December 20, 2006
Quinine (Qualaquin®) and Leg Cramps
THE ISSUE anticoagulation. Cimetidine may reduce the clearance of
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Recently Qualaquin was approved by the FDA for the quinine, increasing the risk of adverse effects. Digoxin
treatment of malaria. The marketing of other formulations concentrations are increased during concurrent use of
has been banned. This event and the turbulent history of quinine. Quinine also interacts with mefloquine, rifabutin,
quinine prompt the question of whether quinine should be rifampin and neuromuscular blocking agents. Other agents,
used for prevention of benign nocturnal leg cramps. both over-the-counter and prescription, have been used in
the treatment of leg cramps including diphenhydramine,
BACKGROUND verapamil, nifedipine, phenytoin, carbamazepine,
In 1994, the FDA withdrew quinine from the over-the-counter procainamide, calcium and magnesium. However, there is
market in response to reports of health problems related to no conclusive clinical evidence to support the use of any of
quinine use. In 1995, the FDA removed labeling for leg 6
these products. Vitamin E has been found to have no
cramps from prescription products. Reasons cited include 7
benefit. Calf stretching exercises have been shown to be
lack of efficacy, major health risks outweighing small potential ineffective; however, when patients taking quinine were
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benefits and the benign nature of leg cramps. Since 1969, encourage to discontinue the drug and use stretching
the FDA has received 665 reports of quinine-related health 8
exercises, no worsening of symptoms was noted. Benign
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problems including 93 that resulted in death. In August of leg cramps should be differentiated from peripheral
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2005, the FDA approved Qualaquin , the Mutual neuropathy, restless legs syndrome, claudication and hypnic
Pharmaceutical Company formulation of quinine sulfate and jerks which have safe and effective treatments available.
has ordered the discontinuation of all unapproved
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formulations in December of 2006. Quinine was the only WHAT THE PATIENT SHOULD KNOW
treatment for leg cramps that has been shown to be Quinine may cause nausea and vomiting, diarrhea, stomach
efficacious; however, its adverse effects can be severe. cramps or pain, and ringing in the ears. Quinine may also
cause blurred vision, vertigo, restlessness, or confusion.
WHAT YOU NEED TO KNOW While taking quinine, caution should be exercised while
Quinine is approved for the treatment of malaria. However, it driving or performing activities requiring alertness. Taking
has been used for many years for the treatment of benign leg quinine with food or after a meal may help with stomach
cramps. A meta-analysis of four published and three upset. Quinine should not be taken in pregnancy, as it has
unpublished randomized, double-blind, placebo-controlled been shown to cause fetal harm. The drug should be
cross-over trials demonstrated that quinine provided a stopped if allergy symptoms are noted (such as rash, fever,
significant reduction in the number of leg cramps experienced flushing, or difficulty breathing) and the prescriber should be
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over a four-week period. The analysis found an absolute contacted. Ringing in the ears or vision problems should also
reduction in the number of leg cramps over the four week trial ®
be reported. Patients should be told that Qualaquin is the
period of 3.6 (95% CI 2.15-5.05) and a relative risk reduction only form of quinine currently available and may be more
of 0.21 (95% CI 0.12-0.3). Another randomized, double-blind, expensive than what they have purchased in the past. Calf
placebo-controlled, parallel group study showed no significant stretching exercises or heating pads applied before bed are
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difference in efficacy between quinine and placebo. The safe and may be helpful in preventing leg cramps in place of
equivocal nature of the evidence in the treatment of a benign quinine.
condition has prompted the FDA to declare it unsafe for use
in the prevention of leg cramps. Quinine is associated with a CONCLUSION
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cluster of symptoms known as cinchonism, manifested as Qualaquin is the only FDA-approved quinine product.
flushing, dizziness, tinnitus, nausea, vomiting and diarrhea. Substitution is inappropriate, as all other firms marketing
These symptoms may range from mild to severe. Most quinine have been ordered to discontinue production. In light
concerning is the risk of thrombocytopenia which may appear of increased cost and the risk of adverse events, patients
at any time during treatment independent of the dose used. should be encourage to try safer non-pharmacological
Quinine is second only to quinidine in incidence of induced prevention such as stretching exercises and heating pads
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thrombocytopenia. In addition, quinine may cause hemolytic before bed. Careful monitoring for adverse reactions should
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anemia in people with a G-6-PD deficiency, agranulocytosis, be performed for patients using quinine. Qualaquin is
and hypoprothrombinemia. Quinine is designated category X available as 324 mg tablets with an AWP of $131.25 for 30
for use in pregnancy and lactation. Drug interactions to be tablets.
aware of include warfarin, which results in enhanced
The information provided was developed by the Center for Drug Policy at the
University of Wisconsin Hospitals and Clinics and published by the Pharmacy Society of Wisconsin.
REFERENCES
1. FDA Updates. Available at: http://www.fda.gov/fdac/departs/695_updates.html. Accessed Dec 13, 2006
2. FDA Orders Unapproved Quinine Drugs from the Market and Cautions Consumers About “Off-Label” Use of Quinine to Treat
Leg Cramps. Available at: http://www.fda.gov/bbs/topics/NEWS/2006/NEW01521.html. Accessed 12/13/2006
3. Man-Son-Hing M, Wells G, Lau A. Quinine for nocturnal leg cramps: a meta-analysis including unpublished data. Journal of
General Internal Medicine 1998;13:600-606
4. Dierner HC, Dethlefsen U, Dethlefsen-Gruber S, Verbeek P. Effectiveness of quinine in treating muscle cramps: a double-blind,
placebo-controlled, parallel-group, multicentre trial. International Journal of Clinical Practice 2002;56:243-246
5. Brinker AD, Belitz J. Spontaneous reports of thrombocytopenia in association with quinine: clinical attributes and timing related to
regulatory action. American Journal of Hematology 2002;70:313-317.
6. eFacts: Quinine. Available at http://online.factsandcomparisons.com. Accessed Nov 28, 2006 (Subscription required)
7. Connolly PS, Shirley EA, Wasson JH, Nierenberg DW. Treatment of nocturnal leg cramps: a crossover trial of quinine vs. vitamin
E. Archives of Internal Medicine. 1992;152(9):1877-80
8. Coppin RJ, Wicke DM, Little PS. Managing nocturnal leg cramps—calf-stretching exercises and cessation of quinine treatment: a
factorial randomized controlled trial. British Journal of General Practice 2005;55:186-191.
DISCLAIMER
This publication is intended to provide key practical information regarding this drug product in a brief format. It does not contain
sufficient information upon which to base formulary or other medication use policy decisions.
The information provided was developed by the Center for Drug Policy at the
University of Wisconsin Hospitals and Clinics and published by the Pharmacy Society of Wisconsin.