SESSION A2. Top Medication Side Effects and Interactions 2014 Genevieve Pagaglilauan, MD, FACP

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1 37th Annual Advanced Practice in Primary and Acute Care Conference: October 9-11, :55 SESSION A2 Session Description: Top Medication Side Effects and Interactions 2014 Genevieve Pagaglilauan, MD, FACP S E S S I O N A2 This session is a case-based update on important medication interactions and idiosyncratic medication side-effects of commonly used medications in the care of adult primary care patients. Participants will learn a general and customizable approach to assessing for side-effects in the ever expanding array of pharmacological options. Learning Objectives: Following my presentation, participants will be able to: 1. Review common mechanisms for medication interactions. 2. Develop a general and personalized approach to medication interactions. 3. Review important side effects and medication interactions including statins, antibiotics, warfarin, and antidepressants.

2 Objectives Top Medication Side Effects and Interactions 2014 Genevieve Pagalilauan MD FACP UW Department of Medicine Div. General Internal Medicine Common mechanisms for medication interactions General and personalizable approach Important medication interactions and idiosyncratic side effects Participation in cases P450 P450 P450 Enzyme P450 Enzyme Inducer Inhibitor Binding D2 D2 D2 D2 D2 D2 1

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4 CYP inducers Rifampin Carbamazepine Dilantin Phenobarbitol Thiozolidinediones RULE 1: CHECK MED INTERACTIONS WITH SEIZURE MEDS RULE 2: CHECK MED INTERACTIONS WITH ANTIFUNGALS Rules of Thumb RULE 3: CHECK MED INTERACTIONS WITH HIV MEDS CYP inhibitors Clarithro/Erythromycin Fluconozole/voriconazole/it raconazole/ketoconazole Diltiazem/verapamil Fluoxetine/bupropion/parox etine > duloxetine Gemfibrozil Indinavir/nelfinavir/ritonavi r Amiodarone Substrate Watch out for meds with a narrow therapeutic index Cyclosporine, tacrolimus Theophylline Warfarin Phenytoin Common medications with risk for toxicity or failure Statins (except pravastatin, rosuvastatin, fluvastatin) Macrolides (except azithromycin) TCAs Calcium channel blockers RULE 4 A 65 yo man presents with cough and fever. He has had severe diarrhea for 2 days. He was on a cruise with a friend who was diagnosed with Legionella yesterday. PMH diabetes, hyperlipidemia,hypertension. Meds: Lisinopril, simvastatin, amlodipine, gemfibrozil,metformin. Chest Xray shows patchy bilateral infiltrates. WBC 17,000 Na 125. What is the most appropriate treatment? A)Amoxicillin/clavulanate B)Clarithromycin C)Levofloxacin D)Cefuroxime E)Trimethoprim/sulfa Interactions in This Case Gemfibrozil- simvastatin (rhabdomyolysis) Simvastatin- clarithromycin (rhabdomyolysis) Amlodipine- clarithromycin (hypotension) Safety Labeling for Simvastatin 80 mg >12 mo, no side-effects -> Ok to continue 80 mg, no side-effects + interacting med -> change Contraindicated: Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol 10 mg: Amiodarone, verapamil, diltiazem 20 mg: Amlodipine, ranolazine 40 mg, inadequate LDL -> switch to more potent med TAKE HOME: Actively review all patients on simvastatin, make adjustments based on risk factors. PMID: Statins Max Dose LDL Metabolism Fluvastatin 80 mg 31% CYP 2C9 Pravastatin80 mg 34% liver, not CYP Lovastatin 80 mg 40% CYP 3A4 prodrug Pitavastatin 4 mg 41% CYP 2C8/9 minor Simvastatin 80 mg 46% CYP 3A4, 2D6 Atorvastatin 80mg 57% CYP 3A4 Rosuvastatin 40 mg 63% CYP 2C9 minimal TAKE HOME: Pravastatin for low potency, low cost. Pitavastatin moderate potency, high cost. Rosuvastatin high potency, high cost. 2

5 Rules of Thumb - Statins CYP inducers Rifampin Carbamazepine Dilantin Phenobarbitol Thiozolidinediones St. John s Wort Warfarin CYP inhibitors Clarithro/Erythromycin/ Telithromycin Fluconozole/voriconazole/itrac onazole/ketoconazole Diltiazem/verapamil Fluoxetine/bupropion/paroxeti ne > duloxetine Gemfibrozil Indinavir/nelfinavir/ritonavir Amiodarone Top Medication Interactions and Side Effects Statin med interactions rhabdomyolysis A 60 yo man with CAD returns for followup. He has stopped his pravastatin because of myalgias. He previously had myalgias with simvasatin and lovastatin. He is wary of trying another statin because of myalgias. He has been taking coenzyme Q10 without benefit. What do you recommend? A) Restart pravastatin and take naproxen daily B) Red yeast rice 1800 mg BID C) Rosuvastatin 10 mg 2X a week D) Ezetimibe 10 mg a day Side Effects of Statins Rhabdomyolysis (rare) 0.01% Hepatotoxicity (rare) Liver failure % Myalgias 5-18 % Cataracts? Approach to Management of Myalgias on Statins Check CK,TSH. Stop statin, when symptoms disappear restart statin at lower dose or change statin Recurrent symptoms Fluvastatin 80mg XL QD or alternate day 2X weekly 10mg atorvastatin Low dose rosuvastatin QD,QOD or weekly If symptoms continue try ezetimibe PMID: Twice Weekly Rosuvastatin for Statin Myalgias Retrospective chart review of previously statin intolerant patients in a lipid lowering clinic 40 patients received rosuvastatin 5mg twice a week (30) or rosuvastatin 10mg twice a week (10) Mean LDL reduction was 43, with 54% reaching NCEP goal 8 patients (20%) discontinued rosuvastatin due to side effects PMID:

6 Myalgias Case 69M with HTN, HLD, discharging from the hospital after a completed NSTEMI. His FBG in hospital was 123. Discharge Meds: Ec ASA 325 mg qday Metoprolol XL 25 mg qday HCTZ 25 mg qday Lisinopril 40 mg qday Atorvastatin 80 mg qday Ranitidine 150 mg BID Which med his risk for DM2? Which med his risk? Diuretics, B blockers, and Statins May Risk for DM PEACE trial 7000 pts, no DM, stable CAD 60% on beta blocker at randomization. Placebo or ACEI (trandolapril) B blocker + placebo DM2, HR 1.63 p=0.001 B blocker + ACEI no DM2, HR 1.11 p=0.39 ACEI risk DM2, HR 0.83 p=.009 NAVIGATOR trial 24K pts, glucose intolerance New onset DM2 Diuretic HR 1.23 Statin HR 1.32 No risk with B blocker or CCB TAKE HOME: B blockers, diuretics and statins may risk for DM. PMID: , PMID: Statins and Diabetes Risk BMJ Nov 2013 New Zealand national cohort 32K y.o. diclofenac v antihtn v statin Rx metformin 5y Statin HR 3.31 HTN HR 2.32, HR 1.59 Multiple MA data: Statins risk for DM 9-13% all statin Rosuvastatin (20mg) 25%, Atorvastatin (80 mg) 15%, Pravastatin (40 mg) 7% JUPITER Rosuvastatin incident DM2 3.0% vs. 2.4% over 2 y, 26% RR WOSCOPS Pravastatin DM2 by 30% (HR) over 5 y. PMID , PMID: Statins and DM Risk Increased risk Higher potency statins Elderly Women (WOSCOPS all male) Possibly type of statin, lipophilic > hydrophilic Obesity, and other DM risk factors Statins and DM2 Take Home Discuss risks vs. benefits 9:1 benefit:risk. 9 CV events prevented per 1 incident DM2, NNT 155 CV events, NNH 498 DM2 Intensive dose statins 3:1 : 3 CV events prevented, 1 incident DM2 Consider implications of new lipid guidelines 12 M more y.o. qualify for statins (48% total) 87% men and 54% women qualify Consider the specific statin Atorvastatin and rosuvastatin greatest risk, simvastatin and pravastatin may have some risk Pitavastatin seems neutral or protective Consider statin dosing doses of atorvastatin conferred risk PMID:

7 Myalgias, Diabetes Case 69M with HTN, HLD, discharging from the hospital after a completed NSTEMI. Requests to speak to you about his DC meds. Discharge Meds: Ec ASA 81 mg qday Metoprolol XL 25 mg qday Lisinopril 40 mg qday Atorvastatin 80 mg qday Ranitidine 150 mg BID He is worried about the risks of memory loss and will not take which medication? Statins and Memory JUPITER 16K, RCT Rosuvastatin (Crestor) v placebo 18 v 4 pts had confusional state 69 v 76 pt nervous disorder 515 v 533 pt psychiatric disorder FDA 2003 retrospective case report 60 reports, 14/25 improved off statins Lypophylic statins reported more (simvastatin, atorvastatin, lovastatin) Observational studies Cochrane No evidence for protection, started late? Ginko trial 2011, 3000 >75 y.o, All cause dementia HR 0.79, Alzheimers HR City trial 2012, 6.8K, no effect Annals Nov 2013 SR No risk AD, dementia, MCI, memory, attention, motor FDA post marketing low report rates, similar to other cardiac meds 2014 review in CNS Meds Insufficient evidence that statins are protective for AD PMID: ) PMID: , 2) PMID: , 3) PMID: ) PMID: Statins and Memory Take Home TAKE HOME POINT: Rare if any risk for statins causing cognition worsening. Unclear if protective. For concerns use pravastatin, or rosuvastatin. Myalgias, diabetes Minor risk for memory loss 5

8 A 60 yo man develops pain in his feet over the past week. He describes the pain as burning, and sharp. No swelling, or redness. PMH: alcoholism (quit drinking 3 years ago), hypertension, CAD, prostatitis, and diabetes. Meds: rosuvastatin, lisinopril, metformin, levofloxacin, amlodipine. Exam- hyperasthesia both feet. What do you recommend? A) Start B12 supplementation B) Stop Rosuvastatin C) Stop Metformin D) Stop Levofloxacin E) Stop Amlodipine Known since 1990 s Onset 1-7 days Symptoms: paresthesias most common initial symptom (81%) Duration: months to years after discontinuation, maybe permanent Fluoroquinolone Side Effects Tendinopathy, Tendon Rupture % Achilles>shoulder, hand risk with prednisone, elderly Black box warning 2008 PMID: Glycemia Hypoglycemia (rare) elderly, CKD, female, liver disease, sulfonylurea, insulin Gatifloxicin OR Hyperglycemia (still uncommon) DM1 DM2, elderly, steroids, illness Gatifloxicin > levofloxacin. No risk with cipro or moxifloxicin Quinolone Side Effects and Interactions Insomnia/confusion Arrhythmia (QTc prolongation) Levoflox = moxiflox Amiodarone, sotalol, methadone, clarithromycin, erythromycin, thiazide diuretics, hypokalemia Retinal detachment? PMID: , PMID: , PMID: , PMID: Quinolone Treatment Failure Common supplements/otcs Calcium Magnesium Iron Antacids Foods Dairy (potential moderate interaction) Clinical pearl: Risk of quinolone treatment failure with antacids, MVI, supplements via chelation, 16-66%. Dose 2h pre or 4-6 h post quinolone. Micromedex accessed 1/3/ Myalgias, diabetes Minor risk for memory loss Fluoroquinolone side effects Peripheral neuropathy, tendon rupture Fluoroquinolone risk for failure with antacids 6

9 35 F presents to urgent care for an anaphylactic reaction. She was treated by her partner with an epinephrine pen. The 3 days prior she was treated for sinusitis by a provider with moxifloxicin, fluticasone nasal spray, and alternating ibuprofen and naproxen. PMH: Asthma, eczema, allergic rhinitis Baseline Meds: Omalizumab (Xolair), TAC cream prn, diphenhydramine prn Which medication was most likely to blame for the anaphylactic reaction? 2014 Top 10 Meds: Anaphylaxis and Severe Hypersensitivity Name Hypersensitvity Anaphylaxis 1. Omalizumab 65 (10.4) 59 (9.4) 2. Moxifloxacin 57 (25.6) 39 (17.5) 3. Infliximab 64 (2.3) 35 (1.2) 4. Gadopentetate dimeglumine 32 (21.1) 29 (19.1) 5. Cetuximab 33 (6.7) 23 (4.7) 6. Glatiramer 26 (3.2) 22 (2.8) 7. Amlodipine 28 (5.4) 20 (3.9) 8. Ibuprofen 34 (4.1) 18 (2.2) 9. Lisinopril 146 (20.9) 17 (2.4) 10. Naproxen 26 (2.7) 17 (1.8) Adapted from ISMP Quarterwatch 3/14: Table 2. Anaphylactic shock and overall severe hypersensitivity most frequently reported drugs Myalgias, diabetes Minor risk for memory loss Fluoroquinolone side effects Peripheral neuropathy, tendon rupture Fluoroquinolone risk for failure with antacids Top meds causing hypersensitivity 66 M with spinal stenosis, binge ETOH use, HTN presents with tremor, nausea, and violent thoughts. He feels angry but not depressed or overtly anxious. His last drink was 1 week ago. Meds: Pregabalin, amlodipine, APAP/hydrocodone PRN, duloxetine (stopped 1 week ago), pantoprazole. What is the likely cause of his symptoms? A) Wernicke's encephalopathy due to ETOH + PPI B) Pregabalin C) Narcotic withdrawal D) Duloxetine withdrawal E) Hyponatremia Duloxetine Withdrawal Common symptoms Dizziness, headache, nausea, paresthesias, Short acting antidepressants Duloxetine, paroxetine Ely-Lilly studies on duloxetine 44-50% experience withdrawal with abrupt DC 10% experienced severe symptoms 54% had withdrawal symptoms persist >2 weeks ISMP Quarterwatch Oct 2012 Management of Duloxetine Withdrawal Taper over 6-8 weeks Taper by 10% per week Taper over 8-30 weeks Communicate clearly with patient about risks for withdrawal and monitor ISMP Quarterwatch Oct

10 2014 Top 10 Meds: Suicidal and Homicidal Ideation Indication Number % 1. Varenicline Smoking cessation Montelukast Asthma Paroxetine Major depression Quetiapine Schizophrenia Venlafaxine Major depression Interferon beta Multiple sclerosis Isotretinoin Resistant acne Duloxetine Major depression Pregabalin Neuropathic pain Bupropion Major Depression SSRI s and Hyponatremia Patient Risk Factors Older age Female Concomitant diuretic use Low body weight Meds Associated with Hyponatremia Hydrochlorathiazide/indapa mide (38%) SSRI s SNRI s NSAIDs Carbemazipine MDMA (ecstasy) * Adapted from ISMP 9/14 Quarterwatch: Table 1. Leading suspect drugs in suicidal/self-injurious and homicidal ideation cases, 2007 to 2013 Q3 PMID: PMID: PMID: PMID: Myalgias, diabetes Minor risk for memory loss Fluoroquinolone side effects Peripheral neuropathy, tendon rupture Fluoroquinolone risk for failure with antacids Top meds causing hypersensitivity Duloxetine withdrawal Top meds causing suicidal ideation A 72 y.o. male S/P AVR replacement two years ago for aortic stenosis presents with wide spread bruising on his back/legs and some bruising on the back of both hands. His last INR was three weeks ago and was 3.0. He states he saw an M.D. six days ago for a cough and was put on a medication described as a white tablet. Baseline meds: Coumadin 5 mg qd, Albuterol inhaler 2 puffs 4 times a day and Nortryptiline 25 mg qhs. What medication was he placed on? a) Amoxicillin b) Codeine c) Cefixime d) Azithromycin e) TMP/Sulfa Warfarin A Interactions Antifungals Anti-arrhythmics Amiodarone, propafenone Antibiotics Bactrim, metronidazole, erythromycin > clarithromycin, azithromycin, fluoroquinolones OK to use - cephalosporins, nitrofurantoin, PCNs Antacid PPIs (omeprazole) 8

11 A 39 y.o. woman with a prosthetic aortic valve presents with bruising. Her last INR 6 weeks ago was 2.4, today s INR is 6.5. She has not taken any extra Coumadin. Which of the following when taken on a daily basis could explain her increased INR? a) Acetaminophen b) Calcium carbonate c) OCP d) Ranitidine e) DOSS Warfarin and Acetaminophen 4 studies acetaminophen + warfarin INR > 9100 mg/week led to 10 x risk of having INR > 6* In double blind crossover trial patients on Warfarin + 4 g/d of Acetaminophen had PT 1.75 x control Patients received 2 g or 4 g acetaminophen or placebo with warfarin, 54% of those receiving acetaminophen overshot INR goal vs 17% of placebo. The mean maximal INR increase was 0.70 ± 0.49 and 0.67 ± 0.62 in patients receiving acetaminophen at 2 g/day and 3 g/day PMID: , PMCID: PMC , PMID: , PMID: Warfarin A Interactions Antifungals Anti-arrhythmics Amiodarone, propafenone Antibiotics Bactrim, metronidazole, erythromycin > clarithromycin, azithromycin, fluoroquinolones OK to use - cephalosporins, nitrofurantoin, PCNs Antacid PPIs (omeprazole) Acetaminophen Myalgias, diabetes Minor risk for memory loss Fluoroquinolone side effects Peripheral neuropathy, tendon rupture Fluoroquinolone risk for failure with antacids Top meds causing hypersensitivity Duloxetine withdrawal Top meds causing suicidal ideation Warfarin Interactions: A A 62 yo man with a hx of MI 4 years ago presents with right hip pain. He has had discomfort with walking for the past 6 months. Xray reveals moderate osteoarthritis. Most recent labs: Bun 6 Cr.8 Glu 100 What would be the most appropriate management plan? A) Acetaminophen B) Oxycodone C) Ibuprofen D) Diclofenac E) Celecoxib Risk of MI with NSAID Use Nationwide cohort study in Denmark. 99,187 patients with a mean age of 69 Studied pharmacy records and medical records for all patients over age 30 with a first time admission for MI Subsequent NSAID use was tracked Death with NSAID use HR 1.59 at 1year, 1.63 at 5 years Recurrent MI HR 1.3 at 1 year, 1.41 at 5 years. Even short-term treatment with most NSAIDs was associated with risk of death and recurrent MI in patients with prior MI. PMID: , PMID:

12 Risks of NSAIDS and Coxibs Lancet 2013 Large meta-analysis of 639 RCT. >225,000 participants looking at NSAID/Coxib risk Coxibs and diclofenac were associated with RR of major vascular events Ibuprofen risk of MI All NSAIDS and Coxibs risk for CHF hospitalizations All GI bleeding risk lowest coxibs RR 1.8 highest naproxen RR 4.33 Myalgias, diabetes Minor risk for memory loss Fluoroquinolone side effects Peripheral neuropathy, tendon rupture Fluoroquinolone risk for failure with antacids Top meds causing hypersensitivity Duloxetine withdrawal Top meds causing suicidal ideation Warfarin Interactions: A NSAIDS risk for cardiovascular and GI risks PMID: Resources Institute for Safe Medication Practices ismp.org Prescriber s Letter or Medical Letter Epocrates or Micromedex Check for interactions online or handheld Cochrane Review CAM Natural Standard Natural Medicines About Herbs (handheld) 10