Pharmacokinetics of the 12.3 generation and the two generation HarvoniabsorbThe pharmacokinetics of ledipasvir, sofosbuvir, and the major ci
Pharmacokinetics of the 12.3 generation and the two generation Harvoni
The pharmacokinetics of ledipasvir, sofosbuvir, and the major circulating metabolite GS-331007 were evaluated in healthy adult subjects and in patients with chronic hepatitis C. After oral administration of HARVONI, the median peak concentration of ledipasvir was observed between 4 and 4.5 hours after treatment. Sofosbuvir was rapidly absorbed and plasma peak concentration was observed after ~0.8 to 1 h. The peak concentration of GS-331007 in plasma was observed at 3.5 to 4 hours after treatment.
According to the analysis of population pharmacokinetics in HCV- infected subjects, the ledipasvir (N=2113), sofosbuvir (N=1542), and GS-331007 (N=2113) of the geometric mean steady-state AUC0-24 were 72901320, 12000 and ng• hr/mL. The steady-state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323618, and 707 ng/mL, respectively. AUC0-24 and Cmax were similar to Sofosbuvir and GS-331007 in healthy adult subjects and HCV infected subjects. Compared with healthy subjects (N=191), the AUC0-24 and ledipasvir of in the HCV- infected subjects were 24% lower and lower than those of Cmax.
Influence of food
Relative to oral condition. Given a single dose of HARVONI with a moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal increased sofosbuvir AUC0-inf about 2- times, but did not significantly affect sofosbuvir Cmax. Meal type does not change GS-331007 and ledipasvir exposure. In the 3 phase of the trial, HCV- infected subjects had similar rates of HARVONI response to food or no food. Food can not be given to HARVONI.
Ledipasvir is > 99.8% binds to human plasma protein. After a single dose of 90 mg of [14C]-ledipasvir in healthy subjects, the ratio of blood to plasma ratio of 14C- was between 0.51 and 0.66.
Sofosbuvir is associated with human plasma protein binding of approximately 61 - 65% and is independent of drug concentrations spanning the range from 1 g/mL to 20 g/mL. Minimal protein binding to GS-331007 in human plasma. After a single dose of 400 mg of [14C]-sofosbuvir in healthy subjects, the ratio of 14C- to plasma was about 0.7.
In vitro, human CYP1A2, CYP2C8, CYP2C9, CYP, CYP2D6, and CYP3A4 were not observed to be able to detect ledipasvir metabolism in vitro, and were not observed by human 2C19. Evidence of slow oxidative metabolism was observed by an unknown mechanism. After a single dose of 90 mg[14C]-ledipasvir, systemic exposure was almost exclusively associated with maternal drug (>). No change in ledipasvir is the main type of manure.
Sofosbuvir is extensively metabolized in the liver to form pharmacologically active nucleoside three phosphate analogue GS-461203. The metabolic activation pathway involving human cathepsin A (CatA) or carboxylesterase 1 (CES1) carboxyester hydrolysis and continuous three histidine triad nucleotide binding protein 1 (HINT1) phosphate is then phosphorylated cleavage of pyrimidine nucleotide biosynthesis pathway. Dephosphorylation leads to the formation of nucleoside metabolite GS-331007, which is not effectively phosphorylated and the lack of anti -HCV activity in vitro. A single dose of 400 mg of [14C]-sofosbuvir, GS-331007 accounted for about > of total body exposure.
After a single oral dose of 90 [14C]-ledipasvir of Mg, the average number of [14C]- radioactivity in feces and urine was recovered to about 87%, with the recovery of most of the radiation dose from feces (about 86%). The change of ledipasvir in fecal excretion accounted for 70% of the average dose and M19 of the oxidized metabolite accounted for about 2.2%. These data suggest that the biliary excretion of ledipasvir is the major route of elimination, and renal excretion is a minor pathway (ca. 1%). The median half-life of ledipasvir was 47 hours after HARVONI administration.
After a single oral dose of 400 [14C]-sofosbuvir of Mg, the mean total recovery dose was greater than 92%, urine, feces, and exhaled breath recovery components were about 80%, 14%, and 2.5%, respectively. The majority of sofosbuvir recovered in urine was GS-331007 (78%) and was recovered to sofosbuvir (). These data suggest that GS-331007 clearance is the main route of elimination. The median half-life of sofosbuvir and GS-331007 after administration of HARVONI was 0.5 and 27 hours, respectively.
Patients with renal impairment: HCV negative in patients with severe renal impairment (eGFR< 30 mL/min by Cockcroft-Gault) with a single dose of 90 mg ledipasvir pharmacokinetic study of ledipasvir. Clinically significant differences in ledipasvir pharmacokinetics were not observed between healthy subjects and subjects with severe renal impairment.
In the HCV negative with mild (eGFR = 50 and < 80 mL/min/1.73m2), moderate (eGFR = 30 and < 50 mL/min/1.73m2), severe renal impairment (eGFR < 30; 400=" " esrd=" " egfr=" " > mL/min/1.73m2, 80) in light, moderate, and severe renal damage by the subjects of sofosbuvir AUC0-inf were 61%, 107%, and 171% higher, GS331007 and AUC0-inf were 55%, 88%, and 451% higher. In ESRD subjects, compared with subjects with normal kidney function, sofosbuvir and GS-331007 AUC0-inf were 28% and 1280% higher when sofosbuvir is given and compared in before hemodialysis, when sofosbuvir is in the given after hemodialysis were 60% and 2070% higher. A 4 hour hemodialysis time was removed for approximately 18% of the given dose [see dose and method of Administration (2.2) and use in special populations (8.6)].
Race: analysis of population pharmacokinetics in HCV- infected subjects showed no clinically relevant effects of race on ledipasvir, sofosbuvir, and GS331007 exposure.
Gender: population pharmacokinetic analysis in HCV- infected subjects showed that gender had no clinically relevant effects on sofosbuvir and GS-331007 exposure. Ledipasvir AUC and Cmax were higher in women than in men 77% and 58%; however, the relationship between gender and ledipasvir exposure is not considered to be clinically relevant, because over 3 research subjects in men and women who achieve a high response rate (SVR > 90%) and similar in women and men of the security pattern.
Pediatric patients: the pharmacokinetics of ledipasvir or sofosbuvir have not been identified in pediatric patients [see the use of special populations (8.4)].
Elderly patients: in HCV- infected subjects in a population pharmacokinetic analysis showed that age range (18 to 80) in the analysis of age on ledipasvir, sofosbuvir, and GS-331007 exposure no clinically relevant effects [see special people use (8.5)].
Patients with impaired liver: the pharmacokinetics of ledipasvir in a HCV negative subjects with severe liver impairment (Child-Pugh class C) with a single dose of 90 mg ledipasvir. Ledipasvir plasma exposure (AUC0-inf) was similar in subjects with severe liver impairment and those with normal liver function. Population pharmacokinetic analysis of HCV- infected subjects showed no clinically relevant effect of liver cirrhosis on ledipasvir exposure [see use in special populations (8.7)].
Pharmacokinetics of sofosbuvir were studied in HCV- infected subjects with moderate and severe liver impairment (Child-Pugh class B and C) given -7 400 days after sofosbuvir administration of mg. Compared with normal liver function subjects, sofosbuvir and AUC0-24 in moderate and severe liver lesions were 126% and 143% higher, respectively, while GS-331007 AUC0-24 was higher by a factor of 18% and 9%, respectively. Population pharmacokinetic analysis of HCV- infected subjects showed no clinically relevant effects of liver cirrhosis on sofosbuvir and GS-331007 exposure [see use in special populations (8.7)].
Drug interaction study
Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP, whereas GS-331007 is not. P-gp inducers (e.g., rifampicin or Saint John grass) might reduce the plasma concentration of sofosbuvir and ledipasvir, resulting in the treatment effect to reduce HARVONI, and the proposed HARVONI not with P-gp inducers [see warnings and precautions (5.1)]. Inhibition of P-gp and / or BCRP drug co administration may increase plasma concentrations of ledipasvir and sofosbuvir without increasing plasma concentrations of GS-331007; HARVONI may be co administered with P-gp and / or BCRP inhibitors. Ledipasvir is not sofosbuvir nor is it a substrate for liver uptake transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a substrate for renal transporters, including the organic anion transporter OAT1 or OAT3, or the organic cation transporter OCT2.
Ledipasvir slows down oxidative metabolism by an unknown mechanism. In vitro, CYP metabolism of ledipasvir was not observed. Biliary excretion of ledipasvir is the main route of elimination. Sofosbuvir is not a substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions are not predicted by CYP or UGT1A1 enzyme mediated HARVONI.
Table 4 shows the effects of CO administration of drugs on ledipasvir, sofosbuvir, and GS331007 exposure [see drug interactions (7.2)].
Ledipasvir, sofosbuvir, and GS-331007 with abacavir and lamivudine or emtricitabine, [lamivudine], [emtricitabine], and horse Wei Lin [rilpivirine], DF[tenofovir DF] and tenofovir, or raltegravir combined with [raltegravir] was observed on Ledipasvir, sofosbuvir, and GS-331007 pharmacokinetic parameters influence.
Ledipasvir is a drug transporter P-gp and an inhibitor of breast cancer resistance protein (BCRP) and may increase intestinal absorption of CO administration of these transporters to substrate drugs. Ledipasvir is a transporter of OATP1B1, OATP1B3, and BSEP inhibitors only at concentrations exceeding their clinical reach. Ledipasvir is not an inhibitor of transporter MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug drug interaction potential of Ledipasvir is mainly restricted to the small intestinal inhibitory effect of P-gp and BCRP. The inhibition of ledipasvir associated clinically relevant transporters in the systemic circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007 are not inhibitors of P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and OCT1 drug transporters, whereas GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1. Ledipasvir, sofosbuvir, and GS-331007 are not CYP or UGT1A1 enzyme inhibitors or inducers.
In Table 5, the effects of ledipasvir or sofosbuvir on CO administration of drug exposure [see drug interactions (7.2)].
Using ledipasvir or sofosbuvir observed no effect on the pharmacokinetic parameters of CO administered drugs: abacavir, cyclosporine, Da Lu indinavir / ritonavir, efavirenz, emtricitabine, lamivudine, methadone, or horse Li Wei Lin.
Ledipasvir is an inhibitor of HCV NS5A protein required for viral replication. Drug resistance selection in cell cultures and cross resistance studies indicate that ledipasvir targeting NS5A acts as its model.
Sofosbuvir is an inhibitor of HCV NS5B RNA- dependent RNA polymerase for viral replication. Sofosbuvir is a nucleotide prodrug of metabolism in the formation of pharmacologically active three phosphate guanosine analogue cells (GS-461203), it is incorporated into the pit by NS5B polymerase to HCV RNA and acts as a chain terminator, a biochemical analysis, GS-461203 inhibition from HCV genotype 1b, 2a, 3a and of the recombinant 4A NS5B polymerase activity with IC50 values ranging from 0.7 to 2.6 M. GS-461203 is not an inhibitor of human DNA and RNA polymerase inhibitors nor mitochondrial RNA polymerase.
In the analysis of HCV replicon, the EC50 values of ledipasvir for full-length replicon derived from genotype 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 value of the NS5A coding sequence of the chimeric replicon derived from the clinical isolates was 0.018 nM (range 0.009-0.085 nM; N=30) and genotype 1b0.006 nM (range, 0.004 to 0.007 nM; N=3); Ledipasvir. Compared with genotype 1 for genotype 4a, 5A, and 6a, Ledipasvir had lower antiviral activity, with EC50 values of 0.39 nM, 0.15 nM, and 1.1 nM, respectively. For genotype 2a, 2b, 3a, and 6e, Ledipasvir had substantially lower activity, with EC50 values of 21 - 249 nM, respectively, of 16 - 530 nM, 168 nM, and 264 nM.
In HCV replicon analysis, 1a, 1b, 2a, 3a, and 4a, and sofosbuvir 110, derived from genotype 2B, 5A, or 6A chimeric 1b replicon encoding NS5B, ranged from EC50 to nM. The median EC50 from clinical isolates of chimeric replicon encoding NS5B sequence sofosbuvir, of genotype 1a was 62 nM (range 29 - 128 nM; N=67, nM) of genotype 1b102 (range 45 - 170 nM; N=29, nM) of genotype 229 (range 14 - 81 nM; N=15) and, for 3a81 genotype nM (range 24 - 181 nM; N=106). The EC50 values of sofosbuvir and 2A were 30 nM and 20 nM, respectively, in the replication analysis of 1a. The evaluation of the combination of Sofosbuvir and ledipasvir in replicon cells showed no antagonistic effect on reducing the level of HCV RNA.
In cell culture
1A and 1b have been selected in cell cultures to genotype ledipasvir with reduced susceptibility to HCV replicon. Both 1a and 1b have a reduced sensitivity to ledipasvir with major NS5A amino acid substitutions in Y93H. In addition, there is a kind of Q30E substitution in the genotype 1a replicon. In the genotype 1a and 1b two, the Y93H site - directed mutation occurs, and the Q30E substitution in genotype 1a, which gives rise to a high level of sensitivity to ledipasvir (a change in EC50 multiple times greater than 1000-).
In a variety of genes including 1b, 2a, 2b, 3a, 4a, 5A, sofosbuvir, and 6A cell cultures have been selected to reduce the sensitivity of HCV replicon. The sensitivity to sofosbuvir reduction was associated with the major NS5B substitution of S282T in all of the replicon genotypes examined. In the 8 genotypes of S282T, the occurrence of the point to point mutation of the donor 18- reduced the sensitivity to sofosbuvir by 2-.
In clinical trials
In the phase 3 trial with analysis of HARVONI subjects, 37 subjects (29 cases with genotype 1a and 8 cases with genotype 1b) due to virologic failure (35 cases with virological relapse, 2 cases due to non-compliance with a breakthrough on record - treatment) on drug resistance of qualified. Baseline NS5A and NS5B depth sequencing data (analysis cutoff 1%) were available for subjects with virus 37/37 and 36/37, respectively.
In 29 patients with genotype 1a virological failure, 55% (16/29) of the subjects failed to have a virus associated with NS5A resistance to replace K24R, M28T/V, Q30R/H/K/L, L31M, or Y93H/N. These 5/16 patients also had a baseline NS5A polymorphism at the site of drug resistance associated amino acid. The most common substitute for Q30R, Y93H or N, and L31M was detected at failure.
In 8 patients with genotype 1b virological failure, 88% (7/8) failed to have a virus associated with NS5A resistance when replacing L31V/M/I or Y93H. These 3/7 subjects also had a baseline NS5A polymorphism in the drug resistance associated location. The most commonly detected substitution is Y93H.
At the time of failure, 38% (14/37) of the virological failure subjects had a or a more NS5A substitution in the drug resistance related position.
In the phenotypic analysis, baseline isolates were derived from subjects who failed to show a reduction in ledipasvir sensitivity to 20- to > at the time of failure; 243- times the association of NS5A resistance.
Treatment - the emergence of NS5B substituted L159 (n=1) and V321 (n=2) was accompanied by a previously detected substitution in the phase 3 trial of sofosbuvir failure. In addition, NS5B at highly conserved positions of substituted D61G (n=3), A112T (n=2), E237G (n=2), and S473T (n=1) was detected in patients infected with HCV GT1a treatment failure by next-generation sequencing with low frequency. Prior to a liver transplant trial, subjects with HCV GT1a infection previously described D61G substitution. The clinical significance of these substitutions is unclear at present.
Isolates from any of the 3 trials failed to detect sofosbuvir- associated resistance in NS5B to replace S282T. In a phase 2 trial in 1 patients who were treated with HARVONI for a period of 8 weeks, S282T was substituted for NS5B, L320V/I, and V321I and NS5A, Y93H, L31M, and Q30L were detected at failure.
Ledipasvir resistance to sofosbuvir in association with S282T substitution in NS5B is completely active whereas all ledipasvir resistance associated substitutions in NS5A are completely sensitive to sofosbuvir. Sofosbuvir and ledipasvir are both direct acting antiviral agents that have different mechanisms of substitution for other classes of drug resistance and are fully active, such as NS5B non nucleoside inhibitors and NS3 protease inhibitors. NS5A substitution confers resistance to ledipasvir may reduce antiviral activity of other NS5A inhibitors. The efficacy of ledipasvir/sofosbuvir in patients who failed to be treated with other regimens including a NS5A inhibitor has not been determined.
Persistence of drug resistance Association
There is no data available on the persistence of drug resistance Association substitution. It has been found in some patients that NS5A resistance associated with substitution of other NS5A inhibitors continued to total > 1 years.
Effects of baseline HCV polymorphism on treatment response
Analysis was performed to explore the association between pre-existing baseline NS5A polymorphisms and the prevalence of drug resistance associated sites. In the combined analysis of phase 3 trials, the group or deep sequencing 23% (370/1589) in subjects with baseline virus NS5A polymorphisms in drug resistance associated location (in the NS5A amino acid position 24, 28, 30, 31, 58, 92, or 93 from any change in the reference).
In the study of ION-1 and ION-3 in the untreated subjects, the virus had a baseline NS5A polymorphism at the site of drug resistance Association, and the recurrence rate was 6% (3/48) and () after HARVONI8 weeks of treatment (1/113). The relapse rate was 5% (8/167) and (3/306) at week 12 after treatment with HARVONI in patients with no baseline NS5A polymorphism in the drug resistance Association site.
The baseline NS5A polymorphism of the virus in the drug resistance Association site was 12 weeks after treatment with HARVONI (5/23) and at a rate of 22% () at week 24 (0/19).
In the genotype 1a there was a relapse in patients who were observed to have specific baseline NS5A resistance Association polymorphisms for M28T/V, Q30H, Q30R, L31M, H58P, Y93H, and Y93N, and L28M, A92T, and 1B in genotype Y93H. There were multiple NS5A polymorphisms in the drug resistance Association locations that seemed to have a higher recurrence rate.
In all 24 subjects (N=20 had L159F+C316N; N=1 had L159F; and N=3 had N142T) there was a baseline polymorphism associated with a sustained virological response to NS5B nucleoside inhibitor resistance (SVR). In the 3 phase of the trial, Sofosbuvir was not detected in the NS5B sequence of any of the subjects by group or depth sequencing. No association with S282T was identified.
13 non clinical toxicology
13.1 cancer, mutation, impaired fertility
Carcinogenesis and mutation
Ledipasvir: in vitro or in vivo, a group of trials, including bacterial mutagenicity, chromosome aberrations in human peripheral lymphocytes, and in vivo rat micronucleus test, Ledipasvir without genetic toxicity.
Carcinogenicity studies of ledipasvir in mice and rats.
Sofosbuvir: in vitro or in vivo, a group of trials, including bacterial mutagenicity, chromosomal aberrations in human peripheral lymphocytes, and in vivo rat micronucleus assay, Sofosbuvir had no genetic toxicity.
2- study of carcinogenicity in mice and rats using sofosbuvir. Male mice were administered a dose of 200 mg/kg/day and a female of 600 mg/kg/day, while male and female rats were administered doses up to 750 mg/kg/day. In mice and rats at the highest dose tested to observe drug related tumor incidence increased, leading to the major circulating metabolite GS-331007AUC exposure about people exposed to the male and female were 4- and 18- times in the recommended clinical dose (mice) and 8- and 10- times (rat).
No adverse effect on the Ledipasvir:Ledipasvir mating and fertility. In female rats, maternal exposure of corpus luteum in people exposed to the recommended clinical dose of about 3- times and number of implantation sites were slightly lower. At the highest dose level, no effect was observed in males and females exposed to ledipasvirAUC exposure at approximately 5- and 2- times as recommended clinical dose.
Sofosbuvir: when the effect of Sofosbuvir on embryo fetal viability or fertility in rats of free evaluation. At the highest dose, exposure to the major circulating metabolite GS-331007AUC was approximately 5- times as high as the recommended clinical dose.
13.2 animal toxicology and / or pharmacology
Sofosbuvir: cardiac degeneration and inflammation were observed in rats after GS-9851 (a mixture of stereoisomers containing about 50% sofosbuvir) at a dose of 2000 mg/kg/day for a total of 5 days. At this dose, exposure to AUC, the major circulating metabolite of GS-331007, was approximately 17- times higher at the recommended clinical dose. In mice, rats or dogs in the study to 3 months, 6 months, or 9 months of exposure, than in the recommended clinical dose exposure were higher in about 24-, GS-331007 AUC 5-, or 17- times is not observed when heart degeneration or inflammation. In addition, the rat 2- carcinogenicity study at sofosbuvir 750 to mg/kg/day after exposure to GS-331007 AUC exposure was not observed in patients with clinically recommended doses of cardiac degeneration or inflammation at approximately 9- times.
14 clinical studies
14.1 clinical trials overview
In the three phase 3 trials in 1518 patients with genotype 1 chronic hepatitis C (CHC) HARVONI efficacy evaluation and compensatory liver disease in a subject:
The study of ION-3: non cirrhotic untreated subjects [see clinical research (14.2)],
The study of ION-1: the cirrhotic and non cirrhotic untreated subjects [see clinical research (14.2)], and
The study of ION-2: the cirrhotic and non cirrhotic subjects used an interferon treatment based on failure, including an HCV protease inhibitor solution [see clinical research (14.3)].
All three phase 3 trials evaluated the efficacy of HARVONI (with a fixed dose of 90 mg of ledipasvir and a daily dose of 400 mg of sofosbuvir per day for 1 times) with or without ribavirin. Fixed time for each trial. Serum HCV RNA values were measured using the COBAS TaqMan HCV test (version 2) during a clinical trial using a high purity system. Quantitative low limit (LLOQ) 25 IU/mL.
The sustained virologic response (SVR) was the primary endpoint and was defined as the cessation of treatment at 12 weeks after HCV RNA was less than LLOQ. Recurrence was the secondary end point, defined as HCV RNA greater than or equal to LLOQ with 2 consecutive values or after treatment at the end of the HCV RNA less than LLOQ after the treatment period was available after the end of treatment measurements.
14.2 clinical trials in untreated subjects
Adult without cirrhosis (ION-3 0108)
ION-3 was a randomized, open trial in untreated, non cirrhotic patients with genotype 1 CHC. The subjects were randomized to one of three treatment group and HCV genotype according to the ratio of 1:1:1 (1A: HARVONI layer compared to 1b) for 8 weeks, HARVONI 12 weeks or HARVONI plus ribavirin for 8 weeks.
Demographics and baseline characteristics were balanced across treatment groups. 647 cases were treated subjects, the median age was 55 years (range: 20 to 75); 58% male subjects; 78% were white; 19% black; 6% are Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV the level of RNA is greater than or equal to 800000 IU/mL; 80% 1A genotype HCV infection; 73% had non -C/C IL28B allele (CT or TT).
Table 6 shows the response rate of ION-3 in the HARVONI treated group at 8 and 12 weeks after HARVONI treatment. Leigh Bhave Lin and HARVONI showed no increase in observed response rate. Therefore, in Table 6 did not display HARVONI + ribavirin.
The difference in treatment between 8- weeks of HARVONI and HARVONI of the 12- was 2.3% (97.5% confidence interval - 7.2% to 2.5%). With a baseline HCV RNA< 6 million IU/mL subjects, sustained virologic response (SVR) was treated with HARVONI for 8- weeks (119/123) and treated with HARVONI for 12- weeks (126/131) of 96% ().
Table 7 shows the recurrence rate according to the baseline viral load.
Adults with or without cirrhosis (ION-1 0102)
ION-1 is in 865 cases of untreated genotype 1 CHC including cirrhosis subjects in a randomized, open evaluation test with HARVONI with or without ribavirin for 12 and 24 weeks. The subjects were randomized to receive HARVONI for 12 weeks with the ratio of 1:1:1:1, HARVONI and ribavirin for 12 weeks, HARVONI 24 weeks or HARVONI plus ribavirin for 24 weeks. Stratified randomization according to the presence or absence of cirrhosis and HCV genotype (1a compared to 1b). The median duration of sustained virologic response (SVR) analysis of the primary end point was included in all patients enrolled in the 12- week treatment group (N=431). For all patients enrolled in the 24- week treatment group (N=434), the SVR rate could not be obtained in the interim analysis.
Demographics and baseline characteristics were balanced across treatment groups. 865 cases were treated subjects, the median age was 54 years (range: 18 to 80); 59% subjects were male; 85% were white; 12% black; 12% are Hispanic or Latino; mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline the HCV level of RNA Yu Huo is equal to 800000 IU/mL; 67% 1A genotype HCV infection; 70% had non -C/C IL28B allele (CT or TT); and 16% had liver cirrhosis. Table 8 shows the response rate of HARVONI in the treatment of ION-1 for a total of 12 weeks. Leigh Bhave Lin and HARVONI showed no increase in the observed reaction rate, so that the HARVONI + Leigh Bhave Lin was not shown in table 8.
14.3 clinical trials in patients with previously treated failure
Previously - treated with or without cirrhosis - ION-2 (study 0109)
ION-2 in genotype 1 HCV- infection with or without cirrhosis subjects with a previous interferon based scheme, including a randomized treatment failure with a protease inhibitor HCV scheme, evaluation of open test HARVONI with or without ribavirin for 12 and 24 weeks of treatment. The subjects were randomized to receive HARVONI for 12 weeks with the ratio of 1:1:1:1, HARVONI and ribavirin for 12 weeks, HARVONI 24 weeks or HARVONI plus ribavirin for 24 weeks. Stratified randomization was performed in the presence or absence of cirrhosis, HCV genotype (1a compared to 1b) and response to previous HCV treatment (relapse / breakthrough compared to nonresponse).
Demographics and baseline characteristics were balanced across treatment groups. 440 cases were treated subjects, the median age was 57 years (range: 24 to 75); 65% subjects were male; 81% were white; 18% black; 9% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline the HCV level of RNA is greater than or equal to 800000 IU/mL; 79% 1A genotype HCV infection; 88% had non -C/C IL28B allele (CT or TT); and 20% had liver cirrhosis. Pegylated interferon and Leigh Bhave Lin previously failed treatment subjects 47%. Of these subjects, 49% were recurrence / breakthrough and the other was non responders in 51%. Previously pegylated interferon and Leigh Bhave Lin failed with a HCV protease inhibitor in subjects who were 53%. Of these subjects, 62% were recurrence / breakthrough and 38% were non responders.
Table 10 shows the response rate to the HARVONI treatment group in the ION-2 trial. Leigh Bhave Lin did not show increased response rates observed with HARVONI. Therefore, in table 10 show no the HARVONI + ribavirin arm.
There were available SVR12 and SVR24 data (206/218) subjects in the ION-2 study, all achieved SVR12 subjects also achieved SVR24.
In Table 11 and 12 show on selected response rate and recurrence rate of sub group.
16 how to supply / store and dispose
HARVONI film is orange, diamond, film coating, in the side of the film depression has "GSI" and the other side "7985". Each bottle contains 28 pieces (NDC 61958-1801-1), silica gel desiccant, polyester sheet, and is sealed in a child resistant cap.
Stored at room temperature below 30 C (86 F).
The only distribution in the original container.
- such as sealing cap damage or loss do not use open.
17 patient information
Advise patients to read FDA- approved patient instructions (patient information).
Informing the patient that HARVONI may interact with other drugs. Advise patients to use any other prescription or over-the-counter medicines or herbal products including Saint John grass to report their health care provider [see warnings and precautions (5.1) and drug interactions (7)].
The spread of hepatitis C virus
Inform patients do not know on the spread of hepatitis C infection treatment, during treatment and appropriate mainly to prevent HCV transmission or treatment failure should take measures.
Advise patients that HARVONI should be given 1 times a day with or without food in accordance with a regular dosing schedule. If a patient fails to take HARVONI during a specified period of time, it should be taken immediately on the same day in memory. The next day to restore the usual timetable. Advise patients not to take more than 1 HARVONI in one day.
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