SOFGEN-L

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOFGEN-L (SOFGEN-L)

Composition:

Active substances: ledipasvir, sofosbuvir;

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

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II Brown 85F565007 (polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, red iron oxide, yellow iron oxide).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: brown, capsule-shaped, biconvex tablets with beveled edges, film-coated, marked with "H" on one side and "L18" on the opposite side.

Pharmacotherapeutic group.

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

ATC code J05AP51.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Ledipasvir is an HCV inhibitor targeting the HCV NS5A protein, which is essential for HCV RNA replication and virion assembly. Since NS5A lacks enzymatic activity, biochemical confirmation of NS5A inhibition by ledipasvir is currently not feasible. In vitro studies on selective and cross-resistance have demonstrated that ledipasvir acts on NS5A as its target. Sofosbuvir is a pangenotypic inhibitor of the HCV RNA-dependent RNA polymerase NS5B, 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. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA- or RNA-polymerases and does not inhibit 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 by 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 substituted fragment in replicons of 8 genotypes resulted in a 2- to 18-fold decrease in sensitivity to sofosbuvir and a 89–99% reduction in viral replication capacity compared to the corresponding wild type.

In clinical studies, adults: genotype 1

Results from 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 the investigational drug with HCV RNA levels >1000 IU/mL. Deep sequencing data for NS5A and NS5B at baseline (analysis cutoff limit 1%) were obtained for 37/37 and 36/37 patients, respectively.

NS5A resistance-associated variants (RAVs) were detected at baseline 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). Among 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, whereas no NS5A RAVs were detected at failure in the remaining 7/29 patients. The most common variants were Q30R, Y93H, and L31M. Among 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, whereas no NS5A RAVs were detected at failure in 1/8 patients. The most common variant was Y93H. Among the 8 patients without 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 ledipasvir/sofosbuvir treatment course. Phenotypic analyses showed that isolates from patients with NS5A RAVs detected at failure had reduced sensitivity to ledipasvir ranging from 20- to at least 243-fold (highest tested dose). Site-specific mutagenesis of the Y93H substituted fragments in both genotypes 1a and 1b, as well as Q30R and L31M substituted fragments in genotype 1a, resulted in reduced sensitivity to ledipasvir (EC50 fold change from 544 to 1677-fold).

In post-transplant patients with compensated liver disease and patients with decompensated liver disease pre- or post-transplant (SOLAR-1 and SOLAR-2 trials), relapses were associated with the detection of one or more of the following NS5A RAVs: K24R, M28T, Q30R/H/K, L31V, H58D, and Y93H/C in 12 of 14 patients infected with genotype 1a and L31M, Y93H/N in 6 of 6 patients infected with genotype 1b.

The NS5B substitution E237G was detected in 3 patients (1 infected with genotype 1b and 2 with genotype 1a) in phase 3 trials (ION-3, ION-1, and ION-2) and in 3 patients with genotype 1a virus in the SOLAR-1 and SOLAR-2 trials at relapse. The E237G substitution demonstrated a 1.3-fold reduction in sensitivity to sofosbuvir in a genotype 1a replicon assay. The clinical significance of this substitution remains unknown.

The NS5B S282T substitution, associated with resistance to sofosbuvir, was not observed in any isolates at virologic failure in phase 3 trials. However, the NS5B S282T substitution in combination with NS5A substitutions L31M, Y93H, and Q30L was detected in one patient who experienced failure after 8 weeks of ledipasvir/sofosbuvir treatment 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 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 clinical studies, adults: genotypes 2, 3, 4, 5, and 6

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

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

For genotypes 4, 5, and 6, only a small number of patients were evaluated (total of 5 patients with failure). The NS5A Y93C substitution emerged in HCV from 1 patient (genotype 4), while baseline-present NS5A RAVs were observed at failure in all patients. In the SOLAR-2 trial, an NS5B E237G substitution occurred at relapse in one patient infected with genotype 4d. The clinical significance of this substitution remains unknown.

NS5B RAVs: The NS5B S282T substitution emerged in HCV in 1/17 cases of failure with genotype 3, and in HCV 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

Adults: genotype 1

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

After 12 weeks of ledipasvir/sofosbuvir treatment without ribavirin in treatment-experienced patients (Group 1 of the ION-2 trial), 4/4 patients with baseline NS5A RAVs associated with ≤100-fold change in ledipasvir sensitivity achieved SVR. 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 ledipasvir/sofosbuvir treatment with ribavirin in treatment-experienced patients with compensated cirrhosis (SIRIUS, n = 77), 8/8 patients with baseline NS5A RAVs associated with >100-fold reduction in ledipasvir sensitivity 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 proportion of such baseline NS5A RAVs detected by deep sequencing ranged from very low (analysis cutoff limit 1%) to high (majority of the population in selected plasma samples).

The S282T substitution associated with resistance to sofosbuvir was not found in the NS5B sequence at baseline 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, and n = 3 with N142T) who had baseline variants associated with resistance to nucleoside NS5B inhibitors.

After 12 weeks of ledipasvir/sofosbuvir treatment with 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 ledipasvir/sofosbuvir with ribavirin treatment in patients with decompensated liver disease (regardless of liver transplant status), relapse occurred in 3/7 patients with baseline NS5A RAVs associated with >100-fold reduction in ledipasvir sensitivity compared to 4/68 patients without baseline RAVs or with RAVs associated with ≤100-fold reduction in ledipasvir sensitivity.

Adults: 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 genotype 2, 3, 4, 5, or 6 was not fully assessed. 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 fully 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

After oral administration of ledipasvir/sofosbuvir to HCV-infected patients, the median time to maximum plasma concentration of ledipasvir was 4.0 hours post-dose. Sofosbuvir was rapidly absorbed, with median time to maximum plasma concentration occurring approximately 1 hour post-dose. The median time to maximum plasma concentration of GS-331007 was 4 hours post-dose.

Population pharmacokinetic analysis in HCV-infected patients showed that at steady state, the geometric mean AUC0–24 of 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 of 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, AUC of ledipasvir was dose-proportional. Over the dose range of 200 to 400 mg, AUC of sofosbuvir and GS-331007 was nearly dose-proportional.

Effect of food

Compared to fasting, single-dose administration of ledipasvir/sofosbuvir with a moderate- or high-fat meal increased AUC0–∞ of sofosbuvir approximately 2-fold, but had minimal effect on sofosbuvir Cmax. Concentrations of GS-331007 and ledipasvir were not affected by food of any type. The medicinal product Sofgen-L can be taken with or without food.

Distribution

Ledipasvir is >99.8% bound to human plasma proteins. After a single dose in healthy volunteers of 90 mg [14C]-ledipasvir, 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, and binding is independent of drug concentration within the range of 1 to 20 µg/mL. Binding of GS-331007 to human plasma is minimal. After a single dose in healthy volunteers of 400 mg [14C]-sofosbuvir, the blood-to-plasma ratio of [14C]-sofosbuvir concentration was approximately 0.7.

Biotransformation

In vitro, no significant metabolism of ledipasvir by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 enzymes was observed. Slow oxidative metabolism occurred via an unknown mechanism. After a single 90 mg dose of [14C]-ledipasvir, systemic exposure was almost entirely accounted for by the parent drug (>98%). Unchanged ledipasvir is also the main compound excreted in feces.

Sofosbuvir undergoes extensive hepatic metabolism to form the pharmacologically active nucleoside analog triphosphate GS-461203. The active metabolite has not been detected. The metabolic activation pathway involves sequential hydrolysis of the carboxyl-ester moiety, catalyzed by human cathepsin A or carboxylesterase 1, followed by phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 and subsequent phosphorylation via the pyrimidine nucleotide biosynthesis pathway. 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 ledipasvir/sofosbuvir, GS-331007 accounts for approximately 85% of total systemic exposure.

Elimination

After a single oral dose of 90 mg [14C]-ledipasvir, mean total recovery 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 oxidized metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is the primary elimination pathway, with renal excretion being secondary (~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 recovery of the dose exceeded 92%: approximately 80%, 14%, and 2.5% were excreted in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose excreted 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 clinically achievable concentrations, 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-associated protein (MRP) 2, or MRP4. Sofosbuvir and GS-331007 are not inhibitors of drug transporters 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 associations between sex and ledipasvir exposure were not considered clinically significant.

Elderly patients

Population pharmacokinetic analysis in HCV-infected patients showed that within the analyzed age range (18 to 80 years), age had no clinically significant effect on the exposure of ledipasvir, sofosbuvir, or GS-331007. A total of 235 patients (8.6% of the total patient population) aged 65 years and older were included in clinical trials of ledipasvir/sofosbuvir.

Renal impairment

The effect of renal impairment (RI) of varying severity on the exposure of components of the medicinal product Sofgen-L compared to exposure in patients with normal renal function is shown in Table 2.

Table 2. Effect of varying degrees of renal impairment on exposure (AUC) of sofosbuvir, GS-331007, and ledipasvir compared to exposure in patients with normal renal function

↔ No clinically significant changes in ledipasvir exposure.

eGFR — estimated glomerular filtration rate.

ESRD — end-stage renal disease.

The pharmacokinetics of ledipasvir were studied following a single 90 mg dose of ledipasvir administered to HCV-negative patients with acute renal impairment (eGFR < 30 mL/min calculated by the Cockcroft-Gault formula, median [range] CrCl [creatinine clearance] 22 [17–29] mL/min).

The pharmacokinetics of sofosbuvir were studied in HCV-negative patients with mild (eGFR ≥ 50 to < 80 mL/min/1.73 m²), moderate (eGFR ≥ 30 to < 50 mL/min/1.73 m²), severe renal impairment (eGFR < 30 mL/min/1.73 m²), and in patients with end-stage renal disease (ESRD) requiring hemodialysis, after a single 400 mg dose, compared to patients with normal renal function (eGFR > 80 mL/min/1.73 m²). GS-331007 is efficiently removed by hemodialysis, with an extraction coefficient of approximately 53%. After a single 400 mg dose of sofosbuvir, 18% of the administered dose was removed during a 4-hour hemodialysis session.

In HCV-infected patients with severe renal impairment receiving ledipasvir/sofosbuvir treatment for 12 weeks (n = 18), the pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were consistent with those observed in HCV-negative patients with severe renal impairment.

The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were evaluated in HCV-infected patients with ESRD requiring dialysis who received ledipasvir/sofosbuvir treatment (n = 94) for 8, 12, or 24 weeks, and were compared to patients with normal renal function from phase 2/3 ledipasvir/sofosbuvir trials.

Hepatic impairment

The pharmacokinetics of ledipasvir were studied following a single 90 mg dose of ledipasvir administered to HCV-negative patients with acute hepatic impairment (Child-Pugh class C). Plasma exposure of ledipasvir (AUC∞) was similar in patients with severe hepatic impairment and in control subjects with normal hepatic function. Population pharmacokinetic analysis in HCV-infected patients showed that cirrhosis had no clinically significant effect on the exposure of ledipasvir.

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 class B and C). Compared to patients with normal hepatic function, the AUC0–24 of sofosbuvir was 126% and 143% higher in moderate and severe hepatic impairment, respectively, while the AUC0–24 of GS-331007 was 18% and 9% higher, respectively. Population pharmacokinetic analysis in HCV-infected patients showed that cirrhosis had no clinically significant effect on the exposure of sofosbuvir and GS-331007.

Body weight

Body weight did not show a significant effect on sofosbuvir exposure based on population pharmacokinetic analysis. Ledipasvir exposure decreases with increasing body weight; however, this relationship is not considered clinically significant.

Pediatric patients

The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 in children aged 12 to 18 years were similar to those in adults in phase 2/3 trials following administration of ledipasvir/sofosbuvir (90 mg/400 mg). The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 in pediatric patients under 12 years of age have not been established (see section "Dosage and administration").

Clinical characteristics.

Indications.

Sofgen-L is indicated for the treatment of chronic hepatitis C (CHC) in adult patients and children aged 12 to 18 years (see sections "Dosage and administration", "Special instructions", and "Pharmacodynamics").

For information on hepatitis C virus (HCV) genotype-specific activity, see sections "Special instructions" and "Pharmacodynamics".

Contraindications.

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

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

Use with strong P-glycoprotein inducers

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

Safety precautions.

Unused medicinal product or waste material must be disposed of in accordance with local requirements.

This medicinal product may be hazardous to the environment.

Interaction with other medicinal products and other forms of interaction.

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

Ability of Sofgen-L to affect the action of 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 co-administered substrates of these transporters.

Ability of other medicinal products to affect the action of Sofgen-L

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

Medicinal products that are strong inducers of P-gp (rifampicin, rifabutin, St. John’s wort preparations, carbamazepine, phenobarbital, and phenytoin) may significantly reduce plasma concentrations of ledipasvir and sofosbuvir, resulting in reduced therapeutic efficacy of ledipasvir/sofosbuvir; therefore, their use in combination with Sofgen-L is contraindicated (see section "Contraindications"). Medicinal products that are moderate inducers of intestinal P-gp (e.g., oxcarbazepine) may reduce plasma concentrations of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Sofgen-L. Concomitant use of such medicinal products with Sofgen-L is not recommended (see section "Special instructions"). 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 Sofgen-L with inhibitors of P-gp and/or BCRP is not excluded. Clinically significant drug interactions mediated by CYP450 enzymes or UGT1A1 between ledipasvir/sofosbuvir are unlikely.

Patients receiving vitamin K antagonists

Since liver function may change during treatment with Sofgen-L, close monitoring of international normalized ratio (INR) values is recommended for these patients.

Effect of direct-acting antiviral treatment on drugs metabolized in the liver

The pharmacokinetics of drugs metabolized in the liver (e.g., immunosuppressive agents such as calcineurin inhibitors) may be affected by changes in liver function during treatment with direct-acting antivirals associated with HCV clearance.

Interaction between Sofgen-L and other medicinal products

Table 3 lists established or potentially clinically significant drug interactions (where the 90% confidence interval [CI] of the geometric mean ratio was within «↔», increased «↑», or decreased «↓» relative to pre-defined equivalence limits). The described drug interactions are based on studies conducted either with ledipasvir/sofosbuvir, or with ledipasvir and sofosbuvir as individual medicinal products, or represent probable drug interactions likely to occur with ledipasvir/sofosbuvir. The data in Table 3 are not exhaustive.

Table 3. Interaction between Sofgen-L and other medicinal products

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

b All drug interaction studies were conducted in healthy volunteers.

c Administered as Sofgen-L product.

d Boundaries of absence of pharmacokinetic interaction: 70–143%.

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

f Staggered administration (once every 12 hours) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate or darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Sofgen-L product yielded similar results.

g Study conducted in the presence of two other direct-acting antiviral agents.

h Bioequivalence/equivalence boundaries: 80–125%.

Special precautions for use.

Sofgen-L 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 Sofgen-L for the treatment of adult 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, including those with liver cirrhosis who have not received prior therapy (see section "Dosage and administration"). In cases of infection with genotype 3, the use of Sofgen-L (always in combination with ribavirin) may be considered for patients at high risk of clinical disease progression who have no alternative treatment options.

Clinical data supporting the use of Sofgen-L for the treatment of adult patients infected with HCV genotype 2 and genotype 6 are limited (see section "Pharmacodynamics").

Severe bradycardia and cardiac conduction block

Cases of life-threatening severe bradycardia and cardiac conduction block have been reported when treatment regimens containing sofosbuvir were used concomitantly with amiodarone. Bradycardia typically developed within hours to days, but cases with longer onset periods, mostly up to 2 weeks after initiation of HCV treatment, have also been observed.

Amiodarone should be prescribed to patients undergoing treatment with Sofgen-L only if alternative antiarrhythmic therapies are poorly tolerated or contraindicated.

If concomitant use of amiodarone is considered necessary, it is recommended to monitor patients cardially in an inpatient setting for the first 48 hours of such coadministration, followed by daily outpatient or self-monitoring of heart rate for at least the first 2 weeks of treatment.

Due to the long half-life of amiodarone, cardiac monitoring (as described above) should be ensured for patients who have discontinued amiodarone within the past several months and are initiating treatment with Sofgen-L.

All patients currently or recently taking amiodarone must be informed about the symptoms of bradycardia and cardiac conduction block and should seek immediate medical help if such symptoms occur.

Use in patients with diabetes mellitus

In patients with diabetes mellitus, treatment of HCV with direct-acting antiviral agents may affect glucose control and lead to symptomatic hypoglycemia. Glucose levels in diabetic patients starting treatment with direct-acting antivirals should be closely monitored, especially during the first 3 months, and adjustments to antidiabetic therapy should be made as needed. The physician managing the patient's diabetes should be informed about the initiation of direct-acting antiviral therapy.

Concomitant HCV/HBV (hepatitis B virus) infection

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

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

In patients who did not respond to ledipasvir/sofosbuvir treatment, resistance-associated mutations to NS5A, which reduce sensitivity to ledipasvir, are commonly observed (see section "Pharmacodynamics"). Some data suggest that such NS5A resistance mutations may not persist over prolonged follow-up. Currently, there are no data confirming the efficacy of retreatment with an NS5A inhibitor in patients who did not respond to ledipasvir/sofosbuvir. Similarly, there are no data confirming the efficacy of NS3/4A protease inhibitors in patients who previously failed therapy with these agents. Therefore, such patients may depend on other classes of medicinal products for HCV eradication.

Renal impairment

Safety data in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²) and end-stage renal disease (ESRD) requiring hemodialysis are limited. Sofgen-L may be used to treat these patients without dose adjustment when no other treatment options are available (see sections "Adverse reactions", "Pharmacodynamics", and "Pharmacokinetics"). When Sofgen-L is used in combination with ribavirin in patients with creatinine clearance (CrCl) < 50 mL/min, the prescribing information for ribavirin should also be followed (see section "Pharmacokinetics").

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

The efficacy of ledipasvir/sofosbuvir has not been studied in patients infected with HCV genotype 5 and genotype 6 who have decompensated liver cirrhosis and/or are awaiting or have undergone liver transplantation. Treatment with Sofgen-L 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 inducers of intestinal P-gp (e.g., oxcarbazepine) may reduce plasma concentrations of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Sofgen-L. Concomitant use of such products with Sofgen-L is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Use of certain antiretroviral therapies for HIV treatment

Sofgen-L has been shown to increase tenofovir concentrations, particularly when used concomitantly with HIV therapy containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate when used with Sofgen-L and a pharmacokinetic booster has not been studied. Potential risks and benefits associated with concomitant use of Sofgen-L 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 Sofgen-L together with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate with a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir. Recommendations for renal function monitoring 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 Sofgen-L 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").

Paediatric population

Sofgen-L is not recommended for children under 12 years of age, as safety and efficacy in this population have not been established.

Excipients

Sofgen-L contains lactose. This medicinal product is contraindicated in patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Women of childbearing potential / contraception in men and women

When Sofgen-L is used in combination with ribavirin, maximum efforts must be made to prevent pregnancy in female patients and female partners of male patients. Teratogenic and/or embryocidal effects of ribavirin have been observed in animal studies. Women of childbearing potential and their male partners must use effective contraception during treatment and after completion of treatment, according to the recommendations provided in the ribavirin prescribing information. For additional information, refer to the ribavirin prescribing information.

Pregnancy

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

Animal studies showed no signs of reproductive toxicity. No significant effects on fetal development were observed in rats and rabbits treated with ledipasvir or sofosbuvir. It was not possible to fully establish the exposure levels of sofosbuvir in rats relative to human exposure at the recommended clinical dose.

As a precautionary measure, use of Sofgen-L during pregnancy is not recommended.

Breastfeeding

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

Available animal pharmacokinetic data indicate that ledipasvir and metabolites of sofosbuvir are excreted in breast milk.

Risk to newborns/infants cannot be excluded. Therefore, Sofgen-L should not be used during breastfeeding.

Fertility

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

When Sofgen-L is used concomitantly with ribavirin, contraindications related to ribavirin use during pregnancy or breastfeeding must also be considered (see also the ribavirin prescribing information).

Ability to affect driving and use of machines.

Sofgen-L (when used alone or in combination with ribavirin) does not have a negative effect on the ability to drive or operate machinery. However, patients should be advised that fatigue has been reported more frequently in patients treated with ledipasvir/sofosbuvir than in the placebo group.

Administration and Dosage

Prescription and monitoring of the Sofgen-L medication must be carried out by a physician experienced in managing patients with HCV.

Dosage

The recommended dose of Sofgen-L is 1 tablet once daily, with or without food (see section "Pharmacokinetics").

Table 4. Recommended duration of treatment with Sofgen-L and recommended methods of administration of concomitantly prescribed ribavirin for specific patient subgroups

A Adults: ribavirin dosage is determined according to body weight (< 75 kg — 1000 mg, ≥ 75 kg — 1200 mg), administered orally with food, divided into two doses. Children: see Table 6 below.

B See Table 5 below for ribavirin dosing recommendations in patients with decompensated cirrhosis.

Table 5. Ribavirin dosing recommendations when co-administered with Sofgen-L in patients with decompensated cirrhosis

* If it is not possible to achieve a more normalized ribavirin dose (based on body weight and renal function) due to intolerance, consideration should be given to treating with the Sofogen-L + ribavirin combination for 24 weeks to reduce the risk of relapse.

When used in combination with ribavirin, also refer to the ribavirin instructions for medical use.

Below are the recommended daily doses of ribavirin for children aged 12 to 18 years. The daily dose should be divided into two administrations and taken with food.

Table 6. Dosing recommendations for ribavirin when used concomitantly with the medicinal product Sofogen-L in children aged 12 to 18 years

• Ribavirin should be administered orally in two divided doses with food.

Dose modification of ribavirin for adult patients receiving 1000–1200 mg daily. When Sofovir-L is used in combination with ribavirin and the patient experiences a serious adverse reaction potentially related to ribavirin, the dose of ribavirin should be modified or discontinued as necessary until the adverse reaction is resolved or its severity is reduced. Table 7 provides recommendations for dose modification and discontinuation based on the patient's hemoglobin levels and cardiac status.

Table 7. Recommendations for ribavirin dose modification when used concomitantly with Sofovir-L in adults.

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 per day, with subsequent dose escalation to 800 mg per day. Dose escalation of ribavirin to the initially prescribed dose (from 1000 mg to 1200 mg per day) is not recommended.

Children under 12 years of age. The safety and efficacy of Sofgen-L in children under 12 years of age have not been studied. No data are available.

Missed dose. Patients should be advised that if vomiting occurs within 5 hours after dosing, an additional 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 scheduled dose, the patient should take the tablet as soon as possible and take the next dose at the regularly scheduled time. If 18 hours or more have passed since the missed dose, the patient should wait until the next scheduled dose. Patients must not take a double dose of the medication.

Elderly patients. Dose adjustment for elderly patients is not required.

Renal impairment. Dose adjustment of Sofgen-L is not required in patients with mild or moderate renal impairment. Data on safety in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²) and end-stage renal disease (ESRD) requiring dialysis are limited. Sofgen-L may be used in such patients without dose adjustment when alternative treatment options are unavailable (see sections "Special precautions", "Adverse reactions", "Pharmacodynamics", and "Pharmacokinetics").

Hepatic impairment. Dose adjustment of Sofgen-L is not required in patients with mild, moderate, or severe hepatic impairment (Child-Pugh-Turcotte 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.

Patients must swallow the tablet whole. The tablet may be taken with food or independently of food intake. The film-coated tablets have a bitter taste; therefore, chewing or crushing is not recommended (see section "Pharmacokinetics").

Children

The safety and efficacy of Sofgen-L in children under 12 years of age have not been studied. Data in patients under 12 years of age are not available.

Overdose.

The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and 1200 mg as a single dose, 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 drug is unknown.

There is no specific antidote for overdose with Sofgen-L. In case of overdose, patients should be monitored for signs of toxicity. Management of overdose with Sofgen-L includes general supportive measures, including monitoring of vital functions and 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

In clinical trials, fatigue and headache were observed more frequently in patients receiving ledipasvir/sofosbuvir than in those receiving placebo. When ledipasvir/sofosbuvir was studied in combination with ribavirin, the most commonly observed adverse reactions were consistent with the established safety profile of ribavirin, without an increase in frequency or severity of reactions.

Adverse reactions observed during administration of ledipasvir/sofosbuvir are listed by system organ class and frequency (see Table 8). 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), or very rare (<1/10000).

Table 8. Adverse drug reactions identified during ledipasvir/sofosbuvir treatment

Patients with decompensated cirrhosis and/or patients awaiting liver transplantation, or patients 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 post-liver transplant patients was evaluated in two open-label studies (SOLAR-1 and SOLAR-2). No new adverse drug reactions were identified in decompensated cirrhosis patients and/or post-liver transplant patients receiving ledipasvir/sofosbuvir with ribavirin. Although adverse events, including serious adverse events, occurred more frequently in this study than in studies that did not include patients with decompensation and/or post-liver transplantation, the observed adverse events were predictable clinical consequences of advanced liver disease and/or transplantation or consistent with the established safety profile of ribavirin.

Hemoglobin levels decreased to < 100 g/L and < 85 g/L during treatment in 39% and 13% of patients receiving ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was discontinued in 15% of patients. Immunosuppressive agents were changed in 7% of liver transplant recipients.

Patients with renal impairment

Eighteen patients with genotype 1 HCV and severe renal impairment received ledipasvir/sofosbuvir for 12 weeks in an open-label study. Limited clinical safety data show that the frequency of adverse events was not clearly increased compared to that expected in patients with severe renal impairment.

The safety of ledipasvir/sofosbuvir was evaluated in a 12-week uncontrolled study involving 95 patients with ESRD requiring dialysis. Under these conditions, exposure to the sofosbuvir metabolite GS-331007 was increased 20-fold, exceeding levels at which adverse reactions were observed in nonclinical studies. Limited clinical safety data show that the frequency of adverse events and mortality was not clearly increased compared to that expected in patients with ESRD.

Paediatric patients

The safety profile of ledipasvir/sofosbuvir in children aged 12 to 18 years was evaluated in an open-label phase 2 clinical trial involving 100 patients infected with HCV genotype 1 who received ledipasvir/sofosbuvir for 12 weeks. The adverse reactions observed were consistent with those reported in adult clinical trials of ledipasvir/sofosbuvir (see Table 8).

Specific adverse reactions

Cardiac arrhythmia. Cases of severe bradycardia and heart block have been observed when ledipasvir/sofosbuvir is used concomitantly with amiodarone and/or other drugs that reduce heart rate (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Skin disorders. Cases of Stevens-Johnson syndrome have been reported. Frequency is unknown.

Reporting of adverse reactions

Reporting of adverse reactions following marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

28 tablets in a container; 1 container in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of manufacturing site.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India / Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.