Coadministration of abacavir (in combination with lamivudine) and ledipasvir/sofosbuvir had no effect on the pharmacokinetic parameters of abacavir, ledipasvir or sofosbuvir.

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. Ledipasvir is not involved with this pathway.

Coadministration has not been studied. Acalabrutinib is a CYP3A4 and P-gp substrate. Acalabrutinib concentrations may increase due to inhibition of P-gp by ledipasvir 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 activity and is metabolised by intestinal enzymes and microbial flora.

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 ledipasvir/sofosbuvir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as acenocoumarol is predominantly metabolised via CYP2C9 and ledipasvir/sofosbuvir do not inhibit this enzyme. 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 ledipasvir/sofosbuvir should be separated by 4 hours. [Note: this interaction is not specific for ledipasvir/sofosbuvir, 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. Ledipasvir is primarily eliminated unchanged through biliary excretion. Sofosbuvir is metabolised by non-CYP mediated routes. Adefovir is largely excreted unchanged via renal glomerular filtration and active renal secretion by OAT1. Ledipasvir/sofosbuvir do not inhibit this transporter.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as agomelatine is metabolised predominantly via CYP1A2. [Note, agomelatine is contraindicated in hepatic impairment as increases in exposure of up to 140-times 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. GLP-1 agonists such as albiglutide also have the potential to inhibit gastric secretion and thereby impact drugs whose absorption is gastric dependent, such as ledipasvir. A reduction in ledipasvir exposure is possible with albiglutide, however, this is unlikely to be clinically significant. Albiglutide slows gastric emptying, but this is unlikely to have a clinically relevant effect on ledipasvir/sofosbuvir.

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 ledipasvir/sofosbuvir 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 ledipasvir/sofosbuvir administration. [Note: this interaction is not specific for ledipasvir/sofosbuvir, but for any medication taken with alendronic acid.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as allopurinol is metabolised by xanthine oxidase and aldehyde oxidase which do not appear to be affected by ledipasvir/sofosbuvir. [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.

Coadministration has not been studied but is expected to decrease ledipasvir concentrations. It is recommended to separate aluminium hydroxide and ledipasvir/sofosbuvir administration by 4 hours.

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 ledipasvir/sofosbuvir cannot be ruled out. Doses of ledipasvir/sofosbuvir and alverine should be separated by 4 hours if possible. [Note: this interaction is not specific for ledipasvir/sofosbuvir, 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 metabolised to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. Ledipasvir is a weak inhibitor of intestinal CYP3A4 and also inhibits P-gp. Coadministration with ketoconazole (a potent CYP3A4/P-gp inhibitor) did not result in a clinically significant increase in exposure to ambrisentan. Therefore, ledipasvir/sofosbuvir is unlikely to have any effect on ambrisentan concentrations.

Coadministration is not recommended. Coadministration of ledipasivr/sofosbuvir with amiodarone may result in serious symptomatic bradycardia. The mechanism of this effect is unknown.

Coadministration has not studied but may increase concentrations of amlodipine or ledipasvir due to P-gp inhibition. Although a clinically significant effect of ledipasvir is considered unlikely, close monitoring of heart rate, blood pressure and for increased side effects of amlodipine is recommended.

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

Coadministration has not been studied but is expected to decrease ledipasvir concentrations. It is recommended to separate antacid and ledipasvir/sofosbuvir administration by 4 hours.

Concentrations of apixaban may increase as ledipasvir is a mild to moderate inhibitor of P-gp. However, a large, retrospective, multi-centre cohort study of patients coadministered HCV DAAs and DOACs, including ledipasvir/sofosbuvir 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 but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Ledipasvir is not metabolised by these enzymes  

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dihydroartemisinin (the active metabolite of artesunate) is further metabolised via UGTs 1A9 and 2B7 and has been shown to induce CYP3A4 but ledipasvir is not metabolised by this enzyme.

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 has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No clinically significant interactions were observed when atazanavir/ritonavir and ledipasvir/sofosbuvir were coadministered (ledipasvir Cmax, AUC and Cmin increased by 98%, 113% and 136%; sofosbuvir Cmax decreased by 4% and AUC increased in by 8%; atazanavir Cmax, AUC and Cmin increased by 7%, 33% and 75%; ritonavir Cmax decreased by 7% whereas AUC and Cmin increased by 5% and 56%).

Coadministration with atazanavir/cobicistat has not been studied. Coadministration of cobicistat (with elvitegravir, 150/150 mg once daily) and ledipasvir/sofosbuvir (90/400 mg once daily) increased cobicistat Cmax, AUC and Cmin by 25%, 59% and 325%, respectively. Ledipasvir Cmax, AUC and Cmin increased by 63%, 78% and 91%, respectively and sofosbuvir Cmax and AUC increased by 33% and 36%. Note, coadministration of ledipasvir/sofosbuvir and regimens containing an HIV protease inhibitor/cobicistat and tenofovir may increase tenofovir concentrations. The safety of increased tenofovir concentrations in this setting has not been established. If coadministration with tenofovir is necessary, monitor for tenofovir-associated adverse reactions including frequent renal monitoring. 

No clinically significant interactions were observed when atazanavir/ritonavir and ledipasvir/sofosbuvir were coadministered (ledipasvir Cmax, AUC and Cmin increased by 98%, 113% and 136%; sofosbuvir Cmax decreased by 4% and AUC increased in by 8%; atazanavir Cmax, AUC and Cmin increased by 7%, 33% and 75%; ritonavir Cmax decreased by 7% whereas AUC and Cmin increased by 5% and 56%). Note, coadministration of ledipasvir/sofosbuvir and an HIV protease inhibitor/ritonavir with regimens containing tenofovir may increase tenofovir concentrations. The safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for tenofovir-associated adverse reactions including frequent renal monitoring.

Coadministration has not been studied but may increase atorvastatin concentrations due to inhibition of P-gp and/or BCRP by ledipasvir. A dose reduction of atorvastatin may be required. Statin-associated adverse events such as myopathy should be closely monitored.

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 but based on metabolism and clearance a clinically significant interaction is unlikely. Axitinib is a metabolised by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

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. Bedaquiline is metabolized by CYP3A4 and concentrations may increase due to mild inhibition of CYP3A4 by ledipasvir. 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 ledipasvir.

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. [Note, the European SmPC for bezafibrate contraindicates its use in significant hepatic disease.]

Coadministration of bictegravir/emtricitabine/tenofovir alafenamide (75/200/25 mg once daily) and ledipasvir/sofosbuvir (90/400 mg once daily) had no significant effect on the pharmacokinetics of bictegravir, emtricitabine, tenofovir alafenamide, ledipasvir, sofosbuvir and the GS-331007 metabolite (n=30). Tenofovir AUC, Cmax and Ctau increased by 67%, 43% and 81%, respectively, but these increases were not considered clinically relevant. Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and bictegravir alone (75 mg once daily) had no significant effect on bictegravir, ledipasvir, sofosbuvir and GS-331007 exposures.

Coadministration has not been studied but may increase concentrations of bilastine due to inhibition of P-gp by ledipasvir. 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 ledipasvir/sofosbuvir. The potential interaction can be resolved by giving bisacodyl at least 4 hours after ledipasvir/sofosbuvir. [Note: this interaction is not specific for ledipasvir/sofosbuvir, 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 ledipasvir is only a weak inhibitor of CYP3A4 in vitro. [Note, the European SmPC 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 has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bosutinib is metabolised principally by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. Both ledipasvir and sofosbuvir are transported by P-gp but any potential increase in exposure is unlikely to be of clinical significance. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Brinozolamide is metabolised by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

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 ledipasvir/sofosbuvir is not metabolised by CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bromperidol is metabolised by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro and no clinically significant interaction is expected.

Coadministration has not been studied but based on limited data a clinically significant interaction is unlikely. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Buprenorphine is also a substrate of P-gp. Concentrations of buprenorphine may increase due to mild inhibition of P-gp by ledipasvir, however, this is unlikely to be of clinical significance. Post hoc analysis of multiple clinical trials has revealed no impact on the occurrence of adverse effects in patients receiving buprenorphine with sofosbuvir-based therapies, including ledipasvir/sofosbuvir. No effect on ledipasvir/sofosbuvir concentrations is expected.

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 ledipasvir/sofosbuvir.

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 ledipasvir/sofosbuvir. Canagliflozin is a substrate and inhibitor of P-gp. Ledipasvir/sofosbuvir may increase canagliflozin concentrations due to mild inhibition of P-gp, but this is unlikely to be of clinical significance.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as candesartan is largely eliminated unchanged via urine and bile. [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 with ledipasvir/sofosbuvir has not been formally studied and is not recommended. Induction of P-gp by carbamazepine may significantly decrease plasma concentrations of ledipasvir and sofosbuvir; this may lead to reduced therapeutic effect and potential virological failure. Note - there are a small number of cases reported of patients who have remained on an inducing antiepileptic during HCV DAA therapy (including with ledipasvir/sofosbuvir) and achieved a sustained virologic response. Although every effort to prevent concomitant use of ledipasvir/sofosbuvir and potent inducers should be made, these cases have demonstrated that clinical cure may still be achieved in patients where coadministration cannot be avoided. Therapeutic drug level monitoring could be considered, where available.

Coadministration has not been studied. As both carvedilol and ledipasvir are inhibitors of P-gp, concentrations of both may be increased. The effect on ledipasvir is unlikely to be clinically significant but increased concentrations of carvedilol may cause toxicities including dizziness, bradycardia and GI upset. [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 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 ledipasvir/sofosbuvir levels via this enzyme are unlikely to be clinically significant.

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 metabolised primarily by CYP2C9 and ledipasvir/sofosbuvir do not inhibit CYP2C9. [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 metabolised by CYP2C8 and CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. 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. Ledipasvir/sofosbuvir does not affect these enzymes. [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 ledipasvir/sofosbuvir. [Note, although no interaction is anticipated, ECG monitoring is mandatory prior to treatment with chlorprothixene.]

Coadministration with ledipasvir/sofosbuvir has not been studied. Ciclosporin is a substrate of P-gp and inhibits hepatic uptake transport. Ledipasvir is both a substrate and inhibitor of P-gp. Coadministration may increase concentrations of ciclosporin and ledipasvir. No clinically significant drug interactions were observed with ciclosporin and sofosbuvir alone. No a priori dose adjustment of ledipasvir/sofosbuvir or ciclosporin is required. However, the pharmacokinetics of ciclosporin may be impacted by changes in liver function during DAA therapy and monitoring of ciclosporin levels is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cilazapril is rapidly converted to the active form, cilazaprilat, which is excreted unchanged in the 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 is expected to decrease ledipasvir concentrations. Cimetidine at a dose that does not exceed doses comparable to famotidine 40 mg twice daily should be given simultaneously with or 12 hours apart from ledipasvir/sofosbuvir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cisapride is metabolised by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. However use with caution and with close monitoring.

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 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 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 ledipasvir/sofosbuvir, 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. Clopidogrel is a prodrug that is converted to its active metabolites via CYPs 2C19, 3A4, 2B6, and 1A2. Ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. [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 intestinal CYP3A4 by ledipasvir 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 ledipasvir/sofosbuvir 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. Ledipasvir is a weak inhibitor of intestinal CYP3A4 in vitro, but this is unlikely to be clinically relevant. Ledipasvir and sofosbuvir are substrates of P-gp and BCRP. Colecalciferol does not interact with these pathways.

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 ledipasvir/sofosbuvir, but for any medication taken with colestyramine.]

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. Sofosbuvir is a prodrug and formation of its active metabolite is unlikely to be affected by comedications.

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 may increase dabigatran concentrations due to inhibition of P-gp by ledipasvir. No effect on ledipasvir/sofosbuvir concentrations is expected. Close monitoring (for signs of bleeding and anaemia) is recommended.

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 as dapagliflozin is metabolised by UGT1A9.

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.

Coadministration with darunavir/cobicistat has not been studied. Coadministration of cobicistat with elvitegravir (150/150 mg once daily) and ledipasvir/sofosbuvir (90/400 mg once daily) increased cobicistat Cmax, AUC and Cmin by 25%, 59% and 325%, respectively. Ledipasvir Cmax, AUC and Cmin increased by 63%, 78% and 91%, respectively and sofosbuvir Cmax and AUC increased by 33% and 36%. Note, coadministration of ledipasvir/sofosbuvir and regimens containing an HIV protease inhibitor/cobicistat and tenofovir may increase tenofovir concentrations. The safety of increased tenofovir concentrations in this setting has not been established. If coadministration with tenofovir is necessary, close monitoring for tenofovir-associated adverse reactions including frequent renal monitoring is recommended.

Coadministration with Symtuza has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Data from studies with ledipasvir/sofosbuvir and elvitegravir/cobicistat or emtricitabine/tenofovir alafenamide suggest no clinically significant interaction is expected.

No clinically significant interactions were observed when darunavir/ritonavir and ledipasvir or sofosbuvir were coadministered. Coadministration of darunavir/ritonavir (800/100 mg once daily) and ledipasvir alone (90 mg once daily) increased ledipasvir Cmax, AUC and Cmin by 45%, 39% and 39%; coadministration with sofosbuvir alone (400 mg single dose) increased sofosbuvir Cmax and AUC by 45% and 34%, respectively. No effect on darunavir or ritonavir pharmacokinetics was observed. Note, coadministration of ledipasvir/sofosbuvir and regimens containing an HIV protease inhibitor/ritonavir and tenofovir may increase tenofovir concentrations. The safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for tenofovir-associated adverse reactions including frequent renal monitoring.

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 ledipasvir/sofosbuvir.

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. Ledipasvir is only a weak inhibitor of intestinal CYP3A4 and is unlikely to affect this pathway to any clinically significant extent. Sofosbuvir does not affect CYP enzymes so a clinically significant interaction is unlikely. [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 unlikely. Desogestrel is a prodrug that requires activation to etonogestrel. Activation to etonogestrel is by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Ledipasvir is only a weak inhibitor of CYP3A4 in vitro and no clinically significant interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desvenlafaxine is a substrate of CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Biliary excretion of unchanged ledipasvir is a major route of elimination. Sofosbuvir is a prodrug and formation of its active metabolite is unlikely to be affected by comedications. Ledipasvir and sofosbuvir are substrates of P-gp and BCRP. Dexamethasone is a P-gp inducer in pre-clinical models but this is unlikely to be clinically relevant in this setting.

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. Ledipasvir/sofosbuvir 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 has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dienogest is a substrate of CYP3A4 but ledipasvir is only a weak inhibitor of CYP3A4 in vitro and no clinically significant interaction is expected.

Coadministration has not been studied but may increase digoxin concentrations due to inhibition of P-gp by ledipasvir. No effect on ledipasvir, sofosbuvir and GS-331007 is expected. Therapeutic concentration monitoring of digoxin is recommended.

Coadministration with diltiazem has not been studied. Although diltiazem is an inhibitor of P-gp, a clinically significant effect on ledipasvir and sofosbuvir (both P-gp substrates) is unlikely. However, concentrations of diltiazem may increase due to inhibition of P-gp by ledipasvir. Close monitoring of heart rate and blood pressure is recommended and consider dose reduction if required.

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 ledipasvir/sofosbuvir 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 and ledipasvir/sofosbuvir do not affect this pathway. [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. Ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration has not been studied. Although concentrations of dolutegravir may increase due to inhibition of P-gp and BCRP by ledipasvir, any increase is unlikely to be clinically significant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Although concentrations of dolutegravir may increase due to inhibition of P-gp and BCRP by ledipasvir, any increase is unlikely to be clinically significant. Coadministration of rilpivirine (in combination with emtricitabine and tenofovir) and ledipasvir/sofosbuvir had no effect on the pharmacokinetic parameters of rilpivirine, emtricitabine, ledipasvir or sofosbuvir. No dose adjustment of rilpivirine is required.

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 ledipasvir is only a weak inhibitor of CYP3A4 and no clinically significant interaction is expected.

Coadministration of doravirine (100 mg once daily) and ledipasvir/sofosbuvir (90/400 mg once daily) increased doravirine AUC, Cmax and Cmin by 15%, 11% and 24%, respectively (n=14). This small increase is not considered clinically meaningful. Doravirine did not significantly alter ledipasvir or sofosbuvir exposures (ledipasvir AUC and Cmax decreased by 8% and 9%; sofosbuvir AUC increased by 4%, Cmax decreased by 11%; AUC and Cmax of GS-331007 both increased by 3%).

Coadministration with Delstrigo has not been studied. Coadministration of doravirine (100 mg once daily) and ledipasvir/sofosbuvir (90/400 mg once daily) increased doravirine AUC, Cmax and Cmin by 15%, 11% and 24%, respectively. This small increase is not considered clinically meaningful. Doravirine did not significantly alter ledipasvir or sofosbuvir exposures. Similarly, coadministration of lamivudine and ledipasvir/sofosbuvir had no significant effect on the pharmacokinetics of lamivudine, ledipasvir and sofosbuvir. However, coadministration of tenofovir-DF with ledipasvir/sofosbuvir has been shown to increase tenofovir concentrations, especially when used with an HIV regimen containing a pharmacokinetic enhancer (ritonavir or cobicistat). Increased tenofovir exposure has also been shown with HIV regimens containing efavirenz and rilpivirine. The safety of increased tenofovir concentrations in these settings has not been established. The potential risks and benefits associated with coadministration should be considered, particularly in patients at increased risk of renal dysfunction. For patients receiving a boosted HIV protease inhibitor, consider an alternative HCV or antiretroviral therapy. If coadministration is necessary, monitor for tenofovir-associated adverse reactions, including frequent renal monitoring.

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 ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro and no clinically significant interaction is expected. [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 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. Note, the European SPC for doxazosin does not recommend it 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. Ledipasvir/sofosbuvir do not affect these enzymes. [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. Ledipasvir/sofosbuvir does not interact with these pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Drospirenone is metabolised mainly without involvement of CYP enzymes with little known involvement of transporters.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dulaglutide is degraded by general protein catabolism pathways therefore no metabolic interaction is expected. Dulaglutide delays gastric emptying but interaction studies showed no clinically significant effect on the absorption of concomitantly administered oral medicinal products. GLP-1 agonists such as dulaglutide also have the potential to inhibit gastric secretion and thereby impact drugs whose absorption is gastric dependent, such as ledipasvir. A reduction in ledipasvir exposure is possible with dulaglutide, 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. Duloxetine is metabolised by CYP1A2 and CYP2D6 and ledipasvir/sofosbuvir do not affect these enzymes. 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 ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. [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. Ebastine is metabolised by CY3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration has not been studied but may increase edoxaban concentrations due to inhibition of P-gp by ledipasvir. 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 of ledipasvir/sofosbuvir (90/400 mg once daily) and efavirenz/emtricitabine/tenofovir (600/200/300 mg once daily) had no effect on efavirenz, emtricitabine or sofosbuvir exposure but increased tenofovir AUC by 98% and decreased ledipasvir AUC by 34%. Note, if efavirenz and ledipasvir/sofosbuvir are used in a regimen containing tenofovir-DF no a priori dose adjustment is recommended, but the combination should be used with caution with frequent renal monitoring.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Eliglustat is metabolised primarily by CYP2D6 and to a lesser extent by CYP3A4. Ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro and no clinically significant interaction is expected.

Coadministration of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (150/150/200/10 mg once daily) and ledipasvir/sofosbuvir (90/400 mg once daily) increased ledipasvir and sofosbuvir AUC by 79% and 47%, respectively (most likely via inhibition of P-gp and/or BCRP by cobicistat). Ledipasvir/sofosbuvir increased elvitegravir and cobicistat AUC by 11% and 53%, respectively, but did not impact significantly the pharmacokinetics of tenofovir alafenamide (AUC decreased by 16%), tenofovir (AUC increased by 27%) or emtricitabine. The increase in ledipasvir and sofosbuvir are within the safety window. In addition, the increase in elvitegravir and cobicistat are considered as not clinically relevant based on the safety window. No dose adjustments are needed.

Coadministration of elvitegravir/cobicistat/emtricitabine/tenofovir-DF (150/150/200/300 mg once daily) and ledipasvir/sofosbuvir (90/400 mg once daily) decreased elvitegravir Cmax by 12%, but increased AUC and Cmin by 2% and 36%; cobicistat Cmax, AUC and Cmin increased by 25%, 59% and 325%, respectively. Ledipasvir Cmax, AUC and Cmin increased by 63%, 78% and 91%, respectively and sofosbuvir Cmax and AUC increased by 33% and 36%. The combination is also expected to increase tenofovir concentrations. The safety of increased tenofovir concentrations in this setting has not been established and coadministration is not recommended. The combination should be used with caution with frequent renal monitoring if other alternatives are not available.

Co-administration 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 ledipasvir is a mild to moderate inhibitor of P-gp, data with verapamil (a P-gp inhibitor) suggest a clinically relevant effect on empagliflozin is unlikely.

Coadministration of emtricitabine (in combination with rilpivirine/tenofovir or efavirenz/tenofovir) and ledipasvir/sofosbuvir had no clinically significant effects on the pharmacokinetic parameters of emtricitabine, ledipasvir or sofosbuvir. However, tenofovir exposure increased with these regimens and there should be usual renal monitoring. Coadministration of ledipasvir/sofosbuvir with emtricitabine in combination with elvitegravir, cobicistat, and tenofovir is also expected to increase tenofovir concentrations (see interaction with elvitegravir).

Coadministration with emtricitabine/tenofovir alafenamide alone has not been studied. A clinically significant interaction is unlikely based on studies with emtricitabine/tenofovir alafenamide in combination with elvitegravir/cobicistat or rilpivirine. 

Coadministration of emtricitabine/tenofovir-DF with ledipasvir/sofosbuvir has been shown to increase tenofovir concentrations, especially when used with an HIV regimen containing a pharmacokinetic enhancer (ritonavir or cobicistat), and also with regimens containing efavirenz or rilpivirine. The safety of increased tenofovir concentrations in these settings has not been established. The potential risks and benefits associated with coadministration should be considered, particularly in patients at increased risk of renal dysfunction. If other alternatives are not available, patients receiving ledipasvir/sofosbuvir concomitantly with tenofovir-DF and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir-DF. No dose adjustment is recommended for patients receiving ledipasvir/sofosbuvir concomitantly with tenofovir-DF and efavirenz or rilpivirine. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders and renal function should be closely monitored.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ledipasvir is primarily eliminated unchanged through biliary excretion. Entecavir is eliminated primarily in the urine by glomerular filtration and tubular secretion by OAT1.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Epoprostenol is rapidly hydrolysed; there does not appear to be any involvement with CYP isoenzymes or transporter proteins.

Coadministration has not been studied. Ergometrine is metabolised by CYP3A4 and although ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro, there is the potential for ergot toxicity.

Coadministration has not been studied. Erlotinib is a substrate for CYP3A4 and P-gp. Ledipasvir is only a weak inhibitor of CYP3A4 and no effect on erlotinib is expected by this pathway. However, concentrations may increase due to inhibition of P-gp by ledipasvir. Use with caution and with close monitoring for erlotinib mediated toxicity. A dose reduction may be required for erlotinib, particularly if toxicity is observed.

Coadministration has not been studied but based on metabolism and clearance a clinically relevant interaction is not anticipated. Sofosbuvir and ledipasvir are substrates for P-gp and BCRP but eslicarbazepine does not induce these transporters.

Coadministration has not been studied, but data with omeprazole show only a small decrease in ledipasvir exposure. Proton pump inhibitor doses comparable to omeprazole 20 mg can be administered simultaneously with ledipasvir/sofosbuvir. Proton pump inhibitors should not be taken before ledipasvir/sofosbuvir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolized by CYPs 3A4 and 1A2, and is glucuronidated, but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Estramustine is dephosphorylated and minimal data show it not to undergo any form of CYP metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. [Note, there is a concern of hepatotoxic adverse events in patients with HCV receiving anti-TNF agents. Use with caution and monitor liver enzymes and HCV viral load.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data suggest etelcalcetide is not metabolised by CYP450 nor transported by common transporter proteins.

Coadministration with the combination of ledipasvir and sofosbuvir has not been studied. In drug interaction studies conducted with ledipasvir and sofosbuvir separately there was an increase in exposure of ethinylestradiol of 20% with ledipasvir. However this is not considered to be a clinically significant interaction and hence no dose adjustment of oral contraceptives is required.

Coadministration with an etonogestrel-containing progestogen-only implant has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolized by CYP3A4. Ledipasvir is only a weak inhibitor of CYP3A4 in vitro and no clinically significant interaction is expected. Sofosbuvir does not affect CYP enzymes. 

Coadministration with etonogestrel as a combined vaginal ring (CVR) has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolized by CYP3A4 and is coformulated in the CVR with ethinylestradiol which is released at a dose of 0.015 mg/day. Ethinylestradiol is mainly metabolized by hydroxylation. Ledipasvir is only a weak inhibitor of CYP3A4 in vitro and no clinically significant interaction is expected. Sofosbuvir does not interact with these metabolic pathways.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Etoposide is mainly metabolised by CYP3A4 and UGT1A1 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Eucalyptus is a mild to moderate inhibitor of CYP3A4, however, a clinically relevant effect is unlikely at doses used for supplementation. Sofosbuvir is a prodrug and formation of its active metabolite is unlikely to be affected by comedications.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Exemestane is metabolised by CYP3A4 but coadministration with ketoconazole (a potent CYP3A4 inhibitor) showed no clinically significant effects and no effect is expected as ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration with exenatide has not been studied but based on metabolism and clearance a metabolic interaction is unlikely as exenatide is eliminated by glomerular filtration. GLP-1 agonists such as exenatide also have the potential to inhibit gastric secretion and thereby impact drugs whose absorption is gastric dependent, such as ledipasvir. A reduction in ledipasvir exposure is possible with exenatide, however, this is unlikely to be clinically significant. However, as exenatide slows gastric emptying it is advisable to take ledipasvir/sofosbuvir at least 1 hour before immediate-release exenatide injection. [Note: this interaction is not specific for ledipasvir/sofosbuvir, but for any medication taken with exenatide.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronidation. [Note, use of ezetemibe is not recommended in moderate to severe hepatic dysfunction.]

Coadministration of famotidine (40 mg single dose) simultaneously with or 12 hours prior to ledipasvir/sofosbuvir (90/400 mg single dose) was studied. Simultaneous coadministration decreased ledipasvir Cmax and AUC by 20% and 11% and increased sofosbuvir Cmax and AUC by 15% and 11%. When administered 12 hours apart, ledipasvir Cmax and AUC decreased by 17% and 2%, sofosbuvir Cmax was unchanged and sofosbuvir AUC decreased by 5%. Famotidine may be administered simultaneously with or 12 hours apart from ledipasvir/sofosbuvir at a dose that does not exceed 40 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Febuxostat is extensively metabolised by multiple P450 (CYPs 1A1, CYP1A2, CYP2C8 and CYP2C9) and UGT enzymes (UGTs 1A1, 1A8, and 1A9). A clinically significant interaction is unlikely as febuxostat is metabolised by multiple pathways.

Coadministration has not been studied but may increase felodipine concentrations due to inhibition of P-gp by ledipasvir. Caution is warranted and close monitoring of blood pressure and heart rate is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as fenofibrate is metabolised by multiple enzyme pathways (esterases, UGT2B7 and UGT1A1). [Note, fenofibrate is contraindicated in severe hepatic disease in its European SPC, and its US Prescribing Information contraindicates it in active liver disease.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fentanyl is metabolized by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro. Coadministration of ledipasvir with midazolam, another CYP3A4 substrate, had no effect on midazolam exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flibanserin is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19; ledipasvir/sofosbuvir does not affect these enzymes.

Coadministration has not been studied. Flucloxacillin is mainly eliminated renally, partly by glomerular filtration and partly by active secretion via OAT1. Flucloxacillin is thought to be a weak inducer of P-gp, particularly at higher doses (>2-3 g daily). A modest reduction in plasma concentrations of ledipasvir/sofosbuvir may be observed but this is unlikely to be clinically relevant unless flucloxacillin is prescribed at higher doses for a prolonged course (>10-14 days).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluconazole is mainly excreted in urine. Ledipasvir and sofosbuvir are substrates of P-gp and BCRP.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fludarabine phosphate is rapidly hydrolyzed (non-CYP mediated) to 2F-ara-A, the principal metabolite, which is then eliminated renally.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluinidone is metabolised by CYP2C9 (major) and CYP1A2 (minor) which are not affected by ledipasvir. However, close monitoring of INR is recommended as this may change as a result of improved liver function.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluoxetine is metabolised by CYP2D6 and ledipasvir and sofosbuvir are not known to affect this enzyme. Note, a lower or less frequent dose of fluoxetine should be considered in cases of hepatic insufficiency.

Coadministration has not been studied but may increase concentrations of fluvastatin due to inhibition of BCRP by ledipasvir. Caution is warranted and close monitoring is recommended. A reduced dose of fluvastatin should be considered. Note, use of fluvastatin in active liver disease is contraindicated.

Coadministration has not been studied but based on metabolism and clearance a clinically significant effect on the concentrations of fosamprenavir, ritonavir, ledipasvir or sofosbuvir is unlikely. Note, coadministration of ledipasvir/sofosbuvir and regimens containing a HIV protease inhibitor/ritonavir and tenofovir may increase tenofovir concentrations. The safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for tenofovir-associated adverse reactions including frequent renal monitoring.

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. Fosinopril is a prodrug metabolised in the liver by a non-CYP mechanism to the active metabolite.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gefitinib is a metabolized by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro and no clinically significant interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemfibrozil is metabolised via UGT2B7 and to date there is no evidence that ledipasvir is involved in this pathway. [Note, use of gemfibrozil in hepatic impairment is contraindicated.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Although in vitro data show gingerols moderately inhibit CYP3A4, a clinically relevant effect on DAA exposure is unlikely at standard dietary/supplement dosage. Sofosbuvir is a prodrug and formation of its active metabolite is unlikely to be affected by comedications. 

Co-administration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with standard doses (up to 240 mg) of Ginkgo biloba.

Coadministration of glecaprevir/pibrentasvir with other directly acting antivirals has not been studied and therefore cannot be recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glibenclamide is metabolized by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gliclazide is metabolized by CYPs 2C19 and 2C9 which are not affected by ledipasvir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glimepiride is metabolised by CYP2C9 and ledipasvir/sofosbuvir do not affect this enzyme.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glipizide is mainly metabolised by CYP2C9 and ledipasvir/sofosbuvir do not affect this enzyme.

Coadministration has not been studied. Glycerol phenylbutyrate is metabolised by pancreatic lipases, beta-oxidation, and glutamine conjugation, then eliminated in the urine. Glycerol phenylbutyrate has been shown to be a weak inducer of CYP3A4. This is unlikely to be clinically significant but should be considered in the event of a suboptimal response to HCV treatment. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant concentration is unlikely. Goldenseal is a CYP3A4 inhibitor however this is unlikely to affect ledipasvir/sofosbuvir. Sofosbuvir is a prodrug and formation of its active metabolite is unlikely to be affected by comedications. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. There is minimal metabolism of goserelin acetate and no clinically relevant accumulation with higher doses of the implant. Goserelin acetate is renally cleared with no dose alteration required in renal or hepatic impairment.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Granisetron is metabolised by CYP3A4 but ledipasvir is only a weak inhibitor of intestinal CYP3A4 in vitro.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Studies have shown that CYP3A4 inhibition by grape seed extract is mild, indicating a clinically relevant effect is unlikely. Sofosbuvir is a prodrug and formation of its active metabolite is unlikely to be affected by comedications. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Studies have shown variable CYP involvement with green tea metabolism but the overall effect is likely negligible.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Heroin is metabolised mainly by deacetylation.