[Federal Register: October 1, 2007 (Volume 72, Number 189)]
[Notices]
[Page 55780-55784]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr01oc07-58]
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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:
jennifer.devine@fda.hhs.gov.
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
[[Page 55784]]
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