Ledipasvir And Sofosbuvir Tablets

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.

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%).

Store at room temperature below 30 °C (86 °F).

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%.

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.

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 subjects who had achieved SVR12 maintained SVR through end of study.

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)].

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)].

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)].

• 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)

No dosage adjustment of ledipasvir and sofosbuvir tablets (90 mg/400 mg) is recommended in patients with any degree of renal impairment, including end stage renal disease (ESRD) on dialysis [see Dosage and Administration (2.3)]. Take ledipasvir and sofosbuvir tablets (90 mg/400 mg) with or without ribavirin according to the recommendations in Table 1 [see Adverse Reactions (6.1), Use in Specific Populations (8.6) and Clinical Studies (14.6)]. Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.

No dosage adjustment of ledipasvir and sofosbuvir is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)]. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including those on dialysis. Additionally, no safety data are available in pediatric patients with renal impairment [see Use in Specific Populations (8.4)]. Refer to ribavirin tablet prescribing information regarding use in patients with renal impairment.

No dosage adjustment of ledipasvir and sofosbuvir is recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3) and Clinical Studies (14.5)].

Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with ledipasvir and sofosbuvir and ribavirin [see Adverse Reactions (6.1)].

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 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)].

• 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)

• 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)

• 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)

Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are available as orange, diamond-shaped, film-coated tablets debossed with "ASE" on one side and "9875" on the other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.

The following adverse reactions have been identified during post approval use of ledipasvir and sofosbuvir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Pediatric Use: No data are available regarding the safety of ledipasvir and sofosbuvir in pediatric patients with renal impairment. (8.4)

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.

The recommended dosage of ledipasvir and sofosbuvir in adults with genotype 1, 4, 5 or 6 HCV is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3)].

The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food.

In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels.

For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information [see Dosage and Administration (2.4), Use in Specific Populations (8.6), and Clinical Studies (14.5)].

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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)].

The efficacy and safety of ledipasvir and sofosbuvir were evaluated in four trials in genotype 1 HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A); one trial in genotype 1 or 4 HCV/HIV-1 coinfected subjects; two trials in genotype 4, 5, or 6 HCV mono-infected subjects; two trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis (FCH); two trials in subjects with severe renal impairment (one of which included subjects requiring dialysis); and one trial in genotype 1 or 4 HCV pediatric subjects 3 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table 10 [see Clinical Studies (14.2, 14.3, 14.4, 14.5, 14.6, and 14.7)]:

Ledipasvir and sofosbuvir was administered once daily by mouth in these trials. For subjects without cirrhosis or with compensated cirrhosis who received ribavirin, the ribavirin dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing at least 75 kg. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day regardless of transplantation status. Ribavirin dose adjustments were performed according to the ribavirin labeling.

Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1, ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies. The COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has a lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in studies in adults and the key efficacy endpoint in the study in pediatric subjects 12 years of age and older. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.

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).

The efficacy of ledipasvir and sofosbuvir was evaluated in an open-label trial (Study 1116) in 224 HCV treatment-naïve (N=186) and treatment-experienced (N=38) pediatric subjects 3 years of age or older. This study evaluated 12 weeks of treatment with ledipasvir and sofosbuvir once daily in genotype 1 (N=183) or genotype 4 (N=3) treatment-naive subjects without cirrhosis or with compensated cirrhosis; genotype 1 treatment-experienced subjects without cirrhosis (N=37); and evaluated 24 weeks of treatment with ledipasvir and sofosbuvir once daily in one genotype 1 subject who was both treatment-experienced and cirrhotic.

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)].

If ledipasvir and sofosbuvir is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

If ledipasvir and sofosbuvir is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin [see Dosage and Administration (2.2)].

NDC 72626-2601-1

ASEGUA™

THERAPEUTICS

Ledipasvir and Sofosbuvir

90 mg / 400 mg

tablets

Take 1 tablet once daily

Rx only

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that should

NOT be taken with Ledipasvir and Sofosbuvir

Contents:

Two blister cards

Each blister card contains 14 tablets.

Authorized generic of Harvoni^®

Below are trial descriptions, SVR12 and relapse data in the genotype 4, 5, and 6 HCV populations. Trial results in the genotype 4, 5, and 6 HCV populations are based upon limited number of subjects in some subgroups, particularly in subjects who have been previously treated and subjects with cirrhosis.

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 described are based on studies conducted with either ledipasvir and sofosbuvir tablets (90 mg/400 mg) or ledipasvir and sofosbuvir as individual agents, or are predicted drug interactions that may occur with ledipasvir and sofosbuvir [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg) without ribavirin in HCV treatment-naïve and previously treated adult subjects with genotype 1 or 4 HCV infection who were coinfected with HIV-1. Treatment-experienced subjects had failed prior treatment with Peg-IFN + ribavirin, Peg-IFN + ribavirin + an HCV protease inhibitor, or sofosbuvir + ribavirin. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine, or raltegravir.

Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the subjects were male; 61% were White; 34% were Black; mean body mass index was 27 kg/m² (range: 18 to 66 kg/m²); 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of the subjects were treatment-experienced.

Table 18 presents the SVR12 in the ION-4 trial after 12 weeks of ledipasvir and sofosbuvir treatment.

SVR12 rates were 94% (63/67) in subjects with cirrhosis and 98% (46/47) in subjects who were previously treated and had cirrhosis. The relapse rate in the ION-4 trial in Black subjects was 9% (10/115), all of whom were IL28B non-CC genotype, and none in non-Black subjects (0/220). In the ION-1, ION-2, and ION-3 HCV mono-infection studies, relapse rates were 3% (10/305) in Black subjects and 2% (26/1637) in non-Black subjects.

No subject had HIV-1 rebound during the study. The percentage of CD4+ cells did not change during treatment. Median CD4+ cell count increase of 29 cells/mm³ was observed at the end of treatment with ledipasvir and sofosbuvir tablets for 12 weeks.

The concomitant use of ledipasvir and sofosbuvir and P-gp inducers may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of ledipasvir and sofosbuvir. Therefore, the use of ledipasvir and sofosbuvir with P-gp inducers (e.g., rifampin, St. John's wort) is not recommended [see Drug Interactions (7.2)].

The recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older with genotype 1, 4, 5, or 6 HCV is based on weight (Table 2). Table 3 provides the weight-based dosage of ribavirin when used in combination with ledipasvir and sofosbuvir for pediatric patients. Take ledipasvir and sofosbuvir (with or without food) once daily [see Dosage and Administration (2.5), Clinical Pharmacology (12.3), and Clinical Studies (14.7)]. Ledipasvir and sofosbuvir (HARVONI) oral pellets can be taken in pediatric patients who cannot swallow the tablet formulation.

Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with ledipasvir and sofosbuvir. Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease, may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Coadministration of amiodarone with ledipasvir and sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered ledipasvir and sofosbuvir:

• Counsel patients about the risk of serious symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking ledipasvir and sofosbuvir who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting ledipasvir and sofosbuvir should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems [see Adverse Reactions (6.2), Drug Interactions (7.2)].

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, liver failure, and death can occur.

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with ledipasvir and sofosbuvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with ledipasvir and sofosbuvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Based on drug interaction studies conducted with ledipasvir, sofosbuvir, or ledipasvir and sofosbuvir tablets (90 mg/400 mg) no clinically significant drug interactions have been either observed or are expected when ledipasvir and sofosbuvir is used with the following drugs [see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, lamivudine, methadone, midazolam, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 6 for use of ledipasvir and sofosbuvir with certain HIV antiretroviral regimens [see Drug Interactions (7.2)].

See the ledipasvir and sofosbuvir (HARVONI) oral pellets full Instructions for Use for details on the preparation and administration of ledipasvir and sofosbuvir (HARVONI) pellets.

Do not chew ledipasvir and sofosbuvir (HARVONI) oral pellets. If ledipasvir and sofosbuvir (HARVONI) oral pellets are administered with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice cream. Take ledipasvir and sofosbuvir (HARVONI) oral pellets within 30 minutes of gently mixing with food and swallow the entire contents without chewing to avoid a bitter aftertaste.

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)].

Trial 0154 was an open-label clinical trial that evaluated 12 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg) in 18 treatment-naïve and treatment-experienced (subjects with prior exposure to an HCV NS5B polymerase inhibitor were excluded) genotype 1 HCV-infected adults with severe renal impairment not requiring dialysis. At baseline, two subjects (11%) had cirrhosis and the mean eGFR was 24.9 mL/min (range: 9.0 to 39.6). The SVR rate was 100% (18/18).

As shown in the table below, Trial 4063 was an open-label three-arm clinical trial that evaluated 8, 12, and 24 weeks of treatment with ledipasvir and sofosbuvir in a total of 63 adults with chronic HCV infection and ESRD requiring dialysis. Of the 63 subjects, 10% had cirrhosis, 24% were treatment-experienced, 95% were on hemodialysis, and 5% were on peritoneal dialysis; mean duration on dialysis was 12 years (range: 0.2 to 43 years). The SVR rates for the 8, 12, and 24 week ledipasvir and sofosbuvir treatment groups are shown in Table 20.

SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg) in combination with ribavirin in HCV treatment-naïve and previously treated adult subjects with genotype 1 and 4 infection who had undergone liver transplantation and/or who had decompensated liver disease. The two trials were identical in study design. Subjects were enrolled in one of the seven groups in the trials based on liver transplantation status and severity of hepatic impairment (see Table 19). Subjects with a CPT score greater than 12 were excluded. Within each group, subjects were randomized in a 1:1 ratio to receive ledipasvir and sofosbuvir + ribavirin for 12 weeks or ledipasvir and sofosbuvir + ribavirin for 24 weeks. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day regardless of transplantation status. Ribavirin dose adjustments were performed according to the ribavirin labeling [see Clinical Studies (14.1)].

Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the subjects were male; 91% were White; mean body mass index was 28 kg/m² (range: 18 to 49 kg/m²); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of the subjects failed a prior HCV therapy.

Table 19 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with genotype 1 HCV treated with ledipasvir and sofosbuvir + ribavirin for 12 weeks. The SVR12 rates observed with 24 weeks of ledipasvir and sofosbuvir + ribavirin were similar to the SVR12 rates observed with 12 weeks of treatment. Therefore, the results for the ledipasvir and sofosbuvir + ribavirin 24 weeks arm are not presented in Table 19.

There were 7 subjects with fibrosing cholestatic hepatitis in the 12-week treatment arm, and all subjects achieved SVR12.

In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated cirrhosis treated with ledipasvir and sofosbuvir + ribavirin for 12 weeks (N=12), the SVR12 rate was similar to rates reported with genotype 1; no subjects relapsed. Available data in subjects with genotype 4 HCV who had decompensated cirrhosis (pre- and post-liver transplantation) were insufficient for dosing recommendations; therefore, these results are not presented.

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 concomitant HIV-1 antiviral drugs.

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.

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%).

Store at room temperature below 30 °C (86 °F).

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%.

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.

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 subjects who had achieved SVR12 maintained SVR through end of study.

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)].

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)].

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)].

• 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)

No dosage adjustment of ledipasvir and sofosbuvir tablets (90 mg/400 mg) is recommended in patients with any degree of renal impairment, including end stage renal disease (ESRD) on dialysis [see Dosage and Administration (2.3)]. Take ledipasvir and sofosbuvir tablets (90 mg/400 mg) with or without ribavirin according to the recommendations in Table 1 [see Adverse Reactions (6.1), Use in Specific Populations (8.6) and Clinical Studies (14.6)]. Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.

No dosage adjustment of ledipasvir and sofosbuvir is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)]. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including those on dialysis. Additionally, no safety data are available in pediatric patients with renal impairment [see Use in Specific Populations (8.4)]. Refer to ribavirin tablet prescribing information regarding use in patients with renal impairment.

No dosage adjustment of ledipasvir and sofosbuvir is recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3) and Clinical Studies (14.5)].

Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with ledipasvir and sofosbuvir and ribavirin [see Adverse Reactions (6.1)].

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 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)].

• 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)

• 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)

• 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)

Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are available as orange, diamond-shaped, film-coated tablets debossed with "ASE" on one side and "9875" on the other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.

The following adverse reactions have been identified during post approval use of ledipasvir and sofosbuvir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Pediatric Use: No data are available regarding the safety of ledipasvir and sofosbuvir in pediatric patients with renal impairment. (8.4)

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.

The recommended dosage of ledipasvir and sofosbuvir in adults with genotype 1, 4, 5 or 6 HCV is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3)].

The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food.

In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels.

For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information [see Dosage and Administration (2.4), Use in Specific Populations (8.6), and Clinical Studies (14.5)].

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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)].

The efficacy and safety of ledipasvir and sofosbuvir were evaluated in four trials in genotype 1 HCV mono-infected subjects including one trial exclusively in treatment-experienced subjects with compensated cirrhosis (Child-Pugh A); one trial in genotype 1 or 4 HCV/HIV-1 coinfected subjects; two trials in genotype 4, 5, or 6 HCV mono-infected subjects; two trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0–F3 fibrosis, compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis (FCH); two trials in subjects with severe renal impairment (one of which included subjects requiring dialysis); and one trial in genotype 1 or 4 HCV pediatric subjects 3 years of age and older without cirrhosis or with compensated cirrhosis, as summarized in Table 10 [see Clinical Studies (14.2, 14.3, 14.4, 14.5, 14.6, and 14.7)]:

Ledipasvir and sofosbuvir was administered once daily by mouth in these trials. For subjects without cirrhosis or with compensated cirrhosis who received ribavirin, the ribavirin dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing at least 75 kg. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day regardless of transplantation status. Ribavirin dose adjustments were performed according to the ribavirin labeling.

Serum HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1, ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies. The COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has a lower limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in studies in adults and the key efficacy endpoint in the study in pediatric subjects 12 years of age and older. Relapse was a secondary endpoint, which was defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or last available post-treatment measurement during the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.

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).

The efficacy of ledipasvir and sofosbuvir was evaluated in an open-label trial (Study 1116) in 224 HCV treatment-naïve (N=186) and treatment-experienced (N=38) pediatric subjects 3 years of age or older. This study evaluated 12 weeks of treatment with ledipasvir and sofosbuvir once daily in genotype 1 (N=183) or genotype 4 (N=3) treatment-naive subjects without cirrhosis or with compensated cirrhosis; genotype 1 treatment-experienced subjects without cirrhosis (N=37); and evaluated 24 weeks of treatment with ledipasvir and sofosbuvir once daily in one genotype 1 subject who was both treatment-experienced and cirrhotic.

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)].

If ledipasvir and sofosbuvir is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

If ledipasvir and sofosbuvir is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin [see Dosage and Administration (2.2)].

NDC 72626-2601-1

ASEGUA™

THERAPEUTICS

Ledipasvir and Sofosbuvir

90 mg / 400 mg

tablets

Take 1 tablet once daily

Rx only

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that should

NOT be taken with Ledipasvir and Sofosbuvir

Contents:

Two blister cards

Each blister card contains 14 tablets.

Authorized generic of Harvoni^®

Below are trial descriptions, SVR12 and relapse data in the genotype 4, 5, and 6 HCV populations. Trial results in the genotype 4, 5, and 6 HCV populations are based upon limited number of subjects in some subgroups, particularly in subjects who have been previously treated and subjects with cirrhosis.

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 described are based on studies conducted with either ledipasvir and sofosbuvir tablets (90 mg/400 mg) or ledipasvir and sofosbuvir as individual agents, or are predicted drug interactions that may occur with ledipasvir and sofosbuvir [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg) without ribavirin in HCV treatment-naïve and previously treated adult subjects with genotype 1 or 4 HCV infection who were coinfected with HIV-1. Treatment-experienced subjects had failed prior treatment with Peg-IFN + ribavirin, Peg-IFN + ribavirin + an HCV protease inhibitor, or sofosbuvir + ribavirin. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine, or raltegravir.

Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the subjects were male; 61% were White; 34% were Black; mean body mass index was 27 kg/m² (range: 18 to 66 kg/m²); 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of the subjects were treatment-experienced.

Table 18 presents the SVR12 in the ION-4 trial after 12 weeks of ledipasvir and sofosbuvir treatment.

SVR12 rates were 94% (63/67) in subjects with cirrhosis and 98% (46/47) in subjects who were previously treated and had cirrhosis. The relapse rate in the ION-4 trial in Black subjects was 9% (10/115), all of whom were IL28B non-CC genotype, and none in non-Black subjects (0/220). In the ION-1, ION-2, and ION-3 HCV mono-infection studies, relapse rates were 3% (10/305) in Black subjects and 2% (26/1637) in non-Black subjects.

No subject had HIV-1 rebound during the study. The percentage of CD4+ cells did not change during treatment. Median CD4+ cell count increase of 29 cells/mm³ was observed at the end of treatment with ledipasvir and sofosbuvir tablets for 12 weeks.

The concomitant use of ledipasvir and sofosbuvir and P-gp inducers may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of ledipasvir and sofosbuvir. Therefore, the use of ledipasvir and sofosbuvir with P-gp inducers (e.g., rifampin, St. John's wort) is not recommended [see Drug Interactions (7.2)].

The recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older with genotype 1, 4, 5, or 6 HCV is based on weight (Table 2). Table 3 provides the weight-based dosage of ribavirin when used in combination with ledipasvir and sofosbuvir for pediatric patients. Take ledipasvir and sofosbuvir (with or without food) once daily [see Dosage and Administration (2.5), Clinical Pharmacology (12.3), and Clinical Studies (14.7)]. Ledipasvir and sofosbuvir (HARVONI) oral pellets can be taken in pediatric patients who cannot swallow the tablet formulation.

Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with ledipasvir and sofosbuvir. Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease, may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Coadministration of amiodarone with ledipasvir and sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered ledipasvir and sofosbuvir:

• Counsel patients about the risk of serious symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking ledipasvir and sofosbuvir who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting ledipasvir and sofosbuvir should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems [see Adverse Reactions (6.2), Drug Interactions (7.2)].

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, liver failure, and death can occur.

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with ledipasvir and sofosbuvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with ledipasvir and sofosbuvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Based on drug interaction studies conducted with ledipasvir, sofosbuvir, or ledipasvir and sofosbuvir tablets (90 mg/400 mg) no clinically significant drug interactions have been either observed or are expected when ledipasvir and sofosbuvir is used with the following drugs [see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, lamivudine, methadone, midazolam, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 6 for use of ledipasvir and sofosbuvir with certain HIV antiretroviral regimens [see Drug Interactions (7.2)].

See the ledipasvir and sofosbuvir (HARVONI) oral pellets full Instructions for Use for details on the preparation and administration of ledipasvir and sofosbuvir (HARVONI) pellets.

Do not chew ledipasvir and sofosbuvir (HARVONI) oral pellets. If ledipasvir and sofosbuvir (HARVONI) oral pellets are administered with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice cream. Take ledipasvir and sofosbuvir (HARVONI) oral pellets within 30 minutes of gently mixing with food and swallow the entire contents without chewing to avoid a bitter aftertaste.

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)].

Trial 0154 was an open-label clinical trial that evaluated 12 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg) in 18 treatment-naïve and treatment-experienced (subjects with prior exposure to an HCV NS5B polymerase inhibitor were excluded) genotype 1 HCV-infected adults with severe renal impairment not requiring dialysis. At baseline, two subjects (11%) had cirrhosis and the mean eGFR was 24.9 mL/min (range: 9.0 to 39.6). The SVR rate was 100% (18/18).

As shown in the table below, Trial 4063 was an open-label three-arm clinical trial that evaluated 8, 12, and 24 weeks of treatment with ledipasvir and sofosbuvir in a total of 63 adults with chronic HCV infection and ESRD requiring dialysis. Of the 63 subjects, 10% had cirrhosis, 24% were treatment-experienced, 95% were on hemodialysis, and 5% were on peritoneal dialysis; mean duration on dialysis was 12 years (range: 0.2 to 43 years). The SVR rates for the 8, 12, and 24 week ledipasvir and sofosbuvir treatment groups are shown in Table 20.

SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of treatment with ledipasvir and sofosbuvir tablets (90 mg/400 mg) in combination with ribavirin in HCV treatment-naïve and previously treated adult subjects with genotype 1 and 4 infection who had undergone liver transplantation and/or who had decompensated liver disease. The two trials were identical in study design. Subjects were enrolled in one of the seven groups in the trials based on liver transplantation status and severity of hepatic impairment (see Table 19). Subjects with a CPT score greater than 12 were excluded. Within each group, subjects were randomized in a 1:1 ratio to receive ledipasvir and sofosbuvir + ribavirin for 12 weeks or ledipasvir and sofosbuvir + ribavirin for 24 weeks. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day regardless of transplantation status. Ribavirin dose adjustments were performed according to the ribavirin labeling [see Clinical Studies (14.1)].

Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the subjects were male; 91% were White; mean body mass index was 28 kg/m² (range: 18 to 49 kg/m²); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of the subjects failed a prior HCV therapy.

Table 19 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with genotype 1 HCV treated with ledipasvir and sofosbuvir + ribavirin for 12 weeks. The SVR12 rates observed with 24 weeks of ledipasvir and sofosbuvir + ribavirin were similar to the SVR12 rates observed with 12 weeks of treatment. Therefore, the results for the ledipasvir and sofosbuvir + ribavirin 24 weeks arm are not presented in Table 19.

There were 7 subjects with fibrosing cholestatic hepatitis in the 12-week treatment arm, and all subjects achieved SVR12.

In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated cirrhosis treated with ledipasvir and sofosbuvir + ribavirin for 12 weeks (N=12), the SVR12 rate was similar to rates reported with genotype 1; no subjects relapsed. Available data in subjects with genotype 4 HCV who had decompensated cirrhosis (pre- and post-liver transplantation) were insufficient for dosing recommendations; therefore, these results are not presented.

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 concomitant HIV-1 antiviral drugs.