Data from FDA - Curated by Marshall Pearce - Last updated 07 November 2017

Indication(s)

1 INDICATIONS AND USAGE OLYSIO® is indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection [see Dosage and Administration (2.2) and Clinical Studies (14)]: in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis. OLYSIO is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of adults with chronic hepatitis C virus (HCV) infection: in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis. (1) Limitations of Use: Efficacy of OLYSIO in combination with Peg-IFN-alfa and RBV is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism. (2.1, 12.4) OLYSIO is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO or other HCV protease inhibitors. (1, 12.4) Limitations of Use: Efficacy of OLYSIO in combination with Peg-IFN-alfa and RBV is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism [see Dosage and Administration (2.1) and Microbiology (12.4)]. OLYSIO is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO or other HCV protease inhibitors [see Microbiology (12.4)].

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contraindications
4 CONTRAINDICATIONS Because OLYSIO is used only in combination with other antiviral drugs (including Peg-IFN-alfa and RBV) for the treatment of chronic HCV infection, the contraindications to other drugs also apply to the combination regimen. Refer to the respective prescribing information for a list of contraindications. Because OLYSIO is used only in combination with other antiviral drugs (including Peg-IFN-alfa and RBV) for the treatment of chronic HCV infection, the contraindications to other drugs also apply to the combination regimen. (4)
Adverse reactions
6 ADVERSE REACTIONS Because OLYSIO is administered in combination with other antiviral drugs, refer to the prescribing information of the antiviral drugs used in combination with OLYSIO for a description of adverse reactions associated with their use. The following serious and otherwise important adverse reactions are described below and in other sections of the labeling: Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone [see Warnings and Precautions (5.2) and Drug Interactions (7.3)] Hepatic Decompensation and Hepatic Failure [see Warnings and Precautions (5.3)] Photosensitivity [see Warnings and Precautions (5.5)] Rash [see Warnings and Precautions (5.6)] Most common adverse events reported with OLYSIO with sofosbuvir during 12 or 24 weeks of treatment: fatigue, headache and nausea. (6.1) Most common adverse reactions reported with OLYSIO with Peg-IFN-alfa and RBV during first 12 weeks of treatment: rash (including photosensitivity), pruritus and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 clinical practice. OLYSIO in Combination with Sofosbuvir The safety profile of OLYSIO in combination with sofosbuvir in patients with HCV genotype 1 infection with compensated cirrhosis (Child-Pugh A) or without cirrhosis is based on pooled data from the Phase 2 COSMOS trial and the Phase 3 OPTIMIST-1 and OPTIMIST-2 trials which included 317 subjects who received OLYSIO with sofosbuvir (without RBV) for 12 or 24 weeks [see Clinical Studies (14.2)]. Table 4 lists adverse events (all grades) that occurred with at least 10% frequency among subjects receiving 12 or 24 weeks of treatment with OLYSIO 150 mg once daily in combination with sofosbuvir 400 mg once daily without RBV. The overall safety profile appeared similar among cirrhotic and non-cirrhotic subjects [see Dosage and Administration (2.2)]. The majority of the adverse events reported were Grade 1 or 2 in severity. Grade 3 or 4 adverse events were reported in 4% and 13% of subjects receiving 12 or 24 weeks of OLYSIO with sofosbuvir, respectively. Serious adverse events were reported in 2% and 3% of subjects receiving 12 or 24 weeks of OLYSIO with sofosbuvir, respectively. One percent and 6% of subjects receiving 12 or 24 weeks of OLYSIO with sofosbuvir, respectively, discontinued treatment due to adverse events. Table 4: Adverse Events (all Grades) that Occurred ≥10% Frequency Among Subjects Receiving 12 or 24 Weeks of OLYSIO in Combination with SofosbuvirThe 12 week group represents subjects pooled from COSMOS, OPTIMIST-1, and OPTIMIST-2 trials. The 24 week group represents subjects from COSMOS trial. Adverse Events 12 Weeks OLYSIO + Sofosbuvir N=286 % (n) 24 Weeks OLYSIO + Sofosbuvir N=31 % (n) Headache 17 (49) 23 (7) Fatigue 16 (47) 32 (10) Nausea 14 (40) 13 (4) Rash (including photosensitivity) 12 (34) 16 (5) Diarrhea 6 (18) 16 (5) Dizziness 3 (10) 16 (5) Rash and Photosensitivity In trials of OLYSIO in combination with sofosbuvir, rash (including photosensitivity reactions) was observed in 12% of OLYSIO-treated subjects receiving 12 weeks of treatment compared to 16% of OLYSIO-treated subjects receiving 24 weeks of treatment. Most of the rash events in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). Among 317 subjects, Grade 3 rash was reported in one subject (<1%), leading to treatment discontinuation; none of the subjects experienced Grade 4 rash. Most photosensitivity reactions were of mild severity (Grade 1); Grade 2 photosensitivity reactions were reported in 2 of 317 subjects (<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 SofosbuvirThe 12 week group represents subjects pooled from COSMOS, OPTIMIST-1, and OPTIMIST-2 trials. The 24 week group represents subjects from COSMOS trial. Laboratory Parameter WHO Toxicity Range 12 Weeks OLYSIO + Sofosbuvir N=286 % 24 Weeks OLYSIO + Sofosbuvir N=31 % Chemistry AmylaseNo Grade 4 changes in amylase were observed. Grade 1 ≥ 1.1 to ≤ 1.5 × ULNULN = Upper Limit of Normal 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 InfectionSubjects were treatment-naïve or had previously relapsed after Peg-IFN-alfa and RBV therapy. (Pooled Phase 3Pooled Phase 3 trials: QUEST 1, QUEST 2, PROMISE.) Adverse ReactionAdverse reactions that occurred at ≥ 3% higher frequency in the OLYSIO treatment group than in the placebo treatment group. OLYSIO 150 mg + Peg-IFN-alfa+ RBV First 12 Weeks N=781 % (n) Placebo + Peg-IFN-alfa+ RBV First 12 Weeks N=397 % (n) 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 3Pooled Phase 3 trials: QUEST 1, QUEST 2, PROMISE.; 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 % Chemistry Alkaline phosphataseNo Grade 3 or 4 changes in alkaline phosphatase were observed. Grade 1 > 1.25 to ≤ 2.50 × ULNULN = Upper Limit of Normal 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)]. 6.2 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)].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Testing Prior to the Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. (2.1) Prior to initiation of treatment with OLYSIO in combination with Peg-IFN-alfa and RBV in patients infected with HCV genotype 1a, screening for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and alternative therapy should be considered if Q80K is detected. (2.1, 12.4) Monitor liver chemistry tests before and during OLYSIO combination therapy. (2.1, 5.3) Recommended dosage: One 150 mg capsule taken once daily with food. (2.2) Treatment Regimens and Duration by Patient Population Patient population Treatment regimen Duration Genotype 1 without cirrhosis OLYSIO + sofosbuvir 12 weeks Genotype 1 with compensated cirrhosis (Child-Pugh A) OLYSIO + sofosbuvir 24 weeks Genotype 1 or 4 without cirrhosis or with compensated cirrhosis (Child-Pugh A), with or without HIV-1 co-infection OLYSIO + Peg-IFN-alfa + RBV 12 weeksfollowed by 12 or 36 additional weeks of Peg-IFN-alfa + RBV depending on prior response status and presence of HIV-1 co-infection. (2.2) Refer to the Full Prescribing Information for details on stopping rules when discontinuing OLYSIO in combination with Peg-IFN-alfa + RBV and for information on dosing adjustment and interruption. (2.3, 2.4) OLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child–Pugh B or C). (2.5) 2.1 Testing Prior to the Initiation of Therapy Testing for HBV infection 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 OLYSIO [see Warnings and Precautions (5.1)]. Q80K Testing in HCV Genotype 1a-Infected Patients OLYSIO in Combination with Sofosbuvir In HCV genotype 1a-infected patients with compensated cirrhosis, screening for the presence of virus with the NS3 Q80K polymorphism may be considered prior to initiation of treatment with OLYSIO with sofosbuvir [see Clinical Studies (14.2)]. OLYSIO in Combination with Peg-IFN-alfa and RBV Prior to initiation of treatment with OLYSIO in combination with Peg-IFN-alfa and RBV, screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism [see Indications and Usage (1) and Microbiology (12.4)]. Hepatic Laboratory Testing Monitor liver chemistry tests before and during OLYSIO combination therapy [see Warnings and Precautions (5.3)]. 2.2 OLYSIO Combination Treatment Administer OLYSIO in combination with other antiviral drugs for the treatment of chronic HCV infection. OLYSIO monotherapy is not recommended. The recommended dosage of OLYSIO is one 150 mg capsule taken orally once daily with food [see Clinical Pharmacology (12.3)]. The capsule should be swallowed as a whole. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information. OLYSIO can be taken in combination with sofosbuvir or in combination with Peg-IFN-alfa and RBV. OLYSIO in Combination with Sofosbuvir Table 1 displays the recommended treatment regimen and duration of OLYSIO in combination with sofosbuvir in patients with chronic HCV genotype 1 infection. Table 1: Recommended Treatment Regimen and Duration for OLYSIO and Sofosbuvir Combination Therapy in Patients with Chronic HCV Genotype 1 Infection Patient Population (HCV Genotype 1) Treatment Regimen and Duration Treatment-naïve and treatment-experiencedTreatment-experienced patients include prior relapsers, prior partial responders and prior null responders who failed prior IFN-based therapy [see Clinical Studies (14)]. patients: without cirrhosis 12 weeks of OLYSIO + sofosbuvir with compensated cirrhosis (Child-Pugh A) 24 weeks of OLYSIO + sofosbuvir OLYSIO in Combination with Peg-IFN-alfa and RBV Table 2 displays the recommended treatment regimen and duration of OLYSIO in combination with Peg-IFN-alfa and RBV in mono-infected and HCV/HIV-1 co-infected patients with HCV genotype 1 or 4 infection. Refer to Table 3 for treatment stopping rules for OLYSIO combination therapy with Peg-IFN-alfa and RBV. Table 2: Recommended Treatment Regimen and Duration for OLYSIO, Peg-IFN-alfa, and RBV Combination Therapy in Patients with Chronic HCV Genotype 1 or 4 Infection Patient Population (HCV Genotype 1 or 4) Treatment Regimen and Duration HIV = human immunodeficiency virus. Treatment-naïve patients and prior relapsersPrior relapser: HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected during follow-up [see Clinical Studies (14)].: HCV mono-infected patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) 12 weeks of OLYSIO + Peg-IFN-alfa + RBV followed by additional 12 weeks of Peg-IFN-alfa + RBV (total treatment duration of 24 weeks)Recommended duration of treatment if patient does not meet stopping rules (see Table 3). HCV/HIV-1 co-infected patients without cirrhosis HCV/HIV-1 co-infected patients with compensated cirrhosis (Child-Pugh A) 12 weeks of OLYSIO + Peg-IFN-alfa + RBV followed by additional 36 weeks of Peg-IFN-alfa + RBV (total treatment duration of 48 weeks) Prior non-responders (including partialPrior partial responder: prior on-treatment ≥ 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at end of prior IFN-based therapy [see Clinical Studies (14)]. and null respondersPrior null responder: prior on-treatment < 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 during prior IFN-based therapy [see Clinical Studies (14)].): HCV/HIV-1 co-infected or HCV mono-infected patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) 12 weeks of OLYSIO + Peg-IFN-alfa + RBV followed by additional 36 weeks of Peg-IFN-alfa + RBV (total treatment duration of 48 weeks) 2.3 Discontinuation of Dosing OLYSIO in Combination with Sofosbuvir No treatment stopping rules apply to the combination of OLYSIO with sofosbuvir [see Clinical Studies (14.2)]. OLYSIO in Combination with Peg-IFN-alfa and RBV During treatment, HCV RNA levels should be monitored as clinically indicated using a sensitive assay with a lower limit of quantification of at least 25 IU/mL. Because patients with an inadequate on-treatment virologic response (i.e., HCV RNA greater or equal to 25 IU/mL) are not likely to achieve a sustained virologic response (SVR), discontinuation of treatment is recommended in these patients. Table 3 presents treatment stopping rules for patients who experience an inadequate on-treatment virologic response at Weeks 4, 12, and 24. Table 3: Treatment Stopping Rules in Patients Receiving OLYSIO in Combination with Peg-IFN-alfa and RBV with Inadequate On-Treatment Virologic Response Treatment Week HCV RNA Action Week 4 ≥ 25 IU/mL Discontinue OLYSIO, Peg-IFN-alfa, and RBV Week 12 Discontinue Peg-IFN-alfa, and RBV (treatment with OLYSIO is complete at Week 12) Week 24 Discontinue Peg-IFN-alfa, and RBV (treatment with OLYSIO is complete at Week 12) 2.4 Dosage Adjustment or Interruption To prevent treatment failure, avoid reducing the dosage of OLYSIO or interrupting treatment. If treatment with OLYSIO is discontinued because of adverse reactions or inadequate on-treatment virologic response, OLYSIO treatment must not be reinitiated [see Warnings and Precautions (5.3)]. If adverse reactions potentially related to the antiviral drug(s) used in combination with OLYSIO occur, refer to the instructions outlined in their respective prescribing information for recommendations on dosage adjustment or interruption. If any of the other antiviral drug(s) used in combination with OLYSIO for the treatment of chronic HCV infection are permanently discontinued for any reason, OLYSIO should also be discontinued. 2.5 Not Recommended in Patients with Moderate or Severe Hepatic Impairment OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.3), Adverse Reactions (6.1), Use in Specific Populations (8.8), and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 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. 8.2 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)]. 8.3 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. 8.4 Pediatric Use The safety and efficacy of OLYSIO in pediatric patients have not been established. 8.5 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)]. 8.6 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)]. 8.7 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. 8.8 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.

Interactions

7 DRUG INTERACTIONS Coadministration of amiodarone with sofosbuvir in combination with OLYSIO may result in serious symptomatic bradycardia. (5.2, 7.3) Coadministration of OLYSIO with drugs that are moderate or strong inducers or inhibitors of CYP3A may significantly affect the plasma concentrations of simeprevir. The potential for drug-drug interactions must be considered prior to and during treatment. (5.8, 7, 12.3) 7.1 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). 7.2 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)]. 7.3 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. 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. DigoxinThese 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]. ↑ 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 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., 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: LedipasvirThe 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. ↑ 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 , 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. ↑ simeprevir ↑ darunavir Coadministration is not recommended. Protease Inhibitors (PIs): Ritonavir , 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. ↑ 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 ↑ simeprevirStudied in combination with daclatasvir and RBV in a Phase 2 trial in HCV-infected post-liver transplant patients. 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. 7.4 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, tenofovir disoproxil fumarate, and warfarin. No clinically relevant drug-drug interaction is expected when OLYSIO is coadministered with antacids, azithromycin, bedaquiline, corticosteroids (budesonide, fluticasone, methylprednisolone, and prednisone), dolutegravir, fluvastatin, H2-receptor antagonists, the narcotic analgesics buprenorphine and naloxone, NRTIs (such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine), maraviroc, methylphenidate, and proton pump inhibitors.

More information

Category Value
Authorisation number NDA205123
Agency product number 9WS5RD66HZ
Orphan designation No
Product NDC 59676-225
Date Last Revised 20-09-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1482801
Storage and handling Store OLYSIO capsules in the original bottle in order to protect from light at room temperature below 30°C (86°F).
Marketing authorisation holder Janssen Products LP
Warnings 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 OLYSIO. 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 (5.1)]. WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete boxed warning. Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. (5.1)