Questions and Answers about FDA's Enforcement Action Against Unapproved Quinine Products

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Questions and Answers about FDA’s Enforcement Action
Against Unapproved Quinine Products

What action is FDA taking concerning quinine-containing drugs?

FDA has ordered all firms to cease manufacturing unapproved products containing
quinine, including quinine sulfate and any other salt of quinine on or after February 13,
2007, and to cease shipping such products interstate on or after June 13, 2007. After
these dates only FDA approved quinine products may be manufactured and shipped
interstate. This action is described in the Federal Register of December 15, 2006, [71 FR
75557].

Will drug products containing quinine remain on the market?

This action does not affect quinine drug products marketed with FDA approval. FDA has
approved one quinine drug product, which is manufactured by Mutual Pharmaceutical
Company, Inc. (Mutual), of Philadelphia, PA. It was approved on August 12, 2005, as a
prescription drug solely for the treatment of uncomplicated malaria caused by the parasite
Plasmodium falciparum. It contains quinine sulfate as the active ingredient without any
additional active ingredients in 324 mg. capsules and is sold under the trade name
Qualaquin™ (quinine sulfate) with the following NDC number: 13310-154.

Under today’s action, previously-manufactured unapproved products may still be found
on pharmacy shelves for a short period of time. Patients should talk to their health care
provider about whether to use any unapproved quinine-containing product. Patients and
health care professionals should carefully consider the medical condition being treated,
the patient’s previous response to the drug, and the availability of approved alternatives
as part of discussing the benefits and risks of this treatment.

Why is FDA taking this action?

Numerous drug products containing quinine sulfate are marketed without approved
applications for malaria and many are used off-label to treat and/or prevent nocturnal leg
muscle cramps and related conditions. Quinine is associated with a variety of serious
adverse events, some of them potentially fatal. Additionally, as described in the labeling
of Mutual’s approved product, quinine interacts with many other drugs its use is
contraindicated in many conditions (Quinine interacts with neuromuscular blocking
agents, rifampin, class IA and III antiarrhythmic agents, astemizole (Hismanil), cisapride
(Propulsid), erythromycin, and other medications known to cause QT prolongation, a
change in the heart rhythm that significantly increases the risk of cardiac dysfunction,
and is contraindicated in patients with leg cramps, prolonged QT interval, G-6-PD
deficiency, optic neuritis, myasthenia gravis, and known hypersensitivity to quinine or
related drugs). FDA reviewed the labeling of many unapproved quinine products and
found that they did not provide the most up-to-date information physicians need to use
quinine drugs as safely and effectively as possible, which could contribute to
inappropriate prescribing and unnecessary serious adverse events. Further, quinine

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sulfate is known to have a very narrow margin of safety between doses that are
therapeutic in the treatment of malaria and doses that are toxic, making proper
manufacture and dosing recommendations essential. Only one firm, Mutual, markets a
quinine product that has gone through the approval process to ensure that it is accurately
labeled and properly manufactured, as well as safe and effective for its labeled uses.

What risks are associated with quinine-containing drugs?

Serious safety concerns, including fatalities, associated with drug products containing
quinine are well-documented in the literature and in adverse drug events reported to the
agency. One of these adverse events is quinine toxicity, a cluster of symptoms that
includes tinnitus, dizziness, disorientation, nausea, visual changes, and auditory deficits.
There is also evidence that quinine causes serious cardiac arrhythmias including torsades
de pointes. People taking quinine are at risk of developing hypersensitivity to the drug
and experiencing a serious, life-threatening, or fatal reaction as a consequence. Serious
adverse reactions associated with quinine use also include severe skin reactions,
thrombocytopenia (a decrease in blood platelets that can cause hemorrhage or clotting
problems) and other serious hematological events, permanent visual and hearing
disturbances, hypoglycemia, renal failure and generalized anaphylaxis. Overall, from
1969 through September 11, 2006, FDA received 665 reports of adverse events with
serious outcomes associated with quinine use, including, 93 deaths. Many of the adverse
events associated with quinine are dose-related, and because of age-related differences in
the rate at which quinine is eliminated from the body, the frequency and severity of
adverse effects associated with quinine drug products may be greater in the elderly.

Why does the FDA warn against the use of quinine to treat or prevent leg cramps
and related conditions?

Quinine has been used since at least the 1940’s for the relief of nocturnal leg cramps.
However, over the last decade, there has been significant concern regarding its
unfavorable risk/benefit ratio for this and related conditions.

In the 1990s, as part of FDA’s review of over-the-counter (OTC) drugs, the Agency
evaluated OTC quinine products sold without applications for leg cramps, reviewing
extensive information from studies and adverse drug events reported to the agency
regarding the safety and efficacy of quinine drugs. Citing numerous safety concerns
associated with use of quinine and concluding that the data were not adequate to establish
that quinine is effective for prevention and/or treatment of nocturnal leg muscle cramps,
the Agency concluded that these products could not continue to be sold OTC for leg
cramps without approved applications. Drug Products for the Treatment and/or
Prevention of Nocturnal Leg Muscle Cramps for Over-The-Counter Human Use, 59 Fed.
Reg. 43234, (August 22, 1994)

The labeling for Mutual’s approved prescription quinine sulfate includes numerous
warnings regarding the use of the product for the treatment or prevention of nocturnal leg
cramps. For instance the “Indications and Usage” section notes that “Quinine sulfate oral

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capsules are not approved for the treatment or prevention of nocturnal leg cramps.” In a
paragraph entitled “Use of Quinine Sulfate for Treatment or Prevention of Nocturnal Leg
Cramps” in the “Warnings” section,” the labeling states:

Quinine sulfate may cause unpredictable serious and life-threatening
hypersensitivity reactions, QT prolongation, serious cardiac arrhythmias including
torsades de pointes, and other serious adverse events requiring medical
intervention and hospitalization. Fatalities have also been reported. The risk
associated with the use of quinine sulfate in the absence of evidence of its
effectiveness for treatment or prevention of nocturnal leg cramps, outweighs any
potential benefit in treating and/or preventing this benign, self-limiting condition.

Similar information regarding use of quinine sulfate for leg cramps is included in
information designed for patients that is part of the approved labeling.

Although adverse events associated with quinine drugs also can occur when it is used to
treat the approved indication, because untreated malaria, unlike leg cramps, is life-
threatening, these risks may be justified. Because of the risks associated with use of
quinine drugs, Mutual will be providing written information to physicians regarding the
drug’s unfavorable risk/benefit for treatment of nocturnal leg cramps, as compared with
its favorable risk/benefit ratio for treatment of uncomplicated P. falciparum malaria. As
a matter of policy, FDA does not ordinarily interfere in the practice of medicine. In the
exercise of their professional judgment, physicians may generally prescribe approved
drugs for unapproved uses. These warnings regarding quinine drugs do not change that
policy.

What is FDA’s approach to addressing unapproved, marketed drugs?

In June, 2006, FDA issued a final guidance entitled “Marketed Unapproved Drugs--
Compliance Policy Guide” designed to make sure that all drugs marketed in the United
States, prescription and over-the-counter, have been shown to be safe and effective. For
a variety of historical reasons, some drugs, mostly older products, continue to be
marketed illegally in the United States without required FDA approval. This guidance
clearly articulates FDA’s expectation that manufacturers of products requiring FDA
approval submit applications to FDA to show that their products are safe and effective.
The guidance also outlines the agency’s enforcement policies aimed at efficiently and
rationally bringing all such drugs into the approval process.

Why did FDA issue a final guidance on its approach to unapproved, marketed
prescription drugs?

FDA issued the guidance for reasons directly related to its mission of protecting and
advancing the public health. The drug approval process is essential to providing patients
and prescribers with the assurance that prescription drugs are marketed based on reliable,
scientific data showing that they are safe, effective, well-made, and accurately labeled.
The final guidance emphasizes that illegally marketed prescription drugs must obtain

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FDA approval and explains how the agency will prioritize enforcement actions against
illegally marketed drugs to maximize protection of the public health. This final guidance
is based on careful review and consideration of comments received on a previously
published draft guidance.

Why is FDA acting now on unapproved drugs?

FDA is committed to ensuring the safety and quality of the nation’s drug supply. FDA’s
current actions against unapproved drugs are part of our important role in protecting and
advancing the public’s health. FDA approval means FDA scientists, physicians,
inspectors, and experts have reviewed critical information about a drug and have
concluded that the benefits of the drug exceed its risks. Drugs that are not FDA approved
may be unsafe, ineffective, of poor quality, or have inadequate labeling. FDA’s
unapproved drugs actions reflect FDA’s broader initiative to provide consumers and the
health care community with established and emerging drug safety information so they
can make the best possible medical decisions. Although these unapproved drugs have not
demonstrated their safety and effectiveness through the drug approval process, health
care providers are often unaware of their status and have continued to prescribe them.
Their labels do not disclose that they lack approval, and often they are advertised in
reputable medical journals or are included in widely used pharmaceutical references such
as the Physician’s Desk Reference (PDR). The general lack of awareness about the
approval status of these drugs, the absence of FDA review of their effectiveness, and the
uncertainty about their safety, product quality, and adequacy of labeling, all combine to
make it important that unapproved drugs undergo the FDA approval process.

Has the FDA taken previous actions against unapproved drugs that illustrate the
importance of the approval process?

Yes. Levothyroxine is a widely prescribed and beneficial drug for thyroid hormone
replacement that for years was marketed without FDA approval. FDA received reports of
problems with the quality of unapproved levothyroxine products that made it difficult for
patients and doctors to predict if a patient was getting a consistent amount of the active
ingredient of the drug. In 1997, FDA notified levothyroxine manufacturers that they had
three years (later extended to four) to upgrade their manufacturing and submit new drug
applications for marketing. This approach avoided shortages for patients and allowed
manufacturers time to make the needed improvements, perform testing on the drug, and
submit that information in a drug application for FDA approval. Today, all levothyroxine
that is marketed must be approved by FDA and meet quality standards.
Because FDA considered levothyroxine to be medically necessary, FDA allowed
companies to stay on the market while they were seeking approval and provided ample
time for companies to obtain approval.

In other circumstances, FDA may simply issue warning letters ordering the immediate
cessation of illegal drug manufacturing. As explained in the guidance, the decision about
how to proceed will be made on a case-by-case basis.

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What drugs will FDA take off the market?

FDA’s June, 2006, Compliance Policy Guide outlines a prioritized enforcement approach
encouraging companies currently manufacturing drugs without required FDA approval to
comply with the drug approval process and ensure the safety and efficacy of their
marketed products. If companies do not do so, FDA may take enforcement action. The
highest priorities for enforcement action continue to be drugs with potential safety risks,
drugs that lack evidence of effectiveness, and health fraud drugs. FDA intends to
proceed on a case-by-case basis with these priorities in mind, with every effort made to
avoid adversely affecting public health, imposing undue burdens on consumers, or
unnecessarily disrupting the drug supply.

How does FDA intend to handle situations where there is an approved and
unapproved version of the same drug?

In deciding whether, and in what manner, to take enforcement action against an
unapproved drug, FDA intends to consider, among other factors, whether there is also an
approved drug available to serve consumers who need the drug. Allowing continued
marketing of unapproved drugs that compete against approved counterparts challenges
the integrity of the drug approval system that is designed to avoid the risks associated
with potentially unsafe and ineffective drugs, and puts companies that comply with the
law at a disadvantage. Allowing continued marketing of these unapproved drugs also
undermines the incentives needed to conduct the scientific studies to determine the safety
and effectiveness of drugs, which benefits the public health.

Is FDA required to publish a Federal Register notice before taking any action
against any unapproved drug?

No. FDA may take action against unapproved new drugs without first publishing its
intentions in the Federal Register. However, FDA will continue to be mindful of the
effects of its action on consumers and health professionals and set its priorities according
to their public health impact.

For further information, please see FDA’s Unapproved Drugs Web Page, located at
http://www.fda.gov/cder/drug/unapproved_drugs/default.htm

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