1. Efficiently dealing with new FDA information on drug safety Warnings, Shortages, Withdrawals – Oh My! Efficiently dealing with new FDA information on drug safety Karly Pippitt, MD Karen Gunning, PharmD University of Utah Family Medicine Residency

2. Ambulatory Safety: a lingering problemAmbulatory Safety: a lingering problem  1999 IOM report – not much happened  2011 JAMA editorial with 5 core aims to improve ambulatory safety: 1.Basic epidemiologic data needed to delineate problem. 2.Identify an early achievable goal 3.Engage patients and their families 4.Link to inpatient initiatives 5.Further develop practice based research networks to investigate/impact patient safety Wynia MK, Classen DC. Improving ambulatory patient safety JAMA 2011; 306:2504 - 2505

3. Objectives At the conclusion of the discussion, participants will be able to:  Determine barriers to communication and strategies to overcome barriers in developing alternative drug therapy plans for patients after warnings, shortages, and/or withdrawals.  Given an example drug safety warning, medication market withdrawal, or drug shortage develop a plan of action for dissemination of information to provider and patients.

4. Shortages – What the Heck? Drug shortages 2001 – 2011 Source: University of Utah Drug Information Service http://www.washingtonpost.com/politics/obama-issues-executive-order-aimed-at-curbing-drug-shortages/2011/10/31/gIQAPor4ZM_story.html

5. How to find out what is on shortage...  http://www.fda.gov/Drugs/DrugSafety/DrugShortages/de fault.htm http://www.fda.gov/Drugs/DrugSafety/DrugShortages/de fault.htm  http://www.ashp.org/shortages http://www.ashp.org/shortages

6. Other information sourcesOther information sources  Local pharmacies  Wholesaler or higher level issue  Acute or chronic?  Reason for shortage?

7. Market Withdrawals: Here today, gone tomorrow  Propoxyphene  Midrin  Rosiglitazone

8. Key safety issues with market withdrawals  What is the most appropriate alternative for the individual patient?  Opportunity for medication discontinuation?  Optimization of therapy?  Re-evaluation of indication  Proactive vs reactive?

9. Warnings and precautions and scary things – oh my!  Simvastatin  Citalopram  Pediatric acetaminophen liquid preparations http://www.fda.gov/Safety/MedWatch/ucm168422.htm

10. Simvastatin chaosSimvastatin chaos  Do not use Simvastatin 80 mg in new patients  Continue in pts already on it if they have been taking it > 1 year  Risk: myopathy/rhabdo  Seems to be associated with a genetic variant in simvastatin handling that increases simvastatin concentrations.  So – if you need more than 40 mg of simvastatin – switch to:  Atorvastatin 40 mg daily OR  Rosuvastatin 10 mg – 20 mg daily BUT – the drug interactions mess... www.fda.gov

11. Simvastatin Dosing Limitation WarningsSimvastatin Dosing Limitation Warnings DrugSimvastatin max dose Amiodarone20 mg Amlodipine20 mg Ranolazine20 mg Diltiazem 10 mg Verapamil 10 mg ____________________________________ Contraindicated drugs: Itraconazole, Ketoconazole,Posaconazole,Erythromycin, Clarithromycin,Telithromycin,HIV protease inhibitors, Nefazodone, Gemfibrozil, Cyclosporine, Danazol www.fda.gov

12. FDA - CitalopramFDA - Citalopram  Concern:  Dose-dependent association between citalopram use and increased QT interval and arrhythmias  Doses > 40 mg not associated with clinical benefit in trials – so don’t use  Risk Factors:  Patients with existing heart conditions, such as congestive heart failure or bradyarrhythmias, or those with hypokalemia or hypomagnesemia are especially at risk for this effect www.fda.gov

13. FDA - CitalopramFDA - Citalopram  No more than 20 mg in patients with hepatic impairment or in patients greater than 60 years old  Do not use citalopram in patients with congenital long QT syndrome  Do not use with persistent QTc > 500 msec www.fda.gov

14.  Simvastatin  80 mg  Simvastatin with contraindicated medications  Citalopram Our Plan of AttackOur Plan of Attack

16. Our attempt - SimvastatinOur attempt - Simvastatin

19. Simvastatin – Residency ClinicSimvastatin – Residency Clinic  Following initial warning re: 80mg dose, data pull  3 rd year FM resident on pharmacotherapy rotation  Reviewed charts and contacted providers  2 days, ~4 hours  Clinical Pharmacist and RNs called patients and pharmacies

20. Simvastatin – Residency ClinicSimvastatin – Residency Clinic  ~6 months later, 4 th year FM honors student  Simvastain 80 mg  Simvastatin + contraindicated medications Take home point: continuous process, not single point in time

21. Our try CitalopramOur try Citalopram Patient <60 years of age on citalopram 60 mg Symptoms controlled and pt on dose for > 4 months Decrease citalopram dose to 40 mg daily and evaluate response in 4 weeks Symptoms controlled, but on dose for < 4 months Switch to another high dose SSRI* and evaluate in 4 weeks Symptoms uncontrolled Select an agent from another class: SNRI $ or bupropion # - titrate dose and evaluate in 2 weeks

22. *SSRI high dose options (can switch over directly, no cross-taper needed)  Sertraline: 150-200 mg daily start at 50 mg/day and increase dose by 50 mg daily every week  Fluoxetine: 60-80 mg daily, start at 20 mg/day and increase dose by 20 mg daily every week  Paroxetine: 40-50 mg daily, start at 20 mg/day and increase by 10 mg daily every week Can switch over directly, no cross-taper needed $SNRI switch options (can consider cross-tapering dose of citalopram during initiation but not necessary) Venlafaxine: start at 75 mg daily and titrate up by 75 mg daily weekly to target dose of 150-225 mg/day Duloxetine: start at 30 mg daily, increase to target dose of 60 mg/day after 1 week #Bupropion (consider cross-taper of citalopram with initiation of bupropion): Immediate release: start at 100 mg BID and increase to 100 mg TID after 1 week Sustained release: start at 100 mg daily, titrate up to 300 mg/day in divided doses after 1 week Citalopram

23. Citalopram Patient >60 years of age on citalopram 30-60 mg Symptoms controlled and pt on dose for > 4 months Taper citalopram dose to 20 mg daily over 1-3 weeks, evaluate response in 4 weeks Symptoms controlled, but on dose for < 4 months Switch to another high dose SSRI* and evaluate in 4 weeks Symtptoms uncontrolled Select an agent from another class: SNRI $ or bupropion # - titrate dose and evaluate in 2 weeks

24. *SSRI high dose options (can switch over directly, no cross-taper needed)-  Sertraline: 100-200 mg daily start 25 mg/day and increase dose by 25 mg daily every week  Fluoxetine: 60-80 mg daily, start 10-20 mg/day and increase dose by 10-20 mg daily weekly as tolerated  Paroxetine: 40 mg daily, start at 10 mg/day and increase by 10 mg daily every week $SNRI switch options (can consider cross-tapering dose of citalopram during initiation but not necessary)  Venlafaxine: start at 37.5-75 mg daily and titrate up by 37.5-75 mg daily weekly to target dose of 150-225 mg/day  Duloxetine: start at 20-30 mg daily, increase to target dose of 60 mg/day after 1 week #Bupropion (consider cross-taper of citalopram with initiation of bupropion): Immediate release: start at 100 mg BID and increase to 100 mg TID Sustained release: start at 100 mg daily, titrate up to 300 mg/day in divided doses Citalopram

25. Acetaminophen pediatric liquid: A giant mess  ISSUE: The FDA has requested manufacturers change to a standard and single acetaminophen concentration of 160 mg / 5 ml to reduce overdoses from the use of the 80 mg / 0.8 mL infant drops  PROBLEM: Some manufacturers complied – some did not – creating a mess at the drugstore

26. Acetaminophen pediatric liquid: A giant mess http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm284563.htm?utm_campaign=Google2&utm_ source=fdaSearch&utm_medium=website&utm_term=acetaminophen

27. How could you approach this warning in your system?  With people around you – spend the next few minutes discussing how this might affect your practice, and how you can be proactive to maintain patient safety.  Ideas?

28. Acknowledgments McKay Robinson, PharmD Lee Audd, MSIV Russell Anderson, MD (FM resident) Breanne Chipman, PharmD student