[Federal Register Volume 59, Number 161 (Monday, August 22, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-20449]


[[Page Unknown]]

[Federal Register: August 22, 1994]


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Part IV





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Part 310




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

Food and Drug Administration

21 CFR part 310

[Docket No. 77N-0094]
RIN 0905-AA06

 
Drug Products for the Treatment and/or Prevention of Nocturnal 
Leg Muscle Cramps for Over-The-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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