1. Drug Interactions Pharm 560 2 October 2002 Philip D. Hansten, PharmD Professor, School of Pharmacy University of Washington

2. Drugs Removed from the Market Due to Drug-Drug Interactions Cerivastatin (Baycol): Rhabdomyolysis when combined with gemfibrozil Terfenadine (Seldane): Ventricular arrhythmias with CYP3A4 inhibitors Astemizole (Hismanal): Ventricular arrhythmias with CYP3A4 inhibitors Cisapride (Propulsid): Ventricular arrhythmias with CYP3A4 inhibitors Mebefradil (Posicor): Rhabdomyolysis when combined with simvastatin

3. Hospital Admissions due to Drug Interactions in Elderly (France) Prospective study of 1000 patients > 70 yo admitted to geriatric unit 538 patients exposed to DDIs 130 patients developed ADIs Most common drugs involved were cardiovascular and psychotropic Doucet J et al. J Am Geriatr Soc. 1996;44:944-948.

4. Severe Cimetidine Adverse Drug Interactions Are Rare VA Hospital switched from ranitidine to cimetidine as cost-saving measure Retrospective study of 4570 patients on cimetidine (10% got interacting drugs) Only 4 patients had adverse interactions – 2 theophylline (nausea, vomiting, arrhythmia) – 1 procainamide (arrhythmia) – 1 warfarin (fatal intracerebral hemorrhage) Scott MA et al. Am J Health-Syst Pharm. 1999;56:1890-91.

5. Uncommon Adverse Drug Interactions For an adverse drug interaction that occurs once in 1000 cases, one would have to study 3000 cases to have a 95% chance of observing the event.

6. David Hume (1711-1776) Scientific certainty is not possible using induction – “All swans are white.” Absence of proof is not proof of absence – “Bigfoot does not exist.” – “Those drugs do not interact.”

7. NO ADR OBSERVED Drug A + Drug B Assessing Drug Interactions Using Induction 25 Patients Usual Conclusion: This interaction is not clinically important.

8. NO ADR OBSERVED Drug A + Drug B 25 Patients Correct Conclusion: Available information is insufficient to determine clinical importance. Assessing Drug Interactions Using Induction

9. Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Patient Education Monitoring ADR Drug Interaction Defenses Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Drug Administration Pharmacogenetics Drug A + Drug B Defenses

10. Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Latent Failures Patient Risk Factors Patient Education Monitoring ADR A + B Drug Interactions: “When the Holes Line Up” Defenses Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Drug Administration

11. Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Patient Education Monitoring NO ADR A + B Drug Interaction Errors Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Drug Administration

12. NSAIDs + SSRIs: Increased Risk of Bleeding? Case-control study of 1651 incident cases compared to 10,000 matched controls “The concurrent use of NSAIDs with SSRIs greatly increases risk of upper GI bleeding” SSRIs  platelet uptake of serotonin De Abajo FJ et al. Br Med J 1999;319:1106-1109. 1

13. Clarithromycin (Biaxin)- Induced Digoxin Toxicity 70 YO woman on digoxin 0.25 mg/day for 4 years started on clarithromycin After 4 days, hospitalized with nausea, vomiting, weakness, brown spots in vision, ECG abnormalities Serum digoxin = 5.4 ng/mL Trevedi S et al. Ann Intern Med 1998;128:604. Letter

14. P-glycoprotein (P-gp) Efflux pump:  exposure to xenobiotics Found in numerous tissues: – Intestinal Epithelium – Biliary canaliculi – Renal proximal tubules – Blood-brain barrier – Tumor cells Promiscuous: interacts with wide variety of chemical structures Kovarik JM et al. Clin Pharmacol Ther 1999;66:391-400.

15. P-Glycoprotein Actively Transports Drugs Out of Cell Wall Inside Cell Cell Wall Outside Cell Entry via passive diffusion PGP = Lipophilic Drug

16. P-glycoprotein Involved in Digoxin Pharmacokinetics P-glycoprotein protects against digoxin toxicity by: Decreasing G.I. absorption Increasing biliary excretion Increasing renal tubular secretion Decreasing access to the brain Tanigawara Y. Ther Drug Monit 2000;22:137-140.

17. Itraconazole Increases Levels of Methylprednisolone Randomized crossover study of 14 subjects, 4 days of itraconazole, then single dose of: – Methylpred. 48mg – Prednisolone 60 mg Marked effect on methylprednisolone, but not prednisolone Lebrun-Vignes B. Br J Clin Pharmacol. 2001;51:443-450.

18. Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Patient Education Monitoring NO ADR A + B Drug Interaction Errors Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Drug Administration

19. “Asthma Sufferer Wins $28.6 Million Award” ( Seattle Times 9/3/94) 24-year-old man on theophylline went into ER with infection, and the ER physician gave him ciprofloxacin Theophylline levels doubled, and he was left with permanent brain damage Physician was awarded $22.5 million for “damage to his reputation” 24-year-old man on theophylline went into ER with infection, and the ER physician gave him ciprofloxacin Theophylline levels doubled, and he was left with permanent brain damage Physician was awarded $22.5 million for “damage to his reputation”

20. St. John’s Wort Reduces Simvastatin (Zocor) Levels 16 subjects took 10mg simvastatin alone and after St. John’s Wort 900 mg/day X 14 days AUC of Simvastatin & its active metabolite substantially reduced Induction of CYP3A4 and P-glycoprotein? No effect on Pravastatin Sugimoto K et al. Clin Pharmacol Ther 2001;70:518-24. Simvastatin Acid AUC

21. St. John’s Wort Increases CYP3A4 Activity 12 subjects took probe drugs with St. John’s Wort 900mg/d X 14d – Caffeine (1A2) – Tolbutamide (2C9) – Dextromethorphan (2D6) – Midazolam (3A4) Only midazolam was affected (PO > IV) Wang Z et al. Clin Pharmacol 2001;70:317-26.

22. Garlic Supplements Decrease Saquinavir (Invirase) Levels 9 subjects took 1200 mg saquinavir TID alone and after garlic capsules BID X 20 days Allicin content of garlic capsules confirmed Garlic associated with 51% decrease in AUC of saquinavir Piscitelli SC et al. 8 th Conf. On Retroviruses, 2001, Abst. 743

23. Ibuprofen (Advil) Inhibits the Antiplatelet Effects of Aspirin Catella-Lawson F et al. New Engl J Med. 2001;345:1809-17. Subjects took 81 mg ASA in AM for 6 days with 3 ibuprofen dosing schedules: – 400 mg 2 hours before ASA (  platelet effect) – 400 mg 2 hours after ASA (No effect on ASA) – 400 mg 2, 7 & 12 h after ASA (  platelet effect) Other agents did not reduce platelet effect: – Rofecoxib (Vioxx) 25 mg before or after ASA – Diclofenac DR 75 mg BID (2 & 10 h after ASA) – Acetaminophen 1000 mg before or after ASA Subjects took 81 mg ASA in AM for 6 days with 3 ibuprofen dosing schedules: – 400 mg 2 hours before ASA (  platelet effect) – 400 mg 2 hours after ASA (No effect on ASA) – 400 mg 2, 7 & 12 h after ASA (  platelet effect) Other agents did not reduce platelet effect: – Rofecoxib (Vioxx) 25 mg before or after ASA – Diclofenac DR 75 mg BID (2 & 10 h after ASA) – Acetaminophen 1000 mg before or after ASA

24. Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Patient Education Monitoring NO ADR A + B Drug Interaction Errors Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Drug Administration

25. Rifampin Markedly Reduces Simvastatin Plasma Levels 10 subjects took 40 mg simvastatin alone & after rifampin 600 mg/day for 5 days Simvastatin acid AUC decreased by 93% No effect on half-life of simvastatin; primary effect on first pass metabolism Kyrklund et al. Clin Pharmacol Ther 2000;68:592-597..

26. Sertraline (Zoloft) Levels Reduced by Enzyme Inducers (PHT, CBZ) Sertraline serum levels compared in 9 patients on phenytoin (PHT) or carbamazepine (CBZ) versus 54 patients on just sertraline Concentration/daily dose ratios considerably lower with enzyme inducers Pihlsgard M, Eliasson E. Eur J Clin Pharmacol 2002;57:915-916. Sertraline C/D Ratio

27. Cushing’s Syndrome with Ritonavir + Nasal Fluticasone 30 YO HIV (+) man on ritonavir and nasal fluticasone developed Cushingoid facies Positive dechallenge and rechallenge Similar case reported by Chen (1998) Hillebrand-Haverkort et al. AIDS 1999;13:1803.

28. Fluticazone Susceptible to CYP3A4 Inhibitors? Fluticasone metabolized by CYP3A4 to inactive metabolite Bioavailability of fluticasone after inhalation = 12 to 26% CYP3A4 inhibitors theoretically would increase systemic effects of fluticasone

29. Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Patient Education Monitoring NO ADR A + B Drug Interaction Errors Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Drug Administration

30. Factors Influencing Drug Interaction Outcomes CLINICAL OUTCOME OF DRUG INTERACTIONS PATIENT FACTORS DRUG ADMINISTRATION Genetics Diseases Diet/Nutrition Environment Smoking Alcohol Dose Duration Dosing Times Sequence Route Dosage Form HIGH VARIABILITY Adapted from Hansten. Science & Medicine. 1998;5:16-25.

31. Fluconazole (Diflucan) + Warfarin (Coumadin) 7 people on warfarin given fluconazole 100 mg daily X 7 d Marked increase in the PT response (but high variability) No bleeding occurred Crussell-Porter LL et al. Arch Intern Med 1993;153:102-104.

32. Fatal Hyperkalemia After Amiloride + ACE Inhibitors 5 patients presented to ER with severe hyperkalemia (on ACE inhibitor with amiloride added 8 to 18 days earlier) 5 patients presented to ER with severe hyperkalemia (on ACE inhibitor with amiloride added 8 to 18 days earlier) All 5 were over 50 & had diabetes and 4 had renal impairment All 5 were over 50 & had diabetes and 4 had renal impairment Potassium levels = 9.4 to 11 mEq/L Potassium levels = 9.4 to 11 mEq/L 2 patients died (authors recommend avoiding combination) 2 patients died (authors recommend avoiding combination) Chiu T-F et al. Ann Emerg Med 1997;30:612-615.

33. Hyperkalemia Risk Estimates With Various Combinations of Drugs Patients Predisposed to Hyperkalemia* * e.g., Diabetes, Renal impairment, High dietary potassium, etc.