Resolving Drug Drug Interactions: A Guide for Community Pharmacies to Reduce Potential Hospitalizations

Transcription

1 Resolving Drug Drug Interactions: A Guide for Community Pharmacies to Reduce Potential Hospitalizations Presenter: Jim Kong, RPh, BSc, PharmD Consultant, ISMP Canada Learning Objectives 1. The significance of drug drug interactions (DDIs) in the elderly population 2. Current challenges in preventing DDIs 3. How to identify clinically significant DDIs 4. A review of alternative therapeutic options for empiric treatment of UTI, Strep Throat and CAP 5. Develop confidence in mitigating DDIs Presentation Outline Part 1: Adverse Drug Reactions (ADRs) and Drug Drug Interactions (DDIs) in the Elderly Population Part 2: Evidence and Management of Clinically Relevant DDIs Part 3: Tools to Communicate DTPs and Therapeutic Recommendations to Physicians Part 4: Putting It All Together: A Case Example Part 5: Testing Your Knowledge Part 6: Conclusion 1

2 Part 1: Adverse Drug Reactions and Drug Drug Interactions in the Elderly Population What is an Adverse Drug Reaction? Any noxious, unintended, or undesired effect of a drug occurring at dosages administered in humans for prophylaxis, diagnosis or treatment of disease, or for the modification of physiological function World Health Organization Adverse Drug Reaction Up to 25% of all hospital admissions and emergency department (ED) visits 6 o risk in seniors o financial burden 23 Ontario 2007: $333 per ED visit; $7528 per hospitalization Estimated annual cost in elderly population alone (> 66 yrs) o 13.6 million in Ontario o $35.7 million in Canada o Up to 70% of these visits are preventable!! 2

3 Drug Drug Interactions (DDI) Occurs when one drug alters the pharmacological effect of another drug upon co administration, which may or may not result in increased, decreased, synergistic or new and unanticipated ADEs 2 Classifications 20 Pharmacokinetic: Absorption, distribution, metabolism, and/or excretion (ADME) of one drug is altered by another drug Pharmacodynamic: Response of one drug is altered by another drug without changes in the PK of the original drug DDIs in the Elderly Population Physiological changes suscep bility to DDIs: o Body composition fat mass, total body water Lipophilic drug: Vd, t1/2 Hydrophilic drug: Vd o hepa c blood flow o drug metabolism o renal function o drug clearance DDIs in the Elderly Population Other factors that susceptibility to DDIs 12 : o Multiple comorbidities o Progression of chronic diseases o Polypharmacy Bajcar et al revealed that Rx claims 214% for older adults in Ontario between >>> growth in population of Ontario adults 65+ yrs ( 18.5%) 3

4 DDIs in the Elderly Population Prevalence not well defined 12,13,19 o 1 5% of hospitalizations in elderly risk of morbidity and mortality DDIs resulting in ADEs often predictable and preventable Challenges in Preventing DDIs (1) Detection of DDIs by clinicians is not optimal Glassman et al : Clinicians identified only o 44% of all DDIs o 54% of all contraindicated DDIs Challenges in Preventing DDIs (2) Recognition of DDIs by Clinical Decision Support Systems (CDSS) is not streamlined Hazlet et al : Pharmacy computerized drug drug interaction systems may fail to detect up to 1 in 3 DDIs Lack of regular, reliable updates o Large, continuously number of DDIs o Delays in turnaround time for knowledge transfer/translation Frequent warnings of trivial issues operator fatigue override of more significant DDIs 4

5 Challenges in Preventing DDIs (3) Lack of high quality evidence of clinically significant DDIs Most data derived from case reports, volunteer studies etc. May contribute to sensi vity and specificity of computerized drug interaction systems Novel approach to evaluate DDIs Pharmacoepidemiologic Studies Population based studies derived from databases (i.e. prescription and health insurance claims data, hospitalization records, demographic information from provincial and national databases etc.) linking DDIs with real world, patient experienced ADEs o external validity Identifies novel DDIs not consistently recognized by CDSS Clinically relevant DDIs o Outcome of interest: hospitalization These clinically significant DDI pairs should be actively screened by community pharmacies!! Our Focus Today DDIs involving antibiotics along with one chronic medication Why? Majority of DDIs identified from pharmacoepidemiological studies involved an antibiotic (abx) Abx for community acquired infections usually required for relatively short duration DDIs involving abx can often be resolved with different abx from difference class(es) role for pharmacist intervention!! 5

6 Part 2: Evidence and Management of Clinically Relevant DDIs Trimethoprim/Sulfamethoxazole (TMP/SMX) in the Treatment of Uncomplicated Urinary Tract Infections (UTIs) Uncomplicated UTIs One of the most common indications for antimicrobial exposure in an otherwise healthy population o Second most common infection among community dwelling older patients o Accounts for ~ 25% of all infection in older adults Common Pathogens: o Escherichia coli (75 95%) o Occasional Enterobacteriaceae o Proteus mirabilis o Klebsiella pneumoniae o Staphylococcus saprophyticus o Other gram ( ) and gram (+) are rare 6

7 Empiric Treatment Options for Uncomplicated Urinary Tract Infections First Line: TMP/SMX 160/800 mg (one DS tablet) BID x 3 days Nitrofurantoin monohydrate / macrocrystals 100 mg BID x 5 days Second Line: Fluoroquinolone Ciprofloxacin 500 mg BID x 3 days Norfloxacin 400 mg BID x 7 days B lactams Ampicillin Amoxicillin IDSA Guidelines 2011 Trimethoprim/Sulfamethoxazole Traditional first line agent in uncomplicated UTI Mechanism of Action: interferes with bacterial folic acid synthesis o Bactericidal, time dependent kill Trimethoprim Sulfamethoxazole drugbank.ca Antoniou T et al. Trimethoprim sulfamethoxazole induced hyperkalemia in patients receiving inhibitors of the reninangiotensin system. Arch Intern Med 2010; 170(12): Trial Design Population based, nested case control study Duration of trial Data collected from Apr 1994 to March yrs Case Subjects 66 yrs On continuous therapy of either ACEI or ARB Hospitalized within 14 days of receiving TMP/SMX, amoxicillin, ciprofloxacin, norfloxacin or nitrofurantoin Outcome of interest Hospitalization rates secondary to hyperkalemia 7

8 Results Association Between Hospital Admission Involving Hyperkalemia and Recent Antibiotic Use while on ACEI or ARB therapy Antibiotic Use in Preceding 14 Days Cases No. (%) Controls No. (%) Adjusted Odds Ratio (95% CI) Total TMP/SMX 204 (55.6) 323 (22.8) 6.7 ( ) Norfloxacin 20 (5.4) 163 (11.5) 0.8 ( ) Ciprofloxacin 76 (20.7) 413 (29.1) 1.4 ( ) Nitrofurantoin 18 (4.9) 129 (9.1) 1.1 ( ) Amoxicillin 49 (13.4) 389 (27.5) 1 [Reference] Discussion Hyperkalemia risk with ACEI alone ~ 10% within 1 year of initiation o Risk factors: renal insufficiency, diabetes mellitus, le ventricular function, advanced age, drugs Trimethoprim o Structural and pharmacological similarities to K + sparing diuretic amiloride o K + Amiloride excretion by ~ 40% Trimethoprim drugbank.ca Conclusion Among older patients treated with ACEI or ARB, use of TMP/SMX is associated with ~ 7 fold increased risk of hyperkalemia associated hospitalization relative to other antibiotics. Consider using alternative antibiotic therapy whenever possible. 8

9 Antoniou T et al. Trimethoprim sulfamethoxazole induced hyperkalemia in elderly patients receiving spironolactone: nested case control study. BMJ 2011;343:d5228. Trial Design Population based, nested case control study Duration of trial Data collected from Apr 1992 to March yrs Case Subjects 66 yrs On continuous spironolactone therapy Hospitalized within 14 days of receiving TMP/SMX, amoxicillin, norfloxacin or nitrofurantoin Outcome of interest Hospitalization rates secondary to hyperkalemia Results Association Between Hospital Admission Involving Hyperkalemia and Recent Antibiotic Use while on Spironolactone therapy Antibiotic use in Preceding 14 days Cases No. (%) Controls No. (%) Adjusted Odds Ratio (95% CI) Total TMP/SMX 161 (65) 162 (21) 12.4 ( ) Nitrofurantoin 34 (14) 159 (20) 2.4 ( ) Norfloxacin 17 (7) 137 (17) 1.6 ( ) Amoxicillin 36 (15) 325 (42) 1.0 [Reference] Discussion Hyperkalemia occurs in up to 1/3 of patients on spironolactone o Regular monitoring of electrolytes o Caution/avoidance of other medications that can cause hyperkalemia Trimethoprim o Structural and pharmacological similarities to K + sparing diuretic amiloride o K + excretion by ~ 40% 9

10 Conclusion Among older patients receiving spironolactone, use of TMP/SMX is associated with ~ 12 fold increased risk of hyperkalemia associated hospitalization relative to other antibiotics. Nitrofurantoin was also associated with a modest increased (~2 fold) risk of hyperkalemia. Consider using alternative antibiotic therapy whenever possible. Fischer HD et al. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract antiinfective agents. Arch Intern Med 2010; 170(7): Trial Design Population based, nested case control study Duration of trial Data collected from Apr 1997 to March yrs Case Subjects 66 yrs On continuous warfarin therapy Hospitalized within 14 days of receiving TMP/SMX, amoxicillin, ampicillin, ciprofloxacin, norfloxacin, or nitrofurantoin Outcome of interest Hospitalization rates secondary to upper GI (UGI) hemorrhage Results Association Between Hospital Admission for UGI Tract Hemorrhage and Recent Antibiotic Use while on Warfarin therapy Antibiotic Use in Preceding 14 Days Cases No. (%) Controls No. (%) Adjusted Odds Ratio (95% CI) Total TMP/SMX 25 (1.2) 56 (0.3) 3.84 ( ) Amoxicillin or 30 (1.4) 209 (1.) 1.37 ( ) Ampicillin Ciprofloxacin 31 (1.4) 124 (0.6) 1.94 ( ) Nitrofurantoin 11 (0.5) 64 (0.3) 1.40 ( ) Norfloxacin 5 ( 0.2) 61 (0.3) 0.38 ( ) 10

11 Discussion Many antibiotics interact with warfarin o Abx disrupt gut flora intes nal vitamin K synthesis warfarin effect TMP/SMX inhibits CYP 2C9 o CYP 2C9 metabolizes more biologically active S enantiomer of warfarin o warfarin effect Conclusion Among older patients receiving long term warfarin, use of TMP/SMX is associated with ~ 4 fold increase in risk of hospitalization for UGI tract hemorrhage. Ciprofloxacin was associated with ~ 2 fold increased risk. Consider using alternative antibiotic therapy whenever possible. Juurlink DN et al. Drug drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003; 289(13) Trial Design Population based, nested case control study Duration of trial Data collected from Jan 1994 to Dec yrs Case Subjects 66 yrs On continuous glyburide therapy Hospitalized within 1, 2, and 3 weeks of receiving TMP/SMX or amoxicillin (comparator) Outcome of interest Hospitalization rates secondary to hypoglycemia 11

12 Results Association Between Hospital Admission for Hypoglycemia and Recent TMP/SMX Use while on Glyburide therapy Antibiotic Use Cases No. (%) Controls No. (%) Adjusted Odds Ratio (95% CI) Hospitalization Within 1 Week of Exposure to Antibiotic TMP/SMX 35 (3.9) 189 (0.4) 6.6 ( ) Amoxicillin 10 (1.1) 246 (0.6) 1.5 ( ) Hospitalization Within 2 Weeks of Exposure to Antibiotic TMP/SMX 49 (5.4) 319 (0.7) 5.7 ( ) Amoxicillin 13 (1.4) 433 (1.0) 1.1 ( ) Hospitalization Within 3 Weeks of Exposure to Antibiotic TMP/SMX 56 (6.2) 447 (1.0) 4.9 ( ) Amoxicillin 19 (2.1) 611 (1.4) 1.2 ( ) Discussion Mechanism not fully understood Hypotheses: o Inhibition of sulfonylurea metabolism (glyburide) by sulfonamides? o Displacement of sulfonylureas from protein binding sites free frac on of sulfonylureas? Conclusion Among older patients receiving glyburide, use of TMP/SMX is associated with ~ 6 fold increase in risk of hospitalization for hypoglycemia. Recommend close blood glucose monitoring during concomitant therapy dose adjustments may be necessary. 12

13 Antoniou T et al. Trimethoprim sulfamethoxazole induced phenytoin toxicity in the elderly: a population based study. Br J Clin Pharmacol 2011; 71(4): Trial Design Population based, nested case control study Duration of trial Data collected from Apr 1992 to March yrs Case Subjects 66 yrs On continuous phenytoin therapy Hospitalized within 30 days of receiving TMP/SMX or amoxicillin (comparator) Outcome of interest Hospitalization rates secondary to phenytoin toxicity Results Association Between Hospital Admission Involving Phenytoin Toxicity and Recent TMP/SMX Use while on Phenytoin Therapy Antibiotic Use in Preceding 30 Days Cases No. (%) Controls No. (%) Adjusted Odds Ratio (95% CI) Total TMP/SMX 25 (3.1) 47 (1.5) 2.11 ( ) Amoxicillin 25 (3.1) 61 (1.9) 1.22 ( ) Discussion Phenytoin o Saturable, non linear pharmacokinetics unpredictable serum concentrations o Metabolized by CYP 2C9, 2C8, 2C19 Trimethoprim o Potent inhibitor of CYP 2C8 can phenytoin concentration o Small PK study demonstrated phenytoin clearance was by 30% when combined with TMP 13

14 Conclusion Among older patients on phenytoin therapy, use of TMP/SMX is associated with ~ 2 fold increased risk of phenytoin toxicity requiring hospitalization relative to other antibiotics. Consider using alternative antibiotic therapy whenever possible. Drug Interaction Pairs Chronic Medication DDIs involving TMP/SMX Added Antibiotic Adverse Outcome Comments ACEI or ARB TMP/SMX Hyperkalemia Antoniou et al. (2010) found patients on ACEI or ARB who received TMP/SMX had 7x risk for hospitalization due to hyperkalemia within 7 days Spironolactone TMP/SMX Hyperkalemia Antoniou et al. (2011) found patients on spironolactone who received TMP/SMX had 12x risk for hospitalization due to hyperkalemia within 14 days Warfarin TMP/SMX Hemorrhagic complications Fischer et al. (2010) found patients on warfarin who received TMP/SMX had 4x risk for hospitalization due to hemorrhagic complications within 14 days Glyburide TMP/SMX Hypoglycemia Juurlink et al. (2003) found patients on glyburide therapy who received TMP/SMX had 6x risk for hospitalization due to hypoglycemia within 7 days Phenytoin TMP/SMX Phenytoin toxicity ACEI: Angiotensin converting enzyme inhibitor ARB: Angiotensin receptor blocker Antoniou et al. (2011) found patients on phenytoin who received TMP/SMX had 2x risk for hospitalization due to phenytoin toxicity within 30 days Empiric Therapeutic Alternatives to TMP/SMX for the Treatment of Uncomplicated UTI to Reduce Hospitalization Risk > 65 years of age Uncomplicated UTI Prescribed TMP/SMX Patient receiving long term therapy of: ACEI / ARB Spironolactone Warfarin or Phenytoin Glyburide Nitrofurantoin Switch Norfloxacin TMP/SMX to: Ciprofloxacin Norfloxacin Ciprofloxacin Nitrofurantoin Norfloxacin Nitrofurantoin or Monitor BG TMP/SMX + ACEI or ARB 7 fold risk of hyperkalemia TMP/SMX + spironolactone 12 fold risk of hyperkalemia Nitrofurantoin + spironolactone 2 fold risk of hyperkalemia TMP/SMX + warfarin 4 fold risk of UGI bleed Cipro + warfarin 2 fold risk of UGI bleed TMP/SMX + PHT 2 fold risk of PHT toxicity Cipro + PHT may [PHT] TMP/SMX + glyburide 7 fold risk of hypoglycemia Fluoroquinolones may risk of hypoglycemia 14

15 Macrolides in the Treatment of Group A Streptococcal Pharyngitis Pharyngitis Etiology: o 30 65% idiopathic o 30 60% viral o 5 10% bacterial Most common: Group A streptococcus (GAS) aka strep throat Significant cause of community associated infections Hallmark signs and symptoms o +++ sore throat o Temperature > 38.5 C Empiric Treatment Options for Group A Streptococcal Pharyngitis Penicillin VK 300 mg TID x 10 days *Amoxicillin 500mg BID x 10 days Cephalexin 250 mg QID x 10 days Azithromycin 500 mg x 1, then 250 mg once daily x 4 days Clarithromycin 250 mg BID x 10 days MUMS Guidelines 2013 IDSA Guidelines

16 Macrolides Mechanism of Action: interferes with bacterial protein synthesis Bacteriostatic may be cidal depending on concentration and pathogen Time dependent kill Azithromycin and clarithromycin also exhibit AUC 24 /MIC clarithromycin erythromycin azithromycin drugbank.ca Macrolides CYP Inhibition P gp Inhibition QTc Prolongation GI Tolerability Erythromycin 3A4 1A2 Yes Yes Worst Clarithromycin 3A4 Yes Yes Better Azithromycin None?Yes? Yes Best DDIs involving Macrolides Drug Interaction Pairs Chronic Medication Added Antibiotic Adverse Outcome Digoxin Clarithromycin Digoxin toxicity Azithromycin Erythromycin Comments Gomes et al. (2009) found patients on digoxin who received clarithromycin had 15x risk for hospitalization due to digoxin toxicity, while azithromycin or erythromycin use had 4x risk for hospitalization due to digoxin toxicity Calcium Channel Blockers (CCB) Clarithromycin Erythromycin Hypotension Wright et al. (2011) found patients on nondihydropyridine CCBs who received clarithromycin or erythromycin had a 4x or 6x risk for hospitalization due to hypotension, respectively 16

17 Gomes T et al. Macrolide induced digoxin toxicity: a population based study. Clinical Pharmacology and Therapeutics 2009; 86(4): Trial Design Population based, nested case control study Duration of trial Data collected from Apr 1993 to March yrs Case Subjects 66 yrs On continuous digoxin therapy Hospitalized within 14 days of receiving erythromycin, clarithromycin, azithromycin, or cefuroxime (comparator) Outcome of interest Hospitalization rates secondary to digoxin toxicity Results Association Between Hospital Admission Involving Digoxin Toxicity and Recent Antibiotic Use while on Digoxin Therapy Antibiotic Use in Preceding 14 Days Cases No. (%) Controls No. (%) Adjusted Odds Ratio (95% CI) Total Clarithromycin 55 (3.3) 16 (0.2) ( ) Erythromycin 19 (1.1) 15 (0.2) 3.69 ( ) Azithromycin 16 (0.3) 7 (0.1) 3.71 ( ) Cefuroxime 5 ( 0.3) 15 (0.2) 0.85 ( ) Discussion Mechanism behind interaction: Digoxin o High affinity substrate for multidrug efflux transporter P glycoprotein (P gp) Macrolides inhibit P gp o risk of digoxin toxicity 17

18 Conclusion Among older patients receiving digoxin therapy, use of clarithromycin is associated with ~ 15 fold increased risk of digoxin toxicity requiring hospitalization. Erythromycin and azithromycin is associated with a modest, ~ 4 fold increased risk. Consider using alternative antibiotic therapy whenever possible. Wright A et al. The risk of hypotension following coprescription of macrolide antibiotics and calcium channel blockers. CMAJ 2011; 183(3): Trial Design Population based, nested case cross over study Duration of trial Data collected from Apr 1994 to March yrs Case Subjects Outcome of interest 66 yrs On continuous calcium channel blocker (CCB) therapy Hospitalized within 7 days of receiving erythromycin, clarithromycin, or azithromycin Hospitalization rates secondary to hypotension or shock Results Association Between Hospital Admission Involving Hypotension or Shock and Recent Macrolide Use while on CCB Therapy Macrolide Use in Preceding 7 Days Use During Risk Interval Use During Control Interval Odds Ratio (95% CI) Total Cases of Macrolide Use in Subjects Receiving Long Term CCB Therapy = 176 Erythromycin ( ) Clarithromycin ( ) Azithromycin ( ) 18

19 Results Association Between Hospital Admission Involving Hypotension or Shock and Recent Macrolide Use while on Dihydropyridine CCB Therapy Macrolide Use in Preceding 7 Days Use During Risk Interval Use During Control Interval Odds Ratio (95% CI) Total Cases of Macrolide Use in Subjects Receiving Long Term CCB Therapy = 176 Erythromycin ( ) Clarithromycin ( ) Azithromycin ( ) Discussion Mechanism behind interaction: Calcium channel blockers (Dihydropyridine and Non dihydropyridine) o Substrates for CYP 3A4 Erythromycin and clarithromycin inhibit CYP 3A4 o CCB effect o Bailey DG et al. found erythromycin use associated with felodipine levels by ~ 300% in 12 patients Conclusion Among older patients receiving CCB therapy, use of erythromcyin is associated with ~ 6 fold increased risk of hypotension or shock requiring hospitalization. Clarithromycin is associated with a ~ 4 fold increased risk. Consider azithromycin when macrolide therapy is necessary. 19

20 DDIs involving Macrolides Drug Interaction Pairs Chronic Medication Added Antibiotic Adverse Outcome Digoxin Clarithromycin Digoxin toxicity Azithromycin Erythromycin Comments Gomes et al. (2009) found patients on digoxin who received clarithromycin had 15x risk for hospitalization due to digoxin toxicity, while azithromycin or erythromycin use had 4x risk for hospitalization due to digoxin toxicity Calcium Channel Blockers (CCB) Clarithromycin Erythromycin Hypotension Wright et al. (2011) found patients on nondihydropyridine CCBs who received clarithromycin or erythromycin had a 4x or 6x risk for hospitalization due to hypotension, respectively Therapeutic Alternatives to Macrolides for the Treatment of Group A Streptococcal Pharyngitis to Reduce Hospitalization Risk > 65 years of age Group A strep pharyngitis Prescribed a macrolide Clarithromycin or Erythromycin Azithromycin Patient on long term therapy with: CCB Digoxin CCB Digoxin Switch macrolide to: Penicillin VK Cephalexin Azithromycin Amoxicillin Penicillin VK Cephalexin Amoxicillin Continue Azithromycin Penicillin VK Cephalexin Amoxicillin Erythromycin + CCB 6 fold risk of hypotension Clarithromycin + CCB 4 fold risk of hypotension Clarithromycin + digoxin 15 fold risk of digoxin toxicity Erythromycin + digoxin 4 fold risk of digoxin toxicity No evidence of hypotension risk with azithromycin + CCB Azithromycin + digoxin 4 fold risk of digoxin toxicity Macrolides in the Treatment of Community Acquired Pneumonia in Outpatients 20

21 Community Acquired Pneumonia Lower respiratory tract infection in a non hospitalized person that is associated with symptoms of acute infection with or without new infiltrate on chest radiographs Clinical Presentation o Cough +/ sputum o Fever > 38 C o Dyspnea o Rales, ronchi, wheezing o Malaise, fatigue Common Etiologies: o Streptococcus pneumoniae o Mycoplasma pneumoniae o Haemophilus influenzae o Chlamydiophila pneumoniae o Respiratory viruses Risk Factors for CAP Age > 65 yrs Immunocompromised state or on immunosuppressants Recent antibiotic use or history of antibiotic resistance Comorbidities o Asthma o COPD o Chronic renal failure o Heart failure o Diabetes o Liver disease Empiric Treatment Options for CAP without comorbidities Azithromycin 500 mg on first day, then 250 mg daily x 4 days Clarithromycin 500 mg BID or 1000 mg XL daily x 7 days Doxycycline 200 mg on first day, then 100 mg once daily x 7 days IDSA Guidelines 2007 Canadian Infectious Disease Society and Canadian Thoracic Society Guidelines

22 Empiric Treatment Options for CAP with comorbidities Respiratory Fluoroquinolones Moxifloxacin 400 mg daily x 5 days Levofloxacin mg daily x 5 10 days B lactam + macrolide Cefuroxime 500 mg twice daily x days OR Amoxicillin mg TID x days OR Amoxicillin/Clavulanate 875/125 mg BID x days IDSA Guidelines 2007 Canadian Infectious Disease Society and Canadian Thoracic Society Guidelines 2000 Therapeutic Alternatives to Macrolides for the Treatment of Community Acquired Pneumonia to Reduce Hospitalization Risk > 65 years of age CAP without comorbidities Prescribed a macrolide Clarithromycin or Erythromycin Azithromycin Patient on long term therapy with: CCB Digoxin CCB Digoxin Switch macrolide to: Azithromycin Doxycycline Doxycycline Continue Azithromycin Doxycycline Erythromycin + CCB 6 fold risk of hypotension Clarithromycin + CCB 4 fold risk of hypotension Clarithromycin + digoxin 15 fold risk of digoxin toxicity Erythromycin + digoxin 4 fold risk of digoxin toxicity No evidence of hypotension risk with azithromycin + CCB Azithromycin + digoxin 4 fold risk of digoxin toxicity Therapeutic Alternatives to Macrolides for the Treatment of Community Acquired Pneumonia to Reduce Hospitalization Risk > 65 years of age CAP with comorbidities Prescribed a macrolide Clarithromycin or Erythromycin (+ B lactam) Azithromycin (+ B lactam) Patient on long term therapy with: Azithromycin Switch + B lactam macrolide to: Moxifloxacin Levofloxacin CCB Digoxin CCB Digoxin Moxifloxacin Levofloxacin Continue Azithromycin + B lactam Moxifloxacin Levofloxacin Erythromycin + CCB 6 fold risk of hypotension Clarithromycin + CCB 4 fold risk of hypotension Clarithromycin + digoxin 15 fold risk of digoxin toxicity Erythromycin + digoxin 4 fold risk of digoxin toxicity No evidence of hypotension risk with azithromycin + CCB Azithromycin + digoxin 4 fold risk of digoxin toxicity 22

23 Part 3: Tools to Communicate Therapeutic Recommendations to Prescribers Helpful tools for practice Pre scripted, customizable cover letter to prescriber 23

24 for Safe Medication Practices Canada (ISMP Canada). All Rights Reserved. Pharmaceutical Opinion Program Documentation Tool Patient Information Pharmacist Information Name: M F Name: OCP #: Birth date: OHIP #: Address: Contact #: City: Postal Code: Fax #: Telephone: Date: Category of Drug Related Problem (DRP): Adverse drug reaction due to allergy or conflict with another medication or food Select ONE of the following Drug Drug Interaction Pairs Potential Outcome Glyburide Trimethoprim sulfamethoxazole (TMP SMX) Hypoglycemia Digoxin Azithromycin or Clarithromycin or Erythromycin Digoxin toxicity ACEIs TMP SMX Hyperkalemia Warfarin TMP SMX Hemorrhagic complications Warfarin Ciprofloxacin Hemorrhagic complications Calcium Channel Clarithromycin or Erythromycin Hypotension Blockers (CCBs) Phenytoin TMP SMX Phenytoin toxicity Spironolactone TMP SMX Hyperkalemia Spironolactone Nitrofurantoin Hyperkalemia ARBs TMP SMX Hyperkalemia Other: Pharmacist s Recommendation on Current DRP: Prescriber Review and Comments Comments: Pharmacy Use Only (Please check one outcome) Pharmacist Action Plan & Discussion with Patient & Comments: Note: Pharmacist, please attach a copy of the original Rx as a second page for auditing purposes and/or for the prescriber s reference. Prescriber Information Name: Prescriber ID #: Prescriber signature Office #: Pharmacist signature Fax #: Check here if prescriber authorization is verbal Date of transaction: Patient and Pharmacist Information Drug Therapeutic Problem: Drug Interaction Pairs 24

25 Documentation of Drug Interaction Pair Prescriber Information and Signature Part 4: Putting It All Together CASE EXAMPLE 25

26 Case Example ST, a 68 year old female, walks into your community pharmacy and states that she has been experiencing increased frequency and a burning sensation upon urination for the past 2 days. She presents you with the following prescription: Case Example Ms. S T 144 College St. 09/15/2014 Trimethoprim/ Sulfamethoxazole 1 DS tablet BID x 5 days Case Example As you begin processing her prescription, you notice she is currently on several chronic medications, which include: Amlodipine 5 mg daily Digoxin mg daily Glyburide 5 mg BID Hydrochlorothiazide 25 mg daily Metformin 500 mg TID cc Salbutamol MDI 1 2 puffs QID prn 26

27 Question #1 ST is at risk of experiencing a drug drug interaction. True or False? Question #1 ST is at risk of experiencing a drug drug interaction. True or False? Question #2 Which drug pair may potentially cause an adverse effect resulting in hospitalization? (a) TMP/SMX and Amlodipine (b) Amlodipine and Digoxin (c) TMP/SMX and Hydrochlorothiazide (d) Glyburide and TMP/SMX (e) Glyburide and Digoxin 27

28 Question #2 Which drug pair may potentially cause an adverse effect resulting in hospitalization? (a) TMP/SMX and Amlodipine (b) Amlodipine and Digoxin (c) TMP/SMX and Hydrochlorothiazide (d) Glyburide and TMP/SMX (e) Glyburide and Digoxin Question #3 What clinically relevant adverse outcome may be of concern when TMP/SMX is given with glyburide? (a) Hyperglycemia with risk of diabe c ketoacidosis (b) Hypoglycemia symptoms with blood glucose < 4 mmol/l (c) Unresolved UTI due to efficacy of TMP/SMX (d) Skin rash due to sensi vity to sulfa medica ons (e) B and C Question #3 What clinically relevant adverse outcome may be of concern when TMP/SMX is given with glyburide? (a) Hyperglycemia with risk of diabe c ketoacidosis (b) Hypoglycemia symptoms with blood glucose < 4 mmol/l (c) Unresolved UTI due to efficacy of TMP/SMX (d) Skin rash due to sensi vity to sulfa medica ons (e) B and C 28

29 DTP ST is at risk of experiencing hypoglycemia (weakness, confusion, tremors, headache) secondary to receiving glyburide and TMP/SMX concomitantly and would benefit from reassessment of her UTI therapy Question #4 ST weighs 70 kg. Her recent bloodwork shows a serum creatinine of 73 umol/l. What is/are appropriate therapeutic recommendation(s) for ST? (a) Ciprofloxacin 500 mg BID x 3 days (b) Nitrofurantoin 100 mg BID x 5 days (c) Patient self monitoring of blood glucose (d) A or B and C (e) B and C Question #4 ST weighs 70 kg. Her recent bloodwork shows a serum creatinine of 73 umol/l. What is/are appropriate therapeutic recommendation(s) for ST? (a) Ciprofloxacin 500 mg BID x 3 days (b) Nitrofurantoin 100 mg BID x 5 days (c) Patient self monitoring of blood glucose (d) A or B and C (e) B and C 29

30 Devise a monitoring plan for Ms. ST Efficacy Safety Monitoring Plan Parameter Change/Desired Effect Timeframe Dysuria (pain/burning) Absent 2 3 days Urinary frequency Normalize 2 3 days Flank pain Absent (no change) Ongoing Parameter Change/Desired Effect Timeframe Urine discolouration (dark Absent Throughout therapy orange/brown) GI upset Absent Throughout therapy Part 5: Testing Your Knowledge 30

31 Scenario #2 PA, a 65 year old female with NKDA, walks into your pharmacy stating that she has been feeling terrible for the past day. She woke up this morning with a fever of 38.3 C (axilla) and the worst throat ache she has ever experienced. She states that her doctor s diagnosis is strep throat, and gives you a prescription for clarithromycin 250 mg BID x 10 days. As you begin processing her prescription, you notice she is currently on several chronic medications, which include: Diltiazem ER 240 mg once daily Ramipril 5 mg once daily Metformin 1000 mg BID CC Warfarin 3 mg once daily (last INR 2 weeks ago: 2.8) Lorazepam 1 mg QHS prn Question #1 PA is at risk of experiencing a drug drug interaction. True or False? Question #1 PA is at risk of experiencing a drug drug interaction. True or False? 31

32 Question #2 Which drug pair may potentially cause an adverse effect resulting in hospitalization? (a) Diltiazem and Clarithromycin (b) Diltiazem and Metformin (c) Clarithromycin and Ramipril (d) Warfarin and Diltiazem (e) Clarithromycin and Lorazepam Question #2 Which drug pair may potentially cause an adverse effect resulting in hospitalization? (a) Diltiazem and Clarithromycin (b) Diltiazem and Metformin (c) Clarithromycin and Ramipril (d) Warfarin and Diltiazem (e) Clarithromycin and Lorazepam Question #3 What clinically relevant adverse outcome may be of concern when clarithromycin is given with diltiazem? (a) Hypotension (b) Bradycardia (c) Syncope (d) Shock (e) All of the above 32

33 Question #3 What clinically relevant adverse outcome may be of concern when clarithromycin is given with diltiazem? (a) Hypotension (b) Bradycardia (c) Syncope (d) Shock (e) All of the above Question #4 What is/are appropriate therapeutic recommendation(s)? (a) Azithromycin 250 mg once daily x 5 days (b) Erythromycin ethylsuccinate 400 mg Q6H x 10 days (c) Amoxicillin 500 mg once daily x 10 days (d) Penicillin VK 300 mg TID x 10 days (e) A and D Question #4 What is/are appropriate therapeutic recommendation(s)? (a) Azithromycin 250 mg once daily x 5 days (b) Erythromycin ethylsuccinate 400 mg Q6H x 10 days (c) Amoxicillin 500 mg once daily x 10 days (d) Penicillin VK 300 mg TID x 10 days (e) A and D 33

34 Question #5 What is/are appropriate monitoring parameters for PA? (a) Phonophobia (b) Throat ache severity (c) Neck stiffness/rigidity (d) Photophobia (e) B and C Question #5 What is/are appropriate monitoring parameters for PA? (a) Phonophobia (b) Throat ache severity (c) Neck stiffness/rigidity (d) Photophobia (e) B and C Part 6: Conclusion 34

35 Conclusion DDIs are preventable adverse drug events that are associated with significant morbidity and mortality Research has demonstrated an association between specific drug drug interaction pairs with hospitalization in the elderly population Healthcare practitioners are encouraged to familiarize themselves with these drug drug interaction pairs to prevent clinically significant adverse drug events Pharmacists can intervene by identifying DDIs in practice and communicating these findings concisely and seamlessly with physicians, thereby optimizing safe and effective therapies for patients 35