[Federal Register Volume 73, Number 27 (Friday, February 8, 2008)]
[Notices]
[Pages 7565-7567]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 08-564]



[[Page 7565]]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-N-0014]


Drug Products Containing Colchicine for Injection; Enforcement 
Action Dates

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing its 
intention to take enforcement action, as described in this notice, 
against unapproved drug products containing colchicine for injection 
(hereinafter ``colchicine for injection products''), and persons who 
manufacture or cause the manufacture of such products or their shipment 
in interstate commerce. All colchicine for injection products are 
administered intravenously. Colchicine is associated with a variety of 
serious adverse events, some of them potentially fatal. Furthermore, a 
narrow margin of safety exists between a therapeutic dose of colchicine 
and a toxic dose of the drug. Colchicine for injection products are new 
drugs that require approved applications because they are not generally 
recognized as safe and effective. Manufacturers who wish to market a 
colchicine for injection product must obtain FDA approval of a new drug 
application (NDA).

DATES: Effective February 8, 2008. For information about enforcement 
dates, please see the SUPPLEMENTARY INFORMATION section.

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. FDA-2008-N-0014 and directed to the 
appropriate office listed as follows:
    Regarding applications under section 505(b) of the act (21 U.S.C. 
355(b)): Parinda Jani, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Silver 
Spring, MD 20993-0002, 301-796-1232, [email protected].
    All other communications: See the FOR FURTHER INFORMATION CONTACT 
section.

FOR FURTHER INFORMATION CONTACT: Jennifer Devine, Center for Drug 
Evaluation and Research (HFD-310), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-8965, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Enforcement Dates

    FDA intends to take enforcement action to enforce section 505(a) of 
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 255(a)) 
against any unapproved colchicine for injection product that does not 
have a National Drug Code (NDC) number listed with FDA in full 
compliance with section 510 of the act (21 U.S.C. 360) before February 
6, 2008, that is manufactured, shipped, or otherwise introduced or 
delivered for introduction into interstate commerce by any person\1\ on 
or after February 8, 2008, or against any colchicine for injection 
product that has an NDC number listed with FDA and is not commercially 
used or sold in the United States before February 6, 2008, but is 
manufactured, shipped, or otherwise introduced or delivered for 
introduction into interstate commerce by any person on or after 
February 8, 2008.
---------------------------------------------------------------------------

    \1\A ``person'' includes individuals, partnerships, 
corporations, or associations (21 U.S.C. 321(e)).
---------------------------------------------------------------------------

    However, for unapproved colchicine for injection products that are 
commercially used or sold in the United States and have an NDC number 
listed with FDA in full compliance with section 510 of the act before 
February 6, 2008 (``currently marketed and listed''), the agency 
intends to exercise its enforcement discretion after as identified 
elsewhere in this document. FDA intends to initiate enforcement action 
against any currently marketed and listed colchicine for injection 
product that is manufactured on or after March 10, 2008, or that is 
shipped, introduced, or delivered for introduction (``shipped'') on or 
after August 6, 2008. Further, FDA intends to take enforcement action 
against any person who manufactures or ships such products after the 
dates set forth previously. Any person who submits a new drug 
application (NDA) for a colchicine for injection product but has not 
received approval must comply with this notice. Unapproved colchicine 
for injection products that are not currently marketed, or that are 
currently marketed but are not listed with the agency before February 
6, 2008 must, as of the date of this notice, have approved applications 
prior to their introduction or delivery for introduction into 
interstate commerce.

II. 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 available in both as a 
single ingredient and in combination with probenecid, but these 
products are not covered by this notice. Colchicine for injection has 
been available in the United States since the 1950s and has been 
administered intravenously for the treatment of acute attacks of gout. 
Because of toxicities associated with the use of intravenous (IV) 
colchicine and the emergence of safer alternative therapies, IV 
colchicine is rarely used in current practice for acute gout treatment.

III. Current Status of Colchicine for Injection Products

    There are currently no approved applications for colchicine for 
injection products. FDA is aware of only one manufacturer of a 
currently marketed unapproved colchicine for injection product. This 
manufacturer has notified the agency that it has ceased manufacturing 
colchicine for injection.

IV. Safety Issues in Use of Colchicine for Injection Products

    Serious safety concerns, including fatalities, associated with 
colchicine for injection products are well documented in the literature 
and in adverse drug events reported to the agency. Many of these 
adverse events are caused by colchicine toxicity, which typically 
occurs in three phases. The initial phase, occurring within 24 hours of 
administration of a toxic dose of colchicine, is characterized by 
abdominal pain, anorexia, nausea, vomiting, diarrhea, leukocytosis, 
hypovolemia, and electrolyte imbalance. The second phase, 2 to 7 days 
after colchicine administration, involves bone marrow aplasia, 
coagulopathies, cardiac arrhythmia, renal failure, rhabdomyolysis, 
seizures, peripheral neuropathy with ascending paralysis, and 
respiratory distress. If the patient survives, the third phase is a 
recovery phase involving leukocytosis and alopecia. Overall, FDA is 
aware of 50 reports of adverse events associated with IV colchicine 
use, including 23

[[Page 7566]]

deaths, through June 2007.\2\ Three of these deaths occurred in March 
and April of 2007 and were associated with the use of compounded IV 
colchicine. Among the commonly reported events (n=50) that had medical 
significance were neutropenia, acute renal failure, thrombocytopenia, 
congestive heart failure, and pancytopenia.
---------------------------------------------------------------------------

    \2\Data in the current system adverse event reporting system 
(AERS) dates back to when the AES was first implemented in 1969.
---------------------------------------------------------------------------

    Compared to oral administration of colchicine, there is an 
increased likelihood of colchicine toxicity when the drug is 
administered intravenously. For oral dosing in the treatment of acute 
gout, the dose is usually titrated by administering the drug over time 
until symptoms resolve or the patient begins to experience side 
effects, which are typically gastrointestinal. This emergence of side 
effects during oral dosing provides a margin of safety that often 
prevents serious and fatal overdoses. In the case of IV administration, 
side effects are generally not experienced until the patient has 
already received toxic levels of colchicine. Therefore, extreme care 
must be exercised when colchicine is administered by this route.
    Colchicine is also known to have a narrow therapeutic index, with a 
narrow margin of safety between doses that are therapeutic in the 
treatment of gout and doses that are toxic. Many of the adverse events 
associated with colchicine are dose-related. Overdosing of colchicine, 
as discussed previously, can result in bone marrow suppression, organ 
failure, and death. The rate of clearance of colchicine tends to 
decline in persons with diminished renal or hepatic function. This 
means that the blood level of colchicine in persons with diminished 
renal or hepatic function tends to be higher for a longer period of 
time for a given dose compared to persons with normal renal or hepatic 
function. The frequency and severity of adverse effects, including 
colchicine toxicity, may also be greater in these populations.
    FDA is generally aware of the use of IV colchicine as a treatment 
for back pain and that compounding pharmacies often produce colchicine 
for injection products that are administered intravenously for back 
pain treatment. FDA has not approved colchicine in any dosage form for 
the treatment of back pain. FDA's policy regarding the practice of 
pharmacy compounding is articulated in the Agency's Compliance Policy 
Guide Sec. 460.200 on Pharmacy Compounding (Pharmacy Compounding CPG). 
This notice does not affect the applicability or interpretation of the 
Pharmacy Compounding CPG.
    FDA wants to underscore that there are serious risks associated 
with IV colchicine products, because there is a limited margin of 
safety due to both the narrow therapeutic index and serious toxicity of 
colchicine. Any dosing errors with the administration of IV colchicine 
could have potentially serious and fatal consequences.

V. Legal Status

A. Colchicine Products for Injection Are New Drugs Requiring Approved 
Applications

    Based on the safety considerations described previously, colchicine 
for injection products are not generally recognized as safe and 
effective under section 201(p) of the act (21 U.S.C. 321(p)) for the 
treatment or prevention of gout or any other condition. Therefore, an 
injectable drug product containing colchicine, 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. As set forth in this notice, approval of an NDA or an 
abbreviated new drug application under section 505 of the act is 
required as a condition for manufacturing or marketing all colchicine 
for injection products. After the dates identified in this notice, FDA 
intends to take enforcement action as described in this notice against 
any person who is marketing or shipping unapproved colchicine for 
injection products. Any person who submits an NDA for a colchicine for 
injection product but has not received approval must comply with this 
notice. Furthermore, this notice does not affect the applicability or 
interpretation of the Pharmacy Compounding CPG.
    This notice does not affect the legal status of products containing 
colchicine in oral dosage forms, which FDA intends to address at a 
later date.

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 persons who are marketing 
unapproved colchicine for injection products that the agency intends to 
take enforcement action against such products and those who market them 
or cause them to be marketed or shipped in interstate commerce. 
Consistent with the priorities identified in the agency's CPG Sec. 
440.100 entitled ``Marketed Unapproved Drugs--Compliance Policy Guide'' 
(Marketed Unapproved Drugs CPG), the agency is taking action at this 
time against unapproved colchicine for injection products because, as 
described in section III of this notice, colchicine for injection is a 
drug with significant safety risks.
    Manufacturing or shipping unapproved colchicine for injection 
products can result in enforcement action, including seizure, 
injunction, or other judicial or administrative 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 colchicine for injection 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.\3\
---------------------------------------------------------------------------

    \3\The agency's general approach in dealing with these products 
in an orderly manner is spelled out in the Marketed Unapproved Drugs 
CPG. That CPG, however, 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.
---------------------------------------------------------------------------

    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 grounds that it lacks an 
approved application under section 505 of the act. With respect to 
unapproved colchicine for injection products, the agency intends to 
exercise its enforcement discretion for only a limited period of time 
for the following reasons: (1) Colchicine for injection is a drug with 
significant safety risks, (2) colchicine is available in an oral dosage 
form for those patients for whom use of the drug is medically 
necessary, and (3) colchicine in combination with probenecid as an oral 
tablet has FDA approval and is indicated for the treatment of gout. 
Therefore, the agency intends to implement this notice as identified 
elsewhere in this document.
    FDA intends to take enforcement action to enforce section 505(a) of 
the act against any unapproved colchicine for injection product that is 
not listed in full compliance with section 510 of the act before 
February 6, 2008, that is

[[Page 7567]]

manufactured, shipped, or otherwise introduced or delivered for 
introduction into interstate commerce by any person on or after 
February 8, 2008, or is not currently marketed but is subsequently 
manufactured, shipped, or otherwise introduced or delivered for 
introduction into interstate commerce by any person on or after 
February 8, 2008.
    However, for currently marketed and listed unapproved colchicine 
for injection products, the agency intends to exercise its enforcement 
discretion after February 8, 2008, as identified elsewhere in this 
document. FDA intends to initiate enforcement action against any 
currently marketed and listed colchicine for injection product that is 
manufactured on or after March 10, 2008, or that is shipped on or after 
August 6, 2008\4\. Further, FDA intends to take enforcement action 
against any person who manufactures or ships such products after the 
dates set forth previously. Any person who submits an NDA for a 
colchicine for injection product but has not received approval must 
comply with this notice.
---------------------------------------------------------------------------

    \4\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 defendent'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 
enforement 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 Phamaceuticals, 210 F3d 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'')).
---------------------------------------------------------------------------

    The agency, however, does not intend to exercise its enforcement 
discretion as outlined previously if the following apply: (1) A 
manufacturer or distributor of an unapproved injectable colchicine 
product covered by this notice is violating other provisions of the 
act, including but not limited to, violations related to FDA's current 
good manufacturing practices, adverse drug event reporting, 
misbranding, or other violations, or (2) it appears that a firm, in 
response to this notice, increases its manufacture or interstate 
shipment of injectable colchicine drug products above its usual volume 
during these periods.
    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 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 or 
becomes enjoined from marketing unapproved drugs may not resume 
marketing of unapproved injectable colchicine products 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 colchicine for injection products that are marketed under 
an NDC number listed with the agency before February 6, 2008. As 
previously stated, unapproved colchicine for injection products that 
are currently marketed and not listed with the agency on the date of 
this notice must, as of the effective date of this notice, have 
approved applications prior to their shipment in interstate commerce. 
Moreover, any person or firm that submits an NDA but has yet to receive 
approval for such products is still responsible for full 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 NDC number(s), and stating that the product(s) has (have) 
been discontinued and will not be marketed again without FDA approval. 
The letter should be sent to Jennifer Devine, (see ADDRESSES). Firms 
should also update the listing of their products under section 510(j) 
of the act to reflect discontinuation of unapproved colchicine for 
injection 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 the act (sections 502 (21 U.S.C. 352)) 
and 505 and under authority delegated to the Deputy Commissioner for 
Policy under section 1410.10 of the FDA Staff Manual Guide.

    Dated: January 29, 2008.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 08-564 Filed 2-6-08; 8:45 am]
BILLING CODE 4160-01-S