[Federal Register Volume 72, Number 189 (Monday, October 1, 2007)]
[Notices]
[Pages 55780-55784]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-19340]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2007N-0353]


Drug Products Containing Hydrocodone; 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

[[Page 55781]]

unapproved drug products containing hydrocodone bitartrate, or any 
other salt or ester of hydrocodone (hereinafter collectively 
``hydrocodone''), and persons who manufacture or cause the manufacture 
of such products or their shipment in interstate commerce. Unapproved 
hydrocodone products have been implicated in reports of medication 
errors, including improper dosing and dispensing the wrong drug. Some 
of these products omit important labeling warnings and information or 
are inappropriately labeled for use in young children. Drug products 
containing hydrocodone are new drugs that require approved applications 
because they are not generally recognized as safe and effective. 
Manufacturers who wish to market a drug product containing hydrocodone 
must obtain FDA approval of a new drug application (NDA) or an 
abbreviated new drug application (ANDA).

DATES: This notice is effective October 1, 2007.
    Subject to the limitations set forth in section II.B of this 
notice, for marketed unapproved drug products containing hydrocodone 
that have a National Drug Code (NDC) number listed with FDA under 
section 510 of the Federal Food, Drug, and Cosmetic Act (the act) (21 
U.S.C. 360) on the effective date of this notice (``currently marketed 
and listed hydrocodone products''), the agency intends to exercise its 
enforcement discretion after October 1, 2007 as follows. FDA does not 
intend to initiate action to enforce section 505(a) of the act (21 
U.S.C. 355(a)) (``drug enforcement actions'') against a person\1\ based 
solely on the person manufacturing, or otherwise introducing or 
delivering for introduction into interstate commerce (``shipping''), 
currently marketed and listed hydrocodone products, unless such a 
person is still manufacturing or shipping such products on or after 
October 31, 2007 with a label or labeling that, as of October 1, 2007, 
indicates any use for children under 6 years of age. FDA does not 
intend to initiate drug enforcement actions based solely on a person 
manufacturing currently marketed and listed hydrocodone products that 
are not labeled for use in children under 6 years of age unless such 
person is still manufacturing them on or after December 31, 2007. 
Further, FDA does not intend to initiate drug enforcement actions based 
solely on a person shipping currently marketed and listed hydrocodone 
products that are not labeled for use in children under 6 years of age 
unless such person is still shipping them on or after March 31, 2008. 
Unapproved drug products containing hydrocodone that are not currently 
marketed, or that are currently marketed but are not listed with the 
agency on the effective date of this notice, must, as of the effective 
date of this notice, have approved applications prior to the drug 
products' introduction or delivery for introduction into interstate 
commerce. Submission of an application does not excuse timely 
compliance with this notice.
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    \1\A ``person'' includes individuals, partnerships, 
corporations, or associations (21 U.S.C. 321(e)).

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. 2007N-0353 and directed to the appropriate 
office listed as follows:
    Regarding applications under section 505(b) of the act: Division of 
Analgesics, Anesthetics, and Rheumatology Products (for analgesic 
formulations/indications), or Division of Pulmonary and Allergy 
products (for antitussive formulations/indications), Office of New 
Drugs, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD 
20993-0002.
    Regarding applications under section 505(j) of the act: Office of 
Generic Drugs, Center for Drug Evaluation and Research (HFD-600), Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.
    All other communications: Jennifer Devine, Center for Drug 
Evaluation and Research (HFD-310), Food and Drug Administration, 11919 
Rockville Pike, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Jennifer Devine, Center for Drug 
Evaluation and Research (HFD-310), Food and Drug Administration, 11919 
Rockville Pike, Rockville, MD 20852, 301-827-8965, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

A. The Drug Efficacy Study Implementation (DESI) Review

    When initially enacted in 1938, the act required that ``new drugs'' 
be approved for safety by FDA before they could legally be sold in 
interstate commerce. To this end, the act made it the sponsor's burden 
to show FDA that its drug was safe through the submission of an NDA. 
Between 1938 and 1962, if a drug obtained approval, FDA considered 
drugs that were identical, related, or similar (IRS)\2\ to the approved 
drug to be ``covered'' by that approval, and allowed those IRS drugs to 
be marketed without independent approval.
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    \2\ Section 310.6(b)(1) (21 CFR 310.6(b)(1)) provides: ``An 
identical, related, or similar drug includes other brands, 
potencies, dosage forms, salts, and esters of the same drug moiety 
as well as of any drug moiety related in chemical structure of known 
pharmacological properties.''
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    In 1962, Congress amended the act to require that new drugs be 
proven effective for their labeled indications, as well as safe. This 
amendment also required FDA to conduct a retrospective evaluation of 
the effectiveness of the drug products that FDA had approved as safe 
between 1938 and 1962. FDA contracted with the National Academy of 
Science/National Research Council (NAS/NRC) to make an initial 
evaluation of the effectiveness of more than 3,400 products that were 
approved only for safety. The NAS/NRC reports for these drug products 
were submitted to FDA in the late 1960s and early 1970s. The agency 
reviewed and reevaluated the reports and published its findings in 
Federal Register notices. DESI was FDA's administrative implementation 
of the NAS/NRC reports. DESI covered the 3,400 products specifically 
reviewed by NAS/NRC, as well as the even larger number of IRS products 
that entered the market without FDA approval.
    All drugs covered in the DESI review are ``new drugs'' under the 
act. If FDA's final DESI determination classifies a drug product as 
ineffective, that drug product and those IRS to it can no longer be 
marketed and are subject to enforcement action as unapproved new drugs. 
If FDA's final DESI determination classifies the drug product as 
effective for its labeled indications, the drug can be marketed 
provided it is the subject of an application approved for safety and 
efficacy. Those drug products with NDAs approved before 1962 for safety 
therefore require approved supplements to their original applications; 
IRS drug products require an approved NDA or ANDA, as appropriate. 
Furthermore, labeling for drug products classified as effective may 
contain only those indications for which the review found the product 
effective unless the firm marketing the product has received an 
approval for the additional indication(s).

B. DESI Review of Hydrocodone Products

    FDA first approved hydrocodone for use as an antitussive in the 
United States on March 23, 1943 (NDA 5-213,

[[Page 55782]]

HYCODAN, submitted by ENDO Laboratories, Inc.). A subtherapeutic amount 
of homatropine methylbromide was later added to this product to help 
prevent abuse or intentional overdose. Two different hydrocodone 
products (including HYCODAN) were reviewed under the DESI program. In 
March 1982, FDA determined that the application holder of NDA 6-529, 
CODITRATE SYRUP containing hydrocodone bitartrate and potassium 
guaiacolsulfonate, held by The Central Pharmaceutical Co., failed to 
demonstrate that each component made a contribution to the claimed 
effect of the CODITRATE SYRUP (47 FR 11973, March 19, 1982). In May 
1982, FDA withdrew approval of NDA 6-529 based on lack of substantial 
evidence of effectiveness (47 FR 21301, May 18, 1982). In June 1982, 
FDA classified HYCODAN syrup, tablets, and powder containing 
hydrocodone bitartrate and homatropine methylbromide (NDA 5-213) as 
effective for symptomatic relief of cough, and further classified the 
product as a new drug for which an approved NDA was required prior to 
marketing (47 FR 23809, June 1, 1982). As described in Sec.  310.6, 
agency determinations regarding new drug status set forth in these 
notices also apply to any drug products that are IRS to the drugs named 
in the DESI notices. Currently marketed analgesic formulations were 
first marketed after the 1962 amendments to the act, and thus were not 
reviewed under the DESI program.

C. Hydrocodone Products

    Hydrocodone is an opioid derived from codeine and is recognized for 
both analgesic and antitussive effects. FDA has approved applications 
for prescription hydrocodone drug products intended to treat pain and 
for prescription hydrocodone products intended to suppress cough. 
Hydrocodone (bulk or single entity product) is a Schedule II narcotic 
under the Controlled Substances Act (21 U.S.C. 801 et seq.), and 
combination products with hydrocodone and non-narcotic active 
ingredients, which are labeled either for use as analgesics or for use 
as antitussives, are Schedule III. Hydrocodone is one of the most 
potent drugs available to relieve pain and treat cough symptoms. 
Despite its medical benefit for such purposes, however, hydrocodone is 
also a potentially lethal drug of abuse. Overdose can produce 
respiratory depression, coma, and cardiac arrest, in addition to other 
adverse events. Hydrocodone use can also impair physical or mental 
capabilities needed to drive, operate machinery, or perform other 
potentially hazardous activities. It can also lead to psychological and 
physical drug dependence. Analysis of population-based epidemiologic 
data from the Substance Abuse and Mental Health Services Administration 
National Survey on Drug Use and Health shows that the misuse and abuse 
associated with the opioid class overall has been increasing in recent 
years. For example, in 2005, more than 17 million Americans aged 12 or 
older reported non-medical use of a hydrocodone pain reliever at least 
once in their lifetime, representing eight percent of the population 
aged 12 years or older. Of those 17 million individuals, more than 8 
million reported using hydrocodone in the past year.
    As of 2005,\3\ FDA has received more than 400 spontaneous 
reports\4\ of serious adverse events associated with all antitussive 
hydrocodone-containing products. While significant under-reporting of 
adverse events from spontaneous sources in the general population 
occurs, the adverse event categories most often reported in association 
with such hydrocodone-containing products involve: (1) The central 
nervous system, including psychotic behavior and drug abuse; (2) the 
gastrointestinal tract, including nausea, vomiting, and constipation; 
(3) the cardiopulmonary system, including cardiac arrest and 
respiratory depression; (4) hypersensitivity, including pruritis, 
dermatitis, and pharyngeal edema; and (5) intentional and unintentional 
overdose.
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    \3\Data in the current system dates back to 1969, when FDA first 
implemented an adverse event reporting system.
    \4\A ``spontaneous report'' is a report from an individual 
(e.g., a healthcare professional or consumer) to a sponsor or FDA 
that describes a suspected adverse event.
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    While many of the types of adverse events associated with approved 
and unapproved products are generally similar, there are additional 
risks associated with the unapproved products. For instance, the agency 
has received reports of medication errors associated with formulation 
changes, such as changing the strength of the active ingredient, and 
reports of confusion based on similarity between the proprietary names 
of unapproved hydrocodone-containing antitussive products and other 
drug products. Look-alike and sound-alike similarities between the 
product names may have contributed to reported medication errors. FDA 
reviews and approves proposed proprietary names as part of the drug 
approval process, thereby helping to minimize potential safety issues 
that could be associated with product name confusion. In addition, 
changes in the formulation of unapproved products may cause healthcare 
practitioners to inadvertently prescribe the wrong dose or combination 
of active ingredients. The drug approval requirement allows the agency 
to evaluate proposed changes to approved product formulations to ensure 
that such modifications meet FDA standards for safety and efficacy, and 
can also help ensure that formulation changes are accompanied by any 
appropriate changes in product trade names or labeling, or other 
measures that may be warranted to minimize confusion and risks to 
patients. Modifications of product formulation that skirt FDA's drug 
approval process thus pose an increased risk of confusing healthcare 
practitioners and causing harm to consumers, such as under- or 
overdose, particularly in pediatric patients.
    Variations and omissions in labeling information for unapproved 
hydrocodone-containing antitussive drug products also pose significant 
safety concerns. For example, labeling for approved antitussive 
products explains that the safety and effectiveness of such products in 
pediatric patients under 6 years old have not been established, and 
does not indicate any approved dosage for that population. By contrast, 
there is unapproved drug product labeling that, for example, states 
that children as young as 2 years old may use the product ``as directed 
by a physician,'' or that includes dosage instructions purported to be 
appropriate for children as young as 2 years old. Moreover, some 
unapproved product labeling omits or changes safety warnings or other 
information that is important to ensure safe use, such as drug 
interactions or potential adverse experiences.
    Finally, even the expected risks associated with use of approved 
products that contain hydrocodone are potentially greater for 
unapproved products because the quality, safety, and efficacy of 
unapproved formulations have not been demonstrated to FDA. For example, 
the ingredients and bioavailability of unapproved products have not 
been submitted for FDA review, nor has FDA had the opportunity to 
assess the adequacy of their chemistry, manufacturing, and controls 
specifications.

[[Page 55783]]

II. Legal Status

A. Hydrocodone Products Are New Drugs Requiring Approved Applications

    Under its DESI review, FDA determined that hydrocodone bitartrate 
is a new drug. Firms must, therefore, have an approved application 
before marketing any drug product that contains hydrocodone bitartrate, 
or any other salt or ester of hydrocodone (collectively, 
``hydrocodone''). There are numerous approved formulations available 
for both analgesic and antitussive indications. There are many approved 
applications for hydrocodone-containing analgesic products, generally 
in combination with acetaminophen, ibuprofen, or, less commonly, 
aspirin. It appears that all currently marketed analgesic formulations 
that have an NDC number listed with the agency are approved. There are 
several approved antitussive formulations, including HYCODAN syrup and 
tablets, and their approved generic equivalents. There is also an 
approved application for a hydrocodone polistirex and chlorpheniramine 
polistirex combination suspension, extended-release product (NDA 19-
111), marketed as TUSSIONEX. However, there are hundreds of unapproved 
hydrocodone-containing products marketed as antitussives that are 
listed with FDA. Such products include, but are not limited to, 
combinations with an expectorant, such as guaifenesin, or a 
decongestant, such as phenylephrine or pseudoephedrine.

B. Notice of Enforcement Action

    Although not required to do so by the Administrative Procedure Act 
(5 U.S.C. Subchapter II), 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 products containing hydrocodone 
that the agency intends to take enforcement action against such 
products and those who manufacture them or cause them to be 
manufactured or shipped in interstate commerce. Consistent with the 
priorities identified in the agency's guidance entitled ``Marketed 
Unapproved Drugs--Compliance Policy Guide'' (the Marketed Unapproved 
Drugs CPG), the agency is taking action at this time against these 
products because: (1) As described in section I of this document, 
hydrocodone is a drug with significant safety risks and (2) there are 
FDA-approved drug products containing hydrocodone; thus the continued 
marketing of unapproved versions is a direct challenge to the drug 
approval process.
    Manufacturing or shipping unapproved products containing 
hydrocodone 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 drug products containing 
hydrocodone 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.\5\
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    \5\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, exercise its enforcement discretion and identify a 
period of time during which the agency does not intend to initiate an 
enforcement action against a currently marketed unapproved drug on the 
ground that it lacks an approved application under section 505 of the 
act in order to, for example, preserve access to medically necessary 
drugs or ease disruption to affected parties. With respect to 
unapproved hydrocodone drug products, the agency intends to exercise 
its enforcement discretion for only a limited period of time because: 
(1) The lack of uniformity in the labeling of unapproved drug products 
poses serious safety risks (particularly for unapproved products 
inappropriately labeled for use in young children); (2) there are 
numerous approved products, including ones containing hydrocodone, that 
may be used to treat the symptoms of cough in most instances; and (3) 
there are numerous approved hydrocodone analgesic formulations on the 
market. Therefore, the agency intends to implement this notice as 
follows.
    This notice is effective October 1, 2007. However, for unapproved 
drug products containing hydrocodone that are currently marketed and 
listed (i.e., that have an NDC number listed with FDA on the date of 
this notice), the agency intends to exercise its enforcement discretion 
as follows. FDA does not intend to initiate action to enforce section 
505(a) of the act (``drug enforcement actions''), against a person 
based solely on the person manufacturing or otherwise introducing, or 
delivering for introduction into interstate commerce (``shipping''), 
such products unless such a person is still manufacturing or shipping 
such products on or after October 31, 2007 with a label or labeling 
that, as of October 1, 2007 indicates any use for children under 6 
years of age. FDA does not intend to initiate drug enforcement actions 
based solely on a person manufacturing currently marketed and listed 
unapproved hydrocodone products that are not labeled for use in 
children under 6 years of age unless the person is still manufacturing 
them on or after December 31, 2007. FDA does not intend to initiate 
drug enforcement actions based solely on a person shipping currently 
marketed and listed unapproved hydrocodone drug products that are not 
labeled for use in children under 6 years of age unless a person is 
still shipping them on or after March 31, 2008.\6\
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    \6\If FDA finds it necessary to take enforcement action against 
a product covered by this notice, the agency may take action 
relating to all of the defendant's other violations of the act at 
the same time. For example, if a firm continues to manufacture or 
market a product covered by this notice after the applicable 
enforcement date has passed, to preserve limited agency resources, 
FDA may take enforcement action relating to all of the firm's 
unapproved drugs that require applications at the same time (see, 
e.g., United States v. Sage Pharmaceuticals, 210 F.3d 475, 479-480 
(5th Cir. 2000) (permitting the agency to combine all violations of 
the act in one proceeding, rather than taking action against 
multiple violations of the act in ``piecemeal fashion'')).
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    The agency, however, does not intend to exercise its enforcement 
discretion as outlined previously if: (1) A person manufacturing or 
shipping an unapproved product covered by this notice is violating 
other provisions of the act or (2) it appears that a person, in 
response to this notice, increases the manufacture or interstate 
shipment of unapproved drug products covered by this notice above the 
person's 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

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unapproved hydrocodone products based on FDA's exercise of enforcement 
discretion as set forth in this notice. FDA also will not exercise its 
enforcement discretion with respect to continued manufacturing or 
shipping of any combination drug product that contains a drug subject 
to an earlier deadline for the exercise of agency enforcement 
discretion.\7\
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    \7\For example, if a person is marketing an unapproved product 
containing both hydrocodone bitartrate and timed-release guaifenesin 
on or after August 27, 2007, then under the notice FDA issued May 
29, 2007 (72 FR 29517), that person is subject to immediate 
enforcement; FDA will not extend the exercise of its enforcement 
discretion to the later dates set out in this notice.
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    Drug manufacturers and distributors should be aware that the agency 
is exercising its enforcement discretion as described previously only 
in regard to unapproved drug products containing hydrocodone that are 
marketed under an NDC number listed with the agency on the effective 
date of this notice. Unapproved drug products containing hydrocodone 
that are not currently marketed, or that are currently marketed but are 
not listed with the agency on the effective date of this notice, must, 
as of the effective date of this notice, have approved applications 
prior to their introduction or delivery for introduction into 
interstate commerce. Moreover, submission of an application does not 
excuse timely 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 the product NDC number(s), and stating that the product(s) 
has (have) been discontinued. The letter should be sent to Jennifer 
Devine (see ADDRESSES) with a copy to the district director of the 
firm's FDA district office. Firms should also update the listing of 
their product(s) under section 510(j) of the act to reflect 
discontinuation of unapproved hydrocodone products. FDA plans to rely 
on its existing records, the results of a subsequent inspection, or 
other available information when we evaluate whether to initiate 
enforcement action.

D. Reformulated Products

    In addition, FDA cautions firms against reformulating their 
products into unapproved new drugs without hydrocodone that are 
marketed under the same name or substantially the same name (including 
a new name that contains the old name) in anticipation of an 
enforcement action based on this notice. In the Marketed Unapproved 
Drugs CPG, FDA stated that it intends to give higher priority to 
enforcement actions involving unapproved drugs that are reformulated to 
evade an anticipated FDA enforcement action. In addition, reformulated 
products marketed under a name previously identified with a different 
active ingredient, or combination of active ingredients, have the 
potential to confuse healthcare practitioners and harm patients.
    This notice is issued under sections 502 and 505 of the act (21 
U.S.C. 352) and under authority delegated to the Deputy Commissioner 
for Policy under section 1410.10 of the FDA Staff Manual Guide.

    Dated: September 25, 2007.
Randall W. Lutter,
Deputy Commissioner for Policy.
[FR Doc. E7-19340 Filed 9-28-07; 8:45 am]
BILLING CODE 4160-01-S