Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus [see Microbiology]. Pharmacodynamics Cardiac Electrophysiology The effect of sofosbuvir 400 and 1200 mg (three times the recommended dosage) on QTc interval was evaluated in a randomized, single-dose, placebo-and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects. At a dosage three times the maximum recommended dosage, SOVALDI does not prolong QTc to any clinically relevant extent. Pharmacokinetics Absorption The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of SOVALDI, sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5–2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or without pegylated interferon), geometric mean steady state AUC0-24 was 969 ng•hr/mL for sofosbuvir (N=838), and 6790 ng•hr/mL for GS-331007 (N=1695). Relative to healthy subjects administered sofosbuvir alone (N=272), the sofosbuvir AUC0-24 was 60% higher; and GS-331007 AUC0-24 was 39% lower, respectively, in HCV-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg. Effect Of Food Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0-inf . The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, SOVALDI can be administered without regard to food. Distribution Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/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 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, sofosbuvir and GS-331007 accounted for approximately 4% and greater than 90% of drug related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively. Elimination 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 were 0.4 and 27 hours, respectively. Specific Populations Race Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. Gender No clinically relevant pharmacokinetic differences have been observed between men and women for sofosbuvir and GS-331007. Pediatric Patients The pharmacokinetics of sofosbuvir and GS-331007 were determined in 50 pediatric subjects 12 years of age and older, infected with HCV genotype 2 or 3, receiving a daily dose of SOVALDI (400 mg sofosbuvir). The pharmacokinetic properties of sofosbuvir and GS-331007 in pediatric subjects 12 years of age and older are provided in Table 7. Exposures in pediatric subjects were similar to those observed in adults. Table 7 Pharmacokinetic Properties of SOVALDI in HCV-infected Pediatric Subjects 12 Years of Age and Oldera Geometric Mean Sofosbuvirb GS-331007b AUCtau (ng•hr/mL) 1060 7570 Cmax (ng/mL) 472 572 a.Population PK derived parameters b.Sofosbuvir N=28; GS-331007 N=50 The pharmacokinetics of sofosbuvir have not been established in pediatric subjects less than 12 years of age [see Use In Specific Populations]. Geriatric Patients Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007 [see Use In Specific Populations]. Patients With Renal Impairment The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73m2), moderate (eGFR between 30 to less than 50 mL/min/1.73m2), severe renal impairment (eGFR less than 30 mL/min/1.73m2) and subjects with end stage renal disease (ESRD) requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73m2), the sofosbuvir AUC0-inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0inf 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, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose. No dosage adjustment is required for patients with mild or moderate renal impairment. The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment or ESRD. No dosage recommendation can be given for patients with severe renal impairment or ESRD [see DOSAGE AND ADMINISTRATION and Use In Specific Populations]. Patients With Hepatic Impairment The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dosage adjustment of SOVALDI is recommended for patients with mild, moderate or severe hepatic impairment [see Use In Specific Populations]. Assessment Of Drug Interactions Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not recommended [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters. The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs. The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table 8. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 9 [see DRUG INTERACTIONS]. Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir and the Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered Druga Coadministered Drug Dose of Coadministered Drug (mg) Sofosbuvir Dose (mg) N Mean Ratio (90% CI) of Sofosbuvir and GS331007 PK With/Without Coadministered Drug No Effect=1.00 Cmax AUC Cmin Cyclosporine 600 single dose 400 single dose 19 sofosbuvir 2.54 (1.87, 3.45) 4.53 (3.26, 6.30) NA GS-331007 0.60 (0.53, 0.69) 1.04 (0.90, 1.20) NA Darunavir (boosted with ritonavir) 800/100 once daily 400 single dose 18 sofosbuvir 1.45 (1.10, 1.92) 1.34 (1.12, 1.59) NA GS-331007 0.97 (0.90, 1.05) 1.24 (1.18, 1.30) NA Efavirenzc 600 once daily 400 single dose 16 sofosbuvir 0.81 (0.60, 1.10) 0.94 (0.76, 1.16) NA Emtricitabinec 200 once daily Tenofovir disoproxil fumaratec 300 once daily GS-331007 0.77 (0.70, 0.84) 0.84 (0.76, 0.92) NA Methadone 30 to 130 once daily 400 once daily 14 sofosbuvir 0.95b (0.68, 1.33) 1.30b (1.00, 1.69) NA GS-331007 0.73b (0.65, 0.83) 1.04b (0.89, 1.22) NA Rilpivirine 25 once daily 400 single dose 17 sofosbuvir 1.21 (0.90, 1.62) 1.09 (0.94, 1.27) NA GS-331007 1.06 (0.99, 1.14) 1.01 (0.97, 1.04) NA Tacrolimus 5 single dose 400 single dose 16 sofosbuvir 0.97 (0.65, 1.43) 1.13 (0.81, 1.57) NA GS-331007 0.97 (0.83, 1.14) 1.00 (0.87, 1.13) NA NA = not available/not applicable a.All interaction studies conducted in healthy volunteers b.Comparison based on historic control c.Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was observed with raltegravir. Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvira Coadministered Drug Dose of Coadministered Drug (mg) Sofosbuvir Dose (mg) N Mean Ratio (90% CI) of Coadministered Drug PK With/Without Sofosbuvir No Effect=1.00 Cmax AUC Cmin Norelgestromin norgestimate 0.18/0.215/0.25/ ethinyl estradiol 0.025 once daily 400 once daily 15 1.07 (0.94, 1.22) 1.06 (0.92, 1.21) 1.07 (0.89, 1.28) Norgestrel 1.18 (0.99, 1.41) 1.19 (0.98, 1.45) 1.23 (1.00, 1.51) Ethinyl estradio 1.15 (0.97, 1.36) 1.09 (0.94, 1.26) 0.99 (0.80, 1.23) Raltegravir 400 twice daily 400 single dose 19 0.57 (0.44, 0.75) 0.73 (0.59, 0.91) 0.95 (0.81, 1.12) Tacrolimus 5 single dose 400 single dose 16 0.73 (0.59, 0.90) 1.09 (0.84, 1.40) NA Tenofovir disoproxil fumarateb 300 once daily 400 single dose 16 1.25 (1.08, 1.45) 0.98 (0.91, 1.05) 0.99 (0.91, 1.07) NA = not available/not applicable a.All interaction studies conducted in healthy volunteers b.Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, or rilpivirine. Microbiology Mechanism Of Action Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential 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 genotype 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 micromolar. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. Antiviral Activity In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from 0.014 to 0.11 micromolar. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 micromolar for genotype 1a (range 0.029–0.128 micromolar; N=67), 0.102 micromolar for genotype 1b (range 0.045–0.170 micromolar; N=29), 0.029 micromolar for genotype 2 (range 0.014–0.081 micromolar; N=15) and 0.081 micromolar for genotype 3a (range 0.024–0.181 micromolar; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 micromolar, respectively. The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Resistance In Cell Culture HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. An M289L substitution developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2-to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types. In Clinical Trials In a pooled analysis of 982 subjects who received SOVALDI in Phase 3 trials, 224 subjects had post-baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%). Treatment-emergent substitutions L159F (n=6) and V321A (n=5) were detected in post-baseline samples from GT3a-infected subjects across the Phase 3 trials. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. The sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials. However, an S282T substitution was detected in one genotype 2b subject who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P79770523 [ELECTRON]. The isolate from this subject displayed a mean 13.5-fold reduced susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer detectable at Week 12 post-treatment by next generation sequencing with an assay cutoff of 1%. In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse). Furthermore, the presence of substitutions L159F and/or C316N at baseline was associated with sofosbuvir breakthrough and relapse post-transplant in multiple subjects infected with GT1b HCV. In addition, S282R and L320F substitutions were detected on-treatment by next generation sequencing in a subject infected with GT1a HCV with a partial treatment response. The clinical significance of these substitutions is not known. Cross Resistance HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were susceptible to NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirinassociated substitutions T390I and F415Y were susceptible to sofosbuvir. Sofosbuvir was active against HCV replicons with NS3/4A protease inhibitor, NS5B non-nucleoside inhibitor and NS5A inhibitor resistant variants. Clinical Studies Description Of Clinical Trials The safety and efficacy of SOVALDI was evaluated in five Phase 3 trials in a total of 1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C virus, one Phase 3 trial in 223 HCV/HIV-1 coinfected subjects with genotype 1, 2 or 3 HCV, and one trial in 50 pediatric subjects 12 years of age and older with genotype 2 or 3 HCV, as summarized in Table 10 [see Clinical Trials In Subjects With Genotype 1 Or 4 HCV, Clinical Trials In Subjects With Genotype 2 Or 3 HCV, Clinical Trials In Adult Subjects Coinfected With HCV And HIV-1 and Clinical Trial In Pediatrics]. Table 10 Trials Conducted with SOVALDI with Peginterferon Alfa and/or Ribavirin in Subjects with Chronic HCV Genotype 1, 2, 3, or 4 Infection Trial Population Study Arms (Number of Subjects Treated) NEUTRINO Treatment naïve (TN) (GT1, 4, 5 or 6) SOVALDI+Peg-IFN alfa+RBV 12 weeks (327) FISSION TN (GT2 or 3) SOVALDI+RBV 12 Weeks (256) Peg-IFN alfa+RBV 24 weeks (243) POSITRON Interferon intolerant, ineligible or unwilling subjects (GT2 or 3) SOVALDI+RBV 12 Weeks (207) Placebo 12 weeks (71) FUSION Previous interferon relapsers or nonresponders (GT2 or 3) SOVALDI+RBV 12 Weeks (103) SOVALDI+RBV 16 Weeks (98) VALENCE TN or previous interferon relapsers or nonresponders (GT2 or 3) SOVALDI+RBV 12 Weeks for GT2 (73) SOVALDI+RBV 12 Weeks for GT3 (11) SOVALDI+RBV 24 Weeks for GT3 (250) Placebo for 12 weeks (85) PHOTON-1 HCV/HIV-1 coinfected TN (GT1) HCV/HIV-1 coinfected TN or previous interferon relapsers or nonresponders (GT2 or 3) SOVALDI+RBV 24 Weeks for GT1 (114) SOVALDI+RBV 12 Weeks for GT2 or 3 TN (68) SOVALDI+RBV 24 Weeks for GT2 or 3 previous interferon relapsers or nonresponders (41) Study 1112 (open-label) GT2 or GT3 pediatric subjects 12 years of age and older SOVALDI+RBV 12 Weeks for GT2 (13) SOVALDI+RBV 24 Weeks for GT3 (37) Subjects in the adult trials did not have cirrhosis or had compensated cirrhosis. SOVALDI was administered at a dose of 400 mg once daily. The ribavirin (RBV) dosage for adult subjects was weight-based at 1000-1200 mg daily administered in two divided doses when used in combination with SOVALDI, and the peginterferon alfa 2a dosage, where applicable, was 180 micrograms per week. Treatment duration was fixed in each trial and was not guided by subjects’ HCV RNA levels (no response guided algorithm). Plasma 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. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR12) was the primary endpoint which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment. Clinical Trials In Subjects With Genotype 1 Or 4 HCV Treatment-Naïve Adults – NEUTRINO (Study 110) NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with SOVALDI in combination with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical control. Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the subjects were male; 79% were White, 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1; 9% had HCV genotype 4 and 2% had HCV genotype 5 or 6. Table 11 presents the SVR12 for the treatment group of SOVALDI + peginterferon alfa + ribavirin in subjects with genotype 1 or 4 HCV. Available data on subjects with genotype 5 or 6 HCV treated with SOVALDI + peginterferon alfa + ribavirin for 12 weeks were insufficient for dosing recommendations; therefore these results are not presented in Table 11 [see Use In Specific Populations]. Table 11 Study NEUTRINO: SVR12 for Treatment-Naïve Subjects with Genotype 1 or 4 HCV SOVALDI + Peg-IFN alfa + RBV 12 weeks N=320 Overall SVR 90% (289/320) Genotype 1a 90% (262/292) Genotype 1a 92% (206/225) Genotype 1b 83% (55/66) Genotype 4 96% (27/28) Outcome for subjects without SVR On-treatment virologic failure 0/320 Relapseb 9% (28/319) Otherc 1% (3/320) a.One subject had genotype 1a/1b mixed infection. b.The denominator for relapse is the number of subjects with HCV RNA 800,000 IU/mL 71% (37/52) SVR12 rates were 99% (89/90) in subjects with genotype 1 or 4 HCV and baseline IL28B C/C allele and 87% (200/230) in subjects with genotype 1 or 4 HCV and baseline IL28B non-C/C alleles. It is estimated that the SVR12 in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed SVR12 in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment (Table 12). The SVR12 rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA greater than 800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52). Clinical Trials In Subjects With Genotype 2 Or 3 HCV Treatment-Naïve Adults – FISSION (Study 1231) FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks of treatment with SOVALDI and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 2 and 3 HCV. The ribavirin dosage used in the SOVALDI + ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 1000-1200 mg per day and 800 mg per day regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified by cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA level (less than 6 log10 IU/mL vs. at least 6 log10 IU/mL). Subjects with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio. Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the subjects were male; 87% were White, 3% were Black; 14% were Hispanic or Latino; mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype 3. Table 13 presents the SVR12 for the treatment groups of SOVALDI + ribavirin and peginterferon alfa + ribavirin in subjects with genotype 2 HCV. SVR12 for genotype 3 subjects treated with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these results are not presented in Table 13. Table 13 Study FISSION: SVR12 in Treatment-Naïve Subjects with Genotype 2 HCV SOVALDI + RBV 12 weeks Peg-IFN alfa + RBV 24 weeks N=73a N=67a SVR12 95% (69/73) 78% (52/67) Outcome for subjects without SVR12 On-treatment virologic failure 0/73 4% (3/67) Relapseb 5% (4/73) 15% (9/62) Otherc 0/73 4% (3/67) a.Including three subjects with recombinant genotype 2/1 HCV infection. b.The denominator for relapse is the number of subjects with HCV RNA

Drug Description

Find Lowest Prices on SOVALDI® (sofosbuvir) Tablets WARNING RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with SOVALDI. 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]. DESCRIPTION SOVALDI (sofosbuvir) is a nucleotide analog inhibitor of HCV NS5B polymerase. The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir 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. SOVALDI tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

Indications & Dosage

INDICATIONS Adult Patients SOVALDI is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection as a component of a combination antiviral treatment regimen [see DOSAGE AND ADMINISTRATION, and Clinical Studies] genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis for use in combination with pegylated interferon and ribavirin genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin. Pediatric Patients SOVALDI is indicated for the treatment of chronic HCV genotype 2 or 3 infection in pediatric patients 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis for use in combination with ribavirin [see DOSAGE AND ADMINISTRATION and Clinical Studies]. DOSAGE AND ADMINISTRATION Testing Prior To The Initiation Of Therapy 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 SOVALDI [see WARNINGS AND PRECAUTIONS]. Recommended Dosage In Adults The recommended dosage of SOVALDI is one 400 mg tablet, taken orally, once daily with or without food [see CLINICAL PHARMACOLOGY]. Administer SOVALDI in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of HCV. The recommended treatment regimen and duration for SOVALDI combination therapy is provided in Table 1. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimen and Duration in Adult Patients with Genotype 1, 2, 3, or 4 HCV Patient Population Treatment Regimen and Duration Genotype 1 or 4 Treatment-naïve without cirrhosis or with compensated cirrho SOVALDI + peginterferon alfaa + ribavirinb 12 weeks Genotype 2 Treatment-naïve and treatment-experiencedc without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirinb 12 weeks Genotype 3 Treatment-naïve and treatment-experiencedc without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirinb24 weeks a.See peginterferon alfa prescribing information for dosage recommendation for patients with genotype 1 or 4 HCV. b.Dosage of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dosage of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require ribavirin dosage reduction; refer to ribavirin prescribing information. c.Treatment-experienced patients have failed an interferon based regimen with or without ribavirin. Patients With Genotype 1 HCV Who Are Ineligible To Receive An Interferon-Based Regimen SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for patients with genotype 1 infection who are ineligible to receive an interferon-based regimen [see Clinical Studies]. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient. Patients With Hepatocellular Carcinoma Awaiting Liver Transplantation Administer SOVALDI in combination with ribavirin for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection [see Use In Specific Populations]. Recommended Dosage In Pediatric Patients 12 Years Of Age And Older Or Weighing At Least 35 kg The recommended dosage of SOVALDI in pediatric patients 12 years of age and older or weighing at least 35 kg is one 400 mg tablet taken orally once daily with or without food in combination with ribavirin [see CLINICAL PHARMACOLOGY and Clinical Studies]. The recommended treatment regimen and duration for SOVALDI combination therapy is provided in Table 2. Table 3 provides the weight-based dosage of ribavirin when used in combination with SOVALDI for pediatric patients. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 2 and Table 3. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 2 Recommended Treatment Regimen and Duration in Pediatric Patients 12 Years of Age and Older or Weighing at Least 35 kg Patient Population Treatment Regimen and Duration Genotype 2 Treatment-naïve and treatmentexperienceda without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirinb 12 weeks Genotype 3 Treatment-naïve and treatmentexperienceda without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOVALDI + ribavirinb 24 weeks a.Treatment-experienced patients have failed an interferon based regimen with or without ribavirin. b.See Table 3 for weight-based ribavirin dosing recommendations. Table 3 Recommended Dosing for Ribavirin in Combination Therapy with SOVALDI for Pediatric Patients 12 Years of Age and Older or Weighing at Least 35 kg Body Weight kg Ribavirin Daily Dosagea less than 47 15 mg/kg/day 47–49 600 mg/day 50–65 800 mg/day 66–80 1000 mg/day greater than 80 1200 mg/day a. The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. Dosage Modification Dosage reduction of SOVALDI is not recommended. If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dosage should be reduced or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dosage. Discontinuation Of Dosing If the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued. Severe Renal Impairment And End Stage Renal Disease No dosage recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. HOW SUPPLIED Dosage Forms And Strengths SOVALDI is available as a yellow-colored, capsule-shaped, film-coated tablet debossed with “GSI” on one side and “7977” on the other side. Each tablet contains 400 mg sofosbuvir. Storage And Handling SOVALDI tablets are yellow, capsule-shaped, film-coated tablets containing 400 mg sofosbuvir debossed with “GSI” on one side and “7977” on the other side. Each bottle contains 28 tablets (NDC 61958-1501-1), a silica gel desiccant and polyester coil with a child-resistant closure. Store at room temperature below 30°C (86°F). Dispense only in original container Do not use if seal over bottle opening is broken or missing Manufactured and distributed by: Gilead Sciences, Inc.Foster City, CA 94404. Revised: April 2017.

Medication Guide

PATIENT INFORMATION SOVALDI® (soh-VAHL-dee) (sofosbuvir) Tablets Important: SOVALDI is used in combination with other antiviral medicines. When taking SOVALDI with ribavirin or in combination with peginterferon alfa and ribavirin you should also read those Medication Guides.The information in this Patient Information Leaflet talks about SOVALDI when it is used with ribavirin and in combination with peginterferon alfa and ribavirin. What is the most important information I should know about SOVALDI? SOVALDI can cause serious side effects, including: Hepatitis B virus reactivation: Before starting treatment with SOVALDI, your healthcare provider will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment of hepatitis C virus with SOVALDI. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking SOVALDI. For more information about side effects, see the section “What are the possible side effects of SOVALDI?” What is SOVALDI? SOVALDI is a prescription medicine used with other antiviral medicines to treat adults with chronic (lasting a long time) hepatitis C virus (HCV): genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis in combination with peginterferon alfa and ribavirin genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with ribavirin SOVALDI is used to treat children 12 years of age and older or weighing at least 77 pounds (at least 35 kg) with chronic HCV genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with ribavirin. It is not known if SOVALDI is safe and effective in children under 12 years of age and weighing less than 77 pounds (less than 35 kg) with HCV genotype 2 or 3 infection, or with HCV genotype 1 or 4 infection. It is not known if SOVALDI is safe and effective in people who have had a liver transplant. Before taking SOVALDI, tell your healthcare provider about all of your medical conditions, including if you: have ever had hepatitis B virus infection have liver problems other than hepatitis C infection have had a liver transplant have severe kidney problems or you are on dialysis have HIV infection are pregnant or plan to become pregnant. It is not known if SOVALDI will harm your unborn baby. Males and females who take SOVALDI in combination with ribavirin should also read the ribavirin Medication Guide for important pregnancy, contraception, and infertility information. are breastfeeding or plan to breastfeed. It is not known if SOVALDI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with SOVALDI. Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. SOVALDI and other medicines may affect each other. This can cause you to have too much or not enough SOVALDI or other medicines in your body. This may affect the way SOVALDI or your other medicines work, or may cause side effects. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with SOVALDI. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take SOVALDI with other medicines. How should I take SOVALDI? Take SOVALDI exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to. Do not stop taking SOVALDI without first talking with your healthcare provider. Take 1 SOVALDI tablet one time each day only. Take SOVALDI with or without food. If you take too much SOVALDI, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of SOVALDI? SOVALDI can cause serious side effects, including: Hepatitis B virus reactivation. See “What is the most important information I should know about SOVALDI?” Slow heart rate (bradycardia). SOVALDI treatment may result in slowing of the heart rate along with other symptoms when taken with amiodarone (Cordarone®, Nexterone®, Pacerone®), a medicine used to treat certain heart problems. In some cases bradycardia has led to death or the need for a heart pacemaker when amiodarone is taken with SOVALDI. Get medical help right away if you take amiodarone with SOVALDI and get any of the following symptoms: fainting or near-fainting dizziness or lightheadedness not feeling well weakness extreme tiredness shortness of breath chest pain confusion memory problems The most common side effects of SOVALDI when used in combination with ribavirin include: tiredness headache The most common side effects of SOVALDI when used in combination with peginterferon alfa and ribavirin include: tiredness headache nausea difficulty sleeping low red blood cell count These are not all the possible side effects of SOVALDI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088. How should I store SOVALDI? Store SOVALDI at room temperature below 86°F (30°C). Keep SOVALDI in its original container. Do not use SOVALDI if the seal over the bottle opening is broken or missing. Keep SOVALDI and all medicines out of the reach of children. General information about the safe and effective use of SOVALDI. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SOVALDI for a condition for which it was not prescribed. Do not give SOVALDI to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about SOVALDI that is written for health professionals. For more information, call 1-800-445-3235 or go to www.SOVALDI.com. What are the ingredients in SOVALDI? Active ingredient: sofosbuvir Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablet film-coat contains polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

Overdosage & Contraindications

OVERDOSE The highest documented dosage of sofosbuvir was a single dose of sofosbuvir 1200 mg (three times the recommended dosage) administered to 59 healthy subjects. In that trial, there were no untoward effects observed at this dosage level, and adverse events were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher dosages are not known. No specific antidote is available for overdose with SOVALDI. If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with SOVALDI consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. A 4-hour hemodialysis session removed 18% of the administered dose. CONTRAINDICATIONS When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

Side Effects & Drug Interactions

SIDE EFFECTS The following serious adverse reactions are described below and elsewhere in the labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see WARNINGS AND PRECAUTIONS]. 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. When SOVALDI is administered with ribavirin or peginterferon alfa/ribavirin, refer to the respective prescribing information for a description of adverse reactions associated with their use. Adverse Reactions In Adult Subjects The safety assessment of SOVALDI was based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including: 650 subjects who received SOVALDI + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks, 250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks, 327 subjects who received SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks, and 71 subjects who received placebo (PBO) for 12 weeks [see Clinical Studies]. The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI + ribavirin for 12 weeks, less than 1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks. Adverse events observed in at least 15% of subjects in the Phase 3 clinical trials outlined above are provided in Table 4. A side-by-side tabulation is displayed to simplify presentation; direct comparison across trials should not be made due to differing trial designs. The most common adverse events (at least 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (at least 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia. Table 4 Adverse Events (All Grades and without Regard to Causality) Reported in .15% of Subjects with HCV in Any Treatment Arm Interferon-free Regimens Interferon-containing Regimens PBO 12 weeks SOVALDI + RBVa 12 weeks SOVALDI + RBVa 24 weeks Peg-IFN alfa + RBVb 24 weeks SOVALDI + Peg-IFN alfa + RBVa 12 weeks N=71 N=650 N=250 N=243 N=327 Fatigue 24% 38% 30% 55% 59% Headache 20% 24% 30% 44% 36% Nausea 18% 22% 13% 29% 34% Insomnia 4% 15% 16% 29% 25% Pruritus 8% 11% 27% 17% 17% Anemia 0% 10% 6% 12% 21% Asthenia 3% 6% 21% 3% 5% Rash 8% 8% 9% 18% 18% Decreased Appetite 10% 6% 6% 18% 18% Chills 1% 2% 2% 18% 17% Influenza Like Illness 3% 3% 6% 18% 16% Pyrexia 0% 4% 4% 14% 18% Diarrhea 6% 9% 12% 17% 12% Neutropenia 0% <1% <1% 12% 17% Myalgia 0% 6% 9% 16% 14% Irritability 1% 10% 10% 16% 13% a.Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing≥75 kg). b.Subjects received 800 mg ribavirin per day regardless of weight. With the exception of anemia and neutropenia, the majority of events presented in Table 4 occurred at severity of grade 1 in SOVALDI-containing regimens. Less Common Adverse Reactions Reported in Clinical Trials (less than 1%) The following adverse reactions occurred in less than 1% of subjects receiving SOVALDI in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship. Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant pegylated interferon). Psychiatric Disorders: severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide. Laboratory Abnormalities: Changes in selected hematological parameters are described in Table 5. A side-by-side tabulation is displayed to simplify presentation; direct comparison across trials should not be made due to differing trial designs. Table 5 Percentage of Subjects Reporting Selected Hematological Parameters Hematological Parameters Interferon-free Regimens Interferon-containing Regimens PBO 12 weeks SOVALDI + RBVa 12 weeks SOVALDI + RBVa 24 weeks Peg-IFN alfa + RBVb 24 weeks SOVALDI + Peg-IFN alfa + RBVa 12 weeks N=71 N=650 N=250 N=243 N=327 Hemoglobin (g/dL) <10 0 8% 6% 14% 23% <8.5 1% <1% 2% 2% Neutrophils (x109/L) ≥0.5 – <0.75 1% <1% 12% 15% <0.5 <1% 2% 5% Platelets (x109/L) ≥25 – <50 3% <1% 1% 7% <1% <25 0 0 0 0 0 a.Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing ≥75 kg). b.Subjects received 800 mg ribavirin per day regardless of weight. Bilirubin Elevations Total bilirubin elevation of more than 2.5xULN was observed in none of the subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations. Creatine Kinase Elevations Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10xULN was observed in less than 1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin 12 weeks groups, respectively. Lipase Elevations Isolated, asymptomatic lipase elevation of greater than 3xULN was observed in less than 1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively. Patients With HCV/HIV-1 Coinfection SOVALDI used in combination with ribavirin was assessed in 223 HCV/HIV-1 coinfected subjects [see Clinical Studies]. The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials. Adverse Reactions In Pediatric Subjects 12 Years Of Age And Older The safety assessment of SOVALDI in pediatric subjects 12 years of age and older is based on data from 50 subjects who were treated with SOVALDI plus ribavirin for 12 weeks (genotype 2 subjects) or 24 weeks (genotype 3 subjects) in a Phase 2, open-label clinical trial. The adverse reactions observed were consistent with those observed in clinical studies of SOVALDI plus ribavirin in adults [see Clinical Studies]. Postmarketing Experience The following adverse reactions have been identified during post approval use of SOVALDI. 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 a sofosbuvir-containing regimen [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]. DRUG INTERACTIONS Potentially Significant Drug Interactions Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while the predominant circulating metabolite GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not recommended [see WARNINGS AND PRECAUTIONS]. Information on potential drug interactions with SOVALDI is summarized in Table 6. The table is not all-inclusive [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Table 6 Potentially Significant Drug Interactions: Alteration in Dosage or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interactiona Concomitant Drug Class: Drug Name Effect on Concentrationb Clinical Comment Antiarrhythmics:amiodarone Effect on amiodarone and sofosbuvir concentrations unknown Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with SOVALDI is not recommended; if coadministration is required, cardiac monitoring is recommended [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]. Anticonvulsants:Carbamazepinephenytoinphenobarbitaloxcarbazepine ↓ sofosbuvir↓ GS-331007 Coadministration of SOVALDI with carbamazepine,phenytoin, phenobarbital or oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministrationis not recommended. Antimycobacterials:Rifabutinrifampinrifapentine ↓ sofosbuvir ↓ GS-331007 Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir,leading to reduced therapeutic effect of SOVALDI.Coadministration is not recommended. Coadministration of SOVALDI with rifampin, an intestinal P-gp inducer, is not recommended [see WARNINGS AND PRECAUTIONS]. Herbal Supplements:St. John’s wort (Hypericum perforatum) ↓ sofosbuvir ↓ GS-331007 Coadministration of SOVALDI with St. John’s wort, an intestinal P-gp inducer, is not recommended [see WARNINGS AND PRECAUTIONS]. HIV Protease Inhibitors:tipranavir/ritonavir ↓ sofosbuvir ↓ GS-331007 Coadministration of SOVALDI with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended. a.This table is not all-inclusive. b.↓= decrease. Drugs Without Clinically Significant Interactions With SOVALDI In addition to the drugs included in Table 6, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug [See CLINICAL PHARMACOLOGY]: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

Warnings & Precautions