Velpatasof (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J05AP55 (Sofosbuvir and Velpatasvir)

Active Substances

Sofosbuvir (Rec.INN registered by WHO)

Velpatasvir (Rec.INN registered by WHO)

Dosage Form

Velpatasof

Film-coated tablets 100 mg+400 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – Prescription only
28 pcs. – jars – cardboard packs (28 pcs.) – Prescription only
30 pcs. – jars – cardboard packs (30 pcs.) – Prescription only
7 pcs. – blister packs (4 pcs.) – cardboard packs (28 pcs.) – Prescription only

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.

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

Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active triphosphate (GS-461203), a uridine analog that is incorporated into HCV 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.

Velpatasvir is an HCV inhibitor that targets the HCV nonstructural NS5A protein, which is essential for both RNA replication and the formation of HCV virions.

Selective in vitro resistance and cross-resistance studies indicate that velpatasvir’s mechanism of action is targeting NS5A.

Pharmacokinetics

The pharmacokinetic properties of sofosbuvir, the main circulating inactive metabolite of sofosbuvir (GS-331007), and velpatasvir were evaluated in healthy volunteers and in patients with chronic hepatitis C.

After oral administration of this combination, sofosbuvir is rapidly absorbed, with a mean plasma C_max observed 1 hour after dose administration.

The mean plasma C_max of the inactive metabolite (GS-331007) was observed 3 hours after dose administration.

The mean C_max of velpatasvir was reached 3 hours after administration of the combination.

Based on population pharmacokinetic studies in HCV-infected patients, at steady state, the AUC_0-24 values for sofosbuvir (n=982), the inactive metabolite (GS331007) (n=1428), and velpatasvir (n=1425) were 1260, 13970, and 2970 ng×h/mL, respectively.

The steady-state C_max values for sofosbuvir, the inactive metabolite (GS-331007), and velpatasvir were 566, 868, and 259 ng/mL, respectively.

The AUC_0-24 and C_max of sofosbuvir and the inactive metabolite (GS-331007) were similar in healthy adults and in patients with HCV infection.

Compared to healthy subjects (n=331), the AUC_0-24 and C_max of velpatasvir were 37% and 41% lower, respectively, in HCV-infected patients.

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.

Binding of the inactive metabolite (GS-331007) to human plasma proteins was minimal.

After a single 400 mg dose of [¹⁴C]-sofosbuvir in healthy volunteers, the blood-to-plasma ratio of [¹⁴C]-radioactivity was approximately 0.7.

The binding of velpatasvir to human plasma proteins is >99.5%.

Binding is independent of drug concentration in the range of 0.09 µg/mL to 1.8 µg/mL.

After a single 100 mg dose of [¹⁴C]-velpatasvir in healthy volunteers, the blood-to-plasma ratio of [¹⁴C]-radioactivity ranged from 0.52 to 0.67.

Sofosbuvir is metabolized primarily in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203.

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 inactive metabolite (GS-331007), which is not efficiently rephosphorylated and has no anti-HCV activity in vitro.

Sofosbuvir and the inactive metabolite (GS-331007) are not substrates or inhibitors of UGT1A1 or the CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 isoenzymes.

After a single oral 400 mg dose of [¹⁴C]-sofosbuvir, the proportion of the inactive metabolite (GS331007) accounts for approximately >90% of the total systemic exposure.

Velpatasvir is a substrate of the CYP2B6, CYP2C8, and CYP3A4 isoenzymes with slow turnover.

After a single 100 mg dose of [¹⁴C]-velpatasvir, the majority (>98%) of the radioactivity in plasma was attributed to the parent drug.

Monohydroxylated and demethylated velpatasvir are metabolites identified in human plasma.

Unchanged velpatasvir is the primary substance present in feces.

After a single oral dose of 400 mg [¹⁴C]-sofosbuvir, the mean total recovery of [¹⁴C]-radioactivity was over 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 the inactive metabolite (GS-331007) (78%), with only 3.5% excreted unchanged.

These data indicate that renal clearance is the major route of elimination for the inactive metabolite (GS-331007).

The mean terminal T_1/2 of sofosbuvir and the inactive metabolite (GS-331007) after administration of the drug containing this combination was 0.5 and 25 hours, respectively.

After a single oral dose of 100 mg [¹⁴C]-velpatasvir, the mean total recovery of [¹⁴C]-radioactivity was 95%, with approximately 94% and 0.4% excreted in feces and urine, respectively.

Unchanged velpatasvir was the primary substance present in feces, accounting for a mean of 77% of the administered dose, followed by monohydroxylated velpatasvir (5.9%) and demethylated velpatasvir (3.0%).

These data indicate that biliary excretion of the parent drug was the major route of elimination for velpatasvir.

The median terminal T_1/2 of velpatasvir after administration of this combination was approximately 15 hours.

Indications

Treatment of chronic hepatitis C in patients aged 6 years and older and weighing at least 17 kg.

ICD codes

Dosage Regimen

Take one tablet once daily by oral administration.

Swallow the tablet whole; do not crush or chew.

Administer the tablet with or without food.

For patients aged 6 years and older and weighing at least 17 kg, the standard regimen is one fixed-dose combination tablet daily.

The recommended treatment duration is 12 weeks for most patients with chronic hepatitis C.

Initiate and monitor therapy under the supervision of a physician experienced in managing hepatitis C.

If a dose is missed and it is less than 18 hours until the next scheduled dose, take the missed dose immediately.

If it is more than 18 hours until the next dose, skip the missed dose and resume the normal schedule; do not take a double dose.

For patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease requiring hemodialysis, use with caution as safety has not been established.

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

This combination is contraindicated in children under 6 years of age or weighing less than 17 kg.

Avoid concomitant use with strong P-glycoprotein or CYP450 inducers (e.g., carbamazepine, phenytoin, rifampicin, St. John’s wort).

Adverse Reactions

Nervous system disorders very common – headache.

Gastrointestinal disorders very common – nausea.

Skin and subcutaneous tissue disorders frequency not known – Stevens-Johnson syndrome.

Cardiac disorders cases of severe bradycardia and heart block (in particular, AV or sinoatrial block) have been observed with the use of sofosbuvir.

General disorders very common – fatigue.

Contraindications

Hypersensitivity to sofosbuvir and/or velpatasvir; pregnancy, breastfeeding; children under 6 years of age or weighing less than 17 kg; patients receiving strong inducers of P-glycoprotein or CYP450 isoenzymes (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin, St. John’s wort).

With caution

Severe renal impairment (eGFR < 30 mL/min/1.73 m²) or end-stage renal disease requiring hemodialysis.

Concomitant use with digoxin; dabigatran etexilate;
With a drug containing
Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate and a boosted HIV protease inhibitor.

Concomitant use with drugs that are moderate inducers of P-glycoprotein or CYP450 isoenzymes (e.g., efavirenz, modafinil, oxcarbazepine, or rifapentine) is not recommended; proton pump inhibitors (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole).

Concomitant use with other drugs containing Sofosbuvir should be avoided; with amiodarone.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy.

It is not known whether Sofosbuvir, metabolites of sofosbuvir, or Velpatasvir are excreted in human breast milk. Available animal pharmacokinetic data indicate excretion of velpatasvir and metabolites of sofosbuvir in breast milk. This combination should not be used during breastfeeding, as the risk to the newborn/infant cannot be ruled out.

Use in Hepatic Impairment

Safety and efficacy have not been evaluated in patients with Child-Pugh-Turcott class C cirrhosis.

The safety and efficacy of this combination have not been evaluated in HCV-infected patients who have undergone liver transplantation.

Use in Renal Impairment

For patients with mild or moderate renal impairment, no dose adjustment of this combination is required.

Use with caution in patients with severe renal impairment estimated GFR <30 mL/min/1.73 m² or end-stage chronic renal failure (end-stage CKD) requiring hemodialysis, as the safety of this combination has not been evaluated.

Pediatric Use

Contraindicated for use in children under 6 years of age or weighing less than 17 kg.

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

Concomitant use with amiodarone is life-threatening, so amiodarone should be used in patients receiving a drug containing this combination only if other alternative antiarrhythmic treatments are not possible.

If concomitant administration of amiodarone is deemed necessary, close monitoring of patients starting this combination is recommended. Patients at high risk of bradyarrhythmia should be under continuous monitoring for 48 hours in an appropriate clinical setting.

Due to the long T_1/2 of amiodarone, appropriate monitoring is also required for patients who have discontinued amiodarone within the last few months and are about to start this combination.

All patients taking this 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 (in particular, AV or sinoatrial block) and advised to seek immediate medical attention if they occur.

The potential risks and benefits associated with the concomitant use of this combination and the fixed-dose combination product containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with the use of tenofovir disoproxil fumarate, which is prescribed in combination with a boosted HIV protease inhibitor (e.g., atazanavir or darunavir), should be considered, especially in patients at increased risk of renal impairment.

Patients with diabetes may experience improved glucose control, which may lead to symptomatic hypoglycemia after starting treatment with direct-acting antiviral drugs for hepatitis C. Blood glucose levels should be closely monitored in diabetic patients starting treatment with direct-acting antiviral drugs, especially during the first 3 months, and antidiabetic medication should be adjusted if necessary. The physician responsible for the treatment of the diabetic patient should be informed about the initiation of direct-acting antiviral therapy for hepatitis C.

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 in all patients prior to initiation of 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.

Effect on ability to drive and operate machinery

The use of this combination has no or negligible influence on the ability to drive and operate machinery.

Drug Interactions

When taking drugs containing this fixed-dose combination, any interactions due to the individual active substances listed are possible.

Velpatasvir is an inhibitor of the P-glycoprotein transporter and BCRP, organic anion transporting polypeptide (OATP) 1B1 and OATP1B3.

Concomitant use of this combination with drugs that are substrates of these transporters may increase the exposure of such drugs.

Sensitive substrates of P-glycoprotein include digoxin, BCRP – rosuvastatin, and OATP – pravastatin.

Ledipasvir and Sofosbuvir are substrates of the active substance transporters P-glycoprotein and BCRP.

Velpatasvir is also a substrate of the OATP1B drug transporter.

In vitro studies observed slowed metabolism mediated by CYP2B6, CYP2C8, and CYP3A4.

Drugs that are strong inducers of P-glycoprotein or strong inducers of CYP2B6, CYP2C8, or CYP3A4 may decrease the plasma concentrations of sofosbuvir or velpatasvir, leading to a reduction in the therapeutic effect of sofosbuvir/velpatasvir.

The use of such drugs with this fixed-dose combination is contraindicated.

Drugs that are moderate inducers of P-glycoprotein or moderate inducers of cytochrome P450 system isoenzymes (e.g., oxcarbazepine, modafinil, or efavirenz) may cause a decrease in the plasma concentrations of sofosbuvir or velpatasvir, which may lead to a weakening of the therapeutic effect of the combination drug.

Concomitant use with such drugs is not recommended.

Concomitant use with drugs that inhibit P-glycoprotein or BCRP may increase the plasma concentrations of sofosbuvir or velpatasvir.

Drugs that inhibit OATP, CYP2B6, CYP2C8, or CYP3A4 isoenzymes may increase the plasma concentration of velpatasvir.

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

Storage Conditions

Store at 2°C (36°F) to 30°C (86°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.