[Federal Register Volume 79, Number 7 (Friday, January 10, 2014)]
[Notices]
[Pages 1879-1882]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-00257]
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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.
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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, [email protected].
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.
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\1\ Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm238675.htm#codeine_sulfate.
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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).
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\2\ We note that at dosages exceeding the maximum identified in
Sec. 1308.13 these fixed dose combination drug products would be
Schedule II.
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[[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.
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\3\ We note that at dosages exceeding the maximum identified in
Sec. 1308.13 these fixed-dose combination drug products would be
Schedule II.
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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\
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\4\ 76 FR 2691; for additional regulatory and safety information
concerning acetaminophen, see http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm239871.htm.
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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\
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\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.
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[[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.
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\6\ The term ``person'' includes individuals, partnerships,
corporations, and associations (21 U.S.C. 321(e)).
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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.
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\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.
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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\
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\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'')).
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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: [email protected].
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