Drug-Drug Interactions and Common Side Effects of DAAs. DATE: August 23, 2017 PRESENTED BY: Jenica Lee, PharmD, BCPS

Transcription

1 Drug-Drug Interactions and Common Side Effects of DAAs DATE: August 23, 2017 PRESENTED BY: Jenica Lee, PharmD, BCPS

2 Disclosure Statement Potential conflicts of interest: none Sponsorship: none 2

3 Objectives Review pharmacokinetic basics Highlight clinically significant DDIs of DAAs Identify common side effects of DAAs Recommend side effect management strategies 3

4 DAAs the new chronic HCV treatment standard Side effects Drug-drug interactions 4 Adapted from FDA s Consumer Updates page. Available at:

5 Mechanisms of Drug Interactions Inhibition or induction of Transporters and/or Metabolizing enzymes Fig 1. P-glycoprotein Adapted from DL Kasper et al. Harrison s Principles of Internal Medicine, 19 th ed. 5 Fig 2. Location of CYPs in the cell Adapted from Randa HD et al. Goodman and Gilman s Manual of Pharmacology and Therapeutics, 2 nd ed.

6 FDA Classifications INHIBITOR INDUCER WEAK > 1.25 but < 2-fold in AUC 20-50% in AUC MODERATE > 2-fold but < 5-fold in AUC 50-80% in AUC STRONG > 5-fold in AUC > 80% in AUC 6 Drug Development and Drug Interactions.

7 DAA Metabolizing Pathways 7 Adapted from Smolders EJ et al. Drug Saf. 2016

8 Enzyme & Transporter Pathways LDV/SOF P-gp SOF/VEL SOF/VEL/VOX P-gp CYP2B6, CYP2C8, CYP3A4 P-gp CYP2B6, CYP2C8, CYP3A4 Acid Reducers CYP enzyme inducers GZV/EBV SOF/DCV OATP1B1, OATP1B3 CYP3A P-gp CYP3A OTCs & Herbal Supplements P-gp inducers GPV/PBV P-gp, BCRP, OATP1B1/3 CYP3A Interactions that therapeutic effect 8 Adapted from package inserts. LDV=ledipasvir; SOF=sofosbuvir; VEL=velpatasvir; VOX=voxilaprevir; GZV=grazoprevir; EBV=elbasvir; DCV=daclatasvir; GPV=glecaprevir; PBV=pibrentasvir

9 Clinically Relevant Inducers Anticonvulsants Carbamazepine Phenytoin Phenobarbital Oxcarbazepine Antimycobacterials Rifabutin Rifampin Rifapentine HIV Antiretrovirals Efavirenz Etravirine Nevirapine Tipranavir/ritonavir Other CYP3A Inducers Bosentan Dexamethasone Modafinil Nafcillin St. John s wort 9 Pharmacist's Letter 2013; 29(10):291008

10 OTCs/Herbal Supplements St. John s wort and milk thistle Vitamins Miscellaneous herbal and homeopathic supplements Discontinue, hold, or separate administration 10

11 Acid-Reducing Agents Increased gastric ph decreases solubility of velpatasvir and Equivalent PPI dosages ledipasvir Separate antacids by 4 hours Administer H2RAs simultaneously with or 12 hours apart (max famotidine 40 mg BID) Avoid PPIs if possible. If medically necessary, omeprazole omeprazole 20 mg rabeprazole 20 mg lansoprazole 30 mg 20 mg may be administered: Simultaneously with LDV/SOF under fasted conditions esomeprazole 40 mg 4 hours after SOF/VEL is taken with food pantoprazole 40 mg Simultaneously with SOF/VEL/VOX 11 Pharmacist's Letter 2009; 25(8):250831

12 DAA Effect on Other Drugs SOF, VEL, VOX, EBV, GZV, DCV, GPV, PBV P-gp OATP1B1/B3, OATP2B1 BCRP CYP3A, CYP1A2 Potential to cause adverse events of other coadministered drugs 12 Adapted from package inserts.

13 HIV antiretrovirals Collaborate with HIV practitioner as necessary Be mindful of: Efavirinz, etravirine, nevirapine strong CYP3A inducers Tipranavir strong P-gp inducer LDV, VEL increases tenofovir DCV may need to decrease to 30 mg or increase to 90 mg daily Key resources: AASLD/IDSA guidelines Adapted from AASLD/IDSA 13

14 HMG-CoA Reductase Inhibitors Transporters: OATP1B1, BCRP, P,gp CYP enzymes: 3A4, 2C8, 2C9 Rule of thumb Monitor for statin-associated adverse events and risks (i.e. myalgia, myopathy, rhabdomyolysis) Coadministration not recommended LDV/SOF: rosuvastatin VEL/VOX/SO: rosuvastatin, pitavastatin GCR/PBR: atorvastatin, lovastatin, simvastatin Max doses EBR/GZR: rosuvastatin 10 mg, atorvastatin 20 mg VEL/SOF: rosuvastatin 10 mg VEL/VOX/SOF: pravastatin 40 mg 14 GCR/PBR: rosuvastatin 10 mg

15 Sofosbuvir and Amiodarone Post-marketing cases of symptomatic bradycardia If no other options: Inpatient cardiac monitoring for first 48 hours Daily outpatient or self-monitoring through at least first 2 weeks of treatment Counsel patients to seek immediate medical attention if fainting, dizziness, lightheadedness, weakness, excessive tiredness, shortness of breath, chest pains, confusion 15

16 Go-to DDI Resources Package insert Interaction checker Printable charts Micromedex/LexiComp 16 Adapted from

17 > 5% Frequency in Clinical Trials nausea fatigue headache diarrhea insomnia asthenia LED/SOF X X X X X VEL/SOF X X X X X VEL/VOX/SOF X X X X X X EBR/GZR X X X GCR/PBR X X X X DCV+SOF X X X X 17 Adapted from package inserts.

18 Tips for Headache and Nausea Headache Management Maintain adequate fluid intake (at least eight 8-ounce glasses of water/day) Keep lights dim and avoid other strong stimuli triggers Pain relievers if needed: NSAIDs as directed (if not cirrhotic) Low dose acetaminophen (not to exceed 2g/day) Nausea Management Eat smaller, balanced meals Avoid greasy, spicy, or acidic foods Try ginger ale or tea Try dry white toast or crackers Avoid triggers such as sudden movement or smells Eat food that is chilled rather than hot 18

19 Tips for Fatigue and Insomnia Fatigue Management Maintain good sleep hygiene and a regular sleep schedule Lessen your work schedule if possible Try low-impact exercise as permitted Eat nutritious meals Insomnia Management Avoid electronics or other stimuli before bed Limit daytime naps Do not eat heavy meals or exercise too close to bedtime Develop a relaxation routine before bed Avoid caffeine in the afternoon Avoid extremes in noise, light, and temperature 19

20 Tips for Diarrhea and Itching Diarrhea Management Maintain adequate hydration Try a bland/brat diet Avoid dairy products Loperamide OTC as needed Itching Management Avoid long, hot showers or baths Avoid scratching instead use pressure or ice cube Use moisturizing soaps and lotions Use mild unscented laundry detergents avoid fabric softeners Antihistamines or topical cortisone OTC as needed 20

21 Conclusion Carefully consider the potential for DDIs Ask about all medications prescription, OTC, vitamins, herbal supplements, and homeopathic medicines Educate patients to manage minor side effects Provide encouragement and support 21

22 Thank You