Drug-Drug Interactions - AIDS Institute Clinical Guidelines

Hepatitis C Virus Infection Guideline Committee, updated July 2018

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 3. Online Resources for Identifying Drug-Drug Interactions between DAAs and Common Medications
American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA): Includes charts listing all DAAs University of Liverpool HEP Drug Interactions: Provides guidance on managing HCV drug interactions, especially in those coinfected with HIV; may not include all medications available in the United States

Elbasvir/Grazoprevir

Hepatitis C Virus Infection Guideline Committee, December 2017

Table 34. Elbasvir/Grazoprevir 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 2017 Sep 22]

Glecaprevir/Pibrentasvir

Hepatitis C Virus Infection Guideline Committee, December 2017

Table 35. Glecaprevir/Pibrentasvir 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 2017 Sep 22]

Ledipasvir/Sofosbuvir

Hepatitis C Virus Infection Guideline Committee, December 2017

Table 36. Ledipasvir/Sofosbuvir 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 and simeprevir 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/2015/205834s001lbl.pdf [accessed 2017 Sep 22]

Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir

Hepatitis C Virus Infection Guideline Committee, December 2017

Table 37. Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir (PrOD) Drug-Drug Interactions
Avoid co-administration; see clinical comments
Class (medications)	Clinical Comments
Alpha 1-antagonist (alfuzosin)	Significant increase in alfuzosin level Potential for severe hypotension
Antianginal (ranolazine)	Significant increase in ranolazine level
Antiarrhythmics (amiodarone, dronedarone, dofetilide, disopyramide, flecainide, lidocaine, mexiletine, propafenone, quinidine)	Increased antiarrhythmic drug levels, potential for cardiac arrhythmias Therapeutic concentration monitoring of antiarrhythmic drug level recommended if available
Anticonvulsants (carbamazepine, oxcarbazepine, phenytoin, phenobarbital)	Significant decrease in PrOD levels
Antigout (colchicine)	Significant increase in colchicine level Potential for renal impairment and pancytopenia
Antihyperlipidemic (gemfibrozil)	Significant (10-fold) increase in dasabuvir level leading to increased risk of QT prolongation
Antimycobacterial (rifampin)	Significant decrease in PrOD levels Potential for HCV treatment failure
Antipsychotics, 1st generation, typical (pimozide, lurasidone)	Significant increase in antipsychotic levels
Ergot derivatives (ergotamine, dihydroergot-amine, ergonovine, methylergonovine)	Significant increase in ergot derivative level leading to acute ergot toxicity
Ethinyl estradiol-containing products (oral contraceptives)	Significant increase in PrOD level Alanine transaminase (ALT) elevations associated with concurrent use of ethinyl estradiol
Herbal product (St John’s wort)	Significant decrease in PrOD levels
HIV medication (efavirenz)	Co-administration of efavirenz-based regimens with paritaprevir, ritonavir plus dasabuvir poorly tolerated Results in liver enzyme elevation
HMG-CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin)	Significant increase in atorvastatin, lovastatin, and simvastatin levels Potential for rhabdomyolysis
Immunosuppressants (everolimus, sirolimus, tacrolimus)	Increased potential for immunosuppressant-associated adverse events
Phosphodiesterase-5 inhibitors (sildenafil, when used in pulmonary arterial hypertension)	Increased potential for sildenafil adverse events, such as priapism, visual disturbances, and hypotension
Sedative/hypnotics (oral midazolam, triazolam)	Significant increases in oral midazolam or triazolam level
Co-administration possible; see clinical comment
Class (medications)	Clinical Comments
Angiotensin receptor blockers (ARBs) (candesartan, olmesartan, telmisartan)	Increased ARB drug levels Consider ARB dose reduction Monitor closely for hypotension
Antifungal (oral ketoconazole, voriconazole)	Oral ketoconazole: Increase in ketoconazole level; dose should not exceed 200 mg in a 24-hour period Voriconazole: Significant decrease in voriconazole level
Antipsychotic, 2nd generation, atypical (quetiapine)	Significant increase in quetiapine level Consider alternative HCV therapy or reduce quetiapine dose to 1/6 of current dose Monitor for adverse events, including increased blood pressure
Beta adrenoceptor agonist (long-acting salmeterol)	Significant increase in salmeterol level Monitor for QT prolongation, palpitations, and sinus tachycardia
Calcium channel blockers (CCBs) (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil)	Increased CCB drug levels Consider CCB drug dose reduction Monitor closely for hypotension and bradycardia
Corticosteroids (inhaled or nasal fluticasone)	With nasal or inhaled use, significant increase in fluticasone level, which can lead to Cushing’s Syndrome
Diuretic (furosemide)	Possible increase in furosemide level Monitor closely based upon response
HMG-CoA reductase inhibitors (atorvastatin, pravastatin, rosuvastatin)	Increased HMG-CoA reductase inhibitor drug levels Atorvastatin: Do not exceed 20 mg in a 24-hour period Pravastatin: Do not exceed 40 mg in a 24-hour period Rosuvastatin: Do not exceed 10 mg in a 24-hour period
Immunosuppressants (cyclosporine, tacrolimus)	Increase in cyclosporine and tacrolimus levels Interactions are complex; consult PrOD package insert for additional dosing guidance
Muscle relaxants (carisoprodol, cyclobenzaprine)	Decrease in muscle relaxant drug levels Consider increasing dose of muscle relaxant if clinically indicated
Narcotic analgesics (buprenorphine/naloxone, acetaminophen/hydrocodone)	Buprenorphine/naloxone: Monitor for sedation Acetaminophen/hydrocodone: Reduce hydrocodone dose by 50% Monitor for respiratory depression and sedation
Phosphodiesterase-5 inhibitors, when used for erectile dysfunction (sildenafil, tadalafil, vardenafil)	Increase in phosphodiesterase-5 inhibitor drug level Sildenafil: Do not exceed 25 mg in a 48-hour period Tadalafil: Do not exceed 10 mg in a 72-hour period Vardenafil: Do not exceed 2.5 mg in a 72-hour period
Proton-pump inhibitor (omeprazole)	Decrease in omeprazole level Consider increase in omeprazole dose for patients not well controlled Do not exceed omeprazole 40 mg daily equivalent
Sedative/hypnotics (alprazolam, diazepam)	Alprazolam: Increase in drug level Monitor for excess sedation Consider decrease in alprazolam dose Diazepam: Decrease in drug level Consider increase in diazepam dose if clinically indicated
Source: FDA. Viekira XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208624s001s003lbl.pdf [accessed 2017 Sep 22]

Sofosbuvir

Hepatitis C Virus Infection Guideline Committee, December 2017

Table 38. Sofosbuvir 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 efficacy
Antimycobacterials (rifampin, rifabutin, rifapentine)	Significant decrease in sofosbuvir level expected leading to reduced sofosbuvir efficacy
Herbal product (St John’s wort)	Significant decrease in sofosbuvir level expected leading to reduced sofosbuvir efficacy
Source: FDA. Sovaldi (sofosbuvir) tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204671s002lbl.pdf [accessed 2017 Sep 22]

Sofosbuvir and Velpatasvir

Hepatitis C Virus Infection Guideline Committee, December 2017

Table 39. Sofosbuvir and Velpatasvir 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 2017 Sep 22]

Sofosbuvir/Velpatasvir/Voxilaprevir

Hepatitis C Virus Infection Guideline Committee, December 2017

Table 40. Sofosbuvir and Velpatasvir 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 2017 Sep 22]