
[Federal Register Volume 79, Number 7 (Friday, January 10, 2014)]
[Notices]
[Pages 1879-1882]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-00257]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-1485]


Unapproved and Misbranded Oral and Injectable Drugs Labeled for 
Prescription Use Containing Codeine Sulfate, Codeine Phosphate, or 
Dihydrocodeine Bitartrate; Enforcement Action Dates

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
announcing its intention to take enforcement action against unapproved 
and misbranded oral and injectable drug products labeled for 
prescription use and containing codeine sulfate, codeine phosphate, or 
dihydrocodeine bitartrate, and against persons who manufacture or cause 
the manufacture or distribution of such products in interstate 
commerce. Prescription drug products containing these ingredients pose 
serious risks, including the risk of addiction, and some unapproved 
drug products may lack warnings or other information required in the 
labeling of approved drug products that is important for safe use. 
These unapproved drug products compete with approved drug products and 
thus pose a direct challenge to the drug approval system. This document 
covers the following unapproved drug products labeled for prescription 
use: Single-ingredient codeine sulfate oral tablets and solutions, 
single-ingredient codeine phosphate injection products, fixed-dose 
combination products containing codeine phosphate, and fixed-dose 
combination products containing dihydrocodeine bitartrate. A new drug 
containing codeine sulfate, codeine phosphate, or dihydrocodeine 
bitartrate requires an approved new drug application (NDA) or 
abbreviated new drug application (ANDA) to be legally marketed.

DATES: This document is effective January 10, 2014. For information 
about enforcement dates, see the SUPPLEMENTARY INFORMATION, section IV.

ADDRESSES: All communications in response to this document should be 
identified with Docket No. FDA-2013-N-1485 and directed to the 
appropriate office listed in this ADDRESSES section:
    Applications under section 505(b) of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) (21 U.S.C. 355(b)): Division of Anesthesia, 
Analgesia and Addiction Products (for products with analgesic 
indications) or Division of Pulmonary, Allergy, and Rheumatology 
Products (for products with antitussive indications), 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.
    Applications under section 505(j) of the FD&C Act: Office of 
Generic Drugs, Center for Drug Evaluation and Research, Food and Drug 
Administration, 7519 Standish Pl., Rockville, MD 20855.
    All other communications: Astrid Lopez-Goldberg, Office of 
Unapproved Drugs and Labeling Compliance, Division of Prescription 
Drugs, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5185, Silver 
Spring, MD 20993-0002.

FOR FURTHER INFORMATION CONTACT: Astrid Lopez-Goldberg, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5185, Silver Spring, MD 20993-0002, 301-
796-3485, Astrid.LopezGoldberg@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    Codeine is an opioid used primarily as an analgesic to relieve pain 
or as an antitussive to treat coughs. Codeine sulfate and codeine 
phosphate are different salts of codeine, generally also for analgesic 
or antitussive use. Dihydrocodeine bitartrate is a chemical derivative 
of codeine and an opioid pain reliever that produces effects similar to 
those of codeine.
    Side effects are similar among all opioids and include light-
headedness, dizziness, drowsiness, headache, fatigue, sedation, 
sweating, nausea, vomiting, constipation, itching, and skin reactions. 
Serious adverse effects are respiratory depression, resulting in a slow 
breathing rate, and decreased blood pressure. Multiple active 
ingredients (including acetaminophen, aspirin, butalbital, caffeine, 
carisoprodol, promethazine, or phenylephrine) may be marketed in 
combination with codeine phosphate or dihydrocodeine bitartrate. Some 
of these fixed-dose combination products include more than one sedating 
component.
    Single-ingredient products containing codeine, such as codeine 
sulfate oral tablets and solutions, and codeine phosphate injection 
products, are schedule II narcotics (Sec.  1308.12 (21 CFR 1308.12)) 
under the Controlled Substances Act (21 U.S.C. 801 et seq.). Single-
ingredient prescription codeine sulfate oral tablets and a single-
ingredient prescription codeine sulfate oral solution are approved for 
the relief of mild to moderately severe pain. On October 13, 2009, the 
Agency issued four warning letters to companies manufacturing and/or 
marketing unapproved prescription codeine sulfate oral tablets.\1\ 
However, FDA is aware of at least one unapproved prescription codeine 
sulfate oral tablet that is still listed with FDA's Drug Registration 
and Listing System. Although FDA is unaware of any unapproved single-
ingredient codeine phosphate injection products on the market at this 
time, such products were on the market as recently as 2010.
---------------------------------------------------------------------------

    \1\ Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm238675.htm#codeine_sulfate.
---------------------------------------------------------------------------

    Fixed dose combination products containing codeine phosphate are 
placed on different schedules under the Controlled Substances Act 
depending on their use:
     Fixed-dose combination products containing codeine, which 
are generally used as analgesics in pediatric and adult patients, are 
typically schedule III or schedule V drugs under the Controlled 
Substances Act depending on the amount of codeine contained in the drug 
(Sec. Sec.  1308.13 and 1308.15 (21 CFR 1308.13 and 1308.15)).\2\ FDA 
is aware of a safety concern with an unapproved fixed-dose combination 
product containing codeine phosphate and acetaminophen that is labeled 
for analgesic use. We note that this product does not have the Boxed 
Warning for liver toxicity that would be required if this were an 
approved product (76 FR 2691, January 14, 2011).
---------------------------------------------------------------------------

    \2\ We note that at dosages exceeding the maximum identified in 
Sec.  1308.13 these fixed dose combination drug products would be 
Schedule II.

---------------------------------------------------------------------------

[[Page 1880]]

     Over-The Counter (OTC) Monograph compliant fixed-dose 
combination products containing codeine (21 CFR 341.14) for use as 
antitussives are schedule V drugs under the Controlled Substances Act 
(Sec.  1308.15). Also in schedule V are prescription fixed-dose 
combination drug products containing codeine phosphate that are 
approved to treat coughs in children 6 years old and older. FDA is 
aware of an unapproved prescription fixed dose combination product 
containing codeine phosphate that is labeled for antitussive use in 
children as young as 3 years old.
     Fixed dose combination products containing dihydrocodeine 
bitartrate are schedule III or schedule V drugs under the Controlled 
Substances Act, depending on the amount of dihydrocodeine contained in 
the drug (Sec. Sec.  1308.13 and 1308.15(c)(2)).\3\ There are 
prescription dihydrocodeine fixed dose combination products that have 
approval for the relief of moderate to moderately severe pain. FDA is 
aware of unapproved prescription dihydrocodeine fixed-dose combination 
products that are labeled as antitussives.
---------------------------------------------------------------------------

    \3\ We note that at dosages exceeding the maximum identified in 
Sec.  1308.13 these fixed-dose combination drug products would be 
Schedule II.
---------------------------------------------------------------------------

II. Safety Concerns With Unapproved New Drugs

    Because marketed unapproved new drug products have not been through 
FDA's approval process, there may be safety risks associated with them. 
Some unapproved drug product labeling omits or modifies safety warnings 
or other information that is important to ensure safe use, such as drug 
interactions or potential adverse experiences (e.g., the liver toxicity 
Boxed Warning discussed in section I of this document). Similarly, as 
noted in section I, FDA is aware of an unapproved prescription fixed-
dose combination product that is inappropriately labeled for children 
as young as 3 years of age.
    Furthermore, some of the products covered in this action include 
acetaminophen at doses higher than 325 milligrams (mg) in combination 
with codeine sulfate or dihydrocodeine bitartrate. FDA has taken steps 
to reduce the risk of acetaminophen-related severe liver injury by 
limiting the maximum amount of acetaminophen in approved oral 
prescription products to 325 mg per tablet, capsule, or other dosage 
unit and revising required warning information (76 FR 2691, January 14, 
2011). Severe liver injury can lead to liver failure, liver transplant, 
and death. Limiting the amount of acetaminophen in oral prescription 
drug products increases the margin of safety for persons who mistakenly 
take too many doses or use more than one acetaminophen-containing 
product at the same time.\4\
---------------------------------------------------------------------------

    \4\ 76 FR 2691; for additional regulatory and safety information 
concerning acetaminophen, see http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm239871.htm.
---------------------------------------------------------------------------

    Another concern with unapproved prescription fixed-dose combination 
products containing codeine sulfate or dihydrocodeine bitartrate is 
that they may include more than one sedating component, which may 
result in increased sedation or drowsiness. With an unapproved drug 
product, FDA does not have the opportunity to review the drug product 
before it is marketed to ensure the combination of ingredients is safe 
and that the labeling contains adequate dosing information and 
appropriate warnings and precautions.
    Finally, even the expected risks associated with use of drug 
products containing codeine sulfate, codeine phosphate, or 
dihydrocodeine bitartrate are potentially greater for unapproved drug 
products because the quality, safety, and efficacy of unapproved 
formulations have not been demonstrated to FDA. For example, the 
ingredients and bioavailability of unapproved prescription drug 
products have not been submitted for FDA review, nor has FDA had the 
opportunity to assess the adequacy of their chemistry, manufacturing, 
and control specifications. Unapproved drug products have unapproved 
labeling that may not contain appropriate dosing and warning 
information.

III. Legal Status of Products Identified in This Document

    FDA has reviewed the publicly available scientific literature for 
unapproved prescription single-ingredient codeine sulfate oral tablets, 
single-ingredient codeine sulfate oral solutions, single-ingredient 
codeine phosphate injection products, fixed-dose combination products 
containing codeine phosphate, and fixed-dose combination products 
containing dihydrocodeine bitartrate. In no case did FDA find 
literature sufficient to support a determination that any of these 
prescription products are generally recognized as safe and effective. 
Therefore, these prescription drug products are ``new drugs'' within 
the meaning of section 201(p) of the FD&C Act (21 U.S.C. 321(p)), and 
they require approved NDAs or ANDAs to be legally marketed.
    The unapproved drug products covered by this document are labeled 
for prescription use. Prescription drugs are defined under section 
503(b)(1)(A) of the FD&C Act (21 U.S.C. 353(b)(1)(A)) as drugs that, 
because of toxicity or other potentially harmful effect, are not safe 
to use except under the supervision of a practitioner licensed by law 
to administer such drugs. If an unapproved drug product covered by this 
document meets the definition of ``prescription drug'' in section 
503(b)(1)(A) of the FD&C Act, adequate directions cannot be written for 
it so that a layman can use the product safely for its intended uses 
(21 CFR 201.5). Consequently, it is misbranded under section 502(f)(1) 
of the FD&C Act (21 U.S.C. 352(f)(1)) in that it fails to bear adequate 
directions for use. An approved prescription drug is exempt from the 
requirement in section 502(f)(1) of the FD&C Act that it bear adequate 
directions for use if, among other things, it bears the NDA-approved 
labeling (21 CFR 201.100(c)(2) and 201.115). Because the unapproved 
prescription drug products subject to this document do not have 
approved applications with approved labeling, they fail to qualify for 
the exemptions to the requirement that they bear ``adequate directions 
for use,'' and are misbranded under section 502(f)(1) of the FD&C Act.
    If a drug covered by this document is labeled as a prescription 
drug but does not meet the definition of ``prescription drug'' under 
section 503(b)(1)(A) of the FD&C Act, the drug is misbranded under 
section 503(b)(4)(B). Additionally, the final OTC drug monograph at 
part 341 (21 CFR part 341), ``Cold, Cough, Allergy, Bronchodilator and 
Antiasthmatic Drug Products'' (the final OTC Cold Cough monograph), 
permits the use of codeine, codeine sulfate, and codeine phosphate as 
active ingredients for antitussive use, in the amounts and under the 
conditions specified in the final OTC Cold Cough monograph (see Sec.  
341.14). The final OTC Cold Cough monograph is the only monograph that 
permits OTC use of the active ingredients covered by this document. If 
a product covered by this document does not meet the definition of 
``prescription drug'' under section 503(b)(1)(A) of the FD&C Act, in 
addition to being misbranded, unless the product was reformulated and 
labeled to meet all the requirements of the final OTC Cold Cough 
monograph, the product would still require an approved NDA or ANDA in 
order to be legally marketed.\5\
---------------------------------------------------------------------------

    \5\ In addition to any other applicable requirements, firms that 
manufacture OTC drugs must comply with the labeling requirements at 
21 CFR 201.66. Furthermore, States may have restrictions on the sale 
of OTC products that contain codeine.

---------------------------------------------------------------------------

[[Page 1881]]

IV. Notice of Intent To Take Enforcement Action

    Although not required to do so by the Administrative Procedure Act, 
the FD&C Act (or any rules issued under its authority), or for any 
other legal reason, FDA is providing this notice to persons \6\ who are 
marketing the following unapproved and misbranded drugs labeled for 
prescription use: Single-ingredient codeine sulfate oral tablets, 
single-ingredient codeine sulfate oral solutions, single-ingredient 
codeine phosphate injection products, fixed-dose combination products 
containing codeine phosphate, and fixed-dose combination products 
containing dihydrocodeine bitartrate. The Agency intends to take 
enforcement action against such products and those who manufacture them 
or cause them to be manufactured or shipped in interstate commerce.
---------------------------------------------------------------------------

    \6\ The term ``person'' includes individuals, partnerships, 
corporations, and associations (21 U.S.C. 321(e)).
---------------------------------------------------------------------------

    Manufacturing or shipping the drug products covered by this 
document can result in enforcement action, including seizure, 
injunction, or other judicial or administrative proceeding. Consistent 
with policies described in the Agency's guidance entitled ``Marketed 
Unapproved Drugs--Compliance Policy Guide'' (Marketed Unapproved Drugs 
CPG) (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf), the 
Agency does not expect to issue a warning letter or any other further 
warning to firms marketing drug products covered by this document 
before taking enforcement action. The Agency also reminds firms that, 
as stated in the Marketed Unapproved Drugs CPG, any unapproved drug 
marketed without a required approved application is subject to Agency 
enforcement action at any time. The issuance of this document does not 
in any way obligate the Agency to issue similar documents (or any 
document) in the future regarding marketed unapproved drugs (see 
Marketed Unapproved Drugs CPG, p. 5).
    As described in the Marketed Unapproved Drugs CPG, the Agency may, 
at its discretion, identify a period of time during which the Agency 
does not intend to initiate an enforcement action against a currently 
marketed unapproved drug solely on the grounds that it lacks an 
approved application under section 505 of the FD&C Act. With respect to 
drug products covered by this document, the Agency intends to exercise 
its enforcement discretion for only a limited period of time because 
there are safety issues with respect to the products covered by this 
document, and numerous marketed products that have approved 
applications or comply with an OTC drug final monograph are offered to 
treat the same or similar indications. Therefore, the Agency intends to 
implement this document as follows.
    For the effective date of this document, see the DATES section of 
this document. Any drug product covered by this document that a company 
(including a manufacturer or distributor) began marketing after 
September 19, 2011, is subject to immediate enforcement action. For 
products covered by this document that a company (including a 
manufacturer or distributor) began marketing on or before September 19, 
2011, FDA intends to take enforcement action against any such product 
that is not listed with the Agency in full compliance with section 510 
of the FD&C Act (21 U.S.C. 360) before January 9, 2014, and is 
manufactured, shipped, or otherwise introduced or delivered for 
introduction into interstate commerce by any person on or after January 
9, 2014. FDA also intends to take enforcement action against any drug 
product covered by this document that is listed with FDA in full 
compliance with section 510 of the FD&C Act but is not being 
commercially used or sold \7\ in the United States before January 9, 
2014, and that is manufactured, shipped, or otherwise introduced or 
delivered for introduction into interstate commerce by any person on or 
after January 10, 2014.
---------------------------------------------------------------------------

    \7\ For the purpose of this document, the phrase ``commercially 
used or sold'' means that the product has been used in a business or 
activity involving retail or wholesale marketing and/or sale.
---------------------------------------------------------------------------

    However, for drug products covered by this document that a company 
(including a manufacturer or distributor) (1) began marketing in the 
United States on or before September 19, 2011, (2) are listed with FDA 
in full compliance with section 510 of the FD&C Act before January 9, 
2014 (``currently marketed and listed''), and (3) are manufactured, 
shipped, or otherwise introduced or delivered for introduction into 
interstate commerce by any person on or after January 10, 2014, the 
Agency intends to exercise its enforcement discretion as follows: FDA 
intends to initiate enforcement action regarding any such currently 
marketed and listed product that is manufactured on or after February 
24, 2014, or that is shipped on or after April 10, 2014. Further, FDA 
intends to take enforcement action against any person who manufactures 
or ships such products after these dates. The purpose of these 
enforcement timeframes is to allow manufacturers and distributors to 
deplete their current inventory and ensure a smooth transition for 
consumers. Any person who has submitted or submits an application for a 
drug product covered by this document, but has not received approval, 
must comply with this document.
    The Agency, however, does not intend to exercise its enforcement 
discretion as outlined previously if the following apply: (1) A 
manufacturer or distributor of drug products covered by this document 
is violating other provisions of the FD&C Act, including, but not 
limited to, violations related to FDA's current good manufacturing 
practices, adverse drug event reporting, labeling, or misbranding 
requirements other than those identified in this document or (2) it 
appears that a firm, in response to this document, increases its 
manufacture or interstate shipment of drug products covered by this 
document above its usual volume during these periods.\8\
---------------------------------------------------------------------------

    \8\ If FDA finds it necessary to take enforcement action against 
a product covered by this document, the Agency may take action 
relating to all of the defendant's other violations of the FD&C Act 
at the same time. For example, if a firm continues to manufacture or 
market a product covered by this document after the applicable 
enforcement date, to preserve limited agency resources, FDA may at 
the same time take enforcement action relating to all of the firm's 
unapproved drugs that require applications (see, e.g., United States 
v. Sage Pharmaceuticals, 210 F. 3d 475, 479-480 (5th Cir. 2000) 
(permitting the Agency to combine all violations of the FD&C Act in 
one proceeding, rather than taking action against multiple 
violations of the FD&C Act in ``piecemeal fashion'')).
---------------------------------------------------------------------------

    Nothing in this document, including FDA's intent to exercise its 
enforcement discretion, alters any person's liability or obligations in 
any other enforcement action, or precludes the Agency from initiating 
or proceeding with enforcement action in connection with any other 
alleged violation of the FD&C Act, whether or not related to a drug 
product covered by this document. Similarly, a person who is or becomes 
enjoined from marketing unapproved or misbranded drugs may not resume 
marketing of such products based on FDA's exercise of enforcement 
discretion as described in this document.
    Drug manufacturers and distributors should be aware that the Agency 
is exercising its enforcement discretion as described previously only 
in regard to drug products covered by this document that are marketed 
under a National Drug Code (NDC) number listed with the

[[Page 1882]]

Agency in full compliance with section 510 of the FD&C Act before 
January 9, 2014. As previously stated, drug products covered by this 
document that are currently marketed but not listed with the Agency on 
the date of this document must, as of the effective date of this 
document, have approved applications before their shipment in 
interstate commerce. Moreover, any person or firm that has submitted or 
submits an application but has yet to receive approval for such 
products is still responsible for full compliance with this document.

V. Discontinued Products

    Some firms may have previously discontinued manufacturing or 
distributing products covered by this document without removing them 
from the listing of their products under section 510(j) of the FD&C 
Act. Other firms may discontinue manufacturing or distributing listed 
products in response to this document. Firms are required to 
electronically update the listing of their products under section 
510(j) of the FD&C Act to reflect discontinuation of unapproved 
products covered by this document (21 CFR 207.21(b)). Questions on 
electronic drug listing updates should be sent to: eDRLS@fda.hhs.gov. 
In addition to the required update, firms can also notify the Agency of 
product discontinuation by sending a letter, signed by the firm's chief 
executive officer and fully identifying the discontinued product(s), 
including the product NDC number(s), and stating that the manufacturing 
and/or distribution of the product(s) has (have) been discontinued. The 
letter should be sent electronically to Astrid Lopez-Goldberg (see 
ADDRESSES). FDA plans to rely on its existing records, including its 
drug listing records, the results of any subsequent inspections, or 
other available information when it targets violations for enforcement 
action.

VI. Reformulated Products

    FDA cautions firms against reformulating their products into 
unapproved new drugs without codeine sulfate, codeine phosphate, or 
dihydrocodeine bitartrate, and marketing them under the same name or 
substantially the same name (including a new name that contains the old 
name) in anticipation of an enforcement action based on this document. 
As stated in the Marketed Unapproved Drugs CPG, FDA intends to give 
higher priority to enforcement actions involving unapproved drugs that 
are reformulated to evade an anticipated FDA enforcement action. In 
addition, reformulated products marketed under a name previously 
identified with a different active ingredient have the potential to 
confuse healthcare practitioners and harm patients.

    Dated: January 6, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-00257 Filed 1-9-14; 8:45 am]
BILLING CODE 4160-01-P


