KYRLED-LP

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KURLED-LP (QURLED-LP)

Composition:

Active substances: ledipasvir, sofosbuvir;

One film-coated tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir;

Excipients: copovidone, lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate; tablet coating: Opadry II Brown (85F565071).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: brown, oval-shaped, film-coated tablets with beveled edges, embossed with "SL" 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 J05AP51.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ledipasvir is an HCV inhibitor whose target is the HCV NS5A protein, which is necessary for HCV RNA replication and virion assembly. Since NS5A lacks enzymatic activity, biochemical confirmation of NS5A inhibition by ledipasvir remains impossible. In vitro studies of selective and cross-resistance have demonstrated that ledipasvir acts on NS5A as its target.

Sofosbuvir is a pangenotypic inhibitor of the HCV RNA-dependent RNA polymerase NS5B, which is essential for viral replication.

Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator 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.

Antiviral activity

The EC50 values of ledipasvir and sofosbuvir against full-length or chimeric replicons encoding NS5A and NS5B sequences in clinical isolates are presented in Table 1. The addition of human serum at a concentration of 40% did not affect the antiviral activity of sofosbuvir, but reduced the antiviral activity of ledipasvir against HCV genotype 1a replicons by 12-fold.

Table 1. Activity of ledipasvir and sofosbuvir against chimeric replicons

a Transient replicons containing NS5A or NS5B isolated from patients.

b Chimeric replicons carrying NS5A genes from genotypes 2b, 5a, 6a, and 6e were used in the study of ledipasvir, and chimeric replicons carrying NS5B genes from genotypes 2b, 5a, or 6a were used in the study of sofosbuvir.

Resistance

In cell cultures

HCV replicons with reduced sensitivity to ledipasvir were selected in cell cultures for genotypes 1a and 1b. Reduced sensitivity to ledipasvir was associated with the primary NS5A substitution Y93H in genotypes 1a and 1b. Additionally, the substitution Q30E emerged in replicons of genotype 1a. Site-specific mutagenesis of NS5A RAVs showed that substitutions leading to >100- to ≤1000-fold changes in sensitivity to ledipasvir included Q30H/R, L31I/M/V, P32L, and Y93T in genotype 1a and P58D and Y93S in genotype 1b; substitutions leading to >1000-fold changes included M28A/G, Q30E/G/K, H58D, Y93C/H/N/S in genotype 1a and A92K and Y93H in genotype 1b.

HCV replicons with reduced sensitivity to sofosbuvir were selected in cell cultures 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 replicons of all studied genotypes. Site-specific mutagenesis of the S282T fragment in replicons of 8 genotypes 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 clinical studies, genotype 1

Results from a pooled analysis of patients who received ledipasvir/sofosbuvir in phase III studies (ION-3, ION-1, and ION-2) showed that 37 patients (29 with genotype 1a and 8 with genotype 1b) were eligible for resistance analysis due to virological failure or premature discontinuation of study drug with HCV RNA levels >1000 IU/mL. Deep sequencing data for NS5A and NS5B post-baseline (analysis threshold 1%) were obtained for 37/37 and 36/37 patients, respectively.

NS5A resistance-associated variants (RAVs) were detected post-baseline in isolates from 29/37 patients (22/29 with genotype 1a and 7/8 with genotype 1b) who did not achieve sustained virological response (SVR). Among 29 patients with genotype 1a eligible for resistance analysis, one or more NS5A RAVs at positions K24, M28, Q30, L31, S38, and Y93 were present at failure in 22/29 (76%) patients, while no NS5A RAVs were detected at failure in the remaining 7/29 patients. The most common variants were Q30R, Y93H, and L31M. Among 8 patients with genotype 1b eligible for resistance analysis, one or more NS5A RAVs at positions L31 and Y93 were present at failure in 7/8 (88%) patients, while no NS5A RAVs were detected at failure in 1/8 patients. The most common variant was Y93H. Among 8 patients without NS5A RAVs at failure, 7 patients received an 8-week treatment course (n = 3 with ledipasvir/sofosbuvir; n = 4 with ledipasvir/sofosbuvir + ribavirin), and 1 patient received a 12-week course of ledipasvir/sofosbuvir. Phenotypic analysis showed that isolates from patients with NS5A RAVs detected at failure post-baseline exhibited reduced sensitivity to ledipasvir by 20- to at least 243-fold (highest tested concentration). Site-specific mutagenesis of the Y93H fragments in both genotypes 1a and 1b, as well as Q30R and L31M fragments in genotype 1a, led to reduced sensitivity to ledipasvir (fold change in EC50 from 544 to 1677 times).

The S282T substitution in NS5B, which confers resistance to sofosbuvir, was not observed in any isolate at virological failure in phase III studies. However, the NS5B S282T substitution in combination with NS5A substitutions L31M, Y93H, and Q30L was detected in one patient who experienced failure after 8 weeks of treatment with ledipasvir/sofosbuvir in a phase II study (LONESTAR). This patient subsequently received a retreatment course of ledipasvir/sofosbuvir + ribavirin for 24 weeks and achieved SVR after treatment completion.

In the SIRIUS study, 5 patients with genotype 1 virus experienced relapse after treatment with ledipasvir/sofosbuvir with or without ribavirin. NS5A RAVs at relapse were present in 5/5 patients (in genotype 1a: Q30R/H + L31M/V [n = 1] and Q30R [n = 1]; in genotype 1b: Y93H [n = 3]).

In the SOLAR-1 study, 13 patients with genotype 1 virus experienced relapse after treatment with ledipasvir/sofosbuvir with ribavirin. NS5A RAVs at relapse were present in 11/13 patients (in genotype 1a: Q30R only [n = 2], Y93C [n = 1], Y93H/C [n = 2], Q30R + H58D [n = 1], M28T + Q30H [n = 1]; in genotype 1b: Y93H [n = 3], Y93H/C [n = 1]).

In clinical studies, genotypes 2, 3, 4, 5, and 6

NS5A RAVs: No patient infected with genotype 2 experienced relapse during clinical studies; therefore, data on NS5A RAVs at failure are unavailable.

In patients infected with genotype 3 who experienced virological failure, emergence of NS5A RAVs (including increased prevalence of RAVs present at baseline) was generally not observed at failure (n = 17).

For infections with genotypes 4, 5, and 6, only a small number of patients were evaluated (total of 5 patients with failure). The NS5A Y93C substitution emerged in HCV from one patient (genotype 4), while baseline NS5A RAVs were observed at failure in all patients.

NS5B RAVs: The NS5B S282T substitution emerged in HCV in 1/17 cases of failure with genotype 3, and in 1/3, 1/1, and 1/1 cases of failure with genotypes 4, 5, and 6, respectively.

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

Genotype 1

An analysis was conducted to study the association between baseline NS5A RAVs and treatment outcomes. Pooled analysis results from phase III studies showed that baseline NS5A RAVs were detected by population or deep sequencing in 16% of patients, regardless of subtype. Baseline NS5A RAVs were more pronounced in patients who experienced relapse in phase III studies.

After 12 weeks of treatment with ledipasvir/sofosbuvir without ribavirin in treatment-naïve patients (group 1 of the ION-2 study), SVR was achieved in 4/4 patients with baseline NS5A RAVs whose fold change in ledipasvir sensitivity was ≤100. In the same treatment group, relapse occurred in 4/13 (31%) patients with baseline NS5A RAVs whose fold change was >100, compared to 3/95 (3%) in patients without baseline RAVs or with RAVs showing fold change ≤100.

After 12 weeks of treatment with ledipasvir/sofosbuvir and ribavirin in treatment-naïve patients with compensated cirrhosis (SIRIUS, n = 77), 8/8 patients with baseline NS5A RAVs leading to >100-fold reduced sensitivity to ledipasvir achieved SVR12.

The group of NS5A RAVs leading to >100-fold shift and observed in patients included the following substitutions in genotype 1a (M28A, Q30H/R/E, L31M/V/I, H58D, Y93H/N/C) or in genotype 1b (Y93H). The prevalence of such baseline NS5A RAVs, detected by deep sequencing, ranged from very low (analysis threshold 1%) to high (majority of the population in selected plasma samples).

The S282T substitution associated with resistance to sofosbuvir was not found in the NS5B sequence at baseline in any patient in phase III studies, by population or deep sequencing. SVR was achieved in 24 patients (n = 20 with L159F + C316N; n = 1 with L159F; n = 3 with N142T) who had baseline variants associated with resistance to nucleoside NS5B inhibitors.

After 12 weeks of treatment with ledipasvir/sofosbuvir and ribavirin in post-liver transplant patients with compensated liver disease (SOLAR-1), no relapses occurred in any (n = 8) patients with baseline NS5A RAVs leading to >100-fold change in ledipasvir sensitivity. After 12 weeks of treatment with ledipasvir/sofosbuvir and ribavirin in patients with decompensated disease (regardless of liver transplant status), relapse occurred in 3/7 patients with baseline NS5A RAVs leading to >100-fold reduced sensitivity to ledipasvir, compared to 4/68 patients without baseline RAVs or with RAVs leading to ≤100-fold reduced sensitivity to ledipasvir.

Genotypes 2, 3, 4, 5, and 6

Due to limited data, the impact of baseline NS5A RAVs on treatment outcomes in patients with chronic hepatitis C (CHC) genotypes 2, 3, 4, 5, or 6 was not fully evaluated. No significant differences in treatment outcomes were observed between patients with or without baseline NS5A RAVs.

Cross-resistance

Ledipasvir was fully active against the S282T substitution in NS5B associated with resistance, and all resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and ledipasvir were active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of action, such as non-nucleoside NS5B inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to ledipasvir may reduce the antiviral activity of other NS5A inhibitors.

Pharmacokinetics.

Absorption

Following oral administration of ledipasvir/sofosbuvir to HCV-infected patients, the median maximum plasma concentration (Cmax) of ledipasvir was observed 4.0 hours after dosing. Sofosbuvir was rapidly absorbed, with median Cmax observed approximately 1 hour after administration. The median Cmax of GS-331007 in plasma was observed 4 hours after dosing.

Based on population pharmacokinetic analysis in HCV-infected patients, the geometric mean steady-state area under the pharmacokinetic concentration-time curve over 24 hours (AUC0–24) of ledipasvir (n = 2113), sofosbuvir (n = 1542), and GS-331007 (n = 2113) was 7290, 1320, and 12,000 ng·h/mL, respectively. Steady-state Cmax of ledipasvir, sofosbuvir, and GS-331007 was 323, 618, and 707 ng/mL, respectively. AUC0–24 and Cmax of GS-331007 were similar in healthy adult volunteers and HCV-infected patients. Compared to healthy volunteers (n = 191), AUC0–24 and Cmax of ledipasvir in HCV-infected patients were 24% and 32% lower, respectively. Over the dose range of 3 to 100 mg, the AUC of ledipasvir was dose-proportional. Over the dose range of 200 to 400 mg, AUC of sofosbuvir and GS-331007 was nearly dose-proportional.

Effect of food intake

Compared to fasting conditions, single-dose administration of ledipasvir/sofosbuvir with a meal of moderate or high fat content increased the AUC0–inf of sofosbuvir approximately 2-fold, but had minimal effect on Cmax of sofosbuvir. Concentrations of GS-331007 and ledipasvir were not altered by the presence of food of any type. Therefore, Curled-LP can be taken with or without food.

Distribution

Ledipasvir is >99.8% bound to human plasma proteins. After single-dose administration to healthy volunteers of 90 mg [14C]-ledipasvir, the blood-to-plasma concentration ratio of [14C]-ledipasvir ranged from 0.51 to 0.66.

Sofosbuvir is approximately 61–65% bound to human plasma proteins, with binding independent of drug concentration within the range of 1 to 20 µg/mL. GS-331007 binding to human plasma is minimal. After single-dose administration to healthy volunteers of 400 mg [14C]-sofosbuvir, the blood-to-plasma concentration ratio of [14C]-sofosbuvir was approximately 0.7.

Biotransformation

In vitro, no significant metabolism of ledipasvir by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 enzymes was observed. Slow oxidative metabolism occurred, but the mechanism was not fully elucidated. After single-dose administration of 90 mg [14C]-ledipasvir, systemic exposure was almost entirely due to the parent drug (>98%). Unchanged ledipasvir is also the main compound excreted in feces.

Sofosbuvir undergoes extensive hepatic metabolism to form the pharmacologically active nucleoside analog triphosphate GS-461203. The active metabolite was not detected. The metabolic activation pathway involves sequential hydrolysis of the carboxyl-ester moiety, catalyzed by human cathepsin A or carboxylesterase 1, followed by phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 and subsequent phosphorylation via pyrimidine nucleotide biosynthesis. Defosphorylation results in the nucleoside metabolite GS-331007, which cannot be efficiently phosphorylated and has reduced activity against HCV in vitro. In the ledipasvir/sofosbuvir combination, GS-331007 accounts for approximately 85% of total systemic exposure.

Elimination

After single oral administration of 90 mg [14C]-ledipasvir, mean total elimination of [14C]-radioactive compounds in feces and urine was 87%, with the majority excreted in feces (86%). Unchanged ledipasvir in feces accounted for a mean of 70% of the administered dose, and the oxidized metabolite M19 accounted for 2.2% of the administered dose. Based on these data, biliary excretion of unchanged ledipasvir is the primary elimination pathway, while renal excretion is secondary (approximately 1%). The median terminal half-life of ledipasvir in healthy volunteers after administration of ledipasvir/sofosbuvir under fasting conditions was 47 hours.

After single oral administration of 400 mg [14C]-sofosbuvir, mean total dose recovery exceeded 92%, with approximately 80%, 14%, and 2.5% excreted in urine, feces, and expired air, respectively. The majority 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 primary elimination pathway for GS-331007, with most excretion occurring via active secretion. The median terminal half-life of sofosbuvir and GS-331007 after administration of ledipasvir/sofosbuvir was 0.5 and 27 hours, respectively.

Neither ledipasvir nor sofosbuvir are substrates of hepatic uptake transporters, organic cation transporter (OCT) 1, organic anion transporting polypeptide (OATP) 1B1, or OATP1B3. GS-331007 is not a substrate of renal transporters, including organic anion transporter (OAT) 1, OAT3, or OCT2.

Potential of ledipasvir/sofosbuvir to affect other medicinal products in vitro

At clinically achieved concentrations, ledipasvir did not inhibit hepatic cellular transport, including OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxin extrusion protein (MATE) 1, multidrug resistance protein (MRP) 2, or MRP4. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-glycoprotein (P-gp), BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, or MATE1.

Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP enzymes or uridine diphosphate glucuronosyltransferase (UGT) 1A1.

Pharmacokinetics in special populations

Race and sex

No clinically significant differences in the pharmacokinetics of ledipasvir, sofosbuvir, or GS-331007 were observed based on race. No clinically significant differences in the pharmacokinetics of sofosbuvir or GS-331007 were observed based on sex. AUC and Cmax of ledipasvir were 77% and 58% higher in women than in men, respectively, but the relationship between sex and ledipasvir AUC was not clinically significant.

Elderly patients

Population pharmacokinetic analysis in HCV-infected patients showed that within the analyzed age range (18 to 80 years), age did not have a clinically significant effect on AUC of ledipasvir, sofosbuvir, or GS-331007. A total of 235 patients (8.6% of the total patient population) aged 65 years and older were included in clinical studies of ledipasvir/sofosbuvir.

Renal impairment

The pharmacokinetics of ledipasvir were studied after single-dose administration of 90 mg ledipasvir to HCV-negative patients with severe renal impairment (estimated glomerular filtration rate (eGFR) <30 mL/min by Cockcroft-Gault formula, median [range] creatinine clearance (CrCl) 22 [17–29] mL/min). No clinically significant differences in ledipasvir pharmacokinetics were observed between healthy volunteers and patients with severe renal impairment.

The pharmacokinetics of sofosbuvir were studied in HCV-negative patients with mild (eGFR ≥50 and <80 mL/min/1.73 m²), moderate (eGFR ≥30 and <50 mL/min/1.73 m²), severe renal impairment (eGFR <30 mL/min/1.73 m²), and patients with end-stage renal disease (ESRD) requiring hemodialysis after single-dose administration of 400 mg sofosbuvir. Compared to patients 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, and AUC0–inf of GS-331007 was 55%, 88%, and 451% higher, respectively. In ESRD patients, compared to those with normal renal function, AUC0–inf of sofosbuvir was 28% higher when sofosbuvir was administered 1 hour before hemodialysis and 60% higher when administered 1 hour after hemodialysis. AUC0–inf of GS-331007 in ESRD patients who took sofosbuvir 1 hour before and 1 hour after hemodialysis was at least 10-fold and 20-fold higher, respectively. GS-331007 is efficiently removed during hemodialysis, with a dialysis clearance coefficient of approximately 53%. After single-dose administration of 400 mg sofosbuvir, 18% of the administered dose was removed during a 4-hour hemodialysis session. The safety and efficacy of sofosbuvir in patients with severe renal impairment and ESRD have not been established.

Hepatic impairment

The pharmacokinetics of ledipasvir were studied after single-dose administration of 90 mg ledipasvir to HCV-negative patients with severe hepatic impairment (Child-Pugh class C). Plasma exposure (AUCinf) of ledipasvir was similar in patients with severe hepatic impairment and control patients with normal liver function. Population pharmacokinetic analysis in HCV-infected patients showed that cirrhosis had no clinically significant effect on ledipasvir exposure.

The pharmacokinetics of sofosbuvir were studied after 7 days of 400 mg sofosbuvir administration in HCV-infected patients with moderate and severe hepatic impairment (Child-Pugh classes B and C). Compared to patients with normal liver function, AUC0–24 of sofosbuvir was 126% and 143% higher in moderate and severe hepatic impairment, respectively, and AUC0–24 of GS-331007 was 18% and 9% higher, respectively. Population pharmacokinetic analysis in HCV-infected patients showed that cirrhosis had no clinically significant effect on sofosbuvir and GS-331007 exposure.

Body weight

Body weight had no significant effect on sofosbuvir exposure based on population pharmacokinetic analysis. Ledipasvir exposure decreases with increasing body weight, but this relationship is not considered clinically significant.

Pediatric patients

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

Clinical characteristics.

Indications.

The medicinal product Curled-LP is indicated for the treatment of chronic hepatitis C (CHC) in adult patients (see sections "Pharmacodynamics", "Special precautions for safety", and "Method of administration and dosage").

For genotype-specific activity of hepatitis C virus (HCV), see sections "Pharmacodynamics" and "Special precautions for safety".

Contraindications.

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

Concomitant use with rosuvastatin (see section "Interaction with other medicinal products and other types of interactions").

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

Medicinal products that are strong intestinal P-gp inducers (rifampicin, rifabutin, St John’s wort (Hypericum perforatum), carbamazepine, phenobarbital, and phenytoin). Concomitant use significantly reduces plasma concentrations of ledipasvir and sofosbuvir and may lead to reduced efficacy of Curled-LP (see section "Interaction with other medicinal products and other types of interactions").

Special precautions for safety.

Curled-LP should not be used in combination with other medicinal products containing sofosbuvir.

Genotype-specific activity

Recommended treatment regimens for different HCV genotypes are provided in the section "Method of administration and dosage". Information on genotype-specific virological and clinical activity is provided in the section "Pharmacodynamics".

Clinical data supporting the use of Curled-LP for the treatment of patients infected with HCV genotype 3 are limited (see section "Pharmacodynamics"). The relative efficacy of a 12-week regimen of ledipasvir/sofosbuvir + ribavirin compared to a 24-week regimen of sofosbuvir + ribavirin has not been studied. A 24-week course of conservative treatment is recommended for all patients with genotype 3 who have completed therapy, as well as for treatment-naïve patients with genotype 3 and liver cirrhosis (see section "Method of administration and dosage").

Clinical data supporting the use of Curled-LP for the treatment of patients infected with HCV genotypes 2 and 6 are limited (see section "Pharmacodynamics").

Severe bradycardia and cardiac conduction block

Cases of severe bradycardia and cardiac conduction block have been reported when Curled-LP is used concomitantly with amiodarone, with or without other drugs that slow heart rate. The mechanism of this phenomenon is not fully understood.

Concomitant use of amiodarone during clinical development of sofosbuvir with direct-acting antivirals (DAAs) was limited. Because concomitant use may be life-threatening, amiodarone should be prescribed to patients undergoing treatment with Curled-LP only if alternative antiarrhythmic drugs are poorly tolerated or contraindicated.

If concomitant use of amiodarone is necessary, continuous patient monitoring is recommended after initiation of Curled-LP. If a patient is identified as being at high risk for bradycardia, continuous monitoring for 48 hours in an appropriate healthcare setting is required.

Due to the long half-life of amiodarone, appropriate monitoring should be ensured for patients who discontinued amiodarone within the past several months and have started treatment with Curled-LP.

All patients receiving Curled-LP in combination with amiodarone or other drugs that reduce heart rate, or without such drugs, should be informed about the symptoms of bradycardia and cardiac conduction block and should seek immediate medical attention if such symptoms occur.

Use in patients previously treated with direct-acting antivirals for HCV infection

In patients who did not respond to ledipasvir/sofosbuvir treatment, resistance-associated NS5A mutations that reduce sensitivity to ledipasvir are commonly observed (see section "Pharmacodynamics"). Some data suggest that these NS5A mutations do not re-emerge during long-term follow-up. Currently, there are no data confirming the efficacy of retreatment with an NS5A inhibitor in patients who previously failed ledipasvir/sofosbuvir therapy. Similarly, there are currently no data confirming the efficacy of NS3/4A protease inhibitors in patients who previously failed therapy with NS3/4A protease inhibitors. Therefore, such patients may depend on other drug classes to eliminate HCV infection. Thus, the possibility of extending the treatment duration should be considered for patients with uncertain options for subsequent therapy.

Renal impairment

Dosage adjustment of Curled-LP is not required in patients with mild or moderate renal impairment. The safety of Curled-LP in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring hemodialysis has not been studied. When Curled-LP is used with ribavirin in patients with CrCl <50 mL/min, refer also to the information provided in the ribavirin prescribing information (see section "Pharmacokinetics").

Patients with decompensated liver cirrhosis and/or patients awaiting or who have undergone liver transplantation

The efficacy of ledipasvir/sofosbuvir in HCV genotype 5- and genotype 6-infected patients with decompensated liver cirrhosis and/or those awaiting or who have undergone liver transplantation has not been studied. Treatment with Curled-LP should be administered considering the benefit-risk ratio for each individual patient.

Use with moderate P-gp inducers

Medicinal products that are moderate intestinal P-gp inducers (e.g., oxcarbazepine) may reduce plasma concentrations of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Curled-LP. Concomitant use of such medicinal products with Curled-LP is not recommended (see section "Interaction with other medicinal products and other types of interactions").

Use of certain antiretroviral therapies for HIV treatment

Curled-LP has been shown to increase tenofovir exposure, particularly when used concomitantly with HIV therapy containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the context of Curled-LP and a pharmacokinetic booster has not been studied. Potential risks and benefits associated with concomitant use of Curled-LP and fixed-dose combination tablets of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate with a boosted HIV protease inhibitor (e.g., atazanavir or darunavir) should always be considered, especially when treating patients at increased risk of renal dysfunction. Patients receiving Curled-LP concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor require monitoring for tenofovir-related adverse reactions. Recommendations for monitoring renal function are provided in the prescribing information for tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate.

Use with HMG-CoA reductase inhibitors

Concomitant use of Curled-LP and HMG-CoA reductase inhibitors (statins) may lead to a significant increase in statin concentrations, increasing the risk of myopathy and rhabdomyolysis (see section "Interaction with other medicinal products and other types of interactions").

Concomitant HCV/HBV (hepatitis B virus) infection

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

Paediatric population

Curled-LP is not recommended for children and adolescents under 18 years of age, as safety and efficacy in this patient population have not been established.

Excipients

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Interaction with other medicinal products and other types of interactions.

Since Curled-LP contains ledipasvir and sofosbuvir, any interactions established for these components may occur during treatment with Curled-LP.

Potential of Curled-LP to affect other medicinal products

In vitro, ledipasvir acts as an inhibitor of the drug transporter P-gp and breast cancer resistance protein (BCRP), and may enhance intestinal absorption of co-administered substrates of these transporters. In vitro data indicate that ledipasvir may act as a weak inducer of metabolizing enzymes such as CYP3A4, CYP2C, and UGT1A1. When substances that are substrates of these enzymes are administered concomitantly with ledipasvir/sofosbuvir, their plasma concentrations may decrease. In vitro, ledipasvir has been shown to inhibit CYP3A4 and UGT1A1 in the intestine. Medicinal products with a narrow therapeutic index, as well as those metabolized by these enzymes, should be used with caution and require continuous monitoring.

Potential of other medicinal products to affect Curled-LP

Ledipasvir and sofosbuvir are substrates of the drug transporters P-gp and BCRP, unlike GS-331007.

Medicinal products that are strong P-gp inducers (e.g., rifampicin, rifabutin, St John’s wort products, carbamazepine, phenobarbital, and phenytoin) may significantly reduce plasma concentrations of ledipasvir and sofosbuvir, thereby reducing the therapeutic efficacy of ledipasvir/sofosbuvir; therefore, their use with Curled-LP is contraindicated (see section "Contraindications"). Medicinal products that are moderate intestinal P-gp inducers (e.g., oxcarbazepine) may reduce plasma concentrations of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of Curled-LP. Concomitant use of such medicinal products with Curled-LP is not recommended (see section "Special precautions for safety"). Concomitant use with medicinal products that inhibit P-gp and/or BCRP may increase plasma concentrations of ledipasvir and sofosbuvir without increasing GS-331007 concentrations; concomitant use of Curled-LP with P-gp and/or BCRP inhibitors is not excluded. Clinically significant drug interactions with ledipasvir/sofosbuvir mediated by CYP450 enzymes or UGT1A1 are unlikely.

Patients receiving vitamin K antagonists

Given that liver function may change during treatment with Curled-LP, careful monitoring of International Normalized Ratio (INR) values is recommended for such patients.

Interaction of Curled-LP with other medicinal products

Table 2 lists established or potentially clinically significant drug interactions (where the 90% confidence interval [CI] of the geometric mean ratio [GMR] was within "↔", increased "↑", or decreased "↓" relative to predefined equivalence limits). The described drug interactions are based on studies conducted with ledipasvir/sofosbuvir or with ledipasvir and sofosbuvir as separate medicinal products, or represent probable drug interactions expected with ledipasvir/sofosbuvir. The data in the table are not exhaustive.

Table 2. Interaction of Curled-LP with other medicinal products

a Mean ratio (90% CI) of pharmacokinetics of the concomitant drug administered alone or in combination with the investigational drugs. No effect = 1.00.

b All interaction studies were conducted in healthy volunteers.

c Administered as Curdel-LP formulation.

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

e These drugs belong to a class of drugs where such types of interactions cannot be predicted.

f Staggered administration (every 12 hours) of atazanavir/ritonavir + emtricitabine/tenofovir alafenamide fumarate or darunavir/ritonavir + emtricitabine/tenofovir alafenamide fumarate and Curdel-LP formulation resulted in similar outcomes.

g Study conducted with two other direct-acting antiviral agents.

h Bioequivalence/equivalence limits: 80–125%.

Special precautions for use.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception in men and women

When using Curled-LP with ribavirin, maximum efforts must be made to prevent pregnancy in female patients and female partners of male patients. Teratogenic and/or embryocidal effects have been observed in animals administered ribavirin. Women of childbearing potential and their partners must use effective contraception during treatment and after completion of therapy, according to the recommendations provided in the ribavirin prescribing information. For additional information, refer to the ribavirin prescribing information.

Pregnancy

Data on the use of ledipasvir, sofosbuvir, or Curled-LP in pregnant women are limited or nonexistent (fewer than 300 pregnancy outcomes).

Animal studies have not shown signs of reproductive toxicity. In rats and rabbits, no significant effects on fetal development were observed with ledipasvir or sofosbuvir. It was not possible to fully establish the extent of sofosbuvir exposure in rats relative to human exposure at the recommended clinical dose.

As a precautionary measure, use of Curled-LP during pregnancy should be avoided.

Breastfeeding period

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

Available pharmacokinetic data in animals have shown that ledipasvir and sofosbuvir metabolites are present in breast milk.

Risk to newborns/infants cannot be excluded. Therefore, Curled-LP should not be used during breastfeeding.

Fertility

There are no data on the effect of Curled-LP on human fertility. Animal studies have not shown any negative effects of ledipasvir or sofosbuvir on fertility.

When ribavirin is used concomitantly with Curled-LP, contraindications related to the use of ribavirin during pregnancy or breastfeeding apply (see also the ribavirin prescribing information).

Ability to influence reaction speed when driving or operating machinery.

Curled-LP (when used as monotherapy or in combination with ribavirin) does not have a negative effect on the ability to drive or operate machinery. However, patients should be advised that fatigue has been observed more frequently with ledipasvir/sofosbuvir than with placebo.

Method of administration and dosage.

Prescription and monitoring of Curled-LP therapy must be performed by a physician experienced in managing patients with chronic hepatitis C (CHC).

Dosage

The recommended dose of Curled-LP is 1 tablet once daily. Administer independently of food intake (see section "Pharmacokinetics").

Table 3. Recommended duration of Curled-LP treatment and recommended methods of administration of concomitantly prescribed ribavirin for specific patient subgroups

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

When used in combination with ribavirin, see also the ribavirin prescribing information.

In patients with decompensated cirrhosis requiring addition of ribavirin to the treatment regimen (see Table 3), the daily dose of ribavirin is based on body weight (<75 kg = 1000 mg and ≥75 kg = 1200 mg); two separate doses should be taken orally with food.

For patients with decompensated cirrhosis, ribavirin should be initiated at a starting dose of 600 mg given as a divided daily dose. If the starting dose is well tolerated, dose titration up to the maximum dose of 1000–1200 mg per day is permitted (1000 mg if patient’s body weight is <75 kg, and 1200 mg if patient’s body weight is ≥75 kg). If the starting dose is well tolerated, it should be adjusted downward based on clinical indications according to hemoglobin levels.

Dose adjustment of ribavirin in patients receiving 1000–1200 mg/day.

When Curated-LP is used in combination with ribavirin and the patient develops a serious adverse reaction potentially related to ribavirin, ribavirin dose adjustment or discontinuation may be necessary until the adverse reaction resolves or its severity decreases. Table 4 provides recommendations for dose adjustment and discontinuation based on hemoglobin levels and the patient’s cardiac status.

Table 4. Recommendations for ribavirin dose adjustment when used concomitantly with Curated-LP

After discontinuation of ribavirin due to laboratory abnormalities or development of clinical manifestations, reinitiation of ribavirin at a dose of 600 mg/day should be attempted, with subsequent dose escalation to 800 mg/day. Dose escalation of ribavirin to the initially prescribed dose (from 1000 mg to 1200 mg per day) is not recommended.

Patients should be advised that if vomiting occurs within 5 hours of dosing, they should take the next tablet. If vomiting occurs more than 5 hours after dosing, no additional dose is required (see section "Pharmacodynamics").

If a dose is missed and less than 18 hours have passed since the missed dose, the patient should take the tablet as soon as possible, and the next dose should be taken at the scheduled time. If 18 hours have passed since the missed dose, the patient should wait until the next scheduled dose. Patients must not take a double dose of the medication.

Elderly patients

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

Renal impairment

Dose adjustment of Curated-LP is not required for patients with mild or moderate renal impairment. The safety of ledipasvir/sofosbuvir in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring hemodialysis has not been established (see section "Pharmacokinetics").

Hepatic impairment

Dose adjustment of Curated-LP is not required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) (see section "Pharmacokinetics"). The safety and efficacy of ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis (see section "Pharmacodynamics").

Route of administration

For oral use.

The tablet should be swallowed whole. It may be taken with or without food. The film-coated tablets have a bitter taste; therefore, chewing or crushing is not recommended (see section "Pharmacokinetics").

Pediatric population

The safety of Curated-LP in children and adolescents under 18 years of age has not been established. Data are lacking.

Overdose

The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and a single dose of 1200 mg, respectively. In studies conducted in healthy volunteers, no unexpected effects were observed at these dose levels, and the frequency and severity of adverse events were similar to those in the placebo group. The effects of higher doses of the drug are unknown.

There is no specific antidote for overdose with Curated-LP. In case of overdose, the patient should be monitored for toxicity. Management of overdose with Curated-LP includes general supportive measures, including monitoring of vital functions and observation of the patient's clinical status. Hemodialysis is unlikely to effectively remove ledipasvir due to its high plasma protein binding. Hemodialysis can effectively remove the major circulating metabolite of sofosbuvir, GS-331007, with a removal efficiency of 53%.

Adverse reactions.

General information on the safety profile

The safety analysis of ledipasvir/sofosbuvir is based on pooled data from three Phase III clinical trials (ION-3, ION-1, and ION-2) involving 215, 539, and 326 patients who received ledipasvir/sofosbuvir for 8, 12, and 24 weeks, respectively, and 216, 328, and 328 patients who received ledipasvir/sofosbuvir + ribavirin as part of combination therapy for 8, 12, and 24 weeks, respectively. In these studies, there was no control group that did not receive ledipasvir/sofosbuvir. Additional data include a double-blind comparison of the safety of ledipasvir/sofosbuvir (12 weeks) versus placebo in 155 patients with cirrhosis.

The proportion of patients who discontinued treatment prematurely due to adverse events was 0%, <1%, and 1% among patients receiving ledipasvir/sofosbuvir for 8, 12, and 24 weeks, respectively, and <1%, 0%, and 2% among patients receiving ledipasvir/sofosbuvir + ribavirin as part of combination therapy for 8, 12, and 24 weeks, respectively.

In clinical trials, fatigue and headache were observed more frequently in patients receiving ledipasvir/sofosbuvir compared to those receiving placebo. When ledipasvir/sofosbuvir was studied in combination with ribavirin, the most common adverse reactions associated with ledipasvir/sofosbuvir + ribavirin in combination therapy were consistent with the established safety profile of ribavirin, without an increase in the frequency or severity of expected adverse reactions.

Adverse reactions observed during administration of the medicinal product Curled-LP are listed below by system organ class and frequency (see Table 5). Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).

Table 5. Adverse drug reactions identified during administration of Curled-LP

Patients with decompensated cirrhosis and/or patients awaiting liver transplantation or post-liver transplantation

The safety profile of ledipasvir/sofosbuvir with ribavirin administered for 12 or 24 weeks in patients with decompensated liver disease and/or patients post-liver transplantation was evaluated in an open-label study (SOLAR-1). No new adverse reactions were identified in patients with decompensated cirrhosis and/or post-liver transplantation receiving ledipasvir/sofosbuvir with ribavirin. Although adverse events, including serious ones, occurred more frequently than in studies not including patients with decompensation and/or post-liver transplantation, the observed adverse events were predictable as clinical consequences of advanced liver disease and/or transplantation or consistent with the established safety profile of ribavirin.

Hemoglobin levels decreased to <10 g/dL and <8.5 g/dL during treatment in 39% and 13% of patients receiving ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was discontinued in 19% of patients.

Immunosuppressive agents were modified in 10% of liver transplant recipients.

Pediatric patients

The safety of Curled-LP in children and adolescents under 18 years of age has not been established. Data are lacking.

Description of selected adverse reactions

Cardiac arrhythmia

Cases of severe bradycardia and atrioventricular conduction block have been observed when Curled-LP was coadministered with amiodarone and/or other drugs that reduce heart rate (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach 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 winder. One bottle is packed in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Strides Pharma Science Limited.

Manufacturer’s address and location of operations.

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

Marketing authorization holder.

Strides Pharma Science Limited.

Address of the marketing authorization holder.

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