Virdac

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIRDAC (VIRDAC)

Composition:

Active substance: daclatasvir;

One tablet contains daclatasvir dihydrochloride, equivalent to 30 mg or 60 mg of daclatasvir;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry yellow 03B520025 (tablets 30 mg), Opadry yellow 03B520090 (tablets 60 mg) (hypromellose (E 464), titanium dioxide (E 171), polyethylene glycol (E 1521), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

30 mg: film-coated tablets, yellow in color, round-shaped, beveled edge, biconvex, with the imprint «D 14» on one side and «H» on the other;

60 mg: film-coated tablets, light yellow in color, round-shaped, beveled edge, biconvex, with the imprint «D19» on one side and «H» on the other.

Pharmacotherapeutic group. Direct-acting antiviral agents for the treatment of hepatitis C virus infections. ATC code J05AP07.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Daclatasvir is an inhibitor of the nonstructural protein 5A (NS5A)—a multifunctional protein that is a key component of the hepatitis C virus (HCV) replication complex. Daclatasvir suppresses HCV RNA replication and virion assembly.

Antiviral Activity in Cell Culture

Daclatasvir inhibits HCV replication of genotypes 1a and 1b in replicon assays in cell cultures, with effective concentration values (50% reduction, EC50) ranging from 0.003–0.050 nmol and 0.001–0.009 nmol, respectively, depending on the assay method. EC50 values of daclatasvir in the replicon system were 0.003–1.25 nmol for genotypes 3a, 4a, 5a, and 6a, and 0.034–19 nmol for genotype 2a, as well as 0.020 nmol for genotype 2a (JFH-1) viruses.

Daclatasvir demonstrated additive or synergistic interactions with interferon alfa, HCV NS3 protease inhibitors, non-nucleoside inhibitors of HCV NS5B polymerase, and nucleoside analogs of HCV NS5B in combination studies using the HCV replicon cell system. No antagonism of antiviral activity was observed.

No clinically relevant antiviral activity against various RNA and DNA viruses, including HIV, was observed, confirming that daclatasvir, as an HCV-specific inhibitor, has high selectivity for HCV.

Resistance in Cell Culture

Resistance-associated substitutions to daclatasvir in genotypes 1–4 were observed within the N-terminal 100-amino acid region of NS5A in the cell-based replicon system. For genotype 1b, resistance-associated substitutions L31V and Y93H were commonly observed, whereas for genotype 1a, substitutions M28T, L31V/M, Q30E/H/R, and Y93C/H/N were frequently observed. These substitutions led to a low level of resistance (EC50 <1 nmol) in genotype 1b and higher resistance levels in genotype 1a (EC50 up to 350 nmol). The most resistant single amino acid substitution variants in genotype 2a and genotype 3a were F28S (EC50 >300 nmol) and Y93H (EC50 >1000 nmol), respectively. In genotype 4, amino acid substitutions at positions 30 and 93 were common (EC50 <16 nmol).

Cross-resistance

HCV replicons expressing daclatasvir-associated resistance substitutions remained fully sensitive to interferon alfa and other anti-HCV agents with different mechanisms of action, such as NS3 protease inhibitors and NS5B polymerase inhibitors (nucleoside and non-nucleoside).

Clinical Efficacy and Safety

In clinical trials of daclatasvir in combination with sofosbuvir or peginterferon alfa and ribavirin, plasma HCV RNA levels were measured using the COBAS TaqMan HCV test (version 2.0) for use on the High Pure System, with a lower limit of quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint for assessing treatment efficacy against HCV, defined as HCV RNA below LLOQ 12 weeks after the end of treatment (SVR12), and also as undetectable HCV RNA 24 weeks after the end of treatment (SVR24).

Pharmacokinetics

The pharmacokinetic properties of daclatasvir were evaluated in healthy adult volunteers and patients with chronic HCV infection. After multiple oral doses of daclatasvir 60 mg once daily in combination with peginterferon alfa and ribavirin in treatment-naïve patients with chronic HCV genotype 1, the maximum concentration (Cmax) of daclatasvir was 1534 (58) ng/mL, the area under the concentration-time curve (AUC0–24h) was 14,122 (70) ng·h/mL, and the minimum concentration (Cmin) was 232 (83) ng/mL.

Absorption

After oral administration as tablets, daclatasvir is rapidly absorbed, with Cmax in plasma reached within 1–2 hours after multiple dosing.

Cmax, AUC, and Cmin of daclatasvir increase almost proportionally with dose. Steady state is achieved within 4 days of once-daily dosing. At the 60 mg dose, AUC of daclatasvir was similar in healthy volunteers and HCV patients.

In vitro and in vivo studies demonstrated that daclatasvir is a substrate of P-glycoprotein (P-gp). The absolute bioavailability after tablet administration is 67%.

Effect of Food on Oral Absorption

In studies involving healthy volunteers, administration of 60 mg daclatasvir after a high-fat meal resulted in a 28% and 23% reduction in Cmax and AUC, respectively, compared to administration in the fasting state. Administration of 60 mg daclatasvir after a light meal did not reduce AUC of daclatasvir.

Distribution

At steady state, protein binding of daclatasvir in HCV-infected patients was approximately 99% and was independent of dose (tested in the range of 1 to 100 mg). In patients receiving oral daclatasvir 60 mg followed by intravenous administration of 100 μg [13C,15N]-daclatasvir, the estimated volume of distribution at steady state was 47 L. In vitro studies indicate that daclatasvir actively and passively penetrates hepatocytes. Active transport is mediated by organic cation transporters (OCT1) and other unidentified uptake transporters, but not by organic anion transporter (OAT) 2, sodium-taurocholate cotransporting polypeptide (NTCP), or organic anion transporting polypeptides (OATPs).

Daclatasvir is an inhibitor of P-gp, OATP 1B1, and breast cancer resistance protein (BCRP). In vitro, daclatasvir inhibits renal uptake transporters, organic anion transporters (OAT1 and 3), and organic cation transporters (OCT2), but a clinically significant effect on the pharmacokinetics of substrates of these transporters is not expected.

Biotransformation

In vitro and in vivo studies demonstrate that daclatasvir is a substrate of CYP3A, with CYP3A4 being the primary CYP isoform responsible for its metabolism. No metabolites circulated at levels exceeding 5% of the parent compound concentration. In vitro, daclatasvir did not inhibit (IC50 > 40 μmol) the CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.

Elimination

After a single oral dose of 14C-daclatasvir administered to healthy volunteers, 88% of the total radioactive dose was excreted in feces (53% as unchanged drug), and 6.6% was excreted in urine (predominantly as unchanged drug). These data indicate that the liver is the primary organ for daclatasvir clearance in humans. In vitro studies suggest that daclatasvir actively and passively penetrates hepatocytes, with active transport mediated by OCT1 and other unidentified uptake transporters. After multiple dosing in HCV-infected patients, the terminal half-life of daclatasvir ranged from 12 to 15 hours. In patients receiving oral daclatasvir 60 mg tablets followed by intravenous administration of 100 μg [13C,15N]-daclatasvir, total clearance was 4.24 L/hour.

Special Patient Populations

Renal Impairment

The pharmacokinetics of daclatasvir after a single 60 mg oral dose were studied in HCV-noninfected patients with renal impairment. The estimated AUC of unbound daclatasvir was 18%, 39%, and 51% higher in patients with creatinine clearance of 60 mL/min, 30 mL/min, and 15 mL/min, respectively, compared to those with normal renal function. In patients with end-stage renal disease requiring hemodialysis, AUC of daclatasvir increased by 27% and AUC of unbound daclatasvir by 20% compared to those with normal renal function (see section "Dosage and Administration").

Hepatic Impairment

The pharmacokinetics of daclatasvir after a single 30 mg oral dose were studied in HCV-noninfected patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to patients with normal hepatic function. Cmax and AUC of total daclatasvir (free and protein-bound) were lower in patients with hepatic impairment; however, hepatic impairment did not have a clinically significant effect on free daclatasvir concentrations (see section "Dosage and Administration").

Elderly Patients

Population pharmacokinetic analysis of clinical trial data showed that age has no apparent effect on the pharmacokinetics of daclatasvir.

Pediatric Patients

The pharmacokinetics of daclatasvir in pediatric patients have not been evaluated.

Gender

Population pharmacokinetic analysis showed that gender is a statistically significant covariate for apparent oral clearance (CL/F) of daclatasvir, with slightly lower CL/F in females; however, the effect on daclatasvir exposure is not clinically significant.

Race

Population pharmacokinetic analysis of clinical trial data showed that race (categories "other" [subjects not of Caucasian, Black, or Asian race] and "Black") is a statistically significant covariate for apparent oral clearance (CL/F) and apparent volume of distribution (Vc/F) of daclatasvir, resulting in slightly higher exposure compared to Caucasian patients, but the effect on daclatasvir exposure is not clinically significant.

Clinical characteristics.

Indications.

The medicinal product Virdac is indicated in combination with other medicinal products for the treatment of chronic hepatitis C in adult patients.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the product.

Concomitant use with medicinal products that are strong inducers of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) transporter, which may lead to reduced exposure and loss of efficacy of daclatasvir. Such active substances include, but are not limited to, phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, systemic dexamethasone, and the herbal product St. John's wort (Hypericum perforatum).

Interaction with other medicinal products and other forms of interaction.

Contraindications regarding concomitant use (see section "Contraindications")

The medicinal product Virdac is contraindicated in combination with other medicinal products that are strong inducers of CYP3A4 and P-gp (e.g., phenytoin, carbamazepine, oxcarbazepine, phenobarbital, rifampicin, rifabutin, rifapentine, systemic dexamethasone, and the herbal product St. John's wort (Hypericum perforatum)), as this may result in reduced exposure and loss of efficacy of Virdac.

Potential interactions with other medicinal products

Daclatasvir is a substrate of CYP3A4, P-gp, and organic cation transporter (OCT) 1. Strong and moderate inducers of CYP3A4 and P-gp may reduce daclatasvir plasma concentrations and its therapeutic effect. Concomitant use with strong inducers of CYP3A4 and P-gp is contraindicated; dose adjustment of Virdac is recommended when used concomitantly with moderate inducers of CYP3A4 and P-gp (see Table 1). Strong inhibitors of CYP3A4 may increase daclatasvir plasma concentrations. Dose adjustment of Virdac is recommended when used concomitantly with strong CYP3A4 inhibitors (see Table 1). Concurrent use with medicinal products that inhibit P-gp or OCT1 is expected to have limited impact on daclatasvir exposure.

Daclatasvir is an inhibitor of P-gp, organic anion transporting polypeptide (OATP) 1B1, OCT1, and breast cancer resistance protein (BCRP). Use of Virdac may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1, OCT1, or BCRP, potentially enhancing or prolonging their therapeutic effects and adverse reactions. Caution should be exercised when the co-administered medicinal product has a narrow therapeutic index (see Table 1).

Daclatasvir is a very weak inducer of CYP3A4 and results in a 13% reduction in midazolam exposure. However, since this effect is limited, dose adjustment of concomitantly administered CYP3A4 substrates is not required.

Refer to the prescribing information of other medicinal products included in the treatment regimen for information on interactions.

Patients receiving vitamin K antagonist therapy

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

Summary of interactions

Table 1 provides information obtained from daclatasvir drug interaction studies, including clinical recommendations for established or potentially significant interactions with other medicinal products. Clinically significant increases in concentration are denoted as "↑", clinically significant decreases as "↓", and absence of clinically significant changes as "↔". Where available, the coefficients of geometric mean values with 90% confidence interval (CI) are indicated in parentheses. Studies presented in Table 1 were conducted in healthy adults unless otherwise specified. The table does not include all available data.

Table 1

Interactions and dosing recommendations when used with other medicinal products

Medicinal products by therapeutic areas	Interaction	Recommendations for concomitant use
ANTIVIRAL AGENTS, anti-HCV
Nucleotide polymerase inhibitors
Sofosbuvir 400 mg once daily (daclatasvir 60 mg once daily). The study was conducted in patients with chronic HCV infection	↔ daclatasvir* AUC: 0.95 (0.82; 1.10) Cmax: 0.88 (0.78; 0.99) Cmin: 0.91 (0.71; 1.16) ↔ GS-331007** AUC: 1.0 (0.95; 1.08) Cmax: 0.8 (0.77; 0.90) Cmin: 1.4 (1.35; 1.53) * comparison of daclatasvir with historical reference (data from 3 studies of daclatasvir 60 mg once daily with peginterferon alfa and ribavirin); **GS-331007 is the major circulating metabolite of the prodrug sofosbuvir.	No dose adjustment of daclatasvir or sofosbuvir is required.
Protease inhibitors (PI)
Boceprevir	Interaction not studied. Expected due to CYP3A4 inhibition by boceprevir: ↑ daclatasvir	The dose of daclatasvir should be reduced to 30 mg once daily when co-administered with boceprevir or other strong CYP3A4 inhibitors.
Simeprevir 150 mg once daily (daclatasvir 60 mg once daily)	↑ daclatasvir AUC: 1.96 (1.84; 2.10) Cmax: 1.50 (1.39; 1.62) Cmin: 2.68 (2.42; 2.98) ↑ simeprevir AUC: 1.44 (1.32; 1.56) Cmax: 1.39 (1.27; 1.52) Cmin: 1.49 (1.33; 1.67)	No dose adjustment of daclatasvir or simeprevir is required.
Telaprevir 500 mg every 12 hours (daclatasvir 20 mg once daily) telaprevir 750 mg every 8 hours (daclatasvir 20 mg once daily)	↑ daclatasvir AUC: 2.32 (2.06; 2.62) Cmax: 1.46 (1.28; 1.66) ↔ telaprevir AUC: 0.94 (0.84; 1.04) Cmax: 1.01 (0.89; 1.14) ↑ daclatasvir AUC: 2.15 (1.87; 2.48) Cmax: 1.22 (1.04; 1.44) ↔ telaprevir AUC: 0.99 (0.95; 1.03) Cmax: 1.02 (0.95; 1.09) CYP3A4 inhibition by telaprevir	The dose of daclatasvir should be reduced to 30 mg once daily when co-administered with telaprevir or other strong CYP3A4 inhibitors.
Other antiviral agents against HCV
Peginterferon alfa 180 mcg once weekly and ribavirin 1000 mg or 1200 mg daily in two divided doses (daclatasvir 60 mg once daily). The study was conducted in patients with chronic HCV infection.	↔ daclatasvir AUC: ↔∗ Cmax: ↔∗ Cmin: ↔∗ ↔ peginterferon alfa Cmin: ↔∗ ↔ ribavirin AUC: 0.94 (0.80; 1.11) Cmax: 0.94 (0.79; 1.11) Cmin: 0.98 (0.82; 1.17) * PK parameters for daclatasvir when administered with peginterferon alfa and ribavirin in this study were similar to those observed in a study of HCV-infected patients receiving daclatasvir as monotherapy for 14 days; PK levels of peginterferon alfa in patients receiving peginterferon alfa, ribavirin, and daclatasvir were similar to those in patients receiving peginterferon alfa, ribavirin, and placebo.	No dose adjustment of daclatasvir, peginterferon alfa, or ribavirin is required.
ANTIVIRAL AGENTS, against human immunodeficiency virus (HIV) or hepatitis B virus (HBV)
Protease inhibitors (PI)
Atazanavir 300 mg/ritonavir 100 mg once daily (daclatasvir 20 mg once daily)	↑ daclatasvir AUC*: 2.10 (1.95; 2.26) Cmax*: 1.35 (1.24; 1.47) Cmin*: 3.65 (3.25; 4.11) CYP3A4 inhibition by ritonavir *results dose-normalized to 60 mg dose.	The dose of daclatasvir should be reduced to 30 mg once daily when co-administered with atazanavir/ritonavir, atazanavir/cobicistat, or other strong CYP3A4 inhibitors.
Atazanavir/cobicistat	Interaction not studied. Expected due to CYP3A4 inhibition by atazanavir/cobicistat: ↑ daclatasvir
Darunavir 800 mg/ritonavir 100 mg once daily (daclatasvir 30 mg once daily)	↔ daclatasvir AUC: 1.41 (1.32; 1.50) Cmax: 0.77 (0.70; 0.85) ↔ darunavir AUC: 0.90 (0.73; 1.11) Cmax: 0.97 (0.80; 1.17) Cmin: 0.98 (0.67; 1.44)	No need to change the dose of daclatasvir 60 mg once daily, darunavir/ritonavir (800/100 mg once daily or 600/100 mg twice daily), or darunavir/cobicistat.
Darunavir/cobicistat	Interaction not studied. Expected: ↔ daclatasvir
Lopinavir 400 mg/ritonavir 100 mg twice daily (daclatasvir 30 mg once daily)	↔ daclatasvir AUC: 1.15 (1.07; 1.24) Cmax: 0.67 (0.61; 0.74) ↔ lopinavir* AUC: 1.15 (0.77; 1.72) Cmax: 1.22 (1.06; 1.41) Cmin: 1.54 (0.46; 5.07) * effect of 60 mg daclatasvir on lopinavir may be greater.	No dose adjustment of daclatasvir 60 mg once daily or lopinavir/ritonavir is required.
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
Tenofovir disoproxil fumarate 300 mg once daily (daclatasvir 60 mg once daily)	↔ daclatasvir AUC: 1.10 (1.01; 1.21) Cmax: 1.06 (0.98; 1.15) Cmin: 1.15 (1.02; 1.30) ↔ tenofovir AUC: 1.10 (1.05; 1.15) Cmax: 0.95 (0.89; 1.02) Cmin: 1.17 (1.10; 1.24)	No dose adjustment of daclatasvir or tenofovir is required.
Lamivudine Zidovudine Emtricitabine Abacavir Didanosine Stavudine	Interaction not studied. Expected: ↔ daclatasvir, ↔ NRTI	No dose adjustment of daclatasvir or NRTIs is required.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg once daily (daclatasvir 60 mg once daily/120 mg once daily)	↓ daclatasvir AUC*: 0.68 (0.60; 0.78) Cmax*: 0.83 (0.76; 0.92) Cmin*: 0.41 (0.34; 0.50) CYP3A4 induction by efavirenz * results dose-normalized to 60 mg dose.	The dose of daclatasvir should be increased to 90 mg once daily when co-administered with efavirenz.
Etravirine Nevaripine	Interaction not studied. Expected due to CYP3A4 induction by etravirine or nevirapine: ↓ daclatasvir	Due to lack of data, concomitant use of daclatasvir with etravirine or nevirapine is not recommended.
Rilpivirine	Interaction not studied. Expected: ↔ daclatasvir, ↔ rilpivirine	No dose adjustment of daclatasvir or rilpivirine is required.
Integrase inhibitors
Dolutegravir 50 mg once daily (daclatasvir 60 mg once daily)	↔ daclatasvir AUC: 0.98 (0.83; 1.15) Cmax: 1.03 (0.84; 1.25) Cmin: 1.06 (0.88; 1.29) ↑ dolutegravir AUC: 1.33 (1.11; 1.59) Cmax: 1.29 (1.07; 1.57) Cmin: 1.45 (1.25; 1.68) P-gp and BCRP inhibition by daclatasvir	No dose adjustment of daclatasvir or dolutegravir is required.
Raltegravir	Interaction not studied. Expected: ↔ daclatasvir, ↔ raltegravir	No dose adjustment of daclatasvir or raltegravir is required.
Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate	Interaction not studied for this fixed-dose combination tablet. Expected due to CYP3A4 inhibition by cobicistat: ↑ daclatasvir	The dose of daclatasvir should be reduced to 30 mg once daily when co-administered with cobicistat or other strong CYP3A4 inhibitors.
Fusion inhibitor
Enfuvirtide	Interaction not studied. Expected: ↔ daclatasvir, ↔ enfuvirtide	No dose adjustment of daclatasvir or enfuvirtide is required.
CCR5 receptor antagonist
Maraviroc	Interaction not studied. Expected: ↔ daclatasvir, ↔ maraviroc	No dose adjustment of daclatasvir or maraviroc is required.
ACID-REDUCING AGENTS
H2-receptor antagonists
Famotidine 40 mg, single dose (daclatasvir 60 mg, single dose)	↔ daclatasvir AUC: 0.82 (0.70; 0.96) Cmax: 0.56 (0.46; 0.67) Cmin: 0.89 (0.75; 1.06) increased gastric pH	No dose adjustment of daclatasvir is required.
Proton pump inhibitors (PPIs)
Omeprazole 40 mg once daily (daclatasvir 60 mg, single dose)	↔ daclatasvir AUC: 0.84 (0.73; 0.96) Cmax: 0.64 (0.54; 0.77) Cmin: 0.92 (0.80; 1.05) Increased gastric pH	No dose adjustment of daclatasvir is required.
ANTIBACTERIAL AGENTS
Clarithromycin Telithromycin	Interaction not studied. Expected due to CYP3A4 inhibition by antibacterial agents: ↑ daclatasvir	The dose of daclatasvir should be reduced to 30 mg once daily when co-administered with clarithromycin, telithromycin, or other strong CYP3A4 inhibitors.
Erythromycin	Interaction not studied. Expected due to CYP3A4 inhibition by antibacterial agents: ↑ daclatasvir	Co-administration of daclatasvir with erythromycin may lead to increased daclatasvir concentrations. Caution is recommended.
Azithromycin Ciprofloxacin	Interaction not studied. Expected: ↔ daclatasvir, ↔ azithromycin or ciprofloxacin	No dose adjustment of daclatasvir, azithromycin, or ciprofloxacin is required.
ANTICOAGULANTS
Dabigatran etexilate	Interaction not studied. Expected due to P-gp inhibition by daclatasvir: ↑ dabigatran etexilate	Monitoring of safety is recommended when initiating daclatasvir treatment in patients receiving dabigatran etexilate or other intestinal P-gp substrates with a narrow therapeutic index.
Warfarin or other vitamin K antagonists	Interaction not studied. Expected: ↔ daclatasvir, ↔ warfarin	No dose adjustment of daclatasvir or warfarin is required. Final monitoring of INR values is recommended with all vitamin K antagonists. This is related to liver function, which may change during daclatasvir treatment.
ANTICONVULSANTS
Carbamazepine Oxcarbazepine Phenobarbital Phenytoin	Interaction not studied. Expected due to CYP3A4 induction by anticonvulsants: ↓ daclatasvir	Concomitant use of daclatasvir with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or other strong CYP3A4 inducers is contraindicated (see section "Contraindications").
ANTIDEPRESSANTS
Selective serotonin reuptake inhibitors (SSRIs)
Escitalopram 10 mg once daily (daclatasvir 60 mg once daily)	↔ daclatasvir AUC: 1.12 (1.01; 1.26) Cmax: 1.14 (0.98; 1.32) Cmin: 1.23 (1.09; 1.38) ↔ escitalopram AUC: 1.05 (1.02; 1.08) Cmax: 1.00 (0.92; 1.08) Cmin: 1.10 (1.04; 1.16)	No dose adjustment of daclatasvir or escitalopram is required.
ANTIFUNGAL AGENTS
Ketoconazole 400 mg once daily (daclatasvir 10 mg, single dose)	↑ daclatasvir AUC: 3.00 (2.62; 3.44) Cmax: 1.57 (1.31; 1.88) CYP3A4 inhibition by ketoconazole	The dose of daclatasvir should be reduced to 30 mg once daily when co-administered with ketoconazole or other strong CYP3A4 inhibitors.
Itraconazole Posaconazole Voriconazole	Interaction not studied. Expected due to CYP3A4 inhibition by antifungal agents: ↑ daclatasvir
Fluconazole	Interaction not studied. Expected due to CYP3A4 inhibition by antifungal agents: ↑ daclatasvir ↔ fluconazole	A moderate increase in daclatasvir concentration is expected; however, no dose adjustment of daclatasvir or fluconazole is required.
ANTIMYCOBACTERIAL AGENTS
Rifampicin 600 mg once daily (daclatasvir 60 mg, single dose)	↓ daclatasvir AUC: 0.21 (0.19; 0.23) Cmax: 0.44 (0.40; 0.48) CYP3A4 induction by rifampicin	Concomitant use of daclatasvir with rifampicin, rifabutin, rifapentine, or other strong CYP3A4 inducers is contraindicated (see section "Contraindications").
Rifabutin Rifapentine	Interaction not studied. Expected due to CYP3A4 induction by antimycobacterial agents: ↓ daclatasvir
CARDIOVASCULAR AGENTS
Antiarrhythmic agents
Digoxin 0.125 mg once daily (daclatasvir 60 mg once daily)	↑ digoxin AUC: 1.27 (1.20; 1.34) Cmax: 1.65 (1.52; 1.80) Cmin: 1.18 (1.09; 1.28) P-gp inhibition by daclatasvir	Digoxin should be used with caution when co-administered with daclatasvir. Start with the lowest digoxin dose. Serum digoxin concentrations should be monitored and used to titrate digoxin dose to achieve the desired clinical effect.
Amiodarone	Interaction not studied.	Use only when no alternative is available. If these agents are administered with daclatasvir in combination with sofosbuvir, careful monitoring is recommended (see sections "Special warnings and precautions for use" and "Adverse reactions").
Calcium channel blockers
Diltiazem Nifedipine Amlodipine	Interaction not studied. Expected due to CYP3A4 inhibition by calcium channel blockers: ↑ daclatasvir	Co-administration of daclatasvir with any of these calcium channel blockers may lead to increased daclatasvir concentrations. Caution is recommended.
Verapamil	Interaction not studied. Expected due to CYP3A4 and P-gp inhibition by verapamil: ↑ daclatasvir	Co-administration of daclatasvir with verapamil may lead to increased daclatasvir concentrations. Caution is recommended.
CORTICOSTEROIDS
Systemic dexamethasone	Interaction not studied. Expected due to CYP3A4 induction by dexamethasone: ↓ daclatasvir	Concomitant use of daclatasvir with systemic dexamethasone or other strong CYP3A4 inducers is contraindicated (see section "Contraindications").
HERBAL PREPARATIONS
St. John's wort (Hypericum perforatum)	Interaction not studied. Expected due to CYP3A4 induction by St. John's wort: ↓ daclatasvir	Concomitant use of daclatasvir with St. John's wort or other strong CYP3A4 inducers is contraindicated (see section "Contraindications").
HORMONAL CONTRACEPTIVES
Ethinylestradiol 35 mcg once daily for 21 days + norgestimate 0.180/0.215/0.250 mg once daily for 7/7/7 days (daclatasvir 60 mg once daily)	↔ ethinylestradiol AUC: 1.01 (0.95; 1.07) Cmax: 1.11 (1.02; 1.20) ↔ norelgestromin AUC: 1.12 (1.06; 1.17) Cmax: 1.06 (0.99; 1.14) ↔ norgestrel AUC: 1.12 (1.02; 1.23) Cmax: 1.07 (0.99; 1.16)	Oral contraceptives containing ethinylestradiol 35 mcg and norgestimate 0.180/0.215/0.250 mg are recommended with daclatasvir. Other oral contraceptives have not been studied.
IMMUNOSUPPRESSANTS
Cyclosporine 400 mg, single dose (daclatasvir 60 mg once daily)	↔ daclatasvir AUC: 1.40 (1.29; 1.53) Cmax: 1.04 (0.94; 1.15) Cmin: 1.56 (1.41; 1.71) ↔ cyclosporine AUC: 1.03 (0.97; 1.09) Cmax: 0.96 (0.91; 1.02)	No dose adjustment or administration changes are required when daclatasvir is co-administered with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil.
Tacrolimus 5 mg, single dose (daclatasvir 60 mg once daily)	↔ daclatasvir AUC: 1.05 (1.03; 1.07) Cmax: 1.07 (1.02; 1.12) Cmin: 1.10 (1.03; 1.19) ↔ tacrolimus AUC: 1.00 (0.88; 1.13) Cmax: 1.05 (0.90; 1.23)
Sirolimus Mycophenolate mofetil	Interaction not studied. Expected: ↔ daclatasvir, ↔ immunosuppressants
LIPID-MODIFYING AGENTS
HMG-CoA reductase inhibitors
Rosuvastatin 10 mg, single dose (daclatasvir 60 mg once daily)	↑ rosuvastatin AUC: 1.58 (1.44; 1.74) Cmax: 2.04 (1.83; 2.26) Inhibition of OATP1B1 and BCRP by daclatasvir	Caution is required when co-administering daclatasvir with rosuvastatin or other OATP1B1 or BCRP substrates.
Atorvastatin Fluvastatin Simvastatin Pitavastatin Pravastatin	Interaction not studied. Expected due to OATP1B1 and/or BCRP inhibition by daclatasvir: ↑ statin concentration
NARCOTIC ANALGESICS
Buprenorphine/naloxone, 8/2 – 24/6 mg once daily individualized dose* (daclatasvir 60 mg once daily). * Evaluated in opioid-dependent adults on stable buprenorphine/naloxone maintenance therapy.	↔ daclatasvir AUC: ↔* Cmax: ↔* Cmin: ↔* ↑ buprenorphine AUC: 1.37 (1.24; 1.52) Cmax: 1.30 (1.03; 1.64) Cmin: 1.17 (1.03; 1.32) ↑ norbuprenorphine AUC: 1.62 (1.30; 2.02) Cmax: 1.65 (1.38; 1.99) Cmin: 1.46 (1.12; 1.89). * Compared with historical data.	Dose adjustment of daclatasvir or buprenorphine may not be necessary, but monitoring for signs of opioid toxicity is recommended.
Methadone, 40-120 mg once daily, individualized dose* (daclatasvir 60 mg once daily). * Evaluated in opioid-dependent adults on stable methadone maintenance therapy.	↔ daclatasvir AUC: ↔* Cmax: ↔* Cmin: ↔* ↔ R-methadone AUC: 1.08 (0.94; 1.24) Cmax: 1.07 (0.97; 1.18) Cmin: 1.08 (0.93; 1.26). * Compared with historical data.	No dose adjustment of daclatasvir or methadone is required.
SEDATIVES
Benzodiazepines
Midazolam 5 mg, single dose (daclatasvir 60 mg once daily)	↔ midazolam AUC: 0.87 (0.83; 0.92) Cmax: 0.95 (0.88; 1.04)	No dose adjustment of midazolam, other benzodiazepines, or other CYP3A4 substrates is required when co-administered with daclatasvir.
Triazolam Alprazolam	Interaction not studied. Expected: ↔ triazolam, ↔ alprazolam

A clinically significant effect on the pharmacokinetics of medicinal products is not expected when daclatasvir is used concomitantly with any of the following drugs: PDE-5 inhibitors, medicinal products of the angiotensin-converting enzyme (ACE) inhibitor class (e.g., enalapril), medicinal products of the angiotensin II receptor antagonist class (e.g., losartan, irbesartan, olmesartan, candesartan, valsartan), disopyramide, propafenone, flecainide, mexiletine, quinidine, or antacids.

Children

Interaction studies have been performed only in adults.

Special precautions for use.

The medicinal product Virdak is not used as monotherapy. It should be used in combination with other medicinal products for the treatment of chronic HCV infection (see sections "Indications" and "Dosage and administration").

Severe bradycardia and heart block

Cases of severe bradycardia and heart block have been observed when daclatasvir is used in combination with sofosbuvir and amiodarone, with or without other drugs that reduce heart rate. The mechanism is not established.

Concomitant use of amiodarone was limited during the clinical development of sofosbuvir plus direct-acting antiviral agents (DAAs). These reactions are potentially life-threatening; therefore, amiodarone should be administered to patients receiving daclatasvir and sofosbuvir only when alternative antiarrhythmic agents are not tolerated or are contraindicated.

If concomitant use of amiodarone is considered necessary, careful monitoring of patients is recommended at the initiation of Virdak in combination with sofosbuvir. Patients at high risk of bradyarrhythmias should be continuously monitored for 48 hours under appropriate clinical conditions.

Due to the long half-life of amiodarone, appropriate monitoring should also be ensured for patients who have discontinued amiodarone within the past few months and are starting daclatasvir in combination with sofosbuvir.

All patients receiving Virdak and sofosbuvir in combination with amiodarone and/or other drugs that reduce heart rate should also be warned about the symptoms of bradycardia and heart block and advised to seek immediate medical attention if such symptoms occur.

Genotype-specific activity

Recommended treatment regimens for different HCV genotypes are described in the section "Dosage and administration".

There are limited data on the treatment of genotype 2 infection with daclatasvir and sofosbuvir.

Data from study ALLY-3 (A1444218) support a 12-week regimen of daclatasvir + sofosbuvir for patients with genotype 3 infection without cirrhosis, both treatment-naïve and previously treated. Lower sustained virologic response (SVR) rates were observed in patients with cirrhosis (see section "Pharmacodynamics"). Data from a compassionate use program including patients with genotype 3 infection and cirrhosis support a 24-week regimen of daclatasvir + sofosbuvir for these patients. The role of adding ribavirin to this regimen is unknown.

There are limited clinical data to support the use of daclatasvir and sofosbuvir in patients with HCV genotypes 4 and 6. There are no clinical data in patients with genotype 5.

Patients with hepatic impairment (Child-Pugh class C)

The safety and efficacy of daclatasvir for the treatment of HCV in patients with hepatic impairment (Child-Pugh class C) have been evaluated in the clinical trial ALLY-1 (A1444215, daclatasvir + sofosbuvir +/- ribavirin for 12 weeks), but SVR rates were lower than in patients with Child-Pugh class A or B hepatic impairment. Therefore, a conservative treatment approach with daclatasvir + sofosbuvir +/- ribavirin for 24 weeks is recommended for patients with Child-Pugh class C (see section "Dosage and administration"). Ribavirin may be added to treatment based on individual clinical assessment.

Concomitant HCV/HBV infection

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

Retreatment with daclatasvir

The efficacy of daclatasvir for retreatment of patients previously treated with an NS5A inhibitor has not been established.

Pregnancy and contraceptive requirements

The medicinal product Virdak must not be used during pregnancy or in women of childbearing potential who are not using contraceptive measures. Highly effective contraception should be continued for 5 weeks after completion of treatment with Virdak (see section "Pregnancy and breastfeeding").

If Virdak is used in combination with ribavirin, contraindications and special warnings related to ribavirin use must be considered. In animal studies across all species, ribavirin showed marked teratogenic and/or embryocidal effects. Therefore, extreme caution must be taken to avoid pregnancy in female patients and in female partners of male patients (see ribavirin product information).

Interactions with other medicinal products

Concomitant use of Virdak may affect the concentrations of other drugs, or other drugs may alter the concentration of daclatasvir. See section "Contraindications" for a list of drugs contraindicated with Virdak due to potential loss of therapeutic effect. See section "Interaction with other medicinal products and other forms of interaction" for established and potentially significant interactions with other drugs.

Use in diabetic patients

After initiating HCV treatment with a direct-acting antiviral agent (DAA), improved glucose control has been observed in diabetic patients, potentially leading to symptomatic hypoglycemia. Blood glucose levels in diabetic patients initiating DAA therapy should be closely monitored, especially during the first 3 months, and antidiabetic medications adjusted as needed. The physician managing the patient's diabetes should be informed about the initiation of DAA therapy.

Paediatric population

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

Important information on certain components of Virdak

The product contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Patients on a sodium-controlled diet

The product contains less than 1 mmol sodium (23 mg) per maximum dose of 90 mg, i.e., essentially "sodium-free".

Use during pregnancy and breastfeeding.

Pregnancy

There are no data on the use of daclatasvir in pregnant women.

Animal studies with daclatasvir have shown embryotoxic and teratogenic effects. The potential risk in humans is unknown.

The medicinal product Virdak must not be used during pregnancy or in women of childbearing potential who are not using contraception (see section "Special precautions for use"). Highly effective contraception must be used for 5 weeks after completion of Virdak treatment (see section "Interaction with other medicinal products and other forms of interaction").

When Virdak is used in combination with other medicinal products, contraindications and warnings related to those products must be considered.

Detailed recommendations regarding pregnancy and contraception can be found in the product information for ribavirin and peginterferon alfa.

Breastfeeding

It is unknown whether daclatasvir passes into human breast milk. Available pharmacokinetic and toxicological data from animal studies show that daclatasvir and its metabolites are excreted in breast milk. Risk to the newborn/infant cannot be excluded. Breastfeeding mothers should be instructed not to breastfeed while taking Virdak.

Fertility

There are no data on the effect of daclatasvir on human reproductive function.

In rats, no effect on mating or fertility was observed.

Ability to affect performance of skilled tasks such as driving vehicles or operating machinery.

Dizziness has been reported during treatment with daclatasvir in combination with sofosbuvir. During treatment with daclatasvir in combination with peginterferon alfa and ribavirin, cases of dizziness, impaired concentration, blurred vision, and decreased visual acuity have been reported.

Administration and Dosage

The drug should be administered under the supervision of a physician experienced in managing chronic hepatitis C.

Dosage

The recommended dose of the drug is 60 mg once daily. Administer orally, independent of food intake.

Virdak should be used in combination with other medicinal products. Prior to initiating therapy with this drug, the Instructions for Medical Use of the other medicinal products regarding the treatment regimen should also be reviewed.

Table 2

Recommended interferon-free combination therapy with daclatasvir

Category of patients*	Regimen and duration
HCV genotype 1 or 4
Patients without cirrhosis	Daclatasvir + sofosbuvir for 12 weeks
Patients with cirrhosis Child-Pugh class A or B Child-Pugh class C	Daclatasvir + sofosbuvir + ribavirin for 12 weeks or Daclatasvir + sofosbuvir (without ribavirin) for 24 weeks Daclatasvir + sofosbuvir +/- ribavirin for 24 weeks (see sections “Pharmacological properties” and “Special precautions”)
HCV genotype 3
Patients without cirrhosis	Daclatasvir + sofosbuvir for 12 weeks
Patients with cirrhosis	Daclatasvir + sofosbuvir +/- ribavirin for 24 weeks (see section “Pharmacological properties”)
Recurrent HCV infection after liver transplantation (genotype 1, 3 or 4)
Patients without cirrhosis	Daclatasvir + sofosbuvir + ribavirin for 12 weeks (see section “Pharmacological properties”)
Patients with cirrhosis Child-Pugh class A or B genotype 1 or 4 genotype 3	Daclatasvir + sofosbuvir + ribavirin for 12 weeks Daclatasvir + sofosbuvir +/- ribavirin for 24 weeks
Patients with cirrhosis Child-Pugh class C	Daclatasvir + sofosbuvir +/- ribavirin for 24 weeks (see sections “Pharmacological properties” and “Special precautions”)

* Includes patients infected with human immunodeficiency virus (HIV). For dosing recommendations with HIV antiviral agents, see section "Interaction with other medicinal products and other forms of interaction".

Daclatasvir + peginterferon alfa + ribavirin

This regimen is an alternative recommended regimen for patients with genotype 4 infection, without cirrhosis or with compensated cirrhosis. Daclatasvir should be administered for 24 weeks in combination with 24–48 weeks of peginterferon alfa and ribavirin:

• if HCV RNA is undetectable at both treatment weeks 4 and 12, all three components of the regimen should be continued for a total duration of 24 weeks;
• if undetectable HCV RNA is achieved, but not at both treatment weeks 4 and 12, daclatasvir should be discontinued at week 24, while peginterferon alfa and ribavirin should be continued for 48 weeks.

Dosing recommendations for ribavirin

The dose of ribavirin in combination with daclatasvir depends on body weight (1000 mg or 1200 mg for patients < 75 kg or ≥ 75 kg, respectively). Refer to the Summary of Product Characteristics for ribavirin.

For patients with Child-Pugh A, B, or C cirrhosis and HCV recurrence after liver transplantation, the recommended initial dose of ribavirin is 600 mg daily with food. If the initial dose is well tolerated, the dose may be titrated up to a maximum of 1000–1200 mg daily (cutoff at 75 kg). If the initial dose is not well tolerated, the dose should be reduced based on clinical judgment according to hemoglobin measurements and creatinine clearance (see Table 3).

Table 3

Dosing recommendations for ribavirin when used concomitantly with daclatasvir in patients with liver cirrhosis or post-liver transplantation

Haematological parameters / clinical criteria	Ribavirin dosing recommendations
Haemoglobin
>12 g/dL	600 mg daily
>10 to ≤12 g/dL	400 mg daily
>8.5 to ≤10 g/dL	200 mg daily
≤8.5 g/dL	Discontinue ribavirin
Creatinine clearance
>50 mL/min	Follow haemoglobin-based dosing recommendations above
>30 to ≤50 mL/min	200 mg every other day
≤30 mL/min or haemodialysis	Discontinue ribavirin

Dose Modification, Interruption, and Discontinuation

Dose modification of daclatasvir for management of adverse reactions is not recommended. If interruption of treatment with components of the regimen is required due to adverse reactions, daclatasvir should not be administered as monotherapy.

There are no virological stopping rules applicable to the combination of daclatasvir with sofosbuvir.

Discontinuation of treatment in patients with inadequate virological response during treatment with daclatasvir, peginterferon alfa, and ribavirin

Patients with an inadequate virological response to therapy are unlikely to achieve a sustained virological response (SVR); therefore, discontinuation of treatment is recommended for these patients. HCV RNA thresholds leading to treatment discontinuation (i.e., stopping rules) are provided in Table 4.

Table 4

Stopping rules for treatment discontinuation in patients receiving daclatasvir in combination with peginterferon alfa and ribavirin due to inadequate virological response to treatment

HCV RNA	Action
4 weeks of treatment: > 1000 IU/mL	Discontinue daclatasvir, peginterferon alfa, and ribavirin
12 weeks of treatment: ≥ 25 IU/mL	Discontinue daclatasvir, peginterferon alfa, and ribavirin
24 weeks of treatment: ≥ 25 IU/mL	Discontinue peginterferon alfa and ribavirin (daclatasvir treatment ends at week 24)

Recommended dosage for concomitant medicinal products

Strong inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4)

The dose of daclatasvir should be reduced to 30 mg once daily when co-administered with strong CYP3A4 inhibitors.

Moderate inducers of CYP3A4

The dose of daclatasvir should be increased to 90 mg once daily when administered concomitantly with moderate CYP3A4 inducers (see section "Interaction with other medicinal products and other forms of interaction").

Missed doses

Patients should be advised that if they miss a dose of daclatasvir, the dose should be taken as soon as possible if remembered within 20 hours of the scheduled dosing time. However, if the missed dose is remembered more than 20 hours after the scheduled dosing time, the dose should be omitted and the next dose taken at the usual time.

Special populations

Elderly patients

No dose adjustment of daclatasvir is required for patients aged ≥ 65 years (see section "Pharmacological properties").

Renal impairment

No dose adjustment of daclatasvir is required for patients with any degree of renal impairment (see section "Pharmacological properties").

Hepatic impairment

No dose adjustment of daclatasvir is required for patients with mild (score 5–6, Child-Pugh class A), moderate (score 7–9, Child-Pugh class B), or severe (score ≥10, Child-Pugh class C) hepatic impairment (see sections "Pharmacological properties" and "Special precautions for use").

Children

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

Method of administration

The medicinal product Virdak should be taken independently of food intake. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed due to the unpleasant taste of the active substance.

Children.

The medicinal product Virdak is not recommended for use in children and adolescents under 18 years of age, as safety and efficacy have not been established in this patient group.

Overdose.

Experience with accidental overdose of daclatasvir in clinical trials is limited. In phase I clinical studies, healthy volunteers who received up to 100 mg once daily for 14 days or single doses up to 200 mg did not experience unexpected adverse reactions.

There is no known antidote for daclatasvir overdose. Management of daclatasvir overdose should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Because daclatasvir is highly protein-bound (99%) and has a molecular mass > 500, dialysis is unlikely to significantly reduce plasma concentrations of daclatasvir.

Adverse reactions.

Summary of safety profile

The overall safety profile of daclatasvir is based on data from 2215 patients with chronic HCV infection who received daclatasvir once daily either in combination with sofosbuvir with or without ribavirin (n = 679, pooled data) or in combination with peginterferon alfa and ribavirin (n = 1536, pooled data) across a total of 14 clinical trials.

Daclatasvir in combination with sofosbuvir

The most commonly reported adverse reactions were fatigue, headache, and nausea. Grade 3 adverse reactions were reported in less than 1% of patients, and no patient experienced a Grade 4 adverse reaction. Four patients discontinued daclatasvir due to adverse reactions, only one of which was considered related to the investigational treatment.

Daclatasvir in combination with peginterferon alfa and ribavirin

The most commonly reported adverse reactions were fatigue, headache, pruritus, anemia, influenza-like illness, nausea, insomnia, neutropenia, asthenia, rash, decreased appetite, dry skin, alopecia, pyrexia, myalgia, irritability, cough, diarrhea, dyspnea, and arthralgia. The most commonly reported adverse reactions of at least Grade 3 severity (incidence ≥1%) were neutropenia, anemia, lymphopenia, and thrombocytopenia. The safety profile of daclatasvir in combination with peginterferon alfa and ribavirin was similar to that observed with peginterferon alfa and ribavirin alone, including in patients with liver cirrhosis.

Tabulated list of adverse reactions

Adverse reactions are listed in Table 5 by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing severity.

Table 5

Adverse reactions observed in clinical trials

System organ class	Adverse reactions
Frequency	Daclatasvir + sofosbuvir + ribavirin n= 203	Daclatasvir + sofosbuvir n = 476
Blood and lymphatic system disorders
very common	anemia
Metabolism and nutrition disorders
common	decreased appetite
Psychiatric disorders
common	insomnia, irritability	insomnia
Nervous system disorders
very common	headache	headache
common	dizziness, migraine	dizziness, migraine
Vascular disorders
common	flushing
Respiratory, thoracic and mediastinal disorders
common	dyspnea, exertional dyspnea, cough, nasal congestion
Gastrointestinal disorders
very common	nausea
common	diarrhea, vomiting, abdominal pain, gastroesophageal reflux disease, constipation, dry mouth, flatulence	nausea, diarrhea, abdominal pain
Skin and subcutaneous tissue disorders
common	rash, alopecia, pruritus, dry skin
Musculoskeletal and connective tissue disorders
common	arthralgia, myalgia	arthralgia, myalgia
General disorders
very common	fatigue	fatigue

Laboratory abnormalities

In clinical trials, grade 3 reduction in hemoglobin levels was observed in 2% of patients receiving daclatasvir in combination with sofosbuvir with or without ribavirin; all these patients received daclatasvir + sofosbuvir + ribavirin. Grade 3/4 increases in total bilirubin were observed in 5% of patients (all were HIV-coinfected patients receiving concomitant atazanavir, with Child-Pugh A, B, or C cirrhosis or post-liver transplantation).

Description of selected adverse reactions

Cardiac arrhythmias

Cases of severe bradycardia and heart block have been reported when daclatasvir is used in combination with sofosbuvir and concomitant amiodarone and/or other drugs that reduce heart rate (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Paediatric population

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

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua .

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, protect from moisture and light.

Keep out of reach and sight of children.

Packaging. 28 tablets in a container; 1 container in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's location and address of the site of operation.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.