[Federal Register Volume 68, Number 165 (Tuesday, August 26, 2003)]
[Rules and Regulations]
[Pages 51167-51170]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-21749]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 1980N-0050]
RIN 0910-AA01


Anorectal Drug Products for Over-the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
establishing that any over-the-counter (OTC) drug product containing a 
combination of hydrocortisone and pramoxine hydrochloride (HCl) for 
anorectal use is not generally recognized as safe and effective and is 
misbranded. This combination product is not currently marketed OTC. 
This final rule discusses data on the combination of hydrocortisone and 
pramoxine HCl that were still under review when an earlier final rule 
on OTC anorectal drug products was issued. This rule is part of FDA's 
ongoing review of OTC drug products.

DATES: This rule is effective September 25, 2003.

FOR FURTHER INFORMATION CONTACT: Michael T. Benson, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of May 27, 1980 (45 FR 35576), FDA 
published an advance notice of proposed rulemaking to establish a 
monograph for OTC anorectal drug products together with the 
recommendations of the Advisory Review Panel on OTC Hemorrhoidal Drug 
Products (the Hemorrhoidal Panel), which was the advisory review panel 
responsible for evaluating the data on the active ingredients in this 
class of drugs. The agency's tentative final monograph (TFM) on OTC 
anorectal drug products was published in the Federal Register of August 
15, 1988 (53 FR 30756). Hydrocortisone as a single ingredient or in 
combination with pramoxine HCl was not discussed in the TFM. In 
response to the TFM, the agency received a submission, containing data, 
information, analyses, views, legal arguments, and a hearing request, 
to support monograph status for a combination OTC drug product 
containing hydrocortisone and pramoxine HCl for use as an anti-
inflammatory, antipruritic, anesthetic agent (Ref. 1). The requester 
asked that: (1) The definition section of the proposed anorectal 
monograph (Sec.  346.3 (21 CFR 346.3)) be amended to provide for a drug 
that has anti-inflammatory properties, such as hydrocortisone, (2) 
hydrocortisone be allowed to be combined with other appropriate 
ingredients at OTC strengths, including a topical anesthetic such as 
pramoxine HCl and, (3) a combination of hydrocortisone 0.5 percent and 
1 percent pramoxine HCl be generally recognized as safe and effective.
    When the OTC anorectal drug products final monograph was published 
on August 3, 1990 (55 FR 31776 at 31779), the hearing request relating 
to hydrocortisone individually and in combination had not been 
evaluated and, therefore, was not addressed in that document. After 
publication of the final rule, the agency responded to the submission 
(Ref. 1) and stated that: (1) It does not provide sufficient evidence 
to demonstrate that each of the active ingredients in the combination 
product contributes to the claimed effects and (2) it has not been 
shown that the combination is generally recognized as safe and 
effective, whether under the TFM for OTC external analgesic drug 
products (48 FR 5852, February 8, 1983), the TFM or FM for OTC 
anorectal drug products, current regulations, or the agency's OTC 
combination drug product guidelines. The agency's detailed comments are 
on file in the Division of Dockets Management (Ref. 2).
    Subsequently, the requester submitted additional information (Ref. 
3). In this final rule, the agency responds to the additional 
information and includes the combination of hydrocortisone with 
pramoxine HCl as a nonmonograph (not generally recognized as safe and 
effective) anorectal drug product in new Sec.  310.545(a)(26)(xi) (21 
CFR 310.545(a)(26)(xi)). Any such product marketed OTC would be subject 
to regulatory action if initially introduced or initially delivered for 
introduction into interstate commerce after the effective date of this 
final rule.

II. The Agency's Final Conclusions on Hydrocortisone Individually and 
in Combination With Pramoxine HCl for Anorectal Use

    The requester contended (Ref. 3) that the proposed combination 
meets, both from a scientific and legal perspective, the agency's OTC 
combination drug product policy in that a combination of hydrocortisone 
(0.25 to 1 percent) and pramoxine HCl 1 percent, is generally 
recognized as safe and effective for use in OTC drug products to 
relieve symptoms associated with idiopathic pruritus ani, such as 
anorectal swelling, pain, itching, and burning. The requester asked the 
agency to amend the OTC external analgesic drug products TFM and the 
anorectal drug products FM to include an external analgesic-anorectal 
OTC drug product containing the active ingredients hydrocortisone and 
pramoxine HCl. In the alternative, the requester asked for an oral 
hearing.
    The requester's arguments and the agency's responses follow:
    (Comment 1) Hydrocortisone is a proposed Category I ingredient and; 
therefore, FDA considers it safe and effective for OTC use. The 
ingredient is included in the OTC external analgesic drug products TFM 
(55 FR 6932 at 6951, February 27, 1990). FDA considers hydrocortisone 
safe and effective to relieve swelling and itching associated with 
various skin conditions, including anal itching (55 FR 6932 at 6933).
    (Agency response) The agency agrees that hydrocortisone as a single 
ingredient is safe and effective for OTC use for the claims proposed in

[[Page 51168]]

Sec.  348.50(b) (21 CFR 348.50(b)) (55 FR 6932 at 6951). However, data 
are lacking to support any combination drug products containing 
hydrocortisone with other OTC drug active ingredients. Further, the 
1990 TFM cited by the requester did not include the term ``swelling'' 
as an acceptable claim.
    (Comment 2) Pramoxine HCl is a Category I ingredient, and thus FDA 
considers it safe and effective for OTC use. The ingredient is included 
in Sec.  346.10(g) (21 CFR 346.10(g)) of the OTC anorectal drug 
products FM for the treatment of various anorectal conditions, 
including pain, burning, itching, discomfort, and/or irritation. The 
requester contended that OTC anorectal drug products containing 
pramoxine HCl in the established dosages of 0.5 to 1 percent that are 
indicated to relieve pruritus ani may be lawfully marketed in 
accordance with the OTC anorectal drug products FM.
    (Agency response) Pramoxine HCl 0.5 to 1 percent is a proposed 
Category I ingredient as a local anesthetic in the TFM for OTC external 
analgesic drug products (48 FR 5852 at 5867). The requester mentioned 
that this concentration range could be used in OTC anorectal drug 
products. However, only a 1 percent concentration is included in Sec.  
346.10(g) of the OTC anorectal drug products monograph as this was the 
only concentration evaluated in that rulemaking. The agency lacks data 
to support a lower concentration for external anorectal use.
    (Comment 3) The agency has the authority to switch the status of a 
product from prescription to OTC when the active ingredient or the 
combination of active ingredients is determined to be safe and 
effective for OTC use. The requester cited the Federal Register of 
August 4, 1976 (41 FR 32580) and May 11, 1972 (37 FR 9464 at 9470) as 
sources for that authority.
    (Agency response) The agency has made the determination that the 
combination of hydrocortisone and pramoxine HCl is not safe and 
effective for OTC use. Therefore, switching the status of the product 
from prescription to OTC is not an option. Although the agency is not 
bound by the recommendations of its advisory panels, the panels that 
reviewed these ingredients did not recognize any combination of 
``amine'' and ``caine'' type local anesthetics with hydrocortisone 
preparations as safe and effective. The requester has also failed to 
provide adequate information to support a determination that the 
combination is safe and effective. The agency lacks sufficient data 
from available sources to propose a combination of hydrocortisone and 
pramoxine HCl for OTC use in the applicable OTC drug rulemakings.
    (Comment 4) Combination products containing hydrocortisone and 
pramoxine HCl should have been reconsidered by the agency when it 
extended the concentration range for hydrocortisone up to 1 percent. 
Specifically, the agency has the obligation to reconsider combination 
products when it determines that all of the active ingredients 
contained in the combination are Category I, and an interested person 
has requested the combination be considered under a particular OTC drug 
rulemaking proceeding (21 CFR Sec.  330.10(a)(7) and (a)(12)) (21 CFR 
330.10(a)(7) and (a)(12)).
    (Agency response) The agency disagrees. The agency's proposal to 
increase the maximum concentration of hydrocortisone from 0.5 to 1 
percent occurred in the rulemaking for OTC external analgesic drug 
products based on data on the single ingredient and not on combination 
products. There were no proposed hydrocortisone combinations in that 
rulemaking. The data on the combination of hydrocortisone 1 percent and 
pramoxine HCl were submitted to the rulemaking on OTC anorectal drug 
products and had not been reviewed by the agency at the time it 
published the amendment to the OTC external analgesic TFM on February 
27, 1990 (55 FR 6932) extending the strength of hydrocortisone up to 1 
percent. The agency published the FM on OTC anorectal drug products on 
August 3, 1990 (55 FR 31776 at 31777), in which it stated that 
hydrocortisone combinations were under review and the agency's 
evaluation would be reported separately in the future. Simultaneous 
publication of the agency's evaluation of the single ingredient 
hydrocortisone in the rulemaking for OTC external analgesic drug 
products and hydrocortisone-pramoxine HCl combinations in the 
rulemaking for OTC anorectal drug products would have delayed 
publication of the anorectal FM for several years.
    (Comment 5) Prior to completing the FM for OTC external analgesic 
drug products, the agency should conduct a retrospective analysis of 
previously reviewed (or ``should have been reviewed'') hydrocortisone 
combinations marketed before 1979.
    (Agency response) The agency previously reviewed combination drug 
products containing hydrocortisone and pramoxine HCl submitted during 
the 1970s and 1980s. In a notice of proposal to withdraw approval of 
abbreviated new drug applications for fixed combination drug products 
containing hydrocortisone acetate and pramoxine HCl, the agency found 
no evidence that pramoxine HCl contributed an effect to the combination 
drug product (53 FR 25013, July 1, 1988).
    (Comment 6) The agency has consistently applied its combination 
policy, except with respect to a hydrocortisone and pramoxine HCl 
combination. The agency did not require additional data in support of 
the effectiveness of combinations in the monographs for OTC antacid 
(simethicone and an antacid), cough-cold (ingredients from different 
pharmacological groups), laxative (bulk and stimulant laxatives), and 
anorectal drug products (not requiring final formulation testing of 
combination products and accepting the combinations as formulated).
    (Agency response) The agency has consistently focused on the safety 
and effectiveness of each active ingredient, the rationale for 
concurrent therapy, the contribution each ingredient makes to the 
combination, and the marketing history to support Category I 
classification of combinations. Marketing history for the products 
cited by the requester provided more extensive data than were available 
for a combination of hydrocortisone and pramoxine HCl for anorectal 
use. There was an extensive marketing history for combinations of an 
antacid and simethicone, an antiflatulent, ingredients with different 
indications. The agency required additional data for a number of cough-
cold combinations in the TFM for those products (53 FR 30522, August 
12, 1988). The combinations in the laxative TFM (50 FR 2124 at 2152 and 
2153, January 15, 1985) and anorectal FM involve ingredients with the 
same indication. The Advisory Review Panel for OTC Laxative Drug 
Products (Laxative Panel) looked at laxative combinations and 
determined that each active ingredient had to make a contribution 
toward laxation. The Laxative Panel recommended monograph status only 
for combinations it determined had sufficient data. FDA agreed with the 
Panel's recommendation, and the agency has requested additional data to 
support other laxative combinations. The Hemorrhoidal Panel evaluated 
and recommended combinations of anorectal ingredients (45 FR 35576 at 
35673), but did not evaluate hydrocortisone because information on that 
ingredient was not submitted for its review. The Advisory Review Panel 
on OTC Topical Analgesic, Antirheumatic,

[[Page 51169]]

Otic, Burn, and Sunburn Prevention and Treatment Drug Products (Topical 
Analgesic Panel) discussed combinations of external analgesic 
ingredients, including hydrocortisone and pramoxine HCl, but did not 
recommend this combination for monograph status (44 FR 69768 at 69790, 
December 4, 1979).
    The agency has not always accepted a panel's recommendation that 
specific combinations should be allowed, without having adequate 
supporting data. For example, the Advisory Review Panel on OTC 
Antimicrobial (II) Drug Products recommended monograph status for 
combinations of up to three antifungal ingredients and hydrocortisone 
or hydrocortisone acetate 0.5 to 1 percent (47 FR 12480, March 23, 
1982). The agency disagreed with that panel's recommendations because 
the agency found that these combinations lacked adequate evidence of 
effectiveness (47 FR 12480 at 12481). The rulemaking for antifungal 
drug products has been completed and, because adequate data were not 
provided to support this combination, it remains nonmonograph. No 
combination containing hydrocortisone has been found to be generally 
recognized as safe and effective for OTC use. Thus, the agency is 
consistent in requiring additional data to support this hydrocortisone-
pramoxine HCl combination.
    (Comment 7) Currently marketed prescription products containing 1 
percent or less hydrocortisone and 1 percent pramoxine HCl meet the 
combination policy implemented by the agency. The OTC drug combination 
policy standards are satisfied because the active ingredients are 
Category I, are present in the established dosage range, and each 
ingredient represents a different therapeutic category. The requester 
also mentioned a previously submitted clinical protocol (Ref. 3) that 
was not initiated because this protocol was suspended following a 
meeting with FDA (Ref. 4).
    (Agency response) The agency's requirements for OTC drug 
combination products in Sec.  330.10(a)(4)(iv) also include that each 
active ingredient makes a contribution to the product's claimed 
effect(s). The agency has no data showing that the combination of 
hydrocortisone and pramoxine HCl has been clinically tested against 
each individual active ingredient and a placebo. As the agency 
discussed in its January 13, 1994, letter to the requester (Ref. 2), 
the submitted data did not include these types of studies. Further, the 
studies from the literature did not involve a patient population where 
the product is intended for OTC use, nor were they for the proposed OTC 
anorectal indication. Therefore, based on the available data, the 
agency is unable to conclude that each active ingredient makes a 
contribution to the product's claimed effect(s) and that this 
combination is generally recognized as safe and effective. After the 
agency received a letter indicating that the requester's client had 
suspended an ongoing study of the combination (Ref. 4), the agency was 
under the impression that there was no longer interest in having the 
protocol reviewed. The requester should notify the agency if there is 
still interest in conducting the appropriate study and having the 
protocol reviewed.
    (Comment 8) The combination of 1 percent or less hydrocortisone and 
1 percent pramoxine HCl is warranted because hydrocortisone is a 
therapeutic equivalent of other active antipruritic ingredients that 
may be combined with a local anesthetic such as pramoxine HCl. In the 
past, the agency has permitted active ingredient substitutions with 
pharmacological classes. Further, while the method of action of 
hydrocortisone is different than other antipruritic agents, the 
requester suggests that it can be properly combined with local 
anesthetics, because it is therapeutically equivalent, if not superior, 
to other approved antipruritic agents.
    (Agency response) The agency's response under section II, comment 6 
of this document applies here also. The requester's belief that the 
combination of an antipruritic/analgesic with a local anesthetic is 
permitted by implication is incorrect. Section 346.22 (21 CFR 346.22) 
provides for the combination of an ``antipruritic/analgesic and a local 
anesthetic with an astringent.'' The ingredients under proposed Sec.  
348.10 (48 FR 5852 at 5868) are classified as ``analgesic/anesthetic/
antipruritic.''
    Listed combinations of external analgesic active ingredients under 
proposed Sec.  348.50 include ingredients listed under Sec.  348.10(a), 
(b), and (c) exclude hydrocortisone preparations which are listed under 
proposed Sec.  348.10(d)(1) as hydrocortisone and under (d)(2) as 
hydrocortisone acetate. The Topical Analgesic Panel classified 
hydrocortisone preparations in a listing of ingredients that depress 
cutaneous sensory receptors (analgesics, anesthetics, and 
antipruritics) (44 FR 69768 at 69865, December 4, 1979). The agency 
subdivided the analgesic, anesthetic antipruritic ingredients into 
separate classes, i.e., ''caine'' type local anesthetics, alcohols and 
ketones, antihistamines, and hydrocortisone preparations (48 FR 5852 at 
5867 and 5868, February 8, 1983). The Topical Analgesic Panel did not 
have adequate data to consider hydrocortisone and pramoxine HCl 
interchangeable, and the agency has no basis to recommend their 
interchangeability and inclusion in any OTC drug product monograph.
    (Comment 9) If the agency is unable to conclude from the 
information presented that the proposed combination is Category I, the 
agency should grant a hearing in this matter.
    (Agency response) The agency has evaluated all of the evidence in 
support of a combination of hydrocortisone and pramoxine HCl in the 
administrative record for the rulemaking for OTC anorectal drug 
products submitted on behalf of the requester's client. The agency has 
discussed this information in its letter of January 13, 1994 (Ref. 2) 
and in this document. The agency does not find an oral hearing 
warranted.

III. Analysis of Impacts

    FDA has examined the impacts of this final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). 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). Under the Regulatory 
Flexibility Act, if a rule has a significant impact on a substantial 
number of small entities, an agency must analyze regulatory options 
that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
expenditure in any one year by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation). The final rule that led to the development of 
this supplemental final rule was published in 1990, before the Unfunded 
Mandates Reform Act of 1995 was enacted. The agency explains in this 
final rule that the final rule will not result in an expenditure in any 
one year by State, local, and tribal governments, in the aggregate, or 
by the private sector, of $100 million.
    The agency concludes that this final rule is consistent with the 
principles set out in the Executive order and in these two statutes. 
The final rule is not a

[[Page 51170]]

significant regulatory action as defined by the Executive order and so 
is not subject to review under the Executive order. Further, since this 
final rule makes no mandates on government entities and will result in 
expenditures less than $100 million in any one year, FDA need not 
prepare additional analyses under the Unfunded Mandates Reform Act.
    The purpose of this final rule is to establish that OTC anorectal 
drug products containing a combination of hydrocortisone and pramoxine 
HCl are not generally recognized as safe and effective. Because no such 
products are currently marketed OTC, the final rule will not have an 
economic impact on any entity (no reformulations or relabeling are 
necessary) and will not require any new reporting or recordkeeping 
activities.
    The agency has no alternative course of action as the data are 
inadequate to support monograph status for this combination product. 
Therefore, no additional professional skills are needed. The 
Commissioner of Food and Drugs certifies that this final rule will not 
have a significant economic impact on a substantial number of small 
entities. No further analysis is required under the Regulatory 
Flexibility Act (5 U.S.C. 605(b)).

IV. Paperwork Reduction Act of 1995

    This 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.

V. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Federalism

    FDA has analyzed this 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, a 
federalism summary impact statement is not required.

VII. References

    The following references are on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852, in Docket No. 1980N-0050 and may be seen 
by interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Comment No. HER1.
    2. LET26.
    3. Comment No. C25.
    4. OTC vol. 12FR3.

List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
310 is amended as follows:

PART 310--NEW DRUGS

0
1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 
263b-263n.

0
2. Section 310.545 is amended by adding paragraph (a)(26)(xi), by 
revising paragraph (d) introductory text, by revising paragraph 
(d)(13), and by adding paragraph (d)(37) to read as follows:


Sec.  310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (26) * * *
    (xi) Combination drug products. Any combination drug product 
containing hydrocortisone and pramoxine hydrochloride.
* * * * *
    (d) Any OTC drug product that is not in compliance with this 
section is subject to regulatory action if initially introduced or 
initially delivered for introduction into interstate commerce after the 
dates specified in paragraphs (d)(1) through (d)(37) of this section.
* * * * *
    (13) August 5, 1991, for products subject to paragraph (a)(26) of 
this section, except for those that contain live yeast cell derivative 
and a combination of hydrocortisone and pramoxine hydrochloride.
* * * * *
    (37) September 25, 2003, for products subject to paragraph 
(a)(26)(xi) of this section.

    Dated: August 18, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-21749 Filed 8-25-03; 8:45 am]
BILLING CODE 4160-01-S