[Federal Register Volume 71, Number 235 (Thursday, December 7, 2006)]
[Rules and Regulations]
[Pages 70870-70873]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-20797]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. 2006N-0416]
RIN 0910-AF93


Use of Ozone-Depleting Substances; Removal of Essential Use 
Designations

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulation on the use of ozone-depleting substances (ODSs) in 
pressurized containers to remove the essential use designations for 
beclomethasone, dexamethasone, fluticasone, bitolterol, salmeterol, 
ergotamine tartrate, and ipratropium bromide used in oral pressurized 
metered-dose inhalers (MDIs). Under the Clean Air Act, FDA, in 
consultation with the Environmental Protection Agency (EPA), is 
required to determine whether an FDA-regulated product that releases an 
ODS is essential. None of these products is currently being marketed, 
which provides grounds for removing their essential use designation. We 
are using direct final rulemaking for this action because the agency 
expects that there will be no significant adverse comment on the rule. 
In the proposed rule section in this issue of the Federal Register, we 
are concurrently proposing and soliciting comments on this rule. If

[[Page 70871]]

significant adverse comments are received, we will withdraw this final 
rule and address the comments in a subsequent final rule. FDA will not 
provide additional opportunity for comment.

DATES: The direct final rule is effective April 23, 2007, except for 
Sec.  2.125(e)(4)(v) (21 CFR 2.125(e)(4)(v)), which is effective August 
1, 2007. Submit written or electronic comments on or before February 
20, 2007. If we receive no timely significant adverse comments, we will 
publish a document in the Federal Register before March 22, 2007, 
confirming the effective date of the direct final rule. If we receive 
any timely significant adverse comments, we will publish a document of 
significant adverse comment in the Federal Register withdrawing this 
direct final rule before April 23, 2007.

ADDRESSES: You may submit comments, identified by Docket No. 2006N-0416 
and RIN Number 0910-AF93, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and docket number and Regulatory Information Number (RIN) for this 
rulemaking. All comments received will be posted without change to 
http://www.fda.gov/ohrms/dockets/default.htm, including any personal 
information provided. For additional information on submitting 
comments, see the ``Request for Comments`` heading of the SUPPLEMENTARY 
INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number, found in brackets in the heading of this 
document, into the ``Search'' box and follow the prompts and/or go to 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Martha Nguyen or Wayne H. Mitchell, 
Center for Drug Evaluation and Research (HFD-7), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA, in consultation with EPA, determines whether a medical product 
is essential for purposes of Title VI of the Clean Air Act (42 U.S.C. 
7671 et seq.). If a medical product, including a drug, is determined to 
be essential and meets the other elements of the definition found in 
section 601 of the Clean Air Act, the product will be considered a 
``medical device.'' ``Medical devices'' are exempt from the general 
prohibition on nonessential uses of chlorofluorocarbons (CFCs) (a class 
of ODSs) found in section 610 of the Clean Air Act. ODSs produced for 
use in ``medical devices'' may also be exempt, if other conditions are 
met, from the general prohibitions on production and consumption of 
ODSs found in sections 604 and 605 of the Clean Air Act.
    In 1978, we published a rule listing several essential uses of CFCs 
and providing criteria for adding new essential uses (43 FR 11301 at 
11316, March 17, 1978). The rule was codified as Sec.  2.125 (21 CFR 
2.125) and Sec.  2.125 was amended at various times to add new 
essential uses.
    Over the years, alternatives were developed to ODS products whose 
uses were listed in Sec.  2.125 as being essential, while other listed 
ODS products were removed from the market. In light of these facts, and 
in furtherance of our obligations under the Clean Air Act and the 
Montreal Protocol on Substances that Deplete the Ozone Layer (September 
16, 1987, 26 I.L.M. 1541 (1987)), we determined that it would be 
appropriate to revise Sec.  2.125 to remove the essential use 
designations of some products and provide criteria for the removal of 
additional essential use designations in the future. Thus, the rule 
revising Sec.  2.125 was published in the Federal Register of July 24, 
2002 (67 FR 48370). Among other provisions, the rule removed the 
essential use designations of various specific products that, at the 
time the rule was being prepared, were no longer being marketed. The 
rule went into effect on January 20, 2003. That rule also revised Sec.  
2.125(g)(1) (21 CFR 2.125(g)(1)) to provide that if any product that 
releases an ODS is no longer being marketed, the product may have its 
essential use designation revoked through notice-and-comment 
rulemaking.

II. Citizen Petition From Glaxosmithkline

    In a citizen petition dated November 15, 2005, GlaxoSmithKline 
(GSK) requested that MDIs containing the single active moieties 
beclomethasone, fluticasone, and salmeterol be removed from the 
essential use list of ODSs. GSK stated that because beclomethasone, 
fluticasone, and salmeterol are no longer being marketed in MDIs that 
release ODSs, all three active moieties meet the criterion under 
revised Sec.  2.125(g) for being removed from the essential use list. 
GSK requested that the essential use designation for beclomethasone, 
fluticasone, and salmeterol be revoked through a direct final rule.
    In addition, we have determined that dexamethasone, bitolterol, 
ergotamine tartrate, and ipratropium bromide are no longer being 
marketed in MDIs that release ODSs, which provides grounds for removing 
their essential use designation.

III. Direct Final Rulemaking

    We have determined that the subject of this rulemaking is suitable 
for a direct final rule. The actions taken should be noncontroversial, 
and the agency does not anticipate receiving any significant adverse 
comments on this rule. However, in the even that significant adverse 
comment is received, we are also publishing a companion proposed rule 
to satisfy the requirement under Sec.  2.125(g) that essential uses be 
removed through notice-and-comment rulemaking.
    If we receive no significant adverse comment, we will publish a 
document in the Federal Register, confirming the effective date of the 
direct final rule. A significant adverse comment is one that explains 
why the rule would be inappropriate, including challenges to the rule's 
underlying premise or approach, or would be ineffective or unacceptable 
without a change. A comment recommending a rule change in addition to 
this rule will not be considered a significant adverse comment, unless 
the comment states why this rule would be ineffective

[[Page 70872]]

without the additional change. If timely significant adverse comments 
are received, we will publish a notice of significant adverse comment 
in the Federal Register withdrawing this direct final rule within 30 
days after the comment period ends.
    Elsewhere in this issue of the Federal Register, we are publishing 
a companion proposed rule, identical in substance to this direct final 
rule, that provides a procedural framework from which to proceed with 
standard notice and comment rulemaking in the event the direct final 
rule is withdrawn because of significant adverse comment. The comment 
period for the direct final rule runs concurrently with that of the 
companion proposed rule. Any comments received under the companion 
proposed rule will be treated as comments regarding the direct final 
rule. Likewise, significant adverse comments submitted to the direct 
final rule will be considered as comments to the companion proposed 
rule, and we will consider those comments in developing a final rule. 
We will not provide additional opportunity for comment on the companion 
proposed rule.
    If a significant adverse comment applies to part of this rule and 
that part may be severed from the remainder of the rule, we may adopt 
as final those parts of the rule that are not the subject of a 
significant adverse comment. A full description of our policy on direct 
final rule procedures may be found in a guidance document published in 
the Federal Register of November 21, 1997 (62 FR 62466).

IV. Beclomethasone, Dexamethasone, Fluticasone, Bitolterol, Salmeterol, 
Ergotamine Tartrate, and Ipratropium Bromide

    The manufacturers of all approved beclomethasone, dexamethasone, 
fluticasone, bitolterol, salmeterol, ergotamine tartrate, and 
ipratropium bromide oral pressurized MDIs containing an ODS have 
provided information that leads us to conclude that they have removed 
these products from the market.\1\ Accordingly, we are amending our 
regulation to remove beclomethasone, dexamethasone, fluticasone, 
bitolterol, salmeterol, ergotamine tartrate, and ipratropium bromide 
from the list of essential use drugs found in Sec.  2.125(e) (21 CFR 
2.125(e)). Essential uses for metered-dose corticosteroid human drugs 
for oral inhalation, metered-dose short-acting adrenergic 
bronchodilator human drugs for oral inhalation, and metered-dose 
salmeterol, ergotamine tartrate, and ipratropium bromide drug products 
for oral inhalation, are listed in Sec.  2.125(e)(1), (e)(2), and 
(e)(4) by active moiety. ``Active moiety'' is defined in 21 CFR 
314.108(a) as follows: ``the molecule or ion, excluding those appended 
portions of the molecule that cause the drug to be an ester, salt 
(including a salt with hydrogen or coordination bonds), or other 
noncovalent derivative (such as a complex, chelate, or clathrate) of 
the molecule, responsible for the physiological or pharmacological 
action of the drug substance.''
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    \1\ The drug products discussed in this direct final rule were 
all approved for marketing under section 505 of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 355). We are unaware of any 
unapproved beclomethasone, dexamethasone, fluticasone, bitolterol, 
salmeterol, ergotamine tartrate, and ipratropium bromide oral 
pressurized MDIs using an ODS as a propellant that are marketed in 
the United States.
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    MDIs that contain the active moieties beclomethasone, 
dexamethasone, fluticasone, bitolterol, salmeterol, ergotamine 
tartrate, and ipratropium bromide, use certain forms of these moieties. 
Specifically, MDIs that have beclomethasone or fluticasone as their 
active moieties use those moieties in the forms of beclomethasone 
dipropionate and fluticasone propionate, respectively. Similarly, MDIs 
that have dexamethasone, bitolterol, or salmeterol as their active 
moieties use those moieties in the forms of dexamethasone sodium 
phosphate, bitolterol mesylate, and salmeterol xinafoate, respectively. 
Ergotamine tartrate is a salt of ergotamine, and it was used in oral 
MDIs for the treatment of migraines. Its essential use designation is 
for the ergotamine tartrate salt rather than the active moiety 
ergotamine.

A. Beclomethasone

    Oral pressurized MDIs that contain beclomethasone are listed in 
Sec.  2.125(e)(1)(i) as an essential use. BECLOVENT and VANCERIL are 
the only two oral pressurized MDIs that have been marketed and contain 
beclomethasone with an ODS. On January 10, 2002, GSK, the manufacturer 
of BECLOVENT, requested that we withdraw approval of their new drug 
application (NDA) for BECLOVENT ODS MDIs (NDA 18-153) and informed us 
that they had stopped marketing BECLOVENT ODS MDIs. On May 2, 2001, 
Schering-Plough Corp. (Schering), the manufacturer of VANCERIL, 
requested that we withdraw approval of NDA, for VANCERIL ODS MDIs, 84 
micrograms per inhalation (microg/inh), and informed us that they had 
stopped marketing VANCERIL 84 microg/inh MDIs in November 1999. Also, 
on July 25, 2002, Schering informed us that they were removing VANCERIL 
42 microg/inh from the market. On April 14, 2005, Schering requested 
withdrawal of approval of NDA 17-573 for VANCERIL 42 microg/inh.

B. Dexamethasone

    Oral pressurized MDIs that contain dexamethasone are listed in 
Sec.  2.125(e)(1)(ii) as an essential use. DEXACORT ORAL MDI is the 
only oral pressurized MDI that has been marketed and contains 
dexamethasone with an ODS. On September 13, 2002, Celltech 
Pharmaceuticals, Inc., the manufacturer of DEXACORT ORAL MDI, requested 
that we withdraw approval of NDA 01-3413 for DEXACORT ORAL MDIs and 
informed us that they had stopped marketing DEXACORT ORAL MDIs on 
August 15, 1996.

C. Fluticasone

    Oral pressurized MDIs that contain fluticasone are listed in Sec.  
2.125(e)(1)(iv) as an essential use. FLOVENT CFC MDI is the only oral 
pressurized MDI that has been marketed and contains fluticasone with an 
ODS. GSK, the manufacturer of FLOVENT CFC MDIs, has informed us that 
they stopped marketing FLOVENT CFC MDIs in November 2004.

D. Bitolterol

    Oral pressurized MDIs that contain bitolterol are listed in Sec.  
2.125(e)(2)(ii) as an essential use. TORNALATE MDI is the only oral 
pressurized MDI that has been marketed and contains bitolterol with an 
ODS. On January 28, 2003, Sanofi-Synthelabo, Inc., the manufacturer of 
TORNALATE MDIs, informed us that they had stopped marketing TORNALATE 
MDIs on October 1, 2000.

E. Salmeterol

    Metered-dose salmeterol drug products are listed in Sec.  
2.125(e)(4)(i) as an essential use. SEREVENT MDI is the only metered-
dose salmeterol drug product with an ODS that has been marketed. GSK, 
the manufacturer of SEREVENT MDIs, has informed us that they stopped 
marketing SEREVENT MDIs in January 2003.

F. Ergotamine Tartrate

    Oral pressurized MDIs that contain ergotamine tartrate are listed 
in Sec.  2.125(e)(4)(ii) as an essential use. MEDIHALER ERGOTAMINE is 
the only oral pressurized MDI that has been marketed and contains 
ergotamine tartrate with an ODS. 3M Pharmaceuticals, the manufacturer 
of MEDIHALER ERGOTAMINE, has informed us that they stopped

[[Page 70873]]

marketing MEDIHALER ERGOTAMINE in November 1991.

G. Ipratropium Bromide

    Oral pressurized MDIs that contain ipratropium bromide are listed 
in Sec.  2.125(e)(4)(v) as an essential use. ATROVENT CFC MDI is the 
only oral pressurized MDI that has been marketed and contains 
ipratropium bromide with an ODS. Boehringer Ingelheim Pharmaceuticals, 
the manufacturer of ATROVENT CFC MDI, has informed us that they stopped 
marketing ATROVENT CFC MDIs in January 2006. This direct final rule 
does not affect MDIs containing ipratropium bromide and albuterol 
sulfate in combination, marketed as COMBIVENT, which are listed in 
Sec.  2.125(e)(4)(viii) as a separate essential use.

H. Wholesale and Retail Stocks

    Based on information given to us by the manufacturers, we have 
concluded that any beclomethasone, dexamethasone, fluticasone, 
bitolterol, salmeterol, and ergotamine tartrate ODS MDIs that may be in 
retail or wholesale stocks will have passed their expiration dates by 
the effective date for removal of Sec.  2.125(e)(1)(i), (e)(1)(ii), 
(e)(1)(iv), (e)(2)(ii), (e)(4)(i), and (e)(4)(ii). Boehringer Ingelheim 
Pharmaceuticals, the manufacturer of ipratropium bromide, has informed 
us that any ipratropium bromide that may be in retail or wholesale 
stocks will have passed its expiration date by July 2007. Accordingly, 
we have set the effective date for removal of Sec.  2.125(e)(4)(v) as 
August 1, 2007.

V. Environmental Impact

    We have carefully considered, under 21 CFR part 25, the potential 
environmental effects of this action. We have concluded that the action 
will not have a significant impact on the human environment and that an 
environmental impact statement is not required. Our finding of no 
significant impact and the evidence supporting that finding, contained 
in an environmental assessment, may be seen in the Division of Dockets 
Management (see ADDRESSES) between 9 a.m. and 4 p.m., Monday through 
Friday.

VI. Analysis of Impacts

    FDA has examined the impacts of the direct final rule under 
Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this direct final rule is not a significant regulatory action as 
defined by the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because we are removing the essential use 
designations for certain drug products that are either no longer being 
marketed or are no longer being marketed in a formulation containing 
ODSs, the agency certifies that the direct final rule will not have a 
significant economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $118 million, using the most current (2004) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
direct final rule to result in any 1-year expenditure that would meet 
or exceed this amount.

VII. The Paperwork Reduction Act of 1995

    This direct final rule contains no collections of information. 
Therefore, clearance by the Office of Management and Budget under the 
Paperwork Reduction Act of 1995 is not required.

VIII. Federalism

    FDA has analyzed this direct final rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the rule does not contain policies that have substantial direct effects 
on the States, on the relationship between the National Government and 
the States, or on the distribution of power and responsibilities among 
the various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, we do 
not plan to prepare a federalism summary impact statement for this 
rulemaking procedure. We invite comments on the federalism implications 
of this direct final rule.

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two copies of any 
written comments are to be submitted, except that individuals may 
submit one paper copy. Comments are to be identified with the docket 
number found in brackets in the heading of this document. Received 
comments may be seen in the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 2

    Administrative practice and procedure, Cosmetics, Drugs, Foods.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Clean 
Air Act, and under authority delegated to the Commissioner of Food and 
Drugs, after consultation with the Administrator of the Environmental 
Protection Agency, 21 CFR part 2 is amended as follows:

PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS

0
1. The authority citation for 21 CFR part 2 continues to read as 
follows:

    Authority: 15 U.S.C. 402, 409; 21 U.S.C. 321, 331, 335, 342, 
343, 346a, 348, 351, 352, 355, 360b, 361, 362, 371, 372, 374; 42 
U.S.C. 7671 et seq.


Sec.  2.125  [Amended]

0
2. Section 2.125 is amended by removing and reserving paragraphs 
(e)(1)(i), (e)(1)(ii), (e)(1)(iv), (e)(2)(ii), (e)(4)(i), (e)(4)(ii), 
and (e)(4)(v).

    Dated: October 13, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-20797 Filed 12-6-06; 8:45 am]
BILLING CODE 4160-01-S