Ledipasof (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J05AP51 (Sofosbuvir and Ledipasvir)

Active Substances

Sofosbuvir (Rec.INN registered by WHO)

Ledipasvir (Rec.INN registered by WHO)

Dosage Form

Ledipasof

Film-coated tablets 90 mg+400 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
28 pcs. – jars – cardboard packs (28 pcs.) – By prescription
7 pcs. – blister packs (4 pcs.) – cardboard packs (28 pcs.) – By prescription

Clinical-Pharmacological Group

Antiviral drug active against hepatitis C virus

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; antiviral agents for the treatment of hepatitis C

Pharmacological Action

Combined antiviral agent.

Ledipasvir is an inhibitor of the hepatitis C virus (HCV) that targets the non-structural 5A (NS5A) protein of HCV, which is necessary for RNA replication and the formation of HCV virions. Biochemical confirmation of NS5A inhibition by ledipasvir is currently not possible because NS5A has no enzymatic function. Selective in vitro resistance and cross-resistance studies indicate that the mechanism of action of ledipasvir is its effect on NS5A.

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is necessary for virus replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active triphosphate (GS-461203), a uridine analog that is incorporated into the hepatitis C virus RNA by the NS5B polymerase and acts as a chain terminator. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases, nor is it an inhibitor of mitochondrial RNA polymerase.

Pharmacokinetics

After oral administration of the Ledipasvir/Sofosbuvir combination to HCV-infected patients, the mean C_max of ledipasvir in plasma was observed 4 hours after administration. Sofosbuvir was rapidly absorbed, and its mean C_max in plasma was observed approximately 1 hour after administration. The mean C_max of GS-331007 in plasma was observed 4 hours after administration.

Based on population pharmacokinetic studies in HCV-infected patients, at steady state, the AUC_0-24 values for ledipasvir (n=2113), sofosbuvir (n=1542), and GS-331007 (n=2113) were 7290 ng×h/mL, 1320 ng×h/mL, and 12000 ng×h/mL, respectively. At steady state, the C_max for ledipasvir, sofosbuvir, and GS-331007 were 323 ng/mL, 618 ng/mL, and 707 ng/mL, respectively. The AUC_0-24 and C_max of sofosbuvir and GS-331007 were similar in healthy adult volunteers and HCV-infected patients. The AUC_0-24 and C_max values for ledipasvir were 24% and 32% lower in HCV-infected patients than in healthy volunteers (n=191). Over the dose range of 3 mg to 100 mg, ledipasvir AUC values are proportional to the dose administered. Sofosbuvir and GS-331007 AUC values are approximately proportional to the dose administered over the dose range of 200 mg to 400 mg.

The binding of ledipasvir to human plasma proteins is >99.8%. After a single 90 mg dose of [¹⁴C]-ledipasvir in healthy volunteers, the blood-to-plasma [¹⁴C]-radioactivity ratio ranged from 0.51 to 0.66.

The binding of sofosbuvir to human plasma proteins is 61-65%. Binding is independent of drug concentration in the range of 1 µg/mL to 20 µg/mL. The binding of GS-331007 to human plasma proteins is minimal. After a single 400 mg dose of [¹⁴C]-sofosbuvir in healthy volunteers, the blood-to-plasma [¹⁴C]-radioactivity ratio was approximately 0.7.

Slow oxidative metabolism was observed, the mechanism of which is unknown. After a single 90 mg dose of [¹⁴C]-ledipasvir, systemic exposure was almost entirely associated with unchanged ledipasvir (>98%). In feces, ledipasvir is primarily found unchanged.

Sofosbuvir is metabolized primarily in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The active metabolite has not been isolated. The activation metabolic pathway involves sequential hydrolysis of the carboxylic acid ester, catalyzed by human cathepsin A or carboxylesterase 1, and cleavage of the phosphoramidate by histidine triad nucleotide-binding protein 1, followed by phosphorylation via pyrimidine nucleotide biosynthesis. Dephosphorylation leads to the formation of the nucleoside metabolite GS-331007, which cannot be efficiently rephosphorylated and has no anti-HCV activity in vitro. In the Ledipasvir/Sofosbuvir combination, GS-331007 accounts for approximately 85% of the total systemic drug exposure.

After a single oral dose of 90 mg [¹⁴C]-ledipasvir, the mean total recovery of the [¹⁴C]-radioactive component in feces and urine was 87%, with the majority found in feces (86%). 70% of ledipasvir was excreted in feces unchanged, and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is the primary route of elimination, and renal excretion is secondary (approximately 1%). The mean T_1/2 of ledipasvir in healthy volunteers after administration of the Ledipasvir/Sofosbuvir combination on an empty stomach was 47 hours.

After a single oral dose of 400 mg [¹⁴C]-sofosbuvir, the mean total recovery of the dose was more than 92%, of which approximately 80%, 14%, and 2.5% was excreted in urine, feces, and exhaled air, respectively. The majority of sofosbuvir excreted in urine was the metabolite GS-331007 (78%), and only 3.5% was excreted unchanged. These data show that the renal mechanism is the primary route of elimination for GS-331007, and most of it is excreted via active secretion. The mean T_1/2 of sofosbuvir and GS-331007 after administration of the Ledipasvir/Sofosbuvir combination was 0.5 and 27 hours, respectively.

Indications

Treatment of chronic hepatitis C (CHC) in adults and adolescents aged 12 to 18 years.

ICD codes

Dosage Regimen

Take one tablet orally once daily with or without food.

Swallow the tablet whole; do not crush or chew.

The standard treatment duration is 12 weeks for most patients.

Extend treatment to 24 weeks for patients with cirrhosis who have previously failed interferon-based therapy.

Complete the full prescribed course of therapy even if symptoms improve.

If a dose is missed and less than 18 hours have passed, take the missed dose immediately.

If more than 18 hours have passed, skip the missed dose and take the next dose at the regular time.

Do not take a double dose to make up for a missed one.

Use in adolescents aged 12 years and older is at the same dosage as for adults.

No dose adjustment is required for elderly patients or for patients with mild or moderate hepatic impairment.

Use with caution in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease requiring hemodialysis; monitor these patients closely.

Adverse Reactions

Nervous system disorders very common – headache.

Skin and subcutaneous tissue disorders common – rash; frequency unknown – angioedema, Stevens-Johnson syndrome.

Cardiovascular system disorders cases of severe bradycardia and heart block have been observed when taking this combination in conjunction with amiodarone and/or other drugs that lower heart rate.

General disorders very common – fatigue.

Contraindications

Hypersensitivity to ledipasvir and sofosbuvir; pregnancy, breastfeeding period; children under 12 years of age; concomitant use with rosuvastatin; in patients receiving potent inducers of intestinal P-glycoprotein (rifampicin, rifabutin, St. John’s wort, carbamazepine, phenobarbital, phenytoin); concomitant use with drugs containing Sofosbuvir.

With caution

In patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease requiring hemodialysis; simultaneously with amiodarone, digoxin, with combinations of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir used in combination with tenofovir disoproxil fumarate; use with the combination elvitegravir/cobicistat/emtricitabine/tenofovir. Not recommended for use with moderate inducers of intestinal P-glycoprotein (including oxcarbazepine, rifapentine, tipranavir boosted with ritonavir).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Used for liver diseases as indicated.

Use in Renal Impairment

Use with caution in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease.

Pediatric Use

Contraindicated for use in children under 12 years of age.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

In patients receiving this combination, amiodarone should be used only if other alternative antiarrhythmic drugs are poorly tolerated or contraindicated. If concomitant use of amiodarone is considered necessary, careful monitoring of patients starting the Ledipasvir/Sofosbuvir combination is recommended. Patients at high risk of bradyarrhythmia should be continuously monitored for 48 hours in appropriate clinical settings. Due to the long half-life of amiodarone, appropriate monitoring should also be performed for patients who have discontinued amiodarone within the last few months and are about to start the Ledipasvir/Sofosbuvir combination. All patients taking the Ledipasvir/Sofosbuvir combination in conjunction with amiodarone, regardless of the use of other heart rate-lowering drugs, should also be warned about the symptoms of bradycardia and heart block and advised to seek immediate medical attention if they occur.

After initiation of treatment for CHC with direct-acting antiviral drugs, blood glucose control may improve in patients with diabetes mellitus, which may potentially lead to the development of hypoglycemia. Blood glucose levels should be carefully monitored in patients with diabetes mellitus after initiation of direct-acting antiviral drug treatment, especially during the first 3 months, and the dose of diabetes medications should be adjusted if necessary. The treating physician managing the patient with diabetes should be informed that the patient has started treatment with direct-acting antiviral drugs.

Cases of hepatitis B virus (HBV) reactivation have been reported during or after treatment with direct-acting antiviral drugs, some of which have been fatal. Screening for HBV should be performed for all patients before starting treatment. Patients with concomitant HCV/HBV co-infection are at risk of HBV reactivation, so their condition should be monitored and managed according to current clinical guidelines.

In patients with previous treatment failure with ledipasvir/sofosbuvir, virus mutations associated with resistance to NS5A inhibitors, which significantly reduced susceptibility to ledipasvir, were observed in most cases. Limited data indicate that during long-term follow-up, such NS5A mutations do not revert to the baseline state. Currently, there are no data confirming the effectiveness of re-treating patients who have failed previous ledipasvir/sofosbuvir treatment with a regimen containing an NS5A inhibitor. Also, there are currently no data confirming the effectiveness of NS3/4A protease inhibitors in patients who have shown no response to previous therapy containing an NS3/4A protease inhibitor. Therefore, such patients may rely on other drug classes for the treatment of HCV infection. Consequently, the possibility of longer treatment for patients with undefined subsequent options for re-treatment should be considered.

Safety data in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or with end-stage renal disease requiring dialysis are limited. This combination can be used in these patient groups (no dose adjustment is required) in cases where other possible treatment options are not available.

The effectiveness of ledipasvir/sofosbuvir in HCV-infected patients – genotypes 5 and 6, with decompensated cirrhosis and/or awaiting or having undergone liver transplantation has not been studied. The decision regarding the use of this combination should be guided by an assessment of the potential risks and benefits for each patient.

Effect on ability to drive vehicles and operate machinery

Patients should be informed that fatigue and headache may occur when using this combination.

Drug Interactions

This combination should not be used simultaneously with monodrugs containing one of the components.

Ledipasvir is an in vitro inhibitor of the P-glycoprotein transporter and the breast cancer resistance protein (BCRP), so it may enhance the intestinal absorption of co-administered substrates of these transporters.

Drugs that are strong inducers of P-glycoprotein (rifampicin, rifabutin, St. John’s wort, carbamazepine, phenobarbital, and phenytoin) can significantly reduce the plasma concentrations of ledipasvir and sofosbuvir, leading to a reduction in the therapeutic effect of the Ledipasvir/Sofosbuvir combination, so they are contraindicated for concomitant use with this combination.

Drugs that are moderate inducers of intestinal P-glycoprotein (e.g., oxcarbazepine) may cause a decrease in the plasma concentrations of ledipasvir and sofosbuvir and weaken the therapeutic effect of this combination. Concomitant use of this combination with such drugs is not recommended.

Concomitant use with drugs that inhibit P-glycoprotein and/or BCRP may increase the plasma concentrations of ledipasvir and sofosbuvir, while the plasma concentration of GS-331007 (which is not a substrate of P-glycoprotein and BCRP) does not increase. This combination can be prescribed together with inhibitors of P-glycoprotein and/or BCRP. There is no prediction of clinically significant drug interactions with the Ledipasvir/Sofosbuvir combination mediated by CYP450 or UGT1A1 enzymes.

In patients receiving vitamin K antagonists concomitantly with this combination, liver function may change, and careful monitoring of INR is recommended.

This combination increases the exposure to tenofovir, especially when used concomitantly with an HIV treatment regimen containing tenofovir and pharmacokinetic boosters (ritonavir or cobicistat). The safety of tenofovir during the use of this combination and a pharmacokinetic booster has not been established. The benefits and potential risks associated with the simultaneous use of this combination and a fixed-dose combination drug containing elvitegravir/cobicistat/emtricitabine/tenofovir, or with the use of tenofovir prescribed together with a boosted HIV protease inhibitor (e.g., atazanavir or darunavir), especially in patients at increased risk of renal dysfunction, should be assessed. Patients taking this combination together with drugs such as elvitegravir/cobicistat/emtricitabine/tenofovir or tenofovir and a boosted HIV protease inhibitor should be monitored for the occurrence of adverse reactions associated with tenofovir.

Concomitant use of this combination and HMG-CoA reductase inhibitors (statins) may significantly increase the concentration of the statin, and thus increase the risk of myopathy and rhabdomyolysis.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.