Hepcinat-LP

Hepcinat-LP is a 2-drug fixed-dose combination product containing Ledipasvir (Hepcinat-LP) 90 mg and Sofosbuvir (Hepcinat-LP) 400 mg in a single tablet, for oral administration.

Each tablet contains Ledipasvir (Hepcinat-LP) 90 mg and Sofosbuvir (Hepcinat-LP) 400 mg.

It also includes the following excipients: Colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Film-Coating: FD&C yellow no. 6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Ledispavir is a hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor and Sofosbuvir (Hepcinat-LP) is a nucleotide analog inhibitor of HCV NS5B polymerase.

Ledipasvir (Hepcinat-LP) is methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]3 methylbutanoyl}-2-azabicyclo(2.2.1)hept-3-yl)-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro(2.4)hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate. It has a molecular formula of C₄₉H₅₄F₂N₈O₆ and a molecular weight of 889.

Ledipasvir (Hepcinat-LP) is practically insoluble (<0.1 mg/mL) across the pH range of 3-7.5 and is slightly soluble below pH 2.3 (1.1 mg/mL).

Sofosbuvir (Hepcinat-LP) is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy (phenoxy)phosphorylamino)propanoate. It has a molecular formula of C₂₂H₂₉FN₃O₉P and a molecular weight of 529.45.

Sofosbuvir (Hepcinat-LP) is a white to off-white crystalline solid with a solubility of ≥2 mg/mL across the pH range of 2-7.7 at 37°C and is slightly soluble in water.

See also: Hepcinat-LP

​Adult Patients:

​Hepcinat-LP Tablets are indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) :

• ​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

​Pediatric Patients:

​Hepcinat-LP Tablets are indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with HCV genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.

Hepcinat-LP are antiviral medications that prevent hepatitis C virus (HCV) cells from multiplying in your body.

Hepcinat-LP is a combination medicine used to treat hepatitis C in adults.

Hepcinat-LP may also be used for purposes not listed in this medication guide.

Recommended Dosage

The recommended dosage of Hepcinat-LP is one tablet taken orally once daily with or without food.

Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups.

Table 1 shows the recommended Hepcinat-LP treatment regimen and duration based on patient population.

For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to DRUG INTERACTIONS for dosage recommendations for concomitant HIV-1 antiviral drugs.

Table 1 : Recommended Treatment Regimen and Duration for Hepcinat-LP in Patients with Genotype 1, 4, 5 or 6 HCV

Drugs Without Clinically Significant Interactions With Hepcinat-LP

Based on drug interaction studies conducted with the components of Hepcinat-LP (Ledipasvir (Hepcinat-LP) or Sofosbuvir (Hepcinat-LP)) or Hepcinat-LP, no clinically significant drug interactions have been either observed or are expected when Hepcinat-LP is used with the following drugs : abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 4 for use of Hepcinat-LP with certain HIV antiretroviral regimens.

See also:
What is the most important information I should know about Hepcinat-LP?

If Hepcinat-LP Tablets are 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.

Use Hepcinat-LP as directed by your doctor. Check the label on the medicine for exact dosing instructions. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Hepcinat-LP. Talk to your pharmacist if you have questions about this information.
• Take Hepcinat-LP by mouth with or without food.
• Do not take an antacid that has aluminum or magnesium in it within 4 hours of Hepcinat-LP.
• If you take cimetidine, dexlansoprazole, esomeprazole, famotidine, lansoprazole, nizatidine, omeprazole, pantoprazole, rabeprazole, or ranitidine, ask your doctor or pharmacist how to take it with Hepcinat-LP.
• Hepcinat-LP works best if it is taken at the same time each day.
• Continue to take Hepcinat-LP even if you feel well. Do not miss any doses.
• If you miss a dose of Hepcinat-LP, take it as soon as you remember the same day and go back to your regular dosing schedule. Do not take more than 1 dose of Hepcinat-LP in the same day. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Hepcinat-LP.

Use: Labeled Indications

Chronic hepatitis C: Treatment of chronic hepatitis C virus genotype 1, 4, 5, or 6 infection in adult and pediatric patients ≥3 years of age, without cirrhosis or with compensated cirrhosis; genotype 1 in adult patients with decompensated cirrhosis, in combination with ribavirin; and genotype 1 or 4 in adult liver transplant patients without cirrhosis or with compensated cirrhosis, in combination with ribavirin.

Off Label Uses

Chronic hepatitis C, genotype 1 or 4 (kidney transplant recipients)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, Hepcinat-LP is recommended and effective for treatment of hepatitis C virus genotype 1 or 4 infection in kidney transplant recipients without cirrhosis or with compensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C, genotype 4, 5, or 6 (with decompensated cirrhosis)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, Hepcinat-LP, with or without concomitant ribavirin, is recommended and effective for treatment of hepatitis C virus genotype 4, 5, or 6 infection in patients with decompensated cirrhosis, including patients who have prior Sofosbuvir (Hepcinat-LP)-based treatment failure. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C, genotype 5 or 6 (liver transplant recipients)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, Hepcinat-LP, with concomitant ribavirin, is recommended and effective for treatment of hepatitis C virus genotype 5 or 6 infection in liver transplant recipients with or without cirrhosis (including decompensated cirrhosis). Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

See also:
What are the possible side effects of Hepcinat-LP?

The following serious adverse reactions are described below and elsewhere in labeling:

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone.

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 Hepcinat-LP is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.

The safety assessment of Hepcinat-LP 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 Hepcinat-LP once daily by mouth for 8, 12 and 24 weeks, respectively.

The proportion of subjects who permanently discontinued treatment due to adverse events was 0%, less than 1%, and 1% for subjects receiving Hepcinat-LP 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 Hepcinat-LP.

Table 2 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 treatment with Hepcinat-LP in clinical trials. The majority of adverse reactions presented in Table 2 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 2 : Adverse Reactions (All Grades) Reported in ≥ 5% of Subjects Receiving 8, 12, or 24 Weeks of Treatment with Hepcinat-LP

The safety assessment of Hepcinat-LP 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). The subjects received Hepcinat-LP 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 Hepcinat-LP 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 Hepcinat-LP once daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of Hepcinat-LP once daily by mouth + ribavirin. Table 3 presents the adverse reactions, as defined above, that occurred with at least 5% greater frequency in subjects treated with 24 weeks of Hepcinat-LP or 12 weeks of Hepcinat-LP + ribavirin, compared to those reported for 12 weeks of placebo. The majority of the adverse reactions presented in Table 3 were Grade 1 or 2 in severity.

Table 3 : Adverse Reactions with ≥ 5% Greater Frequency Reported in Treatment-Experienced Subjects with Cirrhosis Receiving Hepcinat-LP for 24 Weeks or Hepcinat-LP + RBV for 12 Weeks Compared to Placebo for 12 weeks

Adverse Reactions In Subjects Co-infected With HIV-1

The safety assessment of Hepcinat-LP was based on an open-label clinical trial in 335 genotype 1 or 4 subjects with HCV/HIV-1 co-infection who were on stable antiretroviral therapy in Study ION-4. The safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were headache (20%) and fatigue (17%).

Adverse Reactions In Liver Transplant Recipients And/Or Subjects With Decompensated Cirrhosis

The safety assessment of Hepcinat-LP with ribavirin (RBV) in liver transplant recipients and/or those who had decompensated liver disease was based on pooled data from two Phase 2 open-label clinical trials including 336 subjects who received Hepcinat-LP plus RBV for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were excluded from the trials.

The adverse events observed were consistent with the expected clinical sequelae of liver transplantation and/or decompensated liver disease, or the known safety profile of Hepcinat-LP and/or ribavirin.

Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 38% and 13% of subjects treated with Hepcinat-LP plus RBV for 12 weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated with Hepcinat-LP plus RBV for 12 weeks.

Liver Transplant Recipients With Compensated Liver Disease

Among the 174 liver transplant recipients with compensated liver disease who received Hepcinat-LP with RBV for 12 weeks, 2 (1%) subjects permanently discontinued Hepcinat-LP due to an adverse event.

Subjects With Decompensated Liver Disease

Among the 162 subjects with decompensated liver disease (pre-or post-transplant) who received Hepcinat-LP with RBV for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects underwent liver transplantation, and 1 subject ( < 1%) underwent liver transplantation and died during treatment or within 30 days after discontinuation of treatment. Because these events occurred in patients with advanced liver disease who are at risk of progression of liver disease including liver failure and death, it is not possible to reliably assess the contribution of drug effect to outcomes. A total of 4 (2%) subjects permanently discontinued Hepcinat-LP due to an adverse event.

Less Common Adverse Reactions Reported in Clinical Trials (less than 5%): The following adverse reactions occurred in less than 5% of subjects receiving Hepcinat-LP in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.

Psychiatric disorders: depression (including in subjects with pre-existing history of psychiatric illness). Depression (particularly in subjects with pre-existing history of psychiatric illness) occurred in subjects receiving Sofosbuvir (Hepcinat-LP) containing regimens. Suicidal ideation and suicide have occurred in less than 1% of subjects treated with Sofosbuvir (Hepcinat-LP) in combination with ribavirin or pegylated interferon/ribavirin in other clinical trials.

Laboratory Abnormalities

Bilirubin Elevations: Bilirubin elevations of greater than 1.5xULN were observed in 3%, less than 1%, and 2% of subjects treated with Hepcinat-LP for 8, 12, and 24 weeks, respectively. Bilirubin elevations of greater than 1.5xULN were observed in 3%, 11% and 3% of subjects with compensated cirrhosis treated with placebo, Hepcinat-LP + ribavirin for 12 weeks and Hepcinat-LP for 24 weeks, respectively, in the SIRIUS trial.

Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3xULN were observed in less than 1%, 2%, and 3% of subjects treated with Hepcinat-LP for 8, 12, and 24 weeks, respectively. Transient, asymptomatic lipase elevations of greater than 3x ULN were observed in 1%, 3% and 9% of subjects with compensated cirrhosis treated with placebo, Hepcinat-LP + ribavirin for 12 weeks and Hepcinat-LP for 24 weeks, respectively, in the SIRIUS trial.

Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials ION-3, ION-1 or ION-2 of Hepcinat-LP. Creatine kinase was assessed in the ION-4 trial. Isolated, asymptomatic creatine kinase elevations of greater than or equal to 10xULN was observed in 1% of subjects treated with Hepcinat-LP for 12 weeks in the ION-4 trial and has also been previously reported in subjects treated with Sofosbuvir (Hepcinat-LP) in combination with ribavirin or peginterferon/ribavirin in other clinical trials.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Hepcinat-LP. 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.

Cardiac Disorders

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with Hepcinat-LP.

Skin And Subcutaneous Tissue Disorders

Skin rashes, sometimes with blisters or angioedema-like swelling