Ledipasvir And Sofosbuvir

FDA Drug Information • Also known as: Harvoni, Ledipasvir And Sofosbuvir

Brand Names: Harvoni, Ledipasvir And Sofosbuvir
Drug Class: Hepatitis C Virus NS5A Inhibitor [EPC], Hepatitis C Virus Nucleotide Analog NS5B Polymerase 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 ledipasvir and sofosbuvir. 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 Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are fixed-dose combination tablets containing ledipasvir and sofosbuvir for oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Ledipasvir: The IUPAC name for ledipasvir is methyl [(2 S )-1-{(6 S )-6-[5-(9,9-difluoro-7-{2-[(1 R ,3 S ,4 S )-2-{(2 S )-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1 H -benzimidazol-6-yl}-9 H -fluoren-2-yl)-1 H -imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate. It has a molecular formula of C 49 H 54 F 2 N 8 O 6 and a molecular weight of 889.00. It has the following structural formula: Ledipasvir is practically insoluble (less than 0.1 mg/mL) across the pH range of 3.0–7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL). Chemical Structure 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. Chemical Structure

What Is Ledipasvir And Sofosbuvir Used For?

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

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 ) Recommended treatment regimen and duration in patients 3 years of age and older: ( 2.2 ) HCV Genotype Patient Population Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Treatment-experienced without cirrhosis Ledipasvir and sofosbuvir 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 24 weeks Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Recommended dosage in adults: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food. ( 2.3 ) Recommended dosage in pediatric patients 3 years and older: Recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older is based on weight. Refer to Table 2 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.4 ) Instructions for Use should be followed for preparation and administration of ledipasvir and sofosbuvir (HARVONI) oral pellets. ( 2.5 ) HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables in the full prescribing information. ( 2.3 , 2.4 ) If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. ( 2.3 , 2.4 ) For patients with any degree of renal impairment, including end stage renal disease on dialysis, no ledipasvir and sofosbuvir dosage adjustment is recommended. ( 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 ledipasvir and sofosbuvir [see Warnings and Precautions (5.1) ] . 2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV Table 1 shows the recommended ledipasvir and sofosbuvir treatment regimen and duration based on patient population . Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14) ]. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1 [see Clinical Studies (14) ]. Refer to Drug Interactions (7) for dosage recommendations for...

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 with treatment with ledipasvir and sofosbuvir were fatigue, headache, and asthenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Asegua Therapeutics at 1-800-445-3235 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 ledipasvir and sofosbuvir is administered with ribavirin to adults, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects The safety assessment of ledipasvir and sofosbuvir was based on pooled data from three randomized, open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1 HCV with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth for 8, 12, and 24 weeks, respectively [see Clinical Studies (14) ]. The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, less than 1%, and 1% for subjects receiving ledipasvir and sofosbuvir for 8, 12, and 24 weeks, respectively. The most common adverse reactions (at least 10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of ledipasvir and sofosbuvir. Table 4 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks of treatment with ledipasvir and sofosbuvir in clinical trials. The majority of adverse reactions presented in Table 4 occurred at severity of grade 1. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 4 Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with Ledipasvir and Sofosbuvir Ledipasvir and Sofosbuvir 8 weeks (N=215) Ledipasvir and Sofosbuvir 12 weeks (N=539) Ledipasvir and Sofosbuvir 24 weeks (N=326) Fatigue 16% 13% 18% Headache 11% 14% 17% Nausea 6% 7% 9% Diarrhea 4% 3% 7% Insomnia 3% 5% 6% The safety assessment of ledipasvir and sofosbuvir was also based on pooled data from three open-label trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis) [see Clinical Studies (14.3) ] . The subjects received ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth for 12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease was similar to that observed in subjects with chronic HCV genotype 1 infection with compensated liver disease. The most common adverse reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%), and fatigue (10%). Adverse Reactions in Subjects with Cirrhosis The safety assessment of ledipasvir and sofosbuvir with or without ribavirin was based on a randomized, double-blind and placebo-controlled trial in treatment-experienced genotype 1 subjects with compensated cirrhosis and was compared to placebo in the SIRIUS trial . Subjects were randomized to receive 24 weeks of ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of ledipasvir and sofosbuvir tablets (90 mg/400 mg) once daily by mouth + ribavirin...

Drug Interactions

7 DRUG INTERACTIONS Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of ledipasvir and sofosbuvir with amiodarone is not recommended. ( 5.2 , 6.2 , 7.2 ) P-gp inducers (e.g., rifampin, St. John's wort): May alter concentrations of ledipasvir and sofosbuvir. Use of ledipasvir and sofosbuvir with P-gp inducers is not recommended. ( 5.3 , 7 , 12.3 ) Consult the full prescribing information prior to use for potential drug interactions. ( 5.2 , 5.3 , 7 , 12.3 ) 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. ( 7.2 ) 7.1 Potential for Drug Interaction Any interactions that have been identified with ledipasvir or sofosbuvir individually may occur with ledipasvir and sofosbuvir. After oral administration of ledipasvir and sofosbuvir, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic analyses. Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin, St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of ledipasvir and sofosbuvir, and the use with P-gp inducers is not recommended with ledipasvir and sofosbuvir [see Warnings and Precautions (5.3) ] . 7.2 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 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions...

Contraindications

4 CONTRAINDICATIONS If ledipasvir and sofosbuvir is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin [see Dosage and Administration (2.2) ] . If used in combination with ribavirin, all contraindications to ribavirin also apply to ledipasvir and sofosbuvir combination therapy. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary If ledipasvir and sofosbuvir 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 ledipasvir and sofosbuvir pose a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with ledipasvir or sofosbuvir at exposures greater than those in humans at the recommended human dose (RHD) [see Data ] . During organogenesis in the rat and rabbit, systemic exposures (AUC) to ledipasvir were approximately 4 (rats) and 2 (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥3 (rats) and 7 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) to ledipasvir and GS-331007 were approximately 5 and 7 times, respectively, the exposure 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 Animal Data Ledipasvir: Ledipasvir was administered orally to pregnant rats (up to 100 mg/kg/day) and rabbits (up to 180 mg/kg/day) on gestation days 6 to 18 and 7 to 20, respectively, and also to rats (oral doses up to 100 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. Systemic exposures (AUC) to ledipasvir were ≥4 (rats) and 2 (rabbits) times the exposure in humans at the RHD. Sofosbuvir:...

Overdosage

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

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are orange, diamond-shaped, film-coated, debossed with "ASE" on one side and "9875" on the other side of the tablet. Each carton contains 28 tablets (2 blister cards each containing 14 tablets) (NDC 72626-2601-1). Store at room temperature below 30 °C (86 °F).

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.