Mayhep

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MyHep (MyHep)

Composition:

Active substance: sofosbuvir;

One film-coated tablet contains 400 mg of sofosbuvir;

Excipients: mannite (E 421), microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: Opadry® II Orange 85F530025: talc; titanium dioxide (E 171); iron oxide red (E 172); polyvinyl alcohol, partially hydrolyzed; iron oxide yellow (E 172); iron oxide black (E 172); macrogol.

Pharmaceutical form. Film-coated tablets.

Basic physicochemical properties: biconvex capsule-shaped film-coated tablets, peach-colored, with beveled edges, embossed with "SF400" on one side and "M" on the other.

Pharmacotherapeutic group

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

ATC code J05A P08.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Sofosbuvir is a pangenotypic inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In biochemical assays, GS-461203 inhibited recombinant NS5B polymerase activity of HCV genotypes 1b, 2a, 3a, and 4a with 50% inhibitory concentration (IC50) values ranging from 0.7 to 2.6 µM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA- and RNA-polymerases, nor is it an inhibitor of mitochondrial RNA polymerase.

Antiviral Activity

In HCV replication assays, the effective concentration (EC50) values of sofosbuvir against full-length replicons of genotypes 1a, 1b, 2a, 3a, and 4a were 0.04, 0.11, 0.05, 0.05, and 0.04 µM, respectively. The EC50 values of sofosbuvir against hybrid replicons containing NS5B from genotypes 2b, 5a, or 6a were between 0.014 and 0.015 µM. The mean ± SD EC50 of sofosbuvir against hybrid replicons encoding NS5B sequences from clinical isolates was 0.068 ± 0.024 µM for genotype 1a (n = 67), 0.11 ± 0.029 µM for genotype 1b (n = 29), 0.035 ± 0.018 µM for genotype 2 (n = 15), and 0.085 ± 0.034 µM for genotype 3a (n = 106). In these assays, the in vitro antiviral activity of sofosbuvir against less common genotypes 4, 5, and 6 was similar to that observed against genotypes 1, 2, and 3.

The presence of 40% human serum had no effect on the antiviral activity of sofosbuvir against HCV.

Resistance

Cell Culture. HCV replicons with reduced sensitivity to sofosbuvir were selected in cell culture for multiple genotypes, including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced sensitivity to sofosbuvir was associated with the primary NS5B substitution S282T across all tested replicon genotypes. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes resulted in 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, recombinant NS5B polymerase from genotypes 1b, 2a, 3a, and 4a expressing the S282T substitution showed reduced sensitivity to GS-461203 compared to the corresponding wild-type enzymes.

Clinical Studies. Adults. In a pooled analysis of 991 patients receiving sofosbuvir in phase 3 trials, 226 patients were selected for resistance analysis due to virologic failure or early discontinuation of treatment and had HCV RNA > 1000 IU/mL. Baseline NS5B sequencing was available for 225 of the 226 patients; deep sequencing (analysis cutoff 1%) was performed on 221 of these patients. The S282T substitution associated with resistance to sofosbuvir was not detected in any of these patients by deep sequencing or population sequencing. The S282T substitution in NS5B was detected in one patient who received sofosbuvir monotherapy in a phase 2 study. This patient had <1% HCV S282T at baseline and S282T (>99%) at week 4 of treatment, resulting in a 13.5-fold change in EC50 for sofosbuvir and reduced viral replication capacity. The S282T substitution reverted to wild-type within the following 8 weeks and was no longer detectable by deep sequencing at week 12 post-treatment.

Two NS5B substitutions—L159F and V321A—were detected in post-treatment samples from three patients infected with HCV across multiple genotypes in phase 3 clinical trials. No change in phenotypic sensitivity to sofosbuvir or ribavirin was observed in isolates from patients with these substitutions. Additionally, substitutions S282R and L320 were detected during treatment by deep sequencing in a patient pre-transplant with partial response to therapy. The clinical significance of these findings is unknown.

Impact of Baseline HCV Polymorphisms on Treatment Outcome

Adults

Baseline NS5B sequences were obtained for 1292 patients in phase 3 trials using population sequencing, and the S282T substitution was not detected in any patient with available baseline sequence. In the analysis assessing the impact of baseline polymorphisms on treatment outcome, no statistically significant association was observed between the presence of any baseline HCV NS5B variant and treatment outcomes.

Cross-resistance

HCV replicons expressing the S282T substitution associated with resistance to sofosbuvir remained fully sensitive to other classes of HCV antiviral agents. Sofosbuvir retained activity against NS5B substitutions (L159F and L320F) associated with resistance to other nucleoside inhibitors. Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting antivirals with different mechanisms of action: non-nucleoside NS5B inhibitors, NS3 protease inhibitors, and NS5A inhibitors.

Clinical Studies in Patients with Renal Impairment

Study 0154 was an open-label clinical trial evaluating 24 weeks of treatment with sofosbuvir in combination with ribavirin in 20 HCV-infected patients with genotype 1 or 3 and end-stage renal disease (ESRD) not requiring dialysis. After treatment with sofosbuvir at doses of 200 mg or 400 mg in combination with ribavirin, the SVR12 rates in patients with ESRD were 40% and 60%, respectively. The safety and efficacy of 12-week treatment with ledipasvir/sofosbuvir in 18 HCV genotype 1-infected patients with ESRD not requiring dialysis were also evaluated in Study 0154. At baseline, two patients had cirrhosis, and the estimated glomerular filtration rate (eGFR) was 24.9 mL/min (range: 9.0–39.6). SVR12 was achieved in 100% (18/18) of patients treated with ledipasvir/sofosbuvir.

Study 4063 was an open-label clinical trial evaluating fixed-dose combination ledipasvir/sofosbuvir treatment in 95 HCV-infected patients with ESRD requiring dialysis. The SVR rates for the 8-, 12-, and 24-week treatment groups were 93% (42/45), 100% (31/31), and 79% (15/19), respectively. Of the 7 patients who did not achieve SVR12, none had virologic failure or relapse.

Study 4062 was an open-label clinical trial evaluating 12-week treatment with sofosbuvir/velpatasvir combination in 59 HCV-infected patients with ESRD requiring dialysis. The overall SVR rate was 95% (56/59): 3 patients did not achieve SVR12, and one patient experienced relapse after completion of treatment with sofosbuvir/velpatasvir.

Pharmacokinetics

Sofosbuvir is a nucleotide prodrug that undergoes extensive metabolism. The active metabolite is formed in hepatocytes and is not detectable in plasma. The major (>90%) circulating metabolite, GS-331007, is inactive. It is formed through sequential and parallel pathways leading to the formation of the active metabolite.

Absorption

The pharmacokinetic properties of sofosbuvir and its major circulating metabolite GS-331007 were evaluated in healthy adult volunteers and patients with chronic hepatitis C. After oral administration, sofosbuvir was rapidly absorbed, with peak plasma concentrations observed approximately 0.5–2 hours after dosing, regardless of food intake. Peak plasma concentrations of GS-331007 were observed 2–4 hours after dosing. Based on population pharmacokinetic analysis in patients with HCV genotypes 1–6 (n = 986), the steady-state AUC0-24 of sofosbuvir and GS-331007 was 1010 ng•h/mL and 7200 ng•h/mL, respectively. In healthy volunteers (n = 284), the AUC0-24 of sofosbuvir was 57% higher and that of GS-331007 was 39% lower compared to HCV-infected patients.

Effect of Food. Administration of a single dose of sofosbuvir with a high-fat meal under fed conditions slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir was increased by approximately 1.8-fold with minimal effect on peak concentration. The exposure of GS-331007 was not affected by food, including high-fat meals.

Distribution

Sofosbuvir is not a substrate for hepatic drug uptake transporters, organic anion transporting polypeptides (OATP) 1B1 or 1B3, or organic cation transporter (OCT) 1. Regarding active tubular secretion, GS-331007 is not a substrate for renal transporters, including organic anion transporters (OAT) 1 or 3, OCT2, MRP2, P-gp, BCRP, or MATE1. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, or OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, or MATE1.

Sofosbuvir is approximately 85% bound to human plasma proteins (ex vivo data), and this binding is independent of drug concentration in the range of 1–20 µg/mL. Plasma protein binding of GS-331007 is minimal. After a single 400 mg dose of [14C]-sofosbuvir in healthy volunteers, the blood-to-plasma ratio of radioactivity was approximately 0.7.

Biological Transformation

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 moiety by histidine triad nucleotide-binding protein 1 (HINT1), and subsequent phosphorylation via the pyrimidine nucleotide biosynthesis pathway. 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, or CYP2D6 enzymes.

After a single oral dose of 400 mg [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of systemic exposure to drug-related materials (sum of AUC of sofosbuvir and its metabolites, corrected for molecular weight), respectively.

Elimination

After a single oral dose of 400 mg [14C]-sofosbuvir, mean total recovery of the dose exceeded 92%, consisting of approximately 80%, 14%, and 2.5% excreted in urine, feces, and expired air, respectively. The majority of the dose excreted in urine was GS-331007 (78%), while sofosbuvir accounted for 3.5%. This indicates that renal clearance is the major route of elimination for GS-331007, with most of it being actively secreted. The mean terminal half-life of sofosbuvir and GS-331007 was 0.4 and 27 hours, respectively.

Linearity / Non-linearity

The dose proportionality of sofosbuvir and its major metabolite GS-331007 was evaluated in healthy volunteers under fasting conditions. AUC values of sofosbuvir and GS-331007 were nearly proportional to doses administered between 200 and 400 mg.

Pharmacokinetics in Special Populations

Sex and Race

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

Elderly Patients

Population pharmacokinetic analysis in HCV-infected patients showed that within the analyzed age range (19–75 years), age had no clinically significant effect on the exposure of sofosbuvir and GS-331007. In clinical trials, 65 patients aged 65 years and older were included. The treatment response rates observed in patients aged 65 years and older were similar to those in younger patients.

Renal Impairment

A brief description of the impact of varying degrees of renal impairment (RI) on the components of MyHep compared to patients with normal renal function is provided in Table 1.

Table 1

Impact of varying degrees of renal impairment on AUC values of sofosbuvir and GS-331007 compared to patients with normal renal function

	Patients without HCV					Patients with HCV
	Mild renal impairment (eGFR ≥50 and <80 mL/min/ 1.73 m²)	Moderate renal impairment (eGFR ≥30 and <50 mL/min/ 1.73 m²)	Severe renal impairment (eGFR <30 mL/min/ 1.73 m²)	ESRD requiring hemodialysis		Severe renal impairment (eGFR <30 mL/min/ 1.73 m²)	ESRD requiring hemodialysis
				Dose administered 1 hour before dialysis	Dose administered 1 hour after dialysis
Sofosbuvir	↑ 1.6-fold	↑ 2.1-fold	↑ 2.7-fold	↑ 1.3-fold	↑ 1.6-fold	↑ ~2-fold	↑ 1.9-fold
GS-331007	↑ 1.6-fold	↑ 1.9-fold	↑ 5.5-fold	↑ ≥10-fold	↑ ≥20-fold	↑ ~6-fold	↑ 1-fold

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

In HCV-infected adult patients with severe renal impairment who received sofosbuvir 200 mg with ribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 2 weeks, or ledipasvir/sofosbuvir 90 mg/400 mg for 12 weeks (n=18), the pharmacokinetics of sofosbuvir and GS-331007 were similar to those observed in HCV-negative adult patients with severe renal impairment.

The pharmacokinetics of sofosbuvir and GS-331007 were also studied in adult HCV-infected patients with ESRD requiring dialysis who received ledipasvir/sofosbuvir (n=94) for 8, 12, or 24 weeks or sofosbuvir/velpatasvir (n=59) for 12 weeks, compared to patients without renal impairment, in Phase 2/3 combination studies (see section "Special instructions").

Hepatic impairment

Pharmacokinetics of sofosbuvir were evaluated after 7 days of 400 mg sofosbuvir dosing in HCV-infected adult patients with moderate and severe hepatic impairment (Child-Pugh class B and C). Compared to patients with normal liver function, AUC₀–₂₄ of sofosbuvir was 126% and 143% higher in moderate and severe hepatic impairment, respectively, while AUC₀–₂₄ of GS-331007 was 18% and 9% higher, respectively. Population pharmacokinetic analysis in HCV-infected patients showed that cirrhosis had no clinically relevant effect on exposure to sofosbuvir or GS-331007. Dose adjustment is not recommended for patients with mild, moderate, or severe hepatic impairment (see section "Dosage and administration").

Pediatric population

The pharmacokinetics of sofosbuvir and GS-331007 have not been studied in pediatric patients.

Pharmacokinetic/pharmacodynamic relationship

Efficacy, as measured by rapid virologic response, was found to be associated with exposure to sofosbuvir and GS-331007. However, neither of these parameters was identified as a general surrogate marker of efficacy (SVR12) at the therapeutic dose of 400 mg.

Preclinical safety data

In repeated-dose toxicity studies in rats and dogs, high doses of the diastereomeric (1:1) mixture caused adverse effects on the liver (in dogs) and heart (in rats) and induced gastrointestinal reactions (in dogs). Sofosbuvir-related effects were not observed in rodent studies, likely due to high esterase activity, although exposure to the major metabolite GS-331007 was 29 times (rats) and 123 times (dogs) higher than clinical exposure at the 400 mg sofosbuvir dose. No liver or heart abnormalities were observed in chronic toxicity studies when exposure was 9 times (rats) and 27 times (dogs) higher than clinical exposure.

Sofosbuvir was not genotoxic in in vitro or in vivo tests, including bacterial mutagenicity, chromosomal aberration using human peripheral blood lymphocytes, and in vivo micronucleus tests in mice.

Carcinogenicity studies in mice and rats showed no carcinogenic potential of sofosbuvir at doses up to 600 mg/kg/day in mice and 750 mg/kg/day in rats. Exposure to GS-331007 in these studies was up to 30 times (mice) and 15 times (rats) higher than clinical exposure with 400 mg sofosbuvir.

Sofosbuvir did not affect embryo-fetal viability or fertility in rats and was not teratogenic in rats or rabbits in developmental studies. No adverse effects on behavior, reproduction, or offspring development were observed in rats. In rabbit studies, sofosbuvir exposure was 9 times higher than expected clinical exposure. In rat studies, sofosbuvir exposure could not be determined, but exposure to the major human metabolite ranged from 8 to 28 times higher than clinical exposure with 400 mg sofosbuvir.

Sofosbuvir-derived substances crossed the placenta in pregnant rats and were excreted into milk in lactating rats.

Clinical Characteristics

Indications

MayHep is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult patients (see sections "Special Instructions", "Dosage and Administration", and "Pharmacodynamics").

For specific activity against hepatitis C virus (HCV) genotypes, see sections "Special Instructions" and "Pharmacodynamics".

Contraindications

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

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

Medicinal products that are potent inducers of intestinal P-gp (rifampicin, rifabutin, St. John’s wort [Hypericum perforatum], carbamazepine, phenobarbital, and phenytoin). Concomitant use significantly reduces plasma concentrations of sofosbuvir and may result in reduced efficacy of MayHep (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Interaction with Other Medicinal Products and Other Forms of Interaction

Sofosbuvir is a nucleotide prodrug. Following oral administration of MayHep, sofosbuvir is rapidly absorbed and undergoes extensive first-pass metabolism in the liver and intestine. Intracellular hydrolytic cleavage of the prodrug, catalyzed by enzymes including carboxylesterase 1, and subsequent phosphorylation, catalyzed by nucleotide kinases, lead to the formation of the pharmacologically active triphosphate, a uridine nucleoside analog. The major circulating inactive metabolite, GS-331007, which accounts for more than 90% of systemic exposure to drug-derived materials, is formed through sequential and parallel pathways prior to formation of the active metabolite. The parent sofosbuvir accounts for approximately 4% of systemic exposure to drug-derived materials (see section "Pharmacokinetics"). In pharmacological clinical studies, both sofosbuvir and GS-331007 were monitored for pharmacokinetic analysis.

Sofosbuvir is a substrate of the drug transporter P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), whereas GS-331007 is not.

Medicinal products that are strong inducers of intestinal P-gp (e.g., rifampicin, St. John’s wort, carbamazepine, phenobarbital, and phenytoin) may significantly reduce plasma concentrations of sofosbuvir, leading to reduced therapeutic effect of MayHep; therefore, their use is contraindicated with MayHep (see section "Contraindications"). Medicinal products that are moderate inducers of intestinal P-gp (e.g., oxcarbazepine, rifapentine, and modafinil) may reduce plasma concentrations of sofosbuvir, resulting in reduced therapeutic efficacy of MayHep. Concomitant use of such medicinal products with MayHep is not recommended (see section "Special Instructions"). Concomitant use of MayHep with medicinal products that are inhibitors of P-gp and/or BCRP may increase plasma concentrations of sofosbuvir without increasing GS-331007 concentrations; therefore, MayHep may be used with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-glycoprotein or BCRP; therefore, enhanced effects of drugs that are substrates of these transporters are not expected.

The metabolic activation pathway of sofosbuvir within cells is mediated by generally low-affinity and high-efficiency hydrolysis, as well as nucleotide phosphorylation pathways, which are unlikely to be affected by concomitant medicinal products (see section "Pharmacokinetics").

Patients receiving vitamin K antagonists

Because liver function may change during treatment with MayHep, careful monitoring of International Normalized Ratio (INR) values is recommended for these patients.

Effect of direct-acting antiviral (DAA) therapy on medicinal products metabolized in the liver

The pharmacokinetics of medicinal products metabolized in the liver (e.g., immunosuppressive agents such as calcineurin inhibitors) may be altered due to changes in liver function during DAA therapy associated with HCV clearance.

Other forms of interaction

Information on interactions between MayHep and potential concomitant medications is summarized briefly in Table 2 below (where 90% confidence interval [CI] limits of the geometric least-squares mean ratio [LSMR] were within "↔", increased "↑", or decreased "↓" relative to predefined equivalence boundaries). This table is not comprehensive.

Table 2

Interaction between MayHep and other medicinal products

Drug according to therapeutic indication	Effect on drug levels. Geometric mean ratio (90% confidence interval) for AUC, Cmax, Cmin	Recommendations for concomitant use with MyHep
STIMULANTS
Modafinil	Interaction not studied. Expected: ↓ Sofosbuvir ↔ GS‑331007 (P-gp induction)	Concomitant use of MyHep with modafinil is expected to decrease sofosbuvir concentrations, resulting in reduced therapeutic effect of MyHep. This combination is not recommended.
ANTIARRHYTHMICS
Amiodarone	Effect on amiodarone and sofosbuvir concentrations is unknown.	Concomitant use of amiodarone with a sofosbuvir-containing regimen may lead to serious symptomatic bradycardia. Should be prescribed only if no alternatives exist. If this drug is used together with MyHep, careful monitoring is recommended (see sections "Special precautions" and "Adverse reactions").
ANTICOAGULANTS
Vitamin K antagonists	Interaction not studied.	INR monitoring is recommended for all vitamin K antagonists, as liver function may change during treatment with MyHep.
ANTICONVULSANTS
Phenytoin Phenobarbital	Interaction not studied. Expected: ↓ Sofosbuvir ↔ GS‑331007 (P-gp induction)	Concomitant use of MyHep with phenobarbital or phenytoin is contraindicated (see section "Contraindications").
Oxcarbazepine	Interaction not studied. Expected: ↓ Sofosbuvir ↔ GS‑331007 (P-gp induction)	Concomitant use of MyHep with oxcarbazepine is expected to reduce sofosbuvir concentrations, leading to diminished therapeutic effect of MyHep. This combination is not recommended (see section "Special precautions").
Carbamazepine	Sofosbuvir ↓ Cmax 0.52 (0.43; 0.62) ↓ AUC 0.52 (0.46; 0.59) Cmin (NA) GS-331007 ↔ Cmax 1.04 (0.97; 1.11) ↔ AUC 0.99 (0.94; 1.04) Cmin (NA) (P-gp induction)	Concomitant use of sofosbuvir with carbamazepine is contraindicated (see section "Contraindications").
ANTITUBERCULOSIS AGENTS
Rifampicinf (single 600 mg dose)	Sofosbuvir ↓ Cmax 0.23 (0.19; 0.29) ↓ AUC 0.28 (0.24; 0.32) Cmin (NA) GS-331007 ↔ Cmax 1.23 (1.14; 1.34) ↔ AUC 0.95 (0.88; 1.03) Cmin (NA) (P-gp induction)	Concomitant use of MyHep with rifampicin is contraindicated (see section "Contraindications").
Rifapentine	Interaction not studied. Expected: ↓ Sofosbuvir ↔ GS‑331007 (P-gp induction)	Concomitant use of MyHep with rifapentine is expected to reduce sofosbuvir concentrations, leading to diminished therapeutic effect of MyHep. This combination is not recommended (see section "Special precautions").
Rifabutin	Sofosbuvir ↓ Cmax 0.64 (0.53; 0.77) ↓ AUC 0.76 (0.63; 0.91) Cmin (NA) GS-331007 ↔ Cmax 1.15 (1.03; 1.27) ↔ AUC 1.03 (0.95; 1.12) Cmin (NA) (P-gp induction)	No dose adjustment of sofosbuvir is required when used concomitantly with rifabutin.
HERBAL SUPPLEMENTS
St. John’s wort (Hypericum perforatum)	Interaction not studied. Expected: ↓ Sofosbuvir ↔ GS‑331007 (P-gp induction)	MyHep is contraindicated for use with St. John’s wort (see section "Contraindications").
ANTIVIRAL AGENTS HCV: HCV PROTEASE INHIBITORS
Boceprevir (BOC) Telaprevir (TPV)	Interaction not studied. Expected: ↑ Sofosbuvir (TPV) ↔ Sofosbuvir (BOC) ↔ GS‑331007 (TPV or BOC)	There is no information on interaction between MyHep and boceprevir or telaprevir.
OPIOID ANALGESICS
Methadonef (methadone maintenance therapy [30−130 mg/day])	R-methadone ↔ Cmax 0.99 (0.85; 1.16) ↔ AUC 1.01 (0.85; 1.21) ↔ Cmin 0.94 (0.77; 1.14) S-methadone ↔ Cmax 0.95 (0.79; 1.13) ↔ AUC 0.95 (0.77; 1.17) ↔ Cmin 0.95 (0.74; 1.22) Sofosbuvir ↓ Cmax 0.95c (0.68; 1.33) ↑ AUC 1.30c (1.00; 1.69) Cmin (NA) GS-331007 ↓ Cmax 0.73c (0.65; 0.83) ↔ AUC 1.04c (0.89; 1.22) Cmin (NA)	No dose adjustment of either sofosbuvir or methadone is required when administered concomitantly.
IMMUNOSUPPRESSANTS
Cyclosporinee (single 600 mg dose)	Cyclosporine ↔ Cmax 1.06 (0.94; 1.18) ↔ AUC 0.98 (0.85; 1.14) Cmin (NA) Sofosbuvir ↑ Cmax 2.54 (1.87; 3.45) ↑ AUC 4.53 (3.26; 6.30) Cmin (NA) GS-331007 ↓ Cmax 0.60 (0.53; 0.69) ↔ AUC 1.04 (0.90; 1.20) Cmin (NA)	No dose adjustment of sofosbuvir or cyclosporine is required at the start of concomitant use. Subsequent careful monitoring is recommended, with dose adjustment of cyclosporine as needed.
Tacrolimuse (single 5 mg dose)	Tacrolimus ↓ Cmax 0.73 (0.59; 0.90) ↔ AUC 1.09 (0.84; 1.40) Cmin (NA) Sofosbuvir ↓ Cmax 0.97 (0.65; 1.43) ↑ AUC 1.13 (0.81; 1.57) Cmin (NA) GS-331007 ↔ Cmax 0.97 (0.83; 1.14) ↔ AUC 1.00 (0.87; 1.13) Cmin (NA)	No dose adjustment of sofosbuvir or tacrolimus is required at the start of concomitant use. Subsequent careful monitoring is recommended, with dose adjustment of tacrolimus as needed.
ANTIVIRAL AGENTS HIV: REVERSE TRANSCRIPTASE INHIBITORS
Efavirenzf (600 mg once daily)d	Effavirenz ↔ Cmax 0.95 (0.85; 1.06) ↔ AUC 0.96 (0.91; 1.03) ↔ Cmin 0.96 (0.93; 0.98) Sofosbuvir ↓ Cmax 0.81 (0.60; 1.10) ↔ AUC 0.94 (0.76; 1.16) Cmin (NA) GS-331007 ↓ Cmax 0.77 (0.70; 0.84) ↔ AUC 0.84 (0.76; 0.92) Cmin (NA)	No dose adjustment of either sofosbuvir or efavirenz is required when administered concomitantly.
Emtricitabinef (200 mg once daily)d	Emtricitabine ↔ Cmax 0.97 (0.88; 1.07) ↔ AUC 0.99 (0.94; 1.05) ↔ Cmin 1.04 (0.98; 1.11) Sofosbuvir ↓ Cmax 0.81 (0.60; 1.10) ↔ AUC 0.94 (0.76; 1.16) Cmin (NA) GS-331007 ↓ Cmax 0.77 (0.70; 0.84) ↔ AUC 0.84 (0.76; 0.92) Cmin (NA)	No dose adjustment of either sofosbuvir or emtricitabine is required when administered concomitantly.
Tenofovir disoproxilf (245 mg once daily)d	Tenofovir ↑ Cmax 1.25 (1.08; 1.45) ↔ AUC 0.98 (0.91; 1.05) ↔ Cmin 0.99 (0.91; 1.07) Sofosbuvir ↓ Cmax 0.81 (0.60; 1.10) ↔ AUC 0.94 (0.76; 1.16) Cmin (NA) GS-331007 ↓ Cmax 0.77 (0.70; 0.84) ↔ AUC 0.84 (0.76; 0.92) Cmin (NA)	No dose adjustment of either sofosbuvir or tenofovir disoproxil is required when administered concomitantly.
Rilpivirinef (25 mg once daily)	Rilpivirine ↔ Cmax 1.05 (0.97; 1.15) ↔ AUC 1.06 (1.02; 1.09) ↔ Cmin 0.99 (0.94; 1.04) Sofosbuvir ↑ Cmax 1.21 (0.90; 1.62) ↔ AUC 1.09 (0.94; 1.27) Cmin (NA) GS-331007 ↔ Cmax 1.06 (0.99; 1.14) ↔ AUC 1.01 (0.97; 1.04) Cmin (NA)	No dose adjustment of either sofosbuvir or rilpivirine is required when administered concomitantly.
ANTIVIRAL AGENTS HIV: HIV PROTEASE INHIBITORS
Darunavir boosted with ritonavirf (800/100 mg once daily)	Darunavir ↔ Cmax 0.97 (0.94; 1.01) ↔ AUC 0.97 (0.94; 1.00) ↔ Cmin 0.86 (0.78; 0.96) Sofosbuvir ↑ Cmax 1.45 (1.10; 1.92) ↑ AUC 1.34 (1.12; 1.59) Cmin (NA) GS-331007 ↔ Cmax 0.97 (0.90; 1.05) ↔ AUC 1.24 (1.18; 1.30) Cmin (NA)	No dose adjustment of either sofosbuvir or darunavir (ritonavir-boosted) is required when administered concomitantly.
ANTIVIRAL AGENTS HIV: INTEGRASE INHIBITORS
Raltegravirf (400 mg twice daily)	Raltegravir ↓ Cmax 0.57 (0.44; 0.75) ↓ AUC 0.73 (0.59; 0.91) ↔ Cmin 0.95 (0.81; 1.12) Sofosbuvir ↔ Cmax 0.87 (0.71; 1.08) ↔ AUC 0.95 (0.82; 1.09) Cmin (NA) GS-331007 ↔ Cmax 1.09 (0.99; 1.20) ↔ AUC 1.03 (0.97; 1.08) Cmin (NA)	No dose adjustment of either sofosbuvir or raltegravir is required when administered concomitantly.
ORAL CONTRACEPTIVES
Norgestimate / ethinylestradiol	Norgestrel ↔ Cmax 1.06 (0.93; 1.22) ↔ AUC 1.05 (0.92; 1.20) Cmin (NA) Norgestrel ↔ Cmax 1.18 (0.99; 1.41) ↔ AUC 1.19 (0.98; 1.44) Cmin (NA) Ethinylestradiol ↔ Cmax 1.14 (0.96; 1.36) ↔ AUC 1.08 (0.93; 1.25) Cmin (NA)	No dose adjustment of either sofosbuvir or norgestimate / ethinylestradiol is required when administered concomitantly.

NA – not available / not applicable

a Mean ratio (90 % confidence interval) for the pharmacokinetics of the co-administered drug with/without sofosbuvir and mean ratio of sofosbuvir and GS-331007 with/without the co-administered drug. No effect = 1.00.

b All drug interaction studies were conducted in healthy volunteers.

c Comparison is based on a historical control.

d Administered as a fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil 245 mg (as fumarate).

e Bioequivalence limit of 80–125 %.

f Equivalence limit of 70–143 %.

Special precautions for use

General

MyHep is not recommended for use as monotherapy and should be prescribed in combination with other medicinal products for the treatment of hepatitis C virus (HCV) infection. If treatment with other medicinal products in combination with MyHep is completely discontinued, MyHep should also be discontinued (see section "Dosage and administration"). Before initiating treatment with MyHep, the prescribing information for concomitant medicinal products should be reviewed.

Severe bradycardia and cardiac conduction disorders

Cases of life-threatening severe bradycardia and heart block have been observed when regimens containing sofosbuvir were used in combination with amiodarone. Bradycardia generally occurred within hours or days, but cases with longer onset times have been reported, most commonly within 2 weeks after initiation of HCV treatment.

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

If concomitant use of amiodarone is considered necessary, cardiac monitoring is recommended for 48 hours after initiation of MyHep in an appropriate healthcare setting. Thereafter, outpatient monitoring or daily self-monitoring of heart rate should be continued for at least the first 2 weeks of treatment.

Due to the long half-life of amiodarone, appropriate monitoring should also be ensured in patients who have discontinued amiodarone within the previous several months and are initiating treatment with MyHep.

All patients who have recently taken amiodarone or are taking it concomitantly with MyHep should be informed about the symptoms of bradycardia and cardiac conduction disorders and should seek immediate medical attention if such symptoms occur.

Patients with HCV genotypes 1, 4, 5, and 6 who have been previously treated

The efficacy of MyHep in patients with HCV genotypes 1, 4, 5, and 6 who have been previously treated has not been studied in phase 3 trials. Therefore, the optimal duration of treatment in this population has not been established (also see sections "Pharmacodynamics" and "Dosage and administration").

Careful consideration should be given to treating these patients, and if possible, extending the duration of treatment with sofosbuvir, peginterferon alfa, and ribavirin beyond 12 weeks up to 24 weeks. This is particularly relevant for subgroups of patients with one or more factors historically associated with lower response rates to interferon-based therapy (marked fibrosis/cirrhosis, high baseline viral load, non-Caucasian race, IL28B other than CC genotype).

Treatment of patients with HCV genotypes 5 or 6

Data on the use of MyHep in patients with HCV genotypes 5 and 6 are very limited (see section "Pharmacodynamics").

Interferon-free treatment of patients with HCV genotypes 1, 4, 5, and 6

Interferon-free regimens using MyHep in patients with HCV genotypes 1, 4, 5, and 6 have not been studied in phase 3 trials (see section "Pharmacodynamics"). The optimal regimen and duration of treatment have not been established. Such regimens should be used only in patients who are intolerant to or ineligible for interferon therapy and have an urgent need for treatment.

Concomitant use with other direct-acting antiviral agents against HCV

MyHep should be used concomitantly with other direct-acting antiviral agents only if, based on available data, the expected benefits outweigh the risks. There are no data supporting the concomitant use of MyHep with telaprevir or boceprevir. Concomitant use is not recommended (also see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy and concomitant use with ribavirin

When MyHep is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use effective contraception during treatment and for the post-treatment period as recommended in the ribavirin prescribing information. For additional information, see the ribavirin prescribing information.

Use with moderate P-gp inducers

Medicinal products that are moderate inducers of intestinal P-glycoprotein (P-gp) (such as oxcarbazepine, rifapentine, and modafinil) may reduce plasma concentrations of sofosbuvir, potentially leading to reduced therapeutic effect of MyHep. Such medicinal products are not recommended for use with MyHep (see section "Interaction with other medicinal products and other forms of interaction").

Use in patients with diabetes

Improvement in blood glucose control may occur in patients with diabetes after initiation of direct-acting antiviral therapy for HCV, potentially leading to symptomatic hypoglycemia. Blood glucose levels in diabetic patients initiating direct-acting antiviral therapy should be closely monitored, especially during the first 3 months, and antidiabetic medications should be adjusted as needed. The physician managing the patient's diabetes should be informed about the initiation of direct-acting antiviral therapy.

Renal impairment

Safety data for MyHep in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) or end-stage renal disease requiring hemodialysis are limited. This medicinal product may be used in such patients without dose adjustment if no other treatment options are available (see sections "Pharmacodynamics", "Pharmacokinetics", and "Adverse reactions").

When MyHep is used in combination with ribavirin or peginterferon alfa/ribavirin, also refer to the ribavirin prescribing information for patients with creatinine clearance (CrCl) < 50 mL/min (also see section "Pharmacokinetics").

HCV/HBV (hepatitis B virus) co-infection

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

Excipients

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Paediatric population

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

Use during pregnancy or breastfeeding

Women of childbearing potential / contraception in men and women

When MyHep is used with ribavirin or peginterferon alfa/ribavirin, all efforts must be made to prevent pregnancy in female patients and female partners of male patients. Ribavirin has shown significant teratogenic and/or embryocidal effects in all animal species tested (see section "Special precautions for use"). Women of childbearing potential and their partners must use effective contraception during treatment and for the post-treatment period as recommended in the ribavirin prescribing information. For additional information, see the ribavirin prescribing information.

Pregnancy

There are no or limited data on the use of sofosbuvir in pregnant women (less than 300 pregnancy cases).

Animal studies have not shown direct or indirect harmful effects with regard to reproductive toxicity. In studies using the highest doses in rats and rabbits, no effect on embryofetal development was observed. However, it is not possible to fully extrapolate the exposure levels of sofosbuvir in rats to humans at the recommended clinical dose (see section "Safety preclinical data").

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

However, if ribavirin is used concomitantly with sofosbuvir, the contraindications for ribavirin use during pregnancy must be strictly followed (also see ribavirin prescribing information).

Breastfeeding

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

Available pharmacokinetic data in animals indicate excretion of metabolites in milk (for detailed information, see section "Safety preclinical data").

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

Fertility

There are no data on the effect of MyHep on human fertility. Animal studies do not indicate harmful effects on fertility.

Ability to influence the ability to drive and use machines

MyHep has a moderate influence on the ability to drive and use machinery. Patients should be informed that during treatment with sofosbuvir in combination with peginterferon alfa and ribavirin, cases of increased fatigue, impaired concentration, dizziness, and blurred vision have been reported (see section "Adverse reactions").

Dosage and Administration

Treatment with MayHep should be initiated and supervised by a physician experienced in managing patients with chronic hepatitis C (CHC).

Adults

The recommended dose is 400 mg as a tablet taken orally once daily with food.

MayHep should be used in combination with other medicinal products. Monotherapy with MayHep is not recommended. See also the prescribing information for the medicinal products used in combination with MayHep. The recommended medicinal products for co-administration and the duration of combination therapy with MayHep are provided in Table 3.

Table 3

Recommended co-administered medicinal products and duration of combination therapy with MayHep

Patient population*	Therapy	Treatment duration
Patients with CHC genotype 1, 4, 5 or 6	MyHep + ribavirin + peginterferon alfa	12 weeksa,b
	MyHep + ribavirin Only for patients for whom peginterferon alfa is not suitable or who are intolerant to it (see section «Special instructions»)	24 weeks
Patients with CHC genotype 2	MyHep + ribavirin	12 weeksb
Patients with CHC genotype 3	MyHep + ribavirin + peginterferon alfa	12 weeksb
	MyHep + ribavirin	24 weeks
Patients with CHC awaiting liver transplantation	MyHep + ribavirin	Until liver transplantationc

* Including patients with human immunodeficiency virus (HIV) co-infection.

a For patients with HCV genotype 1 infection who are treatment-experienced, there are no data on the combination of MyHep, ribavirin, and peginterferon alfa (see section "Special instructions for use").

b Consider extending the duration of treatment from 12 to 24 weeks. This is particularly applicable to subgroups of patients with one or more factors historically associated with lower response rates to interferon-based therapy (e.g., marked fibrosis/cirrhosis, high baseline viral load, non-Caucasian race, IL28B other than CC genotype, prior non-response to peginterferon alfa and ribavirin therapy).

c See section "Patients awaiting liver transplantation" below.

The dose of ribavirin in combination with MyHep should be based on the adult patient's body weight (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg) and administered orally in two divided doses with food.

For information on concomitant use with other direct-acting antiviral agents against HCV, see section "Special instructions for use".

Dosage adjustment in adults

Dose reduction of MyHep is not recommended.

If sofosbuvir is used in combination with peginterferon alfa and the patient develops serious adverse reactions related to this agent, the dose of peginterferon alfa should be reduced or its administration discontinued. For further information on how to reduce the dose and/or discontinue peginterferon alfa, refer to the prescribing information for peginterferon alfa.

If a patient develops serious adverse reactions potentially related to ribavirin, the dose of ribavirin should be adjusted or its administration discontinued (as needed) until the adverse reaction resolves or its severity decreases. Table 4 provides recommendations for dose adjustment and discontinuation based on the patient's hemoglobin concentration and cardiac status.

Table 4

Recommendations for ribavirin dose adjustment when used in combination with MyHep

Laboratory test data	Reduce ribavirin dose to 600 mg/day if:	Discontinue ribavirin if:
Hemoglobin level in patients without heart disease	< 10 g/dl	< 8.5 g/dl
Hemoglobin level in patients with a history of stable heart disease	hemoglobin decreases by ≥ 2 g/dl during any 4-week treatment period	< 12 g/dl despite dose reduction over a 4-week period

After discontinuation of ribavirin due to laboratory abnormalities or clinical manifestations of disease, ribavirin therapy may be resumed at a dose of 600 mg per day and later increased to 800 mg per day. However, increasing the previously prescribed dose of ribavirin (from 1000 to 1200 mg per day) is not recommended.

Discontinuation of dosing in adults and adolescents

If treatment with other medicinal products used in combination with MyHep is discontinued, MyHep should also be discontinued (see section "Special precautions").

Special patient populations

Elderly patients

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

Renal impairment

No dose adjustment of MyHep is required in patients with mild or moderate renal impairment. The safety and appropriate dosing of MyHep in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) or end-stage renal disease requiring hemodialysis have not been established. The medicinal product may be used in such patients without dose adjustment if no other suitable treatment options are available (see sections "Pharmacodynamics", "Pharmacokin游戏副本", "Special precautions", and "Undesirable effects").

Hepatic impairment

Dose adjustment of MyHep 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 MyHep in patients with decompensated cirrhosis have not been established.

Patients awaiting liver transplantation

The duration of MyHep treatment in patients awaiting liver transplantation should be determined based on an individual assessment of potential benefits and risks (see section "Pharmacodynamics").

Post-liver transplant patients

MyHep in combination with ribavirin is recommended for 24 weeks in post-liver transplant patients. The recommended initial dose of ribavirin is 400 mg administered orally in two divided doses with food. If the initial ribavirin dose is well tolerated, it may be gradually increased to a maximum of 1000/1200 mg per day (1000 mg for patients with body weight < 75 kg and 1200 mg for patients with body weight ≥ 75 kg). If the initial dose is not well tolerated, it should be reduced based on clinical judgment and hemoglobin levels (see section "Pharmacodynamics").

Method of administration

The film-coated tablet is intended for oral use. Patients should be instructed to swallow the tablet whole. The film-coated tablet must not be chewed or crushed due to the bitter taste of the active substance. The tablet should be taken with food (see section "Pharmacokinetics").

Patients should be advised that if vomiting occurs within 2 hours after dosing, they should take another tablet. If vomiting occurs more than 2 hours after tablet intake, an additional dose is not required. These recommendations are based on the absorption kinetics of sofosbuvir and GS-331007, indicating that the majority of the dose is absorbed within 2 hours after administration.

Patients should be informed that if they miss a dose and less than 18 hours have passed, they should take the missed tablet immediately and then take the next dose at the usual time. If more than 18 hours have passed, the next dose should be taken at the usual time without doubling the dose.

Pediatric population

The safety and efficacy of MyHep in children (aged < 18 years) have not been established. Data are unavailable.

Overdose

The maximum recorded dose of sofosbuvir corresponds to a single supratherapeutic dose of 1200 mg administered to 59 healthy volunteers. In this study, no harmful effects were observed at this dose level, and adverse reactions were similar in frequency and severity to those reported in therapeutic groups receiving placebo or 400 mg of sofosbuvir. The effects of higher doses are unknown.

In case of MyHep overdose, there is no specific antidote. Patients should be monitored for signs of toxicity. Management of MyHep overdose consists of general supportive measures, including monitoring of vital signs and clinical status. Hemodialysis may effectively remove (53% clearance coefficient) the predominant circulating metabolite GS-331007. A 4-hour hemodialysis session removed 18% of the administered dose.

Adverse Reactions

Summary of safety profile in adults

The assessment of adverse reactions is based on pooled data from five Phase 3 clinical trials (both controlled and uncontrolled).

Sofosbuvir 400 mg tablets, film-coated, was primarily studied in combination with ribavirin with or without peginterferon alfa. Therefore, specific adverse drug reactions attributable to sofosbuvir alone have not been identified. The most commonly observed adverse drug reactions in patients receiving sofosbuvir with ribavirin or sofosbuvir with ribavirin and peginterferon alfa were fatigue, headache, nausea, and insomnia.

Tabulated list of adverse reactions

The following adverse drug reactions have been identified when sofosbuvir was used in combination with ribavirin or with peginterferon alfa and ribavirin (Table 5). Adverse reactions are listed in Table 5 by system organ class and frequency. Frequency classification: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), or very rare (< 1/10,000).

Table 5

Adverse reactions associated with the use of sofosbuvir in combination with ribavirin or peginterferon alfa and ribavirin

Frequency	SOFa + RBVb	SOF + PEGc + RBV
Infections and infestations
common	nasopharyngitis
Blood and lymphatic system disorders
very common	decreased hemoglobin	anemia, neutropenia, decreased lymphocyte count, decreased platelet count
common	anemia
Metabolism and nutrition disorders
very common		decreased appetite
common		weight decreased
Psychiatric disorders
very common	insomnia	insomnia
common	depression	depression, anxiety, irritability
Nervous system disorders
very common	headache	dizziness, headache
common	attention disorders	migraine, memory impairment, attention disorders
Eye disorders
common		blurred vision
Respiratory, thoracic and mediastinal disorders
very common		dyspnea, cough
common	dyspnea, exertional dyspnea, cough	exertional dyspnea
Gastrointestinal disorders
very common	nausea	diarrhea, nausea, vomiting
common	abdominal discomfort, constipation, dyspepsia	constipation, dry mouth, gastroesophageal reflux
Hepatobiliary disorders
very common	increased blood bilirubin	increased blood bilirubin
Skin and subcutaneous tissue disorders
very common		rash, pruritus
common	alopecia, dry skin, pruritus	alopecia, dry skin
Musculoskeletal and connective tissue disorders
very common		arthralgia, myalgia
common	arthralgia, back pain, muscle spasms, myalgia	back pain, muscle spasms
General disorders
very common	fatigue, irritability	chills, fatigue, influenza-like illness, irritability, pain, pyrexia
common	pyrexia, malaise	chest pain, malaise

a SOF – sofosbuvir; b RBV – ribavirin; c PEG – pegylated interferon alfa;

Other special patient groups

HIV/HCV co-infection

The safety results of sofosbuvir and ribavirin in adult patients with HCV/HIV co-infection were similar to those observed in Phase 3 clinical trials in patients with HCV mono-infection treated with sofosbuvir and ribavirin (see section "Pharmacodynamics").

Patients awaiting liver transplantation

The safety results of sofosbuvir and ribavirin in adult patients with HCV infection awaiting liver transplantation were similar to those observed in Phase 3 clinical trials in patients treated with sofosbuvir and ribavirin (see section "Pharmacodynamics").

Patients with renal impairment

Data on safety and efficacy are based on results from an open-label clinical study (Study 0154) involving 18 patients with genotype 1 CHC infection who received treatment with the combination of sofosbuvir and ledipasvir for 12 weeks. The safety of sofosbuvir in fixed-dose combination with ledipasvir or velpatasvir was evaluated in 154 patients with end-stage renal disease requiring dialysis (Study 4062 and Study 4063). In this study, exposure to the sofosbuvir metabolite GS-331007 was increased 20-fold, exceeding levels at which adverse reactions were observed in preclinical studies. In this limited sample of clinical safety data, the rate of adverse reactions and mortality was not clearly higher than that observed in patients with end-stage renal disease.

Patients after liver transplantation

The safety profile of sofosbuvir and ribavirin in adult patients with chronic hepatitis C who have undergone liver transplantation was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 clinical trials (see section "Pharmacodynamics"). During treatment in the study, hemoglobin reduction was very commonly observed – in 32.5% (13/40) of patients hemoglobin levels decreased to <10 g/dL, including one patient with levels dropping to <8.5 g/dL. Eight patients (20%) received erythropoietin and/or blood products. In 5 patients (12.5%), treatment with the investigational drugs was discontinued, interrupted, or modified due to adverse events.

Description of selected adverse reactions

Cardiac arrhythmia

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

Skin disorders

Frequency not known: Stevens-Johnson syndrome.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as 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

36 months.

Storage conditions

Store at temperatures not exceeding 30 °C in the original packaging. Keep out of reach of children.

Packaging

28 tablets in a bottle, 1 bottle in a cardboard package.

Prescription status

Prescription only.

Manufacturer

Mylan Laboratories Limited, India.

Manufactured under license from Gilead Sciences Ireland UC.

Manufacturer's address and location of operations

F-4, F-12 M.I.D.C., Malegaon, Sinnar, IN-422113, India.