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Table 4F. Drug-drug interactions between HCV DAAs and JOURNAL OF HEPATOLOGY
immunosuppressants.
in real-life settings. However, substantially higher simeprevir
SIM DCV SOF SOF/ 3D exposures occur in this group and simeprevir is not recom-
LDV mended for these patients.
Azathioprine ••••• No dose adjustment of simeprevir is required in patients with
Cyclosporine ••••• mild, moderate or severe renal impairment. The safety and effi-
cacy of simeprevir have not been studied in patients with a crea-
Etanercept ••••• tinine clearance below 30 ml/min or end-stage renal disease,
including patients on dialysis. However, because simeprevir is
Everolimus ••••• highly protein-bound, dialysis is unlikely to result in significant
removal of simeprevir.
Mycophenolate • • • • •
Adverse reactions with at least 3% higher frequency in
Sirolimus •••••
Tacrolimus ••••• patients receiving simeprevir in combination with PegIFN-a
SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus and ribavirin were rash (including photosensitivity), pruritus
ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir. and nausea. Because simeprevir is an inhibitor of the hepatic
Colour legend. Green: No clinically significant interaction expected. Amber: transporters OATP1B1 and MRP2 [23], mild, transient hyper-
Potential interaction which may require a dosage adjustment, altered timing of bilirubinaemia not accompanied by changes in other liver
administration or additional monitoring. Red: These drugs should not be co- parameters was observed in approximately 10% of cases.
administered.
Some drugs may require dose modifications dependent on hepatic function. Because the primary enzyme involved in the metabolism of
Please refer to the product label for individual drugs for dosing advice. simeprevir is CYP3A4, co-administration of simeprevir with sub-
The symbol (green, amber, red) used to rank the clinical significance of the stances that are moderate or strong inducers or inhibitors of
drug interaction is based on www.hep-druginteractions.org (University of CYP3A4 is not recommended as this may lead to significantly
Liverpool). For additional drug-drug interactions and for a more extensive range lower or higher exposure of simeprevir, respectively. A number
of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer of compounds are contra-indicated in patients receiving
to the above-mentioned website. simeprevir, including anticonvulsants (carbamazepine, oxcar-
bazepine, phenobarbital, phenytoin), antibiotics (erythromycin,
is unknown). The use of rosuvastatin is also not recommended clarithromycin, telithromycin), antimycobacterials (rifampin,
(thought to be due to inhibition of OATP by ledipasvir) and inter- rifabutin, rifapentine), systemically administered antifungals
actions with other statins cannot be excluded. It is important to (itraconazole, ketoconazole, posaconazole, fluconazole,
monitor carefully for statin adverse reactions. Since ledipasvir voriconazole), systemically administered dexamethasone, cis-
solubility decreases as pH increases, drugs that increase gastric apride, herbal products (milk thistle, St John’s wort) and a num-
pH (antacids, H2-receptor antagonists, proton pump inhibitors) ber of antiretroviral drugs, including cobicistat-based regimens,
are likely to decrease concentrations of ledipasvir. H2-receptor efavirenz, etravirine, nevirapine, ritonavir, and any HIV protease
antagonists can be given simultaneously or 12 h apart at a dose inhibitor, boosted or not by ritonavir. Raltegravir, maraviroc, ril-
not exceeding famotidine 40 mg and proton pump inhibitors pivirine, tenofovir, emtricitabine, lamivudine and abacavir have
simultaneously at a dose comparable to omeprazole 20 mg. no interactions with simeprevir and can thus be safely used in
patients receiving this drug. Dose adjustments are needed with
Ledipasvir/sofosbuvir may be given with all antiretrovirals. some antiarrhythmics, warfarin, calcium channel blockers, HMG
However, due to an increase in tenofovir concentrations when a Co-A reductase inhibitors and sedative/anxiolytics.
pharmacokinetic enhancer (ritonavir or cobicistat) is present in
an antiretroviral regimen, these combinations (i.e. atazanavir/ri- No dose changes are required when used in combination with
tonavir, darunavir/ritonavir, lopinavir/ritonavir, elvitegravir/ the immunosuppressants tacrolimus and sirolimus, although
cobicistat, darunavir/cobicistat, all in combination with teno- routine monitoring of blood concentrations of the immunosup-
fovir/emtricitabine) should be used with caution, with frequent pressant is recommended. In contrast, the use of simeprevir with
renal monitoring if other alternatives are not available. There cyclosporine resulted in significantly increased plasma concen-
are currently no safety and efficacy data of the combination of trations of simeprevir (due to hepatic uptake transporter inhibi-
sofosbuvir and ledipasvir administered with boosted HIV pro- tion), such that it is not recommended to co-administer the
tease-containing regimens and the interaction is not mitigated drugs.
by staggering administration by 12 h. Tenofovir is also increased
in efavirenz-containing regimens and caution is required. Daclatasvir should be administered at the dose of 60 mg (one
tablet), or 30 mg (one tablet) when a reduced dose is needed,
Simeprevir should be administered at the dose of 150 mg once per day. Approximately 90% of daclatasvir is eliminated in
(one capsule) once per day. Simeprevir is extensively bound to faeces (half as unchanged drug) and less than 10% is excreted
plasma proteins (>99.9%), primarily to albumin. Simeprevir pri- in the urine (primarily as unchanged drug).
marily undergoes oxidative metabolism by the hepatic CYP3A
system. Elimination occurs via biliary excretion, whereas renal The pharmacokinetics of daclatasvir in non-HCV-infected
excretion is negligible. subjects with mild (Child-Pugh A), moderate (Child-Pugh B),
and severe (Child-Pugh C) hepatic impairment indicate that the
The mean steady-state AUC of simeprevir is 2.4-fold higher in exposure of total daclatasvir (free and protein-bound drug) is
HCV-uninfected subjects with moderate hepatic impairment lower in subjects with hepatic impairment. However, hepatic
(Child-Pugh B). It is 5.2-fold higher in HCV-uninfected subjects impairment does not have a clinically significant effect on the
with severe hepatic impairment (Child-Pugh C). Simeprevir has free drug concentrations of daclatasvir. Thus, no dose adjustment
not been extensively studied in such patients, but has been used of daclatasvir is required for patients with mild (Child-Pugh A),
moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic
impairment.
Journal of Hepatology 2015 vol. xxx j xxx–xxx 9
Please cite this article in press as: EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol (2015), http://dx.doi.org/10.1016/
j.jhep.2015.03.025
immunosuppressants.
in real-life settings. However, substantially higher simeprevir
SIM DCV SOF SOF/ 3D exposures occur in this group and simeprevir is not recom-
LDV mended for these patients.
Azathioprine ••••• No dose adjustment of simeprevir is required in patients with
Cyclosporine ••••• mild, moderate or severe renal impairment. The safety and effi-
cacy of simeprevir have not been studied in patients with a crea-
Etanercept ••••• tinine clearance below 30 ml/min or end-stage renal disease,
including patients on dialysis. However, because simeprevir is
Everolimus ••••• highly protein-bound, dialysis is unlikely to result in significant
removal of simeprevir.
Mycophenolate • • • • •
Adverse reactions with at least 3% higher frequency in
Sirolimus •••••
Tacrolimus ••••• patients receiving simeprevir in combination with PegIFN-a
SIM, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SOF/LDV, sofosbuvir plus and ribavirin were rash (including photosensitivity), pruritus
ledipasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir. and nausea. Because simeprevir is an inhibitor of the hepatic
Colour legend. Green: No clinically significant interaction expected. Amber: transporters OATP1B1 and MRP2 [23], mild, transient hyper-
Potential interaction which may require a dosage adjustment, altered timing of bilirubinaemia not accompanied by changes in other liver
administration or additional monitoring. Red: These drugs should not be co- parameters was observed in approximately 10% of cases.
administered.
Some drugs may require dose modifications dependent on hepatic function. Because the primary enzyme involved in the metabolism of
Please refer to the product label for individual drugs for dosing advice. simeprevir is CYP3A4, co-administration of simeprevir with sub-
The symbol (green, amber, red) used to rank the clinical significance of the stances that are moderate or strong inducers or inhibitors of
drug interaction is based on www.hep-druginteractions.org (University of CYP3A4 is not recommended as this may lead to significantly
Liverpool). For additional drug-drug interactions and for a more extensive range lower or higher exposure of simeprevir, respectively. A number
of drugs, detailed pharmacokinetic interaction data and dosage adjustments, refer of compounds are contra-indicated in patients receiving
to the above-mentioned website. simeprevir, including anticonvulsants (carbamazepine, oxcar-
bazepine, phenobarbital, phenytoin), antibiotics (erythromycin,
is unknown). The use of rosuvastatin is also not recommended clarithromycin, telithromycin), antimycobacterials (rifampin,
(thought to be due to inhibition of OATP by ledipasvir) and inter- rifabutin, rifapentine), systemically administered antifungals
actions with other statins cannot be excluded. It is important to (itraconazole, ketoconazole, posaconazole, fluconazole,
monitor carefully for statin adverse reactions. Since ledipasvir voriconazole), systemically administered dexamethasone, cis-
solubility decreases as pH increases, drugs that increase gastric apride, herbal products (milk thistle, St John’s wort) and a num-
pH (antacids, H2-receptor antagonists, proton pump inhibitors) ber of antiretroviral drugs, including cobicistat-based regimens,
are likely to decrease concentrations of ledipasvir. H2-receptor efavirenz, etravirine, nevirapine, ritonavir, and any HIV protease
antagonists can be given simultaneously or 12 h apart at a dose inhibitor, boosted or not by ritonavir. Raltegravir, maraviroc, ril-
not exceeding famotidine 40 mg and proton pump inhibitors pivirine, tenofovir, emtricitabine, lamivudine and abacavir have
simultaneously at a dose comparable to omeprazole 20 mg. no interactions with simeprevir and can thus be safely used in
patients receiving this drug. Dose adjustments are needed with
Ledipasvir/sofosbuvir may be given with all antiretrovirals. some antiarrhythmics, warfarin, calcium channel blockers, HMG
However, due to an increase in tenofovir concentrations when a Co-A reductase inhibitors and sedative/anxiolytics.
pharmacokinetic enhancer (ritonavir or cobicistat) is present in
an antiretroviral regimen, these combinations (i.e. atazanavir/ri- No dose changes are required when used in combination with
tonavir, darunavir/ritonavir, lopinavir/ritonavir, elvitegravir/ the immunosuppressants tacrolimus and sirolimus, although
cobicistat, darunavir/cobicistat, all in combination with teno- routine monitoring of blood concentrations of the immunosup-
fovir/emtricitabine) should be used with caution, with frequent pressant is recommended. In contrast, the use of simeprevir with
renal monitoring if other alternatives are not available. There cyclosporine resulted in significantly increased plasma concen-
are currently no safety and efficacy data of the combination of trations of simeprevir (due to hepatic uptake transporter inhibi-
sofosbuvir and ledipasvir administered with boosted HIV pro- tion), such that it is not recommended to co-administer the
tease-containing regimens and the interaction is not mitigated drugs.
by staggering administration by 12 h. Tenofovir is also increased
in efavirenz-containing regimens and caution is required. Daclatasvir should be administered at the dose of 60 mg (one
tablet), or 30 mg (one tablet) when a reduced dose is needed,
Simeprevir should be administered at the dose of 150 mg once per day. Approximately 90% of daclatasvir is eliminated in
(one capsule) once per day. Simeprevir is extensively bound to faeces (half as unchanged drug) and less than 10% is excreted
plasma proteins (>99.9%), primarily to albumin. Simeprevir pri- in the urine (primarily as unchanged drug).
marily undergoes oxidative metabolism by the hepatic CYP3A
system. Elimination occurs via biliary excretion, whereas renal The pharmacokinetics of daclatasvir in non-HCV-infected
excretion is negligible. subjects with mild (Child-Pugh A), moderate (Child-Pugh B),
and severe (Child-Pugh C) hepatic impairment indicate that the
The mean steady-state AUC of simeprevir is 2.4-fold higher in exposure of total daclatasvir (free and protein-bound drug) is
HCV-uninfected subjects with moderate hepatic impairment lower in subjects with hepatic impairment. However, hepatic
(Child-Pugh B). It is 5.2-fold higher in HCV-uninfected subjects impairment does not have a clinically significant effect on the
with severe hepatic impairment (Child-Pugh C). Simeprevir has free drug concentrations of daclatasvir. Thus, no dose adjustment
not been extensively studied in such patients, but has been used of daclatasvir is required for patients with mild (Child-Pugh A),
moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic
impairment.
Journal of Hepatology 2015 vol. xxx j xxx–xxx 9
Please cite this article in press as: EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol (2015), http://dx.doi.org/10.1016/
j.jhep.2015.03.025
