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

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

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

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

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

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.

"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.

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

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.

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.

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….

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

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.

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.

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.

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.

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.

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.

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.

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

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 …..

Office of National Drug Control Policy http://www.whitehousedrugpolicy.gov/drugfact/factsht/proper_disposal.html Watch this space for an update to these guidelines…. 22

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. http://www.fda.gov/consumer/updates/drug_disposal062308.html 23

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

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

Safety First!