Elbasvir and Grazoprevir

Elbasvir and grazoprevir are inhibitors of the drug transporter BCRP at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates.

Grazoprevir’s weak inhibition of CYP3A may increase levels of CYP3A substrates. In addition, the plasma concentrations of drugs that are CYP3A substrates may be decreased by improvement in liver function during DAA therapy, related to clearance of HCV. Therefore, close monitoring and potential dose adjustment of CYP3A substrates with a narrow therapeutic index (e.g., calcineurin inhibitors) may be required during therapy, as drug levels may change.

Co-administration of elbasvir/grazoprevir with P-gp inhibitors is expected to have a minimal effect on the plasma concentrations of elbasvir/grazoprevir.

Co-administration of elbasvir/grazoprevir with strong CYP3A inhibitors increases elbasvir and grazoprevir plasma concentrations, and co-administration is not recommended.

As liver function may change during treatment with elbasvir/grazoprevir, a close monitoring of International Normalised Ratio (INR) values is recommended.

The dose of atorvastatin should not exceed a daily dose of 20 mg when co-administered with elbasvir/grazoprevir.

Concentrations of dabigatran may increase when co-administered with elbasvir, with possible increased bleeding risk. Clinical and laboratory monitoring is recommended.

The dose of fluvastatin, lovastatin, or simvastatin should not exceed a daily dose of 20 mg when co-administered with elbasvir/grazoprevir.

Co-administration is not recommended.

The dose of rosuvastatin should not exceed a daily dose of 10 mg when co-administered with elbasvir/grazoprevir.

Co-administration of elbasvir/grazoprevir with sunitinib may increase sunitinib concentrations leading to an increased risk of sunitinib-associated adverse events. Use with caution; dose adjustment of sunitinib may be required.

Frequent monitoring of tacrolimus whole blood concentrations, changes in renal function, and tacrolimus-associated adverse events upon the initiation of coadministration is recommended. Close monitoring and potential dose adjustment of tacrolimus may be required during therapy, as tacrolimus levels may decrease related to clearance of HCV.

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.

The efficacy of elbasvir/grazoprevir has not been demonstrated in HCV genotypes 2, 3, 5 and 6. Elbasvir/grazoprevir is not recommended in patients infected with these genotypes.

Diabetics may experience improved glucose control potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral (DAA) treatment. Glucose levels of diabetic patients initiating DAA therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when DAA therapy is initiated.

There are no adequate and well-controlled studies with elbasvir/grazoprevir in pregnant women. Animal studies do not indicate harmful effects with respect to reproductive toxicity. Because reproduction animal studies are not always predictive of human response, elbasvir/grazoprevir should be used only if the potential benefit justifies the potential risk to the fetus.

If elbasvir/grazoprevir is co-administered with ribavirin, the information for ribavirin with regard to pregnancy testing and pregnancy also applies to this combination regimen (refer to the Summary of Product Characteristics for the co-administered medicinal product for additional information).

It is unknown whether elbasvir or grazoprevir and their metabolites are excreted in human milk. Available pharmacokinetic data in animals has shown excretion of elbasvir and grazoprevir in milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from elbasvir/grazoprevir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

If elbasvir/grazoprevir is co-administered with ribavirin, the information for ribavirin with regard to breast-feeding also applies to this combination regimen (refer to the Summary of Product Characteristics for the co-administered medicinal product for additional information).

Women of childbearing potential / contraception in males and females

When elbasvir/grazoprevir is used in combination with ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded.

Fertility

No human data on the effect of elbasvir and grazoprevir on fertility are available. Animal studies do not indicate harmful effects of elbasvir or grazoprevir on fertility at elbasvir and grazoprevir exposures higher than the exposure in humans at the recommended clinical dose.

Elbasvir/grazoprevir (administered alone or in combination with ribavirin) is not likely to have an effect on the ability to drive and use machines. Patients should be informed that fatigue has been reported during treatment with elbasvir/grazoprevir.

Summary of the safety profile

The safety of elbasvir/grazoprevir was assessed based on 3 placebo-controlled studies and 7 uncontrolled Phase 2 and 3 clinical studies in approximately 2,000 subjects with chronic hepatitis C infection with compensated liver disease (with or without cirrhosis).

In clinical studies, the most commonly reported adverse reactions (greater than 10%) were fatigue and headache. Less than 1% of subjects treated with elbasvir/grazoprevir with or without ribavirin had serious adverse reactions (abdominal pain, transient ischaemic attack and anaemia). Less than 1% of subjects treated with elbasvir/grazoprevir with or without ribavirin permanently discontinued treatment due to adverse reactions. The frequency of serious adverse reactions and discontinuations due to adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis.

When elbasvir/grazoprevir was studied with ribavirin, the most frequent adverse reactions to elbasvir/grazoprevir + ribavirin combination therapy were consistent with the known safety profile of ribavirin.

Tabulated summary of adverse reactions

The following adverse reactions were identified in patients taking elbasvir/grazoprevir without ribavirin for 12 weeks. The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000).

Adverse reactions identified with elbasvir/grazoprevir^*:

^* Based on pooled data from patients treated with elbasvir/grazoprevir for 12 weeks without ribavirin.

Description of selected adverse reactions

Laboratory abnormalities

Changes in selected laboratory parameters are described in the following table.

Selected treatment emergent laboratory abnormalities:

^* Based on pooled data from patients treated with elbasvir/grazoprevir for 12 weeks without ribavirin
^† ULN: Upper limit of normal according to testing laboratory

Serum Late ALT elevations

During clinical studies with elbasvir/grazoprevir with or without ribavirin, regardless of treatment duration, <1% (13/1,690) of subjects experienced elevations of ALT from normal levels to greater than 5 times the ULN, generally at or after treatment week 8 (mean onset time 10 weeks, range 6-12 weeks). These late ALT elevations were typically asymptomatic. Most late ALT elevations resolved with ongoing therapy with elbasvir/grazoprevir or after completion of therapy. The frequency of late ALT elevations was higher in subjects with higher grazoprevir plasma concentration (see sections 4.4, 4.5 and 5.2). The incidence of late ALT elevations was not affected by treatment duration. Cirrhosis was not a risk factor for late ALT elevations. Less than 1% of subjects treated with elbasvir/grazoprevir with or without ribavirin experienced ALT elevations >2.5 – 5 times the ULN during treatment; there were no treatment discontinuations due to these ALT elevations.

Paediatric population

The safety assessment of elbasvir/grazoprevir in paediatric patients aged 12 years and older is based on data from a Phase 2b, open-label clinical study that enrolled 22 patients who were treated with elbasvir/grazoprevir for 12 weeks.The adverse reactions observed were consistent with those observed in clinical studies of elbasvir/grazoprevir in adults.