Drug-Drug Interactions

Drug-Drug Interactions

HCV Guideline Committee, updated August 2020

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 judgment 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 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 August 2020, the following DAAs are no longer used in the United States: Boceprevir, daclatasvir, dasabuvir, elbasvir, grazoprevir, ombitasvir, paritaprevir, simeprevir, and telaprevir.

Glecaprevir/Pibrentasvir

HCV Guideline Committee, May 2019

Table 34: 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 35: 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 36: 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 37: 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 40 mg 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]

Drug-Drug Interactions Between DAAs and ARVs

HCV Guideline Committee, August 2020

Use of DAAs concurrently with ART may lead to clinically relevant drug interactions. Table 38, below, lists the potential drug-drug interactions between DAA regimens and select ART regimens and Box 3, below, lists other resources on drug-drug interactions in patients with HIV/HCV coinfection.

Tenofovir is a nucleoside reverse transcriptase inhibitor used extensively in the treatment of HIV and HBV. Tenofovir drug concentrations, when taken in the disoproxil fumarate form (TDF), are increased in the setting of renal failure and when taken with elvitegravir and cobicistat and are highest with concurrent ritonavir use [German et al. 2015]. Use of TDF with velpatasvir or ledipasvir also increases the level of tenofovir [FDA 2015, 2016a]. When ledipasvir/sofosbuvir is administered with TDF concurrently with efavirenz or ritonavir-boosted atazanavir or darunavir, the TDF exposure may increase even further, raising concern for development of TDF-related nephrotoxicity [German et al. 2014, 2015]. These interactions are also likely to occur with the sofosbuvir/velpatasvir combination [FDA 2016a]. In addition, the use of TDF with sofosbuvir/velpatasvir/voxilaprevir may also increase tenofovir levels; switching from TDF to TAF, changing TDF to ABC, or monitoring for adverse renal effects would be appropriate in this setting [FDA 2017].

Close monitoring of creatinine clearance is recommended when ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir must be co-administered with TDF and efavirenz or a ritonavir-boosted protease inhibitor. Care providers should consider changing the patient’s ART regimen by switching from TDF to TAF or abacavir if the HIV virus is susceptible to these drugs. TAF is associated with much lower peak serum tenofovir concentrations [Garrison et al. 2015]. The current FDA label allows TAF formulations to be used in patients whose CrCl is as low as 30 mL/min [FDA 2016a].

Box 3: Online Resources for Identifying Drug-Drug Interactions between DAAs and ARVs
Table 38: Compatibility of Select ART and DAA Regimens [a] for Nonpregnant Adults (August 2020)
ART Regimen Concurrent DAA Regimen and Clinical Comment
Preferred Initial ART Regimens
Abacavir/lamivudine/dolutegravir
(ABC/3TC/DTG; Triumeq)
  • All DAA regimens are compatible.
Tenofovir alafenamide/
emtricitabine/bictegravir 
(TAF 25 mg/FTC/BIC; Biktarvy)
  • All DAA regimens are compatible, but see note [b] regarding concomitant use of LED or VEL and tenofovir.
Tenofovir alafenamide/emtricitabine
and dolutegravir 
(TAF 25 mg/FTC and DTG; Descovy and Tivicay)
  • All DAA regimens are compatible, but see note [b] regarding concomitant use of LED or VEL and tenofovir.
Tenofovir alafenamide/emtricitabine
and raltegravir
(TAF 25 mg/FTC and RAL HD; Descovy and Isentress HD)
  • All DAA regimens are compatible.
  • GLE/PIB may increase the serum concentration of RAL but no action is needed.
  • See note [b] regarding concomitant use of LED or VEL and tenofovir.
Alternative Initial ART Regimens [b]
Tenofovir alafenamide/
emtricitabine/cobicistat/darunavir 
(TAF 10 mg/FTC/COBI/DRV; Symtuza)
  • Do not co-administer with GLE/PIB.
  • When combining SOF/VEL/VOX with COBI-boosted DRV, levels of VOX may be increased. Until more safety data become available, patients who are taking the combination should be monitored for hepatotoxicity during therapy.
  • See note [b] regarding concomitant use of LED or VEL and tenofovir.
Tenofovir alafenamide/
emtricitabine/cobicistat/elvitegravir
(TAF 10 mg/FTC/COBI/EVG; Genvoya)
  • When combining GLE/PIB with COBI-boosted EVG, levels of GLE/PIB may be increased. Until more safety data become available, patients who are taking the combination should be monitored for hepatotoxicity during therapy.
  • See note [b] regarding concomitant use of LED or VEL and tenofovir.
Tenofovir alafenamide/
emtricitabine/rilpivirine
(TAF 25 mg/FTC/RPV; Odefsey)
  • All DAA regimens are compatible, but see note [b] regarding concomitant use of LED or VEL and tenofovir.
Tenofovir disoproxil fumarate/
lamivudine/doravirine
(TDF/3TC/DOR; Delstrigo)
  • All DAA regimens are considered to be compatible, but there are limited data evaluating the use of doravirine with SOF/VEL or GLE/PIB.
  • See note [b] regarding concomitant use of LED or VEL and tenofovir.
Abacavir/lamivudine and doravirine
(ABC/3TC and DOR; Epzicom and Pifeltro)
  • All DAA regimens are considered to be compatible, but there are limited data evaluating the use of doravirine with SOF/VEL or GLE/PIB.
Tenofovir alafenamide/
emtricitabine and doravirine
(TAF 25 mg/FTC and DOR; Descovy and Pifeltro)
  • All DAA regimens are considered to be compatible, but there are limited data evaluating the use of doravirine with SOF/VEL or GLE/PIB.
  • See note [b] regarding concomitant use of LED or VEL and tenofovir.
Tenofovir disoproxil fumarate/
emtricitabine and dolutegravir
(TDF/FTC and DTG; Truvada and Tivicay)
  • All DAA regimens are compatible, but see note [b] regarding concomitant use of LED or VEL and tenofovir.
Tenofovir disoproxil fumarate/
emtricitabine and raltegravir
(TDF/FTC and RAL HD; Truvada and Isentress HD)
  • All DAA regimens are compatible, but see note [b] regarding concomitant use of LED or VEL and tenofovir.

ARV abbreviation key: Abacavir (ABC); bictegravir (BIC); cobicistat (COBI); darunavir (DRV); dolutegravir (DTG); elvitegravir (EVG); emtricitabine (FTC); lamivudine (3TC); raltegravir (RAL); rilpivirine (RPV); tenofovir alafenamide (TAF); tenofovir disoproxil fumarate (TDF).

Notes:

  1. Available DAA regimens as of August 2020: Glecaprevir/pibrentasvir (GLE/PIB; Mavyret); ledipasvir/sofosbuvir (LED/SOF; multiple brands); sofosbuvir/velpatasvir (SOF/VEL; multiple brands); sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX; Vosevi).
  2. Concomitant use of LED or VEL and tenofovir: When using TAF or TDF concurrently with a DAA regimen containing LED or VEL, renal function should be evaluated with CrCl testing at baseline and 4 weeks after the start of DAA treatment. When LED or VEL is taken with TDF or TAF, the serum concentration of tenofovir may be increased, which may lead to tenofovir-related renal side effects. Concurrent use of a LED- or VEL-containing DAA and TDF should be avoided in patients with a CrCl < 50 mL/min. Options include switching TDF to TAF [c], substituting ABC if patient is HLAB*5701 negative and has no evidence of ABC resistance, or using a different DAA regimen.
  3. Substitutions: 1) In all cases, FTC and 3TC are interchangeable. 2) TAF 10 mg and TAF 25 mg are not interchangeable. 3) COBI and RTV should not be considered interchangeable because of their drug-interaction profiles. See the NYSDOH AI guideline Selecting an Initial ART Regimen.

As new drug approvals for HIV ARVs and HCV DAAs continue, it is important that clinicians stay current on potential drug-drug interactions. Useful online resources for looking up potential drug-drug interactions and for monitoring for new information on drug-drug interactions are listed in Box 3, above.

References

FDA. Harvoni (ledipasvir and sofosbuvir) tablets, for oral use. 2015 Mar. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205834s024lbl.pdf [accessed 2017 Dec 18]

FDA. Descovy (emtricitabine/tenofovir alafenamide). 2016a Dec 30. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208215Orig1_toc.cfm [accessed 2017 Dec 18]

FDA. Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) tablets, for oral use. 2017 Jul. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209195s000lbl.pdf [accessed 2017 Dec 19]

Garrison KL, Custodio JM, Pang PS, et al. Drug interactions between anti-HCV antivirals ledipasvir/sofosbuvir and integrase strand transfer inhibitor-based regimens. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 2015 May 26-28; Washington, DC. http://www.natap.org/2015/Pharm/Pharm_32.htm

German P, Pang PS, West S, et al. Drug interactions between direct-acting anti-HCV antivirals sofosbuvir and ledipasvir and HIV antiretrovirals. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 2014 May 19-21; Washington, DC. http://www.natap.org/2014/Pharm/Pharm_17.htm

German P, Garrison K, Pang PS, et al. Drug-drug interactions between anti-HCV regimen ledipasvir/sofosbuvir and antiretrovirals. CROI; 2015 Feb 23-26; Seattle, WA. http://www.croiconference.org/sessions/drug-drug-interactions-between-anti-hcv-regimen-ledipasvirsofosbuvir-and-antiretrovirals