effect on Symptoms and

Laboratory Values in the Elderly,'' Journal of the American Dietetic

Association, 86(5):625-629, 1986.

(14) Fitzgerald, G. A., and A. R. Brash, ``Endogenous

Prostacyclin and Thromboxane Biosynthesis During Chronic Vitamin E

Therapy in Men,'' Annals of the New York Academy of the Sciences,

393:209-211, 1982.

(15) Corrigan, J. J., ``The Effect of Vitamin E on Warfarin-

Induced Vitamin K Deficiency,'' Annals of the New York Academy of

Sciences, 393:361-368, 1982.

C. Comments on the Effectiveness of Nocturnal Leg Muscle Cramp

Ingredients

12. One comment disagreed with the agency's Category III

classification of quinine sulfate for the treatment and/or prevention

of nocturnal leg muscle cramps on the basis of a lack of adequate

clinical data demonstrating the effectiveness of quinine sulfate for

this indication (50 FR 46588 at 46590). The comment contended that

there is sufficient evidence of quinine's effectiveness for this

indication at present to warrant classifying it in Category I. The

comment subsequently submitted the results of two clinical studies

(Refs. 1 and 2) comparing quinine sulfate, vitamin E, a combination

product containing quinine sulfate and vitamin E, and placebo for the

treatment and prevention of nocturnal leg muscle cramps to support the

effectiveness of the individual ingredients (quinine sulfate and

vitamin E) as well as the combination of these ingredients for this

indication. Another comment provided the results of three clinical

studies (Refs. 3, 4, and 5) that it felt addressed the effectiveness

issues raised by the agency in the tentative final monograph (50 FR

46590). This comment requested an oral hearing if the submitted data

were not found adequate to upgrade quinine sulfate to Category I. In

addition, in response to a citizen petition, one comment included the

results of a clinical study intended to demonstrate the efficacy of a

combination product containing quinine sulfate and vitamin E (Ref. 6).

In the tentative final monograph, the agency concluded, on the

basis of its review of the new data submitted and the studies and

information discussed by the Internal Analgesic and Miscellaneous

Internal Panels, that quinine sulfate for use in OTC drug products for

the treatment and/or prevention of nocturnal leg muscle cramps should

be classified in Category III. The agency stated that adequate clinical

data are necessary to support the reclassification of quinine from

Category III to Category I and that any such studies should address the

following safety and effectiveness issues (50 FR 46588 at 46590):

(1) Is quinine effective in treating and/or preventing nocturnal

leg muscle cramps in low daily doses (e.g., 200 to 325 mg) over short

periods of time (e.g., 7 days or less)?

(2) If short-term quinine treatment with low doses is not

significantly effective in reducing recurrent episodes of nocturnal leg

muscle cramps, must such medication be taken over extended periods of

time to obtain relief? If yes, how long a period of time?

(3) What adverse effects are experienced by subjects exposed to

effective doses of quinine over an effective course of therapy?

The agency has reviewed the additional clinical data that have been

submitted and determined that they are not adequate to support the

reclassification of quinine sulfate to Category I for this use. Three

studies (Refs. 3, 4, and 5) compared quinine to placebo. In one study

(Ref. 3), 75 subjects were enrolled in a double-blind, randomized,

placebo-controlled, crossover study that was conducted over a 10-week

period in five 2-week intervals. Subjects with a history of at least

two cramps per week for at least 3 months were included in this study

and randomized to one of two treatment groups (group I or II). The

initial 2-week period was a baseline period and patients who failed to

have at least two cramps per week were dropped from the study. Subjects

who had a sufficient number of cramps during the baseline period were

either given the placebo (group I) or 325 mg of quinine sulfate per

night (group II) for a period of 2 weeks. No treatment was given for

the next 2-week period and in the fourth 2-week period subjects crossed

over to the alternate treatment. A final 2-week period of no treatment

followed. Subjects were issued weekly case report forms upon which they

were instructed to record the number of cramps experienced per night,

the time of the cramp, and the severity of the cramp. Subjects were

also asked to rate the effectiveness of the medication just completed

at weeks 4 and 8 of the study. According to the protocol, subjects were

assigned to the treatment sequence, on the basis of a predetermined

randomization schedule, prior to entering the baseline period.

Therefore, the removal of subjects from the study in the first 2 weeks

for not having enough events may have biased the study.

In the statistical analysis of the study data, three efficacy

variables were evaluated: The mean frequency of leg cramps (per night),

the mean severity of leg cramps per night, and the total number of

nights per week that leg cramps occurred. The last variable (total

number of nights per week that leg cramps occurred) appears to be

constructed from the primary data because no such variable is listed on

the weekly case report forms from which these variables are derived.

The subjects' overall assessment of the effectiveness of the drug was

collected but not analyzed.

Sixty-two of the 75 subjects enrolled in the study were included in

the data analysis. Of the 13 subjects found to be unevaluable, 8

withdrew from the study on their own accord. No specific reasons for

these withdrawals were given, but it is stated in the study report that

they were unrelated to the treatment. The remaining five subjects were

dropped for various medical reasons and noncompliance with the

protocol. No ``intent-to-treat'' analysis was performed.

A number of analyses were carried out. Two of the analyses treated

the unblinded baseline and washout periods as if they were treatment

periods. This type of analysis is incorrect for a crossover trial. The

relevant comparisons that should be made are between the treatments in

the double-blind periods, possibly with adjustments for baseline,

provided there are no major changes in baseline values for each period.

When Patel's joint test for equal carryover and equal pretreatment

severity (Ref. 7) is applied to the data, however, significant

differences are seen in pretreatment severity before the second period.

Analysis of the second period is thus compromised; therefore, analysis

should be limited to the first treatment period (weeks 3 and 4). This

comparison does not show a significant advantage for quinine sulfate

over placebo for any of the effectiveness variables.

Another clinical study (Ref. 4) used the same study design as the

study discussed above except that the dose of quinine sulfate was 260

mg/night, not the 325 mg/night used in the first study. In addition,

five efficacy variables were analyzed: Frequency, severity, and

duration of leg cramps, and induction and quality of sleep.

Although the predetermined randomization chart submitted for this

study provided for enrollment of 74 subjects, 84 subjects entered the

study. No explanation for entry of the additional 10 subjects was

provided. As in the first study, randomization to treatment sequence

occurred at the time of entry into the baseline period; thus,

subsequent removal of subjects prior to the first double-blind

treatment period may also have introduced bias into this study. Of the

84 subjects entered at baseline, 69 (34 assigned to group I and 35 to

group II) entered the double- blind treatment phase.

The study concluded that significant differences at the 5-percent

level exist between quinine sulfate and placebo for three of the five

variables: Frequency of cramps, induction of sleep, and quality of

sleep. However, no documentation of any statistical analysis supporting

these claims was provided.

The statistical report that accompanied the study addressed the

question of comparing the effectiveness of quinine sulfate and placebo

with a multivariate analysis of covariance which compared the vector of

efficacy variables over four observation periods (two treatment periods

plus two washout periods with the initial baseline value as a

covariate). The conclusion of the analysis was that the treatment

effect was not significant (p = 0.106). Univariate analyses of

covariance comparing these four observation periods were referred to in

the statistical report, but no p-values for treatment effect were

provided (although a significant order by treatment interaction was

reported). Also included in the statistical analyses of the study were

comparisons of the four observation periods separately by sequence

(quinine sulfate-placebo and placebo-quinine sulfate), which included

baseline-adjusted means and comparisons between periods using Duncan's

Multiple Range Test. These comparisons showed that significant

differences were demonstrated between quinine and placebo only for the

placebo-quinine sulfate sequence (group II), and only for three

variables: Frequency of cramps, quality of sleep, and induction of

sleep. However, the adjusted means for the quinine sulfate-placebo

sequence (group I) favored placebo over quinine sulfate for all five

efficacy variables. In addition, as for the first study, the

appropriate statistical analysis for this type of study was not done.

The hypothesis of equal carryover effect was not tested and not

rejected before any of the other statistical tests for treatment effect

were performed. The results of this study are not adequate to support

the effectiveness of quinine sulfate for the treatment and/or

prevention of nocturnal leg muscle cramps.

The study by Jones and Castleden (Ref. 5) also does not provide

adequate evidence of quinine sulfate's effectiveness for this

indication. The study was a double-blind crossover study of nine

patients with four 2-week periods of observation (a run-in period and a

washout period in addition to two treatment periods of placebo or

quinine sulfate 300 mg/day). The same five efficacy values as in the

second study above were evaluated: Frequency, severity, and duration of

leg cramps, and induction and quality of sleep. No raw data were

included to substantiate any of the statistical claims made by the

authors; nor was a protocol included in the article.

Of the five primary efficacy variables, only severity of cramps was

claimed to show a significant difference between quinine sulfate and

placebo (p < 0.025), although an analysis of frequency of cramps after

2 a.m. was also claimed to be significant (p < 0.025). There was no

indication that the time period after 2 a.m. was identified in the

protocol as defining a primary endpoint; thus, this is assumed to be a

post-hoc analysis done after reviewing the data. In general, the

isolated severity finding is not convincing on its face. In addition,

the published article did not provide sufficient information to permit

an independent analysis of the data. For these reasons, the study does

not provide evidence that quinine sulfate is an effective treatment for

nocturnal leg muscle cramps.

Three studies (Refs. 1, 2, and 6) were submitted to support the

effectiveness of quinine sulfate and vitamin E individually and in

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

cramps. The Freiburg study (Ref. 1) was a 5-week, double-blind,

randomized, crossover study in 24 subjects. All subjects received

placebo during week 1 (baseline), week 3, and week 5. Subjects in group

I received quinine in week 2 and the combination of quinine and vitamin

E in week 4, while subjects in group II were given the combination

product in week 2 and quinine in week 4. A statistically significant

difference in frequency of attacks between the combination product and

quinine sulfate was reported, but no difference in duration or severity

of attack was found between these two active treatments. The report

described an ``obvious'' improvement in frequency, duration, and

severity of attacks between the placebo periods and both active

treatments, but no statistical evidence or analysis to support this

conclusion was provided. Moreover, the comparison of treatments and

placebo did not involve randomized patient groups, nor was it blinded.

Only the portion of the study comparing the combination product versus

quinine was a randomized, double-blind trial. The study report did not

include the study protocol, details of the statistical analysis

conducted, or individual subject data. The model described in the

summary of the data analysis did not properly separate carryover effect

from treatment effect. The study provides no evidence from a controlled

trial that quinine is effective for nocturnal leg muscle cramps.

The other study (Ref. 2) also employed a complicated randomized,

four-period, crossover design. There were 205 subjects randomly

assigned to one of four treatment groups: Quinine sulfate 260 mg/day,

vitamin E 1,600 I.U./day, a combination of quinine and vitamin E, or

placebo. The combination of quinine and vitamin E was reported as being

statistically superior to both its components and placebo for six

variables: Effect of cramps on falling asleep, nighttime awakening due

to cramps, number of cramps, severity of cramps, subject global

evaluation, and difficulty falling asleep due to cramps. The study also

reported statistically significant positive findings on quinine sulfate

versus placebo for the first five of these six variables. As in the

Freiburg study, the model used in the statistical analysis does not

properly separate the carryover effect from the treatment effect.

Neither the data listings nor the results by period were provided.

Therefore, the agency was unable to independently analyze the results

of this study or to rely on the analysis provided as evidence that the

reported results were attributable to drug treatment.

The third clinical study compared quinine sulfate, vitamin E, and a

combination of quinine sulfate and vitamin E to placebo, for the

treatment and/or prevention of nocturnal leg muscle cramps (Ref. 6).

This study was a multicenter, randomized, block parallel-design with a

single-blind, placebo, run-in period, followed by a 2-week, double-

blind, randomized, treatment phase. Subjects who had at least one leg

cramp per night for a minimum of 3 nights during the single-blind

placebo week, and met all other selection criteria, were randomly

assigned to one of the four double-blind treatment groups. Capsules,

identical in appearance, contained either placebo, quinine sulfate 64.8

mg, vitamin E 400 I.U., or a combination of quinine sulfate 64.8 mg and

vitamin E 400 I.U. Subjects were instructed to take two capsules

following their evening meal, and two capsules before bedtime, which

provided daily doses of 259.2 mg of quinine sulfate, 1,600 I.U. of

vitamin E, or the combination thereof.

Efficacy endpoints identified in the protocol were: (1) Number of

episodes of nocturnal leg cramps per week, (2) sleep disturbance due to

nocturnal leg cramps, (3) severity of nocturnal leg cramps, and (4)

duration of nocturnal leg cramps. However, none of the parameters was

designated as a primary efficacy variable in the protocol. The protocol

specified that efficacy would be analyzed by analysis of variance with

repeated measures test, as well as other methods deemed appropriate. On

the basis of an estimated 30 percent difference between the combination

product and its components, assuming an alpha of 0.05 and statistical

power of 70 percent, a sample size of 972 evaluable subjects was

planned (243 subjects/group). Enrollment was suspended, however, and

the data were analyzed after 498 evaluable subjects (51 percent)

completed the study. Subjects were approximately evenly distributed

among treatment groups.

In the final report, results were separately analyzed for weeks 1

and 2 of the double-blind treatment. The change from baseline scores

obtained during the single-blind, placebo week was analyzed on seven

variables for each of the treatment groups at days 7 and 14 using a

two-way analysis of variance test with terms for treatment, center, and

treatment by center interaction. The data were not analyzed using the

analysis of variance with repeated measures test, as prospectively

stated in the protocol. The variables were: (1) Number of nights per

week with leg cramps, (2) average number of leg cramps per night, (3)

average severity of leg cramps per night, (4) average duration of leg

cramps per night, (5) average number of leg cramps per night with

sleeping difficulty, (6) average degree of difficulty getting to sleep

per night, and (7) average number of nights per week awakened by leg

cramps. The placebo group was compared with the remaining treatment

groups with the least-significant-difference test using error mean

square from the analysis of variance table. Within each treatment

group, the amount of change from baseline for each efficacy parameter

was compared for each double-blind treatment week using the Wilcoxon

sign rank test. P-values of 0.05 or less were considered statistically

significant.

Twelve centers initially participated in the study. Three centers

were terminated because of low enrollment (less than four evaluable

subjects in at least one treatment group). These low enrollment centers

were combined in the analysis.

In the final report, the number of nights per week with leg cramps

was declared the primary efficacy variable. During the baseline period,

a mean of approximately 5 nights per week with leg cramps was recorded

in all groups (placebo 4.72, combination 4.95, quinine sulfate 5.04,

vitamin E 4.98). All groups improved during week 1 with a reduction in

frequency to approximately 4 nights per week with cramps (placebo 4.04,

combination 3.73, quinine sulfate 3.53, vitamin E 3.97). The greatest

reductions were in subjects given quinine sulfate and the combination

product and the difference in week 1 was found to be statistically

significant compared to placebo for these treatment groups (p less than

or equal to 0.04).

Statistically significant differences between quinine sulfate and

placebo were reported in the first week of the study for four of the

six remaining efficacy variables declared to be secondary parameters in

the final report. Quinine was reported to be significantly better than

placebo in reducing the average number of leg cramps per night, average

severity of leg cramps per night, average duration of leg cramps per

night, and average number of nights per week with sleeping difficulty.

No statistically significant differences between any of the treatment

groups for any variable were reported for the second week of the study.

The comment concluded that quinine sulfate, alone and in combination

with vitamin E, at a daily dose of approximately 260 mg was safe and

effective in the short term (1-week) treatment of nocturnal leg muscle

cramps.

The agency finds that there were a number of flaws in the analysis

of this study. First, the primary endpoint (number of nights per week

with leg cramps) appears to have been arbitrarily chosen after the

study was completed. None of the efficacy variables was declared the

primary endpoint in the protocol. Second, the study was of 2 week's

duration, and there was no provision in the protocol for separate

evaluation of the data from week 1 and week 2. Thus, there is no basis

for the decision to analyze week 1 and week 2 separately in the absence

of such an analysis declared prospectively in the protocol. In fact, an

analysis of both weeks together (see below) does not show a significant

benefit of quinine. Third, an adjustment for multiple comparisons

should have been included in the data analysis. Given seven variables,

two active treatments, and at least three time points at which data

could be analyzed (first week, second week, both weeks), the nominally

significant differences between treatments at the end of week one would

not be expected to retain statistical significance if an adjustment for

multiple comparisons were included in the analysis. Even considering

the retrospectively identified primary endpoint, a correction for three

``looks'' (week 1, week 2, and together) would at least double the

nominal p-value.

Even without correction for multiplicity, the results do not

support the conclusion that quinine sulfate and vitamin E, alone or in

combination, are effective for the treatment and/or prevention of

nocturnal leg muscle cramps. First, week 2 results fail to replicate

the results of week 1. No differences between any of the treatment

groups for any parameter were found at the end of week 2, nor was the

investigators' global assessment, conducted at the end of the 2-week

double-blind period, able to differentiate between treatments. Second,

a significant treatment by center interaction was found for the

reported superiority of quinine sulfate over placebo in week 1 in

reducing the number of nights per week with leg cramps. The result was

driven by two of nine centers. In one of these centers, the combination

product was indistinguishable from placebo, and in the other, the

superiority of placebo over the combination neared statistical

significance (p = 0.10). Thus, in the two clinics responsible for the

favorable week 1 results of treatment with quinine, there was a failure

to replicate the result reported with quinine sulfate alone. Vitamin E

was ineffective in all parameters measured throughout the study.

The four retrospectively-declared secondary endpoints for which

statistically significant reductions were reported in week 1 in the

quinine sulfate group compared to placebo were: (1) The number of

cramps per night, (2) the number of nights with sleeping difficulty,

(3) the severity of the cramps, and (4) the duration of the cramps.

Although a consistent benefit on these endpoints would render a finding

on the primary endpoint more persuasive, as with the primary efficacy

endpoint, none of the differences between active treatment and placebo

persisted through to the end of week 2. For the reasons discussed

above, the post hoc, week-1 analysis of these endpoints fails to

provide convincing evidence to support the efficacy of quinine sulfate

for the treatment and/or prevention of nocturnal leg muscle cramps.

Two additional analyses of the results of the study were submitted

(Refs. 8 and 9). The first (Ref. 8) was an analysis of the number of

leg cramps per day for each day of the study. This analysis showed

occasional days in which quinine was superior to placebo, but is on the

whole not helpful. Given an entry cramp rate of one cramp episode per

night for at least 3 nights per week, significant differences in any

endpoint would not be expected on a day-by-day (i.e., noncumulative)

evaluation.

The second analysis (Ref. 9) was of the total cramp rate (mean

number of cramps per day over the course of the entire study period)

for both the evaluable subset of subjects and the intent-to-treat

population. Two analyses were performed on each group. In one analysis,

only those subjects who completed the study with at least 14 days of

treatment (the completer analysis) were analyzed, while the other

analysis involved the results from all subjects with efficacy

observations (the endpoint analysis) for the quinine sulfate and

placebo treatment groups. In the endpoint analyses, where less than 14

days of treatment was completed, leg cramps for the observed number of

days were calculated, and the mean was carried forward to 14 days. None

of the four analyses revealed statistically significant reductions in

the mean number of leg cramps experienced during 14 days of treatment

in the quinine-treated subjects compared with placebo subjects. The

endpoint analysis for evaluable patients approached statistical

significance for quinine sulfate (p = 0.06), but the results of the

completer analysis for evaluable subjects and both intent-to-treat

analyses were clearly negative. The total cramp rate over the entire

study is the most straightforward effectiveness measure; it did not

show a drug effect on cramps. While the favorable trend on one analysis

could suggest activity, the study was already of very substantial size

and should have been able to detect a clinically meaningful response.

This study, therefore, does not provide evidence of efficacy of quinine

sulfate, vitamin E, or the combination thereof in the treatment and/or

prevention of nocturnal leg muscle cramps.

Based on the above discussion, the agency concludes that the

submitted data are inadequate to establish the effectiveness of quinine

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

cramps. Further, the agency concludes that the submitted data do not

adequately address the safety and effectiveness issues raised by the

agency in the tentative final monograph (see discussion above).

Additional agency comments and evaluations of the data are on file

in the Dockets Management Branch (Refs. 10, 11, and 12).

The Commissioner has determined that there are not reasonable

grounds in support of a hearing and that a hearing on this issue is not

warranted. Six clinical trials have been submitted and have failed to

establish the safety and efficacy of quinine sulfate in treating and/or

preventing nocturnal leg muscle cramps. Occasional significant

differences favoring quinine were not replicated within or between

studies. In two crossover design studies (Refs. 3 and 4), appropriate

analyses revealed no significant differences between quinine sulfate

and placebo. The results of a very large parallel-design, 2-week study

showed no significant effect in an analysis of the 2-week data.

In addition, deficiencies in the studies themselves render the

reported results unreliable. Each of these studies involved multiple

endpoints, none of which was prospectively declared as the primary

efficacy variable(s) in any of the studies. There was no attempt to

correct significance levels for multiple endpoints. The design of one

study did not permit the independent evaluation of the efficacy of

quinine sulfate alone (Ref. 1). In three crossover studies (Refs. 2, 3,

and 4), the treatment effect was confounded by potential carryover

effect and baseline differences. The 2-week, parallel-design study

(Ref. 6) showed no effect overall for the entire treatment period,

including the investigator's global assessment. Only by considering the

results of week 1 separately, an unplanned analysis, was any

significant difference between quinine and placebo found in this study,

and this finding was confounded by a significant treatment-by-center

interaction. For these reasons, the studies cannot be considered

adequate and well-controlled clinical investigations as required under

Sec. 330.10(a)(4)(ii). The Commissioner concludes that a hearing on

this issue is not justified for the reasons stated above.

References

(1) Biodesign GmbH, ``Clinical Evaluation of Q-VELR in Patients

with Nocturnal Leg Muscle Cramps,'' draft of an unpublished paper in

Comment No. SUP00031, Docket No. 77N-0094, Dockets Management

Branch.

(2) Leo Winter Associates, Inc., ``Final Medical Report and Data

Summary Analysis and Final Statistical Report on Double Blind

Randomized Crossover Study of Q-VELR Versus Quinine Sulfate Versus

Vitamin E Versus Placebo in the Treatment of Nocturnal Leg Muscle

Cramps (No. 1285-5082),'' draft of an unpublished paper in Comment

No. SUP00031, Docket No. 77N-0094, Dockets Management Branch.

(3) Hays, R., and J. J. Goodman, ``Clinical Trial of the

Efficacy of Quinine Sulfate in the Treatment of Nocturnal Leg Muscle

Cramps, Protocol 86-48,'' draft of an unpublished paper in Comment

No. C126, Docket No. 77N-0094, Dockets Management Branch.

(4) Bottner, M., ``Clinical Trial of the Efficacy of Quinine

Sulfate in the Treatment of Nocturnal Leg Muscle Cramps, Protocol

84-46,'' draft of an unpublished paper in Comment No. C123, Docket

No. 77N-0094, Dockets Management Branch.

(5) Jones, K., and C. M. Castleden, ``A Double-Blind Comparison

of Quinine Sulphate and Placebo in Muscle Cramps,'' Age and Ageing,

12(2):155-158, 1983.

(6) Draft of an unpublished study entitled ``A Short-Term,

Randomized, Double-Blind, Parallel Study of Q-Vel vs. Quinine

Sulfate vs. Vitamin E vs. Placebo in the Prevention and Treatment of

Nocturnal Leg Cramps,'' Comment No. SUP00033, Docket No. 77N-0094,

Dockets Management Branch.

(7) Patel, H., ``Use of Baseline Measurements in the Two-Period

Cross-Over Design,'' Communications in Statistics-Theory and

Methods, 12(23):2693-2712, 1983.

(8) Comment No. C159, Docket No. 77N-0094, Dockets Management

Branch.

(9) Comment No. SUP00041, Docket No. 77N-0094, Dockets

Management Branch.

(10) Letter from W. E. Gilbertson, FDA, to K. M. O'Brien,

Scholl, Inc., coded LET00059, Docket No. 77N-0094, Dockets

Management Branch.

(11) Letter from W. E. Gilbertson, FDA, to L. D. Fantasia, Ciba

Consumer Pharmaceuticals, coded LET00060, Docket No. 77N-0094,

Dockets Management Branch.

(12) Memorandum of telephone conversation between L. Fantasia,

Ciba Consumer Pharmaceuticals, and L. Geismar, FDA, January 4, 1989,

coded MT0009, Docket No. 77N-0094, Dockets Management Branch.

13. One comment disagreed with the agency's Category III

classification of vitamin E for the treatment and/or prevention of

nocturnal leg muscle cramps on the basis of a lack of adequate clinical

data demonstrating the effectiveness of vitamin E for this indication

(50 FR 46588 at 46591). The comment contended that there is sufficient

evidence of vitamin E's effectiveness for this indication at present to

warrant classifying it in Category I. The comment subsequently

submitted the results of two clinical studies (Refs. 1 and 2) comparing

vitamin E, quinine sulfate, a combination product containing vitamin E

and quinine sulfate, and placebo for the treatment and/or prevention of

nocturnal leg muscle cramps to support the effectiveness of the

individual ingredients (vitamin E and quinine sulfate) as well as the

combination of these ingredients for this indication. In addition, in

responding to a citizen petition, one comment included a clinical study

comparing vitamin E, quinine sulfate, a combination product containing

both ingredients, and placebo (Ref. 3).

In the tentative final monograph, the agency concluded that there

was a lack of controlled studies demonstrating the effectiveness of

vitamin E in the treatment and/or prevention of nocturnal leg muscle

cramps. The agency also determined that a safe and effective OTC dosage

of vitamin E had not been established (50 FR 46588 at 46591).

Therefore, the agency classified vitamin E in Category III for this

use.

The agency has reviewed the additional clinical data that have been

submitted and determined that they are not adequate to support the

reclassification of vitamin E to Category I for this use. In one

double-blind, randomized, crossover study (Ref. 1), a combination

product containing 64.8 mg quinine sulfate and 400 I.U. of vitamin E in

a lecithin base was compared to 64.8 mg of quinine sulfate for the

treatment and/or prevention of nocturnal leg muscle cramps in subjects

with a history of nocturnal leg muscle cramps. Subjects were randomized

into two groups. All subjects took placebo during week 1 and at the end

of week 1 only those subjects reporting at least three cramps per week

were allowed to continue in the study. One group received the

combination product during week 2 and quinine sulfate during week 4,

while for the other group this order was reversed. Both groups also

received placebo during weeks 3 and 5.

Both quinine sulfate and the combination of quinine sulfate and

vitamin E were reported to reduce the frequency of nocturnal leg muscle

cramps in this study. A greater reduction in the frequency of these leg

cramps was observed in subjects taking the combination product compared

to subjects taking quinine alone. The difference was reported to be

statistically significant using Wilcoxon's signed-rank test. No

significant differences were found between treatments for either

duration or severity of attacks. However, as previously discussed (see

section I.C., comment 12), the study report did not include the study

protocol, details of the statistical analysis, or individual subject

data, and the analysis described does not properly separate carryover

effect from treatment effect. Therefore, it is not possible to conclude

that either treatment used in this study was effective for this

indication.

The second clinical study (Ref. 2) was a double-blind, randomized,

crossover study conducted at two sites and involved subjects with at

least a 3-month history of at least two significant nocturnal leg

muscle cramps per week. The subjects did not receive any drug for the

first 1-week run-in period, then received four treatment periods (5

days each) that were separated by a 2-day washout period that included

a 2-day drug-free period after the last treatment period. Thus, each

subject received each of the four treatments (quinine sulfate 64.8 mg

in combination with 400 I.U. vitamin E, 64.8 mg quinine sulfate, 400

I.U. vitamin E, and placebo). A total of 205 subjects (out of 209

subjects originally enrolled) completed the study at the two locations.

Each morning upon arising, subjects recorded on a daily evaluation

form their response to questions regarding their difficulty or failure

to get to sleep due to night leg cramps and whether or not the cramps

had awakened them the previous night. Subjects were also asked to rate

on a scale from 0 (no cramps) to 3 (very difficult) the effect of leg

cramps on their ability to fall asleep and to record the number, time

of occurrence, duration, and severity of leg cramps on the evaluation

form. At the end of each weekly treatment period, subjects were asked

to complete a global evaluation form and to record any change in their

condition during that period, as follows: Greatly improved, slightly

improved, no improvement, or worse. Subjects who selected ``worse''

were asked to explain why.

The comment's statistical analysis of the study evaluated the

following variables based on portions of the subjects' daily evaluation

forms and their global evaluation of treatment effect: (1) Number of

nights per week subjects had difficulty getting to sleep due to night

leg cramps, (2) effect of leg cramps on subject's ability to get to

sleep, (3) number of nights per week that leg cramps prevented subjects

from going to sleep, (4) number of nights per week that leg cramps woke

subjects up, (5) number of leg cramps per week, (6) severity of the leg

cramps, and (7) subjects' global evaluations of how their condition

changed over the previous week. In addition, the following parameters

were derived from these variables and evaluated: (1) Number of nights

per week with leg cramps, (2) mean number of leg cramps per night, (3)

total severity score during each week, (4) mean effect of leg cramps on

sleep per week, and (5) mean severity per cramp. Separate analyses of

the results from each site and analysis of pooled results from both

study cites were reported. Vitamin E was found to be statistically

significantly superior to placebo in 7 of the 12 efficacy variables

evaluated on the basis of the combined data and in 6 of the 12

variables on the basis of data from at least one of the locations. The

combination was found to be statistically superior to the individual

ingredients and placebo on 11 out of the 12 variables evaluated on the

basis of both the combined data and data from at least one of the

locations. On that same basis, quinine sulfate was found to be

statistically superior to placebo in 9 of the 12 variables evaluated

and to vitamin E in 1 of the 12 variables. The comment concluded that

quinine and vitamin E were significantly additive in their effects, and

that it was this additive effect that resulted in the highly

significant superiority of the combination over its individual

components.

The agency has determined that the statistical analysis presented

with this study is inadequate for review because the model used does

not properly separate the carryover effect from the treatment effect.

The model consisted of a sequence or code effect, a subject within code

effect, a visit effect, and a treatment effect. For a given subject,

this model says that code effect is constant over all visits; thus,

carryover effect must be partially confounded with treatment effect.

Therefore, the analysis presented cannot be relied upon to demonstrate

the efficacy of any of the treatments.

The third clinical study was a multicenter, randomized, block,

parallel-design with a single-blind, placebo, run-in period, followed

by a 2-week double-blind, randomized, treatment phase (see section

I.C., comment 12). No statistically significant treatment effect of

vitamin E was detected at the end of the double-blind phase for any

variable in this study.

The agency concludes that the submitted data are inadequate to

establish the effectiveness of vitamin E or the combination of vitamin

E and quinine sulfate for the treatment and/or prevention of nocturnal

leg muscle cramps. Therefore, both vitamin E individually and in

combination with quinine sulfate are nonmonograph conditions.

The agency's detailed comments and evaluation of the data are on

file in the Dockets Management Branch (Refs. 4 and 5).

References

(1) Biodesign GmbH, ``Clinical Evaluation of Q-VELR in Patients

with Nocturnal Leg Muscle Cramps,'' draft of an unpublished paper in

Comment No. SUP00031, Docket No. 77N-0094, Dockets Management

Branch.

(2) Leo Winter Associates, Inc., ``Final Medical Report and Data

Summary Analysis and Final Statistical Report on Double Blind

Randomized Crossover Study of Q-VELR Versus Quinine Sulfate Versus

Vitamine E Versus Placebo in the Treatment of Nocturnal Leg Muscle

Cramps (No. 1285-5082),'' draft of an unpublished paper in Comment

No. SUP00031, Docket No. 77N-0094, Dockets Management Branch.

(3) Draft of an unpublished study entitled ``A Short-Term,

Randomized, Double-Blind, Parallel Study of Q-Vel vs. Quinine

Sulfate vs. Vitamin E vs. Placebo in the Prevention and Treatment of

Nocturnal Leg Cramps,'' Comment No. SUP00033, Docket No. 77N-0094,

Dockets Management Branch.

(4) Letter from W. E. Gilbertson, FDA, to L. D. Fantasia, Ciba

Consumer Pharmaceuticals, coded LET00060, Docket No. 77N-0094,

Dockets Management Branch.

(5) Memorandum of telephone conversation between L. Fantasia,

Ciba Consumer Pharmaceuticals, and L. Geismar, FDA, January 4, 1989,

coded MT00009, Docket No. 77N-0094, Dockets Management Branch.

D. Comments on Labeling

14. Several comments requested revisions in parts of the labeling

proposed in the tentative final monograph. Two comments disagreed with

the agency's statement of identity. One comment argued that it was a

restatement of the indication proposed in Sec. 343.150(b). In place of

the agency's proposed statement of identity (``nocturnal leg muscle

cramps treatment and/or prevention''), one comment requested that

``muscle relaxant pain reliever'' or ``analgesic'' be used. The comment

contended that its suggestions were more descriptive of general

pharmacological categories as described in 21 CFR 201.61. Another

comment suggested changing the statement to ``night leg cramp relief,''

arguing that this statement would be more ``meaningful to the layman''

in accord with 21 CFR 201.61. The comment added that its suggested term

is currently used in the labeling of a major OTC quinine product and

reflects a more contemporary description of the condition being

treated.

Referring to the warning proposed in Sec. 343.150(c) that reads

``Discontinue use if ringing in the ears, deafness, skin rash, or

visual disturbances occur,'' one comment requested that the words ``and

consult a physician'' be added following ``discontinue use.'' The

comment believed that such a warning would facilitate further medical

treatment, if deemed necessary. The comment added that the agency had

proposed similar warnings in other OTC drug monographs, for example,

proposed Sec. 333.50(c)(2) and (c)(3) for topical acne drug products

(January 15, 1985, 50 FR 2172 at 2181). The comment explained that this

addition to the warning would better serve the elderly, the population

most likely to use the product.

One comment recommended that the agency distinguish between

treatment and prevention directions for the drug, and proposed the

following: ``When night leg cramps occur, take 200-325 mg at once. To

help prevent further night leg cramps, take 200-325 mg two hours before

bedtime for 14 days. Do not exceed more than 325 mg daily.'' The

comment concluded that, in providing adequate directions for use, it is

appropriate to discuss dosages for initial onset of leg muscle cramps

and for prevention of future cramps.

No ingredients for treating and/or preventing nocturnal leg muscle

cramps are currently generally recognized as safe and effective for

inclusion in an OTC drug monograph; thus, no OTC labeling is being

finalized at this time. Accordingly, the comments' requests are not

being addressed in this document. However, in the event that any

ingredient for treating and/or preventing nocturnal leg muscle cramps

reaches OTC drug monograph status, the agency will determine

appropriate labeling at that time and publish it in a future issue of

the Federal Register.

II. The Agency's Final Conclusions on OTC Drug Products For The

Treatment and/or Prevention of Nocturnal Leg Muscle Cramps

The agency concludes that the data and information submitted are

inadequate to establish the safety and effectiveness of quinine

sulfate, vitamin E, or the combination of quinine sulfate and vitamin E

for the treatment and/or prevention of nocturnal leg muscle cramps.

Three clinical studies of vitamin E, alone or in combination with

quinine sulfate, were submitted. The report of one of the studies

provided no details of the statistical analysis conducted; the model

described in the summary of the analysis failed to separate carryover

effect from treatment effect; and neither the protocol nor the

individual subject data were provided. Independent verification of the

conclusions presented, therefore, was not possible. On the basis of the

information provided in the report, no conclusions about the efficacy

of vitamin E are possible from this study. In another study, a

statistically significant effect of vitamin E was reported in 7 of 12

endpoints, and statistically significant differences from placebo were

reported in 11 of 12 endpoints for the combination product. In this

study, however, treatment effect was confounded by carryover effect

making it impossible to ascribe observed differences to vitamin E.

Further, the third study, a large, multicenter, 2-week, parallel-design

study comparing vitamin E, quinine sulfate, a combination of vitamin E

and quinine sulfate, and placebo showed no significant difference for

vitamin E compared to placebo on any parameter at the end of the

double-blind treatment period.

Six clinical trials were submitted to establish the safety and

efficacy of quinine sulfate in treating and/or preventing nocturnal leg

muscle cramps. Effectiveness results reported as significant were not

replicated within or between studies. In two crossover studies,

significant differences between quinine sulfate and placebo were seen

only in the second leg of the crossover, and there were significant

pretreatment differences. Analysis of the first leg of these crossover

studies showed no effect of quinine. In a large, 2-week, parallel study

of quinine sulfate, vitamin E, and the combination of these ingredients

versus placebo, no statistically significant differences were found

between active treatments and placebo for the full 2 weeks of the

study. Furthermore, each study involved multiple endpoints, none of

which was prospectively declared as the primary efficacy variable(s) in

any study. Statistical analysis was conducted without regard to

adjustment for multiple comparisons, casting doubt on the validity of

claimed statistical significance in many cases. In three crossover

studies, the treatment effect was confounded by potential carryover

effect making it impossible to attribute the results to the study

drugs. The agency concludes that the data and information submitted do

not provide substantial evidence of effectiveness of quinine sulfate,

vitamin E, or a combination of quinine sulfate and vitamin E, in the

treatment and/or prevention of nocturnal leg muscle cramps.

Finally, new information has raised serious safety concerns over

the OTC availability of quinine sulfate for this use. Adverse events

characteristic of quinine toxicity were observed in the healthy

populations enrolled in the clinical efficacy studies at doses of 260

mg 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 even lower doses. Altered pharmacokinetics with age

results in a longer half-life of quinine in older people that suggests

the frequency and severity of adverse effects may be greater in the

elderly.

In addition to these adverse effects, serious and unpredictable

hypersensitivity reactions to quinine occur. Symptoms are often

dramatic, leading people to seek medical treatment. Hospitalization may

be required, and fatalities have been reported. While quinine-induced

thrombocytopenia is the hypersensitivity reaction most frequently

reported to the agency's spontaneous reporting system, estimates of the

incidence of quinine-induced thrombocytopenia are unreliable. Estimates

based on the most direct evidence, however, suggest occurrence rates

between 1:1,000 and 1:3,500. Quinine is the only drug available OTC

that has such a high association with this 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.

Given the benign nature of nocturnal leg muscle cramps, the failure

of the clinical studies to demonstrate efficacy of quinine sulfate in

this condition, the evidence of symptoms 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, the agency concludes that

quinine is not safe for OTC use in the treatment and/or prevention of

nocturnal leg muscle cramps.

No comments were received in response to the agency's request for

specific comment on the economic impact of this rulemaking (47 FR 43562

and 50 FR 46588 at 46593).

An analysis of the cost and benefits of this regulatuion, conducted

under Executive Order 12291, was discussed in the tentative final rule

of November 8, 1985, (50 FR 46588). No comments were received in

response to the agencies tentative final rule, and the substances of

that analysis has not changed. Executive Order 12291 has been

superseded by Executive Order 12866. FDA has examined the impacts of

the final 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 final

rule is consistent with the regulatory philosophy and principles

identified in the Executive Order. In addition, the final rule is not a

significant regulatory action as defined by the Executive Order and,

thus, 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. Although the final rule will result in the removal

of some products from the OTC marketplace, only a limited number of

products are affected. These include: (1) All combination products

containing quinine sulfate and vitamin E, (2) products containing

quinine sulfate alone labeled for the treatment and/or prevention of

nocturnal leg muscle cramps, (3) products containing vitamin E alone

labeled with the same claim, and (4) any other products marketed OTC

for this claim. No further initial introduction or delivery for

introduction into interstate commerce of any OTC drug product labeled

for the treatment and/or prevention of nocturnal leg muscle cramps will

be allowed after the effective date of this final rule. Quinine is

currently available as an OTC drug for treating chills and fever of

malaria. Based on an agency review of currently marketed products, it

appears 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). (OTC quinine drug products for antimalarial use will be

discussed in future issues of the Federal Register.) Vitamin E is

currently available OTC for use as a vitamin. This final rule does not

affect the continued marketing and availability of products containing

this vitamin provided the products are not labeled for the treatment

and/or prevention of nocturnal leg muscle cramps. Products containing

quinine sulfate and/or vitamin E may be relabeled and reformulated

where necessary (e.g., combination products) and remain in the

marketplace with other allowed claims, as described above. Accordingly,

the agency certifies that the final 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 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.

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: 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. 310.546 is added to subpart E to read as follows:

Sec. 310.546 Drug products containing active ingredients offered over-

the-counter (OTC) for the treatment and/or prevention of nocturnal leg

muscle cramps.

(a) Quinine sulfate alone or in combination with vitamin E has been

present in over-the-counter (OTC) drug products for the treatment and/

or prevention of nocturnal leg muscle cramps, i.e., a condition of

localized pain in the lower extremities usually occurring in middle

life and beyond with no regular pattern concerning time or severity.

There is a lack of adequate data to establish general recognition of

the safety and effectiveness of quinine sulfate, vitamin E, or any

other ingredients for OTC use in the treatment and/or prevention of

nocturnal leg muscle cramps. In the doses used to treat or prevent this

condition, quinine sulfate has caused adverse events such as transient

visual and auditory disturbances, dizziness, fever, nausea, vomiting,

and diarrhea. Quinine sulfate may cause unpredictable serious and life-

threatening hypersensitivity reactions requiring medical intervention

and hospitalization; fatalities have been reported. The risk associated

with use of quinine sulfate, in the absence of evidence of its

effectiveness, outweighs any potential benefit in treating and/or

preventing this benign, self-limiting condition. Based upon the adverse

benefit-to-risk ratio, any drug product containing quinine or quinine

sulfate cannot be considered generally recognized as safe for the

treatment and/or prevention of nocturnal leg muscle cramps.

(b) Any OTC drug product that is labeled, represented, or promoted

for the treatment and/or prevention of nocturnal leg muscle cramps is

regarded as a new drug within the meaning of section 201(p) of the

Federal Food, Drug, and Cosmetic Act (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 nocturnal leg muscle cramps 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 February 22, 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: August 4, 1994.

Michael R. Taylor,

Deputy Commissioner for Policy.

[FR Doc. 94-20449 Filed 8-19-94; 8:45 am]

BILLING CODE 4160-01-F