Page 22 - EASL Recommendations on Treatment of Hepatitis C 2015 - Full version
P. 22
Asian ancestry exhibit higher simeprevir exposures. In clinical JOURNAL OF HEPATOLOGY
trials, higher simeprevir exposures have been associated with
increased frequency of adverse reactions, including rash and Recommendations
photosensitivity.
• The patients receiving PegIFN-α and ribavirin should
In the COSMOS trial [11], the most common (>10%) adverse be assessed for clinical side effects at each visit, while
reactions reported during 12 weeks treatment with simeprevir the haematological side effects should be assessed at
in combination with sofosbuvir without ribavirin were weeks 2 and 4 of therapy and at 4 to 8 week intervals
fatigue (25%), headache (21%), nausea (21%), insomnia (14%) thereafter (A1)
and pruritus (11%). Rash and photosensitivity were reported in
11% and 7% of subjects, respectively. During 24 weeks treatment • Renal function should be checked regularly in patients
with simeprevir in combination with sofosbuvir, dizziness receiving sofosbuvir (B1)
(16%) and diarrhoea (16%) were also commonly reported.
• Rashes and indirect bilirubin elevations without ALT
The safety and efficacy of simeprevir has not been studied in elevations may be seen with simeprevir (A1)
HCV-infected patients with severe renal impairment or end-stage
renal disease (creatinine clearance below 30 ml/min) or end- • Indirect bilirubin increases are rarely observed with the
stage renal disease, including patients requiring dialysis. combination of ritonavir-boosted paritaprevir, ombitasvir
and dasabuvir (A1)
Daclatasvir. The overall safety profile of daclatasvir, either in
combination with sofosbuvir with or without ribavirin or in com- • No dose adjustment of simeprevir, sofosbuvir and
ledispavir or daclatasvir is required in patients with mild,
bination with PegIFN-a and ribavirin, suggests that the most moderate or severe renal impairment. The appropriate
dose of sofosbuvir for patients with eGFR <30 ml/
common adverse reactions related to this drug are fatigue, head- min/1.73 m2 is not yet established (B2)
ache and nausea.
• No dose adjustment of sofosbuvir plus ledipasvir or
Sofosbuvir and ledipasvir. The proportion of patients who daclatasvir is required for patients with mild, moderate
permanently discontinued treatment due to adverse events dur- or severe (Child-Pugh C) hepatic impairment (B2)
ing treatment was 0%, <1%, and 1% for patients receiving sofosbu-
vir and ledipasvir for 8, 12, and 24 weeks, respectively; and <1%, • Higher exposures have been observed with the
0%, and 2% for patients receiving sofosbuvir and ledipasvir plus combination of ritonavir-boosted paritaprevir, ombitasvir
ribavirin combination therapy for 8, 12, and 24 weeks, and dasabuvir in patients with severe hepatic
respectively. impairment and their safety in this group requires further
study (B2)
In clinical studies, fatigue and headache were more common
in patients treated with sofosbuvir and ledipasvir compared to Monitoring drug-drug interactions
placebo. When sofosbuvir and ledipasvir were administered
with ribavirin, the most frequent adverse drug reactions were It is important to review all the drugs taken by the patient,
consistent with the known safety profile of ribavirin. Renal including over the counter preparations and recreational drugs.
function should be checked regularly in patients receiving Also, the following series of questions should be asked: (i) are
sofosbuvir. all the co-administered drugs necessary during the period of
HCV treatment (it may be possible to stop a drug, such as a statin,
Ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir. for a period of 8–12 weeks)? (ii) If not, is there an alternative in
Based on an integrated safety analysis, pruritus, fatigue, nausea, the same therapeutic class without a drug interaction? Finally,
asthenia and insomnia were the most common adverse events (iii) can a drug interaction be managed either by a change of dose
encountered in clinical trials with this combination. The more or a clear monitoring plan? For specific drug-drug interactions
frequent side effects were considered related to ribavirin, but and dose adjustments, see above.
pruritus was considered related to the 3 DAAs regimen.
Severe adverse events occurred in <2.5% of cases. Treatment dis- Recommendations
continuation due to adverse events occurred in 1–2% per study.
Haemoglobin reductions were consistent with ribavirin-induced • The efficacy and toxicity of concurrent drugs given
haemolysis, and largely resolved by post-treatment week 4. for comorbidities and potential drug-drug interactions
Haemoglobin reductions may require ribavirin dose should be monitored during treatment (A1)
reductions.
• When possible, an interacting co-medication should
Asymptomatic serum ALT elevations generally occurred be stopped for the duration of HCV treatment or the
within the first 4 weeks of treatment, but all resolved without interacting co-medication should be switched to an
intervention and with continued DAA treatment, none of them alternative drug with less interaction potential (B1)
being synchronous with bilirubin elevations. Transient increases
in indirect serum bilirubin were observed in patients receiving
ribavirin, related to the inhibition of bilirubin transporters
OATP1B1 and OATP1B3 by paritaprevir and associated
haemolysis. A greater frequency of total bilirubin increases
was observed in patients with cirrhosis. Oestrogen containing
medication use was associated with a greater risk of ALT eleva-
tions.
21
trials, higher simeprevir exposures have been associated with
increased frequency of adverse reactions, including rash and Recommendations
photosensitivity.
• The patients receiving PegIFN-α and ribavirin should
In the COSMOS trial [11], the most common (>10%) adverse be assessed for clinical side effects at each visit, while
reactions reported during 12 weeks treatment with simeprevir the haematological side effects should be assessed at
in combination with sofosbuvir without ribavirin were weeks 2 and 4 of therapy and at 4 to 8 week intervals
fatigue (25%), headache (21%), nausea (21%), insomnia (14%) thereafter (A1)
and pruritus (11%). Rash and photosensitivity were reported in
11% and 7% of subjects, respectively. During 24 weeks treatment • Renal function should be checked regularly in patients
with simeprevir in combination with sofosbuvir, dizziness receiving sofosbuvir (B1)
(16%) and diarrhoea (16%) were also commonly reported.
• Rashes and indirect bilirubin elevations without ALT
The safety and efficacy of simeprevir has not been studied in elevations may be seen with simeprevir (A1)
HCV-infected patients with severe renal impairment or end-stage
renal disease (creatinine clearance below 30 ml/min) or end- • Indirect bilirubin increases are rarely observed with the
stage renal disease, including patients requiring dialysis. combination of ritonavir-boosted paritaprevir, ombitasvir
and dasabuvir (A1)
Daclatasvir. The overall safety profile of daclatasvir, either in
combination with sofosbuvir with or without ribavirin or in com- • No dose adjustment of simeprevir, sofosbuvir and
ledispavir or daclatasvir is required in patients with mild,
bination with PegIFN-a and ribavirin, suggests that the most moderate or severe renal impairment. The appropriate
dose of sofosbuvir for patients with eGFR <30 ml/
common adverse reactions related to this drug are fatigue, head- min/1.73 m2 is not yet established (B2)
ache and nausea.
• No dose adjustment of sofosbuvir plus ledipasvir or
Sofosbuvir and ledipasvir. The proportion of patients who daclatasvir is required for patients with mild, moderate
permanently discontinued treatment due to adverse events dur- or severe (Child-Pugh C) hepatic impairment (B2)
ing treatment was 0%, <1%, and 1% for patients receiving sofosbu-
vir and ledipasvir for 8, 12, and 24 weeks, respectively; and <1%, • Higher exposures have been observed with the
0%, and 2% for patients receiving sofosbuvir and ledipasvir plus combination of ritonavir-boosted paritaprevir, ombitasvir
ribavirin combination therapy for 8, 12, and 24 weeks, and dasabuvir in patients with severe hepatic
respectively. impairment and their safety in this group requires further
study (B2)
In clinical studies, fatigue and headache were more common
in patients treated with sofosbuvir and ledipasvir compared to Monitoring drug-drug interactions
placebo. When sofosbuvir and ledipasvir were administered
with ribavirin, the most frequent adverse drug reactions were It is important to review all the drugs taken by the patient,
consistent with the known safety profile of ribavirin. Renal including over the counter preparations and recreational drugs.
function should be checked regularly in patients receiving Also, the following series of questions should be asked: (i) are
sofosbuvir. all the co-administered drugs necessary during the period of
HCV treatment (it may be possible to stop a drug, such as a statin,
Ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir. for a period of 8–12 weeks)? (ii) If not, is there an alternative in
Based on an integrated safety analysis, pruritus, fatigue, nausea, the same therapeutic class without a drug interaction? Finally,
asthenia and insomnia were the most common adverse events (iii) can a drug interaction be managed either by a change of dose
encountered in clinical trials with this combination. The more or a clear monitoring plan? For specific drug-drug interactions
frequent side effects were considered related to ribavirin, but and dose adjustments, see above.
pruritus was considered related to the 3 DAAs regimen.
Severe adverse events occurred in <2.5% of cases. Treatment dis- Recommendations
continuation due to adverse events occurred in 1–2% per study.
Haemoglobin reductions were consistent with ribavirin-induced • The efficacy and toxicity of concurrent drugs given
haemolysis, and largely resolved by post-treatment week 4. for comorbidities and potential drug-drug interactions
Haemoglobin reductions may require ribavirin dose should be monitored during treatment (A1)
reductions.
• When possible, an interacting co-medication should
Asymptomatic serum ALT elevations generally occurred be stopped for the duration of HCV treatment or the
within the first 4 weeks of treatment, but all resolved without interacting co-medication should be switched to an
intervention and with continued DAA treatment, none of them alternative drug with less interaction potential (B1)
being synchronous with bilirubin elevations. Transient increases
in indirect serum bilirubin were observed in patients receiving
ribavirin, related to the inhibition of bilirubin transporters
OATP1B1 and OATP1B3 by paritaprevir and associated
haemolysis. A greater frequency of total bilirubin increases
was observed in patients with cirrhosis. Oestrogen containing
medication use was associated with a greater risk of ALT eleva-
tions.
21
