Virso

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIRSО (VIRSO)

Composition:

Active substance: sofosbuvir;

1 film-coated tablet contains 400 mg of sofosbuvir;

Excipients: mannitol 60 (E 421), microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate; tablet coating: Opadry II Blue (85F505068).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: blue, capsule-shaped, biconvex tablets, film-coated, with "400" embossed on one side and smooth on the other.

Pharmacotherapeutic group.

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

ATC code J05AP08.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action

Sofosbuvir is a pangenotypic inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, an enzyme 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 the polymerase activity of recombinant NS5B from 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) does not inhibit human DNA- or RNA-dependent polymerases, nor does it inhibit 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. EC50 values of sofosbuvir against chimeric replicons encoding NS5B from genotypes 2b, 5a, or 6a were between 0.014 and 0.015 µM. The mean ± SD EC50 of sofosbuvir against chimeric 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 across multiple genotypes, including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced sensitivity to sofosbuvir was associated with the primary NS5B substitution S282T in all tested genotype replicons. Site-directed mutagenesis introducing the S282T substitution into 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. 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 and had HCV RNA >1000 IU/mL. Baseline NS5B sequences were available for 225 of these 226 patients, and deep sequencing (analysis cutoff 1%) was performed on samples from 221 patients. The S282T substitution associated with resistance to sofosbuvir was not detected in any of these patients by either deep sequencing or population sequencing. The S282T substitution in NS5B was detected in one patient receiving monotherapy with Viro (sofosbuvir) in a phase 2 trial. This patient had <1% HCV S282T at baseline and S282T (>99%) at week 4 of treatment, resulting in a 13.5-fold shift 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 genotype 3 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 undergoing transplantation who had a partial response to therapy. The clinical significance of these findings is unknown.

Impact of Baseline HCV Polymorphisms on Treatment Outcome

Baseline NS5B sequences were obtained from 1292 patients in phase 3 trials using population sequencing, and the S282T substitution was not detected in any patient with available baseline sequence. Analysis of the impact of baseline polymorphisms on treatment outcome showed no statistically significant association between the presence of HCV NS5B variants at baseline and treatment outcome.

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, such as non-nucleoside NS5B inhibitors, NS3 protease inhibitors, and NS5A inhibitors.

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 circulating metabolite, GS-331007 (>90%), is inactive. It is formed through sequential and parallel metabolic 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 subjects and patients with chronic hepatitis C. After oral administration, sofosbuvir was rapidly absorbed, with peak plasma concentrations reached within ~0.5–2 hours post-dose, regardless of dose level. 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), steady-state AUC0–24 values for sofosbuvir and GS-331007 were 1010 ng×h/mL and 7200 ng×h/mL, respectively. Compared to healthy subjects (n = 284), the AUC0–24 for sofosbuvir was 57% higher and for GS-331007 was 39% lower in HCV-infected patients.

Effect of Food. Administration of a single dose of sofosbuvir with a high-fat meal slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir increased approximately 1.8-fold, with minimal effect on peak concentration. The exposure of GS-331007 was unchanged when administered with a high-fat meal.

Distribution

Sofosbuvir is not a substrate for hepatic uptake drug transporters, organic anion transporting polypeptides (OATP) 1B1 or 1B3, or organic cation transporters (OCT) 1. Regarding active tubular secretion, GS-331007 is not a substrate for renal transporters OAT1 or OAT3, OCT2, MRP2, P-gp, BCRP, or MATE1. Sofosbuvir and GS-331007 are not inhibitors of the 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 outside the range of 1–20 µg/mL. Binding of GS-331007 to human plasma proteins is minimal. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood-to-plasma ratio of radioactivity was approximately 0.7.

Metabolism

Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate, GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carbonate 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 rephosphorylated and lacks anti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of the enzymes UGT1A1, CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

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

Elimination

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

Linearity/Non-linearity

Dose proportionality of sofosbuvir and its major metabolite GS-331007 was evaluated in healthy subjects on a controlled diet. AUC values for sofosbuvir and GS-331007 were nearly proportional to dose over the range of 200 to 400 mg.

Age, Gender, and Race

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

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

Population pharmacokinetic analysis in HCV-infected patients showed that, within the analyzed age range (19–75 years), age had no clinical effect on exposure to sofosbuvir and GS-331007. A total of 65 patients aged 65 years and older participated in clinical trials. The response rate observed in patients over 65 years of age was similar to that in younger patients.

Renal Impairment

The pharmacokinetics of sofosbuvir were studied in non-HCV-infected subjects 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 end-stage renal disease requiring hemodialysis, after a single 400 mg dose of sofosbuvir. Compared to subjects with normal renal function (eGFR >80 mL/min/1.73 m²), AUC0–inf of sofosbuvir was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, respectively. AUC0–inf of GS-331007 was 55%, 88%, and 451% higher, respectively. In patients with end-stage renal disease compared to those with normal renal function, AUC0–inf of sofosbuvir was 28% higher when the dose was administered 1 hour before hemodialysis and 60% higher when administered 1 hour after hemodialysis. AUC0–inf of GS-331007 in patients with end-stage renal disease could not be reliably determined. Although data suggest exposure to GS-331007 is at least 10- to 20-fold higher in end-stage renal disease compared to healthy subjects when Viro is administered 1 hour before or after hemodialysis, respectively.

Hemodialysis effectively removes the major circulating metabolite GS-331007 (clearance coefficient 53%). Approximately 18% of the administered dose was removed during a 4-hour hemodialysis session. Dose adjustment is not required for patients with mild or moderate renal impairment. The safety of Viro has not been evaluated in patients with severe renal impairment or end-stage renal disease (see section "Special Precautions").

Hepatic Impairment

The pharmacokinetics of sofosbuvir were studied after 7 days of 400 mg daily dosing in HCV-infected patients with moderate and severe hepatic impairment (Child-Pugh class B and C). Compared to patients with normal hepatic 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 and GS-331007. Dose adjustment is not recommended for patients with mild, moderate, or severe hepatic impairment (see section "Dosage and Administration").

Pharmacokinetic/Pharmacodynamic Relationship

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

Non-clinical Safety Data.

In repeat-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), as well as gastrointestinal reactions (in dogs). The effects of sofosbuvir could not be observed in rodent studies, likely due to high esterase activity, although the dose of the major metabolite GS-331007 causing adverse effects was 29 times (rat) and 123 times (dog) higher than the 400 mg clinical dose of sofosbuvir. No liver or heart toxicity was observed in chronic toxicity studies at exposures 9 times (rat) and 27 times (dog) higher than the 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 mouse micronucleus assays.

Carcinogenicity studies in mice and rats did not reveal any 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 the clinical exposure from 400 mg sofosbuvir.

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

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

Clinical characteristics.

Indications.

Virsu is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult patients (see sections "Dosage and administration" and "Special precautions").

For specific activity against hepatitis C virus (HCV) genotypes, see sections "Dosage and administration" and "Special precautions".

Contraindications.

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

Use with strong P-glycoprotein inducers

Medicinal products that are strong inducers of intestinal P-glycoprotein (such as rifampicin, rifabutin, St. John’s wort (Hypericum perforatum), carbamazepine, phenobarbital, and phenytoin) may significantly reduce plasma concentrations of sofosbuvir, leading to reduced therapeutic effect of Virsu. These medicinal products must not be used with Virsu (see section "Interaction with other medicinal products and other forms of interaction").

Special precautions.

Special warnings

Virsu is not recommended for monotherapy and must be prescribed in combination with other medicinal products for the treatment of hepatitis C virus infection. If treatment with other medicinal products in combination with Virsu is interrupted, administration of Virsu should also be discontinued (see section "Dosage and administration"). Prior to initiating treatment with Virsu, the list of medicinal products that can be co-administered with this product should be reviewed.

Severe bradycardia and heart block

Cases of severe bradycardia and heart block have been reported when Virsu is used in combination with other direct-acting antiviral agents (DAAs) (including daclatasvir, simeprevir, and ledipasvir) and concomitantly with amiodarone, with or without other medicinal products that reduce heart rate. The mechanism of action has not been established.

Concomitant use of amiodarone was limited during clinical trials of sofosbuvir and DAAs. Life-threatening events may occur; therefore, amiodarone is recommended only for patients receiving Virsu with other DAAs who cannot tolerate alternative antiarrhythmic therapies or for whom they are contraindicated.

Patients receiving beta-blockers, patients with underlying cardiac comorbidities and/or advanced liver disease may have an increased risk of bradycardia when amiodarone is administered concomitantly.

If concomitant use of amiodarone is considered necessary, continuous monitoring is recommended for patients initiating Virsu and other DAAs. For patients at high risk of bradyarrhythmias, continuous monitoring for 48 hours in an appropriate clinical setting is required.

Due to the long half-life of amiodarone, appropriate monitoring is also recommended for patients who discontinued amiodarone several months prior and are about to start Virsu in combination with other DAAs.

All patients receiving Virsu with other DAAs, together with amiodarone and other medicinal products that reduce heart rate, or without them, should be informed about the symptoms of bradycardia and heart block. They should also be advised to seek immediate medical consultation if such symptoms occur.

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

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

Careful consideration should be given when treating such patients, and if possible, extending the duration of treatment with sofosbuvir, peginterferon alfa-2, and ribavirin from 12 to 24 weeks is recommended. This is particularly relevant for patient subgroups 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 non-CC genotype).

Previously treated patients with HCV genotypes 5 or 6

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

Treatment-experienced patients with HCV genotypes 1, 4, 5, and 6 receiving non-interferon therapy

Non-interferon regimens for treatment-experienced patients with HCV genotypes 1, 4, 5, and 6 using Virsu 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 only be used in patients who are intolerant to or ineligible for interferon therapy, and only when there is an urgent need for treatment.

Concomitant use with other direct-acting antiviral agents against HCV

Virsu may 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 Virsu 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 Virsu is used in combination with ribavirin or peginterferon alfa-2/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 product information. For additional information, see the ribavirin product information.

Use with moderate P-glycoprotein inducers

Medicinal products that are moderate inducers of intestinal P-glycoprotein (such as oxcarbazepine and modafinil) may reduce plasma concentrations of sofosbuvir, resulting in reduced therapeutic effect of Virsu. Concomitant use of such medicinal products with Virsu is not recommended (see also section "Interaction with other medicinal products and other forms of interaction").

Renal impairment

The safety of Virsu in patients with acute renal impairment (eGFR <30 mL/min/1.73 m²) or chronic renal impairment requiring hemodialysis has not been evaluated. The appropriate dosage has not been established. When Virsu is used in combination with ribavirin or peginterferon alfa-2/ribavirin, also refer to the ribavirin product 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 of which were fatal, have been reported during or after treatment with DAAs. All patients should be screened for HBV prior to initiating treatment and should be monitored and managed according to current clinical guidelines.

Paediatric population

Virsu is not recommended for use in children (under 18 years of age) as safety and efficacy have not been established in this population.

Interaction with other medicinal products and other forms of interaction.

Sofosbuvir is a nucleotide prodrug. After administration of Virsu, sofosbuvir is rapidly absorbed and undergoes extensive first-pass metabolism in the liver and stomach. Intracellular hydrolysis of the prodrug, catalyzed in part by carboxylesterase 1, followed by sequential phosphorylation catalyzed by nucleotide kinases, leads to the formation of the pharmacologically active triphosphate, a uridine nucleoside analogue. The major inactive circulating 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 the formation of the active metabolite. Parent sofosbuvir accounts for approximately 4% of systemic exposure to drug-derived materials (see "Pharmacokinetics"). In pharmacological clinical studies, sofosbuvir and GS-331007 were monitored for pharmacokinetic analysis.

Sofosbuvir is a substrate of the P-glycoprotein drug transporter and breast cancer resistance protein (BCRP), whereas GS-331007 is not. Medicinal products that are strong inducers of intestinal P-glycoprotein (e.g., rifampicin, rifabutin, St. John’s wort, carbamazepine, phenobarbital, and phenytoin) may reduce plasma concentrations of sofosbuvir, leading to reduced therapeutic effect of Virsu. Therefore, their concomitant use with Virsu is contraindicated (see section "Special precautions"). Medicinal products that are moderate inducers of intestinal P-glycoprotein (such as oxcarbazepine and modafinil) may reduce plasma concentrations of sofosbuvir, resulting in reduced therapeutic effect of Virsu. Concomitant use of such medicinal products with Virsu is not recommended (see section "Special precautions"). Concomitant use of Virsu with medicinal products that are inhibitors of P-glycoprotein and/or BCRP may increase plasma concentrations of sofosbuvir without increasing plasma concentrations of GS-331007; therefore, Virsu may be used with inhibitors of P-glycoprotein and/or BCRP. Sofosbuvir and GS-331007 are not inhibitors of P-glycoprotein or BCRP, so enhanced effects of drugs that are substrates of these transporters are not expected.

The metabolic activation pathway of sofosbuvir within the cell involves generally low bond formation and efficient hydrolysis, as well as nucleotide phosphorylation pathways unlikely to be influenced by concomitant medicinal products (see section "Pharmacokinetics").

Patients using vitamin K antagonists

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

Other interactions

Information on interactions between Virsu and potential concomitant medications is summarized briefly in Table 1 below (where 90% confidence interval (CI) of the geometric mean ratio calculated by the least squares method (GLSM) was within "↔", increased "↑", or decreased "↓" within predefined equivalence limits). This table is not exhaustive.

Table 1. Interaction between Virsu and other medicinal products

NA – not applicable

a Mean ratio (90 % confidence interval) of 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 Atripla.

e Bioequivalence limit of 80–125 %.

f Equivalence limit of 70–143 %.

Special precautions for use.

Women of childbearing potential / contraception for men and women

When using Virsos in combination with ribavirin or peginterferon alfa-2/ribavirin, special attention must be paid to preventing pregnancy in female patients and in female partners of male patients. Ribavirin has been shown to have significant teratogenic and/or embryotoxic effects in all animal species studied (see section "Safety precautions"). Women of childbearing potential and female partners of male patients must use effective contraception during treatment and for the post-treatment period as recommended in the ribavirin prescribing information. For additional information, refer to the ribavirin prescribing information.

Use during pregnancy or breastfeeding

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

Animal studies have not revealed any direct or indirect adverse effects on reproductive toxicity. No adverse effects on embryonic development were observed in rats and rabbits administered the highest doses. However, it is not possible to fully assess the exposure levels of sofosbuvir in rats relative to those in humans at the recommended clinical dose.

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

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

Breastfeeding

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

Pharmacokinetic data in animals indicate excretion of metabolites into milk.

A risk to newborns/infants cannot be excluded. Therefore, Virsos should not be used in women who are breastfeeding.

Fertility

Data on the effect of Virsos on human fertility are insufficient. Animal studies do not indicate harmful effects on fertility.

Ability to affect reaction speed when driving or operating machinery

Virsos has a moderate influence on the ability to drive vehicles and operate complex machinery. Patients should be informed that fatigue, impaired concentration, dizziness, and blurred vision have been reported during treatment with sofosbuvir in combination with peginterferon alfa-2 and ribavirin (see section "Adverse reactions").

Dosage and Administration

Treatment with Veklury should be initiated under the supervision of a physician experienced in the management of patients with CHC.

Adults

The recommended dose is 400 mg as a tablet to be taken orally once daily with food (see section "Pharmacokinetics").

Veklury should be used in combination with other medicinal products. Monotherapy with Veklury is not recommended (see section "Pharmacodynamics"). Also refer to the package leaflet of the medicinal products used in combination with Veklury. The recommended medicinal products for concomitant use and the duration of combination therapy with Veklury are presented in Table 2.

Table 2 Recommended concomitant medicinal products and duration of Veklury combination therapy

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

a For patients with HCV genotype 1 infection who are treatment-experienced, there are no data on the combination of Viroso, ribavirin, and peginterferon alfa-2 (see section "Special safety precautions").

b Consider extending the duration of treatment from 12 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 (e.g., marked fibrosis/cirrhosis, high baseline viral load, non-Caucasian race, IL28B other than CC genotype, prior non-response to peginterferon alfa-2 and ribavirin therapy).

c See section "Patients awaiting liver transplantation" below.

The dose of ribavirin in combination with Viroso should be weight-based (<75 kg = 1000 mg; ≥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 safety precautions".

Dosage adjustments

Dose reduction of Viroso is not recommended.

If sofosbuvir is used in combination with peginterferon alfa-2 and the patient develops serious adverse reactions related to this agent, the dose of peginterferon alfa-2 should be reduced or its administration discontinued. For further information on dose reduction and/or discontinuation of peginterferon alfa-2, refer to the prescribing information for peginterferon alfa-2.

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 3 provides recommendations for dose adjustment and discontinuation based on hemoglobin concentration and the patient's cardiac status.

Table 3 Recommendations for ribavirin dose adjustment when used in combination with Viroso

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

Discontinuation of dosing

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

Elderly patients

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

Renal impairment

Dose adjustment of Veklury is not required in patients with mild or moderate renal impairment. The safety and appropriate dosing of Veklury have not been established in patients with acute renal failure (calculated glomerular filtration rate [cGFR] <30 mL/min/1.73 m²) or end-stage renal disease requiring hemodialysis (see section "Pharmacokinetics").

Hepatic impairment

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

Patients awaiting liver transplantation

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

Liver transplant recipients

Liver transplant recipients are recommended to take Veklury in combination with ribavirin for 24 weeks. Initiate ribavirin at a dose of 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/day (1000 mg for patients with body weight <75 kg and 1200 mg for patients with body weight ≥75 kg). If the initial ribavirin dose is poorly tolerated, it should be reduced according to clinical judgment and hemoglobin levels.

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 "Pharmacodynamics").

Patients should be advised that if vomiting occurs within 2 hours after dose administration, an additional tablet should be taken. If vomiting occurs more than 2 hours after tablet ingestion, 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 18 hours have not yet 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.

Children

The safety and efficacy of Veklury in children (under 18 years of age) have not been established. Data are unavailable.

Overdose

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

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

Adverse reactions.

Summary of safety profile

During treatment with sofosbuvir in combination with ribavirin or with peginterferon alfa-2 and ribavirin, the most commonly observed adverse drug reactions were consistent with the expected safety profiles of sofosbuvir and peginterferon alfa-2, and the frequency or severity of adverse reactions was not increased.

Assessment of adverse reactions is based on the pooled data from phase 3 clinical trials (both controlled and uncontrolled).

The proportion of patients who discontinued treatment due to adverse reactions was 1.4% in patients receiving placebo, 0.5% in patients receiving sofosbuvir + ribavirin for 12 weeks, 0% in patients receiving sofosbuvir + ribavirin for 16 weeks, 11.1% in patients receiving peginterferon alfa-2 + ribavirin for 24 weeks, and 2.4% in patients receiving sofosbuvir + peginterferon alfa-2 + ribavirin for 12 weeks.

The safety of Viro was primarily evaluated in combination with ribavirin, either with or without peginterferon alfa-2. Therefore, no adverse reactions specifically attributable to sofosbuvir alone have been identified. Among patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin, and peginterferon alfa-2, the most common adverse reactions were fatigue, headache, nausea, and insomnia.

The adverse reactions listed below have been identified when sofosbuvir was used in combination with ribavirin or in combination with peginterferon alfa-2 and ribavirin (Table 4). The adverse reactions are listed below by system organ class and frequency. Frequency classification: 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 4 Adverse reactions associated with sofosbuvir in combination with ribavirin or peginterferon alfa-2 and ribavirin

a SOF – sofosbuvir; b RBV – ribavirin; c PEG – peginterferon alfa-2.

Other special patient populations

HIV/HCV co-infection

The safety profile of sofosbuvir and ribavirin in patients with HCV/HIV co-infection is similar to that observed in phase 3 clinical trials in patients with HCV monoinfection treated with sofosbuvir and ribavirin.

Patients awaiting liver transplantation

The safety profile of sofosbuvir and ribavirin in HCV-infected patients awaiting liver transplantation is similar to that observed in phase 3 clinical trials in patients treated with sofosbuvir and ribavirin.

Liver transplant recipients

The safety profile of sofosbuvir and ribavirin in patients with liver transplantation and chronic hepatitis C is similar to that observed in phase 3 clinical trials in patients treated with sofosbuvir and ribavirin (see section «Pharmacodynamics»). In study 0126, hemoglobin decrease was a very common event: hemoglobin levels decreased to <10 g/dL in 32.5% (13 out of 40) of patients, and to <8.5 g/dL in one patient. Eight patients (20%) received epoetin and/or blood components. In 5 patients (12.5%), the investigational medicinal products were completely or temporarily discontinued or dose-adjusted due to adverse reactions.

Description of selected adverse reactions

Cardiac arrhythmias

Cases of severe bradycardia and heart block have been reported when sofosbuvir is used in combination with other antiviral drugs (including daclatasvir, simeprevir, and ledipasvir) and concomitantly with amiodarone and/or other medicinal products that reduce heart rate (see sections «Special precautions» and «Adverse reactions»).

Reporting suspected adverse reactions

After marketing authorization of a medicinal product, it is important to report suspected adverse reactions to allow ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions to the national pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

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

Keep out of the reach and sight of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Strides Pharma Sciences Limited.

Manufacturer's address.

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

Marketing authorization holder.

Strides Pharma Sciences Limited.

Address of the marketing authorization holder.

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