Daniel Wermeling, Pharm.D. Professor, College of Pharmacy University of Kentucky

Conflict Statement Daniel Wermeling is CEO and owner of AntiOp, Inc., a company that is developing a unit-dose, ready-to use, and disposable naloxone nasal spray.

Practice Gap & Need Naloxone, the opioid antidote, is under-utilized in the prevention and treatment of opioid overdose Healthcare professionals caring for, and families of, high overdose risk patients can reduce overdose morbidity and mortality by learning new ways to prescribe, dispense and administer naloxone.

Objectives: Review the clinical pharmacology and prescribing information for naloxone injection and products Describe the administration of naloxone injection intra-nasally Describe the legal requirements for prescribers and dispensers of naloxone for opioid overdose prevention Describe patient and family counseling necessary for fulfilling naloxone prescriptions Using program materials develop your own protocols for prescribing and dispensing naloxone in your community

2010 Rx Opioid Poisoning Data 16,500 deaths nationally ~1000 deaths in KY Underestimate – why? Common opioids Methadone Oxycodone/hydrocodone Most common co-intoxicant Benzodiazepines Alcohol 5

Who are the Decedents? Middle-aged male nationally but female in KY Injection drug users Mixing drugs illicitly or licitly Morphine equivalents > 100 mg/day Frail pain patients Previous abusers who lose tolerance MENTAL ILLNESS Depression Suicide (10-20% of mortality) Bipolar

National Distribution, By State, of Opioid Overdoses

Highest Mortality Rates National Rate ~ 8/100,000 Top 5 Kentucky counties by annual rate of drug overdose fatalities County Deaths Pop.Rate per 100,000 1 Powell 30 39, Floyd , Martin 24 39, Bell 51 86, Breathitt 25 45, KY Injury Prevention Center 2012

Highest Absolute Count Kentucky counties by number of total drug overdose deaths. Number of drug overdose deaths Jefferson Kenton Fayette Pike 86 5 Floyd 79 6 Boone 72 7 Campbell 67 8 Boyd 61 9 Bell Madison 45 KY Injury Prevention Center 2012

Inpatient Hospital Charges-2010 Self Pay $10,080,783 Workers Compensation $6,397 Medicare $20,779,203 Medicaid $18,741,534 Commercial $13,456,620 CHAMPUS $931,034 Other $536,189 Charity $4,040,607 Total $68,572,368 KY Injury Prevention Center 2012

Reactions to Overdose Epidemic New Laws and Regulations Creating Potential Professional Jeopardy Federal State Local Professional Licensing Boards Professional Societies Pseudo-government agencies Criminal Prosecution Administrative Action Civil Malpractice

A New and Evolving Strategy: Opioid Overdose Prevention and Naloxone Distribution

Harm Reduction Strategy: Provide Naloxone to Individuals at High Risk for Overdose Naloxone approved since 1971 Save Lives Interesting Model Train the addict or close contact to save another person Train family to save the patient Legal issue – Medical Model Prescribe to a person who can not treat themselves Lay person administers to another person Good Samaritan issues Precedents with Epinephrine and Glucagon 13

Potential Indications In a Household or to Co-Prescribe 1. Patient release after emergency medical care involving opioid poisoning/intoxication 2. Suspected history of illicit or nonmedical opioid use 3. High-dose opioid prescription (> 50 mg of morphine equivalence/day) 4. Any methadone prescription to opioid naïve patient Any opioid prescription and … 5. smoking/COPD/emphysema/asthma or other respiratory illness or obstruction 6. renal dysfunction, hepatic disease 7. known or suspected concurrent alcohol use 8. concurrent benzodiazepine prescription 9. concurrent SSRI or TCA anti-depressant prescription 10. Prisoner released from custody 11. Release from opioid detoxification or mandatory abstinence program 12. Voluntary request from patient 13. Patients in methadone or buprenorphine detox/maintenance (for addiction or pain) 14. Patient may have difficulty accessing emergency medical services (distance, remoteness) 14

Naloxone ( ) in the Brain 15 H O MH O M N N N Pain Relief Pleasure Reward Respiratory Depression Reversal of Respiratory Depression Opioid Withdrawal opioids broken down and excreted opioid receptors activated by heroin and prescription opioids N

Naloxone hydrochloride (Narcan®) Mu-opioid receptor antagonist Clear liquid Used in anesthesiology Used in emergency Quick acting Lasts minutes Generic (cheap?) Delivered via injection (IM, SC, IV) or nasal ? 16

Naloxone Duration of Action Naloxone half life about 60 minutes depending on route of administration Duration of action follows – about and hour or so Duration of IR analgesics are 2-6 hours Duration of ER/LA can be 8-24 hours or longer Oral opioid overdose can also be prolonged May need repeat dose of naloxone or infusion to manage PK/PD mismatch

Intranasal Administration Paramedics Already Do This 18

Sporer, 1996 Treatment of Opioid Overdose with Intranasal Naloxone: San Francisco EMS Protocol

Denver EMS Results 2 mg IN vs 1-2 mg IV Naloxone Barton 2002

Harm Reduction Coalition - NY 21 face shield alcohol pads safety IM syringes (2) rubber gloves (2) 1 mL vial of 0.4 mg/mL naloxone (2) carrying case

Massachusetts 22

Factors in Healthcare System Outpatient Access to Naloxone State Medicine, Pharmacy, Nursing Acts Prescribing Dispensing Counseling Reimbursement Drug Administration Liability New Laws Necessary for Prescriber, Dispenser and Good Samaritan

Current Naloxone Injection Products Naloxone injection is labeled for IV/IM/SQ administration Two strengths – 0.4 mg/mL and 1 mg/mL Two manufacturers Hospira IMS/Amphastar – makes prefilled syringe Mucosal Atomization Device – LMA Ltd. 510k FDA approved nasal delivery device Luer-fitting for attachment to syringes Packaging kits Reimbursement

New Naloxone Injection Product Evzio™ Auto-injector A “smart” device Hand held Prefilled 0.4 mg One repeat dose Needle retraction Quite expensive Hundreds of $

Prescribing Options Naloxone Vial and Needle - traditional IM/SQ using 0.4 mg/mL injection vial and needles Least expensive - $ FDA approved IMS/Amphastar 2mg/2mL Prefilled Syringe and Mucosal Atomizer Device $ per kit Products FDA approved but nasal spraying is off-label Evzio Autoinjector $ 200 – 700 per Rx depending on insurance FDA approved in 2014

Which Pharmacies to Use? Retail pharmacies do not routinely stock naloxone A prescriber will need to establish a relationship with a pharmacy to stock naloxone and delivery systems Most pharmacies can accommodate the request with just a phone call and a little background Outpatient pharmacies of hospitals are good starting places since naloxone will be present on the inpatient side of the hospital

Prescriber Reimbursement Check with MCO First Reimburses for training on overdose recognition and proper administration of naloxone Screening, Brief Intervention, and Referral to Treatment (SBIRT) reimbursement codes Commercial Insurance – CPT (15-30 minutes) Medicare – G0396 (15-30 minutes Medicaid – H0050 (per 15 minutes) State has SBIRT as a covered Medicaid service Vision – Pharmacists, with Provider Status, can bill for service using an SBIRT code.

Pharmacy Operations Patient identification Stocking product, labeling templates, kit templates Refill questions Reimbursement practices CMS Medicaid MCOs Private Insurance Cash Donated/Free

Kit Templates Including Naloxone Intranasal Kit Contents 2 IMS Amphastar 2mg/2mL Syringes Zip type clear bag 6 x 10 inch Counseling and Instructions for Use Intranasal Mucosal Atomization Device Intramuscular Kit Contents 2 vials 0.4 mg/mL naloxone injection 22G needles and 3 mL Syringe Counseling and Instructions for Use

Kit Sig Intranasal Naloxone 2mg/2ml prefilled syringe, #2 SIG: Spray one-half of syringe into each nostril upon signs of opioid overdose. Call 911. May repeat x 1. Intramuscular Naloxone 0.4mg/ml single dose vial, #2 SIG Inject 1 ml intramuscularly upon signs of opioid overdose. Call 911. May repeat x 1.

Suspected Opioid Overdose Response by Good Samaritan Stimulation – verbal and physical - check for response Give Naloxone Call 911 Recovery position if breathing Rescue breathe if apneic Stay with patient until help arrives

Administering Naloxone Nasally

When to use Intranasal Naloxone? If a person is not responding to you. If bystanders report drug use and the person is not responding to you. If there are drug bottles, or signs of injection of drugs on the skin (“track marks”) and the person is not responding to you. Call 911 to activate Emergency Services 6/24/2014

Nasal Atomizer Use 6/24/2014 Source: Maine EMS

Preparation: Step 1 6/24/2014 Source: Maine EMS

Preparation: Step 2 6/24/2014 Source: Main EMS

Preparation: Step 3 6/24/2014 Source: Main EMS

Preparation: Step 4 6/24/2014 Source: Maine EMS

Administration (non-EMS) Assemble kit Gently, but firmly, place the atomizer in one side of the nose and spray half the medication, and spray the other half into the other nostril Within a couple of minutes, if the patient is still not breathing adequately, spray another syringe into nose. If only one side of the nose is available, put all of the medication on that side 6/24/2014 Source: Maine EMS

Administration 6/24/2014 Source: Maine EMS

Models for Increasing Access to Naloxone In all cases, work backwards from a pharmacy and patient interaction through to the prescriber and person identifying at risk household Develop your protocols and standard of care Individual Prescriber – High Risk Patient/Household Pain/Substance abuse treatment/known addict Public Health EMS Emergency Rooms Hospitals Community Group Education Mobile Pharmacy

Liability Questions Prescriber/Dispenser Criminal Civil Administrative For a lay-person possessing and administering prescription medication For third party prescribing For calling 911 and authorities finding illicit materials

States with a Naloxone and/or Good Samaritan Law New York Massachusetts Rhode Island North Carolina Virginia New Mexico Connecticut Kentucky Wisconsin Ohio Tennessee Colorado California Washington Florida District of Columbia Illinois Arkansas Maryland New Jersey Georgia

Kentucky Has New Naloxone Law – Part One A NEW SECTION OF KRS TO IS CREATED TO READ AS FOLLOWS: (1)A licensed health-care provider who, acting in good faith, directly or by standing order, prescribes or dispenses the drug naloxone to a patient who, in the judgment of the health-care provider, is capable of administering the drug for an emergency opioid overdose, shall not, as a result of his or her acts or omissions, be subject to disciplinary or other adverse action under KRS Chapter 311, 311A, 314, or 315 or any other professional licensing statute.

New Naloxone Law Part 2 (2) A prescription for naloxone may include authorization for administration of the drug to the person for whom it is prescribed by a third party if the prescribing instructions indicate the need for the third party upon administering the drug to immediately notify a local public safety answering point of the situation necessitating the administration. A person acting in good faith who administers naloxone as the third party under this section shall be immune from criminal and civil liability for the administration, unless personal injury results from the gross negligence or willful or wanton misconduct of the person administering the drug.

Collaborative Care Agreements Between Prescribers & Pharmacists Currently 6 states have explicit regulations expanding pharmacists’ ability to assess patients in the pharmacy and to “prescribe” and dispense naloxone under a state-approved protocol. Protocol jointly developed with the relevant Boards Pharmacists can identify at risk patients and families from prescription receipt, medication history record and KASPER. Some patients may come to the pharmacy seeking access directly and/or may not have physician. Being discussed in KY

Inter-professional Opportunities Prescribers Pharmacists Nurses Social Workers Paramedics Health care system administration Community civic leaders Education, training practice collaboration Increase public awareness (think AEDs) Patient and family counseling

Expected Outcomes Create inter-professional system for naloxone distribution in your community Identify patients at high-risk for opioid overdose Pain management Substance abuse Educate patients and families of naloxone overdose prevention for their home Prescribe naloxone Dispense naloxone Counsel patients and family on overdose recognition and treatment pending EMS arrival

Where to go for more information? SAMHSA Toolkit – SAMHSA Toolkit – pioid-Overdose-Prevention- Toolkit/SMA pioid-Overdose-Prevention- Toolkit/SMA prescribetoprevent.org stopoverdose.org/pharmacy Project Lazarus – NC Integrates interdisciplinary programs for pain management and drug abuse

Where to go for Document Templates? See CE Central Web page for documents you can use and edit to suit the needs of your health care system or community.