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