Objectives. Objectives. Clinically Significant Drug Interactions: the Antimicrobial Version 4/20/2018

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1 Clinically Significant Drug Interactions: the Antimicrobial Version Dr. Barr declares no conflicts of interest, real or apparent, and no financial interests in any company, product or service mentioned in this program, including grants, employment, gifts, stake holdings and honoraria. Viki Barr PharmD, BCPS-AQ ID Assistant Professor Rosalind Franklin University Objectives At the completion of this activity, the pharmacist will be able to: Describe the mechanisms of drug interactions Explain the severity of the interaction and how it applies to a patient Outline clinical decisions using information on interactions between commonly used medications and antimicrobials Objectives At the completion of this activity, the technician will be able to: Identify potential risk factors for drug interactions Describe the mechanisms of drug interactions Discuss the drug-drug interaction severity rating systems 1

2 Pharmacists Under Fire Pharmacists Under Fire In December 2016 The Chicago Tribune published that it tested 255 pharmacies to see how often stores would dispense risky drug pairs without warning patients 52% of the tested pharmacies sold the medications without mentioning the potential interaction Epidemiology of Drug (drug) Interactions True incidence difficult to determine Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs Most data are in the form of case reports Missing or incomplete information 2

3 Risk Factors for Drug Interactions Drug Interactions Poly pharmacy Multiple prescribers Genetic makeup Specific populations Geriatric, obese, critically ill, transplant, etc Disease Specific HIV, renal dysfx, hepatic dysfx, etc Narrow therapeutic index drugs Warfarin Length of hospital stay Lack of pharmacist evaluation Definition: The pharmacologic or clinical response to the administration of a drug combination different from that anticipated from the known effects of the two agents when given alone May be harmful: toxicity, reduced efficacy May be beneficial: Synergistic combinations, pharmacokinetic boosting, increased convenience, reduced toxicity, cost reduction Bjerrum L, et al. EurJ Gen Pract. 2008;14(1):23-29 Janovic SM, et al. J of Crit Care. 2018(43);1-6. Types of Drug Interactions or Mechanisms Pharmacokinetic Drug Interactions Pharmacokinetic What the body does with the drug One drug alters the concentration of another Usually mediated by cytochrome P450 Pharmacodynamic Related to the drug s effects in the body One drug modulates the pharmacologic effect of another: additive, synergistic, or antagonistic Drug absorption Drug metabolism (biotransformation) CYP3A4, CYP2D6, CYP2C9 Transport of the drug inside the body Drug displacement (protein-binding) Drug excretion 3

4 Level of Severity of Interactions Level of Severity of Interactions- Micromedex Many different sites available for level of severity classification Micromedex Lexi-Comp Clinical Pharmacology Typically range from levels 1 to 5 Severe interactions Moderate interactions Minor interactions Cautionary interactions Clinically not significant interactions or not established lindfranklin.edu:showdruginteractionsresults Risk Rating Action Description A B C D X No Known Interaction No Action Needed Monitor Therapy Consider Therapy Modification Avoid Combination Adapted from: Information/Lexi-Interact-Fields Data have not demonstrated either PK/PD interactions between the specified agents Data demonstrate that the specified agents may interact with each other, but there is little to no evidence of clinical concern Data demonstrate that the specified agents may interact with each other in a clinically significant manner. The benefits of concomitant use of these two medications usually outweigh the risks. An appropriate monitoring plan and\or dosage adjustments may be necessary. Data demonstrate that the two medications may interact with each other in a clinically significant manner. A patient-specific assessment must be conducted to determine whether the benefits of concomitant therapy outweigh the risks. Specific actions must be taken in order to realize the benefits and/or minimize the toxicity resulting from concomitant use of the agents. These actions may include aggressive monitoring, empiric dosage changes, choosing alternative agents. Data demonstrate that the specified agents may interact with each other in a clinically significant manner. The risks associated with concomitant use of these agents usually outweigh the benefits. Generally considered contraindicated. Self Assessment Question What are risk factors for exhibiting drug interactions (DI s)? A. Poly pharmacy B. Genetic makeup C. Specific populations D. Narrow therapeutic index drugs E. All the above 4

5 I Have a Cough Case Applications 67 yof came in with a cough where she was prescribed azithromycin 500mg PO x 5 days. She is here now to pick up her new script. Current med list: Esomeprazole 40mg daily Diltiazem XR 240mg daily Lisinopril 10mg daily Fluoxetine 40mg daily Lets Run an DI Check CI use of fluoxetine and azithromyin So what would you do? DC the fluoxetine DC the azithromycin DC both medications Keep both medications and dispense QT Prolongation Prolonged QTcis a heart rhythm condition that can potentially cause fast, chaotic heartbeats A normal QTcinterval generally ranges between milliseconds People with long QTc(QT interval 500 milliseconds) have potentially dangerous QT prolongation Lexicomp Drug Interactions. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Source: MayoClinic.org 5

6 Risk Factors for QT Prolongation Age >65 Female gender Bradycardia Left ventricular failure Recent cardioversion Electrolyte abnormalities Hypomagnesemia, hypokalemia, hypocalcemia Higher concentrations of one or more QTprolonging drugs Genetic predisposition Azithromycin and Risk Cardiovascular Death Retrospective cohort of individuals in the Tennessee Medicaid Program to detect an increased risk of death ( ) Patient were on: Azithromycin Amoxicillin Ciprofloxacin Levofloxacin Roden DM. N EnglJ Med. 2004;350: Yap YG, Camm AJ. Heart. 2003;89: Drew BJ. J Am CollCardiol, 2010, 55(9): Ray WA et al. NEJM 336(20): Azithromycin and Risk Cardiovascular Death Outcomes 5 day course of azithromycin compared to no ABX risk of CV death (HR, 2.88; 95% CI, 1.79 to 4.63; P<0.001) Pts on amoxicillin has no increased risk of death Azithromycin associated with a small absolute increase in the risk of CV death (47 cases per 1 million) Specifically in patients with CV disease (245 cases in 1 million The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ from levofloxacin After 5 day course, even with long T½, risk of cardiovascular death did not persist Azithromycin and Risk Cardiovascular Death In another retrospective population study of US veterans Azithromycin shown to significantly increase the risk of mortality and arrhythmia on days 1 to 5, but not on days 6 to 10 after dispensing the prescription Some conflicting data: Two large retrospective cohort studies did not demonstrate an increased risk of CV events Including all-cause mortality or CV death The implications of these data have yet to be determined Ray WA et al. NEJM 336(20): Rao GA, et al. Ann Fam Med. 2014;12(2): Mortesen EM, et al. JAMA. 2014;311(21): Svanstrom H. et al. NEJM. 2013;368(18):

7 Azithromycin and Risk Cardiovascular Death So what should we take from these studies: In patient with heart defect or on other QT prolonging agent, be more cautious In the hospital-get EKG Outpatient- depends where they are getting med from May want to consider getting baseline if outpatient and has more risk factors Back to the Patient 67 yof came in with a cough where she was prescribed azithromycin 500mg PO x 5 days. She is here now to pick up her new script. Current med list: Esomeprazole 40mg daily Diltiazem XR 240mg daily Lisinopril 10mg daily Fluoxetine 40mg daily What would you do? Self Assessment Question Which of the following are risk factors associated with taking azithromycin QTc prolongation? A. Advanced age B. Heart defect C. Addition of other QT prolonging agent D. All the above Still Have a Cough. Same 67 yof came in with a cough where she was prescribed moxifloxacin 400mg PO x 10 days and prednisone 60mg taper over 2 weeks She is here now to pick up her new scripts. Current med list: Esomeprazole 40mg daily Diltiazem XR 240mg daily Lisinopril 10mg daily Fluoxetine 40mg daily MVI daily 7

8 Lets Run an DI Check Fluoroquinolones (FQ) and QTc Prolongation CI use of moxifloxacin and fluoxetine Monitor therapy for moxifloxacin and prednisone So what would you do? DC fluoxetine DC moxifloxacin DC prednisone DC all medications Keep all medications and dispense Other suggestions? Lexicomp Drug Interactions. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: FQ share the potential to block the cardiac voltage-gated potassium channels Higher the FQ dose and serum AUCs, the higher the QT prolongation risk and subsequently the risk of Td The degree to which FQ block cardiac K+ channels and thereby cause QT prolongation varies by agent Moxi> levo> cipro Rubinstein E. JAC. 2002;4(1): Lexicomp Drug Interactions. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Fluoroquinolones (FQ) and QTc Prolongation MVI s with Fluoroquinolones Case-control analysis that included 605,127 patients receiving treatment for respiratory conditions 1838 cases of serious arrhythmia were identified The rate of serious arrhythmia was elevated with current fluoroquinolone use (RR 1.76, 95% CI ), particularly with new current use Showed ciprohad as high of risk as moxi Nationwide populationbased study in Taiwan Compared the risks of ventricular arrhythmia and CV death within 7 days after initiation of a macrolide, FQ, or amoxicillin-clavulanate Observed an increase in risk of ventricular arrythmia with FQ and azithromycin FQ forms a chelate with the cations resulting in inactive antimicrobials Interaction most significant with aluminum and magnesium ions Lesser with calcium ions The reduction in FQ absorption can significantly affect Cmax and % bioavailability Inhibiting the therapeutic effectiveness Space out 2 hrsbefore MVI or 6 hrsafter Lapi F, et al. CID. 2012;55(11) Chou HW, et al. CID (4): Shimada J, etal. AAC. 1993;36: Lexicomp Drug Interactions. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: 8

9 Steroids and Fluoroquinolones Patients are at an elevated risk of tendinitis and tendon rupture when taking systemic FQ and a steroid together Even more elevated in: Older patients (> 60) receiving steroids Heart, lung, and kidney transplant recipients Achilles Tendon Rupture (ATR) The Achilles tendon is a strong fibrous cord that connects the muscles in the back of your calf to your heel bone Source: MayoClinic.org Overstretch it can cause it to rupture Mainly occurs in people playing recreational sports, but it can happen to anyone Lapi F, et al. CID. 2012;55(11) Chou HW, et al. CID (4): Lexicomp Drug Interactions. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Risk Factors for Achilles Tendon Rupture Drugs Advanced age Decline of physical activity Peak incidence middle age Male gender (2x) Obesity Disease specific: Renal insufficiency Rheumatological diseases (specifically RA) Hyperpaprathyroidism DM Hyperlipidemia Achilles Rupture with FQ and Steroids Proposed mechanisms: FQ: Mice and rat tendons exhibit hypoxic free radical damage which can lead to tendon weakening Human case reports typically within 90 days of start of a FQ (but reported up to a year) Steroids: Injection of steroids into the tendons of rats shown to cause tendon necrosis In humans shown to cause massive hypertrophy of muscles without causing corresponding strengthening of the associated tendons Seeger JD, et al. Pharmacoepiand Drug Safety. 2006;15: MauffulliN, et al. J Bone SurgAm. 1998;81: Seeger JD, et al. Pharmacoepiand Drug Safety. 2006;15:

10 Achilles Rupture with FQ and Steroids Many case reports reporting incidences of ATR with one of both drugs Vander Linden and colleagues found: Steroids with FQ and > 60 yrs of age had a 5 fold increased risk of ATR Wise and colleagues looked at impact of age, sex, obesity and steroid and FQ use and ATR Steroid with FQ with increased age and non obese at increased risk Also found DM and those with renal failure or receiving HD may be in increased risk Achilles Rupture with FQ and Steroids So what should we take from these studies: Combination of FQ and steroids significantly increased the risk of ATR specifically in patients with: Elderly Renal insufficiency with or without HD DM Van der Linden PD, et al. Arch Intern Med. 2003;163: Wise BL, et al. Am J of Medicing. 2012;125: Back to the Patient Same 67 yof came in with a cough where she was prescribed moxifloxacin 400mg PO x 10 days and prednisone 60mg taper over 2 weeks She is here now to pick up her new scripts. Current med list: Esomeprazole 40mg daily Diltiazem XR 240mg daily Lisinopril 10mg daily Fluoxetine 40mg daily MVI daily What would you do?? Self Assessment Question Which of the following statements is true regarding FQ s and MVI s? A. A MVI should always be discontinued when taking a FQ B. The interaction will significantly affect the bioavailability if the FQ C. If taking a MVI the FQ should taken 2 hrs before the MVI or 2 hrsafter 10

11 Self Assessment Question Which of the following are considered risk factors for a tendon rupture? A. Female gender B. Advanced age C. Increased physical activity D. Underweight Can I Please Have my Antibiotic??? 33 yof comes to your pharmacy with a prescription for augmentin875mg BID x 10 days for a UTI Current med list: MVI daily Ortho-tri cyclen Lo daily Lets Run an DI Check No action needed, right? Summary: Penicillinsmay diminish the therapeutic effect of Estrogen Derivatives Antibiotics (PCN) and Oral Contraceptives (OC) 1994, the British Dental Journal published a paper reviewing the possible interactions between antibiotics and OCs Patient needed to be warned that ABX given may interfere with the OC effects and that additional contraceptive methods should be used while taking the antibiotics and for 7 days after stopping Lexicomp Drug Interactions. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Gibson J, et al. Br Dent J. 1994;177:

12 Mechanism of Penicillin's Decreasing Efficacy of Birth Control Penicillin's can alter intestinal flora Wiping out our normal flora in our gut Possibly leading to lower estrogen reabsorption Decreased oral combination contraceptive efficacy Recent Literature on Interaction Helms and colleagues retrospectively examined the effect of commonly prescribed oral antibiotics on the failure rate of Ocs 365 patients use of combination 263 also provided "control" data (during the times they used OCs alone) Additional 162 patients provided control data only 5 pregnancies occurred in 311 woman-years of combined antibiotic/oc exposure (1.6% per year failure rate) vs 12 pregnancies in 1245 woman-years of exposure (0.96% per year) for the 425 control patients This difference was not significant (p = 0.4), 95% CI (-0.81, 2.1) 1-3% failure rate Hemls SE, et al. J Am AcadDerm. 1997;36(5.1): Recent Literature on Interaction PK study by Dogteromand colleagues Evaluated interaction with Nuvaringwith and without amoxicillin and doxycycline Showed no interaction between estrogen containing OCs and oral amoxicillin and doxycycline Stated contraceptive efficacy would also be unaffected Back to Our Patient 33 yof comes to your pharmacy with a prescription for augmentin875mg BID x 10 days for a UTI Current med list: MVI daily Ortho-tri cyclen Lo daily So can she have her antibiotic, or do we need recommend something? Dogteron P, et al. Clin Pharmacokinet. 2005;44(4):

13 Two Patients Same Concern? Lets Run a DI Check 35 yo M currently admitted for a severe SSTI to be started on Linezolid 600mg BID PMH: Depression, back pain (post spine surg) Current meds: Sertraline 100mg D Tramadol 100 q 6 h 65 yo M currently admitted for a severe SSTI to be started on Linezolid 600mg BID PMH: Depression, chronic pain (NSLC), CHF, DM Current meds: Sertraline 50 mg D Fentanyl patch 25mg Lasix 20 mg D Metoprolol 100mg D Lisinopril 20mg D Metformin 1000mg BID Glipizide 5mg D 35 yrold F So what would you do? 65 yrold F Lexicomp Drug Interactions. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Serotonin Syndrome Potentially life-threatening ADR that results from: Therapeutic drug use Prescriptions: SSRI, SNRI, MAOIs, analgesics (fentanyl, meperidine, tramadol), antipsychotics, anticonvulsants, antiparkinsonian agents, dextromethorphan, ondansetron, trazodone, linezolid etc Illicit drugs: LSD, cocaine Herbals: St. John s wort and ginseng Intentional self-poisoning Inadvertent interactions between drugs Boyer EW, et al.nejm. 2005;352: Symptoms of Serotonin Syndrome Clinical manifestations from barely noticeable to lethal Clinical Triad Mental-status changes Autonomic hyperactivity Neuromuscular abnormalities Boyer EW, et al.nejm. 2005;352:

14 Incidence of Serotonin Syndrome Performing a rigorous epidemiologic assessment of the serotonin syndrome is difficult More than 85 % of physicians are unaware of the serotonin syndrome as a clinical diagnosis Assessment has relied on post-marketing surveillance studies Incidence is thought to mirror the increasing number of proserotonergic agents Surveillance Study Reported 26,733 incidences of exposure to SSRI s 7349 (27%) individuals experienced significant toxic effects 93 (0.4%) total deaths Linezolid and Serotonin Syndrome Multiple retrospective case studies exist Taylor and colleagues performed retrospective chart review of inpatients at Mayo Clinic 72 patients received concomitant linezolid and an SSRI/SNRI within 14 days of one another 52(72%) patients received concomitant 20(28%) patients received linezolid within 14 day period 2(3%) patients had high probability of serotonin syndrome based on criteria used by Boyer and colleagues Boyer EW, et al.nejm. 2005;352: Taylor JJ, et al. 2006;43(2): Boyer EW, et al. NEJM. 2005;352: Back to the Patients. 35 yo M currently 65 yo M currently admitted for a severe SSTI admitted for a severe SSTI to be started on Linezolid to be started on Linezolid 600mg BID 600mg BID PMH: Depression, back PMH: Depression, chronic pain (post spine surg) pain (NSLC), CHF, DM Current meds: Current meds: Sertraline 100mg D Sertraline 50 mg D Tramadol 100 q 6 h Fentanyl patch 25mg Lasix 20 mg D Metoprolol 100mg D Lisinopril 20mg D Metformin 1000mg BID Glipizide 5mg D What would you do for each patient? Pharmacists Under Fire: What Has Been Done Companies have invested and upgraded their computer alert systems to better protect patients Provided additional training for thousands of its pharmacists New law enacted 14

15 The New Law for Illinois Effective August 18, 2017, the Illinois Department of Financial and Professional Regulation, adopted new rules related to patient counseling that will affect the practice of pharmacy Required to provide verbalcounseling priorto dispensing a medication: To a new patient For an existing patient: New Drug Used to be required to offer counseling but now you are required to counsel Any changes in route, dose, strength and directions Under the new rules, an offer to provide counseling must still be made on all other prescriptions where counseling is not mandated. Summary Some drug interaction are fluid Always depends on the patient Data is changing for some of these interactions Eg-OC s and PCN s If still unsure or literature is confusing, can always call a pharmacy specialist Know your limitations Clinically Significant Drug Interactions: the Antimicrobial Version Viki Barr PharmD, BCPS-AQ ID Assistant Professor Rosalind Franklin University viktorija.barr@rosalindfranklin.edu 15