Glecaprevir and Pibrentasvir

Co-administration of Maviret with medicinal products that are moderate inducers P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations (e.g. oxcarbazepine, eslicarbazepine, lumacaftor, crizotinib). Co-administration of moderate inducers is not recommended.

Glecaprevir and pibrentasvir are substrates of the efflux transporters P-gp and/or BCRP. Glecaprevir is also a substrate of the hepatic uptake transporters OATP1B1/3. Co-administration of glecaprevir/pibrentasvir with medicinal products that inhibit P-gp and BCRP (e.g. ciclosporin, cobicistat, dronedarone, itraconazole, ketoconazole, ritonavir) may slow elimination of glecaprevir and pibrentasvir and thereby increase plasma exposure of the antivirals. Medicinal products that inhibit OATP1B1/3 (e.g. elvitegravir, ciclosporin, darunavir, lopinavir) increase systemic concentrations of glecaprevir.

Glecaprevir/pibrentasvir combination is not recommended in patients with moderate hepatic impairment (Child Pugh-B).

Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with glecaprevir/pibrentasvir.

Co-administration is not recommended.

Effect on medicinal product levels:

Lopinavir/ritonavir 400/100 mg twice daily:

↑ glecaprevir, C_max: 2.55 (1.84, 3.52), AUC: 4.38 (3.02, 6.36), C_min: 18.6 (10.4, 33.5)

↑ pibrentasvir, C_max: 1.40 (1.17, 1.67), AUC: 2.46 (2.07, 2.92), C_min: 5.24 (4.18, 6.58)

Glecaprevir/pibrentasvir is not recommended for use in patients requiring stable ciclosporin doses >100 mg per day. If the combination is unavoidable, use can be considered if the benefit outweighs the risk with a close clinical monitoring.

Effect on medicinal product levels:

Ciclosporin 100 mg single dose:

↑ glecaprevir^a, C_max: 1.30 (0.95, 1.78), AUC: 1.37 (1.13, 1.66), C_min: 1.34 (1.12, 1.60)

↑ pibrentasvir, C_max: ↔, AUC: ↔, C_min 1.26 (1.15, 1.37)

Ciclosporin 400 mg single dose:

↑ glecaprevir, C_max: 4.51 (3.63, 6.05), AUc: 5.08 (4.11, 6.29), C_min: --

↑ pibrentasvir, C_max: ↔, AUC: 1.93 (1.78, 2.09), C_min: --

^a HCV-infected transplant recipients who received a median ciclosporin dose of 100 mg per day had increased glecaprevir exposures to 2.4-fold of those not receiving ciclosporin.

Co-administration with darunavir is not recommended.

Effect on medicinal product levels:

Darunavir + ritonavir 800/100 mg once daily:

↑ glecaprevir, C_max: 3.09 (2.26, 4.20), AUC: 4.97 (3.62, 6.84), C_min: 8.24 (4.40, 15.4)

↔ pibrentasvir, C_max: ↔, AUC: ↔, C_min: 1.66 (1.25, 2.21)

Caution and therapeutic concentration monitoring of digoxin is recommended.

Effect on medicinal product level:

Digoxin 0.5 mg single dose (Inhibition of P-gp): ↑ digoxin

C_max: 1.72 (1.45, 2.04), AUC: 1.48 (1.40, 1.57), C_min: --

Co-administration with efavirenz may lead to reduced therapeutic effect of glecaprevir/pibrentasvir combination and is not recommended.

No clinically significant interactions are expected with tenofovir disoproxil fumarate.

Efavirenz/emtricitabine/tenofovir disoproxil fumarate 600/200/300 mg once daily:

↑ tenofovir, C_max: ↔, AUC: 1.29 (1.23, 1.35), C_min: 1.38 (1.31, 1.46)

The effect of efavirenz/emtricitabine/tenofovir disoproxil fumarate on glecaprevir and pibrentasvir was not directly quantified within this study, but glecaprevir and pibrentasvir exposures were significantly lower than historical controls.

Interactions with fluvastatin and pitavastatin are likely and caution is recommended during the combination. A low dose of the statin is recommended at the initiation of the direct acting antiviral (DAA) treatment.

Effect on medicinal product levels: Not studied.

Expected: ↑ fluvastatin and ↑ pitavastatin

Co-administration is not recommended. If used, lovastatin should not exceed a dose of 20 mg/day and patients should be monitored.

Lovastatin 10 mg once daily (Inhibition of OATP1B1/3, Pgp, BCRP):

↑ lovastatin, C_max: ↔, AUC: 1.70 (1.40, 2.06), C_min: --

↑ lovastatin acid, C_max: 5.73 (4.65, 7.07), AUC: 4.10 (3.45, 4.87), C_min: --

Caution is recommended. Pravastatin dose should not exceed 20 mg per day and rosuvastatin dose should not exceed 5 mg per day.

Pravastatin 10 mg once daily (Inhibition of OATP1B1/3):

↑ pravastatin, C_max: 2.23 (1.87, 2.65), AUC: 2.30 (1.91, 2.76), C_min: --

Rosuvastatin 5 mg once daily (Inhibition of OATP1B1/3, BCRP):

↑ rosuvastatin, C_max: 5.62 (4.80, 6.59), AUC: 2.15 (1.88, 2.46), C_min: --

The combination of glecaprevir/pibrentasvir with tacrolimus should be used with caution. Increase of tacrolimus exposure is expected. Therefore, a therapeutic drug monitoring of tacrolimus is recommended and a dose adjustment of tacrolimus made accordingly.

Effect on medicinal product levels:

Tacrolimus 1 mg single dose (CYP3A4 and P-gp inhibition):

↑ tacrolimus, C_max: 1.50 (1.24, 1.82), AUC: 1.45 (1.24, 1.70), C_min: --

↔ glecaprevir, C_max: ↔, AUC: ↔, C_min: ↔

↔ pibrentasvir, C_max: ↔, AUC: ↔, C_min: ↔

HBV/HCV co-infected patients are at risk of HBV reactivation, and should, therefore, be monitored and managed according to current clinical guidelines.

Genotype 1-infected (and a very limited number of genotype 4-infected) patients with prior failure on regimens that may confer resistance to glecaprevir/pibrentasvir were studied in studies MAGELLAN-1 and B16-439. The risk of failure was, as expected, highest for those exposed to both classes. A resistance algorithm predictive of the risk for failure by baseline resistance has not been established. Accumulating double class resistance was a general finding for patients who failed re-treatment with glecaprevir/pibrentasvir in MAGELLAN-1.

No re-treatment data is available for patients infected with genotypes 2, 3, 5 or 6. Glecaprevir/pibrentasvir is not recommended for the re-treatment of patients with prior exposure to NS3/4A- and/or NS5A inhibitors.

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

A 12-week treatment duration has been evaluated and is recommended in liver or kidney transplant recipients with or without cirrhosis. A 16-week treatment duration should be considered in genotype 3-infected patients who are treatment experienced with peg-IFN + ribavirin +/- sofosbuvir, or sofosbuvir + ribavirin.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of glecaprevir or pibrentasvir in pregnant women.

Studies in rats/mice with glecaprevir or pibrentasvir do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Maternal toxicity associated with embryo-foetal loss has been observed in the rabbit with glecaprevir which precluded evaluation of glecaprevir at clinical exposures in this species. As a precautionary measure, glecaprevir/pibrentasvir use is not recommended in pregnancy.

It is unknown whether glecaprevir or pibrentasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of glecaprevir and pibrentasvir in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from glecaprevir/pibrentasvir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

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

Glecaprevir/pibrentasvir has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

In pooled Phase 2 and 3 clinical studies of adult subjects receiving glecaprevir/pibrentasvir with genotype 1, 2, 3, 4, 5 or 6 HCV infection the most commonly reported adverse reactions (incidence ≥10%) were headache and fatigue. Less than 0.1% of subjects treated with glecaprevir/pibrentasvir had serious adverse reactions (transient ischaemic attack). The proportion of subjects treated with glecaprevir/pibrentasvir who permanently discontinued treatment due to adverse reactions was 0.1%.

Tabulated list of adverse reactions

The following adverse reactions were identified in registrational Phase 2 and 3 studies in HCV-infected adults with or without cirrhosis treated with glecaprevir/pibrentasvir for 8, 12 or 16 weeks, or during postmarketing experience. 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), very rare (<1/10 000) or not known (cannot be estimated from the available data).

Adverse reactions identified with glecaprevir/pibrentasvir:

Description of selected adverse reactions

Adverse reactions in subjects with severe renal impairment including subjects on dialysis

The safety of glecaprevir/pibrentasvir in subjects with chronic kidney disease (including subjects on dialysis) and genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection with compensated liver disease (with or without cirrhosis) was assessed in adults in EXPEDITION-4 (n=104) and EXPEDITION-5 (n=101). The most common adverse reactions in subjects with severe renal impairment were pruritus (17%) and fatigue (12%) in EXPEDITION-4 and pruritus (14.9%) in EXPEDITION-5.

Adverse reactions in subjects with liver or kidney transplant

The safety of glecaprevir/pibrentasvir was assessed in 100 post-liver or -kidney transplant adult recipients with genotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was comparable to that observed in subjects in the Phase 2 and 3 studies. Adverse reactions observed in greater than or equal to 5% of subjects receiving glecaprevir/pibrentasvir for 12 weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%).

Safety in HCV/HIV-1 co-infected subjects

The overall safety profile in HCV/HIV-1 co-infected adult subjects (ENDURANCE-1 and EXPEDITION-2) was comparable to that observed in HCV mono-infected adult subjects.

Paediatric population

The safety of glecaprevir/pibrentasvir in HCV GT1-6 infected adolescents is based on data from a Phase ⅔ openlabel study in 47 subjects aged 12 years to <18 years treated with glecaprevir/pibrentasvir tablets for 8 to 16 weeks (DORA Part 1). The adverse reactions observed were comparable with those observed in clinical studies of glecaprevir/pibrentasvir in adults.

The safety of glecaprevir/pibrentasvir in HCV GT1-6 infected children aged 3 to less than 12 years is based on data from a Phase ⅔ open-label study in 80 subjects aged 3 to <12 years treated with weight-based glecaprevir/pibrentasvir coated granules for 8, 12, or 16 weeks (DORA Part 2). The pattern of adverse reactions observed was comparable with that observed in clinical studies of glecaprevir/pibrentasvir film-coated tablets in adolescents and adults. Diarrhoea, nausea and vomiting occurred at a slightly higher frequency in paediatric subjects compared to adolescents (adverse reactions: 3.8% vs. 0%, 3.8% vs. 0%, and 7.5% vs. 2.1% respectively).

Serum bilirubin elevations

Elevations in total bilirubin of at least 2x upper limit normal (ULN) were observed in 1.3% of subjects related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubin elevations were asymptomatic, transient, and typically occurred early during treatment. Bilirubin elevations were predominantly indirect and not associated with ALT elevations. Direct hyperbilirubinemia was reported in 0.3% of subjects.