[Federal Register: May 29, 2007 (Volume 72, Number 102)]
[Notices]
[Page 29517-29519]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29my07-56]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2007N-0193]
Timed-Release Drug Products Containing Guaifenesin; 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 against unapproved drug products
in timed-release dosage forms containing guaifenesin and persons who
cause the manufacture or interstate shipment of such products. Hundreds
of unapproved drug products in timed-release form containing
guaifenesin, alone or in combination with other ingredients, are
marketed to relieve the symptoms associated with cough, cold, and
similar conditions. Such drug products require approved applications
because they are not generally recognized as safe and effective for
these uses. One firm has obtained approved applications to market
timed-release products containing guaifenesin. Other firms who wish to
market a drug product in timed-release form containing guaifenesin must
obtain FDA approval of a new drug application (NDA) or an abbreviated
new drug application (ANDA).
DATES: This notice is effective May 29, 2007.
For marketed, unapproved drug products in timed-release form
containing guaifenesin that have a National Drug Code (NDC) number that
is listed with FDA under section 510 of the act (21 U.S.C. 360) on the
effective date of this notice (i.e., ``currently marketed products''),
the agency intends to exercise its enforcement discretion to permit
products properly marketed with those NDC numbers a brief period of
continued marketing after May 29, 2007 as follows. FDA does not intend
to initiate enforcement actions against firms that are manufacturing
such currently marketed products unless those firms are still
manufacturing the products on or after August 27, 2007. Further, FDA
does not intend to initiate enforcement actions related to the shipment
in interstate commerce of currently marketed products made by such
firms unless they are still being shipped on or afterNovember 26, 2007.
Unapproved drug products in timed-release form containing guaifenesin
that are not currently marketed products on the date of this notice
must, as of the date of this notice, have approved applications prior
to their shipment in interstate commerce. Submission of an application
does not excuse timely compliance with this notice.
ADDRESSES: All communications in response to this notice should be
identified with Docket No. 2007N-0193 and directed to the appropriate
office listed as follows:
Regarding applications under section 505(b) of the act (21 U.S.C.
355(b)): Division of Pulmonary and Allergy Products, 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: Sakineh Walther, Division of New Drugs
and Labeling Compliance, Center for Drug Evaluation and Research (HFD-
310), Food and Drug Administration, 11919 Rockville Pike, Rockville, MD
20852.
FOR FURTHER INFORMATION CONTACT: Sakineh Walther, Center for Drug
Evaluation and Research (HFD-310), Food and Drug Administration, 11919
Rockville Pike, Rockville, MD 20852, 301-827-8964, e-mail:
sakineh.walther@FDA.HHS.GOV.
SUPPLEMENTARY INFORMATION:
I. Background
Guaifenesin is an expectorant that has been marketed for decades.
Thousands of products intended to relieve symptoms associated with
cough, colds, allergies and similar conditions are marketed containing
guaifenesin, alone or in combination with other active ingredients,
such as antitussives (for instance, dextromethorphan or hydrocodone),
nasal decongestants (for instance, pseudoephedrine or phenylephrine),
and analgesics (for instance, acetaminophen). These products are
marketed both over-the-counter (OTC) and by prescription, and in
immediate- and timed-release dosage forms.
Guaifenesin in immediate-release form was reviewed in the OTC drug
review and is covered by the OTC monograph in part 341 (21 CFR part
341), ``Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug
Products for Over-the-Counter Human Use.'' OTC products that comply
with this monograph may be marketed without approval.
The OTC monograph system does not include timed-release drug
products, a dosage form that is designed to release the active
ingredients over a prolonged period of time. Since 1959, the agency has
stated that all products in timed-release dosage forms also described
as, for example, sustained release, extended release, controlled
release, or long-acting--are new drugs requiring approved applications
(24 FR 3756, May 9, 1959). Agency review of individual applications is
needed to ensure that the finished product releases its active
ingredients at a rate that is both safe, without ``dumping'' of the
dose, and effective, sustaining the intended effect over the entire
period during which the therapeutic benefit is claimed. Firms
submitting applications are required to establish appropriate release
specifications supported by clinical evidence, along with data showing
that the finished product as manufactured by the firm releases its
active ingredient according to these specifications. The agency's
determination that all products in timed-release form are new drugs
requiring approved applications is codified in Sec. 310.502(a)(14) (21
CFR 310.502(a)(14)). The regulation applies to all products in this
dosage form containing guaifenesin, alone or in combination with other
active ingredients.
II. Current Status of Timed-Release Drug Products Containing
Guaifenesin
One firm has obtained approved applications for products in timed-
release dosage forms containing guaifenesin. Adams Respiratory
Therapeutics, formerly known as Adams Laboratories, Inc. (Adams),
submitted an NDA for single-ingredient guaifenesin tablets in timed-
release form (NDA 021-282), which was approved by FDA on July 12, 2002.
These products are sold OTC under the trade names of MUCINEX (600
milligrams (mg)) and HUMIBID (1,200 mg), with labeling for uses
consistent with expectorant products marketed under an OTC monograph
(Sec. 341.78(b)). Specifically, MUCINEX and HUMIBID are intended to
help ``loosen phlegm (mucus) and thin bronchial secretions to rid the
bronchial passageways of bothersome mucus, and make coughs more
productive.'' On October 11, 2002, the agency notified firms marketing
single-
[[Page 29518]]
ingredient, timed-release products containing guaifenesin without
approved applications that their products were unapproved new drugs
marketed in violation of section 505 of the act and that they must
cease marketing them. The agency did not at that time address products
in timed-release form that combined guaifenesin with other active
ingredients.
Subsequently, Adams submitted applications for OTC timed-release
combination products containing guaifenesin and dextromethorphan, an
antitussive (NDA 21-620), and guaifenesin and pseudoephedrine, a
decongestant (NDA 21-585). The agency approved these applications on
April 29, 2004, and June 22, 2004, respectively. These products are
marketed OTC under the trade names MUCINEX-DM and MUCINEX-D,
respectively. Both products are labeled for use as expectorants. In
addition, MUCINEX-DM is labeled for antitussive uses as permitted under
the OTC monographs (Sec. 341.74(b)) and MUCINEX-D is labeled for nasal
decongestant uses as permitted under the OTC monographs (Sec.
341.80(b)).
Hundreds of products in timed-release form containing guaifenesin
in combination with other active ingredients such as antitussives and
decongestants are marketed without approved applications for relief of
various symptoms associated with cough, cold, allergy, and similar
conditions. Because no applications have been filed and reviewed by the
agency for these products, the safety and effectiveness of the products
cannot be ensured. For instance, the agency does not know if the firms
that market them have established appropriate specifications for
release of the active ingredients; whether the products are properly
formulated and manufactured so as to release their ingredients at a
rate that is both safe and effective; and whether each active
ingredient in the combination makes a contribution to the claimed
effect, as required by 21 CFR 300.50.
Many of these unapproved drug products in timed-release form
containing guaifenesin are marketed, labeled, and dispensed as
prescription products. Section 503(b)(1) of the act (21 U.S.C.
353(b)(1)) establishes the definition of a prescription drug. Drug
products that do not meet the definition of a prescription drug but are
labeled for prescription use are considered misbranded under section
503(b)(4) of the act. Some firms choose to market drugs as
prescription, even though those drugs do not meet the prescription drug
definition, either because of the availability of reimbursement by
insurers or because of familiarity with the distribution channels for
prescription drugs. This is contrary to the act.
III. Legal Status
A. Timed-Release Products Containing Guaifenesin Are New Drugs
Requiring Approved Applications
Under Sec. 310.502(a)(14), drug products in timed-release dosage
forms containing guaifenesin are not generally recognized as safe and
effective for any use because of the need for agency review of
individual applications to ensure the safe and effective release of
active ingredients. Therefore, a drug product in timed-release form
containing guaifenesin, alone or in combination with other drugs, is
regarded as a new drug, as defined in section 201(p) of the act (21
U.S.C. 321(p)), and is subject to the requirements of section 505 of
the act. As set forth in this notice, approval of an NDA under section
505(b) of the act (including section 505(b)(2)) and 21 CFR 314.50 or an
ANDA under section 505(j) of the act and 21 CFR 314.94 is required as a
condition for manufacturing or marketing all such products. After the
dates identified in this notice (see DATES), FDA intends to take
enforcement action, as described in this notice, against unapproved
drug products in timed-release form containing guaifenesin and persons
who cause the manufacture or interstate shipment of such products.
Submission of an application does not excuse timely compliance with
this notice.
The Adams timed-release products containing 1,200 mg of guaifenesin
marketed under NDA 021-282, NDA 21-620, and NDA 21-585, as described in
section I of this notice, have been designated as reference listed drug
products. The review and approval of any applications for timed-release
drug products containing guaifenesin will be subject to the patent
rights of the current NDA holder.
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 firms that are marketing
timed-release drug products containing guaifenesin without an approved
application that the agency intends to take enforcement action against
such products and those who 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 the agency
has approved applications to market timed-release drug products
containing guaifenesin, alone and in combination with other active
ingredients, for relief of cough, cold, and allergy symptoms; thus, the
continued marketing of unapproved timed-release guaifenesin products is
a direct challenge to the drug approval process. Manufacturing or
shipping such unapproved products may result in seizure, injunction, or
other judicial 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 timed-release drug products containing guaifenesin 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 other marketed unapproved drugs.\1\
---------------------------------------------------------------------------
\1\ The agency's general approach in dealing with these products
in an orderly manner is spelled out in the Marketed Unapproved Drugs
CPG. However, the CPG 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,
in its discretion, exercise 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
grounds that it lacks an approved application under section 505 of the
act, to preserve access to medically necessary drugs, or ease
disruption to affected parties, for instance. The agency notes that
there are numerous marketed products that have approved applications or
comply with an applicable OTC drug monograph and that are used to treat
conditions for which products in timed-release form containing
guaifenesin are commonly used. Therefore, the agency intends to
implement this notice as follows.
This notice is effective May 29, 2007. Unapproved timed-release
drug products containing guaifenesin, alone
[[Page 29519]]
or in combination with other active ingredients, that are not currently
marketed products on the effective date of this notice must, as of this
date, have approved applications prior to their shipment in interstate
commerce. However, for unapproved timed-release guaifenesin products
that are currently marketed as of the date of this notice (i.e., timed-
release guaifenesin products that are not approved but have an NDC
number that is listed with the agency on the effective date of this
notice), the agency intends to exercise its enforcement discretion to
permit the products marketed with those NDC numbers a period of
continued marketing after May 29, 2007 as follows. FDA does not intend
to initiate enforcement actions against firms that are manufacturing
currently marketed products unless those firms are still manufacturing
the products on or after August 27, 2007. Further, FDA does not intend
to initiate enforcement actions related to the shipment in interstate
commerce of currently marketed products made by such firms unless they
are still being shipped on or after November 26, 2007.\2\ The agency,
however, does not intend to exercise its enforcement discretion as
outlined in this paragraph if: (1) A manufacturer or distributor of an
unapproved product covered by this notice is violating other provisions
of the act or (2) it appears that a firm, in response to this notice,
increases its manufacture or interstate shipment of drug products
covered by this notice above its usual volume during these periods.
---------------------------------------------------------------------------
\2\ 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 a firm with multiple
violations of the act in ``piecemeal fashion'')).
---------------------------------------------------------------------------
Drug manufacturers and distributors should be aware that the agency
is exercising its enforcement discretion as described previously only
in regard to timed-release drug products containing guaifenesin that
are marketed under an NDC number listed with the agency on the
effective date of this notice. Such unapproved drug products that are
not currently marketed and 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 shipment in 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 its NDC number(s), and stating that the product(s) has (have)
been discontinued and will not be marketed again without FDA approval,
to Sakineh Walther (see ADDRESSES). Firms should also update the
listing of their products under section 510(j) of the act to reflect
discontinuation of unapproved timed-release products containing
guaifenesin. FDA plans to rely on its existing records, the results of
a subsequent inspection, or other available information when it
initiates enforcement action.
D. Reformulated Products
In addition to discontinuing the manufacturing of products covered
by this notice, FDA cautions firms against reformulating their products
into guaifenesin-free unapproved new drugs that are marketed under the
same name or substantially the same name (including a new name that
contains the old name). In the Marketed Unapproved Drugs CPG, FDA
states that it intends to give higher priority to enforcement actions
involving unapproved drugs that are reformulated to evade an 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 health
care practitioners and harm patients. Depending on the circumstances,
these products may be considered misbranded under section 502(a) or (i)
of the act (21 U.S.C. 352(a) and (i)).
This notice is issued under the act (sections 502 and 505) and
under authority delegated to the Deputy Commissioner for Policy under
section 1410.10 of the FDA Staff Manual Guide.
Dated: May 15, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-10266 Filed 5-25-07; 8:45 am]
BILLING CODE 4160-01-S