Sofbuvir (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J05AP08 (Sofosbuvir)

Active Substance

Sofosbuvir (Rec.INN registered by WHO)

Dosage Form

Sofbuvir

Film-coated tablets, 400 mg: 28 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, capsule-shaped, biconvex; the tablet is white or almost white on the break.

Excipients: hypromellose – 80 mg, colloidal silicon dioxide – 6 mg, maltitol – 134 mg, sodium stearyl fumarate – 6 mg, povidone K30 – 14 mg.
The mass of the uncoated tablet is 640 mg.

Film coating composition titanium dioxide – 2 mg, macrogol 4000 – 2.1 mg, polyvinyl alcohol – 4.2 mg, talc – 1.7 mg.
The mass of the film-coated tablet is 650 mg.

7 pcs. – blister packs (4) – cardboard boxes.
10 pcs. – blister packs (3) – cardboard boxes.
28 pcs. – polymer jars (1) – cardboard boxes.

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

Antiviral agent, a pan-genotypic inhibitor of the hepatitis C virus NS5B RNA-dependent RNA polymerase. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine triphosphate analog (GS-461203). With the help of the NS5B polymerase, GS-461203 can be incorporated into the nascent hepatitis C virus RNA chain and act as a chain terminator.

This active metabolite of sofosbuvir (GS-461203) inhibits the polymerase activity of hepatitis C virus genotypes 1b, 2a, 3a, and 4a at concentrations causing 50% inhibition (IC₅₀) in the range of 0.7 to 2.6 µmol.

Pharmacokinetics

After oral administration, Sofosbuvir is rapidly absorbed, with C_max in plasma reached within 0.5-2 hours, regardless of the dose taken. C_max of the inactive metabolite (GS-331007) in plasma was reached 2-4 hours after drug administration.

Based on population analysis of pharmacokinetic data in patients with hepatitis C virus genotypes 1-6, the AUC_0-24 values of sofosbuvir and the inactive metabolite (GS-331007) at steady state are 1010 ng×h/mL and 7200 ng×h/mL, respectively. Compared to healthy volunteers, the AUC_0-24 of sofosbuvir and the inactive metabolite (GS-331007) in patients with chronic hepatitis C is 57% higher and 39% lower, respectively.

Administration of a single dose of sofosbuvir with a high-fat meal slows the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir increases by approximately 1.8 times, with a minor effect on C_max. A high-fat meal does not affect the exposure of the inactive metabolite (GS-331007). It has been established that when sofosbuvir is taken on an empty stomach in doses from 200 mg to 400 mg, the AUC of sofosbuvir and the inactive metabolite (GS-331007) is almost dose-proportional.

Sofosbuvir is approximately 85% bound to human plasma proteins (ex vivo data), and the degree of binding is independent of drug concentration in the range of 1-20 µg/mL. The inactive metabolite (GS-331007) is minimally bound to plasma proteins. After a single dose of [¹⁴C]-sofosbuvir 400 mg in healthy volunteers, the ratio of ¹⁴C radioactivity in blood/plasma was approximately 0.7.

Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside (uridine) analog triphosphate (GS-461203). The metabolic activation pathway involves sequential hydrolysis of the molecule by carboxylesterase cathepsin A (CatA) or carboxylesterase 1 (CES1) and cleavage of the phosphoramidate by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation via pyrimidine nucleotide biosynthesis. Dephosphorylation leads to the formation of a nucleoside inactive (>90%) metabolite, which cannot be fully rephosphorylated and has no activity against HCV in vitro.

After a single oral dose of [¹⁴C]-sofosbuvir 400 mg, the systemic exposure of sofosbuvir and the inactive metabolite (GS-331007) was approximately 4% and >90%, respectively, of the systemic exposure of the drug-related material (sum of AUC of sofosbuvir and its metabolites corrected for molecular weight).

After a single oral dose of [¹⁴C]-sofosbuvir 400 mg, the mean total excretion of the radioactive dose was more than 92%, with approximately 80%, 14%, and 2.5% excreted by the kidneys, intestines, and lungs, respectively. The majority of the sofosbuvir dose excreted by the kidneys was the inactive metabolite (GS-331007) (78%), while 3.5% was excreted as sofosbuvir.

These data indicate that renal clearance is the primary route of elimination for the inactive metabolite (GS-331007) with predominant active secretion. The mean T_1/2 of sofosbuvir and the inactive metabolite (GS-331007) is 0.4 hours and 27 hours, respectively.

Pharmacokinetics in special clinical cases

Compared to patients with normal renal function (CrCl >80 mL/min) not infected with hepatitis C virus, in mild, moderate, and severe renal impairment, the AUC_0-inf of sofosbuvir was higher by 61%, 107%, and 171%, respectively, and the AUC_0-inf of the inactive metabolite (GS-331007) was higher by 55%, 88%, and 451%, respectively.

In patients with chronic renal failure compared to patients with normal renal function, the AUC_0-inf of sofosbuvir was 28% higher if Sofosbuvir was taken 1 hour before a hemodialysis session, and 60% higher if Sofosbuvir was taken 1 hour after a hemodialysis session. The main inactive metabolite (GS-331007) can be effectively removed by hemodialysis (clearance is about 53%). After a 4-hour hemodialysis session, approximately 18% of the administered drug dose is excreted.

Compared to patients with normal liver function, the AUC_0-24 of sofosbuvir was 126% and 143% higher in patients with moderate and severe hepatic impairment, respectively, and the AUC_0-24 of the inactive metabolite (GS-331007) was higher by 18% and 9%, respectively.

Indications

Treatment of chronic hepatitis C in adult patients (in combination with other drugs).

ICD codes

Dosage Regimen

Take orally once daily. The recommended dose is 400 mg (one tablet).

Take with or without food. For optimal absorption, administer with a meal if gastrointestinal upset occurs.

Use only in combination with other antiviral agents for chronic hepatitis C. Monotherapy is not recommended and is ineffective.

Adhere strictly to the prescribed regimen. 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 one at the regular time. Do not double the dose.

The treatment duration is determined by the hepatitis C virus genotype, prior treatment history, presence of cirrhosis, and the specific drug combination used. Typical regimens range from 12 to 24 weeks.

Discontinue Sofbuvir if any partner drug in the regimen is permanently discontinued.

In patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease requiring hemodialysis, the use of Sofbuvir is contraindicated.

No dose adjustment is required for patients with mild or moderate hepatic impairment. The drug is contraindicated in patients with decompensated cirrhosis.

Adverse Reactions

Adverse reactions identified with the use of sofosbuvir in combination with ribavirin

From the hematopoietic system very common – decreased hemoglobin concentration; common – anemia.

Psychiatric disorders very common – insomnia; common – depression.

From the nervous system very common – headache; common – impaired attention.

From the respiratory system common – nasopharyngitis, dyspnea, exertional dyspnea, cough.

From the digestive system very common – nausea, increased blood bilirubin concentration; common – abdominal discomfort, constipation, dyspepsia.

From the skin and subcutaneous tissue common – alopecia, dry skin, pruritus.

From the musculoskeletal system common – arthralgia, back pain, muscle spasms, myalgia.

General disorders very common – irritability, fatigue; common – fever, asthenia.

Adverse reactions identified with the use of sofosbuvir in combination with peginterferon alfa/ribavirin

From the hematopoietic system very common – anemia, neutropenia, decreased lymphocyte count, decreased platelet count.

Psychiatric disorders very common – insomnia; common – depression, anxiety, agitation.

From the nervous system very common – dizziness, headache; common – migraine, memory impairment, impaired attention.

From the organ of vision common – blurred vision.

From the respiratory system very common – dyspnea, cough; common – exertional dyspnea.

From the digestive system very common – decreased appetite, diarrhea, nausea, vomiting, increased blood bilirubin concentration; common – constipation, dry mouth, gastroesophageal reflux.

From the skin and subcutaneous tissue very common – rash, pruritus; common – alopecia, dry skin.

From the musculoskeletal system very common – arthralgia, myalgia; common – muscle spasms.

General disorders very common – chills, fatigue, influenza-like illness, irritability, pain, fever; common – weight loss, back pain, chest pain, asthenia.

Contraindications

Hypersensitivity to sofosbuvir; co-infection with hepatitis C and B viruses (no data on the use of sofosbuvir in this patient population); severe renal impairment (CrCl<30 mL/min) or end-stage renal disease requiring hemodialysis; decompensated liver cirrhosis; concomitant use of potent P-glycoprotein inducers (e.g., rifampicin, St. John’s wort (Hypericum perforatum), carbamazepine, phenytoin, phenobarbital, oxcarbazepine); pregnancy; age under 18 years.

Use in Pregnancy and Lactation

The use of sofosbuvir during pregnancy is contraindicated.

Sofosbuvir should not be used during breastfeeding.

In cases where Sofosbuvir is used in combination with ribavirin or with peginterferon alfa/ribavirin, women of childbearing potential or their partners should use effective contraceptive methods during treatment and for the necessary period after its completion, according to the recommendations for the use of ribavirin.

Use in Hepatic Impairment

Contraindicated in decompensated liver cirrhosis.

Use in Renal Impairment

Contraindicated in severe renal impairment (CrCl<30 mL/min) or end-stage renal disease requiring hemodialysis.

Pediatric Use

Contraindicated in children under 18 years of age (efficacy and safety have not been established in this population).

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Since Sofosbuvir is prescribed in combination with other drugs for the treatment of chronic hepatitis C, if the other drugs are discontinued, Sofosbuvir should also be discontinued.

Sofosbuvir should be used with caution in patients with hepatitis C virus genotype 1, 4, 5, and 6 who have previously received antiviral therapy, especially in cases where there is one or more factors historically associated with a low response rate to interferon therapy (advanced fibrosis/cirrhosis, high baseline viral load, Black race, presence of non-CC IL28B genotype allele); in patients simultaneously taking other antiviral drugs for the treatment of hepatitis C (e.g., telaprevir or boceprevir).

Cases of severe bradycardia and heart block have been reported with the use of the combination of sofosbuvir and daclatasvir in combination with amiodarone and/or other drugs that slow the heart rate. Adverse reactions occurring with such combination therapy are potentially life-threatening, so the use of amiodarone together with the combination of sofosbuvir and daclatasvir is only permissible in case of intolerance or contraindications to alternative antiarrhythmic therapy. In cases where concomitant use of amiodarone is necessary, close monitoring of patients at the beginning of treatment with the combination of sofosbuvir and daclatasvir is recommended.

Sofosbuvir should be used in combination with other direct-acting antiviral drugs only when the benefit of such a combination outweighs the risk based on available data.

When using sofosbuvir in combination with ribavirin or peginterferon alfa/ribavirin in patients with CrCl <50 mL/min, refer to the prescribing information for ribavirin.

Effect on ability to drive vehicles and operate machinery

Sofosbuvir has a moderate effect on the ability to drive vehicles and operate machinery. Patients should be informed that during the use of sofosbuvir in combination with peginterferon alfa and ribavirin, impaired attention, fatigue, dizziness, and blurred vision may occur. If these symptoms occur, patients should refrain from performing potentially hazardous activities such as driving vehicles and operating machinery.

Drug Interactions

Potent intestinal P-glycoprotein inducers (e.g., rifampicin, St. John’s wort, carbamazepine, and phenytoin) may decrease the plasma concentration of sofosbuvir, leading to a reduction in the therapeutic efficacy of the drug.

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.