DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration
Rockville, MD 20857

TRANSMITTED VIA FACSIMILE
Michael Friedman
Executive Vice President and Chief Operating Officer
Purdue Pharma L.P.
The Purdue Frederick Company
One Stamford Forum
201 Tresser Boulevard
Stamford, CT 06901-3431
RE:

NDA 20-553
OxyContin
 (oxycodone HCl controlled-release) Tablets
MACMIS ID# 11400

WARNING LETTER
Dear Mr. Friedman:
This Warning Letter (revised) concerns the dissemination of promotional materials for the
marketing of OxyContin (oxycodone HCl controlled-release) Tablets by Purdue Pharma L.P.
(“Purdue”). Specifically, we refer to two journal advertisements for OxyContin that recently
appeared in the Journal of the American Medical Association (JAMA), one in the October 2,
2002 issue (A7038) (the “October Ad”) and one in the November 13, 2002 issue (A7087) (the
“November Ad”). The Division of Drug Marketing, Advertising, and Communications
(DDMAC) has reviewed these advertisements and has concluded that they are in violation of the
Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C.§§ 331(a) and (b), 352 (n), and its
implementing regulations.
Your journal advertisements omit and minimize the serious safety risks associated with
OxyContin, and promote it for uses beyond which have been proven safe and effective.
Specifically, your journal advertisements fail to present in the body of the advertisements any
information from the boxed warning in the approved product labeling (PI) for OxyContin
regarding the potentially fatal risks associated with the use of OxyContin and the abuse liability
of OxyContin, which is a Schedule II controlled substance, and make unsubstantiated efficacy
claims promoting the use of OxyContin for pain relief. Your journal advertisements also
understate the minimal safety information that is presented.
Your advertisements thus grossly overstate the safety profile of OxyContin by not referring in
the body of the advertisements to serious, potentially fatal risks associated with OxyContin,
thereby potentially leading to prescribing of the product based on inadequate consideration of
risk. In addition, your journal advertisements fail to present in the body of the advertisements

 Michael Friedman
Purdue Pharma, LP
NDA 20-553, MACMIS# 11400

Page 2

critical information regarding limitations on the indicated use of OxyContin, thereby promoting
OxyContin for a much broader range of patients with pain than are appropriate for the drug. The
combination in these advertisements of suggesting such a broad use of this drug to treat pain
without disclosing the potential for abuse with the drug and the serious, potentially fatal risks
associated with its use, is especially egregious and alarming in its potential impact on the public
health.
Background
OxyContin was approved on December 12, 1995. Because the drug has a potential for abuse and
has risks associated with its use that are serious and potentially fatal, the current PI for
OxyContin contains a boxed warning that includes the following important information
(emphasis in original):
•

OxyContin is an opioid agonist and a Schedule II controlled substance with an abuse
liability similar to morphine.

•

Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This
should be considered when prescribing or dispensing OxyContin in situations where the
physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

•

OxyContin 80mg and 160mg Tablets ARE FOR USE IN OPIOID-TOLERANT
PATIENTS ONLY. These tablet strengths may cause fatal respiratory depression when
administered to patients not previously exposed to opioids.

•

OxyContin TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE
BROKEN, CHEWED, OR CRUSHED. TAKING BROKEN, CHEWED, OR
CRUSHED OxyContin TABLETS LEADS TO RAPID RELEASE AND
ABSORPTION OF A POTENTIALLY FATAL DOSE OF OXYCODONE.

Because of safety concerns, there are important limitations on the indicated use of OxyContin.
The boxed warning contains the following bolded statements:
•

OxyContin Tablets are a controlled-release oral formulation of oxycodone
hydrochloride indicated for the management of moderate to severe pain when a
continuous, around-the-clock analgesic is needed for an extended period of time.

•

OxyContin Tablets are NOT intended for use as a prn analgesic.

The Precautions section of the OxyContin PI contains further bolded limitations on the
appropriate use of OxyContin, namely:
•

OxyContin is not indicated for pre-emptive analgesia (administration pre-operatively
for the management of postoperative pain).

 Michael Friedman
Purdue Pharma, LP
NDA 20-553, MACMIS# 11400

Page 3

•

OxyContin is not indicated for pain in the immediate postoperative period (the first 1224 hours following surgery) for patients not previously taking the drug, because its
safety in this setting has not been established.

•

OxyContin is not indicated for pain in the postoperative period if the pain is mild or not
expected to persist for an extended period of time.

•

OxyContin is only indicated for postoperative use if the patient is already receiving the
drug prior to surgery or if the postoperative pain is expected to be moderate to severe
and persist for an extended period of time.

Moreover, because of the serious risks associated with OxyContin, it is contraindicated in a
number of patient populations, including:
•
•
•

Patients with significant respiratory depression (in unmonitored settings or the absence of
resuscitative equipment)
Patients with acute or severe bronchial asthma or hypercarbia
Any patient who has or is suspected of having paralytic ileus.

Lack of Important Risk Information
Promotional materials are misleading if they fail to reveal material facts relating to potential
consequences that may result from the use of the drug as recommended or suggested by the
materials. Promotional materials are also misleading if they fail to include a balanced
presentation of information relating to contraindications, warnings, precautions, and side effects
associated with the use of a drug along with the presentation of promotional claims relating to
the effectiveness and safety of the drug. Your journal advertisements are misleading because
they make prominent claims of effectiveness for pain relief, but omit from the body of the
advertisements crucial facts related to the serious, potentially fatal safety risks associated with
the use of OxyContin, the potential for OxyContin to be abused, and the limitations on its
appropriate indicated use.
Omission of material facts related to abuse liability and fatal risks
Specifically, your November Ad contains a two-page spread picturing a man fishing with a boy
and featuring the prominent headline “THERE CAN BE LIFE WITH RELIEF.” The words
“LIFE WITH RELIEF” are the largest in the advertisement. The ad also features a graphic
of two paper medication dosage cups with “8 AM” and “8 PM” next to them. The logo for
OxyContin is right below, with the prominent tagline “IT WORKS.” Your October Ad
promotes “WHEN IT’S TIME TO CONSIDER Q4-6H OPIOIDS…REMEMBER,
EFFECTIVE RELIEF TAKES JUST TWO.” The claim “REMEMBER, EFFECTIVE
RELIEF TAKES JUST TWO” is prominently highlighted in the middle of the ad, surrounded
by comparative graphics of dosage cups which show only two dosage cups for OxyContin, as
compared to six dosage cups for the other drugs. As with the November Ad, the logo for

 Michael Friedman
Purdue Pharma, LP
NDA 20-553, MACMIS# 11400

Page 4

OxyContin is directly under the graphic of the two dosage cups, with the prominent tagline “IT
WORKS.” Therefore, the principal message of both advertisements appears to be that
OxyContin offers effective pain relief and has convenient dosing.
These ad presentations, however, fail to present in the body of the advertisements critical safety
information related to the use of OxyContin needed to balance these broad claims promoting its
efficacy for pain relief. Neither one of your ads presents in the body of the advertisements any
information from the boxed warning discussing OxyContin’s potential for abuse and the related
considerations when prescribing the drug. Neither one of your ads presents in the body of the
advertisements any information from the boxed warning disclosing that the drug can be fatal if
taken by certain patients or under certain conditions. It is particularly disturbing that your
November Ad would tout “Life With Relief,” yet fail to warn that patients can die from taking
OxyContin.
These ad presentations are accompanied by a brief summary of the prescribing information for
OxyContin, including the boxed warning, and the ads include a reference to the brief summary.
However, presenting important risk information in this manner is not in accordance with FDA’s
prescription drug advertising regulations. See 21 CFR 202.1(e)(3)(i) (Untrue or misleading
information in any part of the advertisement will not be corrected by the inclusion in another
distinct part of the advertisement of a brief statement containing true information relating to side
effects, contraindications, and effectiveness of the drug.) The typical physician reviewing an
advertisement for a prescription drug would expect the most serious risks associated with the
drug to be included in the body of the ad. The body of these ads contains no discussion of the
potentially fatal risks associated with the drug and its potential for abuse. Moreover, the
expectation that the most relevant risks have been disclosed in the body, rather than the brief
summary, of your ads is exacerbated by having a statement in the body of your ads that begins
“The most serious risk…” implying that what follows is a complete statement of the drug’s most
serious risks, not that there are other, more serious risks to be aware of. Therefore, the language
in the body of your ads reinforces the impression that the most serious risks have been disclosed,
when in fact they have not.
Minimization of risk in information presented
Your ads not only omit these important risks, but also understate the minimal safety information
that you do disclose in the body of the advertisements, thus completely misrepresenting the
safety profile of the drug. Your ads state that “The most serious risk with opioids, including
OxyContin, is respiratory depression.” This statement suggests that there are no specific safety
considerations for OxyContin related to respiratory depression, which is false or misleading and
could lead to prescribing of the product based on inadequate consideration of risk. This
statement also fails to warn that this risk can be a fatal one. As stated in the boxed warning,
OxyContin has two tablet strengths that are for use in opioid-tolerant patients only, because they
can cause fatal respiratory depression when administered to patients not previously exposed to
opioids. Also, the boxed warning states that OxyContin tablets are to be swallowed whole and
not broken, crushed or chewed, because that leads to rapid release and absorption of a potentially
fatal dose of OxyContin. It is especially troubling that your ads tout the dosing convenience of

 Michael Friedman
Purdue Pharma, LP
NDA 20-553, MACMIS# 11400

Page 5

OxyContin as a benefit, but fail to warn of these associated serious safety risks that come from
its controlled-release formulation.
Your advertisements, in this context, also minimize the most common adverse events associated
with OxyContin by describing “Common opioid side effects” rather than side effects and safety
risks that have been seen with OxyContin itself. In addition, your advertisements state that
“OxyContin is contraindicated in patients with known hypersensitivity to oxycodone, or in any
situation where opioids are contraindicated,” without giving the specific contraindications noted
above. By essentially suggesting that no safety or tolerability issues have been seen specifically
with OxyContin, and by implying that OxyContin therapy is not associated with the serious and
significant risks outlined above, your advertisements grossly misrepresent the safety profile of
OxyContin. This implication is false or misleading and raises significant public health and
safety concerns.
Overbroadening of Indication
Your advertisements suggest that OxyContin can be used in a much broader range of pain
patients than has been proven to be safe and effective. This is even more problematic from a
public health perspective given the serious safety risks associated with the drug and the serious
deficiencies in the safety information presented in your advertisements.
The only indication information presented in the body of the advertisements (indeed, the only
information from the boxed warning included at all as part of the body of these advertisements)
is the partial language from the Indications and Usage section of the PI, “For moderate to severe
pain when a continuous, around-the-clock analgesic is needed for an extended period of time,”
which you present by itself at the top of these advertisements. In the November Ad, this
information is located in the upper left-hand corner of the picture on the first page of the spread,
in small white type over a background of green leaves and blue sky. It is also the only writing on
that page. This information is not prominent, and is not adequately communicated, especially in
contrast to the prominent claim of “THERE CAN BE LIFE WITH RELIEF” and all the other
text of the advertisement on the next page. Similarly, in the October Ad, this partial indication
language is included at the top of the ad in a much smaller typesize than the prominent claims
related to “effective relief” with the drug. These presentations are insufficient to give appropriate
context and balance to your claims broadly promoting the use of this drug for pain relief. In
addition, in your November Ad, you portray a seemingly healthy, unimpaired man out fishing
and taking care of a child, rather than depicting a more typical person with persistent, moderate
to severe pain taking OxyContin. Therefore your advertisements fail to adequately communicate
the actual indication for OxyContin and suggest its use for pain relief in a much broader range of
patients than indicated.
In addition, your advertisements fail to present in the body of the advertisements the other
important limitations on the indicated use of OxyContin as noted above. Although you
prominently claim effective “relief” and that the product “works,” you fail to qualify that, as per
the boxed warning, OxyContin is not intended to be used as a prn (as needed) analgesic. In fact,
your October Ad prominently directs physicians to prescribe OxyContin “WHEN IT’S TIME TO

 Michael Friedman
Purdue Pharma, LP
NDA 20-553, MACMIS# 11400

Page 6

CONSIDER Q4-6H OPIOIDS,” which could easily suggest prn use. (Q4-6H indicates 4-6 hours
of effectiveness.)
Also of concern, your advertisements, and in particular, your October Ad, represent the dosing
convenience of OxyContin by showing dosage cups of the type used to dispense medication in a
hospital setting, along with your broad claims of efficacy. The body of the advertisements,
however, fails to present the important limitations on the use of OxyContin restricting it to
certain hospitalized patients, as described in the OxyContin PI. Most notably, the PI states that
OxyContin is not indicated for pain in the immediate postoperative period (the first 12-24 hours
following surgery) for patients not previously taking the drug, because its safety in this setting
has not been established. OxyContin is also not indicated for pain in the postoperative period if
the pain is mild or not expected to persist for an extended period of time. The PI also states that
OxyContin is not indicated for pre-emptive analgesia (administration pre-operatively for the
management of postoperative pain). You fail to present in the body of your advertisements any
of these important limitations, thus suggesting the use of OxyContin in inappropriate patients.
Conclusions and Requested Actions
You have disseminated promotional journal advertisements that fail to disclose in the body of the
advertisements serious and significant risks associated with the use of OxyContin and important
limitations on the indicated use of the drug.
Because of the significant public health and safety concerns raised by your advertisements, we
request that you provide a detailed response to the issues raised in this Warning Letter. This
response should contain an action plan that includes:
1)

Immediately ceasing the dissemination of these advertisements and all other
promotional materials that contain the same or similar violations outlined in this
letter.

2)

Providing a plan of action to disseminate accurate and complete information to
the audience(s) that received the misleading messages.

3)

A written statement of your intent to comply with “1” and “2” above.

Please respond in writing to DDMAC by January 24, 2003 of your intent to comply with
DDMAC’s request. If you have any questions or comments, please contact Mark Askine or
Carol Barstow by facsimile at 301-594-6759 or at the Food and Drug Administration, Division
of Drug Marketing, Advertising, and Communications, HFD-42, Rm. 8B-45, 5600 Fishers Lane,
Rockville, MD 20857.
The violations discussed in this letter do not necessarily constitute an exhaustive list. We are
continuing to evaluate other aspects of your promotional campaign for OxyContin, and may
determine that additional remedial messages will be necessary to fully correct the false or
misleading messages resulting from your violative conduct.

 Michael Friedman
Purdue Pharma, LP
NDA 20-553, MACMIS# 11400

Page 7

We remind you that only written communications are considered official. In all future
correspondence regarding this particular matter, please refer to MACMIS ID #11400 in addition
to the ANDA number.
Failure to respond to this letter may result in regulatory action, including seizure or injunction,
without further notice.
Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, R.Ph., MBA
Director
Division of Drug Marketing,
Advertising, and Communications

 --------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
--------------------------------------------------------------------------------------------------------------------/s/
--------------------Thomas Abrams
1/17/03 04:31:31 PM