Drug Interactions Pharm 560 2 October 2002

1. Drug InteractionsPharm 5602 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. Assessing Drug Interactions Using Induction Drug A + Drug B 25 Patients NO ADR OBSERVED Usual Conclusion: This interaction is not clinically important.

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

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

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

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

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 1 De Abajo FJ et al. Br Med J 1999;319:1106-1109.

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 Entry via passive diffusion Outside Cell Cell Wall PGP Inside Cell = 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. Drug Interaction Errors Prescriber’s Knowledge A + B Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990

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”

20. St. John’s Wort Reduces Simvastatin (Zocor) Levels Simvastatin Acid AUC • 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.

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. 8th Conf. On Retroviruses, 2001, Abst. 743

23. Ibuprofen (Advil) Inhibits the Antiplatelet Effects of Aspirin • 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 Catella-Lawson F et al. New Engl J Med. 2001;345:1809-17.

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

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 C/D Ratio • 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.

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

30. Factors Influencing Drug Interaction Outcomes PATIENT FACTORS DRUG ADMINISTRATION Dose Duration Dosing Times Sequence Route Dosage Form Genetics Diseases Diet/Nutrition Environment Smoking Alcohol CLINICAL OUTCOME OF DRUG INTERACTIONS 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) • All 5 were over 50 & had diabetes and 4 had renal impairment • Potassium levels = 9.4 to 11 mEq/L • 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.