Sofosbuvir and Velpatasvir - Mechanism of Action, Uses, and Adverse Drug Reactions

Overview:

A fixed-dose combination medication called Sofosbuvir and Velpatasvir is used to treat adults and children three years of age and older who have chronic hepatitis C (HCV) ((long-standing viral infection that causes liver inflammation) infections. For genotypes one through six, it is more than 90 percent effective. Patients with severe liver disease, however, run the risk of not responding to treatment.

Only four patients stopped taking their medication before week four due to non-hepatic adverse effects. The Food and Drug Administration (FDA) authorized Sofosbuvir and Velpatasvir on June 28, 2016, making them the first treatments for all six major HCV genotypes.

Approval was granted based on three phase III clinical trials involving 1,558 participants with compensated or non-compensated cirrhosis. After 12 weeks of treatment, no virus was found in 95 to 99 percent of the patients receiving Sofosbuvir and Velpatasvir, indicating that their infections had healed.

Drug Group

Two medications that collaborate to stop the hepatitis C virus (HCV) from spreading are Sofosbuvir and Velpatasvir. Hepatitis C virus (HCV) nucleotide NS5B (non-structural protein 5B) polymerase inhibitor Sofosbuvir is transformed into its active metabolite by the body's NS5B RNA polymerase enzyme. As an inhibitor of the HCV NS5A (non-structural protein 5A) replication complex, Velpatasvir prevents the actions of the NS5A protein, which is necessary for viral replication.

Indications

Sofosbuvir and Velpatasvir combinations are usually recommended for the management of chronic hepatitis C virus (HCV) infection in adults and pediatric patients aged three years and older who have genotypes 1, 2, 3, 4, 5, or 6:

• Decompensated cirrhosis (severe liver scarring) to be used in conjunction with Ribavirin.

• Without cirrhosis or with compensated cirrhosis.

Contraindications

It is not advisable to recommend a combination of Sofosbuvir and Velpatasvir along with Ribavirin for patients for whom Ribavirin is contraindicated.

Dosage Forms and Available Strengths

Sofosbuvir and Velpatasvir combinations are available as tablets and oral pellets.

1. The Sofosbuvir and Velpatasvir combination tablets are available in two strengths:

• 400 mg (milligrams) of Sofosbuvir and 100 mg of Velpatasvir combination.

• 200 mg of Sofosbuvir and 50 mg of Velpatasvir combination.

2. The oral Sofosbuvir and Velpatasvir combination pellets are also available in two strengths:

• 200 mg of Sofosbuvir and 50 mg of Velpatasvir combination.

• 150 mg of Sofosbuvir and 37.5 mg of Velpatasvir combination.

Warnings and Precautions

• Risk of Hepatitis B Virus Reactivation: Reactivation of the hepatitis B virus (HBV) has been documented in individuals with coinfected HCV or HBV who were taking HCV direct-acting antivirals or had finished them but not HBV antiviral therapy. Measure HBsAg and anti-HBc before starting Sofosbuvir and Velpatasvir combination HCV treatment to screen all patients for symptoms of past or present HBV infection. During HCV therapy with the Sofosbuvir and Velpatasvir combination and post-treatment follow-up, patients with serologic evidence of HBV infection should be watched for clinical and biochemical indicators of hepatitis flare-up or HBV reactivation. When clinically needed, appropriate patient care for HBV infection should be begun.

• Bradycardia with Amiodarone Coadministration: Individuals on Amiodarone may experience serious symptomatic bradycardia (slow heart rate). This is especially true for individuals who are simultaneously taking beta blockers, have underlying cardiac comorbidities, or have advanced liver disease.

It is not advised to take Amiodarone and Sofosbuvir and Velpatasvir combination concurrently. It is advised that individuals without other effective treatment alternatives undergo cardiac monitoring.

For Patients

What Is Chronic Hepatitis C Virus Genotype 1 Infection?

A type of chronic hepatitis brought on by the hepatitis C virus is known as chronic hepatitis C virus (HCV) genotype 1 infection. Both acute and chronic hepatitis can result from it; often, the acute course results in a chronic infection. Episodes of chronic HCV infection can lead to liver transplantation, cirrhosis, and hepatocellular cancer (primary liver cancer). Every HCV genotype has a distinct response to treatment regimens, including seven primary genotypes and several subgroups. 60 to 70 percent of HCV cases in the US (United States) and Europe are caused by HCV genotype 1, which is the most prevalent. The infection with hepatitis C genotypes one and three is linked to more severe liver disease, a higher chance of cirrhosis and fibrosis (liver scarring), and a higher risk of hepatocellular cancer.

How Does Sofosbuvir and Velpatasvir Combination Work?

Viral load is significantly reduced by Sofosbuvir and Velpatasvir combination therapy, which disrupts the viral life cycle. This implies that the body has less virus, assisting the immune system in warding off the infection.

What Are the Benefits of the Sofosbuvir and Velpatasvir Combination?

In the treatment of chronic hepatitis C virus (HCV) infection, the combination of Sofosbuvir and Velpatasvir offers the following advantages:

• High Efficacy: This combination of medications improves clinical outcomes and produces a sustained virologic response (SVR) by successfully preventing viral replication. Studies conducted in real life show a persistent viral response of over 98 percent.

• Wide Spectrum: It is a pangenotypic treatment because it works with all HCV genotypes (one to six).

• Well-Tolerated: Headache and fatigue were the most frequent side effects seen in clinical trials, indicating that it is typically well-tolerated.

• Suitable for Diverse Patient Groups: It is safe for use in patients who have undergone treatment, have severe fibrosis or compensated cirrhosis, have renal illness, or are coinfected with HIV (human immunodeficiency virus) 1. In contrast to regimens comprising HCV protease inhibitors, it can also be administered to patients with decompensated cirrhosis.

• Convenient: It can increase patient compliance as a single pill taken once daily.

• Pediatric Use: According to preliminary research, it appears to be as effective in children and adolescents as in adults.

How Is the Sofosbuvir and Velpatasvir Combination Administered?

For 12 weeks, tablets and pellets containing a combination of Sofosbuvir and Velpatasvir are given orally. Food is not necessary when taking it. It is recommended that children under the age of six take it with food. For clarity, ask the physician or pharmacist to follow the prescription label instructions. Take no more or less than directed by a doctor.

Pellets can be consumed without food or in combination with food. To prepare a dose, sprinkle the entire package over soft, non-acidic foods such as pudding, chocolate syrup, or ice cream. After scattering the pellets over meals, consume the mixture within 15 minutes. If one feels better, do not stop taking Velpatasvir and Sofosbuvir without discussing them with the doctor.

What Are the Side Effects of the Sofosbuvir and Velpatasvir Combination?

Velpatasvir and Sofosbuvir may have adverse consequences. If any of these symptoms are severe or persistent, let the physician know:

• Headache.

• Exhaustion.

• Diarrhea.

• Vomiting in toddlers under the age of six

• Spitting up the medication (in kids under the age of six).

• Rash.

• Feeling agitated.

• Experiencing depression.

• Difficulty getting to sleep or remaining asleep.

Velpatasvir and Sofosbuvir may have additional adverse effects. If patients have any odd side effects while taking Them, Contact the Doctor.

What Are the Things to Inform the Doctor Before Taking Sofosbuvir and Velpatasvir Combination?

• If patients are allergic to any of the substances in Sofosbuvir and Velpatasvir tablets, other medications, or Sofosbuvir or Velpatasvir itself, let the doctor and pharmacist know before using these drugs.

• Inform the physician and pharmacist of all the vitamins, nutritional supplements, and prescription and over-the-counter medications patients now use or intend to take. The doctor may need to monitor patients closely for any side effects or modify the prescription dosages.

• If patients take them, take antacids four hours before or four hours following Sofosbuvir and Velpatasvir. If patients are taking indigestion, heartburn, or ulcers drugs, such as H2 blockers (Cimetidine, Ranitidine, Famotidine, or Nizatidine), 12 hours before or 12 hours after Sofosbuvir and Velpatasvir.

• The following over-the-counter or natural medications may interact with Velpatasvir and Sofosbuvir: St. John's wort or proton-pump inhibitors like Lansoprazole, Omeprazole, or Esomeprazole. Before beginning to use Sofosbuvir and Velpatasvir, make sure the doctor and pharmacist are aware that patients are taking these drugs. While taking Velpatasvir and Sofosbuvir, do not begin taking any of these medications without consulting the doctor.

• Inform the doctor about any liver transplants patients may have had, HIV positive status, liver illness, kidney disease, or dialysis (helps to remove extra fluid and waste materials from the blood when kidneys are failing) treatment, as well as any liver issues patients currently have or have ever had aside from hepatitis C.

• Inform the physician if patients are nursing a baby, intend to get pregnant, or are already pregnant. Contact the physician if patients become pregnant while taking Velpatasvir and Sofosbuvir. It is advised that patients avoid getting pregnant while taking Sofosbuvir, Velpatasvir, and Ribavirin together, as well as for six months following therapy. The fetus may be seriously harmed by Ribavirin.

Dietary Considerations:

Maintain the usual diet unless advised by the doctor.

Missed Dose:

Take all Sofosbuvir and Velpatasvir doses since this will cause the blood levels of the medication to drop. Before running out, refill medications. If patients miss a dose, take it immediately, skip the one coming up, and refrain from taking two doses at once.

Overdose:

The overdose of Velpatasvir and Sofosbuvir is incurable, and patients need to be closely watched for toxicity. Supportive measures are part of the treatment, and they include the patient's clinical status and vital signs. The metabolite of Sofosbuvir can be effectively eliminated by hemodialysis, but Velpatasvir is unlikely to be appreciably removed because of its strong binding to plasma proteins. There is not a known counteragent.

Storage and Handling:

Velpatasvir and Sofosbuvir should be kept out of children's reach and securely closed in their original containers to ensure safety. They should be kept out of the bathroom and at room temperature between 68°F (degrees Fahrenheit) and 77°F (20°C (degrees Celsius) and 25°C), away from heat and moisture.

Disposal:

Properly disposing of unnecessary prescriptions prevents pets, kids, and others from consuming them. Instead of dumping them down the toilet, use an FDA take-back program to return used medications. To learn more about these community initiatives, speak with the recycling and waste management department or the pharmacy.

For Doctors

Pharmacodynamics

The study assessed the impact of Sofosbuvir 400 mg and 1200 mg on the QTc interval in an active-controlled QT trial involving 400 mg of Moxifloxacin. In an active-controlled QT study with Moxifloxacin 400 mg, Sofosbuvir did not extend QTc to any clinically relevant extent at a dose three times the prescribed dose, while Velpatasvir 500 mg did not prolong QTc interval to any clinically relevant extent at a dose five times the suggested dosage.

Mechanism of Action

Sofosbuvir and Velpatasvir are antiviral medications used to combat the hepatitis C virus. Sofosbuvir inhibits the HCV NS5B RNA-dependent RNA polymerase, while Velpatasvir targets the HCV NS5A protein for viral replication.

Pharmacokinetics

• Absorption: Velpatasvir and Sofosbuvir absorb well orally, making a once-daily dosage feasible.

• Peak Plasma Concentration: Sofosbuvir achieves its maximal median plasma concentration 0.5 to one-hour post-dose following oral administration of Velpatasvir and Sofosbuvir. Velpatasvir reaches its maximum blood plasma levels three hours after oral ingestion.

• Tissue Distribution: Both medications have good tissue penetration, especially in the liver, which is the main location where HCV replication occurs.

• Metabolism: The liver enzymes CYP2B6, CYP2C8, and CYP3A41 slowly metabolize Velpatasvir.

• Plasma Protein Binding: Velpatasvir exhibits a plasma protein binding rate of more than 99.5 percent.

Drug Interactions

• Drugs including Rifampin, St. John's wort, and Carbamazepine that induce P-gp (permeability glycoprotein) or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 may dramatically lower plasma concentrations of Sofosbuvir and Velpatasvir, which may lessen the therapeutic impact of Sofosbuvir and Velpatasvir. It is not advised to use these agents in conjunction with Sofosbuvir and Velpatasvir.

• Take an antacid or Omeprazole at least four hours after taking the Sofosbuvir and Velpatasvir dosages.

• Seek emergency medical treatment if patients use Amiodarone and the Sofosbuvir and Velpatasvir combination and have symptoms including slow heartbeats, chest pain, shortness of breath, confusion, memory issues, weakness, excessive fatigue, or lightheadedness.

• Changes in hepatic function may result from the use of direct-acting antivirals to treat HCV infection, potentially affecting the safe and efficient use of concurrent medicines. It may be required to regularly check relevant laboratory values, such as blood glucose or INR (international normalized ratio), and alter the dosage of some concurrent drugs.

Clinical Studies

A phase 3 clinical trial called the ASTRAL studies assessed the efficacy and safety of Sofosbuvir and Velpatasvir in people with chronic Hepatitis C virus genotypes one through six. Patients with decompensated cirrhosis and HCV genotypes 1, 2, 4, 5, or 6 were enrolled in the trials. When treated with Sofosbuvir and Velpatasvir for 12 weeks, either with or without Ribavirin, the results demonstrated high rates of persistent virologic response. The trials also demonstrated that Velpatasvir and Sofosbuvir are effective for a range of patients, supporting the use of these medications in adult patients with long-term HCV infection. The studies support the use of Velpatasvir and Sofosbuvir to treat HCV infections.

Use in Specific Populations

• Pregnancy: There is no controlled research on human pregnancy, and animal studies have not discovered any evidence of fetal damage with Sofosbuvir and Velpatasvir. Pregnancy avoidance during therapy and for six months following treatment discontinuation is advised for female patients and female partners of male patients on Ribavirin-containing regimens.

• Breastfeeding: It is unknown whether Sofosbuvir and Velpatasvir will affect breast milk because they do not influence human lactation. It is advised to speak with a healthcare professional about the best way to feed while receiving these medications.

• Pediatric Use: For the treatment of hepatitis C virus in children aged six years and older or weighing at least 37 pounds with any of the six genotypes or strains without cirrhosis or mild cirrhosis, the U.S. FDA has approved Sofosbuvir and Velpatasvir. There is no proven safety or effectiveness for children younger than three.

• Geriatric Use: Research indicates that the combination of Sofosbuvir and Velpatasvir is not less effective for the elderly than for younger ones. However, older patients may be more susceptible to its side effects.

• Renal and Hepatic Impairment: The dose of Sofosbuvir and Velpatasvir should not be modified for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) or mild, moderate, or severe renal impairment, including ESRD requiring dialysis.