[Federal Register Volume 72, Number 102 (Tuesday, May 29, 2007)]
[Notices]
[Pages 29517-29519]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-10266]


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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.

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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: 
[email protected].

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\
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    \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.
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    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.
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    \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'')).
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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 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