Virpas

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VĪRPAS (VIRPAS)

Composition:

Active substances: ledipasvir, sofosbuvir;

One film-coated tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir;

Excipients: copovidone, lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate; tablet coating: Opadry II Brown (85F565071).

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties: film-coated, brown-colored, oval-shaped tablets with a bevelled edge, embossed with «SL» on one side and smooth on the other.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Direct-acting antiviral agents. Antiviral agents for the treatment of hepatitis C virus (HCV).

ATC code: J05AP51.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ledipasvir is an HCV inhibitor whose target is the HCV NS5A protein, which is required for HCV RNA replication and virion assembly. Since NS5A lacks enzymatic activity, biochemical confirmation of NS5A inhibition by ledipasvir has not been possible to date. In vitro studies of selection and cross-resistance have demonstrated that ledipasvir acts on NS5A as its target.

Sofosbuvir is a pangenotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication.

Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator of RNA synthesis. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases and is not an inhibitor of mitochondrial RNA polymerase.

Antiviral activity

The EC50 values of ledipasvir and sofosbuvir against full-length or chimeric replicons encoding NS5A and NS5B sequences in clinical isolates are presented in Table 1. The addition of 40% human serum did not affect the antiviral activity of sofosbuvir, but reduced the antiviral activity of ledipasvir against HCV genotype 1a replicons 12-fold.

Table 1. Activity of ledipasvir and sofosbuvir against chimeric replicons

a Transient replicons containing NS5A or NS5B isolated from patients.

b Chimeric replicons carrying NS5A genes from genotypes 2b, 5a, 6a, and 6e were used in studies of ledipasvir, and chimeric replicons carrying NS5B genes from genotypes 2b, 5a, or 6a were used in studies of sofosbuvir.

Resistance

In cell cultures

HCV replicons with reduced sensitivity to ledipasvir were selected in cell cultures for genotypes 1a and 1b. Reduced sensitivity to ledipasvir was associated with the primary NS5A substitution Y93H in genotypes 1a and 1b. Additionally, substitution Q30E emerged in genotype 1a replicons. Site-specific mutagenesis of NS5A RAVs showed that substitutions leading to >100- to ≤1000-fold changes in sensitivity to ledipasvir included Q30H/R, L31I/M/V, P32L, and Y93T in genotype 1a and P58D and Y93S in genotype 1b; substitutions leading to >1000-fold changes included M28A/G, Q30E/G/K, H58D, Y93C/H/N/S in genotype 1a and A92K and Y93H in genotype 1b.

HCV replicons with reduced sensitivity to sofosbuvir were selected in cell cultures for various genotypes, including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced sensitivity to sofosbuvir was associated with the primary NS5B substitution S282T in replicons of all studied genotypes. Site-specific mutagenesis of the S282T substitution in replicons of 8 genotypes resulted in a 2- to 18-fold reduction in sensitivity to sofosbuvir and a reduction in viral replication capacity by 89–99 % compared to the corresponding wild type.

In clinical trials, genotype 1

Results of a pooled analysis of patients who received ledipasvir/sofosbuvir in phase 3 trials (ION-3, ION-1, and ION-2) showed that 37 patients (29 with genotype 1a and 8 with genotype 1b) were eligible for resistance analysis due to virologic failure or premature discontinuation of study drug with HCV RNA levels >1000 IU/mL. Deep sequencing data for NS5A and NS5B post-baseline (analysis threshold 1 %) were obtained for 37/37 and 36/37 patients, respectively.

NS5A resistance-associated variants (RAVs) detected post-baseline were identified in isolates from 29/37 patients (22/29 with genotype 1a and 7/8 with genotype 1b) who did not achieve sustained virologic response (SVR). Of the 29 patients with genotype 1a eligible for resistance analysis, one or more NS5A RAVs at positions K24, M28, Q30, L31, S38, and Y93 were present at the time of failure in 22/29 (76 %) patients, while no NS5A RAVs were detected at failure in the remaining 7/29 patients. The most common variants were Q30R, Y93H, and L31M. Of the 8 patients with genotype 1b eligible for resistance analysis, one or more NS5A RAVs at positions L31 and Y93 were present at failure in 7/8 (88 %) patients, while no NS5A RAVs were detected at failure in 1/8 patients. The most common variant was Y93H. Among the 8 patients who lacked NS5A RAVs at failure, 7 patients received an 8-week treatment course (n = 3 with ledipasvir/sofosbuvir; n = 4 with ledipasvir/sofosbuvir + ribavirin), and 1 patient received a 12-week course of ledipasvir/sofosbuvir. Phenotypic analysis showed that isolates from patients with NS5A RAVs detected at failure post-baseline exhibited reduced sensitivity to ledipasvir by 20- to at least 243-fold (highest tested dose). Site-specific mutagenesis of Y93H substitutions in both genotypes 1a and 1b, as well as Q30R and L31M substitutions in genotype 1a, resulted in reduced sensitivity to ledipasvir (fold change in EC50 ranging from 544 to 1677).

The S282T substitution in NS5B, associated with resistance to sofosbuvir, was not observed in any isolates at virologic failure in phase 3 trials. However, the NS5B S282T substitution, along with NS5A substitutions L31M, Y93H, and Q30L, was detected in one patient who experienced failure after 8 weeks of treatment with ledipasvir/sofosbuvir in a phase 2 trial (LONESTAR). This patient subsequently underwent re-treatment with ledipasvir/sofosbuvir + ribavirin for 24 weeks and achieved SVR after treatment completion.

In the SIRIUS trial, 5 patients with genotype 1 virus experienced post-treatment relapse after treatment with ledipasvir/sofosbuvir with or without ribavirin. NS5A RAVs at relapse were present in 5/5 patients (in genotype 1a: Q30R/H + L31M/V [n = 1] and Q30R [n = 1]; in genotype 1b: Y93H [n = 3]).

In the SOLAR-1 trial, 13 patients with genotype 1 virus experienced post-treatment relapse after treatment with ledipasvir/sofosbuvir with ribavirin. NS5A RAVs at relapse were present in 11/13 patients (in genotype 1a: Q30R only [n = 2], Y93C [n = 1], Y93H/C [n = 2], Q30R + H58D [n = 1], M28T + Q30H [n = 1]; in genotype 1b: Y93H [n = 3], Y93H/C [n = 1]).

In clinical trials, genotypes 2, 3, 4, 5, and 6

NS5A RAVs: No patients infected with genotype 2 experienced relapse during clinical trials; therefore, data on NS5A RAVs at failure are unavailable.

In patients infected with genotype 3 who experienced virologic failure, emergence of NS5A RAVs (including an increase in the number of RAVs present at baseline) was generally not observed at failure (n = 17).

For infections with genotypes 4, 5, and 6, only a small number of patients were evaluated (a total of 5 patients with failure). The NS5A Y93C substitution emerged in HCV from one patient (genotype 4), while baseline NS5A RAVs were observed at failure in all patients.

NS5B RAVs: The NS5B S282T substitution emerged in HCV in 1/17 cases of failure with genotype 3 and in 1/3, 1/1, and 1/1 cases of failure with genotypes 4, 5, and 6, respectively.

Impact of baseline HCV resistance-associated variants on treatment outcomes

Genotype 1

An analysis was conducted to investigate the association between baseline NS5A RAVs and treatment outcomes. Pooled analysis results from phase 3 trials showed that baseline NS5A RAVs were detected in 16 % of patients by population or deep sequencing, regardless of subtype. Baseline NS5A RAVs were more pronounced in patients who experienced relapse in phase 3 trials.

After 12 weeks of treatment with ledipasvir/sofosbuvir without ribavirin in treatment-naive patients (group 1 of the ION-2 trial), SVR was achieved in 4/4 patients with baseline NS5A RAVs associated with ≤100-fold change in ledipasvir sensitivity. In the same group, among patients with baseline NS5A RAVs associated with >100-fold change in sensitivity, relapse occurred in 4/13 (31 %), compared to 3/95 (3 %) in patients without baseline RAVs or with RAVs associated with ≤100-fold change.

After 12 weeks of treatment with ledipasvir/sofosbuvir plus ribavirin in patients with compensated cirrhosis (SIRIUS, n = 77), all 8 patients with baseline NS5A RAVs associated with >100-fold reduced sensitivity to ledipasvir achieved SVR12.

The group of NS5A RAVs associated with >100-fold shift and observed in patients included the following substitutions in genotype 1a (M28A, Q30H/R/E, L31M/V/I, H58D, Y93H/N/C) or in genotype 1b (Y93H). The prevalence of such baseline NS5A RAVs, detected by deep sequencing, ranged from very low (analysis threshold 1 %) to high (majority of the population in selected plasma samples).

The S282T substitution associated with resistance to sofosbuvir was not detected in baseline NS5B sequences in any patient in phase 3 trials, by population or deep sequencing. SVR was achieved in 24 patients (n = 20 with L159F + C316N; n = 1 with L159F; n = 3 with N142T) who had baseline variants associated with resistance to nucleoside NS5B inhibitors.

After 12 weeks of treatment with ledipasvir/sofosbuvir plus ribavirin in post-liver transplant patients with compensated liver disease (SOLAR-1), no relapses occurred in any (n = 8) patients with baseline NS5A RAVs associated with >100-fold change in ledipasvir sensitivity. After 12 weeks of treatment with ledipasvir/sofosbuvir plus ribavirin in patients with decompensated disease (regardless of liver transplant status), relapse occurred in 3/7 patients with baseline NS5A RAVs associated with >100-fold reduced sensitivity to ledipasvir, compared to 4/68 patients without baseline RAVs or with RAVs associated with ≤100-fold reduced sensitivity to ledipasvir.

Genotypes 2, 3, 4, 5, and 6

Due to limited data, the impact of baseline NS5A RAVs on treatment outcomes in patients with chronic hepatitis C (CHC) genotype 2, 3, 4, 5, or 6 was not fully evaluated. No significant differences in treatment outcomes were observed between patients with or without baseline NS5A RAVs.

Cross-resistance

Ledipasvir was fully active against the resistance-associated S282T substitution in NS5B, and all resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and ledipasvir were active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of action, such as non-nucleoside NS5B inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to ledipasvir may reduce the antiviral activity of other NS5A inhibitors.

Pharmacokinetics.

Absorption

Following oral administration of ledipasvir/sofosbuvir to HCV-infected patients, the median maximum plasma concentration (Cmax) of ledipasvir was observed 4.0 hours after dosing. Sofosbuvir was rapidly absorbed, with median Cmax observed approximately 1 hour after administration. The median Cmax of GS-331007 in plasma was observed 4 hours after administration.

Population pharmacokinetic analysis in HCV-infected patients showed that at steady state, the geometric mean area under the pharmacokinetic curve over the dosing interval (AUC0–24) for ledipasvir (n = 2113), sofosbuvir (n = 1542), and GS-331007 (n = 2113) was 7290, 1320, and 12,000 ng•h/mL, respectively. Steady-state Cmax values for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. AUC0–24 and Cmax values for GS-331007 were similar in healthy adult volunteers and HCV-infected patients. Compared to healthy volunteers (n = 191), AUC0–24 and Cmax of ledipasvir in HCV-infected patients were 24 % and 32 % lower, respectively. Over the dose range of 3 to 100 mg, the area under the concentration-time curve (AUC) of ledipasvir was dose-proportional. Over the dose range of 200 to 400 mg, AUC values for sofosbuvir and GS-331007 were nearly dose-proportional.

Effect of food intake

Compared to fasting conditions, a single dose of ledipasvir/sofosbuvir taken with a meal of moderate or high fat content increased the AUC0–inf of sofosbuvir approximately 2-fold, but had minimal effect on sofosbuvir Cmax. GS-331007 and ledipasvir concentrations were not affected by food of any type. Therefore, Virepca can be taken with or without food.

Distribution

Ledipasvir is >99.8 % bound to human plasma proteins. After a single dose of 90 mg [14C]-ledipasvir in healthy volunteers, the blood-to-plasma ratio of [14C]-ledipasvir concentration ranged from 0.51 to 0.66.

Sofosbuvir is approximately 61–65 % bound to human plasma proteins, with binding independent of drug concentration in the range of 1 to 20 µg/mL. Binding of GS-331007 to human plasma proteins is minimal. After a single dose of 400 mg [14C]-sofosbuvir in healthy volunteers, the blood-to-plasma ratio of [14C]-sofosbuvir concentration was approximately 0.7.

Biotransformation

In vitro, no significant metabolism of ledipasvir by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 enzymes of human origin was observed. Slow oxidative metabolism occurred, but the mechanism is not fully understood. After a single 90 mg dose of [14C]-ledipasvir, systemic exposure was almost entirely due to the parent drug (>98 %). Unchanged ledipasvir is also the primary compound excreted in feces.

Sofosbuvir undergoes extensive hepatic metabolism to form the pharmacologically active nucleoside analog triphosphate GS-461203. The active metabolite was not detected. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety, catalyzed by cathepsin A or human carboxylesterase 1, followed by phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 and subsequent phosphorylation via pyrimidine nucleotide biosynthesis. Defosphorylation results in the formation of the nucleoside metabolite GS-331007, which cannot be efficiently phosphorylated and has reduced activity against HCV in vitro. In the combination of ledipasvir/sofosbuvir, GS-331007 accounts for approximately 85 % of total systemic exposure.

Elimination

After a single oral dose of 90 mg [14C]-ledipasvir, the mean total excretion of [14C]-radioactive compounds in feces and urine was 87 %, with the majority excreted in feces (86 %). Unchanged ledipasvir in feces accounted for a mean of 70 % of the administered dose, and the oxidized metabolite M19 accounted for 2.2 % of the administered dose. These data indicate that biliary excretion of unchanged ledipasvir is the primary elimination pathway, with renal excretion being a minor route (approximately 1 %). The median terminal half-life of ledipasvir in healthy volunteers after administration of ledipasvir/sofosbuvir in the fasting state was 47 hours.

After a single oral dose of 400 mg [14C]-sofosbuvir, mean total excretion of the dose exceeded 92 %: approximately 80 %, 14 %, and 2.5 % were excreted in urine, feces, and exhaled air, respectively. The majority of the excreted sofosbuvir dose in urine was in the form of GS-331007 (78 %), while 3.5 % was excreted as sofosbuvir. These data indicate that renal clearance is the primary elimination pathway for GS-331007, with the majority excreted via active secretion. The median terminal half-life of sofosbuvir and GS-331007 after administration of ledipasvir/sofosbuvir was 0.5 and 27 hours, respectively.

Neither ledipasvir nor sofosbuvir are substrates of hepatic uptake transporters, organic cation transporter (OCT) 1, organic anion transporting polypeptide (OATP) 1B1, or OATP1B3. GS-331007 is not a substrate of renal transporters, including organic anion transporter (OAT) 1, OAT3, or OCT2.

Potential of ledipasvir/sofosbuvir to affect other medicinal products in vitro

At concentrations achieved under clinical conditions, ledipasvir did not inhibit hepatic cellular transport, including OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxin extrusion (MATE) 1, multidrug resistance protein (MRP) 2, or MRP4. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-glycoprotein (P-gp), BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, or MATE1.

Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP enzymes or uridine diphosphate glucuronosyltransferase (UGT) 1A1.

Pharmacokinetics in special populations

Race and sex

No clinically significant differences in the pharmacokinetics of ledipasvir, sofosbuvir, or GS-331007 based on race were observed. No clinically significant differences in the pharmacokinetics of sofosbuvir or GS-331007 based on sex were observed. AUC and Cmax of ledipasvir were 77 % and 58 % higher in women than in men, respectively, but the relationship between sex and ledipasvir AUC was not clinically significant.

Elderly patients

Population pharmacokinetic analysis in HCV-infected patients showed that within the analyzed age range (18 to 80 years), age did not have a clinically significant effect on the AUC of ledipasvir, sofosbuvir, or GS-331007. A total of 235 patients (8.6 % of the total number of patients) aged 65 years and older were included in clinical trials of ledipasvir/sofosbuvir.

Renal impairment

The pharmacokinetics of ledipasvir were studied after a single 90 mg dose of ledipasvir administered to HCV-negative patients with severe renal impairment (estimated glomerular filtration rate (eGFR) <30 mL/min by Cockcroft-Gault formula, median [range] creatinine clearance (CrCl) – 22 [17–29] mL/min). No clinically significant differences in ledipasvir pharmacokinetics were observed between healthy volunteers and patients with severe renal impairment.

The pharmacokinetics of sofosbuvir were studied in HCV-negative patients with mild (eGFR ≥50 and <80 mL/min/1.73 m²), moderate (eGFR ≥30 and <50 mL/min/1.73 m²), severe renal impairment (eGFR <30 mL/min/1.73 m²), and patients with end-stage renal disease (ESRD) requiring hemodialysis after a single 400 mg dose of sofosbuvir. Compared to patients with normal renal function (eGFR >80 mL/min/1.73 m²), AUC0–inf of sofosbuvir was 61 %, 107 %, and 171 % higher in mild, moderate, and severe renal impairment, respectively, and AUC0–inf of GS-331007 was 55 %, 88 %, and 451 % higher, respectively. In patients with ESRD, compared to patients with normal renal function, AUC0–inf of sofosbuvir was 28 % higher when sofosbuvir was administered 1 hour before hemodialysis and 60 % higher when administered 1 hour after hemodialysis. AUC0–inf of GS-331007 in ESRD patients who took sofosbuvir 1 hour before and 1 hour after hemodialysis was at least 10 and 20 times higher, respectively. GS-331007 is efficiently removed during hemodialysis, with a removal ratio of approximately 53 %. After a single 400 mg dose of sofosbuvir, 18 % of the administered dose was removed during a 4-hour hemodialysis session. The safety and efficacy of sofosbuvir in patients with severe renal impairment and ESRD have not been established.

Hepatic impairment

The pharmacokinetics of ledipasvir were studied after a single 90 mg dose of ledipasvir administered to HCV-negative patients with severe hepatic impairment (Child-Pugh class C). Plasma exposure (AUCinf) of ledipasvir was similar in patients with severe hepatic impairment and control patients with normal liver function. Population pharmacokinetic analysis in HCV-infected patients showed that cirrhosis did not have a clinically significant effect on ledipasvir exposure.

The pharmacokinetics of sofosbuvir were studied after 7 days of 400 mg sofosbuvir administration in HCV-infected patients with moderate and severe hepatic impairment (Child-Pugh classes B and C). Compared to patients with normal liver function, AUC0–24 of sofosbuvir was 126 % and 143 % higher in moderate and severe hepatic impairment, respectively, and AUC0–24 of GS-331007 was 18 % and 9 % higher, respectively. Population pharmacokinetic analysis in HCV-infected patients showed that cirrhosis did not have a clinically significant effect on sofosbuvir and GS-331007 exposure.

Body weight

Body weight did not have a significant effect on sofosbuvir exposure, according to population pharmacokinetic analysis. Ledipasvir exposure decreases with increasing body weight, but this relationship is not considered clinically significant.

Pediatric patients

The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 in pediatric patients have not been established (see section "Dosage and administration").

Clinical characteristics.

Indications.

VIRPAS is indicated for the treatment of chronic hepatitis C (CHC) in adult patients (see sections “Pharmacodynamics”, “Special precautions”, and “Dosage and administration”).

For genotype-specific activity of hepatitis C virus (HCV), see sections “Pharmacodynamics” and “Special precautions”.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

Concomitant use with rosuvastatin (see section “Interaction with other medicinal products and other forms of interaction”).

Use with strong P-glycoprotein (P-gp) inducers

Medicinal products that are strong intestinal P-gp inducers (rifampicin, rifabutin, St John’s wort (Hypericum perforatum), carbamazepine, phenobarbital, and phenytoin). Concomitant use significantly reduces plasma concentrations of ledipasvir and sofosbuvir and may lead to reduced efficacy of VIRPAS (see section “Interaction with other medicinal products and other forms of interaction”).

Special precautions.

VIRPAS should not be used in combination with other medicinal products containing sofosbuvir.

Genotype-specific activity

Recommended treatment regimens for different HCV genotypes are provided in the section “Dosage and administration”. Information on genotype-specific virological and clinical activity is provided in the section “Pharmacodynamics”.

Clinical data supporting the use of VIRPAS for the treatment of patients infected with HCV genotype 3 are limited (see section “Pharmacodynamics”). The relative efficacy of a 12-week regimen of ledipasvir/sofosbuvir + ribavirin compared to a 24-week regimen of sofosbuvir + ribavirin has not been studied. A 24-week course of conservative treatment is recommended for all patients with genotype 3 who have undergone prior therapy, as well as for treatment-naïve patients with genotype 3 and liver cirrhosis (see section “Dosage and administration”).

Clinical data supporting the use of VIRPAS for the treatment of patients infected with HCV genotypes 2 and 6 are limited (see section “Pharmacodynamics”).

Severe bradycardia and cardiac conduction block

Cases of severe bradycardia and cardiac conduction block have been reported when VIRPAS is used concomitantly with amiodarone, either alone or in combination with other drugs that slow heart rate. The mechanism of this effect is not fully understood.

Concomitant use of amiodarone during clinical development of sofosbuvir with direct-acting antivirals (DAAs) was limited. Because co-administration may be life-threatening, amiodarone should be prescribed to patients undergoing treatment with VIRPAS only if alternative antiarrhythmic medicinal products are poorly tolerated or contraindicated.

If concomitant use of amiodarone is necessary, continuous monitoring of the patient is recommended after initiation of VIRPAS. If a patient is identified as being at high risk for bradycardia, continuous monitoring for 48 hours in an appropriate healthcare setting is required.

Due to the long half-life of amiodarone, appropriate monitoring should be ensured for patients who have discontinued amiodarone within the past several months and have started treatment with VIRPAS.

All patients receiving VIRPAS in combination with amiodarone or other drugs that reduce heart rate, or without such drugs, should be informed about the symptoms of bradycardia and cardiac conduction block and should seek immediate medical attention if such symptoms occur.

Use in patients previously treated with direct-acting antivirals for HCV infection

In patients who did not respond to treatment with ledipasvir/sofosbuvir, resistance-associated NS5A mutations that reduce sensitivity to ledipasvir are commonly observed (see section “Pharmacodynamics”). Some data suggest that these NS5A mutations do not re-emerge during long-term follow-up. There are currently no data confirming the efficacy of retreatment with an NS5A inhibitor in patients who did not respond to ledipasvir/sofosbuvir. Similarly, there are currently no data confirming the efficacy of NS3/4A protease inhibitors in patients who previously failed therapy with NS3/4A protease inhibitors. Therefore, such patients may depend on other classes of antiviral agents to eradicate HCV infection. Thus, the possibility of extending the treatment duration should be considered for patients with uncertain options for subsequent therapy.

Renal impairment

Dose adjustment of VIRPAS is not required in patients with mild or moderate renal impairment. The safety of VIRPAS in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring hemodialysis has not been studied. When VIRPAS is used with ribavirin in patients with CrCl <50 mL/min, refer also to the information provided in the ribavirin prescribing information (see section “Pharmacokinetics”).

Patients with decompensated liver cirrhosis and/or patients awaiting or who have undergone liver transplantation

The efficacy of ledipasvir/sofosbuvir in HCV genotype 5 and genotype 6 infected patients with decompensated liver cirrhosis and/or those awaiting or who have undergone liver transplantation has not been studied. Treatment with VIRPAS should be administered with careful consideration of the benefit-risk ratio for each individual patient.

Use with moderate P-gp inducers

Medicinal products that are moderate intestinal P-gp inducers (e.g., oxcarbazepine) may reduce plasma concentrations of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of VIRPAS. Concomitant use of such medicinal products with VIRPAS is not recommended (see section “Interaction with other medicinal products and other forms of interaction”).

Use of certain antiretroviral therapies for HIV treatment

VIRPAS has been shown to increase tenofovir exposure, particularly when co-administered with HIV therapy containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in combination with VIRPAS and a pharmacokinetic booster has not been studied. The potential risks and benefits associated with concomitant use of VIRPAS and fixed-dose combination tablets of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate with a boosted HIV protease inhibitor (e.g., atazanavir or darunavir) should always be considered, especially when treating patients at increased risk of renal dysfunction. Patients receiving VIRPAS together with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate with a boosted HIV protease inhibitor should be monitored for adverse reactions associated with tenofovir. Recommendations for monitoring renal function are provided in the prescribing information for tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate.

Use with HMG-CoA reductase inhibitors (statins)

Concomitant use of VIRPAS and HMG-CoA reductase inhibitors (statins) may lead to a significant increase in statin concentrations, increasing the risk of myopathy and rhabdomyolysis (see section “Interaction with other medicinal products and other forms of interaction”).

Concomitant HCV/HBV (hepatitis B virus) infection

Cases of hepatitis B virus (HBV) reactivation, some of which were fatal, have been reported during or after treatment with direct-acting antivirals. HBV screening should be performed in all patients prior to initiating treatment. Patients with concomitant HCV/HBV infection are at risk of HBV reactivation and should be monitored and treated according to current clinical guidelines.

Paediatric population

VIRPAS is not recommended for children and adolescents under 18 years of age, as safety and efficacy in this patient population have not been established.

Excipients

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Interaction with other medicinal products and other forms of interaction.

Since VIRPAS contains ledipasvir and sofosbuvir, any interactions established for these components may occur during treatment with VIRPAS.

Ability of VIRPAS to affect other medicinal products

In vitro, ledipasvir acts as an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP), and may increase intestinal absorption of concurrently administered substrates of these transporters. In vitro data suggest that ledipasvir may act as a weak inducer of metabolizing enzymes such as CYP3A4, CYP2C, and UGT1A1. When drugs that are substrates of these enzymes are administered concomitantly with ledipasvir/sofosbuvir, their plasma concentrations may decrease. In vitro, ledipasvir has been shown to inhibit CYP3A4 and UGT1A1 in the intestine. Medicinal products with a narrow therapeutic index, as well as those metabolized by these enzymes, should be used with caution and under continuous monitoring.

Ability of other medicinal products to affect VIRPAS

Ledipasvir and sofosbuvir are substrates of the drug transporters P-gp and BCRP, unlike GS-331007.

Medicinal products that are strong P-gp inducers (e.g., rifampicin, rifabutin, St John’s wort products, carbamazepine, phenobarbital, and phenytoin) may significantly reduce plasma concentrations of ledipasvir and sofosbuvir, thereby reducing the therapeutic efficacy of ledipasvir/sofosbuvir; therefore, their use with VIRPAS is contraindicated (see section “Contraindications”). Medicinal products that are moderate intestinal P-gp inducers (e.g., oxcarbazepine) may reduce plasma concentrations of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of VIRPAS. Concomitant use of such medicinal products with VIRPAS is not recommended (see section “Special precautions”). Concomitant use with medicinal products that inhibit P-gp and/or BCRP may increase plasma concentrations of ledipasvir and sofosbuvir without increasing GS-331007 plasma concentrations; concomitant use of VIRPAS with P-gp and/or BCRP inhibitors is not excluded. Clinically significant drug interactions with ledipasvir/sofosbuvir mediated by CYP450 enzymes or UGT1A1 are unlikely.

Patients receiving vitamin K antagonists

Since liver function may change during treatment with VIRPAS, careful monitoring of International Normalized Ratio (INR) values is recommended for such patients.

Interaction of VIRPAS with other medicinal products

Table 2 lists established or potentially clinically significant drug interactions (where the 90% confidence interval [CI] of the geometric mean [GM] ratio was within “↔”, increased “↑”, or decreased “↓” relative to pre-defined equivalence limits). The described drug interactions are based on studies conducted with ledipasvir/sofosbuvir, or with ledipasvir and sofosbuvir as separate medicinal products, or represent probable drug interactions expected with ledipasvir/sofosbuvir. The data in the table are not exhaustive.

Table 2. Interaction of VIRPAS with other medicinal products

a Mean ratio (90 % CI) of pharmacokinetics of the concomitant drug administered with the investigational drugs alone or in combination. No effect = 1.00.

b All drug interaction studies were conducted in healthy volunteers.

c Administered as Viread.

d Boundaries of no pharmacokinetic interaction: 70–143 %.

e These drugs belong to a class of drugs where such types of interactions cannot be predicted.

f Sequential administration (once every 12 hours) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate or darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Viread resulted in similar outcomes.

g Study conducted using two other direct-acting antiviral agents.

h Bioequivalence/equivalence boundaries: 80–125 %.

Special precautions for use.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception in men and women

When using Virekpas with ribavirin, maximum precautions must be taken to prevent pregnancy in female patients and female partners of male patients. In animals administered ribavirin, significant teratogenic and/or embryocidal effects have been observed. Women of childbearing potential and their partners must use effective contraceptive methods during treatment and after completion of therapy, according to the recommendations provided in the ribavirin product information. For additional information, refer to the ribavirin product information.

Pregnancy

Data on the use of ledipasvir, sofosbuvir, or Virekpas in pregnant women are limited or unavailable (fewer than 300 pregnancy outcomes).

In animal studies, no signs of reproductive toxicity were observed. No significant effects on fetal development were noted in rats and rabbits treated with ledipasvir or sofosbuvir. However, it was not possible to fully establish the extent of sofosbuvir exposure in rats relative to human exposure at the recommended clinical dose.

As a precautionary measure, the use of Virekpas during pregnancy is not recommended.

Breastfeeding period

It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human breast milk.

Available pharmacokinetic data in animals have shown that ledipasvir and sofosbuvir metabolites are present in breast milk.

Risk to newborns/infants cannot be ruled out. Therefore, Virekpas should not be used during breastfeeding.

Fertility

There are no data on the effect of Virekpas on human fertility. Animal studies did not show any negative effect of ledipasvir or sofosbuvir on fertility.

When ribavirin is used concomitantly with Virekpas, the contraindications regarding ribavirin use during pregnancy and breastfeeding apply (see also the ribavirin product information).

Ability to affect reaction speed when driving vehicles or operating machinery.

Virekpas (used as monotherapy or in combination with ribavirin) does not have a negative effect on the ability to drive vehicles or operate machinery. However, patients should be advised that fatigue has been reported more frequently with ledipasvir/sofosbuvir than with placebo.

Method of administration and dosage.

Prescribing Virpas and monitoring its use should be performed by a physician experienced in managing patients with HCV.

Dosage

The recommended dose of Virpas is 1 tablet once daily. It can be taken regardless of food intake (see section "Pharmacokinetics").

Table 3. Recommended duration of treatment with Virpas and recommended methods of administration of concomitantly prescribed ribavirin for specific patient subgroups

* Including patients infected with human immunodeficiency virus (HIV).

If used in combination with ribavirin, see also the ribavirin prescribing information.

In patients with decompensated cirrhosis requiring addition of ribavirin to the treatment regimen (see Table 3), the daily dose of ribavirin is based on body weight (<75 kg = 1000 mg and ≥75 kg = 1200 mg); two separate doses should be taken orally with food.

For patients with decompensated cirrhosis, ribavirin should be initiated at an initial dose of 600 mg, administered as a divided daily dose. If the initial dose is well tolerated, dose titration up to the maximum of 1000–1200 mg per day is permitted (1000 mg if patient’s body weight is <75 kg, and 1200 mg if patient’s body weight is ≥75 kg). If the initial dose is not well tolerated, the dose should be reduced according to clinical judgment based on hemoglobin levels.

Dose adjustment of ribavirin in patients receiving 1000–1200 mg/day.

When Vircase is used in combination with ribavirin and the patient develops a serious adverse reaction potentially related to ribavirin, ribavirin dose adjustment or discontinuation may be necessary until the adverse reaction resolves or its severity decreases. Table 4 provides recommendations for dose adjustment and discontinuation based on hemoglobin levels and the patient's cardiovascular status.

Table 4. Recommendations for ribavirin dose adjustment when used concomitantly with Vircase

After discontinuation of ribavirin due to laboratory abnormalities or development of clinical manifestations, an attempt should be made to reinitiate ribavirin at a dose of 600 mg/day, with subsequent dose escalation to 800 mg/day. Dose escalation of ribavirin to the initially prescribed dose (from 1000 mg to 1200 mg per day) is not recommended.

Patients should be advised that if vomiting occurs within 5 hours of dosing, the next tablet should be taken. If vomiting occurs more than 5 hours after dosing, no additional dose is required (see section "Pharmacodynamics").

If a dose is missed and less than 18 hours have passed since the missed dose, the patient should take the tablet as soon as possible, and the next dose should be taken at the scheduled time. If more than 18 hours have passed since the missed dose, the patient should wait until the next scheduled dose. Patients must not take a double dose of the medicinal product.

Elderly patients

Dose adjustment for elderly patients is not required (see section "Pharmacokinetics").

Renal impairment

Dose adjustment of Virepas is not required for patients with mild or moderate renal impairment. The safety of ledipasvir/sofosbuvir in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring hemodialysis has not been studied (see section "Pharmacokinetics").

Hepatic impairment

Dose adjustment of Virepas is not required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) (see section "Pharmacokinetics"). The safety and efficacy of ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis (see section "Pharmacodynamics").

Route of administration

For oral use.

The tablet should be swallowed whole. It may be taken with or without food. The film-coated tablets have a bitter taste; therefore, chewing or crushing is not recommended (see section "Pharmacokinetics").

Children

The safety of Virepas in children and adolescents under 18 years of age has not been established. Data are lacking.

Overdose

The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and a single dose of 1200 mg, respectively. In studies conducted in healthy volunteers, no unexpected effects were observed at these dose levels, and the frequency and severity of adverse events were similar to those in the placebo group. The effect of higher doses of the medicinal product is unknown.

There is no specific antidote for overdose with Virepas. In case of overdose, the patient should be monitored for signs of toxicity. Management of overdose with Virepas includes general supportive measures, including monitoring of vital functions and observation of the patient's clinical status. Hemodialysis is unlikely to effectively remove ledipasvir due to its high plasma protein binding. Hemodialysis can effectively remove the major circulating metabolite of sofosbuvir, GS-331007, with a removal efficiency of 53%.

Adverse reactions.

General information on safety profile

The safety analysis of ledipasvir/sofosbuvir is based on pooled data from three Phase 3 clinical trials (ION-3, ION-1, and ION-2) involving 215, 539, and 326 patients receiving ledipasvir/sofosbuvir for 8, 12, and 24 weeks, respectively, and 216, 328, and 328 patients receiving ledipasvir/sofosbuvir + ribavirin as part of combination therapy for 8, 12, and 24 weeks, respectively. These studies did not include a control group not receiving ledipasvir/sofosbuvir. Additional data include a double-blind, placebo-controlled safety comparison of ledipasvir/sofosbuvir (12 weeks) in 155 patients with cirrhosis.

The proportion of patients who discontinued treatment prematurely due to adverse events was 0%, <1%, and 1% among patients receiving ledipasvir/sofosbuvir for 8, 12, and 24 weeks, respectively, and <1%, 0%, and 2% among patients receiving ledipasvir/sofosbuvir + ribavirin as part of combination therapy for 8, 12, and 24 weeks, respectively.

In clinical studies, fatigue and headache were observed more frequently in patients receiving ledipasvir/sofosbuvir compared to those receiving placebo. When ledipasvir/sofosbuvir was studied in combination with ribavirin, the most common adverse reactions associated with ledipasvir/sofosbuvir + ribavirin in combination therapy were consistent with the established safety profile of ribavirin, without an increase in frequency or severity of expected adverse reactions.

Adverse reactions observed during administration of Virepax are listed by system organ class and frequency (see Table 5). Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

Table 5. Adverse drug reactions identified during administration of Virepax

Patients with decompensated cirrhosis and/or patients awaiting liver transplantation or post-liver transplantation

The safety profile of ledipasvir/sofosbuvir with ribavirin administered for 12 or 24 weeks in patients with decompensated liver disease and/or patients post-liver transplantation was evaluated in an open-label study (SOLAR-1). No new adverse reactions were identified in patients with decompensated cirrhosis and/or post-liver transplantation receiving ledipasvir/sofosbuvir with ribavirin. Although adverse events, including serious ones, occurred more frequently than in studies not including patients with decompensation and/or post-liver transplantation, the observed adverse events were predictable as clinical consequences of advanced liver disease and/or transplantation or consistent with the established safety profile of ribavirin.

Hemoglobin levels decreased to <10 g/dL and <8.5 g/dL during treatment in 39% and 13% of patients receiving ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was discontinued in 19% of patients.

Immunosuppressive agents were changed in 10% of liver transplant recipients.

Pediatric population

The safety of Virepsa in children and adolescents under 18 years of age has not been established. Data are lacking.

Description of selected adverse reactions

Cardiac arrhythmia

Cases of severe bradycardia and atrioventricular conduction block have been observed when Virepsa was co-administered with amiodarone and/or other drugs that reduce heart rate (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Packaging.

White high-density polyethylene bottle closed with an aluminum foil and a child-resistant polypropylene cap. Each bottle contains 28 film-coated tablets with a silica gel desiccant and a polyester coil. One bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Strides Pharma Science Limited.

Manufacturer's address and location of operations.

No. 36/7, Suragajakkannahalli, Indlavadi Cross, Anekal Taluk, Bangalore, Karnataka 562106, India.

Marketing Authorization Holder.

Strides Pharma Science Limited.

Address of the Marketing Authorization Holder.

201, Devavrata Sector 17, Vasai, Navi Mumbai – 400 703, India.