Velpatasvir And Sofosbuvir

FDA Drug Information • Also known as: Epclusa, Sofosbuvir And Velpatasvir

Brand Names: Epclusa, Sofosbuvir And Velpatasvir
Drug Class: Hepatitis C Virus Nucleotide Analog NS5B Polymerase Inhibitor [EPC], Hepatitis C Virus NS5A Inhibitor [EPC]
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions (5.1) ] . WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete boxed warning. Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. ( 5.1 )

Description

11 DESCRIPTION Tablets EPCLUSA is a fixed-dose combination tablet containing sofosbuvir and velpatasvir for oral administration. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor and velpatasvir is an NS5A inhibitor. Each 400 mg/100 mg tablet contains 400 mg sofosbuvir and 100 mg velpatasvir, and each 200 mg/50 mg tablet contains 200 mg sofosbuvir and 50 mg velpatasvir. The tablets include the following inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Pellets EPCLUSA oral pellets are for oral administration, supplied as small, white to off-white pellets in unit-dose packets. Each unit-dose of EPCLUSA oral pellets contains either 200 mg sofosbuvir and 50 mg velpatasvir or 150 mg sofosbuvir and 37.5 mg velpatasvir and the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The oral pellets are film-coated with a coating material containing the following inactive ingredients: amino methacrylate copolymer, colloidal silicon dioxide, hypromellose, L-tartaric acid, polyethylene glycol, stearic acid, talc, and titanium dioxide. Sofosbuvir: The IUPAC name for sofosbuvir is ( S )-isopropyl 2-(( S )-(((2 R ,3 R ,4 R ,5 R )-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C 22 H 29 FN 3 O 9 P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir is a white to off-white crystalline solid with a solubility of at least 2 mg/mL across the pH range of 2–7.7 at 37 °C and is slightly soluble in water. Velpatasvir: The IUPAC name for velpatasvir is methyl {(1 R )-2-[(2...

What Is Velpatasvir And Sofosbuvir Used For?

1 INDICATIONS AND USAGE EPCLUSA is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection [see Dosage and Administration (2.2 , 2.3 , 2.4) and Clinical Studies (14) ] : without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin. EPCLUSA is a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, and velpatasvir, an HCV NS5A inhibitor, and is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection ( 1 ): without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Testing prior to the initiation of therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. ( 2.1 ) See recommended treatment regimen and duration in patients 3 years of age and older with genotypes 1, 2, 3, 4, 5, or 6 HCV in table below: ( 2.2 ) Patient Population Regimen and Duration Treatment-naïve and treatment-experienced In clinical trials, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). , without cirrhosis and with compensated cirrhosis (Child-Pugh A) EPCLUSA 12 weeks Treatment-naïve and treatment-experienced , with decompensated cirrhosis (Child-Pugh B and C) EPCLUSA + ribavirin 12 weeks Recommended dosage in adults: One tablet (400 mg of sofosbuvir and 100 mg of velpatasvir) taken orally once daily with or without food. ( 2.3 ) Recommended dosage in pediatric patients 3 years and older: Recommended dosage is based on weight. Refer to Table 2 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.4 ) For pediatric patients less than 6 years of age, administer EPCLUSA oral pellets with food. ( 2.4 ) Instructions for Use should be followed for preparation and administration of EPCLUSA oral pellets. ( 2.5 ) HCV/HIV-1 coinfection: For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the table above. ( 2.2 ) For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is EPCLUSA once daily for 12 weeks. ( 2.2 ) If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. ( 2.3 , 2.4 ) For patients with renal impairment including end stage renal disease on dialysis, follow the dosage recommendations in the table above. ( 2.6 ) 2.1 Testing Prior to the Initiation of Therapy Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with EPCLUSA [see Warnings and Precautions (5.1) ]. 2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older Table 1 shows the recommended treatment regimen and duration based on patient population . For patients with HCV/HIV-1 coinfection follow the dosage recommendations in Table 1. For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is EPCLUSA once daily for 12 weeks [see Clinical Studies (14.3 and 14.5) ]. Refer to Drug Interactions (7) for dosage recommendations for concomitant drugs. Table 1 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Patient Population Treatment Regimen and Duration Treatment-naïve and treatment-experienced In...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2) ]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed in adults and pediatric subjects 6 years of age and older with treatment with EPCLUSA for 12 weeks are headache and fatigue. ( 6.1 ) The most common adverse reactions (incidence greater than or equal to 10%, grade 1 or 2) observed in pediatric subjects less than 6 years of age are vomiting and product use issue (spitting up the drug). ( 6.1 ) The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with EPCLUSA and ribavirin for 12 weeks in adult patients with decompensated cirrhosis are fatigue, anemia, nausea, headache, insomnia, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. If EPCLUSA is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects Adverse Reactions in Subjects without Cirrhosis or with Compensated Cirrhosis The adverse reactions data for EPCLUSA in patients without cirrhosis or with compensated cirrhosis were derived from three Phase 3 clinical trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3) which evaluated a total of 1035 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis, who received EPCLUSA for 12 weeks. EPCLUSA was studied in placebo- and active-controlled trials [see Clinical Studies (14.2) ] . The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received EPCLUSA for 12 weeks. The most common adverse reactions (adverse events assessed as causally related by the investigator and at least 10%) were headache and fatigue in subjects treated with EPCLUSA for 12 weeks. Adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with EPCLUSA in ASTRAL-1 include headache (22%), fatigue (15%), nausea (9%), asthenia (5%), and insomnia (5%). Of subjects receiving EPCLUSA who experienced these adverse reactions, 79% had an adverse reaction of mild severity (Grade 1). With the exception of asthenia, each of these adverse reactions occurred at a similar frequency or more frequently in subjects treated with placebo compared to subjects treated with EPCLUSA (asthenia: 3% versus 5% for the placebo and EPCLUSA groups, respectively). The adverse reactions observed in subjects treated with EPCLUSA in ASTRAL-2 and ASTRAL-3 were consistent with those observed in ASTRAL-1. Irritability was also observed in greater than or equal to 5% of subjects treated with EPCLUSA in ASTRAL-3. Adverse Reactions in Subjects Coinfected with HCV and HIV-1 The safety assessment of EPCLUSA in subjects with HCV/HIV-1 coinfection was based on an open-label clinical trial (ASTRAL-5) in 106 subjects who were on stable antiretroviral therapy [see Clinical Studies (14.3) ] . The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were fatigue (22%) and headache (10%). Adverse Reactions in Subjects with Decompensated Cirrhosis The safety assessment of EPCLUSA in subjects infected with genotype 1, 2, 3, 4, or 6 HCV with decompensated cirrhosis was based on one Phase 3 trial (ASTRAL-4) including...

Drug Interactions

7 DRUG INTERACTIONS P-gp inducers and/or moderate to strong CYP inducers (e.g., rifampin, St. John's wort, carbamazepine): May decrease concentrations of sofosbuvir and/or velpatasvir. Use of EPCLUSA with P-gp inducers and/or moderate to strong CYP inducers is not recommended. ( 5.3 , 7 ) Consult the full prescribing information prior to use for potential drug interactions. ( 5.2 , 5.3 , 7 ) Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. ( 7.3 ) 7.1 Potential for Other Drugs to Affect EPCLUSA Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John's wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . EPCLUSA may be coadministered with P-gp, BCRP, and CYP inhibitors. 7.2 Potential for EPCLUSA to Affect Other Drugs Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of EPCLUSA with drugs that are substrates of these transporters may increase the exposure of such drugs. 7.3 Established and Potentially Significant Drug Interactions Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 4 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either EPCLUSA, the components of EPCLUSA...

Contraindications

4 CONTRAINDICATIONS EPCLUSA and ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin [see Dosage and Administration (2.2 , 2.3 , 2.4) ]. EPCLUSA and ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary If EPCLUSA is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy. No adequate human data are available to establish whether or not EPCLUSA poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of EPCLUSA (sofosbuvir or velpatasvir) at exposures greater than those in humans at the recommended human dose (RHD) [see Data ] . During organogenesis in the mouse, rat, and rabbit, systemic exposures (AUC) to velpatasvir were approximately 31 (mice), 6 (rats), and 0.4 (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were approximately 4 (rats) and 10 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) to velpatasvir and GS-331007 were approximately 5 times the exposures of each component in humans at the RHD. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. The systemic exposures (AUC) of the predominant circulating metabolite of sofosbuvir (GS-331007) during...

Overdosage

10 OVERDOSAGE No specific antidote is available for overdose with EPCLUSA. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with EPCLUSA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of velpatasvir since velpatasvir is highly bound to plasma protein.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets EPCLUSA tablets, 400 mg/100 mg, are pink, diamond-shaped, film-coated, debossed with "GSI" on one side and "7916" on the other. Each bottle contains 28 tablets (NDC 61958-2201-1), polyester coil, and is closed with a child-resistant closure. EPCLUSA tablets, 200 mg/50 mg, are pink, oval-shaped, film-coated, debossed with "GSI" on one side and "S/V" on the other. Each bottle contains 28 tablets (NDC 61958-2203-1), polyester coil, and is closed with a child-resistant closure. Store below 30 °C (86 ºF). Dispense only in original container. Oral Pellets EPCLUSA oral pellets, 200 mg/50 mg, are white to off-white, film-coated pellets supplied as unit-dose packets in cartons. Each carton contains 28 packets (NDC 61958-2204-1). EPCLUSA oral pellets, 150 mg/37.5 mg, are white to off-white, film-coated pellets supplied as unit-dose packets in cartons. Each carton contains 28 packets (NDC 61958-2205-1). Store below 30 °C (86 ºF). Do not use if carton tamper-evident seal or packet has been opened or damaged.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.