
[Federal Register Volume 78, Number 63 (Tuesday, April 2, 2013)]
[Notices]
[Pages 19718-19721]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-07528]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-0341]


Modifications To Labeling of Nicotine Replacement Therapy 
Products for Over-the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that we 
have concluded that certain statements set forth in the FDA-approved 
labels of over-the-counter nicotine replacement therapy products, 
related to concomitant use with other nicotine-containing products and 
duration of use, can be modified. In light of currently available 
evidence, these statements are no longer believed to be necessary in 
their current form to ensure the safe and effective use of over-the-
counter nicotine replacement therapy products for their approved 
intended use as aids to smoking cessation. We encourage the submission 
of supplemental new drug applications (labeling supplements) to modify 
these statements as described in this notice.

ADDRESSES: Submit labeling supplements to the Center for Drug 
Evaluation and Research, Food and Drug Administration, Central Document 
Room (CDR), 5901-B Ammendale Rd., Beltsville, MD 20705-1266. Copies of 
the recommended revisions to product labeling may be requested from the 
Center for Drug Evaluation and Research's Division of Nonprescription 
Clinical Evaluation, 10903 New Hampshire Ave., Bldg. 22, Stop 5411, 
Silver Spring, MD 20993, 301-796-2080. Copies of published studies that 
can be used to support labeling supplements will be on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, and can be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.

FOR FURTHER INFORMATION CONTACT: Doris J. Bates, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 4417, Silver Spring, MD 20993, 301-796-
1040, FAX: 301-796-9721, email: doris.bates@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

A. Smoking and Tobacco Dependence

    Tobacco use is the leading preventable cause of death and disease 
in the United States. According to an estimate by the Centers for 
Disease Control and Prevention, cigarette smoking causes 443,000 deaths 
each year in the United States, including nearly 50,000 deaths per year 
from involuntary exposure to tobacco smoke (Ref. 1). Smoking is known 
to cause multiple cancers, heart disease, stroke, complications of 
pregnancy, chronic obstructive pulmonary disease, and many other 
diseases that, on average, shorten smokers' lifespans by 14 years (Ref. 
2).
    Surveys show that approximately 70 percent of current smokers want 
to stop smoking, and nearly half of all smokers make a quit attempt 
each year (Ref. 3). Unfortunately, dependence on nicotine--the primary 
addictive substance in tobacco--is a chronic disease that often 
requires repeated intervention and multiple quit attempts to overcome. 
As a result, only a small percentage of smokers successfully quit each 
year (Ref. 3).

B. Over-the-Counter Nicotine Replacement Therapies

    Nicotine replacement therapy (NRT) products are designed to help 
people stop smoking by supplying controlled amounts of nicotine to ease 
the withdrawal symptoms associated with a quit attempt. NRT products do 
not contain all of the carcinogens and other harmful constituents that 
are found in cigarette smoke. There are currently three types of NRT 
products approved by FDA for over-the-counter (OTC) use as smoking 
cessation aids: Nicotine gum, transdermal nicotine patch, and nicotine 
lozenge products.\1\ The nicotine gum and patch products were 
originally approved through the new drug application (NDA) process 
between 1984 and 1992. Both the gum and the patch were initially 
available by prescription only; these products were switched from 
prescription to OTC status between 1996 and 2002. The nicotine lozenge 
and mini-lozenge were approved directly for OTC use in 2002 and 2009, 
respectively.
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    \1\ A nicotine spray and a nicotine inhaler have also been 
approved as smoking cessation aids. However, these NRT products are 
available by prescription only and are therefore outside the scope 
of this notice.
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    Currently, the FDA-approved labeling for OTC NRT products instructs 
consumers that they should stop smoking when they begin using the 
product and that they should not use

[[Page 19719]]

the product in combination with cigarettes or other nicotine-containing 
products (including other NRT products). The labeling also recommends a 
specific duration of use of up to 12 weeks, depending on the product, 
and instructs consumers to stop using the NRT product at the end of 
that period. Consumers are advised to consult a doctor if they feel 
they need to continue using the NRT product for longer than the 
recommended course of treatment.
    In recent years, a number of stakeholders in the public health and 
health care provider communities have suggested that these labeling 
statements act as barriers to the effective use of OTC NRT products for 
smoking cessation. These stakeholders have argued that the statement 
advising against concomitant use of the NRT products with cigarettes 
may cause some smokers to abandon quit attempts if they experience a 
lapse (e.g., if they have a cigarette while using an NRT product). 
Stakeholders have also argued that use of more than one NRT product 
(e.g., patch plus gum) is more effective for some smokers than use of a 
single NRT product in achieving cessation, and that current labeling 
discourages such use. With regard to duration of use, stakeholders have 
argued that the use of OTC NRT products beyond the labeled treatment 
period may increase the chances of quitting for certain smokers.\2\ 
These stakeholders have asserted that there are no safety concerns 
associated with concomitant use of OTC NRT products with other 
nicotine-containing products, or with the use of OTC NRT products for 
longer than the labeled duration of use.
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    \2\ In this notice, the Agency takes no position on the 
effectiveness of NRT products when used concomitantly with other 
nicotine-containing products, or when used for longer than the 
labeled duration of use.
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    Over the nearly 30 years since NRT products were first approved, 
evidence has accumulated to suggest that the current labeling 
provisions on concomitant use and duration of use may no longer be 
necessary to ensure the safe use of OTC NRT products for smoking 
cessation. Based on this evidence, FDA has concluded that the current 
labeling statements for OTC NRT products concerning concomitant use and 
duration of use can be modified as described in this document. We 
invite the products' sponsors to submit supplemental NDAs (labeling 
supplements) to modify these statements in the labeling of their drug 
products. To facilitate the process, the Agency has identified 
revisions to the labeling of OTC NRT products that can be included in 
these labeling supplements. Those revisions are set forth in section 
II.

II. Proposed Revisions to the Labeling of OTC NRT Products

A. Concomitant Use of OTC NRT Products With Cigarettes or Other 
Nicotine-Containing Products, Including Other NRT

    The ``Drug Facts'' section of the label for OTC NRT products 
currently contains two statements relating to the use of these products 
with other nicotine-containing products. The first statement is found 
under the ``Do not use'' subheading of the ``Warnings'' section. It 
instructs consumers not to use the OTC NRT product if they ``continue 
to smoke, chew tobacco, use snuff, or use [a different NRT product] or 
other nicotine containing products.'' This statement was included in 
the labeling because at the time during which these products were 
switched to OTC use, there was little reliable data on the safety of 
the higher levels of nicotine that would result from using NRT products 
in combination with other nicotine-containing products. The second 
statement appears under the ``Directions'' section, and tells consumers 
to ``stop smoking completely when you begin using the [NRT product].'' 
This statement was included in the label because in the clinical trials 
that were conducted for the original NRT product approvals, individuals 
who stopped smoking completely when they began using NRT were more 
likely to quit.
    Since we first approved NRT products for OTC use, a number of 
studies have been conducted that provide information on the safety of 
using NRT products in combination with other nicotine-containing 
products. Many of these studies focused on the effects of using NRT 
products while smoking. For example, there have been studies on the use 
of NRT products by smokers who were not immediately interested in 
quitting (see Hatsukami et al., 2007), on the use of NRT products as an 
aid to smoking reduction (see Wennike et al., 2003; Batra et al., 
2005), and on the use of NRT products before initiating a quit attempt 
(Lindson and Aveyard, 2011). In addition, several studies have been 
conducted on the use of higher-than-standard-dose NRT products 
(T[oslash]nnesen et al., 1999) and on the concomitant use of more than 
one type of NRT product (see Bohadana et al., 2000; Piper et al., 
2009).
    Upon reviewing the published reports of these and other studies, we 
have determined that the concomitant use of OTC NRT products with 
cigarettes or with other nicotine-containing products does not raise 
significant safety concerns. The published literature contains few 
reports of adverse events arising from the use of NRT products while 
smoking or using another NRT product. The Agency also notes that few 
adverse events have been reported in studies of concomitant use 
conducted under the investigational new drug (IND) process, which 
involves mandatory reporting of adverse events.
    Accordingly, we are announcing that the statements in the current 
labeling of OTC NRT products relating to concomitant use of those 
products with other nicotine-containing products can be modified. The 
following specific changes to the current approved ``Drug Facts'' 
labeling are recommended:
     Warnings. The ``Do not use'' subheading and the statement 
underneath it instructing consumers not to use the NRT product if they 
``continue to smoke, chew tobacco, use snuff, or use [a different NRT 
product] or other nicotine containing products'' should be deleted.
     Directions. The third bullet should be revised from ``stop 
smoking completely when you begin using the [NRT product]'' to ``begin 
using the [NRT product] on your quit day.''

B. Duration of Use of OTC NRT Products

    Currently, the labeling of OTC NRT products recommends a specific 
duration of use of up to 12 weeks, depending on the product. For 
example, the ``Drug Facts'' section of the label for nicotine gum and 
lozenge products recommends that those products be used for 12 weeks; 
the label for certain nicotine patch products recommends a duration of 
use of 8 weeks, others 10 weeks. These labeled durations of use reflect 
the treatment periods that were studied in the clinical trials that 
supported the switch of these products to OTC status. Because NRT 
products treat the acute withdrawal symptoms associated with a quit 
attempt, and those symptoms typically diminish over time, most of the 
clinical trials conducted to support approval were short--generally 
between 6 and 12 weeks in length.
    In addition to recommending a specific duration of use, current OTC 
NRT product labels direct consumers to stop using the product at the 
end of the recommended treatment period and to talk to a doctor if they 
feel they need to use the product longer. This statement was included 
in the labeling because at the time of the first prescription-to-OTC 
switch, there was insufficient data to

[[Page 19720]]

address the Agency's concern that consumers could potentially become 
dependent on NRT products.
    In the years since NRT products became available for OTC use, a 
number of studies have examined the use of NRT products over periods 
longer than 12 weeks. We have reviewed the published literature on this 
longer-term use of NRT products and have not identified any safety 
risks associated with such use. A well-known and highly regarded study 
on the effects of long-term use of NRT products is the Lung Health 
Study, in which almost 6,000 smokers were given access to free nicotine 
gum for up to 5 years (see Murray et al., 1996). In this study, over 
1,000 subjects were still using the gum after 1 year. The adverse 
effects of long-term nicotine gum use reported by these subjects were 
described as minor and transient, and there was no correlation between 
long-term gum use and cardiovascular events. A followup study found 
that long-term ad lib use of nicotine gum neither increased nor 
decreased the Lung Health Study subjects' likelihood of developing 
cancer (see Murray et al., 2009). Other informative studies on the 
effects of long-term use of NRT products include a 52-week study of NRT 
product use in which nearly half of the subjects used two or more OTC 
NRT products in combination (see Joseph et al., 2011), and a trial 
involving the use of nicotine patches for 6 to 12 months by nonsmokers 
with mild cognitive impairment (see Newhouse et al., 2012). Both of 
these studies had high rates of completion and reported few adverse 
events from long-term use of NRT products.
    We also note that although any nicotine-containing product has the 
potential to be addicting, based on the available evidence, currently 
marketed OTC NRT products do not appear to have significant potential 
for abuse or dependence. A 2010 review of historical reports made to 
the Agency's Adverse Event Reporting System and to the Substance Abuse 
and Mental Health Services Administration's Drug Abuse Warning Network 
between 1984 and 2009 suggested that NRT products have a low potential 
for abuse. Several published studies have also found that the abuse 
liability and dependence potential of NRT products is low, especially 
compared to cigarettes (see West et al., 2000; Houtsmuller et al., 
2002).
    Accordingly, we are announcing that the statement in the labeling 
of OTC NRT products directing consumers to stop using the NRT product 
at the end of the recommended treatment period can be modified. The 
following specific change to the current approved ``Drug Facts'' 
labeling is recommended:
     Directions. The last bullet should be revised from ``it is 
important to complete treatment. Stop using the [NRT product] at the 
end of [x] weeks. If you still feel the need to use [the NRT product], 
talk to your doctor'' to ``it is important to complete treatment. If 
you feel you need to use [the NRT product] for a longer period to keep 
from smoking, talk to your health care provider.''

C. Summary of Proposed Labeling Revisions

    In light of currently available evidence on the concomitant use of 
OTC NRT products with cigarettes or other nicotine-containing products, 
and on the use of OTC NRT products beyond the labeled period of 
treatment, the following changes to the ``Drug Facts'' labeling of OTC 
NRT products are recommended:

------------------------------------------------------------------------
      Current drug facts  labeling        Proposed drug facts  labeling
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                                Warnings
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Do not use:
     if you continue to smoke,   None. The ``Do not use''
     chew tobacco, use snuff, or use [a   statement would be deleted.
     different NRT product] or other
     nicotine containing products.
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                               Directions
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 stop smoking completely when     begin using the [NRT
 you begin using the [NRT product].       product] on your quit day.
 it is important to complete      it is important to
 treatment. Stop using the [NRT           complete treatment. If you
 product] at the end of [ x ] weeks. If   feel you need to use [the NRT
 you still feel the need to use [the      product] for a longer period
 NRT product], talk to your doctor.       to keep from smoking, talk to
                                          your health care provider.
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    We have determined that these labeling revisions may be addressed 
through a changes being effected (CBE) supplement under 21 CFR 
314.70(c)(6).
    We are also recommending conforming changes to other FDA-approved 
labeling for OTC NRT products, such as product user guides and 
leaflets. Copies of the recommended changes to these other labeling 
items may be obtained from the Center for Drug Evaluation and 
Research's Division of Nonprescription Clinical Evaluation (see 
ADDRESSES).

III. Conclusions

    We have determined that the current OTC NRT products can be used 
safely and effectively for their approved intended use as aids to 
smoking cessation with the labeling modifications identified in section 
II. We encourage the submission of labeling supplements for these drug 
products. These supplements should modify the labeling statements 
concerning concomitant use and duration of use as described in section 
II. The requirement for data to support these labeling changes may be 
met by citing the published literature we relied on in preparing this 
notice. A list of the published literature and reprints of the reports 
will be available for public inspection in the Division of Dockets 
Management (see ADDRESSES). It is unnecessary to submit copies and 
reprints of the reports from the listed published literature. We invite 
applicants to submit any other pertinent studies and literature of 
which they are aware.

IV. Published Literature Supporting Proposed Labeling Revisions

    The published literature we have relied on in making the 
determinations contained in this notice is listed in this section of 
the document. Copies of the published literature will be on display in 
the Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov.

1. Batra, A., et al., ``Smoking Reduction Treatment With 4-Mg 
Nicotine Gum: A Double-Blind, Randomized, Placebo-Controlled 
Study,'' Clinical

[[Page 19721]]

Pharmacology and Therapeutics, 78(6):689-96, 2005.
2. Benowitz, N.L., et al., ``Suppression of Nicotine Intake During 
Ad Libitum Cigarette Smoking by High-Dose Transdermal Nicotine,'' 
Journal of Pharmacology and Experimental Therapeutics, 287(3):958-
62, 1998.
3. Blondal, T., et al., ``Nicotine Nasal Spray With Nicotine Patch 
for Smoking Cessation: Randomised Trial With Six Year Follow Up,'' 
BMJ, 318(7179):285-8, 1999.
4. Bohadana, A., et al., ``Nicotine Inhaler and Nicotine Patch as a 
Combination Therapy for Smoking Cessation,'' Archives of Internal 
Medicine, 160(20):3128-34, 2000.
5. Bolliger, C.T., et al, ``Smoking Reduction With Oral Nicotine 
Inhalers: Double Blind, Randomised Clinical Trial of Efficacy And 
Safety,'' BMJ, 321(7257):329-33, 2000.
6. Bullen, C., et al., ``Precessation Nicotine Replacement Therapy: 
Pragmatic Randomized Trial,'' Addiction, 105(8):1474-83, 2010.
7. Dale, L.C., et al., ``High-Dose Nicotine Patch Therapy. 
Percentage of Replacement and Smoking Cessation,'' JAMA, 
274(17):1353-58, 1995.
8. Etter, J.F., et al., ``Nicotine Replacement to Reduce Cigarette 
Consumption in Smokers Who Are Unwilling to Quit: A Randomized 
Trial,'' Journal of Clinical Psychopharmacology, 22(5):487-95, 2002.
9. Etter, J.F., et al., ``Postintervention Effect of Nicotine 
Replacement Therapy on Smoking Reduction in Smokers Who Are 
Unwilling to Quit: A Randomized Trial,'' Journal of Clinical 
Psychopharmacology, 24(2):174-79, 2004.
10. Etter, J.F., et al., ``Nicotine Gum Treatment Before Smoking 
Cessation--A Randomized Trial,'' Archives of Internal Medicine, 
169(11):1028-34, 2009.
11. Hajek, P., et al., ``Dependence Potential of Nicotine 
Replacement Treatments: Effects of Product Type, Patient 
Characteristics, and Cost to User,'' Preventive Medicine, 44(3):230-
34, 2007.
12. Hall, S.M., et al., ``Extended Treatment of Older Cigarette 
Smokers,'' Addiction, 104(6):1043-52, 2009.
13. Hatsukami, D., et al., ``Effects of High Dose Transdermal 
Nicotine Replacement in Cigarette Smokers,'' Pharmacology, 
Biochemistry, and Behavior, 86(1):132-39, 2007.
14. Horst, W.D., et al., ``Extended Use of Nicotine Replacement 
Therapy to Maintain Smoking Cessation in Persons With 
Schizophrenia,'' Neuropsychiatric Disease and Treatment, 1(4):349-
55, 2005.
15. Houtsmuller, E.J., et al., ``Flavor Improvement Does Not 
Increase Abuse Liability of Nicotine Chewing Gum,'' Pharmacology, 
Biochemistry, and Behavior, 72(3):559-68, 2002.
16. Hughes, J.R., et al., ``A Randomized, Controlled Trial of NRT-
Aided Gradual Vs. Abrupt Cessation in Smokers Actively Trying to 
Quit,'' Drug and Alcohol Dependence, 111(1-2):105-13, 2010.
17. Joseph, A.M., et al., ``Chronic Disease Management for Tobacco 
Dependence,'' Archives of Internal Medicine, 171(21):1894-1900, 
2011.
18. Lerman, C., et al., ``Genetic Variation in Nicotine Metabolism 
Predicts the Efficacy of Extended-Duration Transdermal Nicotine 
Therapy,'' Clinical Pharmacology and Therapeutics, 87(5):553-57, 
2010.
19. Lindson, N. and Aveyard, P., ``An Updated Meta-Analysis of 
Nicotine Preloading for Smoking Cessation: Investigating Mediators 
of the Effect,'' Psychopharmacology, 214(3):579-92, 2011.
20. Murray, R.P., et al., ``Safety of Nicotine Polacrilex Gum Used 
by 3,094 Participants in the Lung Health Study. Lung Health Study 
Research Group,'' CHEST, 109(2):438-45, 1996.
21. Murray, R.P., et al., ``Does Nicotine Replacement Therapy Cause 
Cancer? Evidence From the Lung Health Study,'' Nicotine & Tobacco 
Research, 11(9):1076-82, 2009.
22. Newhouse, P., et al., ``Nicotine Treatment of Mild Cognitive 
Impairment: A 6-Month Double-Blind Pilot Clinical Trial,'' 
Neurology, 78(2):91-101, 2012.
23. Piper, M.E., et al., ``A Randomized Placebo-Controlled Clinical 
Trial of 5 Smoking Cessation Pharmacotherapies,'' Archives of 
General Psychiatry, 66(11):1253-62, 2009.
24. Rennard, S.I., et al., ``Efficacy of the Nicotine Inhaler in 
Smoking Reduction: A Double-Blind, Randomized Trial,'' Nicotine & 
Tobacco Research, 8(4):555-64, 2006.
25. Rose, J.E., et al., ``Mecamylamine Combined With Nicotine Skin 
Patch Facilitates Smoking Cessation Beyond Nicotine Patch Treatment 
Alone,'' Clinical Pharmacology and Therapeutics, 56(1):86-99, 1994.
26. Rose, J.E., et al., ``Nicotine-mecamylamine Treatment for 
Smoking Cessation: The Role of Precessation Therapy,'' Experimental 
and Clinical Psychopharmacology, 6(3):331-43, 1998.
27. Rose, J.E., et al., ``Precessation Treatment With Nicotine Skin 
Patch Facilitates Smoking Cessation,'' Nicotine & Tobacco Research, 
8(1):89-101, 2006.
28. Rose, J.E., et al., ``Precessation Treatment With Nicotine Patch 
Significantly Increases Abstinence Rates Relative to Conventional 
Treatment,'' Nicotine & Tobacco Research, 11(9):1067-75, 2009.
29. Schuurmans, M.M., et al., ``Effect of Pretreatment With Nicotine 
Patch on Withdrawal Symptoms and Abstinence Rates in Smokers 
Subsequently Quitting With the Nicotine Patch: A Randomized 
Controlled Trial,'' Addiction, 99(5):634-40, 2004.
30. T[oslash]nnesen, P., et al., ``Higher Dosage Nicotine Patches 
Increase One-Year Smoking Cessation Rates: Results From the European 
CEASE Trial,'' European Respiratory Journal, 13(2):238-46, 1999.
31. Wang, D., et al., '' `Cut Down to Quit' With Nicotine 
Replacement Therapies in Smoking Cessation: A Systematic Review of 
Effectiveness and Economic Analysis,'' Health Technology Assessment, 
12(2):iii-iv, ix-xi, 1-135, 2008.
32. Wennike, P., et al., ``Smoking Reduction Promotes Smoking 
Cessation: Results From a Double Blind, Randomized, Placebo-
Controlled Trial of Nicotine Gum With 2-Year Follow-Up,'' Addiction, 
98(10):1395-402, 2003.
33. West, R., et al, ``A Comparison of the Abuse Liability and 
Dependence Potential of Nicotine Patch, Gum, Spray and Inhaler,'' 
Psychopharmacology, 149(3):198-202, 2000.
34. Zevin, S., et al, ``Dose-Related Cardiovascular and Endocrine 
Effects of Transdermal Nicotine,'' Clinical Pharmacology and 
Therapeutics, 64(1):87-95, 1998.

V. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov.

1. Centers for Disease Control and Prevention, ``Annual Smoking-
Attributable Mortality, Years of Potential Life Lost, and 
Productivity Losses--United States, 2000-2004,'' Morbidity and 
Mortality Weekly Report, 57(45):1226-1228; November 14, 2008.
2. Centers for Disease Control and Prevention, ``Annual Smoking-
Attributable Mortality, Years of Potential Life Lost, and 
Productivity Losses--United States, 1995-1999,'' Morbidity and 
Mortality Weekly Report, 51(14):300-303; April 12, 2002.
3. Centers for Disease Control and Prevention, ``Quitting Smoking 
Among Adults--United States, 2001-2010,'' [serial online], Morbidity 
and Mortality Weekly Report, 60(44):1513-1519; November 11, 2011.

    Dated: March 26, 2013.
Peter Lurie,
Acting Associate Commissioner for Policy and Planning.
[FR Doc. 2013-07528 Filed 4-1-13; 8:45 am]
BILLING CODE 4160-01-P


