Sofgen-v

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SOFGEN-V (SOFGEN-V)

Composition:

Active substances: sofosbuvir, velpatasvir;

One film-coated tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir;

Excipients: copovidone, microcrystalline cellulose, sodium croscarmellose, magnesium stearate; film coating: Opadry II Blue 85F505115 [polyvinyl alcohol, polyethylene glycol, titanium dioxide (E171), talc, indigo carmine (E 132), brilliant blue FCF (E133)].

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties: film-coated, oval-shaped, blue tablets with the inscription "H" on one side and "S21" 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 J05A P55.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Sofosbuvir is a pangenotypic inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B, which is essential for viral replication. It 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) does not inhibit human DNA or RNA polymerases and is not an inhibitor of mitochondrial RNA polymerase.

Velpatasvir is an HCV inhibitor targeting the HCV NS5A protein, which is essential for RNA replication and assembly of HCV virions. In vitro studies of selective and cross-resistance indicate that velpatasvir's mechanism of action is directed against NS5A.

Antiviral activity

The 50% effective concentration (EC50) values of sofosbuvir and velpatasvir against full-length or chimeric replicons encoding NS5B and NS5A sequences from laboratory strains are shown in Table 1. EC50 values for sofosbuvir and velpatasvir against clinical isolates are presented in Table 2.

Table 1. Activity of sofosbuvir and velpatasvir against full-length or chimeric laboratory replicons

N/D = no data

a Mean value from several experiments with one laboratory replicon.

b Stable chimeric replicons 1b carrying NS5B genes from genotypes 2b, 5a, or 6a were used for testing.

c Data from different strains of full-length NS5A replicons or chimeric NS5A replicons carrying full-length NS5A genes containing polymorphisms L31 or M31.

d Data from a chimeric NS5A replicon carrying NS5A amino acids 9–184.

Table 2. Activity of sofosbuvir and velpatasvir against chimeric replicons containing NS5A or NS5B from clinical isolates

N/D = no data

The presence of 40% human serum did not affect sofosbuvir activity against HCV, but it reduced velpatasvir activity against HCV genotype 1a replicons by 13-fold.

Evaluation of sofosbuvir in combination with velpatasvir showed no antagonistic effect resulting in reduced HCV RNA levels in replicon cells.

Resistance

In cell culture

HCV replicons with reduced sensitivity to sofosbuvir were selected in cell culture across various genotypes, including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced sensitivity to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes studied. Site-directed mutagenesis of the S282T substitution in replicons of genotypes 1–6 led to a 2- to 18-fold reduction in sensitivity to sofosbuvir and a 89–99% reduction in viral replication capacity compared to the corresponding wild-type. In biochemical assays, the ability of the active triphosphate metabolite of sofosbuvir (GS-461203) to inhibit recombinant NS5B polymerase containing the S282T substitution from genotypes 1b, 2a, 3a, and 4a was reduced compared to inhibition of wild-type recombinant NS5B polymerase, as indicated by an 8.5- to 24-fold increase in the 50% inhibitory concentration (IC50).

Under in vitro conditions, HCV replicons with reduced sensitivity to velpatasvir were selected in cell cultures across various genotypes, including 1a, 1b, 2a, 3a, 4a, 5a, and 6a. Resistant-associated variants (RAVs) selected at NS5A positions associated with resistance were at positions 24, 28, 30, 31, 32, 58, 92, and 93. RAVs selected in two or more genotypes included F28S, L31I/V, and Y93H. Site-directed mutagenesis of known NS5A RAVs demonstrated that substitutions leading to >100-fold reduction in sensitivity to velpatasvir were M28G, A92K, and Y93H/N/R/W in genotype 1a; A92K in genotype 1b; C92T and Y93H/N in genotype 2b; Y93H in genotype 3; and L31V and P32A/L/Q/R in genotype 6. No single substitutions tested in genotypes 2a, 4a, or 5a led to >100-fold reduction in sensitivity to velpatasvir. Combinations of these variants often demonstrated greater reduction in sensitivity to velpatasvir than individual RAVs alone.

In clinical studies

Patients without cirrhosis and patients with compensated cirrhosis

In a combined analysis of data from patients without cirrhosis or with compensated cirrhosis who received sofosbuvir/velpatasvir for 12 weeks in three Phase 3 studies, 12 patients (2 with genotype 1 and 10 with genotype 3) met criteria for resistance analysis due to lack of virologic response. One additional patient with baseline HCV genotype 3 infection was re-infected with HCV genotype 1a in the absence of virologic response and was excluded from virologic data analysis. No lack of virologic response was recorded in patients with HCV genotypes 2, 4, 5, or 6.

Of the 2 patients with genotype 1 infection and lack of virologic response, one had virus with emergence of the NS5A RAV Y93N, and the other had virus with emergence of NS5A RAVs L31I/V and Y93H in the absence of virologic response. Both patients had baseline NS5A RAVs. No NS5B nucleoside inhibitor (NI) RAVs were observed in the 2 non-responder patients.

Of the 10 patients with genotype 3 infection and lack of virologic response, the Y93H substitution was observed in all 10 non-responders (Y93H emerged post-treatment in 6 patients, and Y93H was present at baseline and post-treatment in 4 patients). No NS5B NI RAVs were observed in the 10 non-responder patients.

Patients with decompensated cirrhosis

In one Phase 3 study of patients with decompensated cirrhosis receiving sofosbuvir/velpatasvir + ribavirin for 12 weeks, 3 patients (1 with genotype 1 virus and 2 with genotype 3 virus) met criteria for resistance analysis due to lack of virologic response. No lack of virologic response was recorded in patients with HCV genotype 2 or 4 in the sofosbuvir/velpatasvir + ribavirin treatment group receiving 12 weeks of therapy.

In one patient with HCV genotype 1 infection and lack of virologic response, no NS5A or NS5B RAVs were observed in the absence of response.

Of the 2 patients with genotype 3 virus and lack of virologic response, one had emergence of the NS5A RAV Y93H in the absence of response. The other patient had virus with baseline Y93H substitution and lack of virologic response, and also developed low levels (<5%) of NS5B NI RAVs N142T and E237G in the absence of response. Pharmacokinetic data from this patient indicated non-adherence to the treatment regimen.

In this study, in 2 patients receiving sofosbuvir/velpatasvir for 12 or 24 weeks without ribavirin, emergence of the NS5B S282T variant at low levels (<5%) as well as L159F was observed.

Impact of baseline presence of hepatitis C virus resistance-associated variants on treatment outcomes

Patients without cirrhosis and patients with compensated cirrhosis

Analyses were conducted to investigate the association between baseline NS5A RAVs and treatment outcome in patients without cirrhosis or with compensated cirrhosis in three Phase 3 clinical studies (ASTRAL-1, ASTRAL-2, and ASTRAL-3). Of the 1035 patients treated with sofosbuvir/velpatasvir in the three Phase 3 studies, 1023 patients were included in the NS5A RAV analysis; 7 patients were excluded because they had neither achieved sustained virologic response (SVR12) nor lack of virologic response; an additional 5 patients were excluded due to inability to sequence the NS5A gene. In the combined analysis of Phase 3 study data, virus from 380 of 1023 (37%) patients had baseline NS5A RAVs. Patients with HCV genotype 2, 4, and 6 had higher prevalence of baseline NS5A RAVs (70%, 63%, and 52%, respectively) compared to patients infected with genotype 1 (23%), genotype 3 (16%), and genotype 5 (18%).

Baseline RAVs did not have a significant impact on SVR12 rates in patients with HCV genotypes 1, 2, 4, 5, and 6, briefly summarized in Table 3. Patients with genotype 3 infection and baseline NS5A RAV Y93H had lower SVR12 rates compared to patients without the Y93H substitution after 12 weeks of treatment with sofosbuvir/velpatasvir, briefly summarized in Table 4. In the ASTRAL-3 study, the Y93H RAV was detected at baseline in 9% of patients receiving sofosbuvir/velpatasvir treatment.

Table 3. SVR12 in patients with or without baseline NS5A RAVs by HCV genotype (ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies)

Table 4. SVR12 in patients with and without Y93H at baseline, threshold value 1% (resistance analysis population), study ASTRAL-3

NS5B RAS to NI S282T was not detected at baseline in the NS5B sequence of any patients in the phase 3 studies. SVR12 was achieved in all 77 patients who had baseline NS5B RASs, including N142T, L159F, E/N237G, C/M289L/I, L320F/I/V, V321A/I, and S282G+V321I.

Patients with decompensated cirrhosis (Child–Pugh–Turcotte class B)

Analyses were conducted to evaluate the relationship between baseline NS5A RASs and treatment outcome in patients with decompensated cirrhosis in one phase 3 study (ASTRAL-4). Of the 87 patients treated with sofosbuvir/velpatasvir + ribavirin, 85 patients were included in the NS5A RAS analysis; 2 patients were excluded due to neither achieving SVR12 nor experiencing virologic failure. Among patients receiving sofosbuvir/velpatasvir + ribavirin for 12 weeks, 29% (25 of 85) had baseline NS5A RASs: 29% (19 of 66), 75% (3 of 4), 15% (2 of 13), and 50% (1 of 2) of patients with HCV genotypes 1, 2, 3, and 4, respectively.

SVR12 in patients with or without baseline NS5A RASs in the sofosbuvir/velpatasvir + ribavirin treatment group for 12 weeks in this study is shown in Table 5.

Table 5. SVR12 in patients with or without baseline NS5A RASs by HCV genotype (ASTRAL-4 study)

In one patient with genotype 3 virus who had baseline NS5A RASs and did not achieve SVR12, the baseline NS5A Y93H substitution was present; this patient's pharmacokinetic data were attributed to non-adherence to the treatment regimen.

In three patients in the 12-week sofosbuvir/velpatasvir plus ribavirin treatment group, baseline NS5B RASs to NS5A inhibitors (N142T and L159F) were present; SVR12 was achieved in all three patients.

Cross-resistance

In vitro studies indicate that most NS5A RASs conferring resistance to ledipasvir and daclatasvir remain sensitive to velpatasvir. Velpatasvir retains full activity against the S282T substitution in NS5B associated with resistance to sofosbuvir, while all substitutions associated with resistance to velpatasvir in NS5A remain fully sensitive to sofosbuvir. Sofosbuvir and velpatasvir 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. The efficacy of sofosbuvir/velpatasvir has not been evaluated in patients who previously failed treatment regimens containing an NS5A inhibitor.

Paediatric population

The European Medicines Agency has granted a waiver for the obligation to submit the results of studies with sofosbuvir/velpatasvir in one or more subsets of the paediatric population for the treatment of chronic hepatitis C (for use in paediatric patients, see section "Posology and method of administration").

Elderly patients

Clinical studies of sofosbuvir/velpatasvir included 156 patients aged 65 years and older (12% of the total number of patients in phase 3 clinical trials). The response rate observed in patients aged ≥65 years was the same as in patients aged <65 years across all treatment groups.

Pharmacokinetics

Absorption

The pharmacokinetic properties of sofosbuvir, GS-331007, and velpatasvir were evaluated in healthy adult volunteers and in patients with chronic hepatitis C. After oral administration of the sofosbuvir/velpatasvir medicinal product, sofosbuvir was rapidly absorbed, with median peak plasma concentration observed at 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed at 3 hours post-dose. Median peak plasma concentration of velpatasvir was observed at 3 hours post-dose.

Based on population pharmacokinetic analysis in patients with HCV infection, the mean steady-state area under the pharmacokinetic curve AUC_0–24 for sofosbuvir (n = 982), GS-331007 (n = 1428), and velpatasvir (n = 1425) was 1260, 13970, and 2970 ng×h/mL, respectively. Steady-state C_max values for sofosbuvir, GS-331007, and velpatasvir were 566, 868, and 259 ng/mL, respectively. AUC_0–24 and C_max values for sofosbuvir and GS-331007 were similar in healthy adult volunteers and HCV-infected patients. Compared to healthy volunteers (n = 331), AUC_0–24 and C_max values for velpatasvir were 37% and 41% lower, respectively, in HCV-infected patients.

Effect of food intake

Compared to fasting, administration of a single dose of sofosbuvir/velpatasvir with a meal containing moderate fat (~600 kcal, 30% fat) or high fat (~800 kcal, 50% fat) resulted in a 34% and 21% increase, respectively, in AUC_0–inf and a 31% and 5% increase, respectively, in C_max for velpatasvir. Moderate or high fat content in food increased AUC_0–inf of sofosbuvir by 60% and 78%, respectively, but did not substantially affect C_max of sofosbuvir. Moderate or high fat content in food did not alter AUC_0–inf of GS-331007 but led to a 25% and 37% reduction, respectively, in C_max. Response rates in phase 3 studies were similar in HCV-infected patients who received sofosbuvir/velpatasvir with or without food. The medicinal product Sofgen-V can be administered regardless of food intake.

Distribution

Sofosbuvir is approximately 61–65% bound to human plasma proteins, and binding is independent of drug concentration in the range of 1–20 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 ratio of [14C]-radioactive compounds in blood to plasma was approximately 0.7.

Velpatasvir is >99.5% bound to human plasma proteins, and binding is independent of drug concentration in the range of 0.09–1.8 µg/mL. After a single dose of 100 mg [14C]-velpatasvir in healthy volunteers, the ratio of [14C]-radioactive compounds in blood to plasma ranged from 0.52 to 0.67.

Biotransformation

Sofosbuvir is actively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxylic acid ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1), followed by cleavage of the phosphoramidate by histidine triad nucleotide-binding protein 1 (HINT1), and subsequent phosphorylation via pyrimidine nucleotide biosynthesis. Dephosphorylation leads to the formation of the nucleoside metabolite GS-331007, which cannot be efficiently re-phosphorylated and lacks anti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. After a single 400 mg dose of [14C]-sofosbuvir, GS-331007 accounted for approximately >90% of total systemic exposure.

Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover. After a single 100 mg dose of [14C]-velpatasvir, the majority (>98%) of radioactive compounds in plasma were attributable to the parent drug. Metabolites identified in human plasma included monohydroxylated and demethylated derivatives of velpatasvir. Unchanged velpatasvir is the main compound excreted in feces.

Elimination

After a single oral dose of 400 mg [14C]-sofosbuvir, mean total elimination of [14C]-radioactive compounds exceeded 92%: approximately 80%, 14%, and 2.5% were excreted in urine, feces, and expired air, respectively. The majority of the administered 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 major elimination pathway for GS-331007. The median terminal half-life of sofosbuvir and GS-331007 after administration of sofosbuvir/velpatasvir was 0.5 and 25 hours, respectively.

After a single oral dose of 100 mg [14C]-velpatasvir, mean total elimination of [14C]-radioactive compounds was 95%: approximately 94% and 0.4% were excreted in feces and urine, respectively. Unchanged velpatasvir was the main component in feces, accounting for on average 77% of the administered dose; monohydroxylated velpatasvir accounted for 5.9%, and demethylated velpatasvir for 3.0%. These data indicate that biliary excretion of the parent drug is the main elimination pathway for velpatasvir. The median terminal half-life of velpatasvir after administration of sofosbuvir/velpatasvir was approximately 15 hours.

Linearity/non-linearity

AUC values for velpatasvir increase almost proportionally with dose in the range of 25–150 mg. AUC values for sofosbuvir and GS-331007 are nearly proportional to doses in the range of 200–1200 mg.

Potential in vitro drug interaction between sofosbuvir/velpatasvir medicinal products

Sofosbuvir and velpatasvir are substrates of P-glycoprotein and breast cancer resistance protein (BCRP) transporters, while GS-331007 is not a substrate. Velpatasvir is also a substrate of OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 isoenzymes was observed.

Velpatasvir is an inhibitor of P-glycoprotein, BCRP, OATP1B1, and OATP1B3 transporters; thus, its involvement in drug interactions with these transporters is primarily limited to the absorption phase. At clinically relevant plasma concentrations, velpatasvir is not an inhibitor of hepatic transporters: bile salt export pump (BSEP), sodium-taurocholate co-transporting polypeptide (NTCP), OATP2B1, OATP1A2, or organic cation transporter (OCT) 1; renal transporters: OCT2, OAT1, OAT3, multidrug resistance-associated protein 2 (MRP2), or multidrug and toxin extrusion (MATE) 1; nor of CYP isoenzymes or uridine glucuronosyltransferase (UGT) 1A1 enzymes.

Sofosbuvir and GS-331007 are not inhibitors of P-glycoprotein, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, or OCT1 transporters. GS-331007 is not an inhibitor of OAT1, OCT2, or MATE1.

Pharmacokinetics in specific populations

Race and sex

No clinically significant pharmacokinetic differences based on race or sex were observed for sofosbuvir, GS-331007, or velpatasvir.

Elderly patients

Population pharmacokinetic analysis in HCV-infected patients showed that within the analyzed age range (18–82 years), age had no clinical effect on exposure to sofosbuvir, GS-331007, or velpatasvir.

Renal impairment

The effect of various degrees of renal impairment on exposure to components of sofosbuvir/velpatasvir compared to subjects with normal renal function is presented in Table 6 and described below.

Table 6. Effect of various degrees of renal impairment on exposure (AUC) of sofosbuvir, GS-331007, and velpatasvir compared to subjects with normal renal function

Pharmacokinetics of sofosbuvir were evaluated in non-HCV-infected patients with mild (eGFR [estimated glomerular filtration rate] ≥ 50 to < 80 mL/min/1.73 m²), moderate (eGFR ≥ 30 to < 50 mL/min/1.73 m²), and severe (eGFR < 30 mL/min/1.73 m²) renal impairment, as well as in patients with end-stage renal disease (ESRD) requiring hemodialysis, following a single 400 mg dose of sofosbuvir, compared to patients with normal renal function (eGFR > 80 mL/min/1.73 m²). GS-331007 was efficiently removed by hemodialysis, with a dialysis extraction coefficient of approximately 53%. During a 4-hour hemodialysis session following a single 400 mg dose of sofosbuvir, 18% of the administered dose was removed.

In HCV-infected patients with severe renal impairment receiving sofosbuvir 200 mg with ribavirin (n = 10) or sofosbuvir 400 mg with ribavirin (n = 10) for 24 weeks, or ledipasvir/sofosbuvir 90/400 mg (n = 18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with those observed in non-HCV-infected patients with severe renal impairment.

The pharmacokinetics of velpatasvir were studied after a single 100 mg dose of velpatasvir in non-HCV-infected patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault formula).

The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were evaluated in HCV-infected patients with end-stage renal disease (ESRD) requiring hemodialysis, treated with sofosbuvir/velpatasvir (n = 59) for 12 weeks, compared to those in patients without renal impairment in Phase 2/3 sofosbuvir/velpatasvir trials.

Hepatic impairment

The pharmacokinetics of sofosbuvir were evaluated after 7 days of treatment with 400 mg sofosbuvir in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh-Turcotte class B and C). Compared to patients with normal hepatic function, the AUC₀–₂₄ of sofosbuvir was 126% and 143% higher, respectively, in patients with moderate or severe hepatic impairment, while the AUC₀–₂₄ of GS-331007 was 18% and 9% higher, respectively. Population pharmacokinetic analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on exposure to sofosbuvir and GS-331007.

The pharmacokinetics of velpatasvir were evaluated after a single 100 mg dose of velpatasvir in non-HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh-Turcotte class B and C). Compared to patients with normal hepatic function, total plasma exposure to velpatasvir (AUCinf) was similar in patients with moderate or severe hepatic impairment. Population pharmacokinetic analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no significant clinical effect on velpatasvir exposure (see section "Dosage and administration").

Body weight

Body weight has no clinically significant effect on exposure to sofosbuvir or velpatasvir based on population pharmacokinetic analysis.

Paediatric population

The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir have not been studied in children (see section "Dosage and administration").

Clinical characteristics.

Indications.

Sofgen-V is indicated for the treatment of chronic hepatitis C virus (HCV) in adults (see sections "Dosage and administration", "Special precautions", and "Pharmacodynamics").

Contraindications.

Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition".

Use with potent inducers of P-glycoprotein and CYP

Concomitant use of medicinal products that are potent inducers of P-glycoprotein and/or cytochrome P450 (CYP) (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin, and St. John’s wort preparations) is contraindicated, as this may substantially reduce plasma concentrations of sofosbuvir and velpatasvir, leading to loss of therapeutic efficacy of Sofgen-V (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Since Sofgen-V contains sofosbuvir and velpatasvir, any interactions established for these active substances individually may also occur with Sofgen-V.

Potential effect of Sofgen-V on other medicinal products

Velpatasvir is an inhibitor of drug transporters: P-glycoprotein, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3. Concomitant administration of Sofgen-V with drugs that are substrates of these transporters may increase exposure to these drugs. Examples of interactions with sensitive substrates of P-glycoprotein (digoxin), BCRP (rosuvastatin), and OATP (pravastatin) are shown in Table 7.

Potential effect of other medicinal products on Sofgen-V

Sofosbuvir and velpatasvir are substrates of P-glycoprotein and BCRP transporters. Velpatasvir is also a substrate of the drug transporter OATP1B. In vitro studies have shown slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 isoenzymes. Medicinal products that are potent inducers of P-glycoprotein and/or CYP2B6, CYP2C8, or CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin, and St. John’s wort preparations) may reduce plasma concentrations of sofosbuvir or velpatasvir, resulting in decreased therapeutic effect of sofosbuvir/velpatasvir. Concomitant use of such drugs with Sofgen-V is contraindicated (see section "Contraindications"). Medicinal products that are moderate inducers of P-glycoprotein and/or CYP (e.g., efavirenz, modafinil, oxcarbazepine, or rifapentine) may reduce plasma concentrations of sofosbuvir or velpatasvir, leading to reduced therapeutic effect of Sofgen-V. Concomitant use of such drugs with Sofgen-V is not recommended (see section "Special precautions"). Concomitant use with medicinal products that inhibit P-glycoprotein or BCRP may increase plasma concentrations of sofosbuvir or velpatasvir. Medicinal products that inhibit OATP, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentrations of velpatasvir. Clinically significant interactions of medicinal products with Sofgen-V mediated by inhibitors of P-glycoprotein, BCRP, OATP, or CYP450 are not expected; Sofgen-V may be used concomitantly with inhibitors of P-glycoprotein, BCRP, OATP, and CYP.

Patients receiving vitamin K antagonists

Since liver function may change during treatment with Sofgen-V, careful monitoring of international normalized ratio (INR) values is recommended in such patients.

Effect of direct-acting antivirals on medicinal products metabolized in the liver

Pharmacokinetics of medicinal products metabolized in the liver (e.g., immunosuppressants such as calcineurin inhibitors) may be affected by changes in liver function during therapy with direct-acting antivirals associated with HCV clearance.

Interaction of Sofgen-V with other medicinal products

Table 7 lists established or potentially clinically significant drug interactions (where 90% confidence interval [CI] of the geometric mean ratio calculated by least squares means method was within "↔", increased "↑", or decreased "↓" within defined interaction limits). The described drug interactions are based on studies conducted with sofosbuvir/velpatasvir or velpatasvir and sofosbuvir as individual substances, or are predicted drug interactions likely for sofosbuvir/velpatasvir. The table is not exhaustive.

Table 7. Interaction of Sofgen-V with other medicinal products

a Mean ratio (90 % CI) of pharmacokinetics of co-administered drugs for investigational drugs alone or in combination. No effect = 1.00.

b All drug interaction studies conducted in healthy volunteers.

c Administered as Sofgen-V.

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

e These medicinal products belong to a class where a similar interaction can be predicted.

f Bioequivalence/equivalence boundary: 80–125 %.

g Boundaries of no pharmacokinetic interaction: 50–200 %.

Drugs with no clinically significant interactions with sofosbuvir/velpatasvir

Based on drug interaction studies conducted with sofosbuvir or velpatasvir, no clinically significant drug interactions have been observed or are expected with the following medicinal products:

Sofosbuvir/velpatasvir: atazanavir/ritonavir, buprenorphine/naloxone, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, methadone, naltrexone, or raltegravir.

Sofosbuvir: ethinylestradiol/norgestimate or tacrolimus.

Velpatasvir: ethinylestradiol/norgestimate, ketoconazole, or pravastatin.

Special precautions for use.

Sofgen-V should not be used concomitantly with other medicinal products containing sofosbuvir.

Severe bradycardia and heart block

Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir was administered in combination with amiodarone. Bradycardia typically occurred within hours to days, but cases with later onset have also been reported, mostly within 2 weeks after initiation of hepatitis C virus (HCV) treatment.

Amiodarone should be used in patients receiving Sofgen-V only if alternative antiarrhythmic therapies are intolerable or contraindicated.

If concomitant use of amiodarone is necessary, it is recommended that patients undergo cardiac monitoring in an inpatient setting for the first 48 hours of co-administration, 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, appropriate monitoring is required for patients who have discontinued amiodarone within the previous few months and are initiating Sofgen-V.

All patients receiving amiodarone concomitantly or recently should be warned about symptoms of bradycardia and heart block and advised to seek immediate medical attention if such symptoms occur.

Patients co-infected with hepatitis C virus or hepatitis B virus (HCV/HBV)

Cases of hepatitis B virus (HBV) reactivation, some of which were fatal, have been reported during or after treatment with direct-acting antiviral agents. Testing for hepatitis B virus (HBV) should be performed in all patients prior to initiating treatment. Patients co-infected with hepatitis B and hepatitis C viruses (HBV/HCV) are at risk of HBV reactivation and should therefore be managed according to current clinical guidelines.

Patients who previously failed NS5A inhibitor therapy

There are no clinical data supporting the efficacy of sofosbuvir/velpatasvir in patients who previously failed therapy with an NS5A inhibitor. However, the use of Sofgen-V plus ribavirin for 24 weeks may be considered in patients who previously failed NS5A inhibitor therapy or who are considered to be at high risk of disease progression and for whom no alternative treatment options are available.

Renal impairment

Safety data in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) and end-stage renal disease (ESRD) requiring hemodialysis are limited. Sofgen-V may be used in these patients without dose adjustment if no alternative treatment is available (see sections "Adverse reactions", "Pharmacodynamics", and "Pharmacokinetics"). If Sofgen-V is prescribed in combination with ribavirin, refer also to the ribavirin prescribing information for patients with creatinine clearance < 50 mL/min (see section "Pharmacokinetics").

Use with P-glycoprotein and/or moderate CYP inducers

Medicinal products that are inducers of P-glycoprotein and/or moderate CYP inducers (e.g., efavirenz, modafinil, oxcarbazepine, or rifapentine) may reduce plasma concentrations of sofosbuvir or velpatasvir, leading to reduced therapeutic effect of Sofgen-V. Concomitant use of such agents with Sofgen-V is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Use with certain antiretroviral regimens for HIV infection

Sofgen-V has been shown to increase tenofovir exposure, particularly when used in combination with HIV treatment regimens containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in combination with Sofgen-V and a pharmacokinetic booster has not been established. The potential risks and benefits of concomitant use of Sofgen-V with a fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate in combination with a boosted HIV protease inhibitor (e.g., atazanavir or darunavir) should be carefully considered, especially in patients with increased risk of renal impairment. Patients receiving Sofgen-V concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with a boosted HIV protease inhibitor should be monitored for adverse reactions associated with tenofovir. Recommendations for monitoring renal function can be found in the prescribing information for tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate.

Use in diabetic patients

In patients with diabetes, an effect on glucose control may occur, potentially leading to symptomatic hypoglycemia after initiation of direct-acting antiviral therapy for hepatitis C virus (HCV) infection. Glucose levels in diabetic patients initiating direct-acting antiviral therapy should be closely monitored, particularly during the first 3 months, and their antidiabetic medications adjusted as necessary. The physician managing the patient's diabetes care should be informed about the initiation of direct-acting antiviral therapy.

Child-Pugh-Turcotte class C cirrhosis

The safety and efficacy of sofosbuvir/velpatasvir in patients with Child-Pugh-Turcotte class C cirrhosis have not been evaluated (see sections "Adverse reactions" and "Pharmacodynamics").

Patients with liver transplant

The safety and efficacy of sofosbuvir/velpatasvir for the treatment of HCV infection in patients with liver transplant have not been evaluated. Treatment with Sofgen-V according to the recommended dosage (see section "Dosage and administration") should be prescribed based on an individual assessment of potential benefits and risks for each patient.

People who inject drugs, including those receiving medication-assisted treatment (MAT) for opioid use disorder

Based on phase 2 data from the SIMPLIFY study, the safety and efficacy of sofosbuvir/velpatasvir in patients who self-reported injecting drug use, including those receiving MAT, were similar to the known safety and efficacy profile. Dose adjustment of Sofgen-V is not recommended for patients who inject drugs, including those on MAT for opioid use disorder.

Use during pregnancy or breastfeeding.

Pregnancy

Information on the use of sofosbuvir, velpatasvir, or the medicinal product sofosbuvir/velpatasvir in pregnant women is unavailable or limited (fewer than 300 pregnancy cases).

Sofosbuvir

Animal studies did not indicate direct or indirect toxic effects on the reproductive system.

It was not possible to fully assess the margin of exposure of sofosbuvir in rats compared to exposure in humans at the recommended clinical dose.

Velpatasvir

Animal studies did not reveal any toxic effect on the reproductive system.

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

Breastfeeding

It is unknown whether sofosbuvir, sofosbuvir metabolites, or velpatasvir are excreted in human breast milk.

Available pharmacokinetic data in animals show excretion of velpatasvir and sofosbuvir metabolites into breast milk.

Risk to newborns/infants cannot be excluded. Therefore, Sofgen-V should not be used in women who are breastfeeding.

Fertility

Data on the effect of sofosbuvir/velpatasvir on human fertility are not available. Animal studies do not indicate harmful effects of sofosbuvir and velpatasvir on fertility.

If ribavirin is used concomitantly with Sofgen-V, detailed recommendations regarding pregnancy, contraception, and breastfeeding can be found in the ribavirin prescribing information.

Ability to affect driving and use of machines.

Sofgen-V has no effect or has a negligible effect on the ability to drive and use machines.

Administration and Dosage

Treatment with the medicinal product Sofgen-V should be initiated and supervised by a physician experienced in managing patients with HCV infection.

Dosing

The recommended dose of Sofgen-V is one tablet taken orally once daily, with or without food (see section "Pharmacokinetics").

Table 8. Recommended treatment and its duration for all HCV genotypes

a Includes patients co-infected with human immunodeficiency virus (HIV) and patients with recurrent hepatitis C virus (HCV) after liver transplantation (see section "Special precautions for use").

If used in combination with ribavirin, also refer to the ribavirin medical product information.

The recommended doses below apply when ribavirin is divided into two daily doses and administered with food.

Table 9. Recommended ribavirin dosing when used in combination with Sofgen-V in patients with decompensated cirrhosis

The recommended dose of ribavirin for patients with genotype 3 infection and compensated cirrhosis (pre- or post-liver transplantation) is 1000/1200 mg (1000 mg for patients with body weight < 75 kg and 1200 mg for patients with body weight ≥ 75 kg).

For ribavirin dose modifications, refer to the ribavirin prescribing information.

If vomiting occurs within 3 hours after taking the medicine, patients should take an additional tablet of Sofgen-V. If vomiting occurs more than 3 hours after taking the medicine, an additional dose of Sofgen-V is not required (see section "Pharmacodynamics").

If a dose of Sofgen-V is missed and less than 18 hours have passed since the usual dosing time, patients should be instructed to take the tablet as soon as possible, then take the next dose at the usual time. If more than 18 hours have passed, patients should wait and take the next dose of Sofgen-V at the usual time. Patients should not take a double dose of Sofgen-V.

Patients who have previously failed NS5A inhibitor therapy

Treatment with Sofgen-V + ribavirin for 24 weeks may be considered (see section "Special warnings and precautions for use").

Elderly patients

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

Renal impairment

Dose adjustment of Sofgen-V is not required in patients with mild or moderate renal impairment. Data in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²) and in patients with end-stage renal disease (ESRD) requiring hemodialysis are limited. Sofgen-V may be used in these patients without dose adjustment if no alternative treatment is available (see sections "Special warnings and precautions for use", "Undesirable effects", "Pharmacodynamics" and "Pharmacokinetics").

Hepatic impairment

Dose adjustment of Sofgen-V is not required in patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) (see section "Pharmacokinetics"). The safety and efficacy of Sofgen-V have been evaluated in patients with Child-Pugh class B cirrhosis, but not in patients with Child-Pugh class C cirrhosis (see sections "Special warnings and precautions for use", "Undesirable effects" and "Pharmacodynamics").

Paediatric population

The safety and efficacy of sofosbuvir/velpatasvir in children and adolescents (under 18 years of age) have not been established. There is no data available.

Method of administration

For oral use.

Patients should swallow the tablet whole, with or without food (see section "Pharmacokinetics"). Due to the bitter taste, it is recommended not to chew or crush the film-coated tablet.

Children

The safety and efficacy of sofosbuvir/velpatasvir in children and adolescents (under 18 years of age) have not been established. There is no data available.

Overdose

The highest documented doses of sofosbuvir and velpatasvir were single doses of 1200 mg and 500 mg, respectively. In these studies conducted in healthy volunteers, no adverse effects were observed at these dose levels, and adverse events were similar in frequency and severity to those observed in placebo groups. The effects of higher doses/exposures are unknown.

There is no specific antidote in the event of an overdose with Sofgen-V. In case of overdose, the patient should be monitored for signs of toxicity. Management of overdose consists of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Hemodialysis may effectively remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of velpatasvir due to its high plasma protein binding.

Adverse Reactions

Clinical trial experience

In a Phase 3 clinical trial involving patients with hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection, the proportion of patients who permanently discontinued treatment due to adverse events was 0.2%, and the proportion of patients who experienced any serious adverse events was 3.2% among those who received the sofosbuvir/velpatasvir medicinal product for 12 weeks. In clinical trials, headache, fatigue, and nausea were the most common (incidence ≥ 10%) adverse events reported during treatment with sofosbuvir/velpatasvir for 12 weeks. These and other adverse events were reported at similar frequencies in patients receiving placebo and in patients receiving sofosbuvir/velpatasvir in the Phase 3 pivotal clinical trials.

Adverse reactions in patients who inject drugs, including those receiving medication-assisted treatment (MAT) for opioid use disorder

The safety of sofosbuvir/velpatasvir in individuals who inject drugs is based on an open-label Phase 2 trial (SIMPLIFY), which included 103 adult patients with chronic hepatitis C virus genotypes 1, 2, 3, and 4.

Patients who self-reported injecting drug use within 6 months prior to initiation of treatment were eligible to participate and received sofosbuvir/velpatasvir treatment for 12 weeks. The study included a subgroup of 58 patients who were receiving MAT for opioid use disorder.

Adverse reactions observed in the SIMPLIFY trial, both overall and in patients receiving MAT, were consistent with the known safety profile of sofosbuvir/velpatasvir. The most common adverse reactions overall were fatigue (18%), nausea (13%), and headache (11%). No patient experienced adverse reactions leading to permanent discontinuation of treatment.

Adverse reactions observed with the use of sofosbuvir/velpatasvir are based on safety data from clinical trials and post-marketing experience. All adverse reactions are listed in Table 10. The reactions are categorized by system organ class and frequency. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), or very rare (< 1/10,000).

Table 10. Adverse drug reactions identified during the use of sofosbuvir/velpatasvir

A side effect identified through post-marketing surveillance of medicinal products containing sofosbuvir/velpatasvir.

Patients with decompensated liver cirrhosis

The safety profile of the sofosbuvir/velpatasvir medicinal product was evaluated in one open-label study in which patients with Child-Pugh-Turcotte class B cirrhosis received sofosbuvir/velpatasvir for 12 weeks (n = 90), sofosbuvir/velpatasvir + ribavirin for 12 weeks (n = 87), or sofosbuvir/velpatasvir for 24 weeks (n = 90). The observed adverse events were consistent with the expected clinical complications of decompensated liver disease or the known toxicity profile of ribavirin in patients receiving sofosbuvir/velpatasvir in combination with ribavirin.

Among the 87 patients treated with sofosbuvir/velpatasvir + ribavirin for 12 weeks, hemoglobin reductions to less than 10 g/dL and 8.5 g/dL during treatment were observed in 23% and 7% of patients, respectively. Treatment with ribavirin had to be discontinued due to adverse events in 15% of patients receiving sofosbuvir/velpatasvir + ribavirin for 12 weeks.

Patients with renal impairment

The safety of the sofosbuvir/velpatasvir medicinal product was evaluated in a 12-week uncontrolled study, particularly in 59 subjects with end-stage chronic renal disease (ESRD) requiring dialysis (Study 4062). Under these conditions, exposure to the sofosbuvir metabolite GS-331007 increased 20-fold, exceeding levels at which adverse reactions were observed in preclinical studies. Based on clinical safety data, the frequency of adverse events and death was not clearly increased beyond what is expected in patients with ESRD.

Description of selected adverse reactions

Cardiac arrhythmia

Cases of severe bradycardia and heart block have been observed when medicinal products containing sofosbuvir are used in combination with amiodarone and/or other medicinal products that reduce heart rate (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Skin disorders

Frequency not known: Stevens-Johnson syndrome.

Reporting suspected adverse reactions.

It is important to report suspected adverse reactions after medicinal product authorization. This allows continuous monitoring of the benefit-risk balance associated with the use of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

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

Prescription category.

Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's location and address of the site of operation.

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