was resolute [1%),:<1%). No Grade 3 or 4 photosensitivity reactions were reported and none of the subjects discontinued treatment due to photosensitivity reactions. Laboratory Abnormalities Among subjects who received Olysio in combination with sofosbuvir, the most common Grade 3 and 4 laboratory abnormalities were amylase and lipase elevations (Table 5). Most elevations in amylase and lipase were transient and of mild or moderate severity. Amylase and lipase elevations were not associated with pancreatitis. Table 5: Laboratory Abnormalities (WHO Worst Toxicity Grades 1 to 4) in Amylase, Hyperbilirubinemia and Lipase in Subjects Receiving 12 or 24 Weeks of Olysio in Combination with Sofosbuvir * Laboratory Parameter WHO Toxicity Range 12 Weeks Olysio + Sofosbuvir N=286 % 24 Weeks Olysio + Sofosbuvir N=31 % Chemistry * The 12 week group represents subjects pooled from COSMOS, OPTIMIST-1, and OPTIMIST-2 trials. The 24 week group represents subjects from COSMOS trial. No Grade 4 changes in amylase were observed. ULN = Upper Limit of Normal Amylase Grade 1 1.1 to 1.5 ULN 12 26 Grade 2> 1.5 to 2.0 ULN 5 6 Grade 3 > 2.0 to 5.0 ULN 5 10 Hyperbilirubinemia Grade 1 1.1 to 1.5 ULN 12 16 Grade 2 > 1.5 to 3.0 ULN 3 3 Grade 3 > 3.0 to 5.0 ULN <1 0 Grade 4> 5.0 ULN 0 3 Lipase Grade 1 1.1 to 1.5 ULN 5 3 Grade 2 > 1.5 to 3.0 ULN 8 10 Grade 3 > 3.0 to 5.0 ULN <1 3 Grade 4> 5.0 ULN <1 3 Olysio in Combination with Peg-IFN-alfa and RBV The safety profile of Olysio in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection is based on pooled data from three Phase 3 trials (QUEST-1, QUEST-2 and PROMISE) [see Clinical Studies (14.3) ] . These trials included a total of 1178 subjects who received Olysio or placebo in combination with 24 or 48 weeks of Peg-IFN-alfa and RBV. Of the 1178 subjects, 781 subjects were randomized to receive Olysio 150 mg once daily for 12 weeks and 397 subjects were randomized to receive placebo once daily for 12 weeks. In the pooled Phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with Olysio in combination with Peg-IFN-alfa and RBV were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving Olysio in combination with Peg-IFN-alfa and RBV versus 25% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Serious adverse reactions were reported in 2% of subjects receiving Olysio in combination with Peg-IFN-alfa and RBV and in 3% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Discontinuation of Olysio or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving Olysio with Peg-IFN-alfa and RBV and subjects receiving placebo with Peg-IFN-alfa and RBV, respectively. Table 6 lists adverse reactions (all Grades) that occurred with at least 3% higher frequency among subjects with HCV genotype 1 infection receiving Olysio 150 mg once daily in combination with Peg-IFN-alfa and RBV, compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, during the first 12 weeks of treatment in the pooled Phase 3 trials in subjects who were treatment-naïve or who had previously relapsed after Peg-IFN-alfa and RBV therapy. Table 6: Adverse Reactions (all Grades) that occurred 3% Higher Frequency Among Subjects with HCV Genotype 1 Infection Receiving Olysio Combination with Peg-IFN-alfa and RBV Compared to Subjects Receiving Placebo in Combination with Peg-IFN-alfa and RBV During the First 12 Weeks of Treatment in Subjects with Chronic HCV Infection * (Pooled Phase 3 ) Adverse Reaction Olysio 150 mg + Peg-IFN-alfa+ RBV First 12 Weeks N=781 % (n) Placebo + Peg-IFN-alfa+ RBV First 12 Weeks N=397 % (n) * Subjects were treatment-naïve or had previously relapsed after Peg-IFN-alfa and RBV therapy. Pooled Phase 3 trials: QUEST 1, QUEST 2, PROMISE. Adverse reactions that occurred at 3% higher frequency in the Olysio treatment group than in the placebo treatment group. Rash (including photosensitivity) 28 (218) 20 (79) Pruritus 22 (168) 15 (58) Nausea 22 (173) 18 (70) Myalgia 16 (126) 13 (53) Dyspnea 12 (92) 8 (30) Rash and Photosensitivity In the Phase 3 clinical trials of Olysio or placebo in combination with Peg-IFN-alfa and RBV, rash (including photosensitivity reactions) was observed in 28% of Olysio-treated subjects compared to 20% of placebo-treated subjects during the 12 weeks of treatment with Olysio or placebo in combination with Peg-IFN-alfa and RBV. Fifty-six percent (56%) of rash events in the Olysio group occurred in the first 4 weeks, with 42% of cases occurring in the first 2 weeks. Most of the rash events in Olysio-treated subjects were of mild or moderate severity (Grade 1 or 2). Severe (Grade 3) rash occurred in 1% of Olysio-treated subjects and in none of the placebo-treated subjects. There were no reports of life-threatening (Grade 4) rash. Discontinuation of Olysio or placebo due to rash occurred in 1% of Olysio-treated subjects, compared to less than 1% of placebo-treated subjects. The frequencies of rash and photosensitivity reactions were higher in subjects with higher simeprevir exposures. All subjects enrolled in the Phase 3 trials were directed to use sun protection measures. In these trials, adverse reactions under the specific category of photosensitivity were reported in 5% of Olysio-treated subjects compared to 1% of placebo-treated subjects during the 12 weeks of treatment with Olysio or placebo in combination with Peg-IFN-alfa and RBV. Most photosensitivity reactions in Olysio-treated subjects were of mild or moderate severity (Grade 1 or 2). Two Olysio-treated subjects experienced photosensitivity reactions which resulted in hospitalization. No life-threatening photosensitivity reactions were reported. Dyspnea During the 12 weeks of treatment with Olysio or placebo in combination with Peg-IFN-alfa and RBV, dyspnea was reported in 12% of Olysio-treated subjects compared to 8% of placebo-treated subjects (all grades; pooled Phase 3 trials). All dyspnea events reported in Olysio-treated subjects were of mild or moderate severity (Grade 1 or 2). There were no Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment with Olysio due to dyspnea. Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with Olysio. Laboratory Abnormalities Among subjects who received Olysio or placebo plus Peg-IFN-alfa and RBV, there were no differences between treatment groups for the following laboratory parameters: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, or serum creatinine. Laboratory abnormalities that were observed at a higher incidence in Olysio-treated subjects than in placebo-treated subjects are listed in Table 7. Table 7: Laboratory Abnormalities (WHO Worst Toxicity Grades 1 to 4) Observed at a Higher Incidence in Olysio-Treated Subjects (Pooled Phase 3 * ; First 12 Weeks of Treatment) Laboratory Parameter WHO Toxicity Range Olysio 150 mg + Peg-IFN-alfa + RBV N=781 % Placebo + Peg-IFN-alfa + RBV N=397 % * Pooled Phase 3 trials: QUEST 1, QUEST 2, PROMISE. No Grade 3 or 4 changes in alkaline phosphatase were observed. ULN = Upper Limit of Normal Chemistry Alkaline phosphatase Grade 1> 1.25 to 2.50 ULN 3 1 Grade 2 > 2.50 to 5.00 ULN <1 0 Hyperbilirubinemia Grade 1> 1.1 to 1.5 ULN 27 15 Grade 2 > 1.5 to 2.5 ULN 18 9 Grade 3 > 2.5 to 5.0 ULN 4 2 Grade 4 > 5.0 ULN < 1 0 Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of Olysio. Bilirubin elevations were generally not associated with elevations in liver transaminases. The frequency of elevated bilirubin was higher in subjects with higher simeprevir exposures. Adverse Reactions in HCV/HIV-1 Co-infection Olysio in combination with Peg-IFN-alfa and RBV was studied in 106 subjects with HCV genotype 1/HIV-1 co-infection (C212). The safety profile in HCV/HIV co-infected subjects was generally comparable to HCV mono-infected subjects. Adverse Reactions in HCV Genotype 4 Infection Olysio in combination with Peg-IFN-alfa and RBV was studied in 107 subjects with HCV genotype 4 infection (RESTORE). The safety profile of Olysio in subjects with HCV genotype 4 infection was comparable to subjects with HCV genotype 1 infection. Adverse Reactions in East Asian Subjects Olysio in combination with Peg-IFN-alfa and RBV was studied in a Phase 3 trial conducted in China and South Korea in treatment-naïve subjects with chronic HCV genotype 1 infection (TIGER). The safety profile of Olysio in East Asian subjects was similar to that of the pooled Phase 3 population from global trials; however, a higher incidence of the laboratory abnormality hyperbilirubinemia was observed in patients receiving 150 mg Olysio plus Peg-IFN-alfa and RBV compared to patients receiving placebo plus Peg-IFN-alfa and RBV. Elevation of total bilirubin (all grades) was observed in 66% (99/151) of subjects treated with 150 mg Olysio plus Peg-IFN-alfa and RBV and in 26% (40/152) of subjects treated with placebo plus Peg-IFN-alfa and RBV. Bilirubin elevations were mainly Grade 1 or Grade 2. Grade 3 elevations in bilirubin were observed in 9% (13/151) of subjects treated with 150 mg Olysio plus Peg-IFN-alfa and RBV and in 1% (2/152) of subjects treated with placebo plus Peg-IFN-alfa and RBV. There were no Grade 4 elevations in bilirubin. The bilirubin elevations were not associated with increases in liver transaminases and were reversible after the end of treatment [see Use in Specific Populations (8.6) and Clinical Studies (14.3) ]. Postmarketing Experience The following adverse reactions have been reported during post approval use of Olysio. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship between drug exposure and these adverse reactions. Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with a sofosbuvir-containing regimen [see Warnings and Precautions (5.2) and Drug Interactions (7.3) ]. Hepatobiliary Disorders: hepatic decompensation, hepatic failure [see Warnings and Precautions (5.3) ] . Drug Interactions Potential for Olysio to Affect Other Drugs Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Coadministration of Olysio with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs (see Table 8 ). Simeprevir inhibits OATP1B1/3, P-glycoprotein (P-gp) and BCRP transporters, and does not inhibit OCT2 in vitro . Coadministration of Olysio with drugs that are substrates for OATP1B1/3, and P-gp and BCRP transport may result in increased plasma concentrations of such drugs (see Table 8 ). Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with Olysio. Close monitoring of INR values is recommended during treatment and post-treatment follow-up. Potential for Other Drugs to Affect Olysio The primary enzyme involved in the biotransformation of simeprevir is CYP3A [see Clinical Pharmacology (12.3) ] . Clinically relevant effects of other drugs on simeprevir pharmacokinetics via CYP3A may occur. Coadministration of Olysio with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir. Coadministration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see Table 8 ). Therefore, coadministration of Olysio with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) ] . Established and Other Potentially Significant Drug Interactions Table 8 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of Olysio and/or coadministered drug may be recommended. Drugs that are not recommended for coadministration with Olysio are also included in Table 8. For information regarding the magnitude of interaction, see Tables 9 and 10 [see Clinical Pharmacology (12.3) ] . Table 8: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class Drug Name Effect on Concentration of Simeprevir or Concomitant Drug Clinical Comment The direction of the arrow ( = increase, = decrease, = no change) indicates the direction of the change in PK. * These interactions have been studied in healthy adults with the recommended dose of 150 mg simeprevir once daily unless otherwise noted [see Clinical Pharmacology (12.3) , Tables 9 and 10 ] . The dose of Olysio in this interaction study was 200 mg once daily both when given alone and when coadministered with rifampin 600 mg once daily. The interaction between simeprevir and ledipasvir was evaluated in a pharmacokinetic study in HCV-infected patients by comparing simeprevir exposure following simeprevir + 90/400 mg ledipasvir/sofosbuvir dosing versus simeprevir + 400 mg sofosbuvir dosing and by comparing ledipasvir exposure following simeprevir + 90/400 mg ledipasvir/sofosbuvir dosing versus 90/400 mg ledipasvir/sofosbuvir dosing. The dose of Olysio in this interaction study was 50 mg when coadministered in combination with darunavir/ritonavir, compared to 150 mg in the Olysio alone treatment group. The dose of Olysio in this interaction study was 200 mg once daily both when given alone and when coadministered in combination with ritonavir 100 mg given twice daily. # Studied in combination with daclatasvir and RBV in a Phase 2 trial in HCV-infected post-liver transplant patients. Antiarrhythmics Amiodarone Effect on amiodarone, simeprevir, and sofosbuvir concentrations unknown Coadministration of amiodarone with Olysio in combination with sofosbuvir is not recommended because it may result in serious symptomatic bradycardia. If coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.2) , Adverse Reactions (6.2) ]. amiodarone Caution is warranted and therapeutic drug monitoring of amiodarone, if available, is recommended for concomitant use of amiodarone with an Olysio-containing regimen that does not contain sofosbuvir. Digoxin * digoxin Routine therapeutic drug monitoring of digoxin concentrations is recommended. Oral administration Disopyramide, Flecainide, Mexiletine, Propafenone, Quinidine antiarrhythmics Therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when coadministered with Olysio. Anticonvulsants Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin simeprevir Coadministration is not recommended. Anti-infectives Antibiotics (systemic administration): Erythromycin * simeprevir erythromycin Coadministration is not recommended. Antibiotics (systemic administration): Clarithromycin, Telithromycin simeprevir Coadministration is not recommended. Antifungals (systemic administration): Itraconazole, Ketoconazole, Posaconazole simeprevir Coadministration is not recommended. Antifungals (systemic administration): Fluconazole, Voriconazole simeprevir Coadministration is not recommended. Antimycobacterials: Rifampin * , Rifabutin, Rifapentine simeprevir rifampin, rifabutin, rifapentine Coadministration is not recommended. Calcium Channel Blockers (oral administration) Amlodipine, Diltiazem, Felodipine, Nicardipine, Nifedipine, Nisoldipine, Verapamil calcium channel blockers Clinical monitoring of patients is recommended when Olysio is coadministered with calcium channel blockers. Corticosteroids Systemic Dexamethasone simeprevir Coadministration is not recommended. Gastrointestinal Products Propulsive: Cisapride cisapride Coadministration is not recommended. HCV Products Antiviral: Ledipasvir ledipasvir simeprevir Coadministration of Olysio with products containing ledipasvir is not recommended. Herbal Products Milk thistle ( Silybum marianum ) simeprevir Coadministration is not recommended. St. John's wort ( Hypericum perforatum ) simeprevir Coadministration of Olysio with products containing St. John's wort is not recommended. HIV Products Cobicistat-containing products simeprevir Coadministration is not recommended. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Efavirenz * simeprevir efavirenz Coadministration is not recommended. Other NNRTIs Delavirdine Etravirine, Nevirapine simeprevir simeprevir Coadministration is not recommended. Protease Inhibitors (PIs): Darunavir/ritonavir * , simeprevir darunavir Coadministration is not recommended. Protease Inhibitors (PIs): Ritonavir * , simeprevir Coadministration is not recommended. Other ritonavir-boosted or unboosted HIV PIs (Atazanavir, Fosamprenavir, Lopinavir, Indinavir, Nelfinavir, Saquinavir, Tipranavir) or simeprevir Coadministration of Olysio with any HIV PI, with or without ritonavir is not recommended. HMG CO-A Reductase Inhibitors Atorvastatin, Rosuvastatin, Simvastatin * statin Coadministration of Olysio with statins is expected to increase statin concentrations, which is associated with increased risk of myopathy, including rhabdomyolysis. Use the lowest necessary statin dose, titrate the statin dose carefully, and monitor closely for statin-associated adverse reactions, such as myopathy or rhabdomyolysis. Pitavastatin, Pravastatin, Lovastatin, Fluvastatin statin Immunosuppressants Cyclosporine * cyclosporine simeprevir # Coadministration is not recommended. Sirolimus or sirolimus Routine monitoring of blood concentrations of sirolimus is recommended. Phosphodiesterase Type 5 (PDE-5) Inhibitors Sildenafil, Tadalafil, Vardenafil PDE-5 inhibitors Dose adjustment of the PDE-5 inhibitor may be required when Olysio is coadministered with sildenafil or tadalafil administered chronically at doses used for the treatment of pulmonary arterial hypertension. Consider starting with the lowest dose of the PDE-5 inhibitor and increase as needed, with clinical monitoring as appropriate. No dose adjustment is required when Olysio is coadministered with doses of sildenafil, tadalafil or vardenafil indicated for the treatment of erectile dysfunction. Sedatives/Anxiolytics Midazolam * (oral administration) midazolam Caution is warranted when midazolam, which has a narrow therapeutic index, is coadministered with Olysio. Triazolam (oral administration) triazolam Caution is warranted when triazolam, which has a narrow therapeutic index, is coadministered with Olysio. Drugs Without Clinically Significant Interactions with Olysio In addition to the drugs included in Table 8, the interaction between Olysio and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug [see Clinical Pharmacology (12.3) ] : caffeine, daclatasvir, dextromethorphan, escitalopram, ethinyl estradiol/norethindrone, methadone, midazolam (intravenous administration), omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, and tenofovir disoproxil fumarate. No clinically relevant drug-drug interaction is expected when Olysio is coadministered with antacids, azithromycin, bedaquiline, corticosteroids (budesonide, fluticasone, methylprednisolone, and prednisone), dolutegravir, H 2 -receptor antagonists, the narcotic analgesics buprenorphine and naloxone, NRTIs (such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine), maraviroc, methylphenidate, and proton pump inhibitors. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary If Olysio is administered with RBV, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to prescribing information for RBV and for other drugs used in combination with Olysio for information on use in pregnancy. No adequate human data are available to establish whether or not Olysio poses a risk to pregnancy outcomes. In animal reproduction studies with simeprevir, embryofetal developmental toxicity (including fetal loss) was observed in mice at simeprevir exposures greater than or equal to 1.9 times higher than exposure in humans at the recommended clinical dose while no adverse embryofetal developmental outcomes were observed in mice and rats at exposures similar to the exposure in humans at the recommended clinical dose [see Data ] . Given these findings, pregnant women should be advised of potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 4% and 15 20%, respectively. Data Animal Data In embryofetal development studies in rats and mice, pregnant animals were administered simeprevir at doses up to 500 mg/kg/day (rats) and at 150, 500 and 1000 mg/kg/day (mice) on gestation days 6 to 17 (rats) and gestation days 6 to 15 (mice), resulting in late in utero fetal losses in mice at an exposure greater than or equal to 1.9 times higher than the exposure in humans at the recommended clinical dose. In addition, decreased fetal weights and an increase in fetal skeletal variations were observed in mice at exposures greater than or equal to 1.2 times higher than the exposure in humans at the recommended clinical dose. No adverse embryofetal developmental effects were observed in mice (at the lowest dose tested) or in rats (at up to the highest dose tested) at exposures similar to the exposure in humans at the recommended clinical dose. In a rat pre- and post-natal development study, maternal animals were exposed to simeprevir from gestation day 6 to lactation/post-partum day 20 at doses up to 1000 mg/kg/day. At maternally toxic doses, the developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at maternal exposures similar to the exposure in humans at the recommended clinical dose. Subsequent survival, behavior and reproductive capacity of the offspring were not affected. Lactation Risk Summary It is not known whether Olysio and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rats, simeprevir was detected in plasma of nursing pups, likely due to the presence of simeprevir in milk [see Data ] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Olysio and any potential adverse effects on the breastfed child from Olysio or from the underlying maternal condition. If Olysio is administered with RBV, the nursing mother's information for RBV also applies to this combination regimen. Refer to prescribing information for RBV and for other drugs used in combination with Olysio for more information on use during lactation. Data Animal Data Although not measured directly, simeprevir was likely present in the milk of lactating rats in the pre- and post-natal development study, because systemic exposures (AUC) of simeprevir were observed in nursing pups on lactation/post-partum day 6 at concentrations approximately 10% of maternal simeprevir exposures [see Use in Specific Populations (8.1) ] . Females and Males of Reproductive Potential If Olysio is administered with RBV, follow the recommendations for pregnancy testing and contraception within RBV's prescribing information. Refer to prescribing information for other drugs used in combination with Olysio for additional information on use in females and males of reproductive potential. Infertility There are no data on the effect of simeprevir on human fertility. Limited effects on male fertility were observed in animal studies [see Nonclinical Toxicology (13.1) ] . If Olysio is administered with RBV, the information for RBV with regard to infertility also applies to this combination regimen. In addition, refer to prescribing information for other drugs used in combination with Olysio for information on effects on fertility. Pediatric Use The safety and efficacy of Olysio in pediatric patients have not been established. Geriatric Use Clinical studies of Olysio did not include sufficient numbers of patients older than 65 years to determine whether they respond differently from younger patients. No dosage adjustment of Olysio is required in geriatric patients [see Clinical Pharmacology (12.3) ] . Race Patients of East Asian ancestry exhibit higher simeprevir plasma exposures, but no dosage adjustment is required based on race [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.3) ] . Renal Impairment No dosage adjustment of Olysio is required in patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3) ] . The safety and efficacy of Olysio have not been studied in HCV-infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end-stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir [see Clinical Pharmacology (12.3) ] . Refer to the prescribing information for the other antiviral drug(s) used in combination with Olysio regarding their use in patients with renal impairment. Hepatic Impairment No dosage adjustment of Olysio is required in patients with mild hepatic impairment (Child-Pugh A) [see Clinical Pharmacology (12.3) ] . Olysio is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C). Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh B or C). In clinical trials of Olysio in combination with Peg-IFN-alfa and RBV, higher simeprevir exposures were associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving Olysio combination therapy [see Dosage and Administration (2.5) , Warnings and Precautions (5.3) , Adverse Reactions (6.1 , 6.2) , and Clinical Pharmacology (12.3) ] . The safety and efficacy of Olysio have not been established in liver transplant patients. See the Peg-IFN-alfa prescribing information regarding its contraindication in patients with hepatic decompensation. Overdosage Human experience of overdose with Olysio is limited. There is no specific antidote for overdose with Olysio. In the event of an overdose, the patient's clinical status should be observed and the usual supportive measures employed. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir [see Clinical Pharmacology (12.3) ] . Olysio Description Olysio (simeprevir) is an inhibitor of the HCV NS3/4A protease. The chemical name for simeprevir is (2 R ,3a R ,10 Z ,11a S ,12a R ,14a R )- N -(cyclopropylsulfonyl)-2-[[2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxy-8-methyl-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[ c ]cyclopropa[ g ][1,6]diazacyclotetradecine-12a(1 H )-carboxamide. Its molecular formula is C 38 H 47 N 5 O 7 S 2 and its molecular weight is 749.94. Simeprevir has the following structural formula: Simeprevir drug substance is a white to almost white powder. Simeprevir is practically insoluble in water over a wide pH range. It is practically insoluble in propylene glycol, very slightly soluble in ethanol, and slightly soluble in acetone. It is soluble in dichloromethane and freely soluble in some organic solvents (e.g., tetrahydrofuran and N,N-dimethylformamide). Olysio (simeprevir) for oral administration is available as 150 mg strength hard gelatin capsules. Each capsule contains 154.4 mg of simeprevir sodium salt, which is equivalent to 150 mg of simeprevir. Olysio (simeprevir) capsules contain the following inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate and sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904). Olysio - Clinical Pharmacology Mechanism of Action Simeprevir is a direct-acting antiviral (DAA) agent against the hepatitis C virus [see Microbiology (12.4) ] . Pharmacodynamics Cardiac Electrophysiology In a thorough QT/QTc study in 60 healthy subjects, simeprevir 150 mg (recommended dose) and 350 mg (2.3 times the recommended dose) did not affect the QT/QTc interval. Pharmacokinetics The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma C max and AUC increased more than dose-proportionally after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once-daily dosing. Plasma exposure (AUC) of simeprevir in HCV-infected subjects was about 2- to 3-fold higher compared to that observed in HCV-uninfected subjects. Plasma C max and AUC of simeprevir were similar during coadministration of simeprevir with Peg-IFN-alfa and RBV compared with administration of simeprevir alone. In Phase 3 trials with Peg-IFN-alfa and RBV in HCV-infected subjects, the geometric mean steady-state pre-dose plasma concentration was 1009 ng/mL (geometric coefficient of variation [gCV] = 162%) and the geometric mean steady-state AUC 24 was 39140 ng.h/mL (gCV = 98%). Absorption The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of Olysio in fed conditions is 62%. Maximum plasma concentrations (C max ) are typically achieved between 4 to 6 hours post-dose. In vitro studies with human Caco-2 cells indicated that simeprevir is a substrate of P-gp. Effects of Food on Oral Absorption Compared to intake without food, administration of simeprevir with food to healthy subjects increased the AUC by 61% after a high-fat, high-caloric breakfast (928 kcal) and by 69% after a normal-caloric breakfast (533 kcal), and delayed the absorption by 1 hour and 1.5 hours, respectively. Distribution Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3. Metabolism Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Coadministration of Olysio with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and coadministration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir [see Drug Interactions (7) ] . Following a single oral administration of 200 mg (1.3 times the recommended dosage) 14 C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O -demethylation followed by oxidation. Elimination Elimination of simeprevir occurs via b professional
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