MAYHEP ALL

INSTRUCTIONS for medical use of the medicinal product MyHep ALL

Composition:

Active substances: sofosbuvir, velpatasvir;

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

Excipients: copovidone; lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; colloidal silicon dioxide anhydrous; magnesium stearate;

Film coating: TC-510031 green (partially hydrolyzed polyvinyl alcohol; titanium dioxide (E 171); polyethylene glycol; talc; indigo carmine aluminium lake (E 132); yellow iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Basic physico-chemical properties: film-coated, modified capsule-shaped, biconvex tablet with beveled edges, light green to green in color, imprinted with "M" on one side and "SFV" on the other side.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Antiviral agents for the treatment of hepatitis C virus (HCV). ATC code J05AP55.

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 by the HCV NS5B polymerase into HCV RNA and acts as a chain terminator of RNA synthesis. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases and is not an inhibitor of mitochondrial RNA polymerase.

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

Antiviral activity

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

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

Table 1

N/D = no data

1. Mean value from several experiments with one laboratory replicon.
2. Stable chimeric replicons 1b carrying NS5B genes from genotypes 2b, 5a, or 6a were used for testing.
3. Data from various full-length NS5A replicon strains or chimeric NS5A replicons carrying full-length NS5A genes containing polymorphisms L31 or M31.
4. Data from a chimeric NS5A replicon carrying NS5A amino acids 9–184.

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

Table 2

N/A = not available

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

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

Resistance

In cell culture

HCV replicons with reduced sensitivity to sofosbuvir were selected in cell culture for various genotypes, including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced sensitivity to sofosbuvir was associated with the primary NS5B substitution S282T in 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 of sofosbuvir (GS-461203) to inhibit recombinant NS5B polymerase from genotypes 1b, 2a, 3a, and 4a expressing the S282T substitution was lower than its ability to inhibit 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 for various genotypes, including 1a, 1b, 2a, 3a, 4a, 5a, and 6a. Variants selected at positions associated with NS5A resistance included positions 24, 28, 30, 31, 32, 58, 92, and 93. Variants associated with resistance (RAS) and selected in two or more genotypes were F28S, L31I/V, and Y93H. Site-directed mutagenesis of known NS5A RAS 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 RAS alone.

In clinical trials

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 and velpatasvir in tablet form for 12 weeks in three Phase 3 trials, 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 any patients infected with HCV genotypes 2, 4, 5, or 6.

Of the 2 patients with genotype 1 infection and lack of virologic response, one patient had virus with emergence of NS5A RAS Y93N, and the other had virus with emergence of NS5A RAS L31I/V and Y93H in the absence of virologic response. Both patients had baseline virus infection with NS5A RAS. No NS5B resistance-associated substitutions (RAS) to nucleoside inhibitors (NI) were observed in these two patients at the time of non-response.

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

Patients with decompensated cirrhosis

In one Phase 3 trial involving patients with decompensated cirrhosis who received sofosbuvir and velpatasvir in tablet form + 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 any patient with HCV genotype 2 or 4 in the treatment group receiving sofosbuvir and velpatasvir in tablet form + ribavirin for 12 weeks.

In one patient with HCV genotype 1 infection and lack of virologic response, no NS5A or NS5B RAS were detected at non-response.

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

In this trial, two patients receiving sofosbuvir and velpatasvir in tablet form for 12 or 24 weeks without ribavirin developed emergence of NS5B S282T at low levels (<5%) as well as L159F.

Impact of baseline presence of resistance-associated variants on treatment outcomes

Patients without cirrhosis and patients with compensated cirrhosis

Analyses were conducted to investigate the association between baseline NS5A RAS and treatment outcome in patients without cirrhosis or with compensated cirrhosis in three Phase 3 clinical trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3). Of 1035 patients who received sofosbuvir and velpatasvir treatment in these three Phase 3 clinical trials, 1023 patients were included in the NS5A RAS analysis; 7 patients were excluded due to lack of achievement of sustained virologic response at 12 weeks (SVR12) and lack of virologic response; another 5 patients were excluded due to inability to sequence the NS5A gene. In the combined analysis of data from these Phase 3 trials, virus from 380 of 1023 (37%) patients had baseline presence of NS5A RAS. Patients infected with HCV genotypes 2, 4, and 6 more frequently had NS5A RAS (70%, 63%, and 52%, respectively) compared to patients infected with HCV genotype 1 (23%), genotype 3 (16%), and genotype 5 (18%).

The presence of baseline RAS did not significantly affect the SVR12 rate in patients infected with HCV genotypes 1, 2, 4, 5, or 6, as briefly summarized in Table 3. Patients infected with genotype 3 and having baseline NS5A RAS Y93H had a lower SVR12 rate than patients without the Y93H substitution after 12 weeks of treatment with sofosbuvir and velpatasvir in tablet form, as briefly summarized in Table 4. In the ASTRAL-3 study, the Y93H RAS was detected at baseline in 9% of patients receiving sofosbuvir and velpatasvir in tablet form.

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

SVR12 in patients with baseline Y93H and without, cutoff value 1% (resistance analysis population), study ASTR 3

Table 4

Viral variants conferring resistance to NS5B inhibitor S282T were not detected at baseline in the NS5B sequence in any patients in the phase 3 studies. SVR12 was achieved in all 77 patients who had baseline NS5B resistance-associated variants, 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 association between baseline NS5A resistance-associated variants (RAVs) and treatment outcome in patients with decompensated cirrhosis in one phase 3 study (ASTRAL-4). Of the 87 patients treated with sofosbuvir and velpatasvir in tablet form plus ribavirin, 85 patients were included in the NS5A RAV analysis; 2 patients were excluded due to lack of achieved SVR12 and absence of virologic response. Among patients treated with sofosbuvir and velpatasvir in tablet form plus ribavirin for 12 weeks, 29% (25/85) had baseline infection with NS5A RAVs: in 29% (19/66), 75% (3/4), 15% (2/13), and 50% (1/2) of patients with HCV genotypes 1, 2, 3, and 4, respectively.

SVR12 in patients with or without baseline NS5A RAVs in the sofosbuvir and velpatasvir in tablet form plus ribavirin treatment group for 12 weeks in this study is shown in Table 5.

SVR12 in patients with or without baseline NS5A resistance-associated variants by HCV genotype (ASTRAL-4 study)

Table 5

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 treatment group receiving sofosbuvir and velpatasvir in tablet form + ribavirin for 12 weeks, baseline NS5B RASs to NI (N142T and L159F) were present; SVR12 was achieved in all three patients.

Cross-resistance

In vitro study data indicate that most NS5A RASs conferring resistance to ledipasvir and daclatasvir remained sensitive to velpatasvir. Velpatasvir retains full activity against the S282T substitution in NS5B associated with resistance to sofosbuvir, whereas 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 antiviral agents with different mechanisms of action, such as non-nucleoside NS5B inhibitors and NS3 protease inhibitors. The efficacy of sofosbuvir and velpatasvir in tablet form has not been evaluated in patients who previously failed treatment with other regimens including an NS5A inhibitor.

Elderly patients

In clinical studies of sofosbuvir and velpatasvir in tablet form, 156 patients aged 65 years or older (12% of the total number of patients in phase 3 clinical trials) participated. The response rate 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 sofosbuvir and velpatasvir in tablet form, sofosbuvir was rapidly absorbed, with median peak plasma concentration observed at 1 hour post-dose. The median peak plasma concentration of GS-331007 was observed at 3 hours post-dose. The median peak plasma concentration of velpatasvir was observed at

3 hours post-dose.

According to population pharmacokinetic analysis data, in patients with HCV infection, mean steady-state pharmacokinetic exposure values (AUC0-24) for sofosbuvir (n = 982), GS-331007 (n = 1428), and velpatasvir (n = 1425) were 1260,

13970, and 2970 ng•h/mL, respectively. Steady-state Cmax values for sofosbuvir, GS-331007, and velpatasvir were 566, 868, and 259 ng/mL, respectively. AUC0-24 and Cmax values for sofosbuvir and GS-331007 were similar in healthy adult volunteers and HCV-infected patients. Compared to healthy volunteers (n = 331), AUC0-24 and Cmax values for velpatasvir in HCV-infected patients were lower by 37% and 41%, respectively.

Effect of food intake

Compared to fasting, single-dose administration of sofosbuvir and velpatasvir in tablet form with a meal of moderate fat content (~600 kcal, 30% fat) or high fat content (~800 kcal, 50% fat) increased AUC0-inf values for velpatasvir by 34% and 21%, respectively, and Cmax values by 31% and 5%, respectively. Administration with a meal of moderate or high fat content increased AUC0-inf for sofosbuvir by 60% and 78%, respectively, but did not substantially affect sofosbuvir Cmax. Food with moderate or high fat content did not affect AUC0-inf of GS-331007 but reduced Cmax values by 25% and 37%, respectively. Response rates in phase 3 studies were similar in HCV-infected patients receiving sofosbuvir and velpatasvir in tablet form with or without food. Sofosbuvir and velpatasvir in tablet form may 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 400 mg dose of [14C]-sofosbuvir administered to healthy volunteers, the blood-to-plasma ratio of [14C]-radioactivity was approximately 0.7.

Velpatasvir is >99.5% bound to human plasma proteins. Binding is independent of drug concentration in the range of 0.09–1.8 µg/mL. After a single 100 mg dose of [14C]-velpatasvir administered to healthy volunteers, the blood-to-plasma ratio of [14C]-radioactivity 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 >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 the parent drug. Metabolites identified in human plasma included monohydroxylated and demethylated derivatives of velpatasvir. Unchanged velpatasvir is the primary compound excreted in feces.

Elimination

After a single 400 mg oral dose of [14C]-sofosbuvir, mean total elimination of [14C]-radioactive compounds was >92%: approximately 80%, 14%, and 2.5% eliminated in urine, feces, and expired air, respectively. The major portion of the sofosbuvir dose excreted in urine was in the form of GS-331007 (78%), while 3.5% was excreted as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-life of sofosbuvir and GS-331007 after administration of sofosbuvir and velpatasvir in tablet form was

0.5 and 25 hours, respectively.

After a single 100 mg oral dose of [14C]-velpatasvir, mean total elimination of [14C]-radioactive compounds was 95%: approximately 94% and 0.4% eliminated in feces and urine, respectively. Unchanged velpatasvir was the primary compound in feces, accounting for a mean of 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 primary elimination pathway for velpatasvir. The median terminal half-life of velpatasvir after administration of sofosbuvir and velpatasvir in tablet form was approximately 15 hours.

Linearity / non-linearity

AUC values for velpatasvir increase nearly 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-drug interactions of sofosbuvir/velpatasvir

Sofosbuvir and velpatasvir are substrates of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), while GS-331007 is not a substrate. Velpatasvir is also a substrate of the organic anion transporting polypeptide (OATP) 1B. In vitro, velpatasvir undergoes a slow metabolic cycle mediated by CYP2B6, CYP2C8, and CYP3A4 isoenzymes.

Velpatasvir is an inhibitor of the drug transporters P-glycoprotein, BCRP, OATP1B1, and OATP1B3. Therefore, its involvement in drug interactions with these transporters is primarily limited to the absorption process. At clinically relevant plasma concentrations, velpatasvir is not an inhibitor of hepatic transporters such as the bile salt export pump (BSEP), sodium-taurocholate cotransporting polypeptide (NTCP), OATP2B1, OATP1A2, or organic cation transporter (OCT) 1, nor of renal transporters such as 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 the drug transporters

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

Pharmacokinetics in specific populations

Race and sex

No clinically significant pharmacokinetic differences related to 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 did not have a clinically significant effect on exposure to sofosbuvir, GS-331007, or velpatasvir.

Renal impairment

A brief description of the impact of various degrees of renal impairment on exposure to components of sofosbuvir/velpatasvir 400 mg/100 mg in film-coated tablets, compared to individuals with normal renal function, is described below and presented in

Table 6.

Impact of various degrees of renal impairment on exposure (AUC) of sofosbuvir,

GS-331007, and velpatasvir compared to individuals with normal renal function

Table 6

Pharmacokinetics of sofosbuvir were evaluated in adult patients without HCV infection with mild (estimated glomerular filtration rate (eGFR) ≥ 50 and < 80 mL/min/1.73 m²), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m²), and severe renal impairment (eGFR < 30 mL/min/1.73 m²), 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 similar to those observed in HCV-negative patients with severe renal impairment.

The pharmacokinetics of velpatasvir were studied in patients without HCV infection and with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault formula) following a single 100 mg dose of velpatasvir. The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were evaluated in HCV-infected patients with ESRD requiring dialysis who were treated with sofosbuvir/velpatasvir 400 mg/100 mg as film-coated tablets for 12 weeks (n = 59), compared to patients without renal impairment who received sofosbuvir/velpatasvir in phase 2/3 studies.

Hepatic impairment

The pharmacokinetics of sofosbuvir were studied after 7 days of treatment with 400 mg sofosbuvir in adult HCV-infected patients with moderate and 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 in patients with moderate and severe hepatic impairment, respectively, whereas the AUC0-24 of GS-331007 was 18% and 9% higher, respectively. Population pharmacokinetic analysis in HCV-infected adult patients indicated that cirrhosis (including decompensated cirrhosis) did not have a clinically significant effect on the exposure of sofosbuvir and GS-331007.

The pharmacokinetics of velpatasvir were studied after a single 100 mg dose of velpatasvir administered to adult patients without HCV infection and with moderate or severe hepatic impairment (Child-Pugh-Turcotte class B and C). Compared to patients with normal hepatic function, total plasma exposure (AUCinf) of velpatasvir was similar in patients with moderate or severe hepatic impairment. Population pharmacokinetic analysis in HCV-infected patients showed that cirrhosis (including decompensated cirrhosis) did not have a clinically significant effect on velpatasvir exposure (see section "Dosage and administration").

Body weight

According to population pharmacokinetic analysis, body weight did not have a clinically significant effect on the exposure of sofosbuvir or velpatasvir in adults.

Pediatric population

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

Clinical characteristics

Indications

The medicinal product MayHep ALL is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults (see sections "Dosage and administration", "Special precautions for use", and "Pharmacodynamics").

Contraindications

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

Use with potent P-glycoprotein and cytochrome inducers

Concomitant use with medicinal products that are potent inducers of

P-glycoprotein (P-gp) or cytochrome P450 (CYP) (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin, and St. John's wort [Hypericum perforatum]) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction

Since the medicinal product MayHep ALL contains sofosbuvir and velpatasvir, any interactions established for these active substances individually may also be possible when using MayHep ALL.

Potential effect of the medicinal product MayHep ALL 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 MayHep ALL with medicinal products that are substrates of these transporters may lead to increased exposure of these medicinal products. 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 the medicinal product MayHep ALL

Sofosbuvir and velpatasvir are substrates of the drug transporters P-glycoprotein and BCRP. In addition, velpatasvir is a substrate of the drug transporter OATP1B. In vitro studies have shown that velpatasvir undergoes a slow metabolic cycle mediated 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, St. John's wort) may reduce plasma concentrations of sofosbuvir or velpatasvir, leading to a decreased therapeutic effect of sofosbuvir/velpatasvir. Concomitant use of such medicinal products with MayHep ALL is contraindicated (see section "Contraindications"). Medicinal products that are moderate inducers of P-glycoprotein or CYP (e.g., efavirenz, modafinil, oxcarbazepine, or rifapentine) may reduce plasma concentrations of sofosbuvir or velpatasvir, resulting in a reduced therapeutic effect of MayHep ALL. Concomitant use of such medicinal products with MayHep ALL is not recommended (see section "Special precautions for use"). Concomitant use with medicinal products that are inhibitors of P-glycoprotein or BCRP may lead to increased plasma concentrations of sofosbuvir or velpatasvir. Medicinal products that are inhibitors of OATP, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentrations of velpatasvir. Clinically significant drug interactions with MayHep ALL due to inhibition of P-glycoprotein, BCRP, OATP, or CYP450 are not expected; MayHep ALL may be co-administered with inhibitors of P-glycoprotein, BCRP, OATP, and CYP.

Patients receiving vitamin K antagonist therapy

Since liver function may change during treatment with MayHep ALL, careful monitoring of the international normalized ratio (INR) is recommended.

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 affected by changes in liver function during DAA therapy associated with HCV clearance.

Interaction of the medicinal product MayHep ALL with other medicinal products

Table 7 provides a list of established or potentially clinically significant drug interactions (where the 90% confidence interval [CI] of the ratio of least-squares geometric mean [GLSM] was within "↔", exceeded the upper limit "↑", or fell below the lower limit "↓" of predefined interaction ranges). The described drug interactions are based on study results of both the sofosbuvir/velpatasvir combination and sofosbuvir and velpatasvir as individual agents, or are predicted interactions that may occur when these agents are used concomitantly with sofosbuvir/velpatasvir. The table is not exhaustive.

Interaction between the medicinal product MayHep ALL and other medicinal products

Table 7

1. Geometric mean ratio (90 % CI) of pharmacokinetic parameters of coadministered drugs for investigational drugs alone or in combination. No effect = 1.00.
2. All interaction studies were conducted in healthy volunteers.
3. Administered as sofosbuvir/velpatasvir 400 mg/100 mg film-coated tablets.
4. Limits for no pharmacokinetic interaction 70–143 %.
5. These medicinal products belong to a class for which a similar interaction could be predicted.
6. Bioequivalence/equivalence boundary 80–125 %.
7. Limits for no pharmacokinetic interaction 50–200 %.

Special precautions for use

The medicinal product MayHep ALL should not be used concomitantly with other medicinal products containing sofosbuvir.

Severe bradycardia and cardiac conduction block

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

Amiodarone should be prescribed to patients receiving MayHep ALL only if alternative antiarrhythmic therapies are poorly tolerated or contraindicated.

If concomitant use of amiodarone is considered necessary, it is recommended that patients undergo cardiac monitoring for 48 hours under appropriate medical facility conditions. Subsequently, outpatient monitoring or daily self-monitoring of heart rhythm should be continued for at least the first 2 weeks of treatment.

Due to the long half-life of amiodarone, appropriate monitoring (as described above) should also be ensured for patients who have discontinued amiodarone within the previous several months and are initiating treatment with MayHep ALL.

All patients receiving MayHep ALL while concurrently or recently using amiodarone must be informed about the symptoms of bradycardia and cardiac conduction block and should seek immediate medical attention if such symptoms occur.

HCV/HBV (hepatitis B virus) co-infection

Cases of hepatitis B virus (HBV) reactivation, some with fatal outcomes, have been reported during or after DAA therapy. All patients should be tested for HBV prior to initiating treatment. Patients with HCV/HBV co-infection are at increased risk of HBV reactivation and require monitoring and management according to current clinical guidelines.

Patients who previously failed NS5A inhibitor-based treatment

Clinical data supporting the efficacy of sofosbuvir/velpatasvir for treating patients who previously failed an NS5A inhibitor-containing regimen are lacking. However, considering the NS5A resistance-associated variants (RAVs) commonly observed in patients who failed prior NS5A inhibitor-containing regimens, as well as the pharmacological properties of velpatasvir in vitro and treatment outcomes with sofosbuvir/velpatasvir in ASTRAL study participants with baseline NS5A RAVs who had not previously received NS5A inhibitors, treatment with MayHep ALL plus ribavirin for 24 weeks may be considered for patients who previously failed an NS5A inhibitor-containing regimen and are at high risk of clinical disease progression, when no other treatment options are available.

Renal impairment

Safety data on the use of MayHep ALL in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring hemodialysis are limited. MayHep ALL may be used in such patients without dose adjustment when no other appropriate treatment options are available (see sections "Pharmacodynamics", "Pharmacokinetics", and "Adverse reactions").

If MayHep ALL is used in combination with ribavirin, the prescribing information for ribavirin should also be consulted, which provides guidance on ribavirin use in patients with creatinine clearance < 50 mL/min (see section "Pharmacokinetics").

Use with moderate P-glycoprotein or CYP inducers

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

Use with certain antiretroviral regimens for HIV infection

Sofosbuvir/velpatasvir 400 mg/100 mg film-coated tablets have been shown to increase tenofovir exposure, particularly when used concomitantly with HIV treatment regimens containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate when used concomitantly with MayHep ALL and a pharmacokinetic booster has not been established. The potential risks and benefits of concomitant use of MayHep ALL with fixed-dose combination tablets containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate plus a boosted HIV protease inhibitor (e.g., atazanavir or darunavir) should be carefully considered, especially in patients at increased risk of renal impairment. Patients receiving MayHep ALL concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate plus a boosted HIV protease inhibitor require close monitoring for tenofovir-related adverse reactions. Monitoring recommendations for renal function are provided in the prescribing information for tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate.

Use in patients with diabetes

In patients with diabetes, improved glycemic control may occur after initiation of direct-acting antiviral (DAA) therapy for HCV infection, potentially leading to symptomatic hypoglycemia. Patients with diabetes should be closely monitored for glucose levels, particularly during the first three months of treatment, and anti-diabetic therapy should be adjusted as needed. The physician managing the patient's diabetes should be informed about the initiation of DAA therapy.

Childs–Pugh–Turcotte Class C cirrhosis

The safety and efficacy of MayHep ALL in patients with Childs–Pugh–Turcotte Class C cirrhosis have not been evaluated (see sections "Adverse reactions" and "Pharmacodynamics").

Post-liver transplant patients

The safety and efficacy of MayHep ALL for the treatment of HCV infection in post-liver transplant patients have not been evaluated. Treatment with MayHep ALL at the recommended doses (see section "Method of administration and dosage") should be undertaken with careful individual assessment of potential benefits and risks for each patient.

Excipients

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially sodium-free.

If the patient has been diagnosed with an intolerance to certain sugars, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of sofosbuvir, velpatasvir, or the combination sofosbuvir/velpatasvir 400 mg/100 mg in film-coated tablets in pregnant women are absent or limited (fewer than 300 pregnancy cases).

Sofosbuvir

Reproductive toxicity studies in animals did not reveal any direct or indirect adverse effects.

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

Velpatasvir

Animal studies have shown a potential for reproductive toxicity.

As a precautionary measure, MayHep ALL is not recommended during pregnancy.

Breastfeeding

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

Available pharmacokinetic data from animal studies indicate that velpatasvir and sofosbuvir metabolites are excreted in milk.

The risk to newborns/infants cannot be excluded. Therefore, MayHep ALL should not be used in women who are breastfeeding.

Fertility

Data on the effect of MayHep ALL on fertility in humans are not available. Animal studies do not indicate harmful effects of sofosbuvir or velpatasvir on fertility.

If ribavirin is used concomitantly with MayHep ALL, refer to the ribavirin prescribing information for detailed recommendations on pregnancy, contraception, and breastfeeding.

Effects on ability to drive and use machines

MayHep ALL has no effect or negligible effect on the ability to drive and use machines.

Dosage and Administration

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

Dosage

The recommended dose of the medicinal product MyHep ALL is 1 tablet orally once daily, regardless of food intake (see section "Pharmacokinetics").

Recommended treatment and its duration for all HCV genotypes

Table 8

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

When used in combination with ribavirin, the prescribing information for ribavirin should also be consulted.

If the daily dose of ribavirin is divided into two doses and taken with food, the recommended dosing is as follows.

Dosage recommendations for ribavirin when used concomitantly with the medicinal product MyHep ALL in patients with decompensated cirrhosis

Table 9

For patients with compensated cirrhosis infected with genotype 3 virus (before or after transplantation), the recommended dose of ribavirin is 1000/1200 mg (1000 mg for patients with body weight < 75 kg and 1200 mg for patients with body weight ≥ 75 kg).

For information on ribavirin dose adjustments, see the ribavirin prescribing information.

Patients should be advised that if vomiting occurs within 3 hours after taking a dose of MyHep ALL, an additional tablet should be taken. If vomiting occurs more than 3 hours after dosing, an additional tablet is not required (see section "Pharmacodynamics").

Patients should be informed that if a dose of MyHep ALL is missed and less than 18 hours have passed since the usual dosing time, the missed tablet should be taken as soon as possible, followed by the next dose at the usual time. If more than 18 hours have passed, the patient should wait and take the next dose of MyHep ALL at the usual time. Patients should be aware that a double dose of MyHep ALL must not be taken.

Patients in whom NS5A inhibitor therapy has failed

Treatment with MyHep ALL + ribavirin for 24 weeks may be considered (see section "Special precautions for use").

Elderly patients

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

Renal impairment

Dose adjustment of MyHep ALL is not required in patients with mild or moderate renal impairment.

Safety data on the use of MyHep ALL in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring hemodialysis are limited. MyHep ALL may be used in such patients without dose adjustment when no other treatment options are available (see sections "Pharmacodynamics", "Pharmacokin游戏副本", "Special precautions for use").

Hepatic impairment

Dose adjustment of MyHep ALL is not required in patients with mild, moderate, or severe hepatic impairment (Child–Pugh classes A, B, or C) (see section "Pharmacokinetics"). The safety and efficacy of MyHep ALL have been studied in patients with cirrhosis classified as Child–Pugh class B, but not in patients with cirrhosis classified as Child–Pugh class C (see sections "Special precautions for use", "Adverse reactions", and "Pharmacodynamics").

Paediatric population

The safety and efficacy of MyHep ALL in children and adolescents (under 18 years of age) have not been established. No data are available.

Method of administration

For oral use.

Patients should be informed that the tablet must be swallowed whole, regardless of food intake (see section "Pharmacokinetics"). Due to the bitter taste, the film-coated tablet should not be chewed or crushed.

Children

The safety and efficacy of MyHep ALL in children and adolescents under 18 years of age have not been established. No data are available.

Overdose

The highest documented doses of sofosbuvir and velpatasvir were single doses of 1200 mg and 500 mg, respectively. In studies involving healthy volunteers, no adverse effects were observed at these dose levels. The effects of higher doses/exposures are unknown.

There is no specific antidote for overdose with MyHep ALL. In case of overdose, the patient should be closely 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 a removal coefficient of 53%. Hemodialysis is unlikely to provide substantial elimination of velpatasvir, as velpatasvir is highly bound to plasma proteins.

Adverse Reactions

Summary of safety profile

The safety profile was defined based on pooled Phase 3 clinical trial data in patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, or 6, as well as post-marketing experience. No adverse reactions to the medicinal product were identified during clinical trials. In the post-marketing period, cases of severe bradycardia and cardiac arrest have been observed when sofosbuvir-containing products were coadministered with amiodarone. Additionally, reactivation of hepatitis B virus has been observed in patients coinfected with hepatitis C and hepatitis B viruses (HCV/HBV) following treatment with direct-acting antiviral agents (see section "Special Warnings and Precautions for Use").

Tabulated list of adverse reactions

The assessment of adverse reactions of sofosbuvir/velpatasvir 400 mg/100 mg in film-coated tablets is based on safety data from clinical trials and post-marketing experience. All adverse reactions are presented in Table 10. The adverse reactions are listed below 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).

Adverse reactions identified for sofosbuvir/velpatasvir 400 mg/100 mg in film-coated tablets

Table 10

Adverse reactions identified during post-marketing use of medicinal products containing sofosbuvir/velpatasvir.

Description of selected adverse reactions

Cardiac arrhythmia

Cases of severe bradycardia and atrioventricular block have been observed when sofosbuvir was used in combination with other direct-acting antivirals (DAAs) and concomitantly with amiodarone and/or other medicinal products that reduce heart rate (see sections "Dosage and Administration" and "Drug Interactions").

Skin disorders

Frequency unknown: Stevens–Johnson syndrome.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any 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 in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging

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

Prescription category
Prescription only.

Manufacturer

Mylan Laboratories Limited / Mylan Laboratories Limited.

Manufactured under license from Gilead Sciences Ireland UC.

Manufacturer's address and place of business

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