[Federal Register: February 8, 2008 (Volume 73, Number 27)]
[Notices]
[Page 7565-7567]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08fe08-59]
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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.
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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, Parinda.Jani@fda.hhs.gov.
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:
Jennifer.Devine@fda.hhs.gov.
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.
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\1\A ``person'' includes individuals, partnerships,
corporations, or associations (21 U.S.C. 321(e)).
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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
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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.
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\2\Data in the current system adverse event reporting system
(AERS) dates back to when the AES was first implemented in 1969.
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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\
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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. 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.
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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 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
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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.
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\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'')).
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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