[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

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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