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💊 LEDIPASVIR AND SOFOSBUVIR

☠ BLACK BOX WARNING
Generic: LEDIPASVIR AND SOFOSBUVIR
ORAL FDA Label
☠
FDA BLACK BOX WARNING

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 w…

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RouteORAL
ManufacturerAsegua Therapeutics LLC
SourceFDA Label
✅ Indications & Usage ›

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 & 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 re... [See full FDA label]

🚫 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 )

⚠️ Warnings & Precautions ›

5 WARNINGS AND PRECAUTIONS Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. ( 5.1 ) Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with ledipasvir and sofosbuvir is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. ( 5.2 , 6.2 , 7.2 )

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, li... [See full FDA label]

🔴 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,... [See full FDA label]

💊 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 chang... [See full FDA label]

🤰 Pregnancy ›

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:... [See full FDA label]

👶 Pediatric Use ›

8.4 Pediatric Use The safety, pharmacokinetics, and efficacy of ledipasvir and sofosbuvir for treatment of HCV genotype 1 and 4 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=226; 186 treatment-naïve, 40 treatment-experienced) and are comparable to that observed in adults. The safety and efficacy of ledipasvir and sofosbuvir for treatment of HCV genotypes 5 or 6 infection in pediatric patients 3 years of age and older are supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and pediatric patients [see Dosage and Administration (2.2 and 2.4) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.3 , 14.6 , 14.7) ] . Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1 infection who have decompensated cirrhosis (Child-Pugh B or C) and for pediatric patients with HCV genotype 1 and 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis. In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical Pharmacology (12.3) ]. No data are available regarding the safety of ledipasvir and sofosbuvir in pediatric patients with renal impairment [see Use in Specific Populations (8.6) ]. The safety and efficacy of ledipasvir and sofosbuvir have not been established in pediatric patients less than 3 years of age. In a 5-year follow-up study, the long-term effects of ledipasvir and sofosbuvir on pediatric growth were assessed in 178 pediatric subjects 3 years of age and older treated with ledipasvir and sofosbuvir in Study 1116. No notable effects on growth from baseline through end of study were observed [see Adverse Reactions (6.1) ] . All subje... [See full FDA label]

👴 Geriatric Use ›

8.5 Geriatric Use Clinical trials of ledipasvir and sofosbuvir included 225 subjects aged 65 and over (9% of total number of subjects in the clinical studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of ledipasvir and sofosbuvir is warranted in geriatric patients [see Clinical Pharmacology (12.3) ] .

🔬 Mechanism of Action ›

12.1 Mechanism of Action Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4) ].

📊 Pharmacokinetics ›

12.3 Pharmacokinetics Absorption The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of ledipasvir and sofosbuvir tablets (90 mg/400 mg), ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose. Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric mean steady-state AUC 0 • 24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng∙hr/mL, respectively. Steady-state C max for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC 0 • 24 and C max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191), ledipasvir AUC 0 • 24 and C max were 24% lower and 32% lower, respectively, in HCV-infected subjects. Effect of Food Relative to fasting conditions, the administration of a single dose of ledipasvir and sofosbuvir tablets (90 mg/400 mg) with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC 0 • inf by approximately 2-fold, but did not significantly affect sofosbuvir C max . The exposures of GS-331007 and ledipasvir were not altered in the presence of either meal type. The response rates in Phase 3 trials were similar in HCV-infected subjects who received ledipasvir and sofosbuvir tablets (90 mg/400 mg) with food or without food. Ledipasvir and sofosbuvir can be administered without regard to food. Distribution Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of [ 14 C]-ledipasvir in healthy sub... [See full FDA label]

☠️ 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%.

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