Kyrled

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KÜRLED (QURLED)

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 film-coated tablets, embossed with "400" 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) is not an inhibitor of human DNA- or 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 chimeric replicons of genotype 1b encoding NS5B from genotypes 2b, 5a, or 6a ranged from 0.014 to 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 susceptibility to sofosbuvir were selected in cell culture for multiple genotypes, including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all tested genotype replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes resulted in a 2- to 18-fold reduction in susceptibility 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 susceptibility to GS-461203 compared to the corresponding wild-type enzymes.

Clinical Studies. In a pooled analysis of 991 patients who received 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 221 of them. 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 Sovaldi 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 several patients infected with HCV genotype 3 in phase 3 clinical trials. No change in phenotypic susceptibility to sofosbuvir or ribavirin was observed in isolates 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

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. In the analysis assessing the impact of baseline polymorphisms on treatment outcome, no statistically significant association was found between the presence of an HCV NS5B variant at baseline and treatment outcome.

Cross-Resistance

HCV replicons expressing the S282T substitution associated with resistance to sofosbuvir remained fully susceptible to other classes of HCV antiviral agents. Sofosbuvir retained activity against NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors. Sofosbuvir remained fully active against substitutions associated with resistance to other direct-acting antiviral agents 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 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 observed at approximately 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. In healthy subjects (n = 284), sofosbuvir AUC0–24 was 57% higher and GS-331007 AUC0–24 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 approximately 1.8-fold, with a minimal effect on peak concentration. The exposure to GS-331007 was not altered by administration with a high-fat meal.

Distribution

Sofosbuvir is not a substrate for hepatic uptake 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 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 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 re-phosphorylated and lacks in vitro anti-HCV activity. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP enzymes CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

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-derived 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 recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% excreted in urine, feces, and expired air, respectively. The majority of the sofosbuvir 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 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 or 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 clinically relevant effect on exposure to sofosbuvir and GS-331007. In clinical trials, 65 patients aged 65 years and older were included. 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 that exposure to GS-331007 is at least 10 and 20 times higher in end-stage renal disease when Sovaldi is administered 1 hour before and 1 hour after hemodialysis, respectively.

Hemodialysis can effectively remove (53% clearance coefficient) the major circulating metabolite GS-331007. 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 Sovaldi has not been established in patients with severe renal impairment or end-stage renal disease (see section "Special Warnings and 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 found to be related to exposure to sofosbuvir and GS-331007. However, neither of these parameters was selected as a general surrogate marker of efficacy (SVR12) at the therapeutic dose of 400 mg.

Nonclinical Safety Data.

In repeat-dose toxicity studies in rats and dogs, high doses of a diastereomeric (1:1) mixture caused adverse effects on the liver (in dogs) and heart (in rats) and 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 behavior, reproduction, or offspring 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.

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

For specific activity against hepatitis C virus (HCV) genotypes, see sections "Posology and method of 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, resulting in reduced therapeutic effect of Kyrled. These medicinal products must not be used with Kyrled (see section "Interaction with other medicinal products and other forms of interaction").

Special precautions.

Special warnings

Kyrled is not recommended for use as monotherapy and should be prescribed in combination with other medicinal products for the treatment of hepatitis C virus infection. If treatment with other medicinal products used in combination with Kyrled is interrupted, administration of Kyrled should also be discontinued (see section "Posology and method of administration"). Prior to initiating treatment with Kyrled, the list of medicinal products that may 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 Kyrled 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 Kyrled with other DAAs who cannot tolerate or are contraindicated for other antiarrhythmic therapies.

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

If concomitant use of amiodarone is considered necessary, continuous monitoring is recommended for patients initiating Kyrled 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 Kyrled in combination with other DAAs.

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

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

The efficacy of Kyrled 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 "Posology and method of administration" and "Pharmacodynamics").

Careful consideration should be given to treating such patients, and, if possible, extending the duration of treatment with sofosbuvir, peginterferon alfa-2 and ribavirin 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 (marked fibrosis/cirrhosis, high baseline viral load, non-Caucasian race, IL28B non-CC genotype).

Patients with HCV genotypes 5 or 6 who have been previously treated

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

Patients with HCV genotypes 1, 4, 5 and 6 who have received interferon-free therapy

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

Concomitant use with other direct-acting antiviral agents against HCV

Kyrled may be used concomitantly with other direct-acting antiviral agents only if available data suggest that benefits outweigh risks. There are no data supporting concomitant use of Kyrled 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 Kyrled is used in combination with ribavirin or peginterferon alfa-2/ribavirin, effective contraception must be used by women of reproductive potential and their male partners during treatment and for the period after treatment completion as recommended in the ribavirin product information. See ribavirin product information for additional details.

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, leading to reduced therapeutic effect of Kyrled. Concomitant use of such medicinal products with Kyrled is not recommended (see also section "Interaction with other medicinal products and other forms of interaction").

Renal impairment

The safety of Kyrled in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease requiring hemodialysis has not been evaluated. An appropriate dosage has not been established. When Kyrled is used in combination with ribavirin or peginterferon alfa-2/ribavirin, also refer to 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 monitored and managed according to current clinical guidelines.

Paediatric population

Kyrled 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 prodrug of a nucleotide. After administration of Kyrled, sofosbuvir is rapidly absorbed and undergoes extensive first-pass metabolism in the liver and stomach. Hydrolytic cleavage of the prodrug within the cell, catalyzed in part by carboxylesterase 1, and subsequent phosphorylation catalyzed by nucleotide kinases, leads to the formation of the pharmacologically active triphosphate, a uridine nucleoside analogue. 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. Parent sofosbuvir accounts for approximately 4% of systemic exposure to drug-derived materials (see "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 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, resulting in reduced therapeutic effect of Kyrled. Therefore, their concomitant use with Kyrled 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, leading to reduced therapeutic effect of Kyrled. Concomitant use of such medicinal products with Kyrled is not recommended (see section "Special precautions"). Concomitant use of Kyrled 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, Kyrled may be used with inhibitors of P-glycoprotein and/or BCRP. 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 intracellular metabolic activation pathway of sofosbuvir involves low chemical binding and efficient hydrolysis, as well as nucleotide phosphorylation pathways unlikely to be influenced by concomitant medicinal products (see section "Pharmacokinetics").

Patients receiving vitamin K antagonists

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

Other forms of interaction

Information on the interaction of Kyrled with potential concomitant medicinal products 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 Kyrled and other medicinal products

NA – not applicable

a Mean ratio (90 % confidence interval) of the pharmacokinetics of the coadministered drug with/without sofosbuvir and the mean ratio of sofosbuvir and GS-331007 with/without the coadministered 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 in men and women

When Curled is used in combination with ribavirin or peginterferon alfa-2/ribavirin, special attention must be paid to preventing pregnancy in female patients and female partners of male patients. Ribavirin has been shown to have significant teratogenic and/or embryocidal effects in all animal species tested (see section "Special 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 product information. For additional information, see the ribavirin product 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 embryotoxic effects were observed in rats and rabbits at the highest tested 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, use of Curled during pregnancy is not recommended.

However, if ribavirin is used concomitantly with sofosbuvir, the contraindications for ribavirin use during pregnancy must be followed (also see ribavirin product 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 into milk.

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

Fertility

There are insufficient data on the effect of Curled on human fertility. Animal studies do not indicate harmful effects on fertility.

Ability to affect reaction speed when driving or operating machinery

Curled has a moderate influence on the ability to drive and operate 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").

Method of administration and dosage.

Initiation of Curredue should be under the supervision of a physician experienced in managing patients with CHC.

Adults

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

Curred should be used in combination with other medicinal products. Monotherapy with Curred is not recommended (see section "Pharmacodynamics"). Also, refer to the prescribing information for medicinal products used in combination with Curred. Recommended medicinal products for concomitant use and duration of combination therapy with Curred are presented in Table 2.

Table 2. Recommended concomitant medicinal products and duration of combination therapy with Curred

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

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

b Consider extending the duration of treatment from 12 to 24 weeks. This particularly applies 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-2 and ribavirin therapy).

c See section "Patients awaiting liver transplantation" below.

The dose of ribavirin in combination with Curalide should be based on patient 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 safety precautions".

Dose adjustment

Dose reduction of Curalide is not recommended.

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

If the patient develops serious adverse reactions potentially related to ribavirin, the dose of ribavirin should be modified 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 Curalide

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 ribavirin dose (from 1000 to 1200 mg/day) is not recommended.

Discontinuation of dosing

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

Elderly patients

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

Renal impairment

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

Hepatic impairment

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

Patients awaiting liver transplantation

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

Liver transplant recipients

Liver transplant recipients are recommended to take Curled in combination with ribavirin for 24 weeks. Begin 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 up 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 ribavirin dose is poorly tolerated, it should be reduced according to clinical indications, taking into account hemoglobin levels.

Administration method

The film-coated tablet is intended for oral administration. 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 dosing, they should take another tablet. If vomiting occurs more than 2 hours after tablet ingestion, no additional dose is 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 regular time without doubling the dose.

Children

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

Overdose

The maximum recorded dose of sofosbuvir was 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 case of Curled overdose, there is no specific antidote. The patient should be monitored for signs of toxicity. Management of Curled overdose consists of general supportive measures, including monitoring of vital signs and the patient's clinical status. Hemodialysis may effectively remove (53% clearance coefficient) the major circulating metabolite GS-331007. 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 reported adverse drug reactions were consistent with those expected based on the safety profiles of sofosbuvir, peginterferon alfa-2, and ribavirin, and the frequency or severity of adverse reactions was not increased.

Assessment of adverse reactions is based on 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% among patients receiving placebo, 0.5% among patients receiving sofosbuvir + ribavirin for 12 weeks, 0% among patients receiving sofosbuvir + ribavirin for 16 weeks, 11.1% among patients receiving peginterferon alfa-2 + ribavirin for 24 weeks, and 2.4% among patients receiving sofosbuvir + peginterferon alfa-2 + ribavirin for 12 weeks.

The safety of sofosbuvir was primarily evaluated in combination with ribavirin, with or without peginterferon alfa-2. Therefore, no adverse reactions specifically attributable to sofosbuvir alone have been identified. Among patients receiving sofosbuvir + ribavirin or sofosbuvir + ribavirin + peginterferon alfa-2, the most commonly observed 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 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 (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), 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 – pegylated interferon alfa-2.

Other special patient populations

HIV/HCV co-infection

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

Patients awaiting liver transplantation

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

Patients with liver transplant

The safety profile of sofosbuvir and ribavirin in patients with liver transplant and chronic hepatitis C was 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 adverse reaction: 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 products. In five patients (12.5%), treatment with the investigational medicinal products was 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 agents (including daclatasvir, simeprevir, and ledipasvir) and concomitantly with amiodarone and/or other drugs that reduce heart rate (see sections "Special precautions" and "Adverse reactions").

Reporting of suspected adverse reactions

After marketing authorization of a medicinal product, it is important to report suspected adverse reactions to ensure continued monitoring of the benefit-risk balance of the 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 reach and sight of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Strides Pharma Sciences Limited.

Manufacturer’s address and place of business.

No. 36/7, Suragajakkanahalli, 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.