[Federal Register Volume 75, Number 190 (Friday, October 1, 2010)]
[Notices]
[Pages 60768-60771]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-24684]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2010-N-0257]
Single-Ingredient Oral Colchicine Products; Enforcement Action
Dates
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA or agency) is announcing
its intention to take enforcement action against unapproved single-
ingredient oral colchicine products and persons\1\ who manufacture or
cause the manufacture of such products or their shipment in interstate
commerce. Unapproved single-ingredient oral colchicine products have
been associated with serious adverse events, including fatalities.
Single-ingredient oral colchicine products are new drugs that require
approved applications because they are not generally recognized as safe
and effective. Currently one firm has obtained approved applications to
market single-ingredient oral colchicine for the treatment of acute
gout flares, prophylaxis of gout flares, and prophylaxis of attacks of
Familial Mediterranean Fever (FMF). All other manufacturers who wish to
market single-ingredient oral colchicine products for these or other
indications must obtain FDA approval of a new drug application (NDA) or
an abbreviated new drug application (ANDA).
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\1\A ``person'' includes individuals, partnerships,
corporations, or associations (section 201 of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 321(e)).
DATES: This notice is effective October 1, 2010. For information about
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enforcement dates, see SUPPLEMENTARY INFORMATION, section III.C.
ADDRESSES: All communications in response to this notice should be
identified with Docket No. FDA-2010-N-0257 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
Anesthesia, Analgesia and Rheumatology 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.
All other communications: See the FOR FURTHER INFORMATION CONTACT
section of this document.
FOR FURTHER INFORMATION CONTACT: Karen Rothschild, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 5237, Silver Spring, MD 20993-0002, 301-
796-3689, e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
Colchicine is an alkaloid of the Colchicum autumnale plant, also
known as autumn crocus or meadow saffron. Colchicum was initially
described in the 1st century A.D. by Dioscorides in the Materia Medica.
Medical use of colchicum for gout pain dates back to the 6th century.
It was used for several centuries, but the use of colchicum in the
treatment of gout substantially declined by the 15th century because of
its toxicity. Colchicum was reintroduced as a treatment for acute gout
beginning in 1763. Colchicine was first isolated from colchicum in 1820
and made available in oral dosage form during the 19th century.
Colchicine in oral dosage form is currently marketed in the United
States as approved and unapproved products, both as a single ingredient
and in combination with probenecid. Colchicine for injection has been
available in the United States since the 1950s and has been
administered intravenously for the treatment of acute gout flares. In
the Federal Register of February 8, 2008 (73 FR 7565), FDA announced
its intention to take enforcement action against unapproved drug
products containing colchicine for injection. Single-ingredient oral
colchicine products, the subject of this notice, have also been
marketed in the United States without approved applications to treat
acute gout flares, and are more commonly marketed in conjunction with
uric acid lowering agents for the daily prophylaxis of flares of gout.
Daily oral colchicine has also been the standard of care since the
1970s for the prophylaxis of attacks of FMF.
One firm, Mutual Pharmaceutical Co., Inc. (Mutual), of
Philadelphia, PA, has received approval for three NDAs for single-
ingredient oral colchicine. These approvals are: NDA 22-352 for the
treatment of FMF,\2\ approved on July 29,
[[Page 60769]]
2009; NDA 22-351 for the treatment of acute gout flares, approved on
July 30, 2009; and NDA 22-353 for the treatment of chronic gout,
approved on October 16, 2009. Mutual is marketing these products under
the trade name COLCRYS. These approvals were based on extensive
evaluation of studies and new data that permitted refinement of dosing
regimens and labeling. When used in accordance with the approved
labeling, single-ingredient oral colchicine was found to be well-
tolerated and safe when taken at therapeutic doses and with appropriate
dose reductions in susceptible populations or with potentially
interacting drugs.
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\2\ Because the incidence of FMF in the United States is rare,
Mutual sought and was granted orphan drug status for its product
covered by NDA 22-352 under section 526 of the act (21 U.S.C.
360bb). 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
sections 525 through 529 (21 U.S.C. 360aa through 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 for the same condition
submitted by another applicant (see 21 CFR 316.3).
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II. Safety Issues in the Use of Single-Ingredient Oral Colchicine
Products
The most frequent adverse effects of oral colchicine in therapeutic
doses are those involving the gastrointestinal tract, with the most
common adverse events being diarrhea, nausea and vomiting, abdominal
pain, and cramping. These events are often the first indication that
colchicine therapy may need to be stopped or the dose reduced. Overdose
with colchicine is uncommon, despite its narrow therapeutic index and
despite wide variation in the dose required for significant morbidity
and mortality. Approximately 20 adverse event reports including 5
deaths are reported to the agency on average per year. However, above
the typical therapeutic doses (which range from a 2.4-milligram (mg)
maximum daily chronic dose to the 4.8-mg maximum acute dose), there
does not seem to be any clear separation between nontoxic, toxic, or
lethal doses of colchicine. Overall, FDA is aware of 751 reports of
adverse events associated with colchicine toxicity, including 169
deaths associated with oral colchicine, through June 2007.\3\
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\3\ Data in the current system (AERS) date back to when the
adverse event reporting system was first implemented in 1969.
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There is also evidence supporting a potentially lethal interaction
between P-glycoprotein (P-gp) inhibitors/strong cytochrome P450 3A4
(CYP3A4) inhibitors (such as clarithromycin) and colchicine. Although
these interactions have been published in the medical literature, fatal
interactions continue to be reported to postmarketing adverse event
databases. Postmarketing adverse event databases, including FDA's AERS
database, reveal that half of non-overdose colchicine fatalities are
related to the concommitant use of colchicine and clarithromycin. This
information suggests that despite the literature, awareness regarding
colchicine interactions may not be widespread in the healthcare
community. Another variable in this equation is that interactions are
potentially more severe and lethal in patients with an underlying
susceptibility. Based on the published literature, a 4-fold decrease in
colchicine clearance is noted in severely renally impaired subjects
undergoing hemodialysis compared to healthy volunteers. A 2.5- to 10-
fold lower clearance has been reported in cirrhotic patients when
compared to healthy subjects. No pharmacokinetic studies have been
performed in the elderly or in pediatric patients. However, because the
elderly are more likely to have significant renal or hepatic
impairment, as a whole, they are more at risk. In light of these safety
concerns, there are specific dose modification and reduction
recommendations in the recently approved colchicine labeling pertaining
to drug interactions and to patients with renal impairment.
Furthermore, a new clinical trial in acute gout that was conducted in
support of the NDA found that a lower dose of oral colchicine than had
been considered the standard of care was just as effective for the
treatment of an acute gout flare, and resulted in fewer adverse events.
The approved labeling for oral colchicine reflects this newly
discovered information.
In general, the labeling for unapproved single-ingredient oral
colchicine products listed with FDA under section 510(j) of the act (21
U.S.C. 360(j)) does not reflect the most current data regarding the
safety and effectiveness of single-ingredient oral colchicine. As noted
previously in this document, the newly approved labeling reflects the
new dosing for acute gout flares. Additionally, based on
pharmacokinetic studies conducted in support of the approved NDAs, new
specific-dose modification and reduction recommendations are provided
in the approved colchicine labeling for its use with drugs that use
certain enzymes, such as CYP3A4 or P-gp, for their metabolism or
absorption. Because no applications have been submitted to and reviewed
by FDA for the unapproved single-ingredient oral colchicine products,
the safety and effectiveness of these unapproved products cannot be
assured.
The expected risks associated with use of oral products that
contain single-ingredient colchicine are potentially greater for
unapproved products because the quality, safety, and efficacy of
unapproved formulations have not been demonstrated to FDA. For example,
the ingredients and bioavailability of unapproved products have not
been submitted for FDA review, nor has FDA had the opportunity to
assess the adequacy of their chemistry, manufacturing, and controls
specifications. Further, as noted previously, a clinical trial revealed
that a substantially lower dose of colchicine is as effective as the
higher dose traditionally considered to be the standard of care, with
significantly reduced adverse reactions. Because FDA has not approved
the labeling for unapproved single-ingredient colchicine products,
their labeling likely does not contain appropriate dosing and drug
interaction information.
III. Legal Status
A. Current Status of Single-Ingredient Oral Colchicine
As stated previously, only one firm, Mutual Pharmaceutical, Inc.
(Mutual), has obtained approved applications for single-ingredient oral
colchicine tablets. Mutual submitted three NDAs for its single-
ingredient colchicine tablets: NDA 22-352 for the indication of FMF,
which was approved on July 29, 2009; NDA 22-351 for the treatment of
acute gout, which was approved on July 30, 2009; and NDA 22-353 for the
prevention of gout flares in the chronic treatment of gout, which was
approved on October 16, 2009. Mutual is marketing these products under
the trade name COLCRYS. As stated previously, because the incidence of
FMF in the United States is rare, Mutual sought and was granted orphan
drug status for its product covered by NDA 22-352 under section 526 of
the act.
Unapproved single-ingredient oral colchicine tablets are also
available on the market. The agency reviewed the labeling of unapproved
colchicine products listed with FDA under section 510(j) of the act. In
general, labeling for the unapproved products does not reflect the most
current data regarding single-ingredient oral colchicine. As noted
previously, the newly approved labeling reflects the new dosing for
acute gout flares. Based on pharmacokinetic studies, new specific-dose
modification and reduction recommendations are provided in the approved
colchicine label for its use
[[Page 60770]]
with drugs that use certain enzymes, such as CYP3A4 or P-gp, for their
metabolism or absorption. Because no applications have been filed and
reviewed by the agency for the unapproved products, the safety and
effectiveness of these products cannot be ensured.
B. Single-Ingredient Oral Colchicine Products Are New Drugs Requiring
Approved Applications
Based on both the safety considerations previously described and
the absence of published literature documenting that single-ingredient
oral colchicine is safe and effective, unapproved single-ingredient
oral colchicine is not generally recognized as safe and effective for
any indication including treatment of acute gout flares or for the
daily prophylaxis of gout. Agency review of individual applications to
ensure appropriate manufacturing and labeling is required to ensure the
safe and effective use of the drug. Therefore, single-ingredient oral
colchicine is regarded as a new drug as defined in section 201(p) of
the act (21 U.S.C. 321(p)) and is subject to the requirements of
section 505 of the act. As set forth in this notice, approval of an NDA
or ANDA under section 505 of the act is required as a condition for
manufacturing or marketing all single-ingredient oral colchicine
products. Any person who submits an application for a single-ingredient
oral colchicine product but has not received approval must comply with
this notice.
C. 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 persons who are marketing
unapproved single-ingredient oral colchicine products that after the
dates identified in this notice, the agency intends to take enforcement
action against such products and those who manufacture them or cause
them to be manufactured or shipped in interstate commerce.
Manufacturing or shipping unapproved single-ingredient oral
colchicine products can result in enforcement action, including
seizure, injunction, or other judicial or administrative proceedings.
Consistent with policies described in the agency's guidance entitled
``Marketed Unapproved Drugs--Compliance Policy Guide'' (the Marketed
Unapproved Drugs CPG), the agency does not expect to issue a warning
letter or any other further warning to firms marketing unapproved
single-ingredient oral colchicine products 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.\4\
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\4\ The agency's general approach for dealing with these
products in an orderly manner is spelled out in the Marketed
Unapproved Drugs CPG.
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As described in the Marketed Unapproved Drugs CPG, the agency may,
at its discretion, identify a period of time during which the agency
does not intend to initiate an enforcement action against a currently
marketed unapproved drug solely on the ground that it lacks an approved
application under section 505 of the act. With respect to unapproved
single-ingredient oral colchicine products, the agency intends to
exercise its enforcement discretion for only a limited period of time
because single-ingredient oral colchicine products are drugs with
potential safety risks and, in light of the fact that the agency has
approved applications for single-ingredient oral colchicine products
for the treatment of acute gout flairs, prophylaxis of gout flares, and
prophylaxis of attacks of FMF, the continued marketing of unapproved
single-ingredient oral colchicine products is a direct challenge to the
drug approval process. Therefore, the agency intends to implement this
notice as follows.
This notice is effective October 1, 2010. FDA intends to take
action to enforce section 505(a) of the act against any unapproved
single-ingredient oral colchicine products that are not listed with FDA
in full compliance with section 510 of the act before September 30,
2010, and that are manufactured, shipped, or otherwise introduced or
delivered for introduction into interstate commerce by any person on or
after October 1, 2010. FDA also intends to take action to enforce
section 505(a) of the act against any unapproved single-ingredient oral
colchicine products that have a National Drug Code (NDC) number listed
with FDA in full compliance with section 510 of the act but were not
being commercially used or sold\5\ in the United States on September
30, 2010, and that are manufactured, shipped, or otherwise introduced
or delivered for introduction into interstate commerce by any person on
or after October 1, 2010.
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\5\ For the purpose of this notice, the term ``commercially used
or sold'' means that the product has been used in a business or
activity involving retail or wholesale marketing and/or sale.
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However, for unapproved single-ingredient oral colchicine products
that are commercially used or sold in the United States, have an NDC
number listed with FDA, and are in full compliance with section 510 of
the act before September 30, 2010 (``currently marketed and listed''),
the agency intends to exercise its enforcement discretion as follows.
FDA intends to initiate enforcement action against any currently
marketed and listed unapproved single-ingredient oral colchicine
products that are manufactured on or after November 15, 2010, or that
are shipped on or after December 30, 2010.\6\ Further, FDA intends to
take enforcement action against any person who manufactures or ships
such products after these dates. Any person who has submitted or
submits an application for a single-ingredient oral colchicine product
but has not received approval must comply with this notice.
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\6\ If FDA finds it necessary to take enforcement action against
a product covered by this notice, the agency may take action
relating to all of the defendant's other violations of the act at
the same time. For example, 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
multiple violations of the act in ``piecemeal fashion'')).
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The agency, however, does not intend to exercise its enforcement
discretion as outlined previously if either of the following applies:
(1) A manufacturer or distributor of an unapproved single-ingredient
oral colchicine product is violating any other provisions of the act
(including but not limited to violations related to FDA's current good
manufacturing practices, adverse drug event reporting, labeling or
misbranding requirements) or (2) it appears that a firm, in response to
this notice, increases its manufacture or interstate shipment of
unapproved single-ingredient oral colchicine products above its usual
volume.
Nothing in this notice, including FDA's intent to exercise its
enforcement discretion, alters any person's liability or obligations in
any other enforcement action or litigation, or precludes the agency
from initiating or proceeding with enforcement action in connection
with any other alleged violation of the act, whether or not related to
an unapproved drug product covered by this notice. Similarly, a person
who is
[[Page 60771]]
or becomes enjoined from marketing unapproved drugs may not resume
marketing of unapproved single-ingredient oral colchicine based on
FDA's exercise of enforcement discretion as set forth in this notice.
Drug manufacturers and distributors should be aware that the agency
is exercising its enforcement discretion as described previously only
in regard to unapproved single-ingredient oral colchicine products that
are marketed under an NDC number listed with the agency in full
compliance with section 510 of the act before September 30, 2010. As
previously stated, unapproved single-ingredient oral colchicine
products that are currently marketed but not listed with the agency on
the date of this notice must, as of the effective date of this notice,
have approved applications before shipment in interstate commerce.
D. 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 the product NDC number(s), and stating that the product(s)
has (have) been discontinued. The letter should be sent electronically
to [email protected]. Firms should also update the listing of their
products under section 510(j) of the act to reflect discontinuation of
unapproved single-ingredient colchicine products. FDA plans to rely on
its existing records, the results of a subsequent inspection, or other
available information when we evaluate whether to initiate enforcement
action.
This notice is issued under the act (sections 502 (21 U.S.C. 352)
and 505) and under authority delegated to the Deputy Commissioner,
Office of Policy, Planning and Budget under section 1410.21 of the FDA
Staff Manual Guide.
Dated: September 27, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-24684 Filed 9-30-10; 8:45 am]
BILLING CODE 4160-01-S