Vosevi

For the treatment of chronic hepatitis C, the standard adult dosage of Sofosbuvir is 400 mg taken orally once daily. It is rarely prescribed as a monotherapy (a single drug). Instead, it is used in conjunction with other medications such as Ribavirin, Daclatasvir, or as part of a fixed-dose combination tablet. The duration of treatment typically ranges from 8 to 24 weeks, depending on the specific viral genotype, the presence of cirrhosis (liver scarring), and whether the patient has failed previous treatments. For example, a common regimen for Genotype 2 involves 12 weeks of Sofosbuvir plus Ribavirin.

Sofosbuvir is approved for use in pediatric patients aged 3 years and older. Dosing in children is strictly based on body weight:

• Weight ≥ 35 kg: 400 mg once daily (one adult tablet).
• Weight 17 kg to < 35 kg: 200 mg once daily (using oral pellets or smaller tablets).
• Weight < 17 kg: 150 mg once daily (using oral pellets).

The safety and efficacy of Sofosbuvir in children under 3 years of age have not yet been established. Healthcare providers will determine the appropriate combination partner and duration for pediatric patients.

Renal Impairment

For many years, Sofosbuvir was used with caution in patients with severe renal impairment. However, updated clinical data and FDA labeling now state that no dosage adjustment is required for patients with any degree of renal impairment, including those with end-stage renal disease (ESRD) on dialysis. The metabolite GS-331007 does accumulate in these patients, but clinical trials have shown the 400 mg dose to be safe and effective.

Hepatic Impairment

No dosage adjustment of Sofosbuvir is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). However, the clinical management of patients with decompensated cirrhosis (advanced liver failure) is complex and requires close supervision by a hepatologist.

Elderly Patients

Clinical studies of Sofosbuvir included sufficient numbers of subjects aged 65 and over to determine that they respond similarly to younger subjects. No specific dose adjustments are recommended for the elderly, though providers should be mindful of concurrent medications and age-related decreases in kidney function.

• Consistency: Take Sofosbuvir at the same time every day to maintain a steady level of the medication in your bloodstream.
• With or Without Food: Sofosbuvir can be taken with or without food. If you are taking it as part of a combination product (like Vosevi), follow the specific instructions for that product, as some require food for better absorption.
• Administration: Tablets should be swallowed whole. Do not chew, crush, or split the tablet, as it has a very bitter taste. For pediatric pellets, sprinkle the dose on a small amount of non-acidic soft food (like pudding or mashed potatoes) and consume within 15 minutes without chewing the pellets.
• Storage: Store the medication at room temperature (below 30°C or 86°F) in its original container to protect it from moisture.

If you miss a dose of Sofosbuvir, take it as soon as you remember on the same day. However, if it is nearly time for your next scheduled dose, skip the missed dose and resume your regular schedule. Do not take two doses at once to make up for a missed one. Maintaining adherence is critical to achieving a 'sustained virologic response' (SVR), which is the clinical term for a cure.

There is limited experience with Sofosbuvir overdose. The highest documented dose was a single 1200 mg dose (three times the standard). In clinical trials, no specific toxicities were observed at this level. In the event of an overdose, patients should be monitored for evidence of toxicity. There is no specific antidote for Sofosbuvir. Hemodialysis can remove the primary metabolite, GS-331007, with an extraction ratio of approximately 53%.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop the medication early, even if you feel better, as this can lead to treatment failure and viral resistance.

Because Sofosbuvir is almost always administered with other antiviral drugs (like Ribavirin or Ledipasvir), it can be difficult to distinguish which drug is causing a specific symptom. However, the following side effects are frequently reported in clinical trials:

• Fatigue: A persistent feeling of tiredness or lack of energy. This is the most common complaint and usually persists throughout the treatment duration.
• Headache: Mild to moderate headaches are common. These can often be managed with over-the-counter pain relievers, but consult your doctor first.
• Nausea: Some patients experience a 'queasy' stomach. Taking the medication with a light snack may help mitigate this.
• Insomnia: Difficulty falling or staying asleep is reported by approximately 10-15% of patients.
• Anemia: When used with Ribavirin, a drop in red blood cell counts is common, which can lead to shortness of breath and dizziness.

• Pruritus (Itching): Some patients develop itchy skin or a mild rash.
• Diarrhea: Loose stools may occur as the body adjusts to the medication.
• Irritability: Changes in mood or feeling 'on edge' have been noted, particularly in regimens containing Ribavirin.
• Decreased Appetite: A lack of interest in food or changes in taste perception.
• Myalgia (Muscle Pain): General aches and pains in the muscles and joints.

• Depression: While more common with older interferon treatments, some patients on DAA therapy report new or worsening depressive symptoms.
• Photosensitivity: Increased sensitivity of the skin to sunlight, leading to easier sunburn.
• Pancytopenia: A rare but serious condition where all types of blood cells (red, white, and platelets) decrease significantly.

> Warning: Stop taking Sofosbuvir and call your doctor immediately if you experience any of these serious symptoms.

• Symptomatic Bradycardia: A dangerously slow heart rate. This has been reported primarily when Sofosbuvir is taken with Amiodarone (a heart rhythm medication). Symptoms include fainting, dizziness, chest pain, and shortness of breath.
• Hepatitis B Reactivation: If you have ever had Hepatitis B, Sofosbuvir can cause that virus to become active again, leading to severe liver inflammation or failure. Watch for yellowing of the skin/eyes (jaundice), dark urine, or severe right-sided abdominal pain.
• Severe Allergic Reaction (Anaphylaxis): Symptoms include swelling of the face, lips, or tongue; difficulty breathing; or a widespread, blistering rash.
• Significant Cognitive Impairment: Confusion, extreme drowsiness, or difficulty concentrating that interferes with daily life.

Sofosbuvir is typically taken for a short duration (8-24 weeks), and long-term side effects are rare. The primary long-term outcome is the clearance of the HCV virus, which significantly reduces the risk of liver cancer and cirrhosis. However, patients who have already developed cirrhosis remain at risk for liver complications even after the virus is cured and should continue regular liver screenings.

Hepatitis B Virus (HBV) Reactivation Risk: The FDA has issued a Black Box Warning for all direct-acting antivirals, including Sofosbuvir. Before starting treatment, healthcare providers must test all patients for evidence of current or prior HBV infection. In patients with a history of HBV, the virus may reactivate during or after HCV treatment. Reactivation can lead to fulminant hepatitis, hepatic failure, and death. Patients should be monitored with blood tests for HBV flare-ups during Sofosbuvir therapy.

Report any unusual symptoms or side effects to your healthcare provider promptly. Many side effects are manageable with supportive care, and completing the full course of treatment is essential for a cure.

Sofosbuvir is a highly effective medication, but it must be used with caution in specific clinical scenarios. The most critical safety consideration is the risk of drug-drug interactions and the potential for viral reactivation. Patients must undergo thorough screening for other viral infections and cardiac conditions before initiating therapy. It is also vital to understand that Sofosbuvir does not prevent the transmission of hepatitis C to others through blood contact or sexual activity; appropriate precautions should continue during treatment.

Risk of Hepatitis B Virus Reactivation: According to the FDA, all patients must be screened for Hepatitis B (HBV) before starting Sofosbuvir. There have been cases where the HBV virus 'wakes up' or reactivates in patients who were co-infected with both HCV and HBV. This can occur because the two viruses compete; when Sofosbuvir suppresses HCV, the HBV is free to replicate rapidly. This can lead to severe liver damage, liver failure, or death. Monitoring of HBV DNA levels is required for at-risk patients.

• Bradycardia with Amiodarone: There is a critical warning regarding the use of Sofosbuvir with Amiodarone (a medication used for heart rhythm disorders). This combination can cause life-threatening slowing of the heart rate (bradycardia). This effect can occur within hours or up to two weeks after starting the combination. If no other heart medication options exist, patients must undergo continuous cardiac monitoring in a hospital for the first 48 hours of co-administration.
• Allergic Reactions: Patients with a known hypersensitivity to Sofosbuvir or any components of the formulation should not take the drug. Signs of a serious reaction include angioedema (swelling under the skin) and respiratory distress.
• Hepatic Monitoring: While Sofosbuvir is safe for the liver, the rapid clearance of HCV can sometimes lead to changes in liver function tests. Patients with advanced cirrhosis are at risk for hepatic decompensation and should be monitored closely for signs of jaundice or encephalopathy (confusion caused by liver toxin buildup).
• Diabetes Management: Some patients with diabetes may experience improved glucose control as the hepatitis C virus is cleared. This could potentially lead to hypoglycemia (low blood sugar) if diabetes medications are not adjusted. Close monitoring of blood glucose is recommended.

To ensure the safety and efficacy of Sofosbuvir, healthcare providers will order regular laboratory tests:

• HCV RNA Levels: To measure the viral load and confirm the drug is working.
• HBV DNA: To monitor for Hepatitis B reactivation.
• Liver Function Tests (LFTs): Including ALT, AST, and bilirubin levels to assess liver health.
• Renal Function: Monitoring serum creatinine and eGFR, especially in patients with pre-existing kidney disease.

Sofosbuvir itself generally does not impair the ability to drive. However, when combined with other medications like Ribavirin, side effects such as fatigue, dizziness, or blurred vision may occur. Patients should assess their reaction to the medication before performing tasks that require mental alertness.

Alcohol consumption is strongly discouraged during Sofosbuvir treatment. Alcohol causes additional stress and damage to the liver, which can interfere with the healing process and potentially reduce the effectiveness of the antiviral therapy. Discuss your alcohol history honestly with your doctor.

Unlike some medications, Sofosbuvir does not require a tapering period. However, it is vital not to stop the medication before the prescribed course is finished. Discontinuing early, even if the virus is undetectable in the blood, can lead to a relapse where the virus returns and may become resistant to future treatments.

> Important: Discuss all your medical conditions, especially heart rhythm problems or prior Hepatitis B infection, with your healthcare provider before starting Sofosbuvir.

Certain drugs can significantly reduce the levels of Sofosbuvir in the body, making the treatment ineffective and potentially leading to viral resistance. The following should NEVER be used with Sofosbuvir:

• Potent P-glycoprotein (P-gp) Inducers: Drugs like Rifampin (used for TB) and Rifabutin significantly lower Sofosbuvir plasma concentrations.
• Anticonvulsants: Carbamazepine, Phenytoin, and Phenobarbital are potent inducers that will reduce the efficacy of the antiviral treatment.

• Amiodarone: As mentioned in the warnings, this combination can cause fatal bradycardia. It is generally recommended to avoid this combination unless no other heart rhythm treatment is available.
• Statin Medications: Sofosbuvir, particularly when used in combination products, can increase the concentration of statins (like Rosuvastatin or Atorvastatin) in the blood, increasing the risk of myopathy (muscle damage) and rhabdomyolysis. Dose reduction of the statin may be necessary.
• Warfarin: Changes in liver function during HCV treatment can alter the way the body processes blood thinners. Frequent monitoring of the INR (International Normalized Ratio) is required.

• HIV Medications: Sofosbuvir is generally compatible with most HIV drugs, but certain combinations (like those containing Tenofovir Disoproxil Fumarate) may require monitoring for increased Tenofovir toxicity, which can affect the kidneys.
• Modafinil: This wakefulness-promoting agent may moderately decrease Sofosbuvir levels.

• General Food: Sofosbuvir can be taken with or without food. There are no known interactions with dairy or caffeine.
• Grapefruit: Unlike many other drugs, Sofosbuvir metabolism is not significantly affected by grapefruit juice, as it does not rely on the CYP3A4 enzyme pathway.
• Alcohol: While not a direct chemical interaction, alcohol should be avoided due to its toxic effects on the liver during the healing process.

• St. John’s Wort (*Hypericum perforatum*): This popular herbal supplement is a potent P-gp inducer. It can drastically lower the levels of Sofosbuvir in the blood, leading to treatment failure. It must be avoided entirely during therapy.
• Milk Thistle: While often used for 'liver support,' there is no evidence it helps during DAA therapy, and patients should consult their doctor before using it.

Sofosbuvir does not typically interfere with standard laboratory assays. However, as the virus is cleared, you may see a rapid normalization of liver enzymes (ALT/AST), which is a positive sign of treatment response rather than a drug-test interaction.

Mechanism of Interactions

The primary mechanism for Sofosbuvir interactions involves the P-glycoprotein (P-gp) transporter and the Breast Cancer Resistance Protein (BCRP). Sofosbuvir is a substrate for these transporters. Drugs that 'induce' or 'turn on' these transporters will pump Sofosbuvir out of the cells and into the gut or urine before it can reach the liver, leading to sub-therapeutic drug levels. Conversely, Sofosbuvir does not significantly inhibit the CYP450 enzyme system, which is why it has fewer interactions than older drugs.

> Important: Tell your doctor about ALL medications, including over-the-counter drugs, vitamins, and herbal products like St. John's Wort, before starting Sofosbuvir.

An absolute contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment due to the harm that it would cause the patient. For Sofosbuvir, these include:

• Hypersensitivity: Patients with a known severe allergic reaction to Sofosbuvir or any of its excipients (inactive ingredients) must not take the medication. Anaphylaxis or severe skin reactions are rare but constitute an absolute contraindication.
• Co-administration with Potent P-gp Inducers: Using Sofosbuvir with drugs like Rifampin or St. John's Wort is contraindicated because it virtually guarantees treatment failure. In clinical practice, this is treated as an absolute contraindication to avoid the development of drug-resistant HCV strains.
• Combination with Ribavirin/Interferon Contraindications: Because Sofosbuvir is rarely used alone, the contraindications for its 'partner drugs' apply. For example, if used with Ribavirin, pregnancy is an absolute contraindication due to Ribavirin's high risk of causing birth defects.

Relative contraindications require a careful risk-benefit analysis by a medical professional:

• Severe Bradycardia Risk: Patients currently taking Amiodarone. While not an absolute contraindication if no other options exist, it is avoided whenever possible due to the risk of cardiac arrest.
• Prior DAA Failure: Patients who have failed a previous course of Sofosbuvir-containing therapy may have developed 'Resistance-Associated Substitutions' (RASs). While not a safety contraindication, it may be a relative contraindication to using the same regimen again, requiring a switch to a more potent combination like Vosevi.
• Decompensated Cirrhosis: While Sofosbuvir is safe, the use of certain combination partners (like Protease Inhibitors) is contraindicated in Child-Pugh B or C patients. Sofosbuvir must be used with extreme care in these populations.

There is no known cross-sensitivity between Sofosbuvir and other classes of antivirals (like those used for Herpes or HIV). However, patients who have had allergic reactions to other HCV nucleotide analogs (though few exist) should be monitored closely.

> Important: Your healthcare provider will evaluate your complete medical history, including all allergies and previous treatment failures, before prescribing Sofosbuvir.

Sofosbuvir is classified as Pregnancy Category B (under the old FDA system). Animal studies have shown no evidence of fetal harm at doses much higher than the human therapeutic dose. However, there are no adequate, well-controlled studies in pregnant women.

Crucial Note: Sofosbuvir is almost always used with other drugs. If Sofosbuvir is used with Ribavirin, the combination is Category X and strictly contraindicated in pregnancy. Ribavirin causes significant birth defects and fetal death. Women of childbearing age and their male partners must use two forms of effective contraception during and for six months after treatment involving Ribavirin.

It is unknown whether Sofosbuvir or its metabolites pass into human breast milk. In animal studies, the metabolite GS-331007 was detected in the milk of lactating rats without adverse effects on the nursing pups. Because the risk to a human infant cannot be entirely ruled out, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for the drug.

As of 2020, the FDA expanded the use of Sofosbuvir to children as young as 3 years old. The drug has been shown to be safe and effective in this population, with cure rates (SVR) exceeding 90%. Growth and development do not appear to be affected by the short course of treatment. Pediatric patients require weight-based dosing and may use oral pellets if they cannot swallow tablets.

Clinical trials included a significant number of patients aged 65 and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. However, elderly patients are more likely to have decreased renal function and be taking multiple medications (polypharmacy), which increases the risk of drug interactions. No specific dose adjustment is needed based solely on age.

Historically, Sofosbuvir was not recommended for patients with an eGFR < 30 mL/min. However, based on the renally impaired cohort data from recent trials, the FDA updated the label in 2019. Sofosbuvir 400 mg once daily is now considered safe for patients with severe renal impairment and those on dialysis. No dose adjustment is required, but these patients should be managed by a specialist.

Sofosbuvir is safe for patients with all stages of liver disease. No dose adjustment is required for mild, moderate, or severe hepatic impairment. In patients with decompensated cirrhosis, Sofosbuvir is often used in combination with Ribavirin for 12 to 24 weeks. These patients require frequent monitoring for signs of worsening liver failure, such as ascites (fluid in the abdomen) or hepatic encephalopathy.

> Important: Special populations require individualized medical assessment. Always inform your doctor if you are pregnant, planning to become pregnant, or have underlying kidney issues.

Sofosbuvir is a direct-acting antiviral (DAA) agent. Specifically, it is a nucleotide analog inhibitor of the HCV NS5B RNA-dependent RNA polymerase. The NS5B protein is an essential enzyme required for the replication of the viral genome.

Sofosbuvir is a phosphoramidate prodrug of a uridine nucleotide analog. Once it enters a liver cell, it is metabolized into the active uridine triphosphate (GS-461203). This active metabolite serves as a 'fake' building block for viral RNA. During viral replication, the NS5B polymerase incorporates GS-461203 into the growing RNA strand. Because the Sofosbuvir molecule lacks the 3'-hydroxyl group necessary for the addition of the next nucleotide, the RNA chain is terminated prematurely. This prevents the virus from creating functional copies of itself.

• Antiviral Activity: Sofosbuvir exhibits high potency against HCV genotypes 1-6. In cell culture, the EC50 (concentration required to inhibit 50% of viral growth) ranges from 14 to 110 nM.
• Resistance: The primary resistance mutation associated with Sofosbuvir is the S282T substitution in the NS5B gene. However, this mutation is rarely seen in clinical practice because it significantly reduces the 'fitness' or ability of the virus to replicate.
• Cardiac Effects: At doses three times the therapeutic dose, Sofosbuvir does not prolong the QT interval (a measure of heart rhythm safety).

| Parameter | Value |

|---|---|

| Bioavailability | High (not precisely quantified, but rapid absorption) |

| Protein Binding | 61% - 65% |

| Half-life (Parent) | 0.4 hours |

| Half-life (Metabolite GS-331007) | 27 hours |

| Tmax | 0.5 - 2 hours |

| Metabolism | Intracellular activation; not CYP450 dependent |

| Excretion | Renal 80%, Fecal 14%, Expired Air 2.5% |

• Molecular Formula: C22H29FN3O9P
• Molecular Weight: 529.45 g/mol
• Solubility: Highly soluble in water and organic solvents like ethanol.
• Structure: It is a white to off-white crystalline solid. Chemically, it is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate.

Sofosbuvir is the first-in-class HCV NS5B nucleotide polymerase inhibitor. It is distinct from 'non-nucleoside' inhibitors, which bind to different sites on the enzyme. Other drugs in the DAA category include NS5A inhibitors (like Ledipasvir) and NS3/4A protease inhibitors (like Grazoprevir).