MYHEP-ALL 400/100MG TABLETS

Indications

• Chronic hepatitis C infection
• HCV genotype 1, 2, 3, 4, 5, or 6
• Treatment in combination with ribavirin or ledipasvir

Dosage

Adults: The typical adult dose for

Mechanism of action

Sofosbuvir is a nucleotide analog that inhibits HCV NS5B RNA-dependent RNA polymerase. It is metabolized intracellularly to the active uridine analog triphosphate, which incorporates into HCV RNA and acts as a chain terminator. By binding to the two Mg2+ ions in the active site of NS5B, sofosbuvir prevents the replication of HCV genetic material. This mechanism effectively halts viral replication, making sofosbuvir a crucial component in the treatment of HCV.

Pharmacodynamics

Sofosbuvir is known for its high efficacy against different genotypes of HCV, functioning as a pan-genotypic polymerase inhibitor. It does not exhibit significant prolongation of QTc interval at doses up to three times the standard recommendation. Its antiviral activity is primarily through the inhibition of viral replication, which is critical for the management of chronic hepatitis C.

Pharmacokinetics

Sofosbuvir is administered orally and undergoes extensive hepatic metabolism, primarily by the enzyme uridine 5′-triphosphate (UTP) to its active form. The pharmacokinetic profile indicates a half-life of about 24 hours, allowing for once-daily dosing. The drug is primarily excreted via the kidneys, and its pharmacokinetics may be influenced by factors such as liver function and co-administration with other drugs. It is advised to monitor patients closely for potential drug interactions that may affect sofosbuvir's efficacy.

Adverse effects

• Alopecia
• Anaemia
• Anxiety
• Decreased appetite
• Arthralgia
• Asthenia
• Chest pain
• Chills
• Concentration impaired
• Constipation
• Cough
• Depression
• Diarrhoea
• Dizziness
• Dry mouth
• Dyspnoea
• Fever
• Gastrointestinal discomfort
• Gastrooesophageal reflux disease
• Headaches
• Influenza-like illness
• Insomnia
• Irritability
• Memory loss
• Muscle complaints

Interactions

• Carbamazepine (severe, decreases exposure)
• St. John's Wort (severe, decreases exposure)
• Amiodarone (unknown, increases risk of severe bradycardia or heart block)
• Tipranavir (unknown, decreases exposure)
• Modafinil (unknown, decreases exposure)
• Rifampicin (unknown, decreases exposure)
• Antiarrhythmics (unknown, increases risk of severe bradycardia or heart block)

Precautions

• Monitor glucose levels closely in diabetic patients during treatment
• Avoid in pregnancy due to limited information
• Avoid in breastfeeding as present in milk in animal studies

Pregnancy

Manufacturer advises to avoid due to limited information available.

Breast-feeding

Manufacturer advises to avoid as sofosbuvir is present in milk in animal studies.

Storage

Dispense in original container (contains desiccant).

Formulations

• Ledipasvir 45 mg, Sofosbuvir 200 mg (Harvoni 45mg/200mg tablets)
• Ledipasvir 90 mg, Sofosbuvir 400 mg (Harvoni 90mg/400mg tablets)

Indications

• Chronic hepatitis C virus infection
• Chronic hepatitis C with genotype 1, 2, 3, 4, 5, or 6
• HCV treatment in combination with sofosbuvir

Dosage

Children: Refer to BNF for Children for appropriate pediatric dosing

Adults: The typical adult dose of velpatasvir is 100 mg taken orally once daily, usually in combination with sofosbuvir 400 mg.

Mechanism of action

Velpatasvir's mechanism of action involves the selective inhibition of the NS5A protein, which is essential for the replication of the hepatitis C virus. By binding to domain I of NS5A, velpatasvir competes with RNA for binding at this site, disrupting the replication process. Additionally, it is believed to cause a redistribution of NS5A protein to lipid droplets, although the precise role of NS5A in RNA replication remains not fully understood.

Pharmacodynamics

As a small molecule antiviral, velpatasvir exhibits potent antiviral activity against HCV. It directly inhibits the replication of the virus, contributing to the reduction of viral load in infected patients. Clinical studies have shown that velpatasvir, even at doses significantly above the recommended levels, does not prolong the QTc interval, indicating a favorable cardiac safety profile.

Pharmacokinetics

Velpatasvir is well-absorbed following oral administration, with peak plasma concentrations typically reached within 4 to 5 hours. The drug is extensively metabolized in the liver, primarily by the enzyme CYP3A4. The elimination half-life of velpatasvir is approximately 15 hours, allowing for once-daily dosing. Excretion occurs mainly through feces, with renal clearance being a minor pathway. Drug interactions can significantly affect velpatasvir exposure, necessitating careful monitoring when coadministered with other medications.

Interactions

• oxcarbazepine+velpatasvir: Severe (decreases exposure)
• dabrafenib+velpatasvir: Severe (decreases exposure)
• mitotane+velpatasvir: Severe (decreases exposure)
• stjohn’swort+velpatasvir: Severe (decreases exposure)
• velpatasvir+dabigatran: Severe (increases exposure)
• velpatasvir+thrombininhibitors: Severe (increases exposure)
• velpatasvir+aliskiren: Unknown (increases exposure)
• amiodarone+velpatasvir: Unknown (increases concentration)
• velpatasvir+fexofenadine: Unknown (increases exposure)
• velpatasvir+colchicine: Unknown (increases exposure)

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Velpatasvir should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is unknown if velpatasvir is excreted in human breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from excess heat and moisture. Keep out of reach of children.

Formulations

• Velpatasvir 100 mg tablet

Mechanism of action

Sofosbuvir is nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator [synthesis, A7533]. More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material. Sofosbuvir is a direct-acting antiviral agent (pan-genotypic polymerase inhibitor) against the hepatitis C virus. HCV RNA replication is mediated by a membrane-associated multiprotein replication complex. The HCV polymerase (NS5B protein) is an RNA-dependent RNA polymerase (RdRp). It is the essential initiating and catalytic subunit of this replication complex and is critical for the viral replication cycle. There is no human homolog for HCV NS5B RdRp. Sofosbuvir is a monophosphorylated pyrimidine nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203). GS-461203 competes with natural nucleotides for incorporation (by HCV NS5B) into the nascent RNA strand during replication of the viral genome. GS-461203 differs from endogenous pyrimidine nucleotides in that it has been modified at the 2' position with the addition of a methyl and a fluoro functional group. Incorporation of GS-461203 into nascent RNA strongly reduces the efficiency of further RNA elongation by RdRp, resulting in premature termination of RNA synthesis. The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

Pharmacodynamics

Sofosbuvir acts against HCV and is categorized as a direct-acting antiviral agent (DAA). At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

Mechanism of action

Velpatasvir's mechanism of action is likely similar to other selective NS5A inhibitors which bind domain I of NS5A consisting of amino acids 33-202. NS5A inhibitors compete with RNA for binding at this site. It is also thought that NS5A inhibitors bind the target during its action in replication when the binding site is exposed. Inhibition of NS5A is also known to produce redistribution of the protein to lipid droplets. The exact role of NS5A in RNA replication is not yet understood although it is known to be an important component.

Pharmacodynamics

Velpatasvir is a small molecule direct-acting antiviral used in the treatment of hepatitis C in combination with sofosbuvir. Velpatasvir prevents viral replication by inhibiting non-structural protein 5A (NS5A). At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent.