[Federal Register Volume 78, Number 75 (Thursday, April 18, 2013)]
[Notices]
[Pages 23273-23275]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-09092]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket Nos. FDA-2001-P-0238, FDA-2010-P-0526, FDA-2010-P-0540, FDA-
2011-P-0473]


Determination That the OXYCONTIN (Oxycodone Hydrochloride) Drug 
Products Covered by New Drug Application 20-553 Were Withdrawn From 
Sale for Reasons of Safety or Effectiveness

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) has determined that 
OXYCONTIN (oxycodone hydrochloride) extended-release tablets (10 
milligrams (mg), 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, and 160 mg) 
approved under new drug application (NDA) 20-553 were withdrawn from 
sale for reasons of safety or effectiveness. The Agency will not accept 
or approve abbreviated new drug applications (ANDAs) for products that 
reference NDA 20-553.

FOR FURTHER INFORMATION CONTACT: Patrick Raulerson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6368, Silver Spring, MD 20993-0002, 301-
796-3522.

SUPPLEMENTARY INFORMATION:

I. Background

    In 1984, Congress enacted the Drug Price Competition and Patent 
Term Restoration Act of 1984 (Pub. L. 98-417) (the 1984 amendments), 
which authorized the approval of duplicate versions of drug products 
under an ANDA procedure. ANDA applicants must, with certain exceptions, 
show that the drug for which they are seeking approval contains the 
same active ingredient in the same strength and dosage form as the 
``listed drug,'' which is a version of the drug that was previously 
approved. ANDA applicants do not have to repeat the extensive clinical 
testing otherwise necessary to gain approval of a new drug application 
(NDA).
    The 1984 amendments include what is now section 505(j)(7) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)), which 
requires FDA to publish a list of all approved drugs. FDA publishes 
this list as part of the ``Approved Drug Products With Therapeutic 
Equivalence Evaluations,'' which is known generally as the ``Orange 
Book.'' Under FDA regulations, drugs are removed from the list if the 
Agency withdraws or suspends approval of the drug's NDA or ANDA for 
reasons of safety or effectiveness or if FDA determines that the listed 
drug was withdrawn from sale for reasons of safety or effectiveness (21 
U.S.C. 355(j)(7)(C); 21 CFR 314.162).
    A person may petition the Agency to determine, or the Agency may 
determine on its own initiative, whether a listed drug was withdrawn 
from sale for reasons of safety or effectiveness. This determination 
may be made at any time after the drug has been withdrawn from sale, 
but must be made before approving an ANDA that refers to the listed 
drug (Sec.  314.161 (21 CFR 314.161)). FDA may not approve an ANDA that 
does not refer to a listed drug.
    OXYCONTIN (oxycodone hydrochloride) extended-release tablets, 10 
mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, and 160 mg (original 
OxyContin), are the subject of NDA 20-553, held by Purdue Pharma LP 
(Purdue) and initially approved on December 12, 1995. A reformulated 
version of these products, OXYCONTIN (oxycodone hydrochloride) 
extended-release tablets, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 
80 mg (reformulated OxyContin), are the subject of NDA 22-272, also 
held by Purdue and initially approved on April 5, 2010. Reformulated 
OxyContin was developed with physicochemical properties that are 
intended to make the tablet more difficult to manipulate for purposes 
of abuse or misuse. Both original and reformulated OxyContin are opioid 
agonist products indicated for the management of moderate to severe 
pain when a continuous, around-the-clock opioid analgesic is needed for 
an extended period of time.
    In correspondence dated August 10, 2010, Purdue notified FDA that 
it had ceased shipment of original OxyContin, and FDA subsequently 
moved original OxyContin to the ``Discontinued Drug Product List'' 
section of the Orange Book. On April 16, 2013, FDA approved a 
supplemental application for reformulated OxyContin, approving changes 
to the product labeling that describe certain abuse-deterrent 
properties of the reformulated product.
    Several parties have submitted citizen petitions under 21 CFR 
10.30, requesting that the Agency determine whether original OXYCONTIN 
(oxycodone hydrochloride) extended-release tablets were voluntarily 
withdrawn from sale for reasons other than safety or effectiveness.\1\
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    \1\ Varam, Inc., Docket No. 2011-P-0473 (June 9, 2011) (10, 15, 
20, 30, 40, 50, 80, and 160 mg); Sheppard, Mullin, Richter & Hampton 
LLP, Docket No. 2010-P-0540 (Oct. 8, 2010) (10, 15, 20, 30, 40, 60, 
and 80 mg); Lachman Consultant Services, Inc., Docket No. FDA-2010-
P-0526) (Sept. 30, 2010) (10, 15, 20, 30, 40, 60, 80, and 160 mg). 
Lachman also submitted a petition in 2001 concerning just Purdue's 
2001 withdrawal of the 160 mg strength. Docket No. FDA-2001-P-0473 
(formerly Docket No. 2001P-0426) (Sept. 18, 2001).
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    Based on the information available at this time, FDA has determined 
under Sec.  314.161 that original OxyContin was

[[Page 23274]]

withdrawn from sale for reasons of safety or effectiveness. FDA has 
reached this determination following a careful review and analysis of 
the following information: (1) The citizen petitions described 
previously; (2) the comments submitted to the dockets associated with 
these petitions; (3) the Agency records and other information 
concerning original and reformulated OxyContin and the withdrawal of 
original OxyContin; and (d) data, literature, and other information 
concerning postmarketing adverse events associated with original 
OxyContin, reformulated OxyContin, and other extended-release oxycodone 
products.

II. Initiatives To Address Abuse of Opioid Analgesics

    Opioid analgesics are an important component of modern pain 
management. Abuse and misuse of these products, however, has grown into 
a public health epidemic. According to the Centers for Disease Control 
and Prevention, sales of prescription opioids in the United States 
increased over 300 percent from 1999 to 2008 (Ref. 1). Overdose deaths 
involving these products increased commensurately over the same period, 
from 4,000 to 14,800 (Refs. 1 and 2). In 2008 prescription opioids were 
involved in more overdose deaths than heroin and cocaine combined (Ref. 
3). In 2010 the number of overdose deaths in which prescription opioids 
were involved rose to 16,651, which represented more than 75 percent of 
all overdose deaths involving prescription drugs (Ref. 4).
    FDA, together with other Federal agencies, is working to address 
this large and growing problem while ensuring that patients in pain 
have appropriate access to opioid analgesics. FDA has worked to improve 
the labeling of OxyContin and other opioid analgesics to better warn 
prescribers and patients of the serious risks associated with abuse and 
misuse. FDA also has worked extensively with the sponsors of OxyContin 
and other extended-release or long-acting prescription (ER/LA) opioid 
analgesics to address these risks through a classwide risk evaluation 
and mitigation strategy (REMS) http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM311290.pdf.
    This REMS, approved on July 9, 2012, requires sponsors of ER/LA 
opioids to make available training for health care professionals on 
proper prescribing practices and also to distribute educational 
materials to prescribers and patients on the safe use of these 
medications.
    FDA considers the development of opioid analgesics that can deter 
abuse and misuse to be a public health priority. Opioid analgesics can 
be abused orally or by injection, snorting, or smoking and also may be 
misused in therapeutic contexts. Products may be designed to deter one 
or more of these methods of abuse or misuse. Following mandates in the 
2011 White House prescription drug abuse prevention plan (Ref. 5) and 
section 1122(c) of the Food and Drug Administration Safety and 
Innovation Act (Pub. L. 112-144) (126 Stat. 1075), FDA recently issued 
a draft guidance to industry on the evaluation and labeling of 
potentially abuse-deterrent opioid analgesics (Ref. 6).

III. Assessment of Abuse-Deterrent Properties of Reformulated OxyContin

    All forms of opioid analgesic abuse are dangerous, and non-oral 
routes of abuse are particularly dangerous. Intranasal and intravenous 
opioid abuse is associated with serious adverse events including 
addiction, overdose, and death (Refs. 7, 8, and 9). Intravenous opioid 
abuse is associated with HIV and hepatitis B and C infection risk (Ref. 
10). Further, as stated in the OxyContin labeling (see section 9.2), 
injection of OxyContin excipients ``can result in death, local tissue 
necrosis, infection, pulmonary granulomas, and increased risk of 
endocarditis and valvular heart injury.'' The label is available at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022272s016lbl.pdf. Intranasal opioid abuse is associated with nasal, 
palatal, and pharyngeal necrosis (Refs. 7 and 11).
    Original OxyContin was often abused by manipulating the product to 
defeat its extended-release mechanism, causing the oxycodone to be 
released more rapidly. Original OxyContin also was manipulated for 
therapeutic purposes, for example, by crushing the product to sprinkle 
it onto food or to administer it through a gastric tube. As noted in 
the boxed warning of the labeling, disruption of the tablet and 
controlled-release mechanism for abuse or misuse ``can lead to rapid 
release and absorption of a potentially fatal dose of oxycodone.''
    FDA has conducted an extensive review of data available to the 
Agency regarding reformulated OxyContin, including in vitro, 
pharmacokinetic, clinical abuse potential, and postmarketing study 
data. The data show that, when compared to original OxyContin, 
reformulated OxyContin has an increased ability to resist crushing, 
breaking, and dissolution using a variety of tools and solvents. The 
data also demonstrate that, when subjected to an aqueous environment, 
reformulated OxyContin gradually forms a viscous hydrogel. The data 
also indicate that insufflation of finely crushed reformulated 
OxyContin was associated with lower ``liking'' compared to finely 
crushed original OxyContin in recreational opioid users with a history 
of intranasal drug abuse. FDA concludes, based on these data and our 
review of all data and information available to the Agency at this 
time, that the physicochemical properties of reformulated OxyContin are 
expected to make abuse via injection difficult and are expected to 
reduce abuse via the intranasal route. In addition, reformulated 
OxyContin also may deter certain types of misuse in therapeutic 
contexts.
    Additional postmarketing studies intended to assess the impact of 
reformulated OxyContin on abuse and misuse in the community also have 
been conducted; some of these are still ongoing. FDA has reviewed the 
available data from these studies and has concluded that they suggest, 
but do not confirm, a reduction in non-oral abuse. The Agency will 
continue to review data from these studies as they become available, as 
well as any other relevant data that may be developed in the future.
    FDA has long considered the abuse potential of a drug in numerous 
regulatory contexts. Where appropriate, FDA may take into account abuse 
potential as part of the safety profile of a drug when weighing its 
benefits and risks. In this case, FDA has considered the abuse 
potential as part of the Agency's determination of whether the original 
formulation of OxyContin was withdrawn from sale for reasons of safety 
or effectiveness. This approach is particularly appropriate here in 
light of the extensive and well-documented history of OxyContin abuse.
    Original OxyContin has the same therapeutic benefits as 
reformulated OxyContin. Original OxyContin, however, poses an increased 
potential for abuse by certain routes of administration, when compared 
to reformulated OxyContin. Based on the totality of the data and 
information available to the Agency at this time, FDA concludes that 
the benefits of original OxyContin no longer outweigh its risks. FDA 
has determined that OXYCONTIN (oxycodone hydrochloride) extended 
release tablets, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, and 
160 mg (approved under new drug application 20-553), were withdrawn 
from sale for reasons of safety or effectiveness. Accordingly, the

[[Page 23275]]

Agency will remove OXYCONTIN (oxycodone hydrochloride) extended-release 
tablets (10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, and 160 mg) 
approved under NDA 20-553 from the list of drug products published in 
the Orange Book. FDA will not accept or approve ANDAs that refer to 
these drug products.

IV. References

    The following references have been placed on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified the Web site addresses in this reference section, but FDA 
is not responsible for any subsequent changes to the Web sites after 
this document publishes in the Federal Register.)

1. National Center for Injury Prevention and Control, Centers for 
Disease Control and Prevention (CDC), ``Policy Impact: Prescription 
Painkiller Overdoses'' (www.cdc.gov/HomeandRecreationalSafety/pdf/PolicyImpact-PrescriptionPainkillerOD.pdf).
2. CDC, ``Vital Signs: Overdoses of Prescription Opioid Pain 
Relievers--United States, 1999-2008,'' Morbidity and Mortality 
Weekly Report, vol. 60, No. 43, pp. 1487-1492, 2011 (www.cdc.gov/mmwr/pdf/wk/mm6043.pdf).
3. National Center for Injury Prevention and Control, CDC, 
``Unintentional Drug Poisoning in the United States'' (www.cdc.gov/HomeandRecreationalSafety/pdf/poison-issue-brief.pdf).
4. Jones, C.M., K.A. Mack, and L.J. Paulozzi, ``Pharmaceutical 
Overdose Deaths, United States, 2010,'' Journal of the American 
Medical Association, vol. 309, pp. 657-659, 2013.
5. FDA, ``FDA Blueprint for Prescriber Education for Extended-
Release and Long-Acting Opioid Analgesics'' (http://www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf).
6. FDA, ``Draft Guidance for Industry: Abuse-Deterrent Opioids--
Evaluation and Labeling,'' (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM334743.pdf).
7. Katz, N., R.C. Dart, E. Bailey, et al., ``Tampering With 
Prescription Opioids: Nature and Extent of the Problem, Health 
Consequences, and Solutions,'' The American Journal of Drug and 
Alcohol Abuse, vol. 37, pp. 205-217, 2011.
8. Silva, K., S.M. Schrager, A. Kecojevic, et al., ``Factors 
Associated With History of Non-Fatal Overdose Among Young Nonmedical 
Users of Prescription Drugs,'' Drug and Alcohol Dependence, vol. 
128, pp. 104-110, 2013.
9. Degenhardt, L., C. Bucello, B. Mathers, et al., ``Mortality Among 
Regular or Dependent Users of Heroin and Other Opioids: A Systematic 
Review and Meta-Analysis of Cohort Studies,'' Addiction, vol. 106, 
pp. 32-51, 2011.
10. CDC, ``Integrated Prevention Services for HIV Infection, Viral 
Hepatitis, Sexually Transmitted Diseases, and Tuberculosis for 
Persons Who Use Drugs Illicitly: Summary Guidance From the CDC and 
the U.S. Department of Health and Human Services,'' Morbidity and 
Mortality Weekly Report, vol. 61, pp. 1-40, 2012.
11. Alexander, D., K. Alexander, and J. Valentino, ``Intranasal 
Hydrocodone-Acetaminophen Abuse-Induced Necrosis of the Nasal Cavity 
and Pharynx,'' The Laryngoscope, vol. 122, pp. 2378-2381, 2012.

    Dated: April 12, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-09092 Filed 4-16-13; 4:15 pm]
BILLING CODE 4160-01-P