Drug Products Containing Colchicine for Injection; Enforcement Action Dates, 7565-7567 [08-564]
Download as PDF
Federal Register / Vol. 73, No. 27 / Friday, February 8, 2008 / Notices
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, Parinda.Jani@fda.hhs.gov.
All other communications: See the
FOR FURTHER INFORMATION CONTACT
section.
pwalker on PROD1PC71 with NOTICES
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:
VerDate Aug<31>2005
17:11 Feb 07, 2008
Jkt 214001
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 person1 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.
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
1A ‘‘person’’ includes individuals, partnerships,
corporations, or associations (21 U.S.C. 321(e)).
PO 00000
Frm 00060
Fmt 4703
Sfmt 4703
7565
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
E:\FR\FM\08FEN1.SGM
08FEN1
pwalker on PROD1PC71 with NOTICES
7566
Federal Register / Vol. 73, No. 27 / Friday, February 8, 2008 / Notices
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.
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
2Data in the current system adverse event
reporting system (AERS) dates back to when the
AES was first implemented in 1969.
VerDate Aug<31>2005
17:11 Feb 07, 2008
Jkt 214001
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
PO 00000
Frm 00061
Fmt 4703
Sfmt 4703
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
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
3The 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.
E:\FR\FM\08FEN1.SGM
08FEN1
Federal Register / Vol. 73, No. 27 / Friday, February 8, 2008 / Notices
pwalker on PROD1PC71 with NOTICES
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, 20084. 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.
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.
4If 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’’)).
VerDate Aug<31>2005
17:11 Feb 07, 2008
Jkt 214001
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
PO 00000
Frm 00062
Fmt 4703
Sfmt 4703
7567
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
Risk Communication Advisory
Committee; Notice of Meeting
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
This notice announces a forthcoming
meeting of a public advisory committee
of the Food and Drug Administration
(FDA). The meeting will be open to the
public.
Name of Committee: Risk
Communication Advisory Committee
General Function of the Committee:
To provide advice and
recommendations to the agency on
effective risk communication.
Date and Time: The meeting will be
held on February 28, 2008, from 8 a.m.
to 5 p.m. and February 29, 2008, from
8 a.m. to 4 p.m.
Location: Washington DC North/
Gaithersburg Hilton, 620 Perry Pkwy.,
Gaithersburg, MD 20877, Salons A, B, C,
and D.
Contact Person: Lee L. Zwanziger,
Office of the Commissioner, Office of
Planning (HFP–60), Food and Drug
Administration, 5600 Fishers Lane,
rm.15–22, Rockville, MD, 20857, 301–
827–2895, Fax: 301–827–5340, Food
and Drug Administration, or FDA
Advisory Committee Information Line,
1–800–741–8138 (301–443–0572 in the
Washington, DC area), code
8732112560. Please call the Information
Line for up-to-date information on this
meeting. A notice in the Federal
Register about last minute modifications
that affect a previously announced
advisory committee meeting cannot
always be published quickly enough to
provide timely notice. Therefore, you
should always check the agency’s Web
site and call the appropriate advisory
committee hot line/phone line to learn
about possible modifications before
coming to the meeting.
Agenda: On February 28, 2008, the
committee will meet for the first time,
for presentations and discussion of the
relation of FDA’s risk communication
programs and FDA’s responsibilities. On
February 29, 2008, the meeting will
continue with presentations and
discussion of FDA’s proposed template
for press releases announcing product
recalls with a view to incorporating best
practices of risk communication.
FDA intends to make background
material available to the public no later
than 2 business days before the meeting.
If FDA is unable to post the background
E:\FR\FM\08FEN1.SGM
08FEN1
Agencies
[Federal Register Volume 73, Number 27 (Friday, February 8, 2008)]
[Notices]
[Pages 7565-7567]
From the Federal Register Online via the Government Printing 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, 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.
---------------------------------------------------------------------------
\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