|
新型丙型肝炎药品OLYSIO(SIMEPREVIR SODIUM)CAPSULE ORAL已获批上市
OLYSIO is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 or 4 infection as a component of a combination antiviral treatment regimen. (1) Limitations of Use: OLYSIO monotherapy is not recommended. (1) OLYSIO combination with peginterferon alfa and ribavirin: 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 if HCV genotype 1a with Q80K is detected. (1, 12) OLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child–Pugh Class B or C). (1) 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) DOSAGE AND ADMINISTRATION One 150 mg capsule taken once daily with food. (2.1) OLYSIO should be administered in combination with other antiviral drugs for the treatment of CHC infection. Recommended treatment duration (2.1): OLYSIO with peginterferon alfa and ribavirin in HCV genotype 1 or 4 mono-infected or HCV/human immunodeficiency virus-1 (HIV-1) co-infected patients: 12 weeks, followed by 12 or 36 additional weeks of peginterferon alfa and ribavirin depending on prior response status and presence of HIV-1 co-infection. OLYSIO with sofosbuvir in HCV genotype 1 mono-infected patients: Treatment–naïve or treatment–experienced without cirrhosis: 12 weeks Treatment–naïve or treatment–experienced with cirrhosis: 24 weeks. For specific dosage instructions for the other antiviral drugs used in combination with OLYSIO, see their respective prescribing information. (2.1) DOSAGE FORMS AND STRENGTHS Capsule: 150 mg (3) CONTRAINDICATIONS All contraindications to other antiviral drugs used with OLYSIO for the treatment of CHC infection also apply to their use in OLYSIO combination treatment. (4) WARNINGS AND PRECAUTIONS Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone: Serious symptomatic bradycardia may occur in patients taking amiodarone with sofosbuvir in combination with OLYSIO, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Co-administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended. In patients without alternative treatment options, cardiac monitoring is recommended. (5.1, 6.2, 7.3) Hepatic Decompensation and Hepatic Failure: Hepatic decompensation and hepatic failure, including fatal cases have been reported in patients with advanced and/or decompensated cirrhosis. Monitor liver chemistry tests before and during OLYSIO combination therapy. (5.2) Photosensitivity: Serious photosensitivity reactions have been observed during OLYSIO combination therapy. Use sun protection measures and limit sun exposure during OLYSIO combination therapy. Consider discontinuation if a photosensitivity reaction occurs. (5.4) Rash: Rash has been observed during OLYSIO combination therapy. Discontinue OLYSIO if severe rash occurs. (5.5) ADVERSE REACTIONS Most common reported adverse reactions (incidence greater than 20%) (6.1): OLYSIO with peginterferon alfa and ribavirin (occurring with at least 3% higher frequency compared to placebo) during first 12 weeks of treatment: rash (including photosensitivity), pruritus and nausea. OLYSIO with sofosbuvir during 12 or 24 weeks of treatment: fatigue, headache and nausea. 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. DRUG INTERACTIONS Co-administration of amiodarone with sofosbuvir in combination with OLYSIO may result in serious symptomatic bradycardia. (5.1) Co-administration 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. (5.7, 7, 12.3) USE IN SPECIFIC POPULATIONS Patients with HCV/HIV-1 co-infection: Safety and efficacy have been studied. (8.11, 14.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 10/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE OLYSIO® is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 or 4 infection as a component of a combination antiviral treatment regimen. Limitations of Use: OLYSIO monotherapy is not recommended. OLYSIO efficacy in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (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 (2.2) and Microbiology (12.4)]. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism. OLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)]. 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)]. 2 DOSAGE AND ADMINISTRATION 2.1 OLYSIO Combination Treatment Administer OLYSIO in combination with other antiviral drugs for the treatment of CHC infection. Monitor liver chemistry tests before and during OLYSIO combination therapy [see Warnings and Precautions (5.2)]. OLYSIO monotherapy is not recommended. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information. Administer OLYSIO in combination with either: Peg-IFN-alfa and RBV: Table 1 displays the recommended dosage regimen and treatment duration of OLYSIO in combination with Peg-IFN-alfa and RBV. Refer to Table 3 for treatment stopping rules for OLYSIO combination therapy with Peg-IFN-alfa and RBV; or Sofosbuvir: Table 2 displays the recommended dosage regimen and treatment duration of OLYSIO in combination with sofosbuvir. The recommended dosage of OLYSIO is one capsule taken orally once daily with food. The capsule should be swallowed as a whole. Table 1: Recommended Dosage Regimens and Treatment Duration for OLYSIO, Peg-IFN-alfa, and RBV Combination Therapy for Treatment of CHC Infection in HCV Genotype 1 or 4 Mono-infected and HCV/HIV-1 Co-infected Patients
* Prior relapser: HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected during follow-up [see Clinical Studies (14)]. Recommended duration of treatment if patient does not meet stopping rules (see Table 3). Prior 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)]. Prior null responder: prior on-treatment < 2 log10 reduction in HCV RNA from baseline at Week 12 during prior IFN-based therapy [see Clinical Studies (14)]. Table 2: Recommended Dosage Regimen and Treatment Duration for OLYSIO and Sofosbuvir Combination Therapy for Treatment of CHC Infection in HCV Genotype 1 Mono-infected Patients
2.2 Testing Prior to Initiation of OLYSIO in HCV Genotype 1a-Infected Patients Prior to initiation of treatment with OLYSIO 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. Prior to initiation of treatment with OLYSIO with sofosbuvir, screening patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism is not strongly recommended but may be considered [see Indications and Usage (1)]. 2.3 Discontinuation of Dosing Use 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 ≥ 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
No treatment stopping rules apply to the combination of OLYSIO with sofosbuvir [see Clinical Studies (14)]. 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. 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 drugs used in combination with OLYSIO for the treatment of CHC infection are permanently discontinued for any reason, OLYSIO should also be discontinued. 2.5 Hepatic Impairment OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Use in Specific Populations (8.8)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Clinical Pharmacology (12.3)]. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)]. OLYSIO in combination with Peg-IFN-alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment) [see Peg-IFN-alfa prescribing information]. 3 DOSAGE FORMS AND STRENGTHS Capsules: 150 mg, white and marked with "TMC435 150" in black ink. 4 CONTRAINDICATIONS There are no specific contraindications to OLYSIO. The contraindications to other antiviral drugs administered with OLYSIO for the treatment of CHC infection also apply to OLYSIO combination treatment. Prescribers should consult the complete prescribing information for these drugs for a description of contraindications. If OLYSIO is administered with Peg-IFN-alfa and RBV, the contraindications for use of Peg-IFN-alfa and RBV also apply to this combination regimen. Refer to the prescribing information for Peg-IFN-alfa and RBV for a list of all contraindications. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with co-administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown. Co-administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co-administered OLYSIO and sofosbuvir: Counsel patients about the risk of serious symptomatic bradycardia Cardiac monitoring in an in-patient setting for the first 48 hours of co-administration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking sofosbuvir in combination with OLYSIO who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone's long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Adverse Reactions (6.2) and Drug Interactions (7.3)]. 5.2 Hepatic Decompensation and Hepatic Failure Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO in combination with peginterferon alfa and ribavirin or in combination with sofosbuvir. Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between treatment with OLYSIO and these events has not been established [see Adverse Reactions (6.2)]. OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5) and Use in Specific Populations (8.8)]. In clinical trials of OLYSIO, modest increases in bilirubin levels were observed without impacting hepatic function [see Adverse Reactions (6.1)]. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during OLYSIO combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored: Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces. Discontinue OLYSIO if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation. 5.3 Risk of Serious Adverse Reactions Associated with Combination Treatment OLYSIO should be used in combination with other antiviral drugs for the treatment of CHC infection. Therefore, consult the prescribing information for these drugs before starting therapy with OLYSIO. Warnings and Precautions related to these drugs also apply to their use in OLYSIO combination treatment. 5.4 Photosensitivity Photosensitivity reactions have been observed with OLYSIO combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with OLYSIO in combination with Peg-IFN-alfa and RBV [see Adverse Reactions (6.1)]. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema. Use sun protective measures and limit sun exposure during treatment with OLYSIO. Avoid use of tanning devices during treatment with OLYSIO. Discontinuation of OLYSIO should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue OLYSIO in the setting of a photosensitivity reaction, expert consultation is advised. 5.5 Rash Rash has been observed with OLYSIO combination therapy [see Adverse Reactions (6.1)]. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of OLYSIO have been reported in subjects receiving OLYSIO in combination with Peg-IFN-alfa and RBV. Most of the rash events in OLYSIO-treated patients were of mild or moderate severity [see Adverse Reactions (6.1)]. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, OLYSIO should be discontinued. Patients should be monitored until the rash has resolved. 5.6 Sulfa Allergy OLYSIO contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of OLYSIO. 5.7 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions Co-administration of OLYSIO with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. 6 ADVERSE REACTIONS OLYSIO should be 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 drug reactions (ADRs) are discussed in detail in another section of the labeling: Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone [see Warnings and Precautions (5.1) and Drug Interactions (7.3)] Hepatic Decompensation and Hepatic Failure [see Warnings and Precautions (5.2)] Photosensitivity [see Warnings and Precautions (5.4)] Rash [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions when Used 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 who were treatment-naïve or who had previously relapsed following interferon therapy with or without RBV is based on pooled data from three Phase 3 trials [see Clinical Studies (14)]. 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. The following table 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 (see Table 4). Table 4: 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 Subjects with CHC Infection* (Pooled Phase 3 Trials†)
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 and Photosensitivity In the Phase 3 clinical trials, 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 Grade 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, 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 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 5. Table 5: Laboratory Abnormalities (WHO Worst Toxicity Grades 1 to 4) Observed at a Higher Incidence in OLYSIO-Treated Subjects (Pooled Phase 3 Trials*; First 12 Weeks of Treatment)
No Grade 3 or 4 changes in alkaline phosphatase were observed. ULN = Upper Limit of Normal 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. OLYSIO in combination with Peg-IFN-alfa and RBV was studied in 106 subjects with HCV genotype 1/HIV-1 co-infection. The safety profile in HCV/HIV co-infected subjects was generally comparable to HCV mono-infected subjects. OLYSIO in combination with Peg-IFN-alfa and RBV was studied in 107 subjects with HCV genotype 4 infection. The safety profile of OLYSIO in subjects with HCV genotype 4 infection was comparable to subjects with HCV genotype 1 infection. Adverse Reactions when Used with Sofosbuvir In the COSMOS trial, the most common (> 10%) adverse reactions reported during 12 weeks treatment with OLYSIO in combination with sofosbuvir without RBV were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with OLYSIO in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported. 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 initiate treatment with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO [see Warnings and Precautions (5.1) and Drug Interactions (7.3)]. Hepatobiliary Disorders: hepatic decompensation, hepatic failure [see Warnings and Precautions (5.2)]. 7 DRUG INTERACTIONS 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. Co-administration of OLYSIO with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs (see Table 6). Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters. Co-administration of OLYSIO with drugs that are substrates for OATP1B1/3 and P-gp transport may result in increased plasma concentrations of such drugs (see Table 6). 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. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir. Co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see Table 6). Therefore, co-administration of OLYSIO with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]. 7.3 Established and Other Potentially Significant Drug Interactions Table 6 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of OLYSIO and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with OLYSIO are also included in Table 6. For information regarding the magnitude of interaction, see Tables 7 and 8 [see Clinical Pharmacology (12.3)]. Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction
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 7 and 8]. The dose of OLYSIO in this interaction study was 200 mg once daily both when given alone and when co-administered with rifampin 600 mg once daily. The dose of OLYSIO in this interaction study was 50 mg when co-administered 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 co-administered in combination with ritonavir 100 mg given twice daily. Studied in combination with an investigational drug and RBV in a Phase 2 trial in HCV-infected post-liver transplant patients. 7.4 Drugs without Clinically Significant Interactions with OLYSIO In addition to the drugs included in Table 6, 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, 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 co-administered with antacids, azithromycin, bedaquiline, the 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy OLYSIO must be administered in combination with other antiviral drugs [see Dosage and Administration (2.1)]. Refer to prescribing information of the drugs used in combination with OLYSIO for information regarding use in pregnancy. Pregnancy Category C Risk Summary Adequate and well-controlled trials with OLYSIO have not been conducted in pregnant women. In animal reproduction studies with simeprevir, embryofetal developmental toxicity was observed at drug exposures higher than human exposure at the recommended clinical dose. OLYSIO should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method. If OLYSIO is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on use in pregnancy. Animal Data Simeprevir showed no teratogenicity in rats and mice at exposures 0.5 times (in rats) and 6 times (in mice) the mean area under the plasma concentration time curve (AUC) in humans at the recommended dose of 150 mg once daily. In a mouse embryofetal study at doses up to 1000 mg/kg, simeprevir resulted in early and late in utero fetal losses and early maternal deaths at an exposure approximately 6 times higher than the mean AUC in humans at the recommended 150 mg daily dose. Significantly decreased fetal weights and an increase in fetal skeletal variations were seen at exposures approximately 4 times higher than the mean AUC in humans at the recommended daily dose. In a rat pre- and postnatal study, maternal animals were exposed to simeprevir during gestation and lactation at doses up to 1000 mg/kg/day. In pregnant rats, simeprevir resulted in early deaths at 1000 mg/kg/day corresponding to exposures similar to the mean AUC in humans at the recommended 150 mg once daily dose. Significant reduction in body weight gain was seen at an exposure 0.7 times the mean AUC in humans at the recommended 150 mg once daily dose. 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 a maternal exposure similar to the mean AUC in humans at the recommended 150 mg once daily dose. Subsequent survival, behavior and reproductive capacity were not affected. 8.3 Nursing Mothers It is not known whether OLYSIO or its metabolites are present in human breast milk. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with OLYSIO, taking into account the importance of the therapy to the mother. If OLYSIO is administered in a regimen containing RBV, the information for RBV with regard to nursing mothers also applies to this combination regimen [see prescribing information for RBV]. 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 dose adjustment of OLYSIO is required in geriatric patients [see Clinical Pharmacology (12.3)]. 8.6 Race Patients of East Asian ancestry exhibit higher simeprevir exposures [see Clinical Pharmacology (12.3)]. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity [see Adverse Reactions (6.1)]. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients of East Asian ancestry. 8.7 Renal Impairment No dose 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 dose adjustment of OLYSIO is required in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)]. The safety and efficacy of OLYSIO have not been established in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Clinical Pharmacology (12.3)]. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)]. Refer to the prescribing information for the antiviral drug(s) used in combination with OLYSIO regarding their use in patients with hepatic impairment. The combination of OLYSIO with Peg-IFN-alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment). 8.9 Other HCV Genotypes The safety and efficacy of OLYSIO have not been established in patients infected with other HCV genotypes. 8.10 Liver Transplantation The safety and efficacy of OLYSIO have not been studied in liver transplant patients. 8.11 HCV/HIV-1 Co-infection No dose adjustment of OLYSIO is required in HCV/HIV-1 co-infected patients [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. For dosing recommendations in HCV/HIV-1 co-infected patients, see Dosage and Administration (2.1). For information on the safety profile of OLYSIO in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1/HIV-1 co-infection, see Adverse Reactions (6.1). For information on interactions with antiretroviral agents, see Warning and Precautions (5.7) and Drug Interactions (7). 10 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)]. 11 DESCRIPTION OLYSIO (simeprevir) is an inhibitor of the HCV NS3/4A protease. The chemical name for simeprevir is (2R,3aR,10Z,11aS,12aR,14aR)-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(1H)-carboxamide. Its molecular formula is C38H47N5O7S2 and its molecular weight is 749.94. Simeprevir has the following structural formula:
The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK (i.e., AUC). Comparison based on historic controls. Interim data from a Phase 2 trial in combination with an investigational drug and RBV in HCV-infected post-liver transplant patients. Individualized dose at the discretion of the physician, according to local clinical practice. Comparison based on historic controls. The interaction between simeprevir and sofosbuvir was evaluated in a pharmacokinetic substudy within a Phase 2 trial. The dose of OLYSIO in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir compared to 150 mg once daily in the OLYSIO alone treatment group. Table8: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of OLYSIO
The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK (i.e., AUC). The interaction between OLYSIO and the drug was evaluated in a pharmacokinetic study in opioid-dependent adults on stable methadone maintenance therapy. Comparison based on historic controls. The interaction between simeprevir and sofosbuvir was evaluated in a pharmacokinetic substudy within a Phase 2 trial. Primary circulating metabolite of sofosbuvir. The dose of OLYSIO in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir which is lower than the recommended 150 mg dose. 12.4 Microbiology Mechanism of Action Simeprevir is an inhibitor of the HCV NS3/4A protease which is essential for viral replication. In a biochemical assay simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively. Antiviral Activity The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 nM (7.05 ng/mL) and 19 nM (14.25 ng/mL), respectively. Chimeric replicons carrying NS3 sequences derived from HCV protease inhibitor treatment-naïve genotype 1a- or genotype 1b-infected patients displayed median fold change (FC) in EC50 values of 1.4 (interquartile range, IQR: 0.8 to 11; N=78) and 0.4 (IQR: 0.3 to 0.7; N=59) compared to reference genotype 1b replicon, respectively. Genotype 1a (N=33) and 1b (N=2) isolates with a baseline Q80K polymorphism resulted in median FC in simeprevir EC50 value of 11 (IQR: 7.4 to 13) and 8.4, respectively. Chimeric replicons carrying NS3 sequences derived from HCV protease inhibitor treatment-naïve genotype 4a-, 4d-, or 4r-infected patients displayed median FC in EC50 values of 0.5 (IQR: 0.4 to 0.6; N=38), 0.4 (IQR: 0.2 to 0.5; N=24), and 1.6 (IQR: 0.7 to 4.5; N=8), compared to reference genotype 1b replicon, respectively. A pooled analysis of chimeric replicons carrying the NS3 sequences from HCV protease inhibitor-naïve patients infected with other HCV genotype 4 subtypes, including 4c (N=1), 4e (N=2), 4f (N=3), 4h (N=3), 4k (N=1), 4o (N=2), 4q (N=2), or unidentified subtype (N=7) displayed a median FC in EC50 value of 0.7 (IQR: 0.5 to 1.1; N=21) compared to reference genotype 1b replicon. The presence of 50% human serum reduced simeprevir replicon activity by 2.4-fold. Combination of simeprevir with IFN, RBV, NS5A inhibitors, nucleoside analog NS5B polymerase inhibitors or non-nucleoside analog NS5B polymerase inhibitors, including NS5B thumb 1-, thumb 2-, and palm-domain targeting drugs, was not antagonistic. Resistance in Cell Culture Resistance to simeprevir was characterized in HCV genotype 1a and 1b replicon-containing cells. Ninety-six percent (96%) of simeprevir-selected genotype 1 replicons carried one or multiple amino acid substitutions at NS3 protease positions F43, Q80, R155, A156, and/or D168, with substitutions at NS3 position D168 being most frequently observed (78%). Additionally, resistance to simeprevir was evaluated in HCV genotype 1a and 1b replicon assays using site-directed mutants and chimeric replicons carrying NS3 sequences derived from clinical isolates. Amino acid substitutions at NS3 positions F43, Q80, S122, R155, A156, and D168 reduced susceptibility to simeprevir. Replicons with D168V or A, and R155K substitutions displayed large reductions in susceptibility to simeprevir (FC in EC50 value greater than 50), whereas other substitutions such as Q80K or R, S122R, and D168E displayed lower reductions in susceptibility (FC in EC50 value between 2 and 50). Other substitutions such as Q80G or L, S122G, N or T did not reduce susceptibility to simeprevir in the replicon assay (FC in EC50 value lower than 2). Amino acid substitutions at NS3 positions Q80, S122, R155, and/or D168 that were associated with lower reductions in susceptibility to simeprevir when occurring alone, reduced susceptibility to simeprevir by more than 50-fold when present in combination. Resistance in Clinical Studies In a pooled analysis of subjects treated with 150 mg OLYSIO in combination with Peg-IFN-alfa and RBV who did not achieve SVR in the controlled Phase 2 and Phase 3 clinical trials, emerging virus with amino acid substitutions at NS3 positions Q80, S122, R155 and/or D168 were observed in 180 out of 197 (91%) subjects. Substitutions D168V and R155K alone or in combination with other substitutions at these positions emerged most frequently (Table 9). Most of these emerging substitutions have been shown to reduce susceptibility to simeprevir in cell culture replicon assays. HCV genotype 1 subtype-specific patterns of simeprevir treatment-emergent amino acid substitutions were observed. HCV genotype 1a predominately had emerging R155K alone or in combination with amino acid substitutions at NS3 positions Q80, S122 and/or D168, while HCV genotype 1b had most often an emerging D168V substitution (Table 9). In HCV genotype 1a with a baseline Q80K amino acid polymorphism, an emerging R155K substitution was observed most frequently at failure. Table 9: Emergent Amino Acid Substitutions in Controlled Phase 2 and Phase 3 Trials: Subjects who did not Achieve SVR with 150 mg OLYSIO in Combination with Peg-IFN-alfa and RBV
May include few subjects infected with HCV genotype 1 viruses of non-1a/1b subtypes. Alone or in combination with other substitutions (includes mixtures). Substitutions only observed in combinations with other emerging substitutions at one or more of the NS3 positions Q80, S122, R155 and/or D168. Subjects with virus carrying these combinations are also included in other rows describing the individual substitutions. X represents multiple amino acids. Other double or triple substitutions were observed with lower frequencies. Emerged alone (n=2) or in combination with R155K (n=3). In the COSMOS trial in HCV genotype 1-infected subjects treated with OLYSIO in combination with sofosbuvir (without or with RBV), virus from 5 out of 6 (83%) subjects with relapse had emerging NS3 amino acid substitutions R155K or D168E. No emerging NS5B amino acid substitutions associated with sofosbuvir resistance were observed. In the RESTORE trial in genotype 4-infected subjects, 30 out of 34 (88%) subjects who did not achieve SVR had emerging amino acid substitutions at NS3 positions Q80, T122, R155, A156 and/or D168 (mainly substitutions at position D168; 26 out of 34 [76%] subjects), similar to the emerging amino acid substitutions observed in genotype 1-infected subjects. Persistence of Resistance–Associated Substitutions The persistence of simeprevir-resistant virus was assessed following treatment failure in the pooled analysis of subjects receiving 150 mg OLYSIO in combination with Peg-IFN-alfa and RBV in the controlled Phase 2 and Phase 3 trials. The proportion of subjects with detectable levels of treatment-emergent, resistance-associated variants was followed post treatment for a median time of 28 weeks (range 0 to 70 weeks). Resistant variants remained at detectable levels in 32 out of 66 subjects (48%) with single emerging R155K and in 16 out of 48 subjects (33%) with single emerging D168V. The lack of detection of virus containing a resistance-associated substitution does not necessarily indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing OLYSIO-resistance-associated substitutions is unknown. Effect of Baseline HCV Polymorphisms on Treatment Response Analyses were conducted to explore the association between naturally-occurring baseline NS3/4A amino acid substitutions (polymorphisms) and treatment outcome. In the pooled analysis of the Phase 3 trials QUEST 1 and QUEST 2, and in the PROMISE trial, the efficacy of OLYSIO in combination with Peg-IFN-alfa and RBV was substantially reduced in subjects infected with HCV genotype 1a virus with the NS3 Q80K polymorphism at baseline [see Clinical Studies (14.2)]. The observed prevalence of NS3 Q80K polymorphic variants at baseline in the overall population of the Phase 2 and Phase 3 trials (PILLAR, ASPIRE, PROMISE, QUEST 1 and QUEST 2) was 14%; while the observed prevalence of the Q80K polymorphism was 30% in subjects infected with HCV genotype 1a and 0.5% in subjects infected with HCV genotype 1b. The observed prevalence of Q80K polymorphic variants at baseline in the U.S. population of these Phase 2 and Phase 3 trials was 35% overall, 48% in subjects infected with HCV genotype 1a and 0% in subjects infected with HCV genotype 1b. With the exception of the NS3 Q80K polymorphism, baseline HCV variants with polymorphisms at NS3 positions F43, Q80, S122, R155, A156, and/or D168 that were associated with reduced simeprevir activity in replicon assays were generally uncommon (1.3%) in subjects with HCV genotype 1 infection in these Phase 2 and Phase 3 trials (n=2007). The Q80K polymorphic variant was not observed in subjects infected with HCV genotype 4 (RESTORE). Cross-Resistance Cross-resistance is expected among NS3/4A protease inhibitors. Some of the treatment-emergent virus detected in OLYSIO-treated subjects who did not achieve SVR in clinical trials, including virus expressing R155K, which emerged frequently, and I170T, which emerged infrequently, have been shown to be less susceptible to the NS3/4A protease inhibitors, boceprevir and/or telaprevir. The most frequently occurring boceprevir or telaprevir treatment-emergent viruses that are expected to impact subsequent treatment with OLYSIO include variants expressing NS3 R155K, A156T, or A156V. Virus expressing the NS3 amino substitutions V36A or G and I170A or T, which displayed slight shifts in susceptibility to simeprevir in replicon cultures, may emerge in patients who do not achieve SVR with boceprevir or telaprevir, and may therefore also impact subsequent treatment with OLYSIO. Failure to achieve SVR with simeprevir does not select virus that is cross-resistant to sofosbuvir or vice versa. 12.5 Pharmacogenomics A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C [cytosine] to T [thymine] substitution) is a strong predictor of response to Peg-IFN-alfa and RBV (PR). In the Phase 3 trials, IL28B genotype was a stratification factor. Overall, SVR rates were lower in subjects with the CT and TT genotypes compared to those with the CC genotype (Tables 10 and 11). Among both treatment-naïve subjects and those who experienced previous treatment failures, subjects of all IL28B genotypes had the highest SVR rates with OLYSIO-containing regimens (Table 10). Table 10: SVR12 Rates by IL28B rs12979860 Genotype in Adult Subjects with HCV Genotype 1 Infection Receiving OLYSIO 150 mg Once Daily with Peg-IFN-alfa and RBV Compared to Subjects Receiving Placebo with Peg-IFN-alfa and RBV (Trials QUEST 1, QUEST 2, PROMISE)
Table 11: SVR12 Rates by IL28B rs12979860 Genotype in Adult Patients Receiving OLYSIO 150 mg Once Daily in Combination with Peg-IFN-alfa and RBV (Trials C212 and RESTORE)
SVR12: sustained virologic response 12 weeks after planned EOT. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Simeprevir was not genotoxic in a series of in vitro and in vivo tests including the Ames test, the mammalian forward mutation assay in mouse lymphoma cells or the in vivo mammalian micronucleus test. Carcinogenicity studies with simeprevir have not been conducted. If OLYSIO is administered in a combination regimen containing RBV, refer to the prescribing information for RBV for information on carcinogenesis and mutagenesis. Impairment of Fertility In a rat fertility study at doses up to 500 mg/kg/day, 3 male rats treated with simeprevir (2/24 rats at 50 mg/kg/day and 1/24 rats at 500 mg/kg/day) showed no motile sperm, small testes and epididymides, and resulted in infertility in 2 out of 3 of the male rats at approximately 0.2 times the mean AUC in humans. If OLYSIO is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on impairment of fertility. 13.2 Animal Toxicology and/or Pharmacology Cardiovascular toxicity consisting of acute endocardial and myocardial necrosis restricted to the left ventricular subendocardial area was seen in 2 out of 6 animals in a 2-week oral dog toxicity study at an exposure approximately 28 times the mean AUC in humans at the recommended daily dose of 150 mg. No cardiac findings were observed in a 6-month and a 9-month oral toxicity study at exposures, respectively, of 11 and 4 times the mean AUC in humans at the recommended daily dose of 150 mg. If OLYSIO is administered in a combination regimen containing sofosbuvir, refer to the prescribing information for sofosbuvir for information on animal toxicology. 14 CLINICAL STUDIES 14.1 Overview of Clinical Trials The efficacy of OLYSIO in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection was evaluated in two Phase 3 trials in treatment-naïve subjects (trials QUEST 1 and QUEST 2), one Phase 3 trial in subjects who relapsed after prior interferon-based therapy (PROMISE), one Phase 2 trial in subjects who failed prior therapy with Peg-IFN and RBV (including prior relapsers, partial and null responders) (ASPIRE), and one Phase 3 trial in subjects with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naïve or failed previous HCV therapy with Peg-IFN and RBV (trial C212). The efficacy of OLYSIO in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 4 infection was evaluated in one Phase 3 trial in treatment-naïve subjects or subjects who failed previous therapy with Peg-IFN and RBV (RESTORE). Prior relapsers were subjects who had HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected during follow-up; prior partial responders were subjects with prior on-treatment greater than or equal to 2 log10 reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at the end of prior therapy with Peg-IFN and RBV; and null responders were subjects with prior on-treatment less than 2 log10 reduction in HCV RNA from baseline at Week 12 during prior therapy with Peg-IFN and RBV. Subjects in these trials had compensated liver disease (including cirrhosis), HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with CHC infection. In subjects who were treatment-naïve and prior relapsers, the overall duration of treatment with Peg-IFN-alfa and RBV in the Phase 3 trials was response-guided. In these subjects, the planned total duration of HCV treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy (RGT) criteria were met: HCV RNA lower than 25 IU/mL (detected or not detected) at Week 4 AND HCV RNA not detected at Week 12. Plasma HCV RNA levels were measured using the Roche COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System (25 IU/mL lower limit of quantification and 15 IU/mL limit of detection). Treatment stopping rules for HCV therapy were used to ensure that subjects with inadequate on-treatment virologic response discontinued treatment in a timely manner. In the Phase 3 trial C212 in HCV/HIV-1 co-infected subjects, the total duration of treatment with Peg-IFN-alfa and RBV in treatment-naïve and prior relapser subjects with cirrhosis was not response-guided; these subjects received a fixed total duration of HCV treatment of 48 weeks. The total duration of treatment with Peg-IFN-alfa and RBV in non-cirrhotic HCV/HIV-1 co-infected treatment-naïve or prior relapser subjects was response-guided using the same criteria. The efficacy of OLYSIO in combination with sofosbuvir without or with RBV was evaluated in a Phase 2 trial (COSMOS) in HCV genotype 1 infected prior null responders with METAVIR fibrosis score F0–F4 or treatment-naïve subjects with METAVIR fibrosis score F3–F4 and compensated liver disease. SVR was defined as HCV RNA not detected 24 weeks after planned end of treatment (SVR24) in the ASPIRE trial and was defined as HCV RNA lower than 25 IU/mL detected or not detected 12 weeks after the planned end of treatment (SVR12) in the COSMOS and Phase 3 trials. 14.2 Treatment with OLYSIO in Combination with Peg-IFN-alfa and RBV Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection The efficacy of OLYSIO in treatment-naïve patients with HCV genotype 1 infection was demonstrated in two randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trials (QUEST 1 and QUEST 2). The designs of both trials were similar. All subjects received 12 weeks of once daily treatment with 150 mg OLYSIO or placebo, plus Peg-IFN-alfa-2a (QUEST 1 and QUEST 2) or Peg-IFN-alfa-2b (QUEST 2) and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa and RBV in accordance with the on-treatment protocol-defined RGT criteria. Subjects in the control groups received 48 weeks of Peg-IFN-alfa-2a or -2b and RBV. In the pooled analysis for QUEST 1 and QUEST 2, demographics and baseline characteristics were balanced between both trials and between the OLYSIO and placebo treatment groups. In the pooled analysis of trials (QUEST 1 and QUEST 2), the 785 enrolled subjects had a median age of 47 years (range: 18 to 73 years; with 2% above 65 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) greater than or equal to 30 kg/m2; 78% had HCV RNA levels greater than 800000 IU/mL; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype; 17% of the overall population and 34% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. In QUEST 1, all subjects received Peg-IFN-alfa-2a; in QUEST 2, 69% of the subjects received Peg-IFN-alfa-2a and 31% received Peg-IFN-alfa-2b. Table 12 shows the response rates in treatment-naïve adult subjects with HCV genotype 1 infection. In the OLYSIO treatment group, SVR12 rates were lower in subjects with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism. Table 12: Response Rates in Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2)
* On-treatment failure was defined as the proportion of subjects with confirmed HCV RNA detected at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough). Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at actual EOT. Includes 4 OLYSIO-treated subjects who experienced relapse after SVR12. Seventy-eight percent (78%; 404/521) of OLYSIO-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404). SVR12 rates were higher for the OLYSIO treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), METAVIR fibrosis score, and IL28B genotype. Table 13 shows the SVR rates by METAVIR fibrosis score. Table 13: SVR12 Rates by METAVIR Fibrosis Score in Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2)
SVR12 rates were higher for subjects receiving OLYSIO with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (88% and 78%, respectively) compared to subjects receiving placebo with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (62% and 42%, respectively) (QUEST 2). Adult Subjects with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy The PROMISE trial was a randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trial in subjects with HCV genotype 1 infection who relapsed after prior IFN-based therapy. All subjects received 12 weeks of once daily treatment with 150 mg OLYSIO or placebo, plus Peg-IFN-alfa-2a and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Subjects in the control group received 48 weeks of Peg-IFN-alfa-2a and RBV. Demographics and baseline characteristics were balanced between the OLYSIO and placebo treatment groups. The 393 subjects enrolled in the PROMISE trial had a median age of 52 years (range: 20 to 71 years; with 3% above 65 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800000 IU/mL; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype; 13% of the overall population and 31% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. The prior IFN-based HCV therapy was Peg-IFN-alfa-2a/RBV (68%) or Peg-IFN-alfa-2b/RBV (27%). Table 14 shows the response rates for the OLYSIO and placebo treatment groups in adult subjects with HCV genotype 1 infection who relapsed after prior interferon-based therapy. In the OLYSIO treatment group, SVR12 rates were lower in subjects infected with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism. Table 14: Response Rates in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE Trial)
On-treatment failure was defined as the proportion of subjects with confirmed HCV RNA detected at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough). Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at actual EOT and with at least one follow-up HCV RNA assessment. Includes 5 OLYSIO-treated subjects who experienced relapse after SVR12. In PROMISE, 93% (241/260) of OLYSIO-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 83% (200/241). Seventy-seven percent (77%; 200/260) of OLYSIO-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200). SVR12 rates were higher for the OLYSIO treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), prior HCV therapy, METAVIR fibrosis score, and IL28B genotype. Table 15 shows the SVR rates by METAVIR fibrosis score. Table 15: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE Trial)
The ASPIRE trial was a randomized, double-blind, placebo-controlled, 7-arm, Phase 2 trial in subjects with HCV genotype 1 infection, who failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Subjects received 12, 24 or 48 weeks of 100 mg or 150 mg OLYSIO in combination with 48 weeks of Peg-IFN-alfa-2a and RBV, or 48 weeks of placebo in combination with 48 weeks of Peg-IFN-alfa-2a and RBV. Demographics and baseline characteristics were balanced between the OLYSIO and placebo treatment groups. The 462 subjects enrolled in the ASPIRE trial had a median age of 50 years (range: 20 to 69 years; with 3% above 65 years); 67% were male; 93% were White, 5% Black or African American, and 2% Asian; 25% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800000 IU/mL; 63% had METAVIR fibrosis score F0, F1, or F2, 19% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 41% had HCV genotype 1a, and 58% HCV genotype 1b; 18% had IL28B CC genotype, 65% IL28B CT genotype, and 18% IL28B TT genotype (information available for 328 subjects); 12% of the overall population and 27% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. Forty percent (40%) of subjects were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with Peg-IFN-alfa and RBV. One hundred ninety-nine subjects received OLYSIO 150 mg once daily (pooled analysis) of which 66 subjects received OLYSIO for 12 weeks and 66 subjects received placebo in combination with Peg-IFN-alfa and RBV. Table 16 shows the response rates for the OLYSIO and placebo treatment groups in prior relapsers, prior partial responders and prior null responders. Table 16: Response Rates in Prior Partial and Null Responders with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy (ASPIRE Trial)
On-treatment virologic failure was defined as the proportion of subjects who met the protocol-specified treatment stopping rules (including stopping rule due to viral breakthrough) or who had HCV RNA detected at EOT (for subjects who completed therapy). Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at EOT and with at least one follow-up HCV RNA assessment. In prior partial responders, SVR24 rates in subjects receiving OLYSIO with Peg-IFN-alfa and RBV were 47% and 77% in subjects with HCV genotype 1a and 1b, respectively, compared to 13% and 7%, respectively, in subjects receiving placebo with Peg-IFN-alfa and RBV. In prior null responders, SVR24 rates in subjects receiving OLYSIO with Peg-IFN-alfa and RBV were 41% and 47% in subjects with HCV genotype 1a and 1b, respectively, compared to 0% and 33%, respectively, in subjects receiving placebo with Peg-IFN-alfa and RBV. SVR24 rates were higher in the OLYSIO-treated subjects compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, regardless of HCV geno/subtype, METAVIR fibrosis score, and IL28B genotype. Subjects with HCV/HIV-1 Co-Infection C212 was an open-label, single-arm Phase 3 trial in HIV-1 subjects co-infected with HCV genotype 1 who were treatment-naïve or failed prior HCV therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Non-cirrhotic treatment-naïve subjects or prior relapsers received 12 weeks of once-daily treatment with 150 mg OLYSIO plus Peg-IFN-alfa-2a and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Prior non-responder subjects (partial and null response) and all cirrhotic subjects (METAVIR fibrosis score F4) received 36 weeks of Peg-IFN-alfa-2a and RBV after the initial 12 weeks of OLYSIO in combination with Peg-IFN-alfa-2a and RBV. The 106 enrolled subjects in the C212 trial had a median age of 48 years (range: 27 to 67 years; with 2% above 65 years); 85% were male; 82% were White, 14% Black or African American, 1% Asian, and 6% Hispanic; 12% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800,000 IU/mL; 68% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 13% METAVIR fibrosis score F4; 82% had HCV genotype 1a, and 17% HCV genotype 1b; 28% of the overall population and 34% of the subjects with genotype 1a had Q80K polymorphism at baseline; 27% had IL28B CC genotype, 56% IL28B CT genotype, and 17% IL28B TT genotype; 50% (n=53) were HCV treatment-naïve subjects, 14% (n=15) prior relapsers, 9% (n=10) prior partial responders, and 26% (n=28) prior null responders. Eighty-eight percent (n=93) of the subjects were on highly active antiretroviral therapy (HAART), with nucleoside reverse transcriptase inhibitors and the integrase inhibitor raltegravir being the most commonly used HIV antiretroviral. HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (except rilpivirine) were prohibited from use in this study. The median baseline HIV-1 RNA levels and CD4+ cell count in subjects not on HAART were 4.18 log10 copies/mL (range: 1.3–4.9 log10 copies/mL) and 677 × 106 cells/L (range: 489–1076 × 106 cells/L), respectively. The median baseline CD4+ cell count in subjects on HAART was 561 × 106 cells/mL (range: 275–1407 × 106 cells/mL). Table 17 shows the response rates in treatment-naïve, prior relapsers, prior partial responders and null responders. Table 17: Response Rates in Adult Subjects with HCV Genotype 1 Infection and HIV-1 Co-Infection (C212 Trial)
* On-treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough). Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT and with at least one follow-up HCV RNA assessment. Includes one prior null responder who experienced relapse after SVR12. Eighty-nine percent (n=54/61) of the OLYSIO-treated treatment-naïve subjects and prior relapsers without cirrhosis were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 87%. Seventy-one percent (n=37/52), 93% (n=14/15), 80% (n=8/10) and 36% (n=10/28) of OLYSIO-treated treatment-naïve subjects, prior relapsers, prior partial responders and prior null responders had undetectable HCV RNA at week 4 (RVR). In these subjects the SVR12 rates were 89%, 93%, 75% and 90%, respectively. Table 18 shows the SVR rates by METAVIR fibrosis scores. Table 18: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection and HIV-1 co-Infection (C212 Trial)
Adult Subjects with HCV Genotype 4 Infection RESTORE was an open-label, single-arm Phase 3 trial in subjects with HCV genotype 4 infection who were treatment-naïve or failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders). Treatment-naïve subjects or prior relapsers received once-daily treatment with 150 mg OLYSIO plus Peg-IFN-alfa-2a and RBV for 12 weeks, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa-2a and RBV in accordance with the protocol-defined RGT criteria. Prior non-responder subjects (partial and null response) received once-daily treatment with 150 mg OLYSIO plus Peg-IFN-alfa-2a and RBV for 12 weeks, followed by 36 weeks of Peg-IFN-alfa-2a and RBV. The 107 enrolled subjects in the RESTORE trial with HCV genotype 4 had a median age of 49 years (range: 27 to 69 years; with 5% above 65 years); 79% were male; 72% were White, 28% Black or African American, and 7% Hispanic; 14% had a BMI greater than or equal to 30 kg/m2; 60% had HCV RNA levels greater than 800,000 IU/mL; 57% had METAVIR fibrosis score F0, F1 or F2, 14% METAVIR fibrosis score F3, and 29% METAVIR fibrosis score F4; 42% had HCV genotype 4a, and 24% had HCV genotype 4d; 8% had IL28B CC genotype, 58% IL28B CT genotype, and 35% IL28B TT genotype; 33% (n=35) were treatment-naïve HCV subjects, 21% (n=22) prior relapsers, 9% (n=10) prior partial responders, and 37% (n=40) prior null responders. Table 19 shows the response rates in treatment-naïve, prior relapsers, prior partial responders and null responders. Table 20 shows the SVR rates by METAVIR fibrosis scores. Table 19: Response Rates in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)
On-treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol-specified treatment stopping rules and/or experienced viral breakthrough). Viral relapse rates are calculated with a denominator of subjects with undetectable (or unconfirmed detectable) HCV RNA at actual EOT. Table 20: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)
Adult Subjects with HCV Genotype 1 Infection The COSMOS trial was an open-label, randomized Phase 2 trial to investigate the efficacy and safety of 12 or 24 weeks of OLYSIO (150 mg once daily) in combination with sofosbuvir (400 mg once daily) without or with RBV in HCV genotype 1-infected prior null responders with METAVIR fibrosis score F0–F2 (Cohort 1), or treatment-naïve subjects and prior null responders with METAVIR fibrosis score F3–F4 and compensated liver disease (Cohort 2). The 80 enrolled subjects without advanced hepatic fibrosis in Cohort 1 had a median age of 56 years (range 27 to 70 years; with 8% above 65 years); 61% were male; 71% were White, 29% Black or African American, and 25% were Hispanic; 30% had a BMI greater than or equal to 30 kg/m2; 98% had HCV RNA levels greater than 800,000 IU/mL; 41% had METAVIR fibrosis score F0 or F1 and 59% had METAVIR fibrosis score F2; 78% had HCV genotype 1a, and the remaining patients had HCV genotype 1b; 39% of the overall population and 50% of the subjects with genotype 1a had the NS3 Q80K polymorphism at baseline; 6% had IL28B CC genotype, 70% IL28B CT genotype, and 24% IL28B TT genotype. All subjects were prior null responders to Peg-IFN-alfa and RBV. The 87 enrolled subjects with advanced hepatic fibrosis in Cohort 2 had a median age of 58 years (range 28 to 70 years; with 3% above 65 years); 67% were male; 91% were White, 9% Black or African American, and 17% were Hispanic; 44% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800,000 IU/mL; 53% had METAVIR fibrosis score F3 and 47% had METAVIR fibrosis score F4 (cirrhosis); 78% had HCV genotype 1a, and 22% HCV genotype 1b; 31% of the overall population and 40% of the subjects with genotype 1a had the NS3 Q80K polymorphism at baseline; 21% had IL28B CC genotype, 56% IL28B CT genotype, and 23% IL28B TT genotype. Fifty-four percent of subjects were prior null responders to Peg-IFN-alfa and RBV and 46% were treatment-naïve. Table 21 shows the response rates by combining prior null responders in Cohort 1 and treatment-naïve subjects and prior null responders in Cohort 2. When treatment arms with and without ribavirin were combined, the overall SVR12 rate was 95% (61/64) in subjects with METAVIR fibrosis score F0-F3 who received 12 weeks treatment of OLYSIO in combination with sofosbuvir with/without RBV when pooling both cohorts. The overall SVR12 rate was 96% (22/23) in subjects with METAVIR fibrosis score F4 who received 24 weeks treatment of OLYSIO in combination with sofosbuvir with/without RBV when pooling both cohorts. Addition of RBV did not increase response rates in comparison with OLYSIO in combination with sofosbuvir alone; and therefore these data are not shown in Table 21. Table 21: Treatment Response by METAVIR Fibrosis Score in Treatment-Naïve Subjects or Prior Null Responders* with HCV Genotype 1 Infection Receiving 12 or 24 Weeks of OLYSIO with Sofosbuvir (COSMOS Trial; Pooled Data for Cohort 1 and 2)
Null Responders to prior Peg-IFN-alfa and RBV therapy. Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at EOT and with at least one follow-up HCV RNA assessment. No subjects experienced virologic on-treatment failure. 16 HOW SUPPLIED/STORAGE AND HANDLING OLYSIO 150 mg capsules are white, marked with "TMC435 150" in black ink. The capsules are packaged into a bottle containing 28 capsules (NDC 59676-225-28) or a bottle of 7 capsules (emergency supply; NDC 59676-225-07). Store OLYSIO capsules in the original bottle in order to protect from light at room temperature below 30°C (86°F). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). OLYSIO should be used in combination with other antiviral drugs for the treatment of CHC infection, and thus contraindications and warnings for these drugs also apply to their use in OLYSIO combination treatment. Symptomatic Bradycardia when used in combination with Sofosbuvir and Amiodarone Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Warnings and Precautions (5.1), Adverse Reactions (6.2), and Drug Interactions (7.3)]. Pregnancy Advise female patients to use an effective contraceptive method during treatment with OLYSIO. Advise patients to see the patient information for other antiviral drugs used in combination with OLYSIO regarding use in pregnancy [see Use in Specific Populations (8.1)]. Hepatic Decompensation and Failure Inform patients to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to contact their healthcare provider immediately if such symptoms occur [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Adverse Reactions (6.2), Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)]. Photosensitivity Advise patients of the risk of photosensitivity reactions related to OLYSIO combination treatment and that these reactions may be severe. Patients should be advised to contact their healthcare provider immediately if they develop a photosensitivity reaction. Patients should not stop OLYSIO due to photosensitivity reactions unless instructed by their healthcare provider [see Warnings and Precautions (5.4)]. Patients should be advised to use sun protection measures (such as a hat, sunglasses, protective clothing, sunscreen) during treatment with OLYSIO. Patients should limit exposure to natural sunlight and avoid artificial sunlight (tanning beds or phototherapy) during treatment with OLYSIO. Rash Advise patients of the risk of rash related to OLYSIO combination treatment and that rash may become severe. Patients should be advised to contact their healthcare provider immediately if they develop a rash. Patients should not stop OLYSIO due to rash unless instructed by their healthcare provider [see Warnings and Precautions (5.5)]. Administration Advise patients that OLYSIO should be used only in combination with other antiviral drugs for the treatment of CHC infection. Advise patients to discontinue OLYSIO if any of the other antiviral drugs used in combination with OLYSIO are permanently discontinued for any reason. Advise patients that the dose of OLYSIO must not be reduced or interrupted, as it may increase the possibility of treatment failure. If the patient misses a dose of OLYSIO and remembers within 12 hours of the usual dosing time, advise the patient to take the missed dose of OLYSIO with food as soon as possible and then take the next dose of OLYSIO at the regularly scheduled time. If a patient misses a dose of OLYSIO by more than 12 hours after the usual dosing time, advise the patient not to take the missed dose of OLYSIO, but to resume the usual dosing of OLYSIO with food at the regularly scheduled time. Inform the patient that he or she should not take more or less than the prescribed dose of OLYSIO at any one time. Hepatitis C Virus Transmission Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and to take appropriate precautions to prevent transmission of the hepatitis C virus.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
