[Federal Register Volume 77, Number 130 (Friday, July 6, 2012)]
[Notices]
[Pages 40069-40072]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-16475]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-N-0563]


Single-Ingredient, Immediate-Release Drug Products Containing 
Oxycodone for Oral Administration and Labeled for Human Use; 
Enforcement Action Dates

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
its intention to take enforcement action against all unapproved single-
ingredient, immediate-release drug products that contain oxycodone 
hydrochloride (hereinafter ``oxycodone'') for oral administration and 
are labeled for human use, and persons who manufacture or cause the 
manufacture or distribution of such products in interstate commerce. 
Unapproved oxycodone drug products have been implicated in reports of 
medication errors causing serious adverse events. In addition, some of 
these products omit important warning information in their labeling. 
Single-ingredient, immediate-release oxycodone drug products are new 
drugs that require approved new drug applications (NDAs) or abbreviated 
new drug applications (ANDAs) to be legally marketed.

DATES: This notice is effective July 6, 2012. For information about 
enforcement dates, see SUPPLEMENTARY INFORMATION, section IV.

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. FDA-2012-N-0563 and directed to the 
appropriate office listed in this document.
    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, 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. 5368, 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. 5368, Silver Spring, MD 20993-0002, 301-
796-3485, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    Oxycodone is an opioid drug that is primarily used as an analgesic 
to relieve

[[Page 40070]]

moderate to severe pain. 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 include respiratory depression, 
decreased blood pressure, coma, respiratory arrest, and death.
    This notice covers all unapproved single-ingredient, immediate-
release drug products containing oxycodone for oral administration 
(including tablets, capsules, and oral solutions) that are labeled for 
human use. Oxycodone is a schedule II narcotic under the Controlled 
Substances Act (21 U.S.C. 801, et seq.) There are FDA-approved single-
ingredient, immediate-release oxycodone tablets, capsules, and oral 
solutions. FDA has approved a number of immediate-release oxycodone 
tablets, ranging in strength from 5 milligrams (mg) to 30 mg. These 
products are indicated for the management of moderate to severe pain 
where the use of an opioid analgesic is appropriate.
    In October 2010, FDA approved NDA 200534 for a single-ingredient 
oxycodone capsule, 5 mg, for the management of moderate to severe acute 
and chronic pain where the use of an opioid analgesic is appropriate, 
and NDA 200535, oxycodone oral solution, 100 mg/5 milliliters (mL), for 
the management of moderate to severe acute and chronic pain in opioid-
tolerant patients. In January 2012, FDA approved NDA 201194, oxycodone 
oral solution, 5 mg/5mL, for the management of moderate to severe pain 
where the use of an opioid analgesic is appropriate.
    FDA is aware of unapproved single-ingredient oxycodone 5 mg 
capsules and unapproved single-ingredient oxycodone oral solutions in 5 
mg/5 mL and 20 mg/mL strengths that are currently being manufactured 
and distributed. In 2009, the Agency sent warning letters to companies 
manufacturing unapproved single-ingredient, immediate-release tablets 
containing oxycodone (available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm238675.htm). This notice 
is issued under sections 502 and 505 of the FD&C Act and applies to any 
unapproved single-ingredient, immediate-release drug products 
containing oxycodone for oral administration and labeled for human use 
that are currently being manufactured or distributed, whether or not 
the drug products were the subject of a prior warning letter.

II. Safety Concerns With Unapproved New Drugs

    Although many of the types of adverse events associated with 
approved and unapproved products are similar, there are additional 
risks associated with unapproved products because the quality, safety, 
and efficacy of unapproved formulations have not been demonstrated to 
FDA. For example, the ingredients and bioavailability of unapproved 
products have not been submitted for FDA review, nor has the Agency had 
the opportunity to assess the adequacy of their chemistry, 
manufacturing, and controls specifications before marketing. 
Additionally, FDA does not have the opportunity to review any changes 
to the formulation of unapproved products prior to implementation, or 
to review product names, to avoid look-alike and sound-alike names that 
may lead to medication errors. Finally, with unapproved products FDA 
does not have the opportunity to review their labeling, e.g., warnings, 
potential adverse experiences, and drug interactions, before marketing 
to help ensure safe use.
    Unapproved new drug products containing oxycodone pose particular 
safety concerns because of their potential for addiction. Oxycodone is 
a derivative of opium, and, like all opioid products, drugs that 
contain oxycodone can produce euphoria (a sense of well-being), have 
the potential to be highly addictive, and are extremely popular drugs 
of abuse. The particular risks associated with unapproved oxycodone-
containing products are illustrated by an unapproved oxycodone 20 mg/mL 
oral solution. FDA found that the INDICATIONS AND USAGE section of the 
labeling of this unapproved product omits critical information, i.e., 
that the product is indicated for opioid-tolerant patients. Such an 
omission increases the chance that the product will be inappropriately 
prescribed for a patient who is not opioid-tolerant, with the potential 
for respiratory depression, respiratory arrest, and death. FDA also 
found that the DOSAGE AND ADMINISTRATION section of the labeling for 
this unapproved product lacks information about how to prevent dosing 
errors and that the WARNINGS AND PRECAUTIONS section does not include 
information regarding risks of medication errors. In addition, this 
product does not include a Medication Guide (see 21 CFR part 208), 
which is required to be issued with the approved oxycodone 20 mg/mL 
oral solution (see www.fda.gov/Drugs/DrugSafety/ucm085729.htm).
    Another example of an unapproved product lacking appropriate 
labeling is a single-ingredient oxycodone 5-mg capsule. The DOSAGE AND 
ADMINISTRATION section of the labeling omits critical information 
regarding individualization of the dosing regimen, initiation of 
therapy in opioid-naive patients, conversion to oral oxycodone 
hydrochloride, maintenance therapy, and cessation of therapy. This 
unapproved capsule's WARNINGS AND PRECAUTIONS section also fails to 
mention precautions for patients taking CYP3A4 (cytochrome P450 3A4) 
inhibitors or inducers.
    FDA has received reports of medication errors associated with 
unapproved oxycodone products and the strength of the active 
ingredient. Two reports were cases of the wrong dose of unapproved 
oxycodone oral solution being administered to the patient. A 21-month-
old patient received a prescription for oxycodone at a strength of 1 
mg/mL, but the product dispensed and administered to the patient was an 
oxycodone 20 mg/mL formulation, resulting in respiratory failure 
secondary to opioid overdose. The patient was admitted to the emergency 
room and successfully resuscitated. The second case was of an 18-year-
old patient who was prescribed oxycodone solution with the direction to 
administer one teaspoonful (5 mg) every 4 hours. However, a 20 mg/mL 
oxycodone oral solution was dispensed, resulting in a 20-fold overdose 
(100 mg oxycodone). The patient went into a coma with organ failure, 
was put on a ventilator, and was admitted to the intensive care unit. 
At the time of the report, the patient was able to speak but only with 
a limited vocabulary. These medication errors may have been due to the 
visual similarity of the container labels and carton labeling of the 
two product strengths. Because unapproved products circumvent the FDA 
drug approval process, the Agency cannot take steps before marketing to 
help ensure that the labels and labeling of multiple strengths by the 
same manufacturer are sufficiently differentiated to prevent such 
medication errors.

III. Legal Status of Products Identified in This Notice

    FDA has reviewed the publicly available scientific literature for 
unapproved single-ingredient, immediate-release drug products 
containing oxycodone for oral administration and labeled for human use. 
In no case did FDA find literature

[[Page 40071]]

sufficient to support a determination that any of these products is 
generally recognized as safe and effective. Therefore, these 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 notice 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. Because any drug product covered by this 
notice meets the definition of ``prescription drug'' in section 
503(b)(1)(A), 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) 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 notice 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 they are misbranded 
under section 502(f)(1).

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 \1\ who are 
marketing unapproved and misbranded single-ingredient, immediate-
release drug products containing oxycodone for oral administration and 
labeled for human use. 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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    \1\ 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 notice 
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 notice 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 notice does not in 
any way obligate the Agency to issue similar notices (or any notice) in 
the future regarding marketed unapproved drugs. 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 notice, 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 notice and there are FDA-
approved products to meet patient needs. Therefore, the Agency intends 
to implement this notice as explained in this document.
    For the effective date of this notice, see the DATES section of 
this document. Any drug product covered by this notice 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 notice that a company (including a 
manufacturer or distributor) began marketing in the United States 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 July 
5, 2012, and is manufactured, shipped, or otherwise introduced or 
delivered for introduction into interstate commerce by any person on or 
after July 5, 2012. FDA also intends to take enforcement action against 
any drug product covered by this notice that is listed with FDA in full 
compliance with section 510 of the FD&C Act but is not being 
commercially used or sold \2\ in the United States before July 5, 2012, 
and that is manufactured, shipped, or otherwise introduced or delivered 
for introduction into interstate commerce by any person on or after 
July 6, 2012.
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    \2\ For purposes of this notice, 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 notice that a company 
(including a manufacturer or distributor) began marketing in the United 
States on or before September 19, 2011, are listed with FDA in full 
compliance with section 510 of the FD&C Act before July 5, 2012 
(``currently marketed and listed''), and are manufactured, shipped, or 
otherwise introduced or delivered for introduction into interstate 
commerce by any person on or after July 6, 2012, 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 August 20, 2012, or that is 
shipped on or after October 4, 2012. Further, FDA intends to take 
enforcement action against any person who manufactures or ships such 
products after these dates. Any person who has submitted or submits an 
application for a drug product covered by this notice but has not 
received approval must comply with this notice.
    The Agency, however, does not intend to exercise its enforcement 
discretion as outlined previously if (1) a manufacturer or distributor 
of drug products covered by this notice is violating other provisions 
of the FD&C Act, including, but not limited to, violations related to 
FDA's current good manufacturing practices, adverse event reporting, 
labeling, or misbranding requirements other than those identified in 
this notice, or (2) it appears that a firm, in response to this notice, 
increases its manufacture or interstate shipment of drug products 
covered by this notice above its usual volume during these periods.\3\
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    \3\ If FDA finds it necessary to take enforcement action against 
a product covered by this notice, 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 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, 
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 notice, including FDA's intent to exercise its 
enforcement

[[Page 40072]]

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 notice. 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 notice.
    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 notice that are marketed 
under an NDC number listed with the Agency in full compliance with 
section 510 of the FD&C Act before July 5, 2012. As previously stated, 
drug products covered by this notice that are currently marketed but 
not listed with the Agency on the date of this notice must, as of the 
effective date of this notice, 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 
notice.

V. Discontinued Products

    Some firms may have previously discontinued manufacturing or 
distributing products covered by this notice 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 notice. Firms that wish to notify the 
Agency of product discontinuation should send 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). Firms should also 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 notice. 
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

    In addition, FDA cautions firms against reformulating their 
products into unapproved new drugs without oxycodone 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 notice. 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 health care practitioners and 
harm patients.

    Dated: June 21, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-16475 Filed 7-5-12; 8:45 am]
BILLING CODE 4160-01-P