1. Drug-Drug Interactions Jim Hoehns, Pharm.D.

2. Objectives  Identify mechanisms for specific clinically relevant drug interactions  Identify methods to predict and prevent drug interactions  Recognize common inducers and inhibitors of CYP450 interactions

3. Drug Interactions  Pharmacokinetic One drug alters the kinetic properties of another One drug alters the kinetic properties of another AbsorptionAbsorption DistributionDistribution MetabolismMetabolism EliminationElimination  Pharmacodynamic One drug alters the sensitivity or responsiveness of tissues to another One drug alters the sensitivity or responsiveness of tissues to another

4. Question  A patient has the following meds. Her doctor wants to start calcium carbonate 500mg BID Synthroid 0.1 mg QD Synthroid 0.1 mg QD Metoprolol 50 mg BID Metoprolol 50 mg BID Procardia XL 60 mg QD Procardia XL 60 mg QD  Any drug-drug interaction concerns?

5. Calcium and Levothyroxine  20 patients with hypothyroidism Added 1200mg calcium QAM with Synthroid Added 1200mg calcium QAM with Synthroid  13/20 pts had reduced free T 4  13/20 pts had increased TSH 4 pts had TSH >nl range 4 pts had TSH >nl range Calcium added JAMA 2000;283:2822-2825.

6. Mechanisms - GI Absorption  Drug binding in GI tract formation of insoluble complexes formation of insoluble complexes iron salts: tetracyclines, Sinemet iron salts: tetracyclines, Sinemet antacids/Carafate: quinolone antimicrobials antacids/Carafate: quinolone antimicrobials Questran/Colestid: Coumadin, Synthroid, Lanoxin Questran/Colestid: Coumadin, Synthroid, Lanoxin

7. ALENDRONATE: EFFECT OF FOOD ON ORAL BIOAVAILABILITY 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 2 h Before Breakfast 1/2 h Before Breakfast <0.11 2 h After Breakfast <0.11 Time of Dose (after overnight fast) Bioavailability (%) 1 h Before Breakfast With Breakfast 0.46 0.76 Gertz BJ et al. Clin Pharmacol Ther. 1995;58:288-298.

8. Mechanisms - GI Absorption  Effects on intestinal flora digoxin and erythromycin/Biaxin digoxin and erythromycin/Biaxin ? oral contraceptives and oral antibiotics ? oral contraceptives and oral antibiotics  Drug metabolism within intestinal wall CYP3A4 is abundant in intestinal epithelium CYP3A4 is abundant in intestinal epithelium  Avoidance of GI drug interactions adjustment of dosing times adjustment of dosing times

9. Question  A patient is on the following meds. His doctor wants to start Glucophage 500mg BID. Cimetidine 400 mg BID Cimetidine 400 mg BID ASA 325 mg QD ASA 325 mg QD Terazosin 10 mg QD Terazosin 10 mg QD Imdur 60 mg QD Imdur 60 mg QD  Any drug-drug interaction concerns?

10. Mechanisms - Drug Excretion Interactions  Active tubular secretion acidic drugs acidic drugs probenecid (Benemid) and penicillins/cephalosporins probenecid (Benemid) and penicillins/cephalosporins probenecid and methotrexate probenecid and methotrexate thiazide diuretics and lithium thiazide diuretics and lithium basic drugs basic drugs quinidine and Lanoxin quinidine and Lanoxin cimetidine and procainamide (Pronestyl) cimetidine and procainamide (Pronestyl) trimethoprim trimethoprim

11. Question  A patient has the following meds. Her doctor wants to start Rifampin 600 mg QD and INH 300 mg QD for TB. Trazodone 50 mg QHS Trazodone 50 mg QHS Prozac 20 mg QD Prozac 20 mg QD Ortho Tri-Cyclen 1 tab QD Ortho Tri-Cyclen 1 tab QD  Any drug-drug interaction concerns?

12. Mechanisms - Enzyme Induction  Increased hepatic P450 enzymes  Examples barbiturates: phenobarbital barbiturates: phenobarbital Tegretol (carbamazepine) or Dilantin Tegretol (carbamazepine) or Dilantin rifampin rifampin cigarette smoking, St. John’s wort cigarette smoking, St. John’s wort  Characteristics time course: gradual time course: gradual dose dependency dose dependency

13. Cytochrome P450 Superfamily CYP 2 D 6 root term family subfamily individual enzyme  Terminology

14. Cytochrome P450 Superfamily

15. Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414. CYP3A CYP2D6 CYP2C CYP1A2 CYP2E1 Relative Importance of P450s in Drug Metabolism CYP3A CYP2C CYP1A2 CYP2E1 ? CYP2D6 Relative Quantities of P450s in Liver CYP450

16. CYP Genetic Variation  CYP2D6 Absent in 7% of Caucasians; 1-2% non-Caucasians Absent in 7% of Caucasians; 1-2% non-Caucasians  CYP2C9 Absent in 1% Caucasians & African-Americans Absent in 1% Caucasians & African-Americans  CYP2C19 Absent in 20-30% Asians; 3-5% Caucasians Absent in 20-30% Asians; 3-5% Caucasians

17. Drugs That Decrease the Effectiveness of OCs American College of Obstetrics and Gynecology Practice Bulletin Number 18, July 2000  Anticonvulsants Barbiturates (including phenobarbital and primidone) Barbiturates (including phenobarbital and primidone) Phenytoin Phenytoin Carbamazepine Carbamazepine Topiramate Topiramate Vigabatin Vigabatin  Anti-infectives Rifampin Griseofulvin www.contraceptiononline. org

18. Drugs That Do Not Decrease the Effectiveness of OCs American College of Obstetrics and Gynecology Practice Bulletin Number 18, July 2000  Anti-infectives Tetracycline Doxycycline Ampicillin Metrondiazole Quinolone antibiotics www.contraceptiononline. org

19. Question  A patient has the following meds. His doctor wants to start Sporanox pulse therapy for onychomycosis. Atenolol 50 mg QD Atenolol 50 mg QD Ativan 1mg BID Ativan 1mg BID Felodipine 20mg QD Felodipine 20mg QD  Any drug-drug interaction concerns?

20. Mechanisms - Enzyme Inhibition  Inhibition of hepatic P450 activity  Most common drug-drug interaction  Characteristics time course: maximum inhibition in 24 hrs time course: maximum inhibition in 24 hrs dose dependency dose dependency specificity specificity CYP2D6 CYP3A3/4

22. Mechanisms - Enzyme Inhibition  CYP3A inhibitors Diltiazem Diltiazem Verapamil Verapamil Itraconazole Itraconazole Ketoconazole Ketoconazole Clarithromycin Clarithromycin Erythromycin Erythromycin Grapefruit juice Grapefruit juice  CYP2D6 inhibitors Clomipramine Quinidine Fluoxetine Haloperidol Paroxetine  CYP2C9 inhibitors Amiodarone Fluconazole

23. Substrates, Inhibitors & Inducers CYPSubstrateInhibitorInducer 2C9warfarinfluconazole, amiodarone rifampin 2C19omeprazole, lansoprazole, pantoprazole omeprazole, fluvoxamine rifampin 2D6desipramineparoxetine, fluoxetine none identified 3A4/3A5midazolam, buspirone, felodipine, lovastatin, simvastatin, sildenafil atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, ritonavir rifampin, carbamazepine fda.gov

24. CYP3A Inhibitors Strong CYP3A Inhibitors Moderate CYP3A Inhibitors Weak CYP3A Inhibitors ≥ 5-fold increase in AUC≥2, but ≤ 5-fold increase in AUC ≥1.25, but < 2-fold increase in AUC atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, telithromycin diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil cimetidine fda.gov

25. Case #5  72 y.o. male with HIV, Afib, CAD, and hyperlipidemia presents with pain, fatigue, and dark orange urine X3 days.  Labs: CK 66,680 U/L CK 66,680 U/L BUN 93 mg/dL BUN 93 mg/dL Creatinine 4.6 mg/dL Creatinine 4.6 mg/dL AST 1,579 U/L AST 1,579 U/L ALT 738 U/L ALT 738 U/L  Dx: rhabdomyolysis  Treatment: hydration and dialysis X 1 month

26. Case #5  Meds Simvastatin 80mg/d (27 days prior) Simvastatin 80mg/d (27 days prior) Amiodarone 200mg/d (19 days prior) Amiodarone 200mg/d (19 days prior) Atazanavir 400mg/d (>2 yrs) Atazanavir 400mg/d (>2 yrs) Stavudine 40mg BID Stavudine 40mg BID Delavirdine 600mg BID Delavirdine 600mg BID Imdur 60mg BID Imdur 60mg BID Plavix 75mg QD Plavix 75mg QD Lopressor 50mg BID Lopressor 50mg BID Hytrin 5mg QHS Hytrin 5mg QHS Pepcid 20mg BID Pepcid 20mg BID

27. Simvastatin Label Update Interacting DrugPrevious LabelUpdated Label Strong 3A4 inhibitors (e.g. itraconazole, keto, posaconazole HIV protease inhibitors, erythromycin, clarithromycin) AvoidContraindicated; posaconazole added to list of examples Gemfibrozil, cyclosporine, danazol Do not exceed 10mg simvastatin daily Contraindicated Amiodarone, verapamilDo not exceed 20mg simvastatin daily Do not exceed 10mg simvastatin daily DiltiazemDo not exceed 40mg simvastatin daily Do not exceed 10mg simvastatin daily Amlodipine, ranolazineNo dose capDo not exceed 20mg simvastatin daily

29. FDA Early Communication  “The FDA is aware of published reports that clopidogrel (marketed as Plavix) is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel, or that using certain drugs with clopidogrel can interfere with how the body metabolizes clopidogrel.” January 26, 2009

30. CYP2C19 Variants White(n=1356) Black (n=966) Chinese (n=573) Extensive metabolism 2C19*1/*1746638 Intermediate metabolism 2C19*1/*2 or *1/*3 262950 Poor metabolism 2C19*2/*2, *2/*3 or *3/*3 2414 CYP2C19 Phenotype and Genotype Frequency (%)

31. Clopidogrel + PPI Controversy  Where are we now? COGENT: only RCT to compare PPI with clopidogrel in patients taking clopidogrel COGENT: only RCT to compare PPI with clopidogrel in patients taking clopidogrel Summary: No concern for interactionSummary: No concern for interaction  Considerations Confounding may have contributed to cohort study findings of interactions with PPIs Confounding may have contributed to cohort study findings of interactions with PPIs Did COGENT have adequate power? Did COGENT have adequate power? Is this controversy now over? Is this controversy now over?  No need to modify PPI regimens in patients receiving clopidogrel at this time?

32. Warfarin  Increased INR Metronidazole Metronidazole Sulfamethoxazole Sulfamethoxazole Amiodarone Amiodarone Cimetidine Cimetidine Fluconazole Fluconazole Erythromycin Erythromycin Voriconazole Voriconazole  Decreased INR Phenobarbital Rifampin Carbamazepine Phenytoin Cholestyramine St. John’s wort

33. Patient Case #3  72 y.o. male (FPC patient) Coumadin 10 mg QD (goal INR 2.5-3.5) Coumadin 10 mg QD (goal INR 2.5-3.5) erythromycin 250 mg TID (bronchitis) erythromycin 250 mg TID (bronchitis) 4 days later 4 days later epistaxis, ecchymosis, hematuria epistaxis, ecchymosis, hematuria INR = 55.4 INR = 55.4 vitamin K (phytonadione) given vitamin K (phytonadione) given

34. Patient Case #4  61 y.o. female medications: medications: lithium 300 mg QD, Nardil 15 mg TID, Sinequan 75 mg QD, Mellaril 50 mg QD, & others lithium 300 mg QD, Nardil 15 mg TID, Sinequan 75 mg QD, Mellaril 50 mg QD, & others Zoloft 100 mg QD started Zoloft 100 mg QD started within 3 hours of first dose: within 3 hours of first dose: semi-comatose, T 41 C, BP 140/110, HR 154, RR 40 semi-comatose, T 41 C, BP 140/110, HR 154, RR 40 ER treatment: ice-packs, dantrolene, Versed and Valium ER treatment: ice-packs, dantrolene, Versed and Valium 3 days later patient was extubated 3 days later patient was extubated  Serotonin syndrome

35. Summary  Understand common mechanisms  Know the “red flag” drugs Inhibitors Inhibitors Oral antifungals, Biaxin, Emycin, Prozac, Paxil, Amiodarone Oral antifungals, Biaxin, Emycin, Prozac, Paxil, Amiodarone Inducers Inducers Rifampin, Tegretol, Dilantin, Phenobarbital, St. John’s wort Rifampin, Tegretol, Dilantin, Phenobarbital, St. John’s wort  Special caution for narrow therapeutic index drugs digoxin, warfarin, lithium, Synthroid digoxin, warfarin, lithium, Synthroid

36. Websites  www.drug-interactions.org www.drug-interactions.org  www.torsades.org www.torsades.org  www.arizonacert.org www.arizonacert.org

37. Inducer or Inhibitor? Erythromycin Itraconazole Carbamazepine Rifampin Phenytoin Fluoxetine Amiodarone St. John’s Wort Phenobarbital Fluvoxamine

38. DI Questions  A 47 y.o. female is newly diagnosed with PE while an inpatient. Her BMI is 58. She is on rifampin 450mg BID and Bactrim DS 1 BID for MRSA infection after hip arthroplasty. What might we anticipate about her warfarin dosage requirement?  A 77 y.o. female with Afib now has UTI. Her most recent INR was 3.0. Now MD prescribed Cipro 250mg BID x 14 days. Current warfarin dose is: 2mg M,W,F,Sat and 3 mg all other days. Plan?

39. Patient Case 1  A 25 y.o. female saw her physician and was diagnosed with a sinus infection. He prescribed a Zpak.  PMedHx: Morbid obesity, depression, headaches  Meds: Citalopram 20mg QD, Implanon, Ibuprofen 600mg PRN

40. Patient Case 2  87 y.o. male presents with Rx for Levaquin 500mg QD x 7 days for UTI. He has also been treated for Cdiff colitis recently and has lost 25 lbs over the past 2 months.  PMedHx: Afib, lymphoma, polymyalgia rheumatica, osteoporosis  Meds: amiodarone 200mg QD, aspirin 81mg QD, prednisone 10mg QD  Allergies: Sulfa