Federal Register / Vol. 73, No. 27 / Friday, February 8, 2008 / Notices 7565 

1A ‘‘person’’ includes individuals, partnerships, 

corporations, or associations (21 U.S.C. 321(e)). 

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 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 

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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7566 Federal Register / Vol. 73, No. 27 / Friday, February 8, 2008 / Notices 

2Data in the current system adverse event 

reporting system (AERS) dates back to when the 

AES was first implemented in 1969. 

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. 

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 

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

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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Federal Register / Vol. 73, No. 27 / Friday, February 8, 2008 / Notices 7567 

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’’)). 

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. 

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 

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 


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