[Federal Register Volume 71, Number 241 (Friday, December 15, 2006)]
[Notices]
[Pages 75557-75560]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 06-9713]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2006N-0476]


Drug Products Containing Quinine; Enforcement Action Dates

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing its 
intention to take enforcement action against unapproved drug products 
containing quinine (including quinine sulfate and any other salt of 
quinine) and persons who cause the manufacture of such products or 
their shipment in interstate commerce. Drug products containing 
quinine, quinine sulfate, and any other salt of quinine are new drugs 
that require approved applications. One firm has an approved 
application to market a drug product containing quinine sulfate to 
treat malaria; this product has been designated an orphan drug product. 
Other manufacturers who wish to market a drug product containing 
quinine, quinine sulfate, or any other salt of quinine must obtain FDA 
approval of a new drug application (NDA) or an abbreviated new drug 
application (ANDA); consideration of any such applications will be 
subject to the rights of the current NDA holder under the Orphan Drug 
Act.

DATES: This notice is effective December 15, 2006.
    For marketed, unapproved drug products containing quinine, quinine 
sulfate, or any salt of quinine that have a National Drug Code (NDC) 
number that is listed with FDA on the effective date of this notice 
(i.e., ``currently marketed products''), however, the agency intends to 
exercise its enforcement discretion to permit products marketed with 
those NDC numbers a brief period of continued marketing after December 
15, 2006 as follows. Any firm manufacturing such an unapproved product 
may not manufacture that product on or after February 13, 2007. Any 
firm distributing such an unapproved product may not ship the product 
in interstate commerce on or after June 13, 2007. Unapproved drug 
products containing quinine, quinine sulfate, or any salt of quinine 
that are not currently marketed products on the effective date of this 
notice must, as of the effective date of this notice, have approved 
applications prior to their shipment in interstate commerce. Submission 
of an application does not excuse timely compliance with this notice.

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. 2006N-0476 and directed to the appropriate 
office listed as follows:
    Regarding applications under section 505(b) of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 355(b)): Division of 
Special Pathogen and Transplant Products, Office of New Drugs, Center 
for Drug Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 22, Silver Spring, MD 20993-0002.
    Regarding applications under section 505(j) of the act: Office of 
Generic Drugs, Center for Drug Evaluation and Research (HFD-600), Food 
and Drug Administration, 7520 Standish Pl., Rockville, MD 20855.
    All other communications: John Loh, Center for Drug Evaluation and 
Research (HFD-310), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: John Loh, Center for Drug Evaluation 
and Research (HFD-310), Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, 301-827-8965, e-mail: <a href="/cdn-cgi/l/email-protection#ff95909791d1939097bf999b9ed197978cd1989089"><span class="__cf_email__" data-cfemail="2e44414640004241466e484a4f0046465d00494158">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION:

I. Background

    Quinine is the chief alkaloid of cinchona, the bark of the cinchona 
tree indigenous to parts of South America. Recorded medical use of 
cinchona dates back to the 17th century. Quinine was first isolated 
from cinchona in 1820. Quinine (the term ``quinine'' as used in this 
notice refers to quinine, quinine sulfate, and other quinine salts) has 
been used to treat malaria since the 19th century. It was used 
extensively for mass prophylaxis in malaria control programs in the 
early 20th century. As more predictable and effective synthetic 
antimalarial drugs began to be developed in the 1930s, the use of 
quinine to treat and/or prevent malaria declined. However, with the 
increasing resistance of the malaria parasite to some of these 
synthetic malarial treatments, quinine is again emerging as an 
important treatment for malaria.
    Quinine also has been used for the treatment and/or prevention of 
nocturnal leg muscle cramps, similar conditions such as a restless leg 
syndrome, and, very rarely, a number of other conditions, including 
Babesiosis (another parasitic infection) and certain myotonic 
disorders. The predominant

[[Page 75558]]

use of quinine in the United States is for leg cramps and similar 
conditions.
    Quinine has a history of being marketed over-the-counter (OTC) and 
by prescription, as a single-ingredient product or sometimes in 
combination with other ingredients, such as vitamin E. Its use as a 
treatment for leg cramps and as an antimalarial agent was considered in 
the OTC drug monograph review. In the Federal Register of August 22, 
1994 (59 FR 43234), the agency announced its conclusion that OTC drug 
products for the treatment and/or prevention of nocturnal leg muscle 
cramps are not generally recognized as safe and effective (GRASE), and 
are therefore new drugs under section 201(p) of the act (21 U.S.C. 
321(p)). In reaching this conclusion, the agency reviewed extensive 
information from studies and adverse drug events reported to the agency 
regarding the safety and efficacy of products containing quinine 
sulfate. The agency identified numerous safety concerns associated with 
use of quinine sulfate (59 FR 43234 at 43235 through 43244). Further, 
the agency's review assessed the effectiveness of quinine sulfate for 
prevention and/or treatment of leg cramps, and concluded that the data 
were not adequate to establish that quinine sulfate, alone or in 
combination with vitamin E, is effective for these uses (59 FR 43234 at 
43245 through 43249). The agency's conclusions regarding OTC drug 
products containing quinine indicated for treatment or prevention of 
nocturnal legs cramps are provided in 21 CFR 310.546.
    Subsequently, in the Federal Register of March 20, 1998 (63 FR 
13526), the agency announced its conclusions regarding OTC drug 
products containing quinine or any quinine salt (e.g., quinine sulfate) 
labeled for the treatment and/or prevention of malaria. Because of the 
safety issues associated with these products, the agency concluded that 
these OTC products are not generally recognized as safe (GRAS) and are 
therefore new drugs as well. The agency's conclusions regarding OTC 
drug products containing quinine indicated for treatment or prevention 
of malaria are provided in 21 CFR 310.547.

II. Safety Issues in Use of Quinine Drug Products

    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, which is known as cinchonism, a cluster of 
symptoms of varying severity that include tinnitus, dizziness, 
disorientation, nausea, visual changes, and auditory deficits. There 
also is evidence that quinine causes QT prolongation and 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 and other serious 
hematological events, permanent visual and hearing disturbances, 
hypoglycemia, 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. 
Among the more common types of events with serious outcomes reported to 
the agency are cardiac events, thrombocytopenia, renal failure, 
hypersensitivity/skin reactions, ophthalmologic events, hearing 
disorders, and thrombotic thrombocytopenic purpura (TTP).\1\
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    \1\Serious adverse reactions include the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, a congenital 
anomaly/birth defect, or an important medical event that may 
jeopardize the patient and may require medical or surgical 
intervention to prevent one of the other mentioned serious outcomes 
(Sec.  314.80 (21 CFR 314.80)).
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    Further, quinine sulfate is known to have a narrow therapeutic 
index, with a very narrow margin of safety between doses that are 
therapeutic in the treatment of malaria and doses that are toxic. Many 
of the adverse events associated with quinine are dose-related (63 FR 
15526 at 13527). Overdosing of quinine sulfate can result in cardiac 
arrhythmia, ototoxicity, blindness, or death. The rate of clearance of 
quinine sulfate tends to decline with age, meaning the blood level of 
quinine tends to be higher for a longer period of time in the elderly 
for a given dose compared to younger persons and the frequency and 
severity of adverse effects may also be greater in the elderly (63 FR 
13526 at 13527).

III. Current Status of Quinine Drug Products

    Mutual Pharmaceutical Company, Inc., (Mutual), of Philadelphia, PA, 
submitted an NDA for single-ingredient quinine sulfate in 324-milligram 
capsules (NDA 21-799), which was approved by FDA on August 12, 2005. 
The product is approved to treat uncomplicated Plasmodium falciparum 
malaria only and is a prescription drug product.
    NDA 21-799 is the only approved application for a product 
containing quinine. Because the incidence of malaria in the United 
States is rare, Mutual sought and was granted orphan drug status for 
its product under section 526 of the act (21 U.S.C. 360bb).\2\
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    \2\The term ``orphan drug'' refers to a product that treats a 
rare disease affecting fewer than 200,000 Americans. Enacted in 
1983, the intent of the Orphan Drug Act is to stimulate the 
research, development, and approval of products that treat rare 
diseases. Under this law, which amended the act and is provided in 
21 U.S.C. 360aa to 360ee, a firm that receives approval for a 
product designated as an orphan drug receives for the product a 
special period of exclusivity of 7 years after the date of approval, 
during which the agency will not approve another application for the 
same drug, as defined in 21 CFR 316.3, for the same condition 
submitted by another applicant.
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    The approved labeling for Mutual's quinine sulfate product provides 
extensive warnings regarding the use of the product. It states that the 
product is not approved for the prevention or treatment of nocturnal 
leg cramps and explicitly warns against the use of the product for 
these indications. It describes findings related to use of quinine 
sulfate and QT interval prolongation, along with the association of the 
drug with potentially fatal cardiac arrhythmias. The labeling 
contraindicates use of the product in patients with prolonged QT 
interval, G-6-PD deficiency, optic neuritis, myasthenia gravis, and 
known hypersensitivity to quinine or related drugs. The labeling also 
identifies numerous drugs that should not be used concomitantly with 
quinine, including neuromuscular blocking agents, rifampin, class IA 
and III antiarrhythmic agents, HISMANIL (astemizole), PROPULSID 
(cisapride), erythromycin, and other medications known to cause QT 
prolongation.
    Because of the risks associated with use of quinine sulfate, Mutual 
agreed, as part of the approval of its product, to implement an 
educational program for physicians and other health care providers 
regarding the safe and effective use of quinine sulfate for treatment 
of uncomplicated P. falciparum malaria. The firm also agreed to provide 
written information to physicians regarding the unfavorable risk/
benefit ratio of oral quinine sulfate for treatment of nocturnal leg 
cramps, as compared with the favorable risk/benefit ratio for treatment 
of uncomplicated P. falciparum malaria. For 3 years following approval, 
Mutual will also provide the agency with twice-yearly analyses of 
postmarketing adverse event data, in addition to 15-day and quarterly 
reports required under Sec.  314.80(c)(1) and (c)(2).

[[Page 75559]]

    Unapproved quinine sulfate products are also available on the 
market. The agency reviewed the labeling of unapproved quinine products 
listed with FDA under the requirement of section 510(j) of the act (21 
U.S.C. 360(j)). In general, labeling for the unapproved products does 
not contain many of the warnings found in the approved product labeling 
and therefore does not reflect the most current data regarding quinine 
sulfate. For instance, unapproved products typically do not provide 
information about prolongation of the QT interval, warn against use of 
the product to treat leg cramps, or identify many of the 
contraindications and drug interactions for quinine sulfate products. 
The agency also reviewed dosing regimens recommended in the labeling of 
unapproved quinine sulfate products and found that many of the 
recommend dosing regimens, for which supporting evidence has not been 
evaluated by the agency, are inconsistent with the dosing 
recommendations for the approved product, which are based on clinical 
evidence. These regimens, at one end of the spectrum of recommended 
doses, could lead to substantial underdosing, risking treatment 
failure, and promoting the development of malarial resistance to 
quinine, and, at the other end of the spectrum, could lead to 
overdosing, increasing the risk of serious adverse events, and death.

IV. Legal Status

A. Quinine Products Are New Drugs Requiring Approved Applications

    Based on the safety and effectiveness considerations described 
previously, drugs containing quinine, quinine sulfate, or any other 
salt of quinine are not GRASE for the treatment or prevention of 
malaria, leg cramps, or any other condition under section 201(p) of the 
act. Therefore, a drug product containing any of these ingredients, 
alone or in combination with other drugs, is regarded as a new drug as 
defined in section 201(p) of the act and is subject to the requirements 
of section 505 of the act. An approved application is required to 
market the product. As set forth in this notice, approval of an NDA 
under section 505(b) of the act (including section 505(b)(2)) and 21 
CFR 314.50 or an ANDA under section 505(j) of the act and 21 CFR 314.94 
is required as a condition for manufacturing or marketing all quinine 
products. After the dates identified in this notice (see DATES), FDA 
intends to take enforcement action, as described in this notice, 
against unapproved drug products containing quinine and persons who 
cause the manufacture or interstate shipment of such products. 
Submission of an application does not excuse timely compliance with 
this notice.
    The Mutual quinine sulfate product (NDA 21-799) described in 
section III of this notice has been designated as the reference listed 
drug product. Firms should be aware that review and approval of any 
applications for quinine products will be subject to the rights of the 
current NDA holder under the Orphan Drug Act, including section 527 of 
the act (21 U.S.C. 360cc) and FDA's regulations in 21 CFR part 316.

B. Notice of Enforcement Action

    Although not required to do so by the Administrative Procedure Act, 
the act, or any rules issued under its authority, or for any other 
legal reason, FDA is providing this notice to firms that are marketing 
drug products containing quinine without an approved application that 
the agency intends to take enforcement action against such products and 
those who cause them to be manufactured or shipped in interstate 
commerce. Consistent with the priorities identified in the agency's 
guidance entitled ``Marketed Unapproved Drugs--Compliance Policy 
Guide'' (the Marketed Unapproved Drugs CPG), the agency is taking 
action at this time against unapproved quinine products because: (1) As 
described in section II of this notice, quinine is a drug with 
significant safety risks; and (2) the agency has approved an 
application to market a drug product containing quinine sulfate, and 
thus the continued marketing of unapproved quinine products is a direct 
challenge to the drug approval process. Manufacturing or shipping 
unapproved quinine products can result in seizure, injunction, or other 
judicial proceeding. Consistent with policies described in the Marketed 
Unapproved Drugs CPG, the agency does not expect to issue a warning 
letter or any other further warning to firms marketing unapproved drug 
products containing quinine prior to taking enforcement action. The 
agency also reminds firms that, as stated in the Marketed Unapproved 
Drugs CPG, any unapproved drug marketed without a required approved 
drug application is subject to agency enforcement action at any time. 
The issuance of this notice does not in any way obligate the agency to 
issue similar notices or any notice in the future regarding marketed 
unapproved drugs.\3\
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    \3\The agency's general approach in dealing with these products 
in an orderly manner is spelled out in the Marketed Unapproved Drugs 
CPG. However, this CPG provides notice that any product that is 
being marketed illegally, and the persons responsible for causing 
the illegal marketing of the product, are subject to FDA enforcement 
action at any time.
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    As described in the Marketed Unapproved Drugs CPG, the agency may, 
at its discretion, exercise its enforcement discretion and identify a 
period of time during which the agency does not intend to initiate an 
enforcement action against a currently marketed unapproved drug on the 
grounds that it lacks an approved application under section 505 of the 
act, to preserve access to medically necessary drugs, or ease 
disruption to affected parties, for instance. The agency notes the 
following: (1) Quinine is a drug with significant safety risks that are 
comprehensively described only in the labeling of the approved product; 
(2) the most common use of quinine is an off-label use for which the 
drug has an unfavorable risk-benefit profile, which is described in the 
labeling of the approved product, but not the unapproved products; (3) 
Mutual can provide the market with enough approved quinine sulfate to 
meet patients' needs for the approved indications; and (4) Mutual has 
now obtained approval of its quinine sulfate product. Therefore, the 
agency intends to proceed as follows.
    This notice is effective December 15, 2006. Unapproved drug 
products containing quinine, quinine sulfate, or any salt of quinine 
that are not currently marketed products on the effective date of this 
notice must, as of this date, have approved applications prior to their 
shipment in interstate commerce. For marketed, unapproved quinine-
containing products that have an NDC number that is listed with the 
agency on the effective date of this notice, however, the agency 
intends to exercise its enforcement discretion to permit products 
marketed with those NDC numbers a period of continued marketing after 
December 15, 2006 as follows. Any firm manufacturing such an unapproved 
drug product containing quinine may not manufacture that product on or 
after February 13, 2007.\4\ Any firm distributing such an unapproved 
product may not ship the

[[Page 75560]]

product in interstate commerce on or after June 13, 2007. The agency, 
however, does not intend to exercise its enforcement discretion as 
outlined in this paragraph if: (1) A manufacturer or distributor of an 
unapproved product covered by this notice is violating other provisions 
of the act; or (2) it appears that a firm, in response to this notice, 
increases its manufacture or interstate shipment of quinine drug 
products above its usual volume during these periods.
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    \4\If a firm continues to manufacture or market a product 
covered by this notice after the applicable enforcement date has 
passed, to preserve limited agency resources, FDA may take 
enforcement action relating to all of the firm's unapproved drugs 
that require applications at the same time. (See, e.g., United 
States v. Sage Pharmaceuticals, 210 F.3d 475, 479-480 (5th Cir. 
2000) (permitting the agency to combine all violations of the act in 
one proceeding, rather than taking action against a firm with 
multiple violations of the act in ``piecemeal fashion'').)
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    Drug manufacturers and distributors should be aware that the agency 
is exercising its enforcement discretion as described previously only 
in regard to drug products containing quinine that are marketed under 
an NDC number listed with the agency on the effective date of this 
notice. Unapproved drug products containing quinine that are not 
currently marketed and listed with the agency on the effective date of 
this notice must, as of the effective date of this notice, have 
approved applications prior to their shipment in interstate commerce. 
Moreover, submission of an application does not excuse timely 
compliance with this notice.

C. Discontinued Products

    Some firms may have previously discontinued the manufacturing or 
distribution of products covered by this notice without removing them 
from the listing of their products under section 510(j) of the act. 
Other firms may discontinue manufacturing or marketing listed products 
in response to this notice. Firms that wish to notify the agency of 
product discontinuation should send a letter, signed by the firm's 
chief executive officer, fully identifying the discontinued product(s), 
including its NDC number(s), and stating that the product(s) has (have) 
been discontinued and will not be marketed again without FDA approval, 
to John Loh (see ADDRESSES). Firms should also update the listing of 
their products under section 510(j) of the act to reflect 
discontinuation of unapproved quinine products. FDA plans to rely on 
its existing records, the results of a subsequent inspection, or other 
available information when it initiates enforcement action.
    This notice is issued under sections 502 and 505 of the act (21 
U.S.C. 352) and under authority delegated to the Deputy Commissioner 
for Policy under section 1410.10 of the FDA Staff Manual Guide.

    Dated: December 11, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-9713 Filed 12-12-06; 11:00 am]
BILLING CODE 4160-01-S


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