Drug-Drug Interactions

HCV Guideline Committee, May 2019

The charts contained in this section are meant to provide guidance on significant interactions between DAAs and common primary care medications. While these guidelines can be helpful, they are not a substitute for sound clinical judgement and practice.

In some cases, the medications listed below are contraindicated in the U.S. Food and Drug Administration (FDA) labeling for the medication, or the label may state elsewhere that co-administration is not recommended. For some, the recommendation may be to “Avoid Co-administration,” but in some clinical situations it may be necessary to use the medications concurrently. When this is the case, clinicians are encouraged to consult additional references or a liver disease specialist for additional guidance.

For more information on drug-drug interactions in patients with HIV/HCV coinfection see the Treatment of Patients with HIV/HCV Coinfection > Drug-Drug Interactions between DAAs and ARVs section of this guideline.

KEY POINT
  • Although significant interactions associated with the use of direct-acting antivirals (DAAs) and drugs used commonly in the treatment of substance use disorders are unlikely, care providers should always monitor for excess sedation when making alterations to a patient’s drug therapy while he/she is taking methadone, buprenorphine, naltrexone, and naloxone.

The links below open pages with tables for each of the following drugs:

Box 2: Online Resources for Identifying Drug-Drug Interactions between DAAs and Common Medications

Note: As of May 2019, the following DAAs are no longer used in the United States: PIs: paritaprevir, simeprevir, telaprevir, boceprevir; NS5A inhibitors: daclatasvir, ombitasvir; NS5V inhibitor: dasabuvir. 

Elbasvir/Grazoprevir

HCV Guideline Committee, May 2019

Table 34: Elbasvir/Grazoprevir (Zepatier) Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications) Clinical Comments
Anticonvulsants (carbamazepine, phenytoin)
  • Significant decrease in elbasvir/grazoprevir levels
Antimycobacterial (rifampin)
  • Significant decrease in elbasvir/grazoprevir levels
Herbal product (St John’s wort)
  • Significant decrease in elbasvir/grazoprevir levels
HIV medications (efavirenz, atazanavir, darunavir, lopinavir, saquinavir, tipranavir)
  • Efavirenz: Significant decrease in elbasvir/grazoprevir levels
  • Atazanavir, darunavir, lopinavir, saquinavir, tipranavir: Significant increase in grazoprevir level
    • May lead to ALT elevation
Immunosuppressant (cyclosporine)
  • Significant increase in grazoprevir level
    • May lead to ALT elevation
Co-administration possible; see clinical comments
Class (medications) Clinical Comments
Antibiotic (nafcillin)
  • Decreased concentrations of elbasvir/grazoprevir levels
Antifungal (ketoconazole)
  • Significant increase in elbasvir/grazoprevir levels
  • Increased risk of hepatotoxicity
Endothelin antagonist (bosentan)
  • Significant decrease in elbasvir/grazoprevir levels
HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, rosuvastatin, simvastatin)
  • Increase in statin drug levels expected
  • Atorvastatin: Maximum daily dose 20 mg
  • Fluvastatin, lovastatin, or simvastatin: Use lowest doses possible; titrate with close monitoring
  • Rosuvastatin: Maximum daily dose 10 mg 
Immunosuppressant (tacrolimus)
  • Significant increase in tacrolimus level expected
  • Frequent monitoring required for tacrolimus level, changes in renal function, and tacrolimus-associated adverse events
Wakefulness-promoting agent (modafinil)
  • Significant decrease in elbasvir/grazoprevir levels
Source: U.S. Food and Drug Administration. Zepatier (elbasvir and grazoprevir) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208261Orig1s000lbl.pdf [accessed 2019 May 9]

Glecaprevir/Pibrentasvir

HCV Guideline Committee, May 2019

Table 35: Glecaprevir/Pibrentasvir (Mavyret) Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications) Clinical Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)
  • Carbamazepine: Significant decrease in glecaprevir/pibrentasvir levels expected
  • Phenobarbital, phenytoin: Significant decrease in glecaprevir/pibrentasvir levels possible
Antimycobacterial (rifampin)
  • Significant decrease in glecaprevir/pibrentasvir levels expected
Ethinyl estradiol
  • Increased risk of ALT elevations
Herbal therapy (St John’s Wort)
  • Decreased glecaprevir/pibrentasvir levels expected
HIV medications (efavirenz, atazanavir, darunavir, lopinavir, saquinavir, tipranavir)
  • Efavirenz: Significant decrease in glecaprevir/pibrentasvir levels expected
  • Atazanavir: Significant increase in glecaprevir/pibrentasvir levels expected; increased ALT elevations
  • Darunavir, lopinavir/ritonavir, other HIV protease inhibitors: Significant increase in glecaprevir/pibrentasvir levels expected
HMG-CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin)
  • Increased levels of atorvastatin, lovastatin, and simvastatin expected; do not co-administer
  • See note below regarding use of alternative statins
Co-administration possible; see clinical comments
Class (medications) Clinical Comments
Antiarrhythmic (digoxin)
  • Increased digoxin levels likely; reduce digoxin dosage 50%
  • Measure serum digoxin level prior to initiating therapy with glecaprevir/pibrentasvir
Anticoagulant (dabigatran etexilate)
  • Refer to dabigatran prescribing information; follow dosage recommendations for concurrent use with P-glycoprotein inhibitors
HMG-CoA reductase inhibitors (fluvastatin, pitavastatin, pravastatin, rosuvastatin)
  • Fluvastatin, pitavastatin: Increased statin levels likely; use lowest statin dosage and monitor for adverse events (e.g., myopathy)
  • Pravastatin: Increased statin level likely; reduce pravastatin dosage by 50% prior to initiating therapy with glecaprevir/pibrentasvir
  • Rosuvastatin: Increased statin level likely; do not exceed rosuvastatin 10 mg daily when combined with glecaprevir/pibrentasvir
Immunosuppressant (cyclosporine)
  • Increased levels of glecaprevir/pibrentasvir expected; do not co-administer in patients requiring cyclosporine doses >100 mg daily
Source: FDA. Mavyret (glecaprevir and pibrentasvir) tablets, for oral use. http://www.natap.org/2017/HCV/mavyret_pi.pdf [accessed 2019 May 9]

Ledipasvir/Sofosbuvir

HCV Guideline Committee, May 2019

Table 36: Ledipasvir/Sofosbuvir (multiple brands) Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications) Clinical Comments
Antiarrhythmic (amiodarone)
  • Significant bradycardia, especially in patients who are taking beta-blockers, have underlying cardiac abnormalities, or have advanced liver disease
  • If concurrent use is required, cardiac monitoring is recommended
  • See package insert for additional information
Herbal product (St John’s wort)
  • Significant decrease in ledipasvir/sofosbuvir levels
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)
  • Significant decrease in ledipasvir/sofosbuvir levels
Antimycobacterials (rifampin, rifabutin, rifapentine)
  • Significant decrease in ledipasvir/sofosbuvir levels
HMG-CoA reductase inhibitor (rosuvastatin)
  • Significant increase in rosuvastatin level
NS3/4A HCV protease inhibitor (simeprevir)
  • Significant increases in ledipasvir levels
Co-administration possible; see clinical comments
 Class (medications) Clinical Comments
Antacids
  • Ledipasvir solubility decreases as pH increases
  • Separate administration of aluminum- and magnesium-containing antacids and ledipasvir/sofosbuvir by 4 hours
Antiarrhythmic (digoxin)
  • Increase in digoxin level expected
  • Monitor digoxin level
H2-receptor antagonists 
  • Administer simultaneously with, or 12 hours apart from, ledipasvir/ sofosbuvir
  • Do not exceed doses comparable to famotidine 40 mg twice daily 
Proton-pump inhibitors 
  • If co-administration is required, doses comparable to omeprazole 20 mg or lower can be administered simultaneously with ledipasvir/sofosbuvir under fasting conditions
Source: FDA. Harvoni (ledipasvir and sofosbuvir) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205834s024lbl.pdf [accessed 2019 May 9]

Sofosbuvir/Velpatasvir

HCV Guideline Committee, May 2019

Table 37: Sofosbuvir/Velpatasvir (multiple brands) Drug-Drug Interactions

Avoid co-administration; see clinical comments
Class (medications) Clinical Comments
Antiarrhythmic (amiodarone)
  • Significant bradycardia, especially in patients who are taking beta-blockers, have underlying cardiac abnormalities, or have advanced liver disease
  • If concurrent use is required, cardiac monitoring is recommended
  • See package insert for additional information
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)
  • Significant decrease in sofosbuvir level expected, leading to reduced sofosbuvir and/or velpatasvir drug levels
Antimycobacterials (rifampin, rifabutin, rifapentine)
  • Potential significant decrease in sofosbuvir and/or velpatasvir drug levels
Herbal product (St John’s wort)
  • May significantly decrease sofosbuvir and/or velpatasvir drug levels
Co-administration possible; see clinical comments
Class (medications) Clinical Comments
Antacids (aluminum and magnesium hydroxide)
  • May decrease concentration of velpatasvir
  • Separate administration of antacid and velpatasvir/sofosbuvir by 4 hours
Antiarrhythmic (digoxin)
  • Increase in digoxin level expected
  • Monitor digoxin level
Anticancer (topotecan)
  • Significant increase in topotecan expected
H2-receptor antagonist (famotidine)
  • Velpatasvir solubility decreases as pH increases
  • May decrease concentration of velpatasvir
  • H2-receptor antagonists may be administered simultaneously with, or 12 hours apart from velpatasvir/sofosbuvir, at a dose that does not exceed doses comparable to famotidine 40 mg twice daily
HMG-CoA reductase inhibitor (rosuvastatin)
  • May significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis
  • Rosuvastatin may be administered at a dose not greater than 10 mg daily
Proton-pump inhibitor (omeprazole)
  • May decrease concentration of velpatasvir
  • Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with velpatasvir/sofosbuvir under fasting conditions
Source: FDA. Epclusa (sofosbuvir and velpatasvir) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208341s000lbl.pdf [accessed 2019 May 9]

Sofosbuvir/Velpatasvir/Voxilaprevir

HCV Guideline Committee, May 2019

Table 38: Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi) Drug-Drug Interactions

Avoid co-administration; see clinical comments
Class (medications) Clinical Comments
Antiarrhythmic (amiodarone)
  • Potential for significant bradycardia, especially in patients who are taking beta-blockers, have underlying cardiac abnormalities, or have advanced liver disease If concurrent use is required, cardiac monitoring is recommended
Herbal product (St John’s wort)
  • Significant decrease in sofosbuvir/velpatasvir/voxilaprevir levels
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)
  • Significant decrease in sofosbuvir/velpatasvir/voxilaprevir levels
Antimycobacterials (rifampin, rifabutin, rifapentine)
  • Significant decrease in sofosbuvir/velpatasvir/voxilaprevir levels
HIV medications (efavirenz, atazanavir, tipranavir)
  • Efavirenz: Significant decrease in velpatasvir and voxilaprevir levels expected
  • Atazanavir: Significant increase in voxilaprevir level expected
  • Tipranavir: Significant decrease in sofosbuvir and voxilaprevir levels expected
HMG-CoA reductase inhibitor (pitavastatin, rosuvastatin)
  • Significant increase in pitavastatin and rosuvastatin levels expected when combined with sofosbuvir/velpatasvir/voxilaprevir
Immunosuppressant (cyclosporine)
  • Significant increases in cyclosporine level expected
Co-administration possible; see clinical comments
Class (medications) Clinical Comments

Acid reducing medications:

  • Aluminum- and magnesium hydroxide- containing antacids
  • H2-receptor antagonists
  • Proton pump inhibitor
  • Separate administration of antacids and sofosbuvir/velpatasvir/voxilaprevir by 4 hours
  • H2-receptor antagonists may be administered simultaneously with or staggered from sofosbuvir/velpatasvir/voxilaprevir at a dose that does not exceed a comparable dose of famotidine 40 mg twice daily
  • Omeprazole 20 mg can be administered with sofosbuvir/velpatasvir/voxilaprevir:
    • Use with other proton pump-inhibitors has not been studied
    • Use with lowest doses of other proton pump inhibitors is unlikely to interact
Antiarrhythmic (digoxin)
  • Sofosbuvir/velpatasvir/voxilaprevir may increase digoxin levels; monitor digoxin levels closely prior to and during therapy
HIV medication (tenofovir disoproxil fumarate [TDF])
  • Significant increase in TDF levels expected; monitor for tenofovir-related adverse events
HMG-CoA reductase inhibitor (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)
  • Atorvastatin, fluvastatin, lovastatin, simvastatin: Potential increase levels of statins when combined with sofosbuvir/velpatasvir/voxilaprevir; use lowest statin dosage
  • Pravastatin: Potential increased levels of pravastatin when combined with sofosbuvir/velpatasvir/voxilaprevir; do not exceed pravastatin 40mg daily when combined
Source: FDA. Vosevi (sofosbuvir and velpatasvir and voxilaprevir) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209195s000lbl.pdf [accessed 2019 May 9]