1. Drug Interactions Sami Shafiq,PharmD, CPh, AAHIVE Lead HIV/AIDS Clinical Liaison, Walgreens, Miami Clinical Assistant Professor of Pharmacy Practice/Adjunct Faculty Nova Southeastern University / College of Pharmacy

2. Remember 1996?

3. Pill Burden Continues to Decline

4. Patients Are living longer… More diseases of the aging: diabetes; High cholesterol; Heart disease; High blood pressure More and newer drugs are available Drug interactions within HIV therapy Drug interactions with other medications

5. Top 10 prescriptions of 2004 Lipitor ® Zocor ® Prevacid ® Nexium ® Procrit ® Zoloft ® Epogen ® Plavix ® Advair Diskus ® Zyprexa ® IMS (Intercontinental Marketing Service) National Sales Perspectives 2/2005

6. Different Types and Effects of Drug interactions  Some drug interactions are related to the effects the body has on the drug such as how your liver or kidneys can effect your drug concentration  Some Drug interactions are related to the effects the drug has on your body. For example, when two drugs are given together, they have :  Synergistic effect (they work better when combined),  Additive effect (when two drugs cause the same toxicity such as Zerit and Videx both cause peripheral neuropathy) or  Antagonistic effect (when one drug can cancel the effect of the other drug (such as Zerit and AZT should not be given together)  Good news is that your healthcare provider will make the right selection for you based on your individual needs

7. Pharmacokinetics (PK): Effect the Body Has on the Drug Absorption : omeprazole, ranitidine, didanosine + atazanavir Distribution : phenytoin, warfarin Metabolism : ritonavir, efavirenz Excretion : trimethoprim-sulfamethoxazole increases the exposure of 3TC by 44% by decreasing its renal clearance Various disease states may affect PK Food also plays an important role in PK Metabolism – most clinically significant interactions

8. Pharmacodynamics (PD): Effect the Drug Has on the Body Synergistic effects Zidovudine (Retrovir) + lamivudine (Epivir) Other examples? Combination regimens Additive effects Didanosine (Videx) + stavudine (Zerit) AZT and Ribavirin Antagonistic effects Zidovudine (Retrovir) + stavudine (Zerit) Lamivudine (Epivir) + emtricitabine (Emtriva)

9. Different Types of Drug Interactions Drug-food Drug-fluids Drug-disease Drug-drug

10. Drug-food Interactions Some medications need to be taken with food for optimal absorption Reyataz Prezista Invirase Intelence Edurant

11. Drug-food Interactions Some medications need to be taken with food to avoid stomach upset AZT Viracept

12. Drug-food Interactions Some medications need to be taken on an empty stomach for optimal absorption or to minimize side effects Videx Crixivan Sustiva

13. Drug-fluid Interactions Some medications need to be taken with a large amount of fluids to prevent kidney stones or minimize other side effects Crixivan Reyataz Bactrim

14. Grapefruit Juice and Antiretroviral Therapy

15. Drug-disease Interactions Your healthcare provider should obtain a complete medical history prior to starting antiretroviral therapy to select the most appropriate regimen for you History of kidney failure or additional risk factors that may lead to chronic kidney disease should be a reason to try to avoid Viread. Pregnancy/Sustiva AZT/Anemia Viramune / CD4 Criteria Kaletra liquid / high alcohol content

16. Drug-drug Interactions Good drug-drug interactions: Norvir Bad drug-drug interactions: Ziagen / alcohol Reyataz and proton pump inhibitors (the purple pill) /H2-Blockers (Zantac; Pepcid) /Antacids (Mylanta; Maalox) Rifampin and protease inhibitors

17. #7 Rifampin Effects on PIs and NNRTIs Finch, et al. Arch Intern Med. 2002;162:985-92, Product Information Reyataz® 2003, Product Information Lexiva® 2003

18. Rifabutin (RFB) Use with PI/NNRTI’s ARV May use RFB RFB Dosing Comments NVPYesRFB 300mg/d or 2-3x/wk DLVNoContraindicated EFV ProbablyRFB 450-600mg/d, 600mg 2-3x/wk SQV ProbablyBoost w/RTV, RFB not established RTV Probably RFB 150mg 2-3x/wk IDVYesRFB 150mg/d or 300mg 2-3x/wk NFVYesRFB 150mg/d or 300mg 2-3x/wk APVYesRFB 150mg/d or 300mg 2-3x/wk LPV/rYesRFB 150mg/d or 300mg 2-3x/wk ATVYesRFB 150mg QOD or 3x/wk FPVYesRFB 150mg/d or 300mg 2-3x/wk FPV/rYesRFB 150mg QOD or 3x/wk MMWR 2000;49:185-9, Product Information Reyataz ® 2003, Product Information Lexiva ® 2003, Product Information Kaletra ® 2003, MMWR 2004;53:37.

19. Herbal Medications and Antiretroviral Therapy

20. St. John’s Wort and Crixivan® Piscitelli, et al. Lancet 2000;355:547-8 Crixivan Alone Crixivan and SJW AUC  57% (p=0.0008) Key Points Healthy volunteer data Concern for treatment failure, resistance, or both Avoid SJW with PI and NNRTI

21. Garlic and Fortovase® Piscitelli, et al. Clin Infect Dis. 2002;34:234-8. AUC  51% (p=0.007) Key Points Garlic = 2 large cloves Healthy volunteer data Cmax and trough decreased Concern for treatment failure, resistance, or both Avoid garlic supplements with PI and NNRTI

22. Milk Thistle and Crixivan® Piscitelli, SC. Pharmacother 2002;22:551-56. Key Points Healthy volunteer data Crixivan reductions likely to not be clinically significant MT use as a hepato-protectant not problematic

23. Herbal/botanical effect on CYP enzymes  Green Tea  3A4Ginseng  Milk thistle 1  3A4 (hepatic);  3A4 (gut)Echinacea 1,2  3A4 (gut);  2C9;  2D6Grapefruit juice  3A4St John’s Wort 2 CYP isoenzymeAgent Increased CYP enzyme is expected to result in lower levels of drugs metabolized through this pathway From: Back D. HIV7, Glasgow 2004, #PL6.2 Additional references: 1. Gurley BJ, et al. Clin Pharmacol Ther 2004;76:428-40; 2. Strandell J, et al. Phytomedicine 2004; 11:98-104 Example  PIs  PIs  PIs Minimal effect  PIs Minimal effect

24. Recreational Drugs and Antiretroviral Medications

25. Problems with Recreational Drug Use Substance abuse is a major contributor to HIV transmission among IDUs Crack cocaine Link established between crack cocaine use and high risk sexual behavior Alcohol Use linked to poor ART adherence Increased incidence of needle sharing among alcoholics Recreational drugs likely to impair adherence and adversely effect HIV care 1. CDC. HIV/AIDS Surveillance Report 2001:13;12.

26. Examples of Interactions Heroin is broken down to morphine Norvir may increase the breakdown of and clearance of morphine which can result in withdrawal Cocaine Interaction could exist between cocaine and inhibitors of P450 PIs, delavirdine, macrolides and ketoconzole Overall, interaction may not be clinically significant Amphetamines Increased likelihood of overdose

27. Interactions Between Club Drugs and ARV GHB Major route of elimination is expired breath as carbon dioxide P450 systems may play a large role in the elimination of drug Potential interaction between GHB and PI’s, delavardine or other potent enzymes inhibitor Narrow recreational/overdose index makes this drug potentially dangerous when combined with other drugs THC Metabolized by several isoforms including 3A3/4,2C9 and 2C6 May have increase or decrease in drug levels by PI Overall, no clinically significant interaction with HIV meds Ketamine Verapamil increases drug [ ] PI may increase drug concentration via inhibition of 3A4 isoform Although wide margin of safety- increased levels may lead led to respiratory depression

28. Drug MetabolismEffects (Street Name ) Cocaine (Coke, blow) Non-specific esterase Resp depression 10% CYP3A4Seizures, arrythmias Ecstasy (X, MDMA) CYP2D6 Tachycardia, HTN, dry mouth dehydration GHB (Liquid X) CYP2D6Seizures, bradycardia, resp depression, hypotension, coma Heroin ( Smack,China, CYP3A4CNS depression, drowsiness, brown junk,White) resp depression, N/V Alcohol CYP2E1, 3AConfusion,disorientation, loss of balance, resp depression

29. Drug MetabolismEffects (Street Name ) Amphetamines (Crystal)CYP2D6Paranoia, anxiety, depression, hallucinations, tachycardia Amyl nitrate (poppers)hydrolytic denitrationInhaled acts as vasodilator hypotension, tachycardia, HA BenzodiazepinesSome via CYP3A4CNS depression, resp depression triaz, midaz, clonaz Ketamine (Special K)Possibly CYP2D1, 3A4Paranoia, hallucinations, anxiety mania LSD (Acid)Liver hydroxylationParanoia, hallucinations Marijuana (pot, THC)CYP3A4, 2C9, 2C6Tachycardia, dry mouth, loss of inhibitions, hallucinations

30. Other Important Drug Interactions Antidepressants

31. Every Healthcare Provider Responsibility Make sure that the therapy is appropriate for the patient New agents are fully supported (protected) Patient understands the importance of adherence Co-morbidities Expertise of the HIV-provider Expertise of the dispensing pharmacies

32. Thank You!!!