# Presentation: 293526

## History of OxyContin: Labeling and Risk Management Program

**Robert B. Shibuya, M.D.**
**Medical Team Leader**
**Division of Anesthesia, Analgesia, and Rheumatology Products**
**Office of Drug Evaluation II**

## OxyContin: Approval

**OxyContin was approved on December 12, 1995.**
**Launched in 1996**
**Approval occurred when:**
**There was increasing recognition that many patients with pain are inadequately treated**
**Diversion and abuse of controlled prescription drugs was increasing**

## OxyContin: Initial product labeling

**Schedule: CII**
**Strengths: 10, 20, and 40 mg controlled-release tablets**
**Clinical trials:**
**Both cancer and non-cancer pain populations**
**Use in opioid-naïve patients**
**Equivalence and open-label studies**

## OxyContin: Initial product labeling

**Indication: **
**“****For the management of moderate to severe pain where use of an opioid analgesic is appropriate for more than a few days.”**

## OxyContin: Initial labeling

**Warnings; Dosage and Administration:**
**“****OxyContin tablets are to be swallowed whole, and are not to be broken, chewed, or crushed.  *****Swallowing broken, chewed, or crushed OxyContin tablets could lead to the rapid release and absorption of a potentially toxic dose of oxycodone*****.”**
**Drug abuse and Dependence:**
**OxyContin...is a schedule II controlled substance.  Oxycodone products are common targets for both drug abusers and drug addicts.  *****Delayed absorption, as provided by OxyContin tablets is believed to reduce the abuse liability of a drug*****.”**

## OxyContin: supplemental NDAs

**80-mg tablet approved in 1996; 160-mg tablet in 2000**
**Notable changes to the product label:**
**Description:**
**80-mg and 160-mg tablets to be used only in opioid tolerant patients.**
**Precautions; Dosage and Administration:**
***OxyContin 80 [160] mg tablets are for use only in opioid tolerant patients requiring daily equivalent dosages of 160 [320] mg or more*****.  ... Patients should be instructed against use by individuals other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences.**

## Increased OxyContin availability

**Purdue implemented an aggressive marketing campaign:**
**Primary care providers**
**Use in non-cancer pain**** **
**Musculoskeletal pain; post-operative pain**
**Use as “first-line” therapy for chronic pain**
**Physician-directed advertising**
**Medical journals; conferences; video**
**Certain promotional claims cited by DDMAC**

## 2000: Initial reports of  OxyContin abuse and diversion

**Increasing media and state reports of abuse and diversion of OxyContin:**
**Crushing of tablets**
**Oral, inhalation, injection administration**
**Adverse events included addiction, withdrawal and fatalities**
**Prominently affected areas:**
**Appalachian states**
**Kentucky, Virginia, W. Virginia, Pennsylvania**
**Maine; Ohio**
**Involved recreational drug users, teenagers, pain patients**

## OxyContin abuse and diversion: Possible contributing factors

**Drug Substance**
- Recent evidence suggests that oxycodone may be more reinforcing than morphine
**Product formulation**
- High oxycodone content
- Although it was initially believed that the PK characteristics of a CR formulation would reduce the reinforcing properties, experience has shown that defeat of the CR mechanisms is associated with abuse

## OxyContin abuse and diversion: Possible contributing factors

**Increased drug availability**
- Increased prescribing of controlled prescription drugs for pain
- Medical community more accepting of the use of opioids to treat pain
- Purdue’s strong marketing strategy
**Product labeling**
- Warning against crushing may have alerted abusers to a method for misuse
- Label language suggesting that OxyContin had lower abuse potential may have impacted product use or prescribing

## OxyContin abuse and diversion: Initial Agency and company actions

**Purdue:**
- Formed a response team to evaluate problem of abuse/diversion in Maine
- Contacted the Agency about the problems (Mar 2001)
- Elected to discontinue marketing of the 160 mg tablet
**FDA:**
- Requested additional information regarding OxyContin abuse
- Reviewed available data to
- Assess for any relationship between OxyContin abuse/misuse and adverse events
- Determine prescribing patterns of OxyContin
- Met with Purdue to discuss the issues (April 2001)

## Changes to OxyContin Label

**Addition of a Boxed Warning**
- Calls attention to the potential for abuse, misuse and diversion of the product.
- Highlights the proper treatment population.
**CLINICAL TRIALS section**
- Restricted to the single adequate and well-controlled clinical study.
**INDICATIONS section revised to reflect the appropriate patient population.**

## Changes to OxyContin Label

**INDICATIONS:**
**OxyContin tablets are... 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 is not intended for intermittent dosing or as a prn analgesic.
- OxyContin is not indicated for pain in the immediate post-operative period if the pain is mild or not expected to persist...

## Changes to OxyContin Label

**Expanded WARNINGS section**
**Warns against breaking, crushing, or chewing the tablets**
**Highlights the potential for misuse, abuse, and diversion of OxyContin**
**Specifies the potential adverse events associated with OxyContin misuse and abuse**
**Deleted: **language regarding reduced abuse liability with a CR formulation.

## OxyContin: Risk Management Plan

**FDA and Purdue began discussion of the importance and features of an RMP in April 2001.**
**Ideally, RMP would comprise**
**Prevention of abuse, misuse and diversion**
- Clear product labeling
- Physician and pharmacist education
- Patient education (e.g. Patient Package Insert)
**Surveillance, monitoring and feedback**
- Incidence of drug abuse and misuse
- Identification of risk factors
- Effectiveness of prevention strategies

## OxyContin: Risk Management Plan

**August 2001: Purdue submitted initial draft RMP**
**Key features**
**Education and outreach**
**Surveillance and monitoring**
**Drug utilization (IMS Health; NDA Health)**
**Drug exposure (e.g. prescription monitoring programs)**
**Drug abuse and misuse**
**DAWN, NHSDA (now NSDUH), TESS, RADARS**
**Intervention – when a signal is detected**

## OxyContin: Public Discussions January 30 & 31, 2002

**Advisory Committee meeting to discuss:**
**Opioid analgesic use and development.**
**Use of opioid analgesics in pediatric patients.**
**Abuse and misuse of opioid analgesics.**
**Notable conclusions:**
**Abuse of opioid analgesics is a considerable public health problem.**
**However, opioid analgesics are an essential component of pain management.**
**Any RMP that restricts opioid treatment may prevent their appropriate utilization.**** **

## OxyContin: Public Discussions September 9 & 10, 2003

**Advisory Committee meeting to discuss: **
- RMPs for opiate analgesic drug products
- Particular attention to modified-release products
- Abuse liability of and RMP for Palladone (extended-released hydromorphone)
**Key conclusions: RMP should include -**
- Appropriate prescriber education
- Surveillance of misuse, abuse, diversion
- Assessment of the source(s) of diverted drugs
- Assessment of the RMP’s impact on opioid prescribing practices

## Current status

**Over the years, FDA and Purdue have negotiated numerous revisions to strengthen the product labeling and the RMP.**
**However, multiple indices show that abuse and diversion of OxyContin continue to be significant public health issues.**
**There are no marketed products with demonstrated or purported reduced abuse liability.**
**Availability of a ER oxycodone product with reduced abuse liability is desirable.**
**What qualitative and quantitative abuse-resistance characteristics confer a benefit?**