Concise Review of Drug Interactions Between Hepatitis C Direct Acting Antiviral Agents and Acid Reducing Agents
By:
- Elizabeth Sherman, PharmD, AAHIVP
South Florida, Southeast AIDS Education & Training Center - Aliethia Mcleod, PharmD Candidate
College of Pharmacy, Nova Southeastern University - Mandy Ariefdien, PharmD Candidate
College of Pharmacy, Nova Southeastern University
Clinical importance of drug-drug interactions between hepatitis C virus direct acting antivirals and acid reducing agents
Maximal efficacy of direct acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) requires adequate drug absorption and bioavailability. However, the use of acid-reducing agents in patients treated with DAAs is common and may induce clinically significant drug-drug interactions that alter plasma DAA concentrations, which may lead to inadequate virologic response or adverse events. As plasma DAA concentrations are not routinely monitored in patients, it is important to understand the risk of these interactions and counsel patients appropriately, thereby maximizing antiviral potential and achieving sustained virologic response.
We therefore reviewed DAA product package inserts and utilized both the Liverpool HIV drug interaction website and Lexicomp database to collect information on the effect of various acid-reducing agents (i.e., proton pump inhibitors, histamine H2 receptor antagonists, and antacids containing aluminum, magnesium, calcium, or sodium) on the pharmacokinetics of DAAs in order to provide clinicians with a single easy-to-use reference for co administering medications from these drug classes (Tables 1-3). We also gathered dose equivalency tables to allow prescribers to switch between acid reducing agents within and between therapeutic classes and to calculate dose equivalencies (Tables 4-5). Certain acid-reducing agents may negatively affect the bioavailability of ledipasvir and velpatasvir to varying degrees. Additionally, reductions in proton pump inhibitor plasma concentrations may occur when combined with paritaprevir, ritonavir, and ombitasvir with and without dasabuvir.
Reviewed resources suggest that some of the interactions between DAAs and acid-reducing agents may be mitigated by temporal separation of dose administration. Educating patients about the importance of reporting the use of any acid-reducing agents, whether prescription or over-the-counter, is essential to optimizing the treatment of HCV infection, as is the need for care providers and patients to agree upon strategies for managing gastric symptoms and HCV simultaneously. Clinicians should be aware of the potential drug-drug interactions between some HCV DAAs and acid-reducing agents.
Table 1: Proton pump inhibitor (PPI) interactions with hepatitis C direct acting antivirals (HCV DAAs) |
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| Dexlansoprazole | Esomeprazole | Lansoprazole | Omeprazole | Pantoprazole | Rabeprazole | |
| Daclatasvir (Daklinza) | Insufficient data.1 | No clinically significant interaction expected. No dose adjustment of daclatasvir is required.2 |
No clinically significant interaction expected. No dose adjustment of daclatasvir is required.2 |
No clinically significant interaction.3 No dose adjustment of daclatasvir is required.2 |
No clinically significant interaction expected. No dose adjustment of daclatasvir is required.2 |
No clinically significant interaction expected. No dose adjustment of daclatasvir is required.2 |
| Elbasvir/Grazoprevir (Zepatier) | No dose adjustment is required.4 |
No dose adjustment is required.2, 4 |
No dose adjustment is required.2, 4 |
No dose adjustment is required.2, 4 |
No dose adjustment is required.2, 4 |
No dose adjustment is required.2, 4 |
| Glecaprevir/Pibrentasvir (Mavyret) | Insufficient data.1 | No dose adjustment is required.2 |
No dose adjustment is required.2 |
No clinically significant interaction. No dose adjustment is required.2, 5 |
No dose adjustment is required.2 |
No dose adjustment is required.2 |
| Ledipasvir/Sofosbuvir (Harvoni) | PPI doses comparable to omeprazole 20 mg or lower can be administered simultaneously under fasted conditions.6 PPI doses should not be taken before Harvoni.2 |
PPI doses comparable to omeprazole 20 mg or lower can be administered simultaneously under fasted conditions.6 PPI doses should not be taken before Harvoni.2 |
PPI doses comparable to omeprazole 20 mg or lower can be administered simultaneously under fasted conditions.6 PPI doses should not be taken before Harvoni.2 |
Omeprazole 20 mg or lower can be administered simultaneously under fasted conditions.6 PPI doses should not be taken before Harvoni.2 |
PPI doses comparable to omeprazole 20 mg or lower can be administered simultaneously under fasted conditions.6 PPI doses should not be taken before Harvoni.2 |
PPI doses comparable to omeprazole 20 mg or lower can be administered simultaneously under fasted conditions.6 PPI doses should not be taken before Harvoni.2 |
| Paritaprevir/Ritonavir/Ombitasvir (Technivie) |
Insufficient data.1 | Monitor for potential decreased efficacy of esomeprazole. Use higher doses of esomeprazole if clinically indicated.2 |
Monitor for potential decreased efficacy of lansoprazole. Use higher doses of lansoprazole if clinically indicated.2 |
Monitor for decreased efficacy of omeprazole.7 Use higher doses of omeprazole if clinically indicated.2 Avoid use of more than 40 mg per day of omeprazole.7 |
Monitor for potential decreased efficacy of pantoprazole. Use higher doses of pantoprazole if clinically indicated.2 |
Monitor for potential decreased efficacy of rabeprazole. Use higher doses of rabeprazole if clinically indicated.2 |
| Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (Viekira) |
Insufficient data.1 | Monitor for potential decreased efficacy of esomeprazole. Use higher doses of esomeprazole if clinically indicated.2 |
Monitor for potential decreased efficacy of lansoprazole. Use higher doses of lansoprazole if clinically indicated.2 |
Monitor for decreased efficacy of omeprazole. Use higher doses of omeprazole if clinically indicated.2 Avoid use of more than 40 mg per day of omeprazole.8 |
Monitor for potential decreased efficacy of pantoprazole. Use higher doses of pantoprazole if clinically indicated.2 |
Monitor for potential decreased efficacy of rabeprazole. Use higher doses of rabeprazole if clinically indicated.2 |
| Sofosbuvir (Sovaldi) | Insufficient data.1 | No clinically significant interaction expected.2 |
No clinically significant interaction expected.2 |
No clinically significant interaction expected.2 |
No clinically significant interaction expected.2 |
No clinically significant interaction expected.2 |
| Sofosbuvir/Velpatasvir (Epclusa) | As per US prescribing information, coadministration with PPIs is not recommended.9As per European SPC, Epclusa could be taken with food and 4 hours before a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
As per US prescribing information, coadministration with PPIs is not recommended.2, 9 As per European SPC, Epclusa could be taken with food and 4 hours before a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
As per US prescribing information, coadministration with PPIs is not recommended.2, 9 As per European SPC, Epclusa could be taken with food and 4 hours before a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
As per US prescribing information, coadministration with PPIs is not recommended. If considered medically necessary; take Epclusa with food and 4 hours before omeprazole 20 mg.2, 9 |
As per US prescribing information, coadministration with PPIs is not recommended.2, 9 As per European SPC, Epclusa could be taken with food and 4 hours before a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
As per US prescribing information, coadministration with PPIs is not recommended.2, 9 As per European SPC, Epclusa could be taken with food and 4 hours before a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
| Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi) |
As per US prescribing information, coadministration of PPIs is not recommended.2 If considered medically necessary, as per European SPC, Vosevi could be taken with a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
As per US prescribing information, coadministration of PPIs is not recommended.2 If considered medically necessary, as per European SPC, Vosevi could be taken with a PPI at a dose not to exceed that comparable to omeprazole 20 mg. |
As per US prescribing information, coadministration of PPIs is not recommended.2 If considered medically necessary, as per European SPC, Vosevi could be taken with a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
Omeprazole 20 mg can be administered with Vosevi.10 |
As per US prescribing information, coadministration of PPIs is not recommended.2 If considered medically necessary, as per European SPC, Vosevi could be taken with a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
As per US prescribing information, coadministration of PPIs is not recommended.2 If considered medically necessary, as per European SPC, Vosevi could be taken with a PPI at a dose not to exceed that comparable to omeprazole 20 mg.2 |
Table 2: Histamine H2 antagonist (H2RA) interactions with hepatitis C direct acting antivirals (HCV DAAs) |
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| Cimetidine | Famotidine | Nizatidine | Ranitidine | |
| Daclatasvir (Daklinza) | No clinically significant interaction expected. 2 |
No clinically significant interaction expected. 2,3 |
No clinically significant interaction expected. 2,3 |
No clinically significant interaction expected. 2,3 |
| Elbasvir/Grazoprevir (Zepatier) | No clinically significant interaction expected. 2,4 |
No clinically significant interaction expected. 2,4 |
No clinically significant interaction expected. 2,4 |
No clinically significant interaction expected. 2,4 |
| Glecaprevir/Pibrentasvir (Mavyret) | No clinically significant interaction expected. 2,5 |
No clinically significant interaction expected. 2,5 |
No clinically significant interaction expected. 2,5 |
No clinically significant interaction expected. 2,5 |
| Ledipasvir/Sofosbuvir (Harvoni) | Acid reducing agents decreases Ledipasvir: May be administered simultaneously with or 12 hours apart or a dose that does not exceed doses comparable to famotidine 40 mg twice daily.6 | |||
| Paritaprevir/Ritonavir/Ombitasvir (Technivie) |
No clinically significant interaction expected. 2,7 |
No clinically significant interaction expected. 2,7 |
No clinically significant interaction expected. 2,7 |
No clinically significant interaction expected. 2,7 |
| Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (Viekira) |
No clinically significant interaction expected. 2,8 |
No clinically significant interaction expected. 2,8 |
No clinically significant interaction expected. 2,8 |
No clinically significant interaction expected. 2,8 |
| Sofosbuvir (Sovaldi) | No clinically significant interaction expected. 2 |
No clinically significant interaction expected. 2 |
No clinically significant interaction expected. 2 |
No clinically significant interaction expected. 2 |
| Sofosbuvir/Velpatasvir (Epclusa) | Acid reducing agents decreases Velpatasvir: May be administered simultaneously with or 12 hours apart from Epclusa at a dose that does not exceed doses comparable to famotidine 40 mg twice daily. 9 | |||
| Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi) |
Acid reducing agents decreases Velpatasvir: May be administered simultaneously with or staggered from Vosevi at a dose that does not exceed doses comparable to famotidine 40 mg twice daily. 10 | |||
Table 3: Antacid interactions with hepatitis C direct acting antivirals (HCV DAAs) |
|
| Antacids containing aluminum hydroxide, calcium carbonate, magnesium hydroxide or sodium bicarbonate | |
| Daclatasvir (Daklinza) | No clinically significant interaction is expected.2, 3 |
| Elbasvir/Grazoprevir (Zepatier) | No dose adjustment is required.2, 4 |
| Glecaprevir/Pibrentasvir (Mavyret) | No dose adjustment is required. 2 |
| Ledipasvir/Sofosbuvir (Harvoni) | Separate administration by 4 hours.2, 6 |
| Paritaprevir/Ritonavir/Ombitasvir (Technivie) | No dose adjustment is required. 2 |
| Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (Viekira) | No dose adjustment is required. 2 |
| Sofosbuvir (Sovaldi) | Separate doses by 2 hours. 2 |
| Sofosbuvir/Velpatasvir (Epclusa) | Separate administration by 4 hours. 2, 9 |
| Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi) | Separate administration by 4 hours 2, 10 |
Table 4: Proton pump inhibitor (PPI) dose comparison11 |
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| Daily Dose Providing Similar Efficacy for GERD and/or Effects on Gastric pH | ||
| PPI | Low Dose | High Dose |
| Dexlansoprazole | 30 mg | 60 mg |
| Esomeprazole | 10 mg | 20 mg to 40 mg |
| Lansoprazole | 15 mg | 30 mg |
| Omeprazole | 10 mg | 20 mg |
| Pantoprazole | 20 mg | 40 mg |
| Rabeprazole | N/A | 20 mg |
Key: GERD= Gastroesophageal reflux disease; N/A= not applicable
Table 5: Histamine H2 antagonist (H2RA) dose comparison12 |
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| Maintenance Dose | Active Ulcer | GERD/Erosive Esophagitis | |
| Cimetidine | 400 mg HS | 800 mg HS | 1600 mg BID or QID |
| Famotidine | 20 mg HS | 40 mg HS | 20 mg BID (GERD), 20 or 40 mg BID (erosive esophagitis) |
| Nizatidine | 150 mg HS | 300 mg HS | 150 mg BID |
| Ranitidine | 150 mg HS | 300 mg HS | 150 mg BID (GERD), 150 mg QID (erosive esophagitis) |
Key: GERD= Gastroesophageal reflux disease; HS= at bedtime
References:
- Interactions. Lexicomp. Riverwoods, IL. Wolters Kluwer Health, Inc. Retrieved August 13, 2018. Available at: http://online.lexi.com
- University of Liverpool HEP Drug Interactions. Retrieved August 9, 2018. Available at https://www.hep-druginteractions.org/checker
- Daklinza [package insert]. Princeton, NJ. Bristol-Myers Squibb Company. Revised November 2017. Available at https://packageinserts.bms.com/pi/pi_daklinza.pdf
- Zepatier [package insert]. Whitehouse Station, NJ. Merck & Co., Inc. Revised June 2018. Available at
https://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf - Mavyret [package insert]. North Chicago, IL. AbbVie Inc. Revised August 2018. Available at https://www.rxabbvie.com/pdf/mavyret_pi.pdf
- Harvoni [package insert]. Foster City, CA. Gilead Sciences, Inc. Revised November 2017. Available at https://www.gilead.com/~/media/Files/pdfs/medicines/liverdisease/harvoni/harvoni_pi.pdf
- Technivie [package insert]. North Chicago, IL. AbbVie Inc. Revised July 2018. Available at https://www.rxabbvie.com/pdf/technivie_pi.pdf
- Viekira pak [package insert]. North Chicago, IL. AbbVie Inc. Revised July 2018. Available at https://www.rxabbvie.com/pdf/viekirapak_pi.pdf
- Epclusa [package insert]. Foster City, CA. Gilead Sciences, Inc. Revised November 2017. Available at http://www.gilead.com/~/media/Files/pdfs/medicines/liverdisease/epclusa/epclusa_pi.pdf
- Vosevi [package insert]. Foster City, CA. Gilead Sciences, Inc. Revised November 2017. Available at http://www.gilead.com/-
/media/a25fc64c75fb4704947d80c0f7390425.ashx - Proton pump inhibitor dose comparison. Pharmacist’s Letter/Prescriber’s Letter 2009;25(8):250801.
- Histamine H2 Blocker Oral Dose Comparison. Pharmacist’s Letter/Prescriber’s Letter 2009; 25 (8): 250801.
