Additional copies of this Guidance are available from:
Office of Training and Communication
Division of Communications Management
Drug Information Branch, HFD-210,
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
(Phone 301-827-4573)
Internet: http://www.fda.gov/cder/guidance/index.htm
February 2001
OTC
TABLE OF CONTENTS
I. INTRODUCTION
II. BACKGROUND
III. FDA RECOMMENDED LABELING EXAMPLES FOR SOME PRODUCTS
IV. SUBMISSION OF NEW LABELING IN AN ANNUAL REPORT
Guidance for Industry1
Labeling OTC Human Drug Products -
Updating Labeling in ANDAs
This draft guidance, when finalized, will represent the Food and Drug Administration's
(FDA's) current thinking on this topic. It does not create or confer any rights for or on
any person and does not operate to bind FDA or the public. An alternative approach may be
used if such approach satisfies the requirements of the applicable statutes and
regulations.
If you plan to submit comments on this draft guidance, to expedite FDA review of
your comments, please:
· Clearly explain each issue/concern and, when appropriate, include a proposed
revision and the rationale/justification for the proposed change.
· Identify specific comments by line number(s); use the PDF version of the
document, if possible.
I. INTRODUCTION
This guidance is intended to assist manufacturers, packers, and distributors of
over-the-counter (OTC) drug products marketed under ANDAs (abbreviated new drug
applications) and the manufacturer of the corresponding reference listed drug (RLD)
implement the Agency_s regulation on standardized content and format requirements for the
labeling of OTC drug products. The guidance contains recommendations on how RLD and ANDA
holders can update their labeling in a timely manner consistent with the regulation on OTC
drug labeling (21 CFR 201.66).
II. BACKGROUND
In the Federal Register of March 17, 1999 (64 FR 13254), the Food and Drug
Administration (FDA) published a final regulation establishing standardized content and
format requirements for the labeling of OTC drug products. Standardized labeling for OTC
drug products is intended to make it easier for consumers to read and understand OTC drug
product labeling and use such products safely and effectively.
The new labeling regulation in 21 CFR 201.66 covers all OTC drug and drug-cosmetic
products, whether marketed under a new drug marketing application (NDA), abbreviated new
drug application (ANDA), or OTC drug monograph (or product not yet the subject of a final
OTC drug monograph). The implementation dates are the same for products that were legally
marketed under an NDA or ANDA before the date of the final rule.
Section 201.66(c)(1) through (c)(9) of the labeling regulation provides the content
requirements for labeling information, including information about active ingredients,
their purpose, use, warnings, directions, other information, and inactive ingredients.
Questions have been submitted to the Agency asking whether products marketed under an
ANDA can use the new labeling content and format requirements prior to the RLD, or must
the ANDA holder wait for the RLD holder to submit revised labeling and then submit
labeling that is the same as that of the RLD. These questions have been raised because
under the Federal Food, Drug, and Cosmetic Act, a drug product marketed under an ANDA must
bear the same labeling as that approved for the RLD (21 U.S.C. 355(j)(2)).
The "same labeling" requirement does not require an ANDA's labeling to be
identical to that of the RLD. Among permissible differences, FDA regulations (21 CFR
314.94(a)(8)(iv)) allow an ANDA holder to include labeling that is different from that of
the RLD where the ANDA labeling revisions are made _to comply with current FDA guidelines
or other guidance._ In this case, the new Drug Facts labeling changes to be made in ANDA
labeling would result from a regulation (21 CFR 201.66). In addition, the preamble to the
OTC drug product labeling final regulation states that the adoption of the new labeling
format for most OTC drug products marketed under an NDA or ANDA would be considered
editorial or minor changes and that the majority of the changes required by the final
regulation could be submitted to the Agency in an annual report to the application under
21 CFR 314.70(d)(3).2
III. FDA RECOMMENDED LABELING EXAMPLES FOR SOME PRODUCTS
The Agency stated in its OTC drug product labeling final regulation that it expects 522
submissions (350 to NDAs and 172 to ANDAs) for labeling changes under 21 CFR 201.66(c) and
(d). Submissions to NDA's will vary as many different products are marketed under NDAs.
However, submissions to ANDAs will be concentrated in the following products:
· ibuprofen tablets: 35 expected
More than 5 ANDA submissions are expected for the following:
· acetaminophen suppositories
· cimetidine tablets
· loperamide tablets and oral solution
· miconazole vaginal cream and suppositories
· minoxidil topical solution
· naproxen sodium tablets
Together, these constitute about 50 percent of all OTC drug product ANDAs. The Agency
believes manufacturers of ANDA products need not wait to implement the new
labeling format until after the RLD holder has submitted its labeling.
To facilitate the implementation of the new Drug Facts labeling for ANDA products, the
Agency is developing labeling examples for manufacturers to follow for each of the
products listed above. Manufacturers of OTC ANDA products for which FDA does not currently
plan to develop labeling examples may implement labeling changes before their RLD's and
may use these labeling examples to guide their own effort to comply with 21 CFR 201.66.
Two labeling examples, which show specific product labeling in the new format, are
included in this draft guidance: One for ibuprofen 200 milligram (mg) in a tablet/capsule
dosage form; and one for minoxidil topical solution 2% for men and women. These labeling
examples may also be found on the OTC Internet website at www.fda.gov/cder/otc/.
The agency intends to develop the additional labeling examples referenced above, and they,
too, will be made available before the close of the comment period at the same OTC
Internet website.
The labeling examples developed as part of this guidance represent the agency's current
thinking on this subject, and they do not create or confer any rights for or on any person
and do not operate to bind FDA or the public. An alternative approach may be used if such
an approach satisfies the requirements of the applicable statutes and regulations.
When using the labeling examples, it should be noted that interchangeable terms can be
used in certain places (see 21 CFR 330.1(i) and (j)). For example, although the Agency
uses the word doctor in its labeling examples, the term physician can also
be used where appropriate.
IV. SUBMISSION OF NEW LABELING IN AN ANNUAL REPORT
Manufacturers can submit their ANDA labeling changes in their annual reports according
to 21 CFR 314.70(d)(3) and need not submit a supplemental application to the Agency for
preapproval under several different circumstances:
· If they use the Agency's labeling examples to make their changes
· If they do not use the Agency's labeling examples, but change their labeling
in accordance with 21 CFR 201.66 and 21 CFR 330.1(i) or (j)
· Where the Agency has not provided any labeling examples, if they change their
labeling in accordance with 21 CFR 201.66 and 21 CFR 330.1(i) or (j)
Manufacturers should submit preapproval supplements to the NDA or ANDA, as appropriate,
if they make changes to the content of the labeling or wording changes that go beyond
those provided for in 21 CFR 330.1(i) or (j).
Example Drug Facts Label for Ibuprofen 200 mg in a
Tablet/Capsule Dosage Form
Drug Facts
Active ingredient (in each [insert dosage unit]) Purposes
Ibuprofen 200
mg...............................................................................Pain
reliever/fever reducer
Uses
_ temporarily relieves minor aches and pains due to:
_ headache _ muscular aches _ minor pain of arthritis _ toothache
_ backache _ the common cold _ menstrual cramps
_ temporarily reduces fever
Warnings
Allergy alert: Ibuprofen may cause a severe allergic reaction which may include:
_ hives _ facial swelling _ asthma (wheezing) _ shock
Alcohol warning: If you consume 3 or more alcoholic drinks every day, ask your
doctor whether you should take ibuprofen or other pain relievers/fever reducers. Ibuprofen
may cause stomach bleeding.
Do not use if you have ever had an allergic reaction to any other pain
reliever/fever reducer
Ask a doctor before use if you have
_ stomach pain
_ problems or serious side effects from taking pain relievers or fever reducers
Ask a doctor or pharmacist before use if you are
_ under a doctor_s care for any serious condition
_ taking any other drug
_ taking any other product that contains ibuprofen, or any other pain reliever/fever
reducer
When using this product take with food or milk if stomach upset occurs
Stop use and ask a doctor if
_ an allergic reaction occurs. Seek medical help right away.
_ pain gets worse or lasts more than 10 days
_ fever gets worse or lasts more than 3 days
_ stomach pain or upset gets worse or lasts
_ redness or swelling is present in the painful area
_ any new symptoms appear
If pregnant or breast-feeding, ask a health professional before use. It is
especially important not to use ibuprofen during the last 3 months of pregnancy unless
definitely directed to do so by a doctor because it may cause problems in the unborn child
or complications during delivery.
Keep out of reach of children. In case of overdose, get medical help or contact
a Poison Control Center right away.
Directions3
_ do not take more than directed
_ adults and children 12 years and older:
_ take 1 [insert dosage unit] every 4 to 6 hours while symptoms persist
_ if pain or fever does not respond to 1 [insert dosage unit], 2 [insert dosage
unit(s)] may be used
_ do not exceed 6 [insert dosage unit(s)] in 24 hours, unless directed by a doctor
_ the smallest effective dose should be used
_ children under 12 years: ask a doctor
Other information
_ optional - tamper evident statement
_ store at 20-250 C (68-770 F).
Avoid high humidity and excessive heat above 400 C
(1040 F).
_ optional - see [end or side] panel for lot number and expiration date
Inactive ingredients [list ingredients in alphabetical order]
Questions or comments? call toll free 1-800-XXX-XXXX
NOTE: The Drug Facts (continued) title should appear wherever the
labeling continues onto another panel of the package.
Example Drug Facts Label for Minoxidil Topical Solution 2% for
Men and Women
Drug Facts
Active ingredient Purpose
Minoxidil 2%
w/v......................................................................................Hair
regrowth treatment
Use
__to regrow hair on the scalp
Warnings
For external use only
Flammability warning: Keep away from fire or flame [Include if product meets the
criteria in 16 CFR 1500.3(b)(10)]
Do not use if
__your degree of hair loss is more than that shown on the side of this carton.
Minoxidil topical solution 2% may not work.
__you have no family history of hair loss
__hair loss is sudden and/or patchy
[Use for products for women]__hair loss is associated with childbirth
__you do not know the reason for your hair loss
__you are under 18 years of age. Do not use on babies and children.
__scalp is red, inflamed, infected, irritated, or painful
__you use other topical prescription products on the scalp
When using this product
__do not apply on other parts of the body
__avoid contact with the eyes. In case of accidental contact, rinse eyes with large
amounts of cool tap water.
__it takes time to regrow hair. You may need to use minoxidil topical solution daily
for
at least 4 months before you see results.
__the amount of hair regrowth is different for each person. Minoxidil topical solution
will not work for everyone.
Stop use and ask a doctor if
__chest pain, rapid heart beat, faintness, or dizziness occurs
__sudden, unexplained weight gain occurs
__your hands or feet swell
__redness or irritation occurs.
__you do not see hair regrowth in [insert 12 for products for men and 8 for products
for women] months
[Use for products for women] If pregnant or breast feeding, ask a health
professional before use.
Keep out of reach of children. If swallowed, get medical help or contact a
Poison Control Center right away.
Directions
__apply one mL 2 times a day directly onto the scalp in the hair loss area
__using more or more often will not improve results
__continued use is necessary to increase and keep your hair regrowth, or hair loss will
begin again
Other information
__see hair loss pictures on side of this carton
__before use, read all information on carton and enclosed booklet
__keep the carton. It contains important information.
__[Use for products for men] in clinical studies of mostly white men aged 18-49 years
with moderate degrees of hair loss, the following response to minoxidil topical solution
2% was reported: 26% of men reported moderate to dense hair regrowth after using minoxidil
topical solution 2% for 4 months (26% had moderate to dense regrowth; 33% had minimal
regrowth). This compares with 11% of men reporting hair regrowth after using the placebo,
the liquid without minoxidil in it, for 4 months (11% had moderate to dense regrowth; 31%
had minimal regrowth).
__[Use for products for women] in clinical studies of mostly white women aged 18-45
years with mild to moderate degrees of hair loss, the following response to minoxidil
topical solution 2% was reported: 19% of women reported moderate hair regrowth after using
minoxidil topical solution 2% for 8 months (19% had moderate regrowth; 40% had minimal
regrowth). This compares with 7% of women reporting moderate hair regrowth after using the
placebo, the liquid without minoxidil in it, for 8 months (7% had moderate regrowth; 33%
had minimal regrowth).
__optional - storage conditions [that are appropriate for the product in both 0
C and 0 F]
Inactive ingredients [list ingredients in alphabetical order; list
alcohol as % v/v]
Questions or comments? call toll free 1-800-XXX-XXXX
NOTE: The Drug Facts (continued) title should appear wherever the
labeling continues onto another panel of the package.
