Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Abacavir is metabolised by UGT, which is not expected to be affected by elbasvir/grazoprevir, and is renally cleared.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Abiraterone has multiple metabolic pathways and is an inhibitor of CYP2D6. Grazoprevir is only a weak inhibitor of CYP3A4 and data from ketoconazole have shown a negligible effect of CYP3A4 inhibitors on abiraterone.

Coadministration has not been studied. Acalabrutinib is a CYP3A4 and P-gp substrate. Acalabrutinib concentrations may increase due to mild inhibition of CYP3A4 and P-gp by elbasvir/grazoprevir which may result in increased toxicity. On treatment monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely as acamprosate does not undergo significant metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. After ingestion of acarbose the majority of active unchanged drug remains in the lumen of the gastrointestinal tract to exert its pharmacological effect and is metabolised by intestinal enzymes and by the gut microflora.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aceclofenac is metabolised by CYP2C9 which is not affected by elbasvir/grazoprevir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acenocoumarol is metabolised by CYPs 2C9 and 1A2 which are not expected to be affected by elbasvir/grazoprevir. However, close monitoring of INR is recommended as this may change as a result of improved liver function.

Coadministration has not been studied. Activated charcoal absorbs substances in the stomach and intestines and may decrease absorption of orally administered medications. If coadministration is required, administration of activated charcoal and elbasvir/grazoprevir should be separated by 4 hours. [Note: this interaction is not specific for elbasvir/grazoprevir, but for any medication taken with activated charcoal.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Adalimumab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body. Elbasvir/grazoprevir is not expected to interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Elbasvir and grazoprevir are both significantly hepatically metabolised. The potential for hepatically metabolised interactions with adefovir is low. Adefovir is eliminated renally via glomerular filtration and active renal secretion by OAT1 which are not expected to be affected by elbasvir/grazoprevir. No dose alteration is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Agomelatine is metabolized predominantly by CYP1A2 which is not expected to be affected by elbasvir/grazoprevir. [Note, agomelatine is contraindicated in hepatic impairment as increases in exposure of 140-fold have been seen in cirrhotic patients.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes.  Albiglutide slows gastric emptying, but this is unlikely to have a clinically relevant effect on elbasvir/grazoprevir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alcohol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase. Acute alcohol use inhibits CYP2E1. Chronic use may induce CYP2E1 and to a lesser extent CYP3A4 but this is unlikely to be clinically relevant. Elbasvir/grazoprevir are CYP3A4 substrates but no clinically significant interaction is expected. Additionally, a study of over 15,000 veterans treated with DAAs found no association between alcohol use and SVR12, suggesting that alcohol does not affect the efficacy of DAAs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as alemtuzumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes.

Coadministration has not been studied but alendronate can be administered with elbasvir/grazoprevir and no dose alteration is required. Alendronate is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, note that alendronate should be separated from food or other medicinal products and therefore should be separated from elbasvir/grazoprevir administration. [Note: this interaction is not specific for elbasvir/grazoprevir, but for any medication taken with alendronic acid.]

Coadministration has not been studied. Concentrations of alfentanil may increase due to mild CYP3A4 inhibition by elbasvir/grazoprevir. Due to the narrow therapeutic index of alfentanil, patients should be monitored closely for adverse effects including respiratory depression. Dose reduction may be required.

Coadministration has not been studied. Aliskiren is a substrate of P-gp and although concentrations may increase due to mild inhibition of P-gp by elbasvir this is considered unlikely to be clinically significant (based on studies with other weak inhibitors of P-gp and aliskiren). 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as allopurinol is metabolised by xanthine oxidase. [Note, the European SmPC and US Prescribing Information for allopurinol recommend a reduced dose in hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Aloe vera is only a weak inhibitor of CYPs in vitro and therefore is unlikely to cause clinically significant interactions. It does not inhibit P-gp and there is no evidence to suggest it impacts UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alogliptin does not undergo extensive metabolism and is excreted mainly unchanged in the urine and metabolism by CYPs is minimal. No transporter interactions have been described.

Antacids can be administered with elbasvir/grazoprevir and no dose alteration is required. Exposure of elbasvir or grazoprevir was not affected in the presence of an acid reducing agent such as pantoprazole or famotidine.

Coadministration has not been studied but based on limited understanding of metabolism and clearance a clinically significant interaction is unlikely. However as alverine citrate affects gastric motility, an effect on the absorption of elbasvir/grazoprevir cannot be ruled out. Doses of elbasvir/grazoprevir and alverine should be separated by 4 hours if possible. [Note: this interaction is not specific for elbasvir/grazoprevir, but for any medication taken with alverine citrate.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ambrisentan is glucuronidated by several UGT isoenzymes and is metabolised to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. Coadministration with ketoconazole (a potent CYP3A4/P-gp inhibitor) did not result in a clinically significant increase in exposure to ambrisentan. Therefore, elbasvir/grazoprevir is unlikely to have any effect on ambrisentan concentrations.

Coadministration has not been studied. Concentrations of amiodarone may increase as it is metabolised by CYP3A4 and grazoprevir is a weak inhibitor of CYP3A4 in vitro. As amiodarone has a narrow therapeutic index and unpredictable therapeutic levels, monitor patients closely for signs and symptoms of toxicity. Use with caution and consider therapeutic drug monitoring and/or ECGs during treatment. Concentrations of elbasvir/grazoprevir may be increased due to weak CYP3A4 and P-gp inhibition by amiodarone. However, this is unlikely to be clinically significant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amlodipine is metabolized by CYP3A4 and is a mild inhibitor of CYP3A4 and P-gp. Elbasvir/grazoprevir are metabolised by CYP3A4 and transported by P-gp. Although amlodipine may increase elbasvir and grazoprevir concentrations, this is unlikely to be of clinically significance. Concentrations of amlodipine may be increased due to weak inhibition of CYP3A4 by grazoprevir and mild inhibition of P-gp by elbasvir, but this is unlikely to be clinically significant.

Coadministration has not been studied and is not recommended. Amobarbital induces CYP3A4 and P-gp and could decrease concentrations of elbasvir/grazoprevir. This may result in loss of efficacy and potential virological failure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Elbasvir/grazoprevir are substrates of CYP3A4 and P-gp. Anakinra does not interact with these pathways. Anakinra is an IL-1 receptor antagonist and is eliminated by glomerular filtration and subsequent tubular metabolism.

Antacids can be administered with elbasvir/grazoprevir and no dose alteration is required. Exposure of elbasvir or grazoprevir was not affected in the presence of an acid reducing agent such as pantoprazole or famotidine.

Apixaban is metabolized mainly by CYP3A4/5 (with minor contributions from CYPs 1A2, 2C8, 2C9, 2C19, and 2J2) and is a substrate of P-gp and BCRP. Concentrations of apixaban may increase due to the additive effect of weak inhibition of CYP3A4 by grazoprevir, mild inhibition of P-gp by elbasvir, and inhibition of BCRP by elbasvir/grazoprevir. However, a large, retrospective, multi-centre cohort study of patients coadministered HCV DAAs and DOACs, including elbasvir/grazoprevir and apixaban, reported a low incidence of bleeding which was similar to historic controls of patients with liver disease on DOACs alone, providing reassurance that any increase in apixaban levels is unlikely to be clinically relevant. Patients should be reminded to promptly report any signs of bleeding or bruising as with anyone who is prescribed DOACs. [Note: product labels state that apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. It is not recommended in severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment.]

Coadministration has not been studied. Concentrations of aripiprazole may increase as it is metabolised by CYP3A4 and grazoprevir is a weak inhibitor of CYP3A4 in vitro. As aripiprazole has a narrow therapeutic index and unpredictable therapeutic levels, monitor patients closely for signs and symptoms of toxicity.

Coadministration has not been studied. Artemisinins undergo rapid metabolism via several CYP450 (CYPs 3A4, 2A6, 2B6). The active metabolite (dihydroartemisinin, which has greater potency than the parent drug) is further metabolized via UGTs 1A9 and 2B7 and has been shown to induce CYP3A4. Dihydroartemisinin may potentially decrease elbasvir/grazoprevir concentrations although the clinical significance of this is uncertain. Caution is advised and monitor closely for therapeutic effect.

Coadministration has not been studied. Dihydroartemisinin (the active metabolite of artesunate) is further metabolised via UGTs 1A9 and 2B7 and has been shown to induce CYP3A4. Dihydroartemisinin may potentially decrease elbasvir/grazoprevir concentrations although the clinical significance of this is uncertain. Caution is advised and monitor closely for therapeutic effect.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (mainly CYP1A2, with minor contributions from CYP3A4 and CYP2D6). As asenapine is metabolised by multiple pathways, a clinically significant effect is unlikely.

Coadministration of elbasvir/grazoprevir with OATP1B inhibitors, such as atazanavir is contraindicated. Coadministration increased grazoprevir AUC, Cmax and Cmin by 10.58-fold, 6.24-fold and 11.64-fold. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Coadministration of elbasvir/grazoprevir with OATP1B inhibitors, such as atazanavir is contraindicated. Coadministration with atazanavir/ritonavir increased grazoprevir AUC, Cmax and Cmin by 10.58-fold, 6.24-fold and 11.64-fold. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Coadministration of elbasvir/grazoprevir with OATP1B inhibitors, such as atazanavir is contraindicated. Coadministration with atazanavir/ritonavir increased grazoprevir AUC, Cmax and Cmin by 10.58-fold, 6.24-fold and 11.64-fold. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Coadministration of elbasvir + grazoprevir (50+ 200 mg once daily) with atorvastatin (10 mg single dose) increased atorvastatin AUC by 94% and increased Cmax by 4.34-fold. The dose of atorvastatin should not exceed a daily dose of 20 mg when coadministered with elbasvir/grazoprevir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Avelumab is primarily metabolised through catabolic pathways and drug-drug interactions are not expected.

Coadministration has not been studied. Axitinib is metabolised by CYP3A4. Grazoprevir is a weak inhibitor of CYP3A4 and therefore could potentially increase axitinib exposure. The clinical relevance of this interaction is unknown. No a priori dosage adjustment is recommended for axitinib. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Aztreonam is only minimally metabolised and is eliminated mainly unchanged in the urine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Elbasvir/grazoprevir are substrates of CYP3A4 and P-gp. Bamlanivimab and etesevimab are IgG1 monoclonal antibodies and are likely to be eliminated via intracellular catabolism, similarly to endogenous IgG. Bamlanivimab and etesevimab are not metabolized by CYP enzymes. Interactions with concomitant medications that are substrates, inducers, or inhibitors of CYP enzymes are unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Elbasvir/grazoprevir are substrates of CYP3A4 and P-gp. Baricitinib is not expected to have a clinically relevant effect on CYP enzymes and does not inhibit or induce P-gp. 

Coadministration has not been studied. Bedaquiline is metabolized by CYP3A4 and concentrations may increase due to weak inhibition of CYP3A4 by grazoprevir. Caution is advised due to the narrow therapeutic index of bedaquiline and risk of serious adverse effects. If coadministration is required, more frequent ECG monitoring and monitoring of transaminases is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendroflumethiazide is mainly eliminated by hepatic metabolism, although the exact pathway is not known. It is unlikely that CYP enzymes are involved in this process and no transporter interactions have been described.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Benralizumab is a humanised IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Benztropine is primarily metabolised by CYP2D6 which is not affected by elbasvir or grazoprevir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. Betahistine undergoes nearly complete metabolism by monoamine oxidase. Based on in-vitro data, no inhibition of cytochrome P450 enzymes by betahistine is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bevacizumab biotransformation involves proteolytic catabolism throughout the body, including endothelial cells, and does not rely primarily on elimination through the kidneys and liver.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bezafibrate is metabolised by hydroxylation, glucuronidation and renal elimination (~50%). Due to the involvement of multiple metabolic pathways and renal elimination, a clinically significant interaction is not expected with elbasvir/grazoprevir. [Note, the European SmPC for bezafibrate contraindicates its use in significant hepatic disease.]

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied but may increase concentrations of bilastine due to inhibition of P-gp by elbasvir. No a priori dose modification is recommended but close monitoring for signs and symptoms of increased bilastine exposure is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No interactions are anticipated since although the drug is metabolised, the systemic concentrations of bimatoprost are extremely low (less than 0.2 ng/ml) following ocular dosing with bimatoprost.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Although limited human data suggest biperiden undergoes hydroxylation in the liver there are no known or documented interactions with other drugs that have an effect on metabolism or transport. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. Absorption of bisacodyl from the GI tract is minimal and the small amount absorbed is excreted in the urine as the glucuronide. However, bisacodyl increases colonic mass movements and may affect absorption of elbasvir/grazoprevir. The potential interaction can be resolved by giving bisacodyl at least 4 hours after elbasvir/grazoprevir. [Note: this interaction is not specific for elbasvir/grazoprevir, but for any medication taken with bisacodyl.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisoprolol is metabolised by CYP3A4 but grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent. [Note, the European product label for bisoprolol recommends a maximum of 10 mg in severe hepatic impairment whereas the US Prescribing Information recommends an initial 2.5 mg in hepatic impairment with caution in further dose titration.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Black cohosh does not appear to be involved in drug metabolism to a clinically significant effect. Standardized black cohosh supplements, when taken at recommended doses, pose little risk for herb-drug interactions.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. An indirect effect of blinatumomab on CYPs may occur due to transient release of cytokines during the first days of therapy which can inhibit CYP450 metabolism however, a clinically relevant interaction is unlikely. The metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Coadministration is contraindicated in the European Summary of Product Characteristics and not recommended in the US Prescribing Information. Coadministration of elbasvir/grazoprevir with bosentan, a moderate CYP3A inducer, may decrease concentrations of elbasvir/grazoprevir, leading to reduced therapeutic effect.

Coadministration has not been studied. Bosutinib is metabolised principally by CYP3A4 and concentrations may increase as elbasvir/grazoprevir is a mild inhibitor of CYP3A4. This may result in adverse effects. Use with caution.

Coadministration has not been studied. Brentuximab vedotin releases the active species MMAE within the tumour cell; MMAE is a substrate of CYP3A4 and possibly CYP2D6 and a weak inhibitor of CYP3A4. Grazoprevir is a mild inhibitor of CYP3A4 and may increase concentrations of MMAE and the incidence of neutropenia, but this is unlikely to be clinically relevant. No a priori dose adjustment is recommended but patients should be monitored for adverse reactions.

Coadministration has not been studied and is contraindicated. Brincidofovir inhibits OATP1B1. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1 inhibition.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Brinzolamide is metabolised by CYP3A4 but grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Brodalumab is degraded into small peptides. Brodalumab may modulate serum levels of some cytokines and may modestly increase the exposure of CYP450 substrates, but no clinically significant effect on elbasvir/grazoprevir is expected due to the large therapeutic safety margins.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bromperidol is a metabolized by CYP3A4 but grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent.

Coadministration has not been studied. Elbasvir/grazoprevir is a substrate and mild inhibitor of CYP3A4 and transported via P-gp and OATP1B1. A clinical interaction study of high dose bulevirtide (administered at 5 mg twice daily) showed a 1.34-fold increase of Cmax and AUC of pravastatin (40 mg single dose) a substrate of OATP1B1/3 and NTCP. When bulevirtide is prescribed at the recommended dose of 2 mg, the risk for clinically relevant interactions with OATP1B1/OATP1B3 and/or NTCP substrates is considered low. However, it should be noted that the product label recommends clinical monitoring if bulevirtide is coadministered with grazoprevir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupivacaine is metabolised by UGT, CYPs 1A2 and 3A4, and amide hydrolysis which are not expected to be affected by elbasvir/grazoprevir.

The interaction between elbasvir/grazoprevir and buprenorphine were evaluated in clinical studies and no dose adjustments are required. Coadministration of multiple doses of grazoprevir and buprenorphine/naloxone or single doses of elbasvir and buprenorphine/naloxone resulted in no clinically relevant effects on the pharmacokinetics of elbasvir, grazoprevir, buprenorphine, and norbuprenorphine.

Coadministration has not been formally studied but based on current knowledge of the effect of vaccines on drug disposition a clinically significant interaction is considered unlikely.

Coadministration with intramuscular cabotegravir and rilpivirine has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Elbasvir/grazoprevir are substrates of CYP3A4 and P-glycoprotein. Cabotegravir does not inhibit or induce CYP3A4 and P-glycoprotein. Coadministration of oral rilpivirine (25 mg daily) and elbasvir + grazoprevir (50 + 200 mg once daily) had no clinically meaningful effect on exposures of grazoprevir, elbasvir, or rilpivirine. No dose adjustments are required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Calcium carbimide is a prodrug requiring catalase and hydrogen peroxide to generate the active metabolite. Calcium carbimide is an inhibitor of ALDH but this enzyme is not involved in the metabolism of elbasvir/grazoprevir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Canagliflozin is primarily metabolised by UGTs 1A9 and 2B4 which are not affected by elbasvir/grazoprevir. Canagliflozin is a substrate and inhibitor of P-gp. Canagliflozin concentrations may increase due to mild inhibition of P-gp by elbasvir but this is unlikely to be of clinical significance. Inhibition of P-gp by canagliflozin is unlikely to have a clinically significant effect on elbasvir/grazoprevir due to the large therapeutic safety margins.

Coadministration has not been studied. Although candesartan inhibits OATP1B1 in vitro any increase in grazoprevir exposure is considered unlikely to be clinically relevant (based on in vitro calculations). However, monitoring for ALT elevations may be required. [Note, use of candesartan in severe hepatic impairment is contraindicated in the European SmPC; the US Prescribing Information recommends caution in moderate hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cannabidiol is mainly metabolized by CYP3A4 and CYP2C19 and is unlikely to significantly inhibit CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent.

Coadministration is contraindicated. Coadministration has not been studied but may significantly decrease elbasvir/grazoprevir concentrations due to induction of CYP3A4 and/or P-gp by carbamazepine; this may lead to reduced therapeutic effect and potential virological failure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carbimazole is a pro-drug which undergoes rapid and virtually complete metabolism to the active metabolite, thiamazole (methimazole). There is little evidence of marked interactions with this drug. Thiamazole has been shown to have inhibitory effects on CYP3A4 in vitro, however, a clinically relevant effect is not anticipated. [Note: The Zepatier SmPC contraindicates its use in patients with moderate or severe hepatic impairment.]

Coadministration has not been studied but carfentanil concentrations may be increased due to weak CYP3A4 inhibition by grazoprevir. The impact of weak CYP3A4 inhibition is unclear since carfentanil is only present at very low concentrations. However, even modest increases of carfentanil levels may lead to an increased risk of severe toxicities, including potentially fatal respiratory depression. Since carfentanil is an extremely strong opiate, reported to be up to 10,000 times more potent than morphine, and multiple deaths have resulted from its use, we would advise patients to avoid.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carvedilol is glucuronidated by UGTs 1A1, 2B4 and 2B7 with additional metabolism by CYP2D6 (and to a lesser extent CYPs 2C9 and 1A2). [Note, the US Prescribing Information contraindicates carvedilol in patients with severe liver impairment and the European SmPC contraindicates it in patients with hepatic dysfunction.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Elbasvir/grazoprevir are substrates of CYP3A4 and P-gp. Casirivimab and imdevimab are IgG1 monoclonal antibodies and are likely to be eliminated via intracellular catabolism, similarly to endogenous IgG. Casirivimab and imdevimab are not metabolized by CYP enzymes. Interactions with concomitant medications that are substrates, inducers, or inhibitors of CYP enzymes are unlikely.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely as caspofungin undergoes spontaneous chemical degradation and non-CYP mediated metabolism. [Note, no dose adjustment is required in patients with normal hepatic function but a dose reduction of caspofungin daily dose to 35 mg is recommended for adults with moderate hepatic impairment. There is no clinical experience in adults with severe hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cat’s claw is an inhibitor of CYP3A4; any increase of elbasvir/grazoprevir levels via this enzyme are unlikely to be clinically significant. Mild CYP3A4 inhibition of grazoprevir is unlikely to affect cat’s claw.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Cefaclor is predominantly eliminated unchanged by the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Cefadroxil is not metabolised and is predominantly eliminated unchanged by the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Cefradine is not metabolised and is predominantly eliminated unchanged by the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Ceftaroline is not metabolised by CYP enzymes and is primarily eliminated by the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Celecoxib is a substrate of CYP2C9 which is not expected to be affected by elbasvir/grazoprevir. [Note, use in patients with severe liver impairment is contraindicated in the European SmPC and not recommended in the US Prescribing Information. In patients with moderate liver impairment (serum albumin 25-35 g/L, Child-Pugh Class B), celecoxib treatment should be started at half the recommended dose.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Like other protein therapeutics, cetuximab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Coadministration has not been studied but a clinically significant interaction is considered unlikely. Very little has been described about chlorambucil metabolism in humans but CYP450 enzymes are not involved.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chloroquine is rapidly metabolised by CYPs 2C8, 3A and 2D6 to the pharmacologically active desethylchloroquine and bisdesethylchloroquine and is also renally eliminated. These pathways are not expected to be affected by elbasvir/grazoprevir. Note, the European SPC and US Prescribing Information for chloroquine both recommend caution in impaired hepatic function.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorpromazine is a substrate of CYPs 2D6 (major), 1A2, and 3A4 in vitro, which are not expected to be affected by elbasvir/grazoprevir. [Note, the European SmPC for chlorpromazine advises that its use should be avoided in patients with hepatic dysfunction.]

Co-administration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorprothixene is metabolised by CYP2D6 which is not affected by elbasvir/grazoprevir. [Note, although no interaction is anticipated, ECG monitoring is mandatory prior to treatment with chlorprothixene.]

Concomitant use of elbasvir/grazoprevir with OATP1B inhibitors, such as ciclosporin is contraindicated. Coadministration of multiple doses of elbasvir/grazoprevir and a single dose of ciclosporin increased grazoprevir AUC by 15-fold. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cilazapril is metabolised by esterases to the active cilazaprilat which is excreted unchanged in urine. [Note, in patients with cirrhosis, a maximum dose of 0.5 mg/day is recommended as significant hypotension may occur.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clinical studies with grazoprevir and elbasvir with famotidine showed no clinically relevant effect on elbasvir or grazoprevir exposure. Elbasvir/grazoprevir may be coadministered with acid-reducing agents and no dose adjustments are required.

Coadministration has not been studied. Cisapride is metabolised by CYP3A4 and grazoprevir is a weak inhibitor of CYP3A4. A clinically significant interaction cannot be ruled out, therefore use with caution and close monitoring due to cisapride’s narrow therapeutic index.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cisatracurium undergoes mainly (80% of overall elimination) spontaneous degradation in plasma and tissues at physiological pH and temperature (Hofmann elimination).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clarithromycin is a substrate and inhibitor of both CYP3A4 and P-gp; elbasvir is a mild inhibitor of P-gp. Coadministration could increase elbasvir, grazoprevir and clarithromycin concentrations due to CYP3A4 and P-gp inhibition, however, any increase is unlikely to be of clinical significance. Any increase in elbasvir or grazoprevir is likely to be within the upper clinical bounds and not clinically significant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Clavulanic acid is extensively metabolized (likely by a non-CYP mediated pathway) and excreted in the urine by glomerular filtration.  

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clevidipine is rapidly metabolised by hydrolysis of the ester linkage and does not undergo CYP metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clobazam is metabolised primarily by CYP3A4 and to a lesser extent by CYP2C19. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent. Clobazam is a weak CYP3A4 inducer and could potentially decrease elbasvir/grazoprevir exposure to a very limited extent. However, this is unlikely to be clinically relevant.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clodronate is not metabolised and is primarily excreted unchanged by the kidney. However, if administered orally, clodronate should be taken more than two hours after and one hour before any other oral drugs. [Note: this interaction is not specific for elbasvir/grazoprevir, but for any oral medication taken with clodronate.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely, Clofazimine is a moderate inhibitor of CYP3A4 and may increase elbasvir/grazoprevir concentrations to a modest extent however this margin of increase is unlikely to be relevant. [Note, the US Prescribing Information for clofazimine recommends to avoid clofazimine in patients with hepatic impairment (Child-Pugh Class A, B, and C) unless the benefit outweighs the risk.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clopidogrel is a prodrug that is converted to its active metabolites by CYPs 2C19, 3A4, 2B6, and 1A2. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent. [Note, the European SmPC for clopidogrel contraindicates it use in severe hepatic impairment but the US Prescribing Information states no dose alteration.]

Coadministration has not been studied. The metabolism of clotiapine has not been well characterised but is likely to involve CYP450 enzymes. Clotiapine concentrations may increase due to mild inhibition of CYP3A4 by elbasvir/grazoprevir but the clinical significance is unclear. No a priori dose modification is recommended but, in the absence of data, monitoring may be required. A clinically significant effect on elbasvir/grazoprevir is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of colecalciferol to active metabolites occurs in the liver and kidneys, and is thought to involve CYP3A4 and CYP24A1. In vitro studies have shown rifampicin (an enzyme inducer) increased metabolism of colecalciferol and introduction of 6',7'-dihydroxybergamottin (a CYP3A4 inhibitor in grapefruit juice) reversed the effects of rifampicin on colecalciferol clearance. Weak inhibition of CYP3A by grazoprevir is not expected to reduce the effect of colecalciferol, but the consequence of CYP3A inhibition on the clinical effect of colecalciferol is not known. Elbasvir and grazoprevir are substrates of CYP3A4 and P-gp. Grazoprevir is also a substrate of OATP1B and possibly BCRP. Colecalciferol does not interact with these pathways. [Note: The Zepatier SmPC contraindicates its use in patients with moderate or severe hepatic impairment.]

Coadministration has not been studied. Colestyramine may delay or reduce the absorption of drugs. Administration of other drugs should be at least 1 hour before or 4-6 hours after colestyramine. [Note: this interaction is not specific for elbasvir/grazoprevir, but for any medication taken with colestyramine.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The metabolism of conjugated estrogens is complex and involves CYP3A4 isoenzymes and glucuronidation in the liver. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cyanocobalamin undergoes enterohepatic recycling and is excreted almost entirely in the urine.

Co-administration has not been studied but based on limited data for the metabolism and clearance of cyclizine, a clinically significant interaction is unlikely. Cyclizine undergoes hepatic metabolism which may include CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cyclophosphamide is activated (major pathway) to 4-hydroxycyclophosphamide by CYPs 2B6 (major), 2C9 and 3A4. Inactivation (minor, 10%) to the neurotoxic chloroacetaldehyde metabolite is performed mainly by CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent.

Coadministration has not been studied but may increase dabigatran exposure due to P-gp inhibition by elbasvir. Close monitoring (for signs of bleeding and anaemia) is recommended due to the narrow therapeutic window of dabigatran. No effect on elbasvir/grazoprevir concentrations is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Danaparoid is renally excreted and no hepatic involvement was shown in animal studies.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dantron is absorbed from the small intestine and acts at the large intestine. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is metabolised by UGT1A9 which is not expected to be affected by elbasvir/grazoprevir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Like other protein therapeutics, daratumumab is expected to be degraded into small peptides and amino acids via catabolic pathways and is not anticipated to alter drug-metabolising enzymes.

Concomitant use of elbasvir/grazoprevir with OATP1B inhibitors, such as darunavir is contraindicated as it may significantly increase grazoprevir plasma concentrations. Coadministration of darunavir/ritonavir increased grazoprevir AUC by 7.5-fold and elbasvir AUC by 66%. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Coadministration of elbasvir/grazoprevir and OATP1B inhibitors such as darunavir/cobicistat is contraindicated as it may significantly increase grazoprevir plasma concentrations. Coadministration of darunavir/ritonavir increased grazoprevir AUC by 7.5 fold and elbasvir AUC by 66%. A similar interaction may occur with darunavir/cobicistat. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition. Emtricitabine and tenofovir alafenamide do not interact with this metabolic pathway.

Coadministration of elbasvir/grazoprevir and OATP1B inhibitors such as darunavir is contraindicated as it may significantly increase grazoprevir plasma concentrations. Coadministration of darunavir/ritonavir increased grazoprevir AUC by 7.5 fold and elbasvir AUC by 66%. A similar interaction may occur with darunavir/cobicistat. The risk of ALT elevations may be increased due to the significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Deferiprone is glucuronidated by UGT1A6 which is not affected by elbasvir/grazoprevir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Delamanid is primarily metabolised by albumin to DM-6705; metabolism of DM-6705 to other metabolites is thought to involve pathways mediated by CYP enzymes, including CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent. [Note, delamanid is not recommended in patients with moderate to severe hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Denosumab is not eliminated via hepatic metabolism but follows the immunoglobulin clearance pathway resulting in degradation to small peptides and individual amino acids.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is not anticipated and contraceptive efficacy is unlikely to be affected. Ethinylestradiol is mainly metabolized by hydroxylation with CYP3A4 and CYP2C9. Desogestrel is a prodrug that requires activation to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent. Administration of ethinylestradiol and another progestogen, levonorgestrel, (0.03/0.15 mg single dose) to 20 subjects was studied. There were no clinically relevant changes in the concentrations of ethinylestradiol or levonorgestrel.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is not anticipated and contraceptive efficacy is unlikely to be affected. Ethinylestradiol is mainly metabolized by hydroxylation with CYP3A4 and CYP2C9. Desogestrel is a prodrug that requires activation to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent. Administration of ethinylestradiol and another progestogen, levonorgestrel, (0.03/0.15 mg single dose) to 20 subjects was studied. There were no clinically relevant changes in the concentrations of ethinylestradiol or levonorgestrel.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desvenlafaxine is a substrate of CYP3A4 but grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent.

Coadministration has not been studied and should be avoided if possible. Dexamethasone is a substrate and moderate inducer of CYP3A4 at doses above 16 mg. Coadministration may decrease elbasvir/grazoprevir concentrations due to moderate induction of CYP3A4 by dexamethasone and this may lead to reduced therapeutic effect. Dexamethasone is also a P-gp inducer in pre-clinical models although the clinical relevance of this is unclear. [Note: The Zepatier SmPC contraindicates its use in patients with moderate or severe hepatic impairment.]

Coadministration has not been studied but based on limited data for metabolism and clearance a clinically significant interaction is unlikely. Note, the role of CYP450 in the metabolism of dexamfetamine has not been fully described.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Dexketoprofen is mainly glucuronidated, with CYP mediated metabolism (CYP2C8/9) playing only a minor role. Elbasvir/grazoprevir is not expected to induce or inhibit UGTs or CYP2C8/2C9. [Note, use in patients with severe hepatic impairment (Child Pugh class C) is contraindicated in the European product label for dexketoprofen.]

Coadministration with elbasvir/grazoprevir has not been studied. No clinically relevant increases in concentrations of digoxin were observed with multiple doses of elbasvir and a single dose of digoxin (digoxin AUC and Cmax increased by 11% and 47%). No dose adjustments are required.

Coadministration has not been studied. Dihydroartemisinin (the active metabolite of artesunate) induces CYP3A4 and may decrease exposure of grazoprevir and elbasvir. The clinical significance is unclear. Close monitoring of therapeutic effect is recommended.

Coadministration with diltiazem has not been studied. Although diltiazem is an inhibitor of CYP3A4 and P-gp, a clinically significant effect on elbasvir/grazoprevir is unlikely with any increase in exposure within the upper clinical bounds. Concentrations of diltiazem may increase modestly due to weak inhibition of CYP3A4 by grazoprevir and mild inhibition of P-gp by elbasvir, but this is not expected to be clinically significant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diosmin is a naturally occurring flavonoid. Diosmin-containing products are available as dietary supplements or on prescription (in certain countries). Interaction studies suggest that diosmin may be a weak inhibitor of CYP3A4 and P-gp, but any effect on elbasvir/grazoprevir is unlikely to be clinically relevant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diphenhydramine is a substrate (and inhibitor) of CYP2D6 which is not expected to be affected by elbasvir/grazoprevir. [Note, diphenhydramine should be used with caution in patients with moderate to severe hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dofetilide is eliminated in the kidney by cationic secretion and is metabolized to a small extent by CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent.

Coadministration of multiple doses of elbasvir/grazoprevir and dolutegravir had no clinically relevant effect on the pharmacokinetics of grazoprevir, elbasvir or dolutegravir. No dose adjustments are required.

Coadministration with dolutegravir/lamivudine has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Coadministration of multiple doses of elbasvir/grazoprevir and dolutegravir had no clinically relevant effect on the pharmacokinetics of grazoprevir, elbasvir, or dolutegravir. The likelihood of metabolic interactions with lamivudine and other medicinal products is low due to the small extent of lamivudine hepatic metabolism (5-10%) and low plasma protein binding. No dose alteration is required.

Coadministration with dolutegravir/rilpivirine has not been studied. Coadministration of multiple doses of elbasvir/grazoprevir and dolutegravir or rilpivirine had no clinically relevant effect on the pharmacokinetics of grazoprevir, elbasvir, dolutegravir or rilpivirine. No dose adjustments are required. Coadministration of dolutegravir (50 mg single dose) and elbasvir + grazoprevir (50 + 200 mg once daily) to 12 subjects decreased elbasvir AUC, Cmax and C24 by 2%, 3% and 2%, respectively, and decreased grazoprevir AUC, Cmax and C24 by 19%, 36% and 14%, respectively. Dolutegravir AUC, Cmax and Ctrough increased by 16%, 22% and14%, respectively. Coadministration of rilpivirine (25 mg once daily) and elbasvir + grazoprevir (50 + 200 mg once daily) to 19 subjects increased elbasvir AUC, Cmax and C24 by 7%, 7% and 4%, respectively; grazoprevir AUC and Cmax decreased by 2% and 3%, with no change in C24. Rilpivirine AUC, Cmax and Ctrough increased by 13%, 7% and 16%, respectively.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Donepezil is metabolised by CYP3A4 and CYP2D6 (minor) but grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent.

Coadministration of doravirine (100 mg once daily) and elbasvir/grazoprevir (50/200 mg once daily) increased doravirine AUC, Cmax and Cmin by 56%, 41%, 61%, respectively (n=12). The increase in doravirine exposure is not considered to be clinically relevant. Elbasvir/grazoprevir exposure was not significantly altered by doravirine (elbasvir AUC, Cmax and C24 all decreased by 4%; grazoprevir AUC and Cmax increased by 7% and 22%, C24 decreased by 10%).

Coadministration with Delstrigo has not been studied. Coadministration of doravirine (100 mg once daily) and elbasvir/grazoprevir (50/200 mg once daily) increased doravirine AUC, Cmax and Cmin by 56%, 41%, 61%, respectively. The increase in doravirine exposure is not considered to be clinically relevant. Elbasvir/grazoprevir exposure was not significantly altered by doravirine. No clinically relevant interaction is expected with lamivudine. The interaction between elbasvir/grazoprevir and tenofovir-DF was evaluated in clinical studies, and no dose adjustments are required. There was no clinically significant effect on tenofovir pharmacokinetics when administered with elbasvir (tenofovir AUC, Cmax, Ctrough increased by 34%, 47%, 29%) or grazoprevir (tenofovir AUC, Cmax, Ctrough increased by 18%, 14%, and 24%). Tenofovir-DF had no clinically significant effect on elbasvir (AUC, Cmax, C24 decreased by 7%, 12%, 8%) or grazoprevir (AUC, Cmax, C24 decreased by 14%, 22%, and 11%).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dosulepin is extensively metabolised in the liver, likely by CYP2D6 (major) and CYP3A4, but grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent. [Note: Dosulepin should be used with caution in mild to moderate hepatic impairment and avoided in severe hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxazosin is extensively metabolised by CYP3A4 and to a lesser extent CYP2D6 and CYP2C19. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent. [Note, the European SmPC for doxazosin does not recommend its use in severe hepatic impairment; the US Prescribing Information has a caution in hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9, none of which are expected to be affected by elbasvir/grazoprevir. [Note, the European and US product labels for doxepin advise caution and monitoring in patients with hepatic impairment as a dosage reduction may be required.]

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxylamine is metabolized primarily by CYP2D6, CYP1A2, and CYP2C9. Elbasvir/grazoprevir does not interact with these pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolized by CYP3A4 and CYP1A2 and is glucuronidated. Drospirenone is metabolised in part by CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely and contraceptive efficacy is unlikely to be affected. Ethinylestradiol is mainly metabolized by hydroxylation with CYP3A4 and CYP2C9. Drospirenone is metabolised in part by CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent. Administration of ethinylestradiol and another progestogen, levonorgestrel, (0.03/0.15 mg single dose) to 20 subjects was studied. There were no clinically relevant changes in the concentrations of ethinylestradiol or levonorgestrel.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely and contraceptive efficacy is unlikely to be affected. Ethinylestradiol is mainly metabolized by hydroxylation with CYP3A4 and CYP2C9. Drospirenone is metabolised in part by CYP3A4. Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent. Administration of ethinylestradiol and another progestogen, levonorgestrel, (0.03/0.15 mg single dose) to 20 subjects was studied. There were no clinically relevant changes in the concentrations of ethinylestradiol or levonorgestrel.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as dulaglutide is presumed to be degraded by general protein catabolism pathways. Dulaglutide delays gastric emptying but interaction studies showed no clinically significant effect on the absorption of concomitantly administered oral medicinal products and no dose adjustment of comedications is recommended.

Coadministration has not been studied but based on metabolism and clearance an interaction is unlikely. Duloxetine is metabolized by CYP2D6 and CYP1A2 which are not expected to be affected by elbasvir/grazoprevir. [Note, duloxetine is contraindicated in patients with hepatic impairment as concentrations may increase due to decreased clearance of duloxetine.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dupilimab is a protein and degrades to small peptides and individual amino acids. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dutasteride is metabolised mainly by CYP3A4 but grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect this pathway to any clinically significant extent. [Note, the European SmPC (but not the US Prescribing Information) cautions against dutasteride use in mild to moderate hepatic impairment and contraindicates it in severe hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolized by CYP3A4 and CYP1A2 and is glucuronidated. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent.

Coadministration has not been studied. Ebastine is metabolised by CYP450 and concentrations may be increased due to mild CYP3A4 inhibition by grazoprevir. ECG monitoring should be considered as increased concentrations of ebastine can prolong the QT interval.

Coadministration has not been studied but may increase edoxaban concentrations due to inhibition of P-gp by elbasvir. No a priori dose modification is recommended. A large, retrospective, multi-centre cohort study of patients coadministered HCV DAAs and DOACs, reported a low incidence of bleeding which was similar to historic controls of patients with liver disease on DOACs alone, providing reassurance that the interaction is unlikely to be clinically relevant in the majority of patients. Patients should be reminded to promptly report any signs of bleeding or bruising as with anyone who is prescribed DOACs. [Note: product labels state that edoxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. It is not recommended in severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment.]

Coadministration is contraindicated. The effect of efavirenz, a moderate inducer of CYP3A/P-gp, on grazoprevir and elbasvir steady-state pharmacokinetics was evaluated in separate studies and decreased elbasvir and grazoprevir AUCs by 54% and 83%, respectively. This may lead to reduced therapeutic effect of elbasvir/grazoprevir.

Coadministration has not been studied. Eliglustat is metabolised primarily by CYP2D6 and to a lesser extent by CYP3A4. Concentrations of eliglustat may increase due to mild inhibition of CYP3A4 by grazoprevir. Caution and monitoring of adverse effects associated with increased eliglustat concentrations is recommended

Coadministration is not recommended as it may substantially increase grazoprevir exposure. Coadministration with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide has not been studied. However, coadministration with elvitegravir/cobicistat/emtricitabine/tenofovir-DF increased grazoprevir exposure by ~5.4-fold. A similar increase would be expected with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.

Coadministration is contraindicated in the European Summary of Product Characteristics and not recommended in the US Prescribing Information due to a substantial (~5.4-fold) increase in grazoprevir exposure. Coadministration of elbasvir/grazoprevir (50/100 mg once daily) and elvitegravir/cobicistat/emtricitabine/tenofovir-DF (150/150/300/150 mg once daily) increased grazoprevir AUC, Cmax and Cmin by 436%, 359% and 178%; elbasvir AUC, Cmax and Cmin increased by 118%, 91% and 138%. There were no clinically relevant effects on the pharmacokinetics of elvitegravir, cobicistat, emtricitabine or tenofovir-DF.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Empagliflozin is metabolised by UGTs and is a substrate of P-gp, BCRP, OAT3 and OATP1B1/1B3. Although elbasvir is a mild inhibitor of P-gp, data with verapamil (a P-gp inhibitor) suggest a clinically relevant effect on empagliflozin is unlikely. Concentrations of empagliflozin may increase due to inhibition of BCRP by elbasvir/grazoprevir but this is not expected to be clinically significant.

Coadministration has not been studied. No clinically relevant drug-drug interaction is expected when elbasvir/grazoprevir is coadministered with emtricitabine. No dose alteration is required.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration with emtricitabine/tenofovir-DF alone has not been studied. No clinically significant interaction is expected with emtricitabine. There was no clinically significant effect on tenofovir pharmacokinetics when administered with elbasvir (tenofovir AUC, Cmax, Ctrough increased by 34%, 47%, 29%) or grazoprevir (tenofovir AUC, Cmax, Ctrough increased by 18%, 14%, and 24%). Tenofovir-DF had no clinically significant effect on elbasvir (AUC, Cmax, C24 decreased by 7%, 12%, 8%) or grazoprevir (AUC, Cmax, C24 decreased by 14%, 22%, and 11%). No dose adjustments are required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Elbasvir and grazoprevir are both significantly hepatically metabolised. Entecavir is not hepatically metabolised and the potential for interactions via this route is low. Entecavir is mainly excreted unchanged by the kidney by both glomerular filtration and active transport.