The US FDA's new warning against the use of quinine sulfate to treat nighttime leg cramps does not sit well with all neurologists.
“Quinine has been used for benign nocturnal muscle cramps for at least a century and is most important for severe cramps that occur with serious neuromuscular disease,” said William M. Landau, MD, a neurologist and researcher at Washington University School of Medicine. “To my knowledge, no other first-world country… has any restriction on the prescription use of quinine.”
At issue is the FDA's July 8 announcement that URL Pharma, the manufacturer of Qualaquin (quinine sulfate), had changed the labeling for the product. A risk management plan for quinine sulfate has been in place since the drug was approved in 2005.
The new plan, developed in conjunction with the FDA, required URL Pharma to issue a “Dear Healthcare Provider” letter warning of the “potential risk of serious and life-threatening blood-related (hematologic) reactions.”
“Due to new safety information that recently came to URL Pharma's attention, the company proactively strengthened the labeling and proposed a stronger risk management plan. The details of the plan were worked out cooperatively between URL Pharma and the FDA,” FDA spokesman Ovidio Torres said in an e-mail to Neurology Today.
Between April 2005 and Oct. 1, 2008, the FDA received reports on 38 US cases of serious side effects associated with the use of quinine, the active drug in Qualaquin. Of those, 24 patients took quinine to prevent or treat leg cramps or restless leg syndrome, the FDA said. Only one patient was taking quinine for the treatment of malaria, its only FDA-approved use.
According to the agency, quinine use resulted in serious and life-threatening reactions in 24 cases. These included a low level of platelets in the blood (thrombocytopenia) and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, a blood disorder that can be associated with kidney damage.
URL Pharma, a subsidiary of AR Scientific, asked the AAN to publicize the drug warning, but the company declined an interview request for this article. A copy of the “Dear Healthcare Provider” letter and Qualaquin Medication Guide are posted on AAN.com.
HISTORY: FDA POSITION
The FDA first issued a warning against off-label use of the drug in 2006, citing earlier post-marketing surveillance reports of serious adverse events.
Despite that, some neurologists have been unconvinced that the risks of quinine outweigh their benefit.
“I believe many physicians continue to prescribe quinine for muscle cramps despite the earlier FDA warning,” said Yuen T. So, MD, PhD, professor of neurology and neurological sciences, and director of neurology clinics at Stanford University School of Medicine in Stanford, CA. “That probably prompted the FDA to renew its warning against off-label use of quinine for anything other than malaria.”
Dr. Landau is among those who consider quinine an appropriate choice for leg cramps. Indeed, his own physician prescribed the product for his own benign nocturnal cramps four years ago and Dr. Landau has benefited from the treatment and experienced no complications.
“He now submits my prescription to an ethical pharmacist in Montreal,” Dr. Landau said. “I advise the use of the same pharmacist for my own patients for whom I prescribe quinine for cramps.”
Dr. Landau said the FDA has not provided enough information to justify its warning against the use of quinine to treat muscle cramps. For one thing, he wants to know the estimated number of patients for whom quinine is prescribed at the small dosage appropriate for leg cramps — 200 to 300 mg per night —so the risk of serious side effects can be accurately calculated for that population.
For another, he thinks the FDA should release details about every case of serious side effects associated with the use of quinine.
“The key issue is the nature of the individual complaints to the FDA,” he said. “Is the alleged toxicity true cause or coincidence?”
Beyond that, Dr. Landau questions the FDA's position in light of the low rate of serious problems reported in conjunction with quinine use. In issuing its earlier warning about the drug, the FDA said it received an average of 18 complaints of serious side effects, including an average of 2.5 deaths, per year between 1969 and 2006. Its most recent warning cited 38 complaints between 2005 and 2008, including two deaths during that period.
“If one accepts quinine deaths at two per year, the risk is 30 times higher for an individual to be killed by lightning,” Dr. Landau said.
HOW TO WEIGH RISK VERSUS BENEFITS
Dr. So agrees that the risk-benefit calculation is difficult.
“My impression is that serious side effects from quinine are very uncommon,” he said, citing the FDA's report of 38 cases of serious side effects over three and a half years. “Even allowing for underreporting, the incidence must be quite low. This is in line with anecdotes from many neuromuscular experts who have seen few or no serious side effects with the drug.”
That said, Dr. So does not advocate for the use of quinine for the routine use of treating muscle cramps.
He recently served on the AAN Therapeutics and Technology Assessment Subcommittee that reviewed all relevant articles about the pharmaceutical or therapeutic options for patients with muscle cramps published between 1950 and 2008. The panel's findings were published in the Feb. 23 issue of Neurology and Dr. So discussed the review in the March 4 edition of Neurology Today.
The review was prompted by the continuing off-label use of quinine to treat cramps following the FDA's 2006 warning. Based on the articles it reviewed, the AAN panel calculated a serious adverse event rate of between 2 percent and 4 percent; no deaths were reported in any of the studies it reviewed.
The panel found that while quinine and its derivatives are likely effective for muscle cramps, the benefits are modest and the risks can be severe. Dr. So said they should be avoided for routine use, although they may be appropriate for patients without hematologic risk factors who suffer disabling cramps, but only if potential side effects are considered and monitored.
“Until we learn how to minimize the risk in individual patients, I believe it is appropriate to be conservative,” he said. “Besides, it is difficult to go against the FDA. They have the data.”
ARTICLE IN BRIEF
Some neurologists are not convinced that the risks of prescribing quinine for nighttime cramps, as highlighted by the FDA, outweigh their benefit.