LEDIKAST

Description

1.0 DESCRIPTION

Composition

Each film-coated tablet Contains:

Ledipasvir 90 mg

Sofosbuvir 400 mg

Colors: Yellow oxide of Iron, Titanium Dioxide IP and FD&C Blue#2

Ledikast is a fixed-dose combination tablet 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 film-coated tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The tablet includes the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablet is film-coated with a coating material containing the following inactive ingredients: Yellow Oxide of Iron, polyethylene glycol, polyvinyl alcohol, talc, FD&C Blue #2 and titanium dioxide IP.

Ledipasvir: The IUPAC name for ledipasvir is Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2azabicyclo[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.

2.0 CLINICAL PHARMACOLOGY

2.1 Mechanism of Action

Ledikast is a fixed-dose combination of ledipasvir and sofosbuvir which are directacting antiviral agents against the hepatitis C virus.

2.2 Pharmacodynamics

Cardiac Electrophysiology

Ledipasvir at a dose of 120 mg twice daily (2.67 times the maximum recommended dosage) and sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three times the maximum recommended dosage) does not prolong QTc in clinical trials.

2.3 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, 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 AUC0-24 for ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) were 7290, 1320, and 12,000 ng•hr/mL. Steady-state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=191),

Effect of Food

In fasting conditions, the administration of a single dose of ledipasvir and sofosbuvir with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect sofosbuvir Cmax. 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 HCVinfected subjects who received Ledipasvir + Sofosbuvir with food or without food. Ledipasvir + Sofosbuvir can be administered without regard to food.

Distribution

Ledipasvir is >99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.51 and 0.66.

Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.

Metabolism

In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative metabolism via an unknown mechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure was almost exclusively to the parent drug (>98%). Unchanged ledipasvir is the major species present in feces. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately >90% of total systemic exposure.

Elimination

In a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of Ledipasvir + Sofosbuvir was 47 hours. Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of Ledipasvir + Sofosbuvir were 0.5 and 27 hours.

Specific Populations

Patients with Renal Impairment:

There is no clinically relevant differences in ledipasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR ≥50 and <80 mL/min/1.73m2 ), moderate (eGFR ≥30 and <50 mL/min/1.73m2), severe renal impairment (eGFR <30 mL/min/1.73m2), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73m2), the sofosbuvir AUC0-inf was 61%, 107%, and 171% higher in mild, moderate, and severe renal impairment, while the GS331007 AUC0-inf was 55%, 88%, and 451% higher. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis.

Race:

Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and GS-331007.

9.0 ADVERSE REACTIONS

9.1 Clinical Trials Experience

The most common adverse reactions (≥10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of Ledikast. Table 2 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in ≥5% of subjects receiving 8, 12, or 24 weeks treatment with Ledipasvir + Sofosbuvir 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.

10.0 DRUG INTERACTIONS

10.1 Potential for Drug Interaction

As Ledikast contains ledipasvir and sofosbuvir, any interactions that have been identified with these agents individually may occur with Ledikast. After oral administration, sofosbuvir is rapidly absorbed and subject to extensive firstpass 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 GS331007 is not. P-gp inducers (e.g., rifampin or St. John’s wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of Ledikast, and the use with P-gp inducers is not recommended with Ledikast.

Mechanism of Action

Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action. Sofosbuvir is an otc xanax bars of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 μM. GS-461203 is neither an inhibitor of human DNA and RNApolymerases nor an inhibitor of mitochondrial RNA polymerase.

Antiviral Activity

In HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 0.018 nM for genotype 1a (range 0.009–0.085 nM; N=30) and 0.006 nM for genotype 1b (range 0.004–0.007 nM; N=3). Ledipasvir has less antiviral activity compared to genotype 1 against genotypes 4a, 5a, and 6a, with EC50 values of 0.39 nM, 0.15 nM, and 1.1 nM, respectively. Ledipasvir has substantially lower activity against genotypes 2a, 2b, 3a, and 6e with EC50 values of 21–249 nM, 16–530 nM, 168 nM, and 264 nM. In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotypes 1a, 1b, 2a, 3a, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 2b, 5a, or 6a ranged from 14–110 nM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 62 Nm for genotype 1a (range 29–128 nM; N=67), 102 nM for genotype 1b (range 45–170 nM; N=29), 29 nM for genotype 2 (range 14–81 nM; N=15), and 81 nM for genotype 3a (range 24–181 nM; N=106). In replication competent virus assays, the EC50 values of sofosbuvir against genotypes 1a and 2a were 30 nM and 20 nM, respectively. Evaluation of sofosbuvir in combination with ledipasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

4.0 INDICATIONS AND USAGE

Ledikast is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.

5.0 DOSAGE AND ADMINISTRATION

5.1 Recommended Dosage in Adults

Ledikast is a two-drug fixed-dose combination product that contains 90 mg of ledipasvir and 400 mg of sofosbuvir in a single tablet. The recommended dosage of Ledikast is one tablet taken orally once daily with or without food.

Duration of Treatment

Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups. Table 1 below provides the recommended Ledikast treatment durations for treatment-naïve and treatment-experienced patients and those with and without cirrhosis

6.0 DOSAGE FORMS AND STRENGTHS

Ledikast is available as Green colored, oval shaped, film-coated tablet debossed with “SL” on one side and plain on other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.

7.0 CONTRAINDICATIONS

Hypersensitivity to the active substances or to any of the excipients.

8.0 WARNINGS AND PRECAUTIONS

8.1 Serious Symptomatic Bradycardia When Coadministered with Amiodarone

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 + 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 Ledikast is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered Ledikast:

  • 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 Ledikast who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.

10.3 Drugs without Clinically Significant Interactions with Ledikast

Based on drug interaction studies conducted with individual drugs Ledipasvir or Sofosbuvir or combination of Ledipasvir + Sofosbuvir, no clinically significant drug interactions have either been observed or are expected when Ledipasvir + Sofosbuvir is used with the following drugs individually: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ ritonavir, efavirenz, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, tenofovir disoproxil fumarate, or verapamil. See Table 3 for use of Ledikast with certain HIV antiretroviral regimens.

12.0 OVERDOSAGE

No specific antidote is available for overdose with Ledikast. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Ledikast 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%.

13.0 HOW SUPPLIED/STORAGE AND HANDLING

Ledikast tablets are Green colored, oval shaped and film-coated. 28 tablets packed in a bottle. One bottle and one literature housed in a carton.

Store below 30°C.

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