FDAJoint Meeting of Anesthetic and Life Support Drugs and the Drug Safety and Risk Management Advisory Committees, May 5, 2008Re: NDA 22-272, OxyContin Art Van Zee, M.D.St. Charles ClinicSt. Charles, VA

---Review the over-all context: the national prescription opioid problem

---Review efficacy & safety OxyContinin relation to other available opioids

---Review risks & benefits of anan abuse resistant OxyContin

---Possible FDA responses

Unintentional drug overdose deaths by specific drug type, United States, 1999-20044

Epidemics of unintentional drug overdose deaths in the United States, 1970-2005HeroinCrack cocainePrescription drugs2

Unintentional drug overdose death rates and total sales of prescription opioid painkillers by year in the United States8

OxyContin abuse: nationalPrevalence of abuse nationally

OxyContin>hydrocodone>other oxycodone>methadone>morphine>hydromorphone

OxyContin abuse the most prevalent

Cicero, Inciardi, Munoz. Trends in abuse of OxyContin & other opioid analgesics in the U.S. 2002-2004. J. Pain, 2005

Availability

Opioid Abuse Data

U.S. Summary Retail Drug Purchases in Millions of gramsARCOS--DEA

Quantity of Controlled Substances in the Supply Chain TOTAL DISPENSED PRESCRIPTIONS

2006 2007

Hydrocodone129,675,900135,465,900Oxycodone 42,292,200 45,878,100Hydromorphone 1,835,400 2,139,200Fentanyl 7,040,000 7,307,900Methadone 3,779,000 4,037,000Alprazolam 39,313,500 41,267,200

IMS Health, C. Gallagher, DEA, Diversion Control 3.08

Quantity of Controlled Substances in the Supply Chain TOTAL DOSAGE UNITS DISPENSED20062007

Hydrocodone 8,096,081,600 8,567,331,900Oxycodone 2,731,569,000 3,075,119,400Hydromorphone 144,180,900 166,964,500Fentanyl 88,028,400 92,017,000Methadone 495,391,000 528,081,000Alprazolam 2,380,796,700 2,507,373,600

IMS Health, C. Gallagher, DEA, Diversion 3.08

Note: Totals may not sum to 100% because of rounding or because suppressed estimates are not shown.1 The Other category includes the sources: Wrote Fake Prescription, Stole from Doctors Office/Clinic/Hospital/Pharmacy, and Some Other Way.Bought/Took from Friend/Relative 14.8%Drug Dealer/ Stranger 3.9%Bought on Internet 0.1%Other 1 4.9%Free from Friend/Relative 7.3%Bought/Took from Friend/Relative 4.9%Drug Dealer/ Stranger 1.6%Other 1 2.2%Source Where Respondent ObtainedSource Where Friend/Relative ObtainedOne Doctor19.1%More than One Doctor1.6%More than One Doctor 3.3%One Doctor80.7%Free from Friend/Relative 55.7%Reported Source of Pain Relievers by Past Year Users Aged 12 or Older: 2006

How does OxyContin compare in efficacy and safety to other available opioids?

The Medical Letter---9/17/01..no evidence that oxycodone offers any advantage over appropriate doses of other opioids, and it appears to have the same potential for addiction as morphine.

OxyContinNDA--1995Medical Officer Review (MOR)

Summary of safety

The best conclusion is that the efficacy of the CR (oxycodone) is equivalent to the IR, with an adverse profile that is as good as the IR. I would not allow a better claim.--Curtis Wright, MRO

OxyContin NDA (cont)Summary of efficacy

CR oxycodone appears to be a BID alternative to conventional QID oxycodone. Approval is recommended. Care should be taken to limit competitive promotion. This product.has not been shown to have a significant advantage beyond reduction in frequency of dosing.

--Curtis Wright, MRO

IR oxycodone vs CR oxycodone

Comparable Efficacy & Safety

Hale Clin J Pain 99 BACK PAIN Kaplan J Clin Oncol 98 CANCER Stambaugh J Clin Pharm 01 CANCER

CR morphine vs. OxyContinComparable Efficacy & Safety in Cancer

Heiskanen, PainMucci-LoRusso, Eur Journ of Pain, 1998Bruera, J Clin Oncol, 1998

Comparative efficacy and safety of long- acting opioids for chronic non-cancer pain: a systematic review

J Pain Symptom Manage, 2003Chou, et al

Risks and Benefits ofan abuse resistant OxyContin

Benefits:

Some Deterrence for abuse:

Reduced snorting & injection

Risks of an abuse resistant OxyContin

--risks of iatrogenic addiction in chronic non-cancer pain patients when taken exactly as prescribed

Risks (cont)

Increased risks of addiction when

preparation is chewed rather than swallowed

Risks (cont)

Risks of inadvertent over-dose

and death

Patrick Stewart, 1980-2004

Risks of abuse resistant OxyContin(cont)Risks of a false sense of security, fueling increased opioid prescribing, increased availability, and increased public health problems.

Risks (cont) Risks of the manner in which this drug

could be marketed and promoted

Recovery of morphine from acontrolled-release preparation: a source of opioid abuse

Crews JC; Denson DD CANCER Dec. 15, 1990over the past 18 months, MS-Contin has surpassed hydromorphoneas the most desirable and abused prescription opioid in this area

Purdue Pharma OxyContin NDA 199568% of the oxycodone could be extracted from an OxyContin tablet when crushedPurdue Pharma, NDA OxyContin, 1995 Pharmacology Review, Abuse liability of oxycodone

Possible FDA ActionsAbuse resistant OxyContin to REPLACE,NOT SUPPLEMENT the current preparation

FDA to have much enhanced over-sight over the marketing

3. To re-evaluate and revise the indications given for SR opioids

Possible FDA responses (cont.)Special called meeting of FDA to formulate new strategies and changes to impact the prescription opioid abuse problem

Source: National Vital Statistics System, multiple cause of death dataset. Drug types identified by use of T codes.Restricted to deaths with underlying cause of Narcotics X42; or Other and unspec X44.Totals add to more than total deaths because more than one drug may be listed per death.Other specified narcotics T code is not shown.Rates are crude rates per 100,000 persons. Source is National Vital Statistics System (NVSS).1970-78 is ICD 8 codes E850-859, (unint. pois. by drugs), as reported in Samkoff, AJPH 1982;72:12511979-98 is ICD 9 codes E850-858, (unint pois. by drugs), source is CDC WONDER1999-2004 is ICD 10 codes X40-44, (unint. pois by drugs), source is WONDER2005 is an estimate: 95% of the unintentional poisoning crude rate of 7.97Sources: unintentional drug poisoning mortality is from the National Vital Statistics System.. The drug poisoning mortality category is defined by E850-E858 in 1990 through 1998 and by X40-X44 in 1999 through 2004. The rate for 2005 is estimated as 95% of the unintentional poisoning death rate. Total sales are from DEA ARCOS. Opioid sales are in total morphine equivalents for all major opioids combined except codeine. The conversions are the same as those used in Paulozzi and Budnitz, Pharmacoepidemiology and Drug Safety, 2006. Sales data for 2006 is estimated from the first 3 quarters of 2006. FOR OXYCODONE IN BACK PAIN AND CANCER.AND CHOU AND COLLEAGUES FROM THE UNIVERSITY OF OREGON REVIEWING THE LITERATURE CONCLUDED THAT THERE WAS INSUFFICIENT EVIDENCE TO SAY THAT SUSTAINED RELEASE PREPARATIONS WERE MORE EFFECITVE OR SAFER THAN IMMEDIATE RELEASE PREPARATIONS, OR THAT THERE WAS ANY ONE PREPARATION SUPERIOR TO THE OTHERS IN ITS CLASS.PATRICK STEWART, BRIGHT, COLLEGE EDUCATED, LOTS OF PROMISE, THE SON OF A PLASTIC SURGEON AND AND EDUCATOR IN CALIFORNIA, NEVER AN ADDICT, DIED FROM DRINKING A COUPLE OF BEERS AND TAKING AN OFFERED AN OXYCONTIN AT A PARTY LAST JULY. How many of us in the room today can say we have not made some unwise choices in our youthful lives, and how many of us can be re-assured our children or our grand-children will not make some unwise choices.