[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
_______________________________________________________________________
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