1. Drug Disposal Labeling to Improve Safety FDA Update on Drug Disposal Labeling Activities
James R. Hunter, R.Ph., MPH
Controlled Substance Staff
Center for Drug Evaluation and Research
Office of the Center Director
Food and Drug Administration
5th Annual Unused Drug Return Conference
November 11, 2008

2. The opinions and information in this presentation are those of the author and do not necessarily reflect the views and policies of the FDA

3. What I’ll Talk About Today…
FDA roles related to prescription drug disposal
Assessing and managing risks during the drug product lifecycle
Disposal instructions in labeling as a risk mitigation strategy for certain drugs.
New legal authorities to improve drug safety
Update on related FDA activities

4. FDA’s Mission is to ensure that…
Americans have access to safe and effective drug products
Foods are safe, wholesome, and properly labeled
Blood used for transfusions and blood products are safe & in adequate supply
Medical devices are safe & effective
Transplanted tissues are safe & effective
Animal drugs and medicated feeds are safe & effective, and food from treated animals is safe for human consumption
Radiation-emitting electronic products are safe
Cosmetics are safe & properly labeled

5. FDA is an active Stakeholder in Drug Disposal Issues
Federal/State Entities:
Environmental Protection Agency
Drug Enforcement Administration
Office of National Drug Control Policy
Substance Abuse and Mental Health Services Administration
U.S. Postal Service
U.S. Fish and Wildlife
State Regulatory Authorities
Non-Government Organizations:
American Pharmacists Association
News media, press
Organizations representing local disposal initiatives
Increased frequency and Intensity
Information sharing
Partnering on some joint interactions.
More coordination and sharing of information
Increased learning curve for all involved

6. FDA Roles related to Drug Disposal
Assessing environmental impact of new drug products
Part of the NDA approval process
Exposure based on estimated drug use
Prescription drug product labeling
Drug disposal information not routinely included
Typically not required
Usually included to improve products safety profile
Two main roles…
-Waivers from a requirement of a full-blown environmental impact study if the assessment based on drug exposure into the environment is negative.
Exposure is calculated assuming 100% of drug goes into the wastewater.
The numerator is the drug in kg, using projected sales as the amount entering into the wastewater each year.
This findng of no environmental impact influences the assessment of risk from the environmental perspective vs benefit decisions
Read slide__for labeling
Will elaborate more on each of these
The labeling for disposal is virtually all directed to the patient, and sometimes the bedside caregiver.

7. "All substances are poisonous, there is none which is not a poison; the right dose differentiates a poison from a remedy"
Paracelsus, circa 1538
Drugs all have risks….and most are dose-related
Drugs are tools to treat illness and symptoms, and some are much more toxic than others….
Therefore on the way to potential drug product marketing approval, there are many decision points where drug risk –toxicities must be on balance with beneficial effects.

8. Drug Approval Safe and effective for use as described in product label
Product’s benefit outweighs its risk
So it would seem very rational that a drug can not be approved for marketing unless its benefits outweigh’s its risk.
For example, the if the benefit of a drug is high, then more risk is tolerated. Drugs to treat cancer and HIV might be examples.
Benefit is low,then less risk is tolerated.
Treating self-limiting conditions such as the common cold may not support a high-degree of risk from a drug product.
Benefits
Risks

9. Risk Assessment During Product Lifecycle
Pre-Clinical
Testing
R&D I N D
Clinical Research
& Development
Post-Marketing
Surveillance
Phase I
Phase III
Phase II A
Phase IV
This assessment of risk vs benefit goes on at every stage of drug development.

10. Risk Management*
The overall and continuing process of minimizing risks throughout a product’s lifecycle to optimize its benefit/risk balance
* From the Concept Paper on Risk Management Programs
-Managing or mitigating risks is one way to improve the benefit risk profile of a drug.
-Getting rid of unused drugs is a great example of reducing the risk of exposure of potentially toxic substances to non-patients.
-SO, safely disposing of a unneeded drug product that may be of especially high risk to non-patients becomes extremely important to the overall safety of the product.

11. Routine Risk Minimization
Labeling (package insert) is the cornerstone of routine risk management efforts for most drugs approved by the FDA
So where do we start….

12. Drug Disposal Instructions in FDA Drug Product Labeling
Voluntary
not usually required
Usually included to increase safety
Drug Product Specific
Comparison of risks and benefits suggests product disposal instructions improve benefit-risk balance.
When health care professional or patients must take special steps that are “unusual” for safety
Required (New!)
- If included in Risk Evaluation and Mitigation Strategy
There is no requirement that disposal information be included or excluded in the labeling.
When a drug contains instructions to flush it down the toilet, it is because FDA, working with the manufacturer, has determined this method to be the most appropriate route of disposal that presents the least risk to safety.
About one dozen drugs (update), such as powerful narcotic pain relievers and other controlled substances, carry instructions for flushing to reduce the danger of unintentional use or overdose and illegal abuse.
Disposal instructions on the label are part of FDA’s “risk mitigation” strategy
The FDA does not support adding drug residues into water systems unnecessarily.
One important new regulatory development are that new regulations create a REQUIREMENT that as part of a Risk Evaluation and Mitigation Strategy – disposal directions may be a required element

13. Types of Patient Information Labeling
Package Insert (PI)
Practitioner to patient instruction
Patient Package Insert (PPI)
May be part of PI or separate document
Voluntary distribution except for oral contraceptives and estrogen products
Medication Guide (MG)
FDA-approved patient labeling
Dispenser required to provide MG when product is dispensed
Everyone’s knows about the package insert- the professional labeling contained in or on the manufacturer’s drug container.
It can contain directions for the practitioner to relay to the patient regarding drug disposal
A PPI is written for the patient and may be on the end of the package insert, or a separate piece of paper. Again it is voluntary
A few FDA products have A Medication Guide which mustcontained approved wording and the dispenser is required to give to the patientupon dispensing. A MG means serious business. And relays critical safety and risk information.

14. FDAAA (New 2008!) FDA Amendments Act of 2007 gives New Authorities
May require:
Postmarketing studies and clinical trials
Safety related labeling changes
Risk Evaluation and Mitigation Strategies (REMS)
Extremely important legislation that became effective in march 2008.
- Important new authorities that are mostly directed at improving safety by requiring sponsors to do more safety related activities.

15. What is a REMS?
A Risk Evaluation and Mitigation Strategy (REMS) is a required risk management plan that utilizes tools beyond routine labeling to ensure that the benefits of a drug outweigh its risks.
Always includes a medication guide which may contain specific disposal instructions.
The previous RiskMapps are now REMS.
- If disposal information is included in a Med Guide it is now part of the dispensed prescription.

16. REMS Scope Before Approval REMS Post-Approval REMS
Prescription drug and biologics only
Before Approval REMS
FDA requires sponsor to submit a REMS
REMS needed to ensure that the benefits outweigh the risks of the drug
Considerations
Size of population likely to use drug
Seriousness of disease
Expected benefit of the drug
Post-Approval REMS
New safety information shows REMS necessary to ensure that the benefits outweigh the risks of the drug
FDA determines REMS is needed
FR Notice FDA-2008N-0174 (March 27, 2008): Identification of Drug and Biological Products “Deemed” to have REMS, 16 drug products
Two Types:
New REMS found to be necessary to assure safety prior to approval.
Post-Approval or “Deemed” REMS. These would include all the Drug products that previous had Risk management plans, basically it is converting existing some existing high risk drugs to the new REMS designation…however, it is not just status quo for these products because now many of the provisions of the previous Risk Map arenow required elements.

17. Three controlled substances have been “deemed”, but do not appear in this list.
Actiq (fentanyl lozenge)
Xyrem (GHB, oxysorbate ) a drug for day time sleepiness and cateplexy.
Oxycontin
These drug products must submit a new REMS in place of the Risk management Plan.

18. MSNBC article highlighting a report published online in September in the Annals of Emergency Medicine.
The study used data from the Researched abuse, addiction and addiction-related system. RADARS.
9,179 toddlers and kids under the age of six were exposed to widely prescribed drugs….
For opioids, one pill is enough to kill. Disposal of unused meds is primary prevention.

19. Disposal Instructions for Controlled Substances
Disposal instructions usually a part of a more comprehensive risk mitigation strategy
Not included in all products containing controlled substances
Potency and formulation contribute to varying potential for misuse, abuse, and accidental overdose
Dangerous amounts of residual drug after use (Fentanyl transdermal patch)
High potency formulations (Extended release oxycodone, fentanyl buccal tablets)
High likelihood of misidentification: Actiq (fentanyl citrate) looks like candy and Xyrem (sodium oxybate) is clear liquid at bedside.
Goal of disposal is to minimize exposure risk of potentially lethal drug to non-patients
Make drug completely unavailable upon disposal
Disposal by Flushing
“Take-back” disposal option in FDA labeling limited by CSA
Because an overdose of opioids can result in respiratory depression and death, and an overdose is more likely in a non-patient, who has never experienced them. It should not be surprising that this class of drug represents the major universe of drugs with disposal directions to reduce such risk.
Formulations important.
Important point in all of this is that an effective risk mitigation strategy for these drugs should include a disposal method that gets rid of the drug quickley and completely. At present, flushing is the method recommended in FDA labeling for these products.
Take Backs might be another option that would fit the functional criteriaof making the drug completely unavailable, but currently the Controlled Substances Act legally limits the transfer of these drugs to entities other than law enforcement. FDA has to respect Federal Law.

20. Fentanyl Buccal Tablet Disposal Instructions
Very quickly, I just wanted to show a label where flushing is the recommended modality…

21. Recent Activities
Identifying FDA approved drug product labeling with drug disposal information
drug label review
Assessing content and consistency of drug disposal information in product labeling
Sponsor-initiated labeling includes take-back disposal option
Developing guidance for FDA reviewers and drug product sponsors
Actively assessing drug disposal labeling policy
Identifying and assessing sources of risk data to develop evidence-based policy guidance
I’d like to quickly shift gears a bit to mention a few finishes and a few starts on FDA activities related to drug disposal.
Last year I said …..

22. Office of National Drug Control Policy
Watch this space for an update to these guidelines…. 22

23. FDA Consumer Health Information June 23, 2008
FDA published a very short consumer directed article highlighting many of the tings I talked about today…product specific risks guide the disposal requirement. 23

24. FDA Supports Drug Take-Back Programs
Store REYATAZ Capsules at room temperature, 59° to 86° F (15° to 30° C). Do not store this medicine in a damp place such as a bathroom medicine cabinet or near the kitchen sink.
Keep your medicine in a tightly closed container.
Keep all medicines out of the reach of children and pets at all times.
Do not keep medicine that is out of date or that you no longer need. Dispose of unused medicines through community take-back disposal programs when available or place REYATAZ in an unrecognizable, closed container in the household trash.
I want to end on a very positive note by saying that FDA is VERY supportive of Take Back programs and see them as a tool to improve drug safety by reducing unnecessary exposures to non-patients.
This is an example of a sponsor-initiated labeling change to a PPI that incorporates elements of the Federal Guidelines and prominently recommends the take-back option. If you like these instructions, please give a well-done to your local Bristol Meyers Squibb sales rep. 24

25. Summary
FDA is focusing increased attention to drug disposal issues and continues to work closely with our federal partners
FDA supports the safe disposal methods as described in the Federal Drug Disposal Guidelines.
For a limited number of higher risk products containing controlled substances, disposal instructions are necessary to improve safety.
FDA has new authorities that could require sponsors to include drug disposal instructions as an added safety measure.
FDA supports take-back programs, recognizing current limitations under in the CSA to collect controlled drug products.
FDA is actively working to develop drug disposal labeling policies that account for the risk associated with products that are disposed of improperly. 25

26. Safety First!