Beginning in 2006, the US Food and Drug Administration (FDA) issued a series of warnings not to prescribe the malaria drug quinine (Qualaquin™) for nocturnal leg cramps -- an off-label use -- because it may result in serious and life-threatening hematologic adverse effects. In 2010, the FDA reiterated its warning and issued a Risk Evaluation and Mitigation Strategy (REMS), which has resulted in a marked decrease in off-label use. However, data as recent as 2011 indicate that the majority of quinine use in this country continues to be related to leg cramps and muscle pain, and serious adverse events continue to be reported. Medscape spoke with Hala H. Shamsuddin, MD, about the FDA's ongoing educational efforts on this issue.
Medscape: What is the regulatory history of quinine? What are the approved indications for quinine, and what are its common off-label uses?
Dr. Shamsuddin: Quinine was approved by the FDA for the treatment of uncomplicated Plasmodium falciparum malaria in August 2005. Before that date, quinine was marketed in the United States as an unapproved product. On December 12, 2006, the FDA ordered unapproved quinine drug products to be removed from the market and cautioned consumers about the off-label use of quinine to treat leg cramps.
The approved indication is for the treatment of uncomplicated malaria caused by P falciparum. However, a common off-label use is for the treatment of leg cramps. As reported from office-based physician practices in the United States, approximately 92% of quinine use is associated with the off-label indication relating to the treatment of leg cramps and muscle pain.
Medscape: What are some of the safety concerns with quinine?
Dr. Shamsuddin: Quinine is derived from cinchona bark. Cinchonism is the most common adverse event associated with quinine use; symptoms of cinchonism may include nausea, headaches, flushing, and tinnitus. However, serious adverse reactions have also been associated with the use of this product, and these are included in the Warnings and Precautions section of the product labeling. These mainly include hematologic events, primarily thrombocytopenia, but also ventricular arrhythmias, hypersensitivity reactions, and optic neuritis.
A review of the FDA's adverse event reporting system (AERS) database identified 38 domestic cases of serious adverse reactions that were reported to the agency between April 1, 2005, and October 1, 2008. In only 1 of the 38 cases, quinine was used for the treatment of malaria; in the remaining cases, it was used for the treatment of leg cramps and other muscle cramps or the treatment of restless leg syndrome or neuropathy. Of these 38 cases, 5 were fatal. One was secondary to hemolysis. One was secondary to thrombotic thrombocytopenic purpura (TTP), and one was secondary to a cardiac event. We did not have further information on the other 2 deaths.
Of the 38 cases of serious adverse reactions, 17 required hospitalization and 11 were considered life-threatening. In 22 of these 38 cases, the adverse reactions were hematologic, with thrombocytopenia accounting for 19 of these cases. In these 19 cases, the median platelet count was 4500 x 106/L (normal range, 150,000-400,000 x 106/L). Of the 3 cases of TTP, 1 resulted in death and 1 resulted in chronic renal impairment requiring maintenance hemodialysis. We do not know the outcome of the third case.
As a follow-up to this 2008 review, the FDA continues to receive reports of thrombocytopenia, renal failure, TTP, and hypersensitivity linked to quinine. In addition to these data reported to AERS, there are several reports in the literature of quinine-induced thrombocytopenia and TTP in the context of treatment of leg cramps.
Medscape: Are the continued reports of adverse events still predominantly associated with off-label use of quinine?
Dr. Shamsuddin: Correct. As I noted, a Physician Drug and Diagnosis Audit between 2008 and 2011 indicated that approximately 92% of quinine use in the United States is for the off-label treatment of leg cramps and muscle pain. The data were collected by Encuity Research and were extracted by the FDA in July 2012.
Medscape: In 2010, the Therapeutics and Technology subcommittee of the American Academy of Neurology conducted an evidence-based review of the literature examining use of quinine for the off-label management of leg cramps. Can you summarize the results?
Dr. Shamsuddin: The authors of that review noted that the benefit resulting from use of quinine was small and there are serious adverse events associated with the use of the drug. Their conclusion was the use of this drug to treat muscle cramps should be avoided.
Medscape: Are the risk/benefit considerations different between approved and off-label use?
Dr. Shamsuddin: When we assess risk/benefit, we have to consider the seriousness of the disease or condition being treated, the duration of drug exposure, and the seriousness of the adverse events. Untreated P falciparum malaria is potentially fatal, and the duration of treatment with quinine is generally limited to 7 days. The risk/benefit assessment of quinine for the treatment of P falciparum malaria is favorable.
In contrast, given the lack of substantial evidence of efficacy and the considerably longer duration of treatment for leg cramps, the risk/benefit assessment for this off-label use of quinine is not favorable. This is reflected in the product labeling for quinine. There is a Boxed Warning, which states that the risk associated with quinine use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit. This is further clarified in the Indications and Usage section and in the Warnings and Precautions section of the labeling.
Medscape: Can you describe the FDA's risk management actions with regard to safety concerns?
Dr. Shamsuddin: Because the majority of quinine use is off-label, the FDA has implemented risk management plans to inform prescribers and users of the potential serious risks associated with quinine use. As a condition for approval in 2005, the FDA required the sponsor to establish an educational program for healthcare providers regarding the safe and effective use of quinine, and to issue a "Dear Healthcare Provider" letter that describes the favorable risk/benefit assessment of quinine for the treatment of P. falciparum malaria in contrast with the unfavorable risk/benefit assessment for the treatment of leg cramps. In addition, the FDA required the sponsor to develop a Website and to continue postmarketing surveys for adverse events.
In 2010, the labeling was updated to include a Boxed Warning and a Risk Evaluation and Mitigation Strategy (REMS) was approved. This REMS included a Medication Guide, which was to be dispensed with every quinine prescription, describing the potential serious adverse events to the user, and a communication plan to prescribers and to professional medical societies, informing them about the risk for serious and life-threatening adverse events and the appropriate use of quinine.
As per this communication plan, the last "Dear Healthcare Provider" letter was disseminated in August 2012. However, the Medication Guide will continue to be distributed to patients in accordance with the 21 Code of Federal Regulations (CFR) 208.24. A drug safety communication is available at the FDA Website, and the FDA issued a news alert in August 2012.
Despite all of these efforts, the outpatient pharmacy drug use data indicate that off-label use of quinine continues to be a concern, although its use has substantially declined over the past 4 years, from approximately 206,000 patients receiving a dispensed prescription for quinine in 2008 to an estimated 51,800 in 2011. The lack of awareness among prescribers regarding the approved indications for quinine and the adverse events associated with its use for the treatment or prevention of leg cramps continues to be concerning. The FDA will continue to monitor quinine use and the adverse events reported, and continue to reassess the need for any additional risk management strategies.
Medscape: Any concluding comments for our members?
Dr. Shamsuddin: The overall message is that with the use of a drug for the treatment of any condition, prescribers have to assess the risk and benefits of that drug. At this time, we don't think that the risk/benefit assessment for quinine in the treatment of leg cramps is favorable. Prescribers and users should be aware that there are serious adverse events associated with its use.
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Cite this: Quinine and Leg Cramps: Not Worth the Risk - Medscape - Oct 08, 2012.