[Federal Register: December 15, 2006 (Volume 71, Number 241)]
[Notices]
[Page 75557-75560]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15de06-86]
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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: john.loh@fda.hhs.gov.
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