[Federal Register Volume 71, Number 111 (Friday, June 9, 2006)]
[Notices]
[Pages 33462-33465]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-9033]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2006N-0229]


Carbinoxamine Products; 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 
containing carbinoxamine and persons who cause the manufacture of such 
products. Numerous drug products containing carbinoxamine are marketed 
without approved applications and many are inappropriately labeled for 
use in infants and young children. Drug products containing 
carbinoxamine are new drugs that require approved applications. One 
firm has approved applications to market products containing 
carbinoxamine. In addition, there is information showing that 
carbinoxamine should not be used in children under 2 years of age. 
Manufacturers who wish to market carbinoxamine products that do not 
already have FDA approval must obtain FDA approval of a new drug 
application (NDA) or an abbreviated new drug application (ANDA). 
Elsewhere in this issue of the Federal Register, FDA is announcing the 
availability of a guidance entitled ``Marketed Unapproved Drugs--
Compliance Policy Guide.''

DATES: This notice is effective June 9, 2006.
    For marketed, unapproved carbinoxamine-containing drug products 
that have a National Drug Code (NDC) number that is listed with FDA on 
the effective date of this notice (i.e., ``currently marketed 
products''), however, the agency intends to exercise its enforcement 
discretion to permit products properly marketed with those NDC numbers 
a brief period of continued marketing after June 9, 2006 as follows. 
Any firm manufacturing such an unapproved drug product containing 
carbinoxamine that is labeled for use in children less than 2 years of 
age or marketed as drops for oral administration may not manufacture 
that product on or after July 10, 2006. Any firm manufacturing any 
other such unapproved drug product containing carbinoxamine may not 
manufacture that product on or after September 7, 2006. Unapproved drug 
products containing carbinoxamine that are not currently marketed and 
listed with the agency on the date of this notice must, as of the date 
of this notice, have approved applications prior to their introduction 
into interstate commerce.

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. 2006N-0229 and directed to the appropriate 
office listed as follows:
    Regarding applications under section 505(j) of the Federal Food, 
Drug, and Cosmetic Act (the act)(21 U.S.C. 355(j)): Office of Generic 
Drugs (HFD-600), Center for Drug Evaluation and Research, Food and Drug 
Administration, 7500 Standish Pl., Rockville, MD 20855.
    Regarding applications under section 505(b) of the act: 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.
    All other communications: John Loh, Division of New Drugs and 
Labeling Compliance, Center for Drug Evaluation and Research (HFD-310), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: John Loh, Division of New Drugs and 
Labeling Compliance, Center for Drug Evaluation and Research (HFD-310), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-827-8965, e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

A. The DESI Review

    When initially enacted in 1938, the act required that ``new drugs'' 
be approved for safety by FDA before they could legally be sold in 
interstate commerce. To this end, the act made it the sponsor's burden 
to show FDA that its drug was safe through the submission of an NDA. 
Between 1938 and 1962, if a drug obtained approval, FDA considered 
drugs that were identical, related, or similar (IRS)\1\ to the approved 
drug to be ``covered'' by that approval, and allowed those IRS drugs to 
be marketed without independent approval.
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    \1\ Section 310.6(b)(1) (21 CFR 310.6(b)(1)) provides: ``An 
identical, related, or similar drug includes other brands, 
potencies, dosage forms, salts, and esters of the same drug moiety 
as well as of any drug moiety related in chemical structure or known 
pharmacological properties.''
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    In 1962, Congress amended the act to require that new drugs also be 
proven effective for their labeled indications, as well as safe. This 
amendment also required FDA to conduct a retrospective evaluation of 
the effectiveness of the drug products that FDA had approved as safe 
between 1938 and 1962. FDA contracted with the National Academy of 
Science/National Research Council (NAS/NRC) to make an initial 
evaluation of the effectiveness of over 3,400 products that were 
approved only for safety. The NAS/NRC reports for these drug products 
were submitted to FDA in the late 1960s and early 1970s. The agency 
reviewed and re-evaluated the reports and published its findings in 
Federal Register notices. FDA's

[[Page 33463]]

administrative implementation of the NAS/NRC reports was called the 
Drug Efficacy Study Implementation (DESI). DESI covered the 3,400 
products specifically reviewed by the NAS/NRCs, as well as the even 
larger number of IRS products that entered the market without FDA 
approval.
    All drugs covered by the DESI review are ``new drugs'' under the 
act. If FDA's final DESI determination classifies a drug product as 
ineffective, that drug product and those IRS to it can no longer be 
marketed and are subject to enforcement action as unapproved new drugs. 
If FDA's final DESI determination classifies the drug product as 
effective for its labeled indications, the drug can be marketed 
provided it is the subject of an application approved for safety and 
efficacy. Those drug products with NDAs approved before 1962 for safety 
therefore require approved supplements to their original applications; 
IRS drug products require an approved NDA or ANDA, as appropriate. 
Furthermore, labeling for drug products classified as effective may 
contain only those indications for which the review found the product 
effective unless the firm marketing the product has received an 
approval for the additional indication(s).

B. DESI Review of Carbinoxamine Products

    Carbinoxamine, often manufactured as carbinoxamine maleate (CM), is 
a histamine H1 receptor blocking agent (i.e., antihistamine) of the 
ethanolamine class.\2\ This class exhibits antihistaminic, 
anticholinergic, and sedative properties. Certain single-ingredient 
carbinoxamine products are approved for treatment of various allergy 
symptoms. Carbinoxamine-containing products are often used for the 
treatment of colds and cough. However, the approved indications for 
carbinoxamine do not include treatment of either cold or cough. 
Carbinoxamine drug products often contain other active ingredients, 
such as decongestants or antitussives.
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    \2\ Unless a specific salt of carbinoxamine is identified, the 
term ``carbinoxamine'' as used in this notice refers to 
carbinoxamine maleate, carbinoxamine tannate, and any related or 
similar drug product as described in Sec.  310.6(b)(1) and (b)(2).
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    CM was initially marketed in the early 1950s. On June 22, 1953, FDA 
approved an NDA submitted by McNeil Laboratories (McNeil) to market 
single-ingredient CM in an immediate-release tablet form under the 
trade name Clistin (NDA 8-915); a tablet in ``repeat action'' form (an 
early timed-release technology), marketed as Clistin RA, was approved 
under the same NDA on June 15, 1954. On June 23, 1953, FDA approved 
McNeil's application to market single-ingredient CM in an elixir form 
under the trade name Clistin (NDA 8-955). On February 5, 1962, the 
agency approved McNeil's NDA 9-248 for a combination product, Clistin 
Expectorant, which contained CM, ammonium chloride, sodium citrate, 
potassium guaiacolsulfonate, and citric acid.
    The Clistin products specifically, and CM generally, were reviewed 
under DESI. In the Federal Register of March 19, 1973 (DESI 6303, 38 FR 
7265), FDA announced its conclusions regarding Clistin elixir and 
Clistin tablets, finding them to be ``new drugs'' that are effective 
for the following indications: (1) For the symptomatic treatment of 
seasonal and perennial allergic rhinitis, vasomotor rhinitis, allergic 
conjunctivitis due to inhalant allergens and foods; (2) for mild, 
uncomplicated allergic skin manifestations of urticaria and angioedema; 
(3) for the amelioration of the severity of allergic reactions to blood 
or plasma in patients with a known history of such reactions; (4) for 
dermographism; and (5) as therapy for anaphylactic reactions adjunctive 
to epinephrine and other standard measures after the acute 
manifestations have been controlled. In the Federal Register of March 
19, 1982 (DESI 6514, 47 FR 11973), FDA announced that Clistin 
Expectorant was found to lack substantial evidence of effectiveness, 
because no well-controlled studies documented the effectiveness of its 
expectorant ingredients and because the combination of an antihistamine 
and an expectorant was found not to be a rational combination. 
Accordingly, FDA proposed to withdraw approval of NDA 9-248 (47 FR 
11973 at 11974). In the Federal Register of April 30, 1982 (DESI 6303, 
47 FR 18667), FDA reclassified Clistin RA as lacking substantial 
evidence of effectiveness because there was no evidence regarding its 
bioavailability and bioequivalence, as required for a timed-release 
dosage form of a safe and effective immediate-release drug, and 
proposed to withdraw approval of NDA 8-915. Because no hearing was 
requested regarding Clistin Expectorant and no further data were 
submitted regarding Clistin RA, FDA announced final withdrawal of 
approval of the NDAs pertaining to these products on May 18, 1982 (47 
FR 21301), and July 29, 1983 (48 FR 34514), respectively. These notices 
also apply to drug products that are IRS to the carbinoxamine products 
reviewed under DESI.

C. Status of Applications for CM Products

    In notices published in the Federal Register on April 5, 1985 (50 
FR 13661), and March 2, 1994 (59 FR 9989), FDA withdrew approval of the 
NDAs for Clistin Elixir and Clistin Tablets, respectively, at the 
request of the application holder because the products were no longer 
marketed. In response to citizen petitions, FDA published notices in 
the Federal Register of May 21, 1998 (63 FR 27986), and April 10, 2000 
(65 FR 18998), confirming that Clistin CM tablets and elixir, 
respectively, were not withdrawn from sale for reasons of safety or 
efficacy and that ANDAs that refer to the products as the listed drug 
could be approved by the agency.
    Mikart, Inc. (Mikart), of Atlanta, GA, submitted ANDAs for single-
ingredient CM products in 4-milligram (mg) tablets (ANDA 40-442) and 4 
mg/5 milliliter solution form (ANDA 40-458), which were approved by FDA 
on March 19, 2003, and April 25, 2003, respectively, to treat the 
indications for which Clistin was found effective in the DESI review. 
The products are approved as prescription-only drug products. 
Currently, ANDAs 40-442 and 40-458 are the only approved applications 
for products containing carbinoxamine.

II. Safety Concerns

    The agency is aware of 21 deaths since 1983 in children under 2 
years of age associated with carbinoxamine-containing products. 
However, in most of those incidents, other active ingredients in the 
drugs or other factors aside from the drug could have been responsible 
for the death. Therefore, a causative relationship between exposure to 
carbinoxamine and death in these infants has not been established. 
Nevertheless, there is scientific support for the proposition that 
infants and young children may be more susceptible to experiencing 
drug-related adverse events, in part due to the normal immaturity of 
their metabolic pathways. Since the safety and efficacy of these drug 
products have not been studied in infants and young children, FDA is 
concerned about the risks of these products; the agency is especially 
concerned about those unapproved CM products that are being promoted 
for and may be associated with serious and life-threatening adverse 
outcomes in this vulnerable age group.
    In addition, infants and young children administered combination 
products containing carbinoxamine are at increased risk of suffering an 
adverse event due to product misidentification or dispensing errors and 
unintentional

[[Page 33464]]

overdose. This is due to the existence of multiple strengths, different 
formulations, and different combinations of active ingredients in 
marketed, unapproved carbinoxamine-containing products. Moreover, the 
appropriate dosing of carbinoxamine has not been established for 
patients under 2 years of age. Dosing suggestions for this age range 
appear to be extrapolated from adult dosing based on body weight (i.e., 
mg/kilograms), which is not scientifically supported and can lead to 
significant dosing errors. Finally, in infants and young children 
administered these products, parents or caregivers may have difficulty 
identifying potentially serious or life-threatening adverse events. By 
the time the serious nature of the event is recognized, it may be too 
late to successfully intervene.
    FDA is also concerned about the potential health risk associated 
with the use of other unapproved antihistamine and decongestant 
products in children under 2 years of age. We recognize that there is a 
similar lack of data regarding use of many of these products in infants 
and young children, and that variations in formulation and labeling of 
these products may also lead to errors and adverse events. FDA is 
evaluating the available scientific data regarding the use of these 
drugs in infants and young children and assessing appropriate 
regulatory approaches to best protect the public health. These kinds of 
products may be high priorities for future FDA enforcement action.

III. Current Status of Carbinoxamine Products

    Currently, the Mikart products covered by ANDA 40-442 and ANDA 40-
458 are the only products containing carbinoxamine with approved 
applications (see section I.C of this document). However, numerous 
unapproved products containing carbinoxamine are on the market; some 
are single-ingredient products and others are combination products 
containing ingredients such as pseudoephedrine, phenylephrine, or 
dextromethorphan.
    As of April 1, 2006, a total of 26 manufacturers had listed with 
FDA, under section 510(j) of the act (21 U.S.C. 360(j)), a total of 120 
prescription drug products containing carbinoxamine. Other unapproved, 
unlisted carbinoxamine products are also on the market. Various firms 
distribute these products under various names. In addition to the 
indications found effective in the DESI review, these products are 
often used to relieve congestion and other cold symptoms, and some 
unapproved versions include treatment of cold symptoms as an indication 
in their labeling.
    Many unapproved carbinoxamine products have labeling indicating 
that they may be used by children under 2 years of age and identify 
specific dosages for these young children, including some with specific 
dosages for infants as young as 1 to 3 months. Until recently, the 
approved carbinoxamine labeling indicated that the product was for use 
in individuals 1 year of age and older. To address the safety concerns 
described in this notice, the agency has approved a supplement 
submitted by Mikart modifying the approved labeling to specifically 
contraindicate use of the product in children under the age of 2 years. 
These changes will be reflected in future Mikart labels.

IV. Legal Status

    Under DESI 6303, as described previously, a drug product containing 
CM, alone or in combination with other drugs, is regarded as a new drug 
(21 U.S.C. 321(p)), and an approved application is required for 
marketing it. Because DESI drugs are ``new drugs,'' DESI-effective 
drugs need approval of an NDA, ANDA, or the required supplement. (See 
also United States v. Sage Pharmaceuticals, 210 F.3d 475 (5th Cir. 
2000) (holding that products containing carbinoxamine are new drugs 
that require an approved application to be lawfully marketed).)
    Thus, the agency intends to take enforcement action against any 
unapproved drug product that contains CM, whether as its sole active 
ingredient or in combination with one or more other active ingredients, 
and anyone who causes the manufacture of such products, as described in 
this notice. Under Sec.  310.6, this notice also applies to drug 
products, and those who cause their manufacture, that are marketed 
without an approved application and that are related or similar to the 
approved CM products reviewed under DESI 6303, including, but not 
limited to, products that contain carbinoxamine tannate, alone or in 
combination with another active ingredient. It is the responsibility of 
every drug manufacturer to review this notice to determine whether the 
notice covers any drug product that the person manufactures. Any person 
may request an opinion of the applicability of this notice to a 
specific drug product by writing to the Division of New Drugs and 
Labeling Compliance (see ADDRESSES). Requesting such an opinion does 
not excuse the person from complying with this notice in the time 
provided herein.
    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 
manufacturing products containing carbinoxamine without an approved 
application that the agency intends to take enforcement action against 
such products and those who cause them to be manufactured. The lack of 
approval for a carbinoxamine product can result in seizure, injunction, 
or other judicial proceeding. Elsewhere in this issue of the Federal 
Register, FDA is announcing the availability of a guidance entitled 
``Marketed Unapproved Drugs--Compliance Policy Guide'' (the Marketed 
Unapproved Drugs CPG), which describes how the FDA intends to exercise 
its enforcement discretion with regard to drugs marketed in the United 
States that do not have required FDA approval for marketing. 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 manufacturing unapproved products containing 
carbinoxamine prior to taking enforcement action.
    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 all carbinoxamine products. Because the 
NDAs for Clistin products were withdrawn at the request of the NDA-
holder, the Mikart carbinoxamine products as described in ANDAs 40-442 
and 40-458 have been designated as the reference listed drug products. 
Submission of an application does not excuse timely compliance with 
this notice. Following the effective dates listed in this notice, 
carbinoxamine products can only be manufactured after obtaining FDA 
approval.
    Consistent with the priorities identified in the Marketed 
Unapproved Drugs CPG, the agency is taking action at this time against 
unapproved carbinoxamine products because: (1) Carbinoxamine is a drug 
with potential safety risks, as described in section II of this 
document; and (2) the agency has approved an application to market a 
carbinoxamine-containing product, and thus the continued marketing of 
unapproved carbinoxamine products is a direct challenge to the drug 
approval process. The agency also reminds firms that, as stated in the 
Marketed Unapproved Drugs CPG, any

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unapproved drug marketed without a required approved drug application 
is subject to agency enforcement action at any time.
    As described in the Marketed Unapproved Drugs CPG, the agency may, 
at its discretion, exercise its enforcement discretion and identify a 
period of time during which the agency will not initiate an enforcement 
action against a currently marketed unapproved drug on the grounds that 
it is an unapproved new drug, 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 over-the-counter drug 
monograph and that are used to treat conditions for which carbinoxamine 
is commonly used. Based on the facts discussed in this notice, and 
especially in light of the availability of these products and the 
special concerns regarding use of carbinoxamine products in children 
under 2 years of age, FDA intends to implement this notice as follows.
    This notice is effective June 9, 2006. For marketed, unapproved 
carbinoxamine-containing products that have an NDC number that is 
listed with the agency on the effective date of this notice, however, 
the agency intends to exercise its enforcement discretion to permit 
products properly marketed with those NDC numbers a period of continued 
marketing after June 9, 2006 as follows. Any firm manufacturing such an 
unapproved drug product containing carbinoxamine that is labeled for 
use in children less than 2 years of age or marketed as drops for oral 
administration may not manufacture that product on or after July 10, 
2006. Any firm manufacturing any other such unapproved drug product 
containing carbinoxamine may not manufacture that product on or after 
September 7, 2006.\3\ The agency, however, does not intend to exercise 
its enforcement discretion as outlined in this paragraph if: (1) The 
manufacturer 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 of carbinoxamine 
drug products above its usual production volume during these 
periods.\4\
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    \3\ 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 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'').)
    \4\We note that the agency does not intend to take action 
against, or require removal from the market of, carbinoxamine 
products already in the drug distribution chain on the dates 
identified in this notice. Such action or removal may be appropriate 
for other products in other circumstances.
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    Drug manufacturers should be aware that the agency is exercising 
its enforcement discretion as described above only in regard to drug 
products containing carbinoxamine that are properly marketed under an 
NDC number listed with the agency on the date of this notice. 
Unapproved drug products containing carbinoxamine that are not 
currently marketed and listed with the agency on the date of this 
notice must, as of the date of this notice, have approved applications 
prior to their introduction into interstate commerce.
    Firms that have discontinued manufacturing products covered by this 
notice may want to contact FDA to advise us that they are no longer 
manufacturing those products. Some firms may have previously 
discontinued the manufacturing of those products without removing them 
from the listing of their products under section 510(j) of the act. 
Other firms may discontinue manufacturing 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, including its NDC number, and 
stating that the product has been discontinued and will not be marketed 
again without FDA approval, to the following address: John Loh, 
Division of New Drugs and Labeling Compliance (see ADDRESSES). Firms 
should also update the listing of their products under section 510(j) 
of the act to reflect discontinuation of unapproved carbinoxamine 
products. FDA plans to rely on its existing records, the results of a 
subsequent inspection, or other available information when it initiates 
enforcement action.
    In addition to discontinuing the manufacture of products that 
contain carbinoxamine, FDA cautions firms against reformulating their 
products into carbinoxamine-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 502(i) of the act (21 U.S.C. 352(a) and (i)).
    FDA notes that the issuance of this notice does not in any way 
obligate the agency to issue similar notices or any notice in the 
future regarding marketed unapproved drugs. Our general approach in 
dealing with these products in an orderly manner is spelled out in the 
Marketed Unapproved Drugs CPG. However, this 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.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (sections 502 and 505 (21 U.S.C. 352 and 355)) and under authority 
delegated to the Deputy Commissioner for Policy (21 CFR 5.20).

    Dated: June 6, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-9033 Filed 6-8-06; 8:45 am]
BILLING CODE 4160-01-S