Cimeprevir Capsules Instructions

Approval date: xxxx on xx　　　　　　　　　　　　　　　　　　　　　
 Cimeprevir Capsules Instructions
Please read the instructions carefully and use under the direction of your physician.
Warning: Risk of HBV reactivation in patients with combined hepatitis B virus (HBV) and hepatitis C virus (HCV) infection
HBV reactivation has been reported in patients with combined HBV/HCV infection who are receiving or have completed direct-acting antiviral therapy for HCV but are not receiving concurrent antiviral therapy for HBV, resulting in fulminant hepatitis, liver failure, and death in some cases. Patients with comorbid HBV/HCV infection were monitored for hepatitis episodes or HBV reactivation during HCV treatment and post-treatment follow-up. Appropriate management of patients with HBV infection based on clinical manifestations (see [Precautions] for details).
 Drug Name]
Generic Name: Simeprevir Capsules
Trade name: Oleson® (OLYSIO®)
English Name: Simeprevir Capsules
Hanyu Pinyin: Ximeiruiwei Jiaonang
Ingredients
Active ingredient: Simeprevir chemical name: (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]cyclopropano[g][1,6]diazacyclotetradecene-12a(1H)-carboxamide Chemical structure formula:Molecular formula:C38H47N5O7S2 Molecular weight:749.94 
 Properties]
This product is a capsule, the content of white to off-white powder.
Indications
This product is indicated for the treatment of hepatitis C virus (HCV) infection in adults (see [Dosage and Administration] and [Clinical Trials] for details).
In combination with sofosbuvir in the treatment of patients with genotype 1 HCV infection without cirrhosis or with compensated cirrhosis.
In combination with pegylated interferon alpha (PegIFNα) and ribavirin (RBV) for the treatment of patients with genotype 1 or 4 HCV infection without cirrhosis or with compensated cirrhosis.
Restrictions on use.
The combination of PegIFNα and RBV in the treatment of patients infected with HCV genotype 1a resulted in significantly reduced efficacy in patients carrying the NS3 Q80K polymorphism at baseline compared to patients without the Q80K polymorphism. (See [Dosage] and [Pharmacology and Toxicology] for more information).
This product is not recommended for patients who have failed prior treatment regimens including this product or other HCV protease inhibitors (see [Pharmacology and Toxicology] for details).
Specification
150 mg
Dosage and Administration
Combination therapy
This product should be given in combination with other antiviral drugs for the treatment of chronic HCV infection. This product is not recommended for monotherapy.
The recommended dose is 150 mg capsule once daily with a meal (see [Pharmacokinetics] for details). Capsules should be swallowed whole. For specific dosing recommendations for antiviral drugs used in combination with this product, please see the prescribing information for each drug.
This product may be used in combination with sofosbuvir or PegIFNα and RBV.
Combination of this product with sofosbuvir.
Table 1 shows the recommended regimen and duration of therapy for the combination of this product with sofosbuvir in the treatment of patients with chronic HCV genotype 1 infection.
Table 1: Recommended regimens and courses of treatment for patients with chronic HCV genotype 1 infection in combination with sofosbuvir Patient population (HCV genotype 1) Regimen/course of treatment Primary and treated patients*: without cirrhosis 12 weeks of this product + sofosbuvir
With compensated cirrhosis (Child-Pugh A) 24 weeks of Benadryl + sofosbuvir
* Treated patients include prior relapsers who have failed prior IFN therapy, prior partial responders, and prior null responders (see [Clinical Trials] for details).
 Combination of this product with PegIFNα and RBV.
Table 2 shows the recommended regimen and duration of therapy for the combination of PegIFNα and RBV in patients with HCV genotype 1 or 4 infection alone or co-infected with HIV. Please see Table 3 for details of the treatment discontinuation principles of this product in combination with PegIFNα and RBV.
Table 2: Recommended regimen and course of treatment for patients with chronic HCV genotype 1 or 4 infection in combination with PegIFNα and RBV Patient population (HCV genotype 1 or 4) Treatment regimen/course Primary patients and prior relapsers*.
Patients with HCV alone without cirrhosis or with compensated cirrhosis (Child-Pugh A) treated with this product in combination with PegIFNα and RBV for 12 weeks, followed by 12 weeks of PegIFNα and RBV (total course of treatment is 24 weeks)† Patients with HCV/HIV co-infection without cirrhosis with compensated cirrhosis (Child-Pugh A) HCV/HIV co-infected patients with compensated cirrhosis (Child-Pugh A) treated with PegIFNα and RBV for 12 weeks followed by PegIFNα and RBV for 36 weeks (48 weeks total) †Previous non-responders (including partial responders‡ and non-responders#): HCV/HIV co-infection without or with compensated cirrhosis (Child-Pugh A) or HCV Patients with mono-infection treated with this product in combination with PegIFNα and RBV for 12 weeks, followed by PegIFNα and RBV given for 36 weeks (total duration of therapy is 48 weeks) †HIV=human immunodeficiency virus.
* Previous relapsers: HCV RNA was undetectable at the end of previous IFN treatment but detectable at follow-up (see [Clinical Trials] for details).
‡ Patients do not meet the recommended treatment regimen when treatment discontinuation principles are met (see Table 3).
§ Previous partial responders: HCV RNA decreased ≥ 2 log10 IU/mL from baseline at week 12 of prior therapy and HCV RNA was detectable at the end of prior IFN therapy (see [Clinical Trials] for details).
§ Previously null responders: HCV RNA decline from baseline <2 log10 IU/mL at week 12 of prior IFN therapy (see [Clinical Trials] for details).
 Tests performed prior to initiation of treatment
HBV infection testing
Prior to initiation of HCV therapy with this product, all patients were tested for current or prior HBV infection by measuring hepatitis B virus surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) values (see [Precautions] for details).
Liver function laboratory tests
Monitor liver biochemistry prior to and during combination therapy (see [Precautions] for details).
Discontinuation of dosing
Combination of this product with sofosbuvir
There are no treatment discontinuation principles applicable to the combination of sofosbuvir with this product (see [Clinical Trials] for details).
Combination of this product with PegIFNα and RBV
On-treatment HCV RNA levels should be monitored as a clinical indication using a sensitive test with a lower limit of quantification of at least 25 IU/mL.
Because patients with poor on-treatment virologic response (i.e., HCV RNA ≥25 IU/mL) are less likely to achieve sustained virologic response (SVR), it is recommended that these patients discontinue therapy. Table 3 shows the principles of treatment discontinuation for patients with poor virologic response occurring at weeks 4, 12 and 24.
Table 3: Treatment discontinuation principles for patients treated with PegIFNα and RBV in combination with PegIFNα and RBV who have a poor virologic response on therapy Week of treatment HCV RNA measures Week 4 ≥ 25 IU/mL Discontinue PegIFNα, PegIFNα and RBV Week 12 Discontinue PegIFNα and RBV (treatment with PegIFNα and RBV completed at Week 12) Week 24 Discontinue PegIFNα and RBV (treatment with PegIFNα and RBV completed at Week 12) RBV (treatment with this product is completed at week 12)
 Dose adjustment or interruption
To avoid treatment failure, the dose of this product should not be reduced or treatment interrupted. If this product is discontinued due to adverse reactions or poor virologic response on treatment, treatment with this product should not be resumed (see [Precautions] for details).
In the event of an adverse reaction potentially associated with an antiviral drug used in combination with this product, refer to the instructions in each drug’s prescribing information for advice on dose adjustment or discontinuation.
In the treatment of chronic HCV infection, if other antiviral drugs used in combination with this product are permanently discontinued for any reason, this product must also be discontinued.
Not recommended for patients with moderate or severe hepatic impairment
No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A) (see [Pharmacokinetics] for details).
This product is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) (see [Precautions], [Adverse Reactions], and [Pharmacokinetics] for more information). Increased simeprevir exposure in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). In clinical studies of this product in combination with PegIFNα and RBV, higher simeprevir exposure was associated with an increased incidence of adverse reactions, including elevated bilirubin, rash, and photosensitivity. Post-marketing reports of hepatic failure, liver failure and death have occurred in patients with advanced or decompensated cirrhosis treated with this product in combination (see [Precautions], [Adverse Reactions] and [Pharmacokinetics] for details).
The safety and efficacy of this product in liver transplant patients have not been established.
For information on contraindications related to the use of PegIFNα in patients with hepatic decompensation, please refer to the PegIFNα prescribing information.
Patients with renal impairment
No dose adjustment of this product is required in patients with mild, moderate, or severe renal impairment (see [Pharmacokinetics] for more information). The safety and efficacy of this product has not been studied in patients with HCV infection with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease (including patients requiring dialysis). Simeprevir has high protein binding and therefore cannot be cleared by hemodialysis (see [Pharmacokinetics] for details).
For information on the use of other antiviral drugs in combination with this product in patients with renal impairment, please refer to the individual drug formulary information.
Ethnicity
Patients of East Asian ancestry exhibit higher simeprevir exposure, but no dose adjustment based on race is required (see [Adverse Reactions], [Pharmacokinetics], and [Clinical Trials] for more information).
Adverse reactions]
Since this product must be used concomitantly with other antiviral drugs, please refer to the prescribing information of these antiviral drugs used in combination with this product for descriptions of adverse reactions in their use.
The following serious or significant adverse reactions are described in detail below and elsewhere in the instruction manual.
Severe symptomatic bradycardia in combination with sofosbuvir and amiodarone (see [Precautions] and [Drug Interactions] for details)
Hepatic decompensation and liver failure (see [Precautions] for details)
Photosensitivity (see [Precautions] for details)
Skin rash (see [Precautions] for details)
Clinical Study Experience
Due to the varying conditions of clinical trials, the rates of adverse reactions observed in the respective clinical trials of different drugs are not directly comparable and do not reflect the incidence observed in clinical practice.
Combination of this product with sofosbuvir
The safety profile of this product in combination with sofosbuvir in patients with HCV genotype 1 infection with or without compensated cirrhosis (Child-Pugh A) is based on pooled data from the Phase II trial COSMOS and the Phase III trials OPTIMIST-1 and OPTIMIST-2, which included a total of 317 subjects treated with this product in combination with sofosbuvir (without RBV) for 12 or 24 weeks in 317 subjects (see [Clinical Studies] for details).
Table 4 lists adverse events with an incidence of ≥10% (all levels) in subjects treated with sofosbuvir 150 mg once daily in combination with sofosbuvir 400 mg once daily (no RBV) for 12 or 24 weeks. The overall safety profile was similar in cirrhotic and non-cirrhotic subjects (see [DOSAGE] for details).
The majority of reported adverse events were Grade 1 or 2 in severity. Grade 3 or 4 adverse events were reported in 4% and 13% of subjects treated with sofosbuvir in combination with this product for 12 or 24 weeks, respectively. Serious adverse events were reported in 2% and 3% of subjects treated with sofosbuvir in combination with sofosbuvir for 12 or 24 weeks, respectively. One percent and 6% of subjects treated with sofosbuvir in combination for 12 or 24 weeks, respectively, discontinued treatment due to adverse events.
Table 4: Adverse events with an incidence of ≥10% in subjects treated with this product in combination with sofosbuvir for 12 or 24 weeks# (all levels)
Adverse events 12 weeks of this product + sofosbuvir
N=286
% (n) 24 weeks of this product + 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) # The 12-week group is a pooled group of COSMOS, OPTIMIST-1 and OPTIMIST-2 trial Subjects. 24-week group is for subjects in the COSMOS trial.
Rash and Photosensitivity
In the trial of sofosbuvir in combination with this product, 12% of the subjects treated with this product who received 12 weeks of treatment developed a rash (including photosensitivity) compared to 16% of the subjects treated with this product who received 24 weeks of treatment.
The severity of the rash events in the treated subjects was mostly mild or moderate (grade 1 or 2). Of the 317 subjects, one subject (<1%) reported a grade 3 rash that led to treatment discontinuation; no subjects experienced a grade 4 rash.
The majority of photosensitivity reactions were mild (grade 1); 2/317 subjects (<1%) reported grade 2 photosensitivity reactions. No grade 3 or 4 photosensitivity reactions were reported, and no subjects discontinued treatment due to photosensitivity reactions.
Abnormal Laboratory Tests
The most common grade 3 and 4 laboratory test abnormalities in subjects receiving sofosbuvir in combination with this product were elevated amylase and lipase (Table 5). Most amylase and lipase elevations were transient and mild or moderate in severity. Amylase and lipase elevations were not associated with pancreatitis.
Table 5: Abnormal amylase, hyperbilirubinemia and lipase laboratory tests in subjects# treated with this product in combination with sofosbuvir for 12 or 24 weeks (WHO severity toxicity class 1-4)
Laboratory parameters WHO toxicity range 12 weeks of this product + sofosbuvir
N=286
% 24 weeks this product + sofosbuvir
N=31
% Biochemical Amylase* Grade 1 ≥ 1.1 and ≤ 1.5 x ULN‡12 26 Grade 2>1.5 and ≤ 2.0 x ULN563 Grade>2.0 and ≤ 5.0 x ULN5 10 Hyperbilirubinemia Grade 1 ≥ 1.1 and ≤ 1.5 x ULN12 16 Grade 2>1.5 and ≤ 3.0 x ULN333 Grade>3.0 and ≤ 5.0 x ULN<104 level>5.0× ULN0 3 lipase level 1 ≥ 1.1 and ≤ 1.5× ULN5 3 level 2>1.5 and ≤ 3.0× ULN8 10 level 3>3.0 and ≤ 5.0× ULN<1 3 level 4>5.0× ULN <1 3 # 12 week groups for COSMOS, OPTIMIST- 1 and OPTIMIST-2 trials for pooled subjects. 24-week group for subjects in the COSMOS trial.
* No grade 4 change in amylase.
‡ ULN: upper limit of normal.
 This product is used in combination with PegIFNα and RBV
The safety profile of this product in combination with PegIFNα and RBV in patients with HCV genotype 1 infection is based on pooled data from three Phase III clinical studies (QUEST-1, QUEST-2 and PROMISE) (see [Clinical Trials] for details). These studies included a total of 1178 subjects treated with PegIFNα and RBV for 24 or 48 weeks in combination with this product or placebo. 781 of the 1178 subjects were randomized to receive 12 weeks of this product at 150 mg once daily and 397 subjects were randomized to 12 weeks of placebo once daily.
In the pooled phase III safety data, the majority of adverse reactions in patients receiving PegIFNα in combination with RBV over 12 weeks were grade 1 and 2 in severity. Grade 3 and 4 adverse reactions were reported in 23% of subjects in the PegIFNα and RBV combination group, compared to 25% in the placebo combination PegIFNα and RBV treatment group. Serious adverse reactions were reported in 2% of subjects in the PegIFNα and RBV group and in 3% of subjects in the placebo-combined PegIFNα and RBV group. The percentage of patients discontinuing this product or placebo due to adverse reactions was 2% and 1% in the treatment group with this product in combination with PegIFNα and RBV and in the group with placebo in combination with PegINFα and RBV, respectively.
Table 6 lists the incidence of adverse reactions (all grades) in the first 12 weeks of treatment in the pooled phase III study in subjects who relapsed after primary or prior PegIFNα and RBV treatment, which were at least 3% higher in the group receiving this product 150 mg once daily in combination with PegIFNα and RBV than in the placebo-combined PegIFNα and RBV treatment group.
Table 6: Incidence of adverse reactions in the first 12 weeks of treatment in subjects with chronic HCV infection* receiving this product in combination with PegIFNα and RBV was higher than in the placebo in combination with PegIFNα and RBV treatment group for ≥3% of adverse reactions (all grades) (Phase III Summary†) Adverse Reactions‡
This product 150 mg+PegIFNα+RBV
First 12 weeks
N=781
% (n) Placebo+PegIFNα+RBV
First 12 weeks
N=397
% (n)Rash (including photosensitivity)28 (218)20 (79)Pruritus22 (168)15 (58)Nausea22 (173)18 (70)Myalgia16 (126)13 (53)Dyspnea12 (92)8 (30)* Subjects on initial treatment or relapse after previous PegIFNα and RBV treatment.
† Pooled Phase III studies: QUEST 1, QUEST 2, PROMISE.
‡ Adverse reactions with a higher incidence in the product-treated group than in the placebo-treated group ≥ 3%. Rash and photosensitivity
In the Phase III clinical trial of this product or placebo in combination with PegIFNα and RBV, the incidence of rash (including photosensitivity) was 28% in the product group and 20% in the placebo group during the first 12 weeks of treatment with this product or placebo in combination with PegIFNα and RBV. Fifty-six percent of the skin rash events in the group occurred in the first 4 weeks, with 42% occurring in the first 2 weeks. The majority of rash events in patients treated with this product were mild or moderate (grade 1 or 2). The incidence of severe (grade 3) rash was 1% in subjects treated with this product and no such events occurred in the placebo group. No life-threatening (grade 4) rash events were reported. The incidence of discontinuation of the product or placebo due to rash was 1% in the product group and less than 1% in the placebo group. The frequency of rash and photosensitivity reactions was also higher in subjects with higher simeprevir exposure.
All subjects enrolled in Phase III clinical studies were required to use sun protection. In the first 12 weeks of treatment with PegIFNα and RBV in combination with this product or placebo in these studies, the proportion of adverse reactions classified as photosensitivity occurred in the product and placebo groups was 5% and 1%, respectively. The majority of the photosensitivity reactions in the group were mild or moderate (grade 1 or 2). 2 subjects in the group experienced a photosensitivity reaction that resulted in hospitalization. No life-threatening photosensitivity reactions were reported.
Respiratory distress
During 12 weeks of treatment with PegIFNα and RBV in combination with this product or placebo, dyspnea was reported in 12% and 8% of the product and placebo groups, respectively (all grades; pooled phase III clinical studies). All dyspnea events in the product group were mild or moderate (grade 1 or 2). No grade 3 or 4 dyspnea events were reported, and no subjects discontinued treatment due to dyspnea. 61% of dyspnea events occurred during the first 4 weeks of treatment with this product.
Abnormal laboratory tests
The following laboratory parameters did not differ between treatment groups in subjects receiving PegIFNα and RBV in combination with this product or placebo: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, and serum creatinine. Table 7 lists the laboratory test abnormalities that occurred more frequently in the Benadryl group than in the placebo group.
Table 7: Laboratory test abnormalities with higher incidence in subjects treated with this product (WHO toxicity class 1 to 4.
Phase III summary*; first 12 weeks of treatment) Laboratory parameters WHO toxicity grade Benadryl 150 mg+PegIFNα+RBV
N=781
% placebo+PegIFNα+RBV
N=397
% Chemical tests Alkaline phosphatase† Grade 1>1.25 and ≤2.50×ULN‡312 Grade>2.50 and ≤5.00×ULN<10 Hyperbilirubinemia Grade 1>1.1 and ≤1.5×ULN27152 Grade>1.5 and ≤2.5×ULN1893 Grade>2.5 and ≤5.0×ULN424 Grade>5.0×ULN<10† Pooled phase III studies: QUEST 1, QUEST 2, PROMISE.
† No grade 3 or grade 4 alkaline phosphatase alterations were observed.
‡ ULN: upper limit of normal
The severity of bilirubin elevation is predominantly mild to moderate (grade 1 or 2) and includes both direct and indirect bilirubin elevations. Bilirubin elevations occur shortly after treatment initiation, with the highest incidence occurring in week 2 of the study, and recover rapidly after discontinuation of the drug. Bilirubin elevations were not usually accompanied by elevations in hepatic transaminases. Bilirubin elevations also occurred more frequently in subjects with higher simeprevir exposure.
Adverse Reactions in HCV/HIV-1 Coinfected Subjects
The combination of PegIFNα and RBV was studied in 106 HCV genotype 1/HIV co-infected subjects (C212). safety profile in HCV/HIV co-infected subjects was comparable to that of HCV alone.
Adverse effects in HCV genotype 4-infected subjects
This product was studied in combination with PegIFNα and RBV in 107 HCV genotype 4-infected subjects (RESTORE). The safety profile in subjects infected with HCV genotype 4 was comparable to that in subjects infected with HCV genotype 1.
Adverse Reactions in East Asian Subjects
A phase III study was conducted in Chinese and Korean subjects with initial chronic HCV genotype 1 infection, in which this product was combined with PegIFNα and RBV (TIGER). The safety profile of this product in East Asian subjects was similar to that of the global study pooled phase III population; however, the incidence of abnormal hyperbilirubinemia on laboratory tests was higher in patients receiving 150 mg of this product in combination with PegIFNα and RBV than in patients receiving placebo in combination with PegIFNα and RBV. 150 mg of this product in combination with PegIFNα and RBV group and The incidence of total bilirubin elevation (all grades) in the placebo combined with PegIFNα and RBV group was 66% (99/151) and 26% (40/152), respectively. Most of the bilirubin elevations were grade 1 or 2. The incidence of grade 3 bilirubin elevations was 9% (13/151) and 1% (2/152) in the 150 mg of this product combined with PegIFNα and RBV group and the placebo combined with PegIFNα and RBV group, respectively. There were no grade 4 bilirubin elevation events. Bilirubin elevations were not accompanied by elevated hepatic transaminases and were reversible at the end of treatment (see [Dosage] and [Clinical Trials] for details).
Post-marketing experience
The following adverse reactions have been reported during post-marketing use of this product. Because postmarketing adverse reactions are derived from spontaneous reports from populations of uncertain size, it is not possible to accurately estimate their frequency or to determine the causal relationship between drug exposure and these adverse reactions.
Cardiac organ disease: Serious symptomatic bradycardia events have been reported in patients taking amiodarone during treatment with sofosbuvir in combination with another HCV direct-acting antiviral drug (including this product) (see [Precautions] and [Drug Interactions] for details).
Hepatobiliary disease: hepatic decompensation, liver failure (see [Precautions] for details).
Contraindications
Since this product can only be used in combination with other antiviral drugs (including PegIFNα and RBV) for the treatment of chronic HCV infection, contraindications to other drugs also apply to the combination regimen. Please refer to the prescribing information of each drug for contraindications.
Precautions]
Risk of HBV reactivation in patients with co-infection with HBV/HCV
HBV reactivation has been reported in patients with combined HBV/HCV infection who are receiving or have completed direct-acting antiviral therapy for HCV but are not receiving concomitant antiviral therapy for HBV, resulting in fulminant hepatitis, liver failure, and death in some cases. Cases have been reported in both HBsAg-positive patients and in patients with serologic indicators indicating recovery of HBV infection (i.e., HBsAg-negative and anti-HBc-positive). HBV reactivation has also been reported in patients treated with certain immunosuppressive or chemotherapeutic agents, and these patients may be at increased risk of HBV reactivation associated with direct-acting antiviral therapy for HCV.
HBV reactivation is characterized by a dramatic increase in HBV replication, as evidenced by a rapid increase in serum HBV DNA levels. The reactivation of HBV replication may be accompanied by hepatitis (i.e., elevated transaminase levels) and, in severe cases, elevated bilirubin levels, liver failure, and death.
All patients are tested for current or prior HBV infection by measuring HBsAg and anti-HBc values prior to initiation of HCV therapy with this product, and patients with clinical and laboratory signs of hepatitis exacerbation or HBV reactivation as indicated by serologic indicators of HBV infection are monitored during HCV treatment with this product and during post-treatment follow-up. Appropriate management of patients infected with HBV based on clinical signs and symptoms.
Q80K testing in patients infected with HCV genotype 1a
This product is used in combination with sofosbuvir
Testing for the presence of the NS3 Q80K polymorphism may be considered prior to initiation of this product in combination with sofosbuvir in patients with genotype 1a HCV infection with compensated cirrhosis (see [Clinical Studies] for details).
Combination with PegIFNα and RBV
Prior to initiating PegIFNα and RBV therapy, it is strongly recommended that patients infected with HCV genotype 1a be tested for the presence of viruses carrying the NS3 Q80K polymorphism and that alternative therapies be considered for patients with detected Q80K polymorphisms (see [Indications] and [Pharmacology and Toxicology] for more information).
Severe symptomatic bradycardia in combination with sofosbuvir and amiodarone
Post-marketing reports of symptomatic bradycardia events and events requiring pacemaker intervention have been reported with sofosbuvir in combination with another HCV direct-acting antiviral agent, including this one, and fatal cardiac arrest was reported in one patient treated with a sofosbuvir-containing regimen (raltegravir/sofosbuvir). Bradycardia usually occurred within hours to days after initiation of HCV therapy, but was observed as late as 2 weeks after HCV therapy. Patients taking concomitant beta-blockers or with underlying cardiac comorbidities and/or advanced liver disease are at increased risk of symptomatic bradycardia when combined with amiodarone. Bradycardia generally subsides after cessation of HCV treatment. The mechanism of action of the bradycardic effect is not known.
Combining amiodarone with sofosbuvir in combination with this product is not recommended. For patients who are on amiodarone and will be combining this product with sofosbuvir because no other alternative therapy is available.
Advise patients of the possible risk of severe symptomatic bradycardia.
Inpatient cardiac monitoring is recommended for the first 48 hours after coadministration, followed by daily heart rate monitoring at the clinic or on your own for at least the first 2 weeks of treatment.
Similar ECG monitoring should be performed as described above for patients who are on combination sofosbuvir and this product and need to start amiodarone therapy because no other alternative therapy is available.
Because of the long elimination half-life of amiodarone, ECG monitoring should also be performed as described above if a patient starts sofosbuvir in combination with this product immediately after discontinuing amiodarone.
Patients presenting with signs or symptoms of bradycardia should be evaluated medically immediately. Symptoms of bradycardia may include near syncope or fainting, dizziness or lightheadedness, malaise, weakness, excessive fatigue, shortness of breath, chest pain, confusion, or memory problems (see [ADVERSE REACTIONS] and [DRUG INTERACTIONS] for more information).
Hepatic Decompensation and Liver Failure
Events of hepatic failure and liver failure (including fatal cases) have been reported in patients treated with this product in combination with PegIFNα and RBV or this product in combination with sofosbuvir since its introduction. The majority of these events occurred in patients with advanced and/or decompensated cirrhosis, who are at increased risk for hepatic decompensation or liver failure. Because these events were spontaneously reported during clinical practice, it is not possible to estimate the frequency, and the causal relationship between this treatment and these events is unclear (see [Adverse Reactions] for details).
This product is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) (see [Dosage] for details).
In clinical studies of this product, moderately elevated bilirubin levels were observed without effects on liver function (see [ADVERSE REACTIONS] for details). There have been post-marketing reports of incidents of hepatic dysfunction with significantly elevated bilirubin levels. Liver chemistry should be monitored prior to and during treatment with this combination (based on clinical indications). Patients with elevated total bilirubin more than 2.5 times the upper limit of normal (ULN) should be monitored closely.
Patients should be instructed to contact medical personnel if they develop symptoms of malaise, weakness, loss of appetite, nausea and vomiting, jaundice, or discolored stools.
If elevated bilirubin is also accompanied by elevated hepatic transaminases or clinical signs and symptoms of hepatic dysfunction, the product should be discontinued.
Risk of serious adverse reactions associated with combination therapy
Because this product is used in combination with other antiviral drugs for the treatment of chronic HCV infection, the prescribing information for these drugs should be consulted prior to initiating treatment with this product. The warnings and precautions associated with these drugs also apply to combination therapy with this product.
Photosensitivity
Photosensitivity reactions have been observed during combination therapy with this product. Serious photosensitivity reactions resulting in hospitalization have been observed during treatment with PegIFNα and RBV in combination with this product (see [Adverse Reactions] for details). Photosensitivity reactions occur most often during the first 4 weeks of treatment, but may occur at any time during treatment. Photosensitivity may manifest as an increased sunburn reaction, usually affecting areas exposed to light (especially the face, the “V” area of the neck, the surface of the forearm extensors and the back of the hands). Symptoms may include burning, erythema, exudation, blistering and edema.
Sun protection and avoidance of sun exposure is required during treatment with this product. Avoid the use of skin tanning devices during treatment with this product. If a photosensitivity reaction occurs, consider discontinuing treatment and monitor the patient until the reaction subsides. If a decision is made to continue treatment in the presence of a photosensitivity reaction, a specialist consultation is recommended.
Skin rash
Rash has been observed during combination therapy with this product (see [Adverse Reactions] for details). The rash occurs most often during the first 4 weeks of treatment, but may occur at any time during treatment. Severe rash and rash requiring discontinuation of the product have been reported in patients treated with PegIFNα and RBV in combination with this product. The majority of rash events in patients treated with this product have been mild or moderate in severity (see [Adverse Reactions] for details). Patients with mild or moderate rash need to be followed for possible progression of the rash, including the development of mucosal signs (e.g., oral damage, conjunctivitis) or systemic symptoms. If the rash progresses to a severe form, the product must be discontinued. Patients should be monitored until the rash subsides.
Sulfanilamide allergy
This product contains a sulfonamide moiety. In subjects with a history of sulfonamide allergy (n=16), no increased incidence of rash or photosensitivity reactions was observed. However, the available data are insufficient to rule out a relationship between sulfonamide allergy and the frequency and severity of adverse reactions observed during the use of this product.
Risk of adverse reactions or reduced efficacy due to drug interactions
Concomitant use of intermediate or potent inducers or inhibitors of cytochrome P450 3A (CYP3A) with this product is not recommended because it may result in significantly lower or higher exposures to simeprevir, resulting in reduced efficacy or adverse reactions (see [Drug Interactions] and [Pharmacokinetics] for details).
Keep out of the reach of children.
Pregnant women and nursing mothers
Pregnancy
Risk Summary
If this product is used in combination with RBV, the combination regimen is contraindicated in pregnant women and men whose spouses are pregnant. Please refer to the prescribing information for RBV and other drugs used in combination with this product for more information on use during pregnancy.
There are insufficient human data to determine whether this product poses a risk for pregnancy outcomes. In animal reproduction studies with simeprevir, embryo-fetal developmental toxicity (including fetal loss) was observed in mice when simeprevir exposure was 1.9 times or greater than human exposure at the recommended clinical dose, while no adverse embryo-fetal developmental outcomes were observed in mice or rats when exposure was similar to human exposure at the recommended clinical dose (see data for details). In view of these findings, pregnant women should be informed of the potential risk of this product to the fetus. The background risks of significant birth defects and miscarriage in the indication population are unknown. In the general US population, the estimated background risks of clinically confirmed major birth defects and miscarriage in pregnancy are 2-4% and 15-20%, respectively.
Animal Data
In embryo-fetal development studies in rats and mice, simeprevir given to pregnant animals at doses up to 500 mg/kg/day (rats) and 150, 500, and 1000 mg/kg/day (mice) on gestation days 6-17 (rats) and 6-15 (mice) at exposures 1.9 times or greater than the human exposure at the recommended clinical dose resulted in mouse Intrauterine litter loss in late gestation. In addition, decreased fetal body weight and increased fetal skeletal variation were observed in mice exposed at 1.2 times or more than the recommended clinical dose in humans. No adverse effects on embryo-fetal development were observed in mice (at the lowest dose tested) or rats (at the highest dose tested) at exposures similar to the recommended clinical dose in humans.
In a prenatal and postnatal developmental study in rats, maternal animals were exposed to up to 1000 mg/kg/day doses of simeprevir from gestation day 6 to lactation/postnatal day 20. At maternal toxic doses, after in utero (via maternal administration) and during lactation (via breast milk to nursing pups) exposure to simeprevir (maternal exposure equivalent to human exposure at recommended clinical doses), developing rat offspring exhibited significant weight loss and negative effects on physical growth (growth retardation and small size) and development (reduced locomotor activity). Subsequent survival, behavior, and reproductive capacity of offspring were not affected.
Lactation
Risk Summary
It is not known whether this product and its metabolites can be secreted into human milk, affect human lactation, or have effects on lactating infants. Simeprevir can be detected in the plasma of lactating rats following administration to lactating rats, and this is likely due to the presence of simeprevir in the milk (see data for details).
The developmental and health benefits of lactation should be considered along with the clinical need of the mother for this product and the potential adverse effects of this product or the mother’s underlying disease on the nursing child.
If this product is used in combination with RBV, the lactation dosing information for RBV also applies to this combination regimen. For more information on lactation dosing, please see the prescribing information for RBV and other drugs used in combination with this product.
Animal Data
Cimeprevir is likely to be present in the milk of lactating rats in prenatal and postnatal developmental studies, although not directly detected, as systemic exposure (AUC) to cimeprevir was observed in nursing littermates at concentrations approximately 10% of maternal cimeprevir exposure at day 6 nursing/postnatal.
Females and males of childbearing potential
If this product is used in combination with RBV, it is important to follow the pregnancy test and contraceptive recommendations in the RBV prescribing information. For additional information on dosing in women of childbearing potential and men, please see the prescribing information for other drugs used in combination with this product.
Fertility
No data are available on the effects of simeprevir on human fertility. Limited effects on male fertility have been observed in animal studies (see [Pharmacology and Toxicology] for more information). If this product is used in combination with RBV, the fertility information for RBV also applies to this combination regimen. In addition, please refer to the prescribing information for other drugs used in combination with this product for more information on fertility.
Pediatric Use]
The safety and efficacy of this product in pediatric patients have not been established.
Geriatric use]
Clinical studies of this product did not include a sufficient number of patients older than 65 years of age, so it is not possible to determine whether there is a difference in response to the drug between elderly patients and younger patients. No dose adjustment is required in elderly patients (see [Pharmacokinetics] for details).
Drug Interactions]
Potential effects of this product on other drugs
Simeprevir slightly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Concomitant use of this product with drugs metabolized primarily by CYP3A4 may result in increased blood concentrations of these drugs (see Table 8).
In vitro, simeprevir inhibits the transport proteins OATP1B1/3, P-glycoprotein (P-gp) and BCRP, but not OCT2. Concomitant use of this product with transport substrates of OATP1B1/3, P-gp and BCRP may result in elevated blood concentrations of these drugs (see Table 8).
Potential effects of other drugs on this product
The major enzyme involved in the biotransformation of simeprevir is CYP3A (see [Pharmacokinetics] for details). Other drugs may have clinically meaningful effects on the pharmacokinetics of simeprevir by affecting CYP3A. Concomitant use of this product with a moderately or potently potent CYP3A inhibitor may significantly increase plasma exposure to simeprevir. Concomitant use of this product with intermediate- or potent-acting CYP3A inducers may significantly reduce plasma exposure to simeprevir, resulting in a loss of efficacy (see Table 8). Therefore, concomitant use of this product with moderate-to-potent CYP3A inducers or inhibitors is not recommended (see [Precautions] and Pro [Pharmacokinetics] for details).
Known or other potentially significant drug-drug interactions
Table 8 presents known or other potentially significant drug-drug interactions for which a change in the dose or regimen of this product and/or the combination of drugs may be recommended. Table 8 also includes drugs that are not recommended for concomitant use with this product. Information regarding the strength of interactions is provided in Tables 24 and 25 (see [Pharmacokinetics] for details).
Table 8: Known or other potentially significant drug-drug interactions: Dose or treatment regimen changes may be recommended based on drug interaction studies or anticipated interactions
Combined drug use
Classification
Drug Name Effect on Concentrations of Simeprevir or Combination Clinical Evaluation of Antiarrhythmic Drug Amiodarone Effect on Concentrations of Amiodarone, Simeprevir, and Sofosbuvir Unknown The combination of amiodarone during treatment with sofosbuvir with this product may result in severe symptomatic bradycardia; therefore, the combination of amiodarone is not recommended. If combination use is required, electrocardiographic monitoring is recommended (see [Precautions], [Adverse Reactions] for details).
Caution is required when combining amiodarone with regimens containing this product (without sofosbuvir), and therapeutic drug monitoring of amiodarone is recommended if conditions permit. Digoxin*
Digoxin Routine therapeutic drug monitoring of digoxin concentrations is recommended. Oral
Propiamine, flecainide, mexiletine, propafenone, quinidine
Antiarrhythmic agents These antiarrhythmic agents are recommended for therapeutic drug monitoring when used concomitantly with this product, if conditions permit. Anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin¯
Simeprevir is not recommended for concomitant use. Anti-infective drugs Antibiotics (systemic agents).
Erythromycin*
Simeprevir
Erythromycin is not recommended for concomitant use. Antibiotics (for systemic use).
Clarithromycin, Telithromycin
Simeprevir is not recommended for concomitant use. Antifungals (systemic).
Itraconazole, Ketoconazole, Posaconazole
Simeprevir is not recommended for concomitant use. Antifungals (systemic).
Fluconazole, voriconazole
Simeprevir is not recommended for concomitant use. Anti-mycobacterial agents.
Rifampin*†, rifabutin, and
Rifapentine¯
Cimeprevir
↔ Rifampin, rifabutin, rifapentine are not recommended for concomitant use. Calcium channel blockers (oral) Amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil
Calcium channel blockers Clinical monitoring of patients is recommended when this product is used concomitantly with calcium channel blockers. Corticosteroids systemic
Dexamethasone¯
Simeprevir is not recommended for concomitant use. Gastrointestinal pharmacokinetics.
Cisapride
Cisapride is not recommended for concomitant use. Herbal milk thistle
(Silymarin)
Simeprevir is not recommended for concomitant use. St. John’s Wort (Hypericum perforatum)¯
Simeprevir is not recommended for concomitant use with products containing St. John’s wort. Anti-HIV drugs containing cobicistat
Simeprevir is not recommended for concomitant use. Non-nucleoside reverse transcriptase inhibitors (NNRTI).
Efavirenz*¯
Simeprevir
↔ Efavirenz is not recommended for concomitant use. Other NNRTIs
(delavirdine, etravirine, nevirapine)
Simeprevir
¯
Simeprevir is not recommended for concomitant use. Protease inhibitors (PI).
Darunavir/ritonavir*‡
Simeprevir
Dalunavir is not recommended for concomitant use. Protease inhibitors (PI).
Ritonavir*#
Simeprevir is not recommended for concomitant use. Other PI anti-HIV drugs with or without ritonavir boost (atazanavir, fosamprenavir, lopinavir, indinavir, nelfinavir, saquinavir, tipranavir)
or ¯
Simeprevir is not recommended for concomitant use with any PI class anti-HIV drug, with or without ritonavir.HMG COA reductase inhibitor Rosuvastatin*
Rosuvastatin is initiated at a dose of 5 mg once daily Rosuvastatin therapy. When used concomitantly with this product, the dose of Rosuvastatin should not exceed 10 mg once daily. Atorvastatin*
When atorvastatin is used concomitantly with this product, use the lowest necessary dose of atorvastatin and do not exceed 40 mg per day. simvastatin*
When simvastatin is used concomitantly with this product, use the lowest necessary dose of simvastatin and adjust the dose carefully, and monitor for safety. Pitavastatin, pravastatin, lovastatin
When pitavastatin, pravastatin, and lovastatin are used concomitantly with this product, use the lowest necessary dose of pitavastatin, pravastatin, or lovastatin and adjust the dose carefully, and conduct safety monitoring. Immunosuppressant cyclosporine*
Cyclosporine
Simeprevir§ is not recommended for concomitant use. Sirolimus
or ¯ sirolimus Routine monitoring of sirolimus blood levels is recommended. phosphodiesterase type 5 (PDE5) inhibitors sildenafil, tadalafil, vardenafil PDE5 inhibitors If this product is used concomitantly with sildenafil or tadalafil at doses administered for the long-term treatment of pulmonary hypertension, dose adjustment of the PDE5 inhibitor may be required. It is recommended that PDE5 inhibitors be administered starting at the lowest dose and increasing as needed, with appropriate clinical monitoring.
No dose adjustment is necessary if this product is used concomitantly with sildenafil, tadalafil, or vardenafil at doses appropriate for the treatment of erectile dysfunction. Sedative/anxiolytic midazolam* (oral)
Midazolam This product should be used with caution when used concomitantly with midazolam for the treatment of index stenosis. Triazolam (oral)
Triazolam This product should be used with caution when used concomitantly with triazolam for the treatment of index stenosis. The direction of the arrow (↑=increased, ↓=decreased, ↔=no change) indicates the direction of pharmacokinetic change.
* Unless otherwise noted, the above interaction study was conducted in healthy subjects at the recommended dose of simeprevir 150 mg administered once daily (see [Pharmacokinetics], Table 24 and Table 25 for details).
† In this interaction study, the dose was 200 mg once daily when administered alone and when administered concomitantly with rifampin 600 mg once daily.
‡ In this interaction study, the dose of this product was 50 mg in the concomitant dose group with darunavir/ritonavir and 150 mg in the dose group with this product alone.
# In this interaction study, the dose was 200 mg once daily in both the dosing alone and the concomitant use with ritonavir 100 mg twice daily.
§ Coadministered with study drug and RBV in a phase II study in HCV-infected post-liver transplant patients. Drugs with which the interaction is not clinically significant
In addition to the drugs in Table 8, the following drugs were evaluated in clinical studies for interaction with this product, both without dose adjustment (see [Pharmacokinetics] for details): caffeine, dextromethorphan, escitalopram, ethinyl estradiol/norethindrone, methadone, midazolam (administered intravenously), omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir disoproxil fumarate, and Warfarin.
Drug-drug interactions are not clinically significant when combined with the following drugs: antacids, azithromycin, bedaquiline, corticosteroids (budesonide, fluticasone, methylprednisolone, and prednisone), dolutegravir, fluvastatin, H2 receptor antagonists, the narcotic analgesics buprenorphine and naloxone, NRTIs (e.g., abacavir, dehydroinositide, emtricitabine, lamivudine, stavudine, zidovudine). (e.g., abacavir, desipramine, emtricitabine, lamivudine, stavudine, zidovudine), maraviroc, methylphenidate and proton pump inhibitors.
Overdose]
There is limited human experience with overdose of this product. There is no specific antidote for overdose. If an overdose occurs, the patient’s clinical status must be observed and routine supportive measures must be taken.
Simeprevir has a high protein binding capacity and therefore cannot be cleared by hemodialysis (see [Pharmacokinetics] for details).
[Clinical Trials].
Overview of clinical studies
In a phase II trial (COSMOS; in previously null responders and primary subjects with compensated cirrhosis [Child-Pugh A] or without cirrhosis) and 2 phase III trials (OPTIMIST-1 and OPTIMIST-2; in subjects without cirrhosis [OPTIMIST-1] or with compensated cirrhosis [ OPTIMIST-2] in primary or treated [previously treated with polyethylene glycol or non-polyethylene glycol IFN, in combination with or without RBV] subjects with HCV) evaluated the efficacy of this product in combination with sofosbuvir in genotype 1 HCV-infected subjects (see Table 9 for details). Efficacy data from the trial OPTIMIST-2, which evaluated this product in combination with sofosbuvir in subjects with compensated cirrhosis, were not shown because subjects in this trial received treatment for a shorter than recommended duration.
Table 9: Study groups related to the study population of the study of this product in combination with sofosbuvir
(Number of treated subjects) COSMOS
(open) GT 1, TN or TE* with or without compensated cirrhosis Benral + sofosbuvir (12 weeks) (28)
Benralbumin + sofosbuvir (24 weeks) (31) OPTIMIST-1
(Open) GT 1, TN, or TE** without cirrhosis Benral + sofosbuvir (12 weeks) (155) OPTIMIST-2
(open) GT 1, TN or TE** with compensated cirrhosis Benadryl + sofosbuvir (12 weeks) (103) GT: genotype; TN: primary treatment; TE: treated
*Includes only those who have failed to respond to prior PegIFN/RBV therapy.
**Includes relapsers and non-responders after prior Peg-IFN (based) therapy (with or without RBV), and IFN intolerant patients.
 The following studies evaluated the efficacy of this product in combination with PegIFNα and RBV in patients infected with HCV genotype 1: three phase III studies in primary-treated subjects (QUEST 1, QUEST 2, and TIGER), one phase III study in subjects who relapsed after prior interferon therapy (PROMISE), and one study in subjects who failed prior PegIFN and RBV (ASPIRE), and a phase III study in HCV genotype 1 and HIV-1 co-infected subjects who failed prior treatment with PegIFN and RBV (C212), which are summarized in Table 10.
A phase III study (RESTORE) conducted in primary subjects or subjects who had previously failed treatment with PegIFN and RBV evaluated the efficacy of this product in combination with PegIFNα and RBV in patients infected with HCV genotype 4 (see Table 10).
Table 10: Study population associated with the study of this product in combination with PegIFNα and RBV Study Group
(Number of treated subjects) QUEST-1
(double-blind) GT 1, TN with compensated cirrhosis or without cirrhosis Benadryl + PegIFNα + RBV (264)
Placebo (130) QUEST-2
(Double-blind) GT 1, TN with compensated cirrhosis or without cirrhosis Benadryl + PegIFNα + RBV (257)
Placebo (134) TIGER
(Double-blind) GT 1, TN with compensated cirrhosis or without cirrhosis Benadryl+PegIFNα+RBV (152)
Placebo (152) PROMISE
(double-blind) GT 1, TE* with compensated cirrhosis or without cirrhosis Benadryl+PegIFNα+RBV (260)
Placebo (133) ASPIRE
(double-blind) GT1, TE with compensated cirrhosis or without cirrhosis Benadryl+PegIFNα+RBV (66)
Placebo (66) C212
(Open) GT 1, TN or TE with compensated cirrhosis or without cirrhosis, combined with HCV/HIV-1 infection Benadryl + PegIFNα + RBV (106) RESTORE
(Open) GT 4, TN or TE with compensated cirrhosis or without cirrhosis Benadryl + PegIFNα + RBV (107) GT: genotype; TN: primary treatment; TE: treated, including previous relapsers, partial responders and null responders after previous treatment with PegIFN and RBV.
* Only includes those who relapsed after previous IFN treatment.
 Previous relapsers are defined as subjects with undetectable HCV RNA at the end of previous INF treatment but with detectable HCV RNA during the follow-up period; previous partial responders are defined as subjects with a ≥2 log10 decrease in HCV RNA from baseline at week 12 of previous PegIFNα and RBV treatment but with detectable HCV RNA at the end of treatment; and non-responders are defined as subjects with a ≥2 log10 decrease in HCV RNA at week 12 of previous PegIFNα and RBV treatment but with detectable HCV RNA at the end of treatment. Subjects with a decrease in HCV RNA at week 12 from baseline in prior treatment with PegIFNα and RBV<2 log10. These trials included subjects with compensated cirrhosis (Child-Pugh A) or without cirrhosis, HCV RNA ≥10,000 IU/mL, and liver histopathology consistent with chronic HCV infection. The total duration of PegIFNα and RBV treatment for first-treatment subjects and prior relapses in Phase III studies was determined based on response guidelines. The total planned duration of HCV treatment for these subjects was 24 weeks if the response-guided therapy (RGT) criteria defined by the study protocol in the following treatments were met: HCV RNA<25 IU/mL (detectable or undetectable) at week 4 and undetectable HCV RNA at week 12. using the Roche COBAS® TaqMan® HCV Analyzer (version 2.0) and High Pure series kits (lower limit of quantification [LLOQ] of 25 IU/mL and limit of detection of 15 IU/mL) were used to detect plasma HCV RNA levels. The HCV treatment discontinuation principle was introduced to ensure that subjects with a poor virological response at the time of treatment could discontinue treatment in a timely manner. In subjects with HCV/HIV-1 co-infection in Phase III study C212, the total regimen of PegIFNα and RBV in primary or previously relapsed subjects with compensated cirrhosis was not applicable to the response-guidance strategy; this group of patients received a fixed 48-week course of HCV therapy. The total course of PegIFNα and RBV for primary or prior relapses without cirrhosis was determined by the response-guidance and was based on the same criteria described above.
Combination of sofosbuvir with this product
Adult subjects with HCV genotype 1 infection
The efficacy of this product (150 mg once daily) in combination with sofosbuvir (400 mg once daily) was demonstrated in a phase II trial (COSMOS) and a phase III trial (OPTIMIST-1) in primary or treated subjects with genotype 1 HCV infection with or without compensated cirrhosis (Child-Pugh A).
The COSMOS study is an open, randomized phase II study designed to evaluate 12 or 24 weeks of this product (150 mg once daily) and sofosbuvir (400 mg once daily) in primary or treated subjects with a METAVIR fibrosis score of F0-F2 with HCV genotype 1 infection in previously null-responding patients or a METAVIR fibrosis score of F3-F4 with compensated liver disease and in previously null-responding subjects. (400 mg once daily), in combination with or without RBV, for 12 or 24 weeks. In this study, 28 subjects received sofosbuvir in combination with this product for 12 weeks and 31 subjects received sofosbuvir in combination with this product for 24 weeks. The median age of these 59 subjects was 57 years (range: 27-68 years; 2% were 65 years or older); 53% were male; 76% were Caucasian and 24% were Black or African-American; 46% had a BMI ≥30 kg/m2; and the median baseline HCV RNA level was 6.75 log10 IU/mL. Subjects with METAVIR fibrosis scores of F0-F1, F2, and F3 accounted for 19%, 31%, and 22%, respectively, and subjects with METAVIR fibrosis scores of F4 (cirrhosis) accounted for 29%; subjects with HCV genotype 1a accounted for 75%, of whom 41% carried Q80K at baseline, and subjects with HCV genotype 1b accounted for 25%; IL28B CC genotype subjects accounted for 14%, IL28B CT genotype for 64%, and IL28B TT genotype for 22%; 75% of the subjects were null responders to PegIFNα and RBV and 25% were primary subjects.
OPTIMIST-1 is an open, randomized, phase III trial in primary or treated (including prior relapsers, non-responders and IFN intolerants) subjects with genotype 1 HCV infection not associated with cirrhosis. Subjects were randomized to treatment groups with different treatment durations. 155 subjects without cirrhosis were treated with sofosbuvir in combination with this product for 12 weeks. The median age of these 155 subjects was 56 years (range: 19-70 years; 7% of subjects over 65 years); 53% were male; 78% were Caucasian, and 20% were Black or African American.
Black or African American 20%, Hispanic 16%; 37% of subjects with BMI ≥30 kg/m2; median baseline HCV RNA level of 6.83 log10 IU/mL; 75% of subjects with HCV genotype 1a, of which 40% had the Q80K polymorphism at baseline, and 25% of subjects with HCV genotype 1b; IL28B CC genotype subjects accounted for 28%, IL28B CT genotype subjects accounted for 55%, and IL28B TT genotype subjects accounted for 17%; 74% were first-treatment subjects and 26% were treated subjects.
In the COSMOS and OPTIMIST-1 trials, 170 of 170 subjects (out of 176) who received this product in combination with sofosbuvir for 12 weeks without cirrhosis, 97% of subjects achieved SVR12, as shown in Table 11. In the COSMOS trial, there were 10 (of 10) subjects with compensated cirrhosis (Child-Pugh A) who received this product in combination with sofosbuvir for 24 weeks, and 100% of subjects achieved SVR12.
Table 11: Virologic regression in adult subjects without cirrhosis treated with this product in combination with sofosbuvir for 12 weeks (pooled data from the OPTIMIST-1 and COSMOS trials)
Response rate Benralin + sofosbuvir*
12 weeks
N=176
% (n/N) Overall SVR1297 (170/176) Regression virologic relapse in subjects without SVR12†3 (5/175) SVR12: sustained virologic response 12 weeks after actual (OPTIMIST-1) or planned (COSMOS) EOT.
* This product 150 mg once daily in combination with sofosbuvir 400 mg once daily for 12 weeks.
† Virologic relapse rates were calculated using subjects with no detectable (or unconfirmed detectable) HCV RNA at EOT as the denominator. In addition to the 5 subjects with virologic relapse, SVR12 was not obtained in 1 subject due to missing SVR12 data. no subjects experienced on-treatment virologic failure.
 In subjects without cirrhosis treated with this product in combination with sofosbuvir for 12 weeks in OPTIMIST-1, SVR12 rates were similar in subgroups including: primary and treated subjects (112/115 [97%] and 38/40 [95%], respectively), subjects with and without the NS3 Q80K polymorphism in HCV genotype 1a (44/46 [ 96%] and 68/70 [97%]), subjects with genotype 1b (38/39 [97%]), and subjects with IL28B CC and non-CC genotypes (43/43 [100%] and 107/112 [96%], respectively).
This product in combination with PegIFNα and ribavirin
HCV genotype 1 infected East Asian primary treatment subjects
TIGER is a phase III, randomized, double-blind, placebo-controlled study in primary-treated subjects infected with HCV genotype 1 in China and Korea.
In this study, 152 subjects received 12 weeks of once-daily 150 mg of this product in combination with PegIFNα-2a and RBV followed by 12 or 36 weeks of PegIFNα-2a and RBV according to the RGT criteria defined by the study protocol; 152 subjects received 12 weeks of placebo in combination with PegIFNα-2a and RBV followed by 36 weeks of PegIFNα-2a and RBV treatment. The median age of the above 304 subjects was 45 years (range: 18-68 years; 2% of subjects aged 65 years or older); 49% of subjects were male; all subjects were of East Asian origin (81% of Chinese subjects and 19% of Korean subjects); 3% of subjects had a BMI ≥30 kg/m2; HCV RNA>800,000 IU/mL at baseline 84% of subjects; 82% of subjects with METAVIR fibrosis score F0, F1 or F2, 12% of subjects with METAVIR fibrosis score F3 and 6% of subjects with METAVIR fibrosis score F4 (cirrhosis); 1% of subjects with HCV genotype 1a and 99% of subjects with HCV genotype 1b; overall population at baseline subjects carrying the Q80K polymorphism were less than 1% of the overall population; subjects with the IL28B CC genotype were 79%, subjects with the IL28B CT genotype were 20%, and subjects with the IL28B TT genotype were 1%. Demographic and baseline characteristics were equally distributed between the 150 mg group and the placebo-treated group.
SVR12 rates were 91% (138/152) and 76% (115/152) in the 150 mg and placebo treatment groups, respectively (see [Adverse Reactions], [Dosage] and [Pharmacokinetics] for details).
HCV Genotype 1 Infection into Beginning Treatment Subjects
Two randomized, double-blind, placebo-controlled, two-arm, multicenter phase III studies (QUEST 1 and QUEST 2) confirmed the efficacy of this product in the treatment of patients with primary treatment of HCV genotype 1 infection. The designs of the two studies were similar. All subjects received 12 weeks of once-daily treatment with 150 mg of this product or placebo in combination with PegIFNα-2a (QUEST 1 and QUEST 2)/PegIFNα-2b (QUEST 2) and RBV followed by 12 or 36 weeks of PegIFNα and RBV according to the RGT criteria defined by the in-treatment study protocol. Control subjects received 48 weeks of PegIFNα-2a/2b and RBV.
In the pooled analysis of QUEST 1 and QUEST 2, the distribution of demographic and baseline characteristics was balanced between the two studies and between this product and placebo treatment groups. In the pooled analysis of QUEST 1 and QUEST 2, the median age of the 785 subjects enrolled was 47 years (range: 18-73 years; 2% of subjects over 65 years); 56% were male; 91% were Caucasian, 7% were Black or African American, 1% were Asian, and 17% were Hispanic; and body mass index (BMI) ≥30 kg/m2 in 23% of subjects; HCV RNA>800,000 IU/mL at baseline in 78% of subjects; METAVIR fibrosis score of F0, F1, or F2 in 74% of subjects; METAVIR fibrosis score of F3 in 16% of subjects; METAVIR fibrosis score of F4 (cirrhosis) in 10%; 48% of subjects with HCV genotype 1a and 51% of subjects with HCV genotype 1b; 29% of subjects with IL28B CC genotype, 56% of subjects with IL28B CT genotype, and 15% of subjects with IL28B TT genotype; 17% and 34% of subjects with the NS3 Q80K polymorphism at baseline in the total population and HCV genotype 1a, respectively and 34%, respectively. In QUEST 1, all subjects were treated with PegIFNα-2a; in QUEST 2, 69% of subjects were treated with PegIFNα-2a and 31% were treated with PegIFNα-2b.
Response rates in adult primed subjects infected with HCV genotype 1 are detailed in Table 12. Among genotype 1a subjects treated with this product, SVR12 rates were lower in subjects with the NS3 Q80K polymorphism at baseline than in subjects without the Q80K polymorphism.
Table 12: Virologic regression in adult primary-treated subjects infected with HCV genotype 1 (pooled data from QUEST 1 and QUEST 2 trials) Response rate Benadryl + PR
N=521
% (n/N) Placebo+PR
N=264
% (n/N) Overall SVR12 (genotypes 1a and 1b)
Genotype 1a
Without Q80K
With Q80K
Gene type 1b 80 (419/521)
75 (191/254)
84 (138/165)
58 (49/84)
85 (228/267) 50 (132/264)
47 (62/131)
43 (36/83)
52 (23/44)
53 (70/133) Failure in regression therapy in subjects without SVR12*8 (42/521)33 (87/264) Virologic relapse†11 (51/470) 23 (39/172) Benzedrine group: 150 mg of Benzedrine (12 weeks) in combination with PegIFNα-2a/2b and RBV (24 or 48 weeks); placebo group: placebo (12 weeks) in combination with PegIFNα-2a/2b and RBV (48 weeks).
SVR12: sustained virologic response 12 weeks after planned EOT.
* On-treatment failure rate was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including, but not limited to, subjects who met protocol-specified treatment cessation principles and/or experienced virologic breakthrough).
† The viral recurrence rate was calculated using the number of subjects with undetectable HCV RNA at the time of actual EOT as the denominator. Includes 4 subjects treated with this product who experienced a relapse after obtaining SVR12.
 In the pooled analysis of QUEST 1 and QUEST 2, 88% (459/521) of the subjects treated with this product met the criteria for a total duration of treatment of 24 weeks. The SVR12 rate in these subjects was 88% (405/459).
In the treatment group, 79% (404/509) of subjects had undetectable HCV RNA (RVR) at week 4; the SVR12 rate in this group was 90% (362/404).
Analysis by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (categorized as ≤800,000 IU/mL and >800,000 IU/mL), METAVIR fibrosis score, and IL28B genotype showed a higher SVR12 rate in this group than in the placebo group. The SVR rates by METAVIR fibrosis score are shown in Table 13.
Table 13: SVR12 rates in subjects infected with HCV genotype 1 adult primary treatment by METAVIR fibrosis score (pooled data from QUEST 1 and QUEST 2 trials) Subgroup Benadryl + PR
% (n/N) placebo + PR
% (n/N)F0-284 (317/378)55 (106/192)F3-468 (89/130)36 (26/72)Benzo group: 150 mg benzo (12 weeks) in combination with PegIFNα-2a/2b and RBV (24 or 48 weeks); placebo group: placebo (12 weeks) in combination with PegIFNα-2a/2b and RBV (48 weeks).
SVR12: sustained virologic response 12 weeks after planned EOT.
 SVR12 rates were higher in subjects treated with this product in combination with PegIFNα-2a/2b and RBV (88% and 78%, respectively) than in subjects treated with placebo in combination with PegIFNα-2a/2b and RBV (62% and 42%, respectively; QUEST 2).
Adult subjects infected with HCV genotype 1 who failed prior treatment with PegIFNα and RBV
The PROMISE study was a randomized, double-blind, placebo-controlled, two-arm, multicenter, phase III study in HCV genotype 1-infected subjects who had relapsed after prior INF treatment. All subjects received 12 weeks of treatment with 150 mg of this product once daily or placebo in combination with PegIFNα-2a and RBV followed by 12 or 36 weeks of treatment with PegIFNα-2a and RBV according to the RGT criteria defined by the study protocol. Control subjects received 48 weeks of PegIFNα-2a and RBV treatment.
Demographic and baseline characteristics were evenly distributed between the product and placebo groups. 393 subjects were enrolled in the PROMISE study, with a median age of 52 years (range: 20-71 years; 3% of subjects over 65 years); 66% male subjects; 94% Caucasian subjects, 3% Black or African American subjects, 2% Asian subjects, and 7% Hispanic subjects ; 26% of subjects with a BMI ≥30 kg/m2; 84% of subjects with HCV RNA>800,000 IU/mL at baseline; 69% of subjects with a METAVIR fibrosis score of F0, F1, or F2, 15% of subjects with a METAVIR fibrosis score of F3, and 15% of METAVIR fibrosis score of F4 (cirrhosis) subjects accounted for 15%; subjects infected with HCV genotype 1a accounted for 42%, subjects infected with HCV genotype 1b accounted for 58%; subjects with IL28B CC genotype accounted for 24%, subjects with IL28B
CT genotype subjects accounted for 64%, IL28B
TT genotype in 12% of subjects; the proportion of subjects with NS3 Q80K polymorphism at baseline was 13% and 31% in the overall population and in subjects infected with HCV genotype 1a, respectively. Prior IFN-based HCV treatment was PegIFNα-2a/RBV (68%) or PegIFNα-2b/RBV (27%).
Response rates in adult subjects infected with HCV genotype 1 who relapsed after prior interferon treatment in the product and placebo groups are shown in Table 14. Among infected genotype 1a subjects treated with this product, SVR12 rates were lower in subjects with the NS3 Q80K polymorphism at baseline than in subjects without the Q80K polymorphism.
Table 14: Virological regression in adult subjects infected with HCV genotype 1 who relapsed after previous IFN treatment (PROMISE study) Response rate Benadryl + PR
N=260
% (n/N) Placebo+PR
N=133
% (n/N) Overall SVR12 (genotypes 1a and 1b)
Genotype 1a
Without Q80K
With Q80K
Gene type 1b 79 (206/260)
70 (78/111)
78 (62/79)
47 (14/30)
86 (128/149) 37 (49/133)
28 (15/54)
26 (9/34)
30 (6/20)
43 (34/79) Failure in regression therapy in subjects without SVR12*3 (8/260)27 (36/133) Virologic relapse†18 (46/249)48 (45/93) Benign group: 150 mg benzo (12 weeks) in combination with PegIFNα-2a and RBV (24 or 48 weeks); placebo group: placebo (12 weeks) in combination with PegIFNα-2a and RBV (48 weeks).
SVR12: sustained virologic response 12 weeks after planned EOT.
* On-treatment failure rate defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including, but not limited to, subjects who met protocol-specified treatment discontinuation principles and/or experienced virologic breakthrough).
† Virologic recurrence rate was calculated as the denominator for the number of subjects with undetectable HCV RNA at the time of actual EOT and who had received at least 1 follow-up HCV RNA assessment. Includes 5 subjects treated with this product who experienced a relapse after obtaining SVR12.
 In the PROMISE study, 93% (241/260) of subjects treated with this product met the criteria for a total course of 24 weeks. The SVR12 rate in these subjects was 83% (200/241).
HCV RNA (RVR) was undetectable at week 4 in 77% (200/259) of the subjects in this treatment group, and the SVR12 rate in this group was 87% (173/200).
Analysis by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (categorized as ≤800,000 IU/mL and >800,000 IU/mL), prior HCV treatment, METAVIR fibrosis score, and IL28B genotype showed a higher SVR12 rate in this group than in the placebo group. SVR rates by METAVIR fibrosis score are shown in Table 15.
Table 15: SVR12 rates in adult patients infected with HCV genotype 1 who relapsed after previous IFN treatment by METAVIR fibrosis score (PROMISE study) Subgroup Benadryl + PR
% (n/N) placebo + PR
% (n/N)F0-282 (137/167)41 (40/98)F3-473 (61/83)24 (8/34)Benzo group: 150 mg benzo (12 weeks) in combination with PegIFNα-2a and RBV (24 or 48 weeks); placebo group: placebo (12 weeks) in combination with PegIFNα-2a and RBV (48 weeks).
SVR12: sustained virologic response 12 weeks after planned EOT.
 The ASPIRE study is a randomized, double-blind, placebo-controlled phase II study in HCV genotype 1-infected subjects who have failed prior treatment with PegIFNα and RBV (including prior relapsers, prior partial responders, and prior null responders).
In this study, 66 subjects received 150 mg of this product (12 weeks) in combination with PegIFNα-2a and RBV (48 weeks), and 66 subjects received placebo in combination with PegIFNα-2a and RBV (48 weeks). The median age of these 132 subjects was 49 years (range: 20-66 years; 1% of subjects over 65 years); 66% were male subjects; 93% were Caucasian subjects, 3% were Black or African American subjects, and 2% were Asian subjects; 27% had a BMI ≥30 kg/m2; HCV RNA at baseline>800,000 IU/ mL in 85% of subjects; METAVIR fibrosis score of F0, F1 or F2 in 64% of subjects, METAVIR fibrosis score of F3 in 18% of subjects and METAVIR fibrosis score of F4 (cirrhosis) in 18% of subjects; infection with HCV genotype 1a in 43% of subjects and infection with HCV genotype 1b in 57% of subjects. The percentage of subjects with IL28B CC genotype was 17%, IL28B CT genotype was 67%, and IL28B TT genotype was 16% (93 subjects for whom information was available); the percentage of subjects with NS3 Q80K polymorphism at baseline was 27% and 23% in the overall population and in subjects infected with HCV genotype 1a, respectively. 40% of subjects were previous recipients of Forty percent of subjects were relapsers after previous treatment with PegIFNα and RBV, 35% were previous partial responders, and 25% were previous null responders. Demographic and baseline characteristics were evenly distributed between the 12-week 150 mg of this product treatment group and the placebo treatment group.
Response rates for prior relapsers, prior partial responders, and prior null responders in the 12-week 150 mg of Benadryl and placebo treatment groups are shown in Table 16.
Table 16: Virologic regression in prior relapsers, partial responders and null responders infected with HCV genotype 1 and who failed prior PegIFNα and RBV treatment (ASPIRE study) Response rates for this product + PR
N=66
% (n/N) placebo+PR
N=66
% (n/N) SVR24 prior relapsers 77 (20/26)37 (10/27) prior partial responders 65 (15/23)9 (2/23) prior null responders 53 (9/17)19 (3/16) regression in SVR24 subjects without virologic failure on treatment* prior relapsers 8 (2/26)22 (6/27) prior partial responders 22 (5/23)78 (18/23)Previous null responders35 (6/17)75 (12/16)Virologic relapse†Previous relapsers13 (3/23)47 (9/19)Previous partial responders6 (1/17)50 (2/4)Previous null responders18 (2/11)25 (1/4)150 mg of this product group: 150 mg of this product (12 weeks) in combination with PegIFNα-2a and RBV (48 weeks); placebo group: placebo in combination with PegIFNα-2a and RBV (48 weeks).
SVR24: sustained virological response (defined as no detectable HCV RNA) at 24 weeks after planned EOT.
* On-treatment virologic failure rate defined as the proportion of subjects who met the protocol-specified treatment discontinuation principles (including those discontinued due to virologic breakthrough) or (subjects who completed treatment) had detectable HCV RNA at the end of treatment.
† Virologic relapse rates were calculated using the number of subjects with undetectable HCV RNA at the time of EOT and who had received at least 1 follow-up HCV RNA assessment as the denominator.
 The SVR24 rate was higher in the present treatment group than in the placebo-conjugated PegIFNα and RBV treatment groups, whether classified by HCV genotype/subtype, METAVIR fibrosis score, or IL28B genotype.
Subjects with HCV/HIV-1 co-infection
C212 is an open, single-arm phase III study in subjects with co-infection with HIV-1 and HCV genotype 1 who have failed primary or prior PegIFNα and RBV therapy for HCV (including prior relapsers, partial responders, or null responders). Primary subjects without cirrhosis or prior relapses received 12 weeks of once-daily treatment with 150 mg of this product in combination with PegINFα-2a and RBV followed by 12 or 36 weeks of PegINFα-2a and RBV according to protocol-defined RGT criteria. Prior non-responders (partial responders and non-responders) and all subjects with cirrhosis (METAVIR fibrosis score of F4) received 12 weeks of this product in combination with PegINFα-2a and RBV followed by 36 weeks of PegINFα-2a and RBV.
The median age of the 106 subjects enrolled in the C212 study was 48 years (range: 27-67 years; 2% of subjects aged 65 years or older); 85% of subjects were male; 82% were Caucasian, 14% were Black or African-American, 1% were Asian, and 6% were Hispanic; 12% had a BMI ≥30 kg/m2; and at baseline HCV RNA>800,000 IU/mL in 86% of subjects; METAVIR fibrosis score of F0, F1, or F2 in 68% of subjects, METAVIR fibrosis score of F3 in 19% of subjects, METAVIR fibrosis score of F4 in 13% of subjects; infection with HCV genotype 1a in 82% of subjects, infection with subjects with HCV genotype 1a and 17% with HCV genotype 1b; 28% and 34% of the overall population and subjects infected with HCV genotype 1a had the Q80K polymorphism at baseline, respectively; 27% of subjects with IL28B CC genotype, 56% of subjects with IL28B CT genotype, and 17% of subjects with IL28B TT genotype; 50% of subjects with primary HCV treatment (n =53), 14% (n=15) of previous relapses, 9% (n=10) of previous partial responders, and 26% (n=28) of previous null responders. 88% (n=93) of subjects received highly active antiretroviral therapy (HAART), and the most commonly used anti-HIV drugs included nucleoside reverse transcriptase inhibitors and integrase inhibitors (raltegravir). HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (except rilpivirine) are prohibited from use in this study.
The median baseline HIV-1 RNA level in subjects not receiving HAART was 4.18 log 10 copies/mL (range: 1.3-4.9 log 10 copies/mL) and the median baseline CD4+ cell count was 677 x 106 cells/mL (range: 489-1076 x 106 cells/mL). baseline in HAART-treated subjects Median CD4+ cell count was 561×106 cells/mL (range: 275-1407×106 cells/mL).
Response rates for first-treatment subjects, prior relapsers, prior partial responders, and null responders are shown in Table 17.
Table 17: Virological regression in adult subjects with HCV genotype 1/HIV-1 co-infection (C212 study) Response rate Primary subjects
N=53
% (n/N) Previously relapsed subjects
N=15
% (n/N) Previous partial responders
N=10
% (n/N) previous non-responders
N=28
% (n/N) Overall SVR12 (genotype 1a and genotype 1b) 79 (42/53) 87 (13/15) 70 (7/10) 57 (16/28) Genotype 1a 77 (33/43) 83 (10/12) 67 (6/9) 54 (13/24) Genotype 1b 90 (9/10) 100 (3/3) 100 (1/1) 75 (3/4) No regression in SVR12 subjects On-treatment failure*9 (5/53) 0 (0/15) 20 (2/10) 39 (11/28) Virologic relapse†10 (5/48) 13 (2/15) 0 (0/7) 12 (2/17) 150 mg of this product (12 weeks) in combination with PegIFNα-2a and RBV (24 or 48 weeks)
SVR12: Sustained virologic response 12 weeks after planned EOT.
* On-treatment failure rate defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including, but not limited to, subjects who meet protocol-specified treatment discontinuation principles and/or who experience virologic breakthrough).
† Virologic recurrence rates were calculated as the denominator for the number of subjects with undetectable HCV RNA at the time of actual EOT and who had received at least 1 follow-up HCV RNA assessment. Includes 1 prior null responder who developed a relapse after obtaining SVR12.
 Eighty-nine percent (n=54/61) of primary subjects without cirrhosis and prior relapses treated with this product met the criteria for a total duration of treatment of 24 weeks. The SVR12 rate in these subjects was 87%.
The proportion of subjects with undetectable HCV RNA (RVR) at week 4 was 71% (n=37/52), 93% (n=14/15), 80% (n=8/10), and 36% (n=10/28) among primary, prior relapsers, prior partial responders, and prior null responders treated with this product, respectively. The SVR12 rates for this subset of subjects were 89%, 93%, 75%, and 90%, respectively.
The SVR rates by METAVIR fibrosis score are shown in Table 18.
Table 18: SVR12 rates in adult subjects with HCV genotype 1/HIV-1 co-infection by METAVIR fibrosis score (C212 study) subgroup of primed subjects
% (n/N) Previously relapsed subjects
% (n/N) Previous partial responders
% (n/N) Prior non-responders
% (n/N)F0-289 (24/27)78 (7/9) 50 (1/2)57 (4/7) F3-457 (4/7)100 (2/2) 67 (2/3)60 (6/10) This product (150 mg, administered for 12 weeks) was combined with PegIFNα and RBV (administered for 24 or 48 weeks).
SVR12: Sustained virologic response 12 weeks after planned EOT.
 HIV virologic failure occurred in 2 subjects, i.e., prior HIV-1 RNA<50 copies/mL followed by confirmation of ≥200 copies/mL; these failures occurred at 36 and 48 weeks after the end of treatment with this product.
Adult Subjects Infected with HCV Genotype 4
RESTORE is an open, single-arm phase III study in HCV genotype 4-infected subjects who have failed primary or prior PegIFNα and RBV therapy (including prior relapsers, partial responders, or null responders). Primary subjects or prior relapsers received 12 weeks of 150 mg of this product once daily in combination with PegIFNα-2a and RBV, followed by 12 or 36 weeks of PegIFNα-2a and RBV treatment according to protocol-defined RGT criteria. Prior non-responders (partial or null responders) received 12 weeks of 150 mg of this product once daily in combination with PegIFNα-2a and RBV, followed by 36 weeks of PegIFNα-2a and RBV.
The median age of the 107 HCV genotype 4-infected subjects enrolled in the RESTORE study was 49 years (range: 27-69 years; 5% of subjects aged 65 years or older); 79% of subjects were male; 72% of subjects were Caucasian, 28% were Black or African American, and 7% were Hispanic; and 14% of subjects had a BMI ≥30 kg/m2. 60% of subjects with baseline HCV RNA levels>800,000 IU/mL; 57% of subjects with METAVIR fibrosis scores of F0, F1, or F2, 14% of subjects with METAVIR fibrosis scores of F3, and 29% of subjects with METAVIR fibrosis scores of F4; subjects infected with HCV genotype 4a 42% of subjects infected with HCV genotype 4a, 24% of subjects infected with HCV genotype 4d; 8% of subjects with IL28B CC genotype, 58% of subjects with IL28B CT genotype, 35% of subjects with IL28B TT genotype; 33% of subjects with primary HCV treatment (n=35), 21% of subjects with previous relapse (n=22), 9% of subjects with previous partial response (n=10), and 37% of subjects with previous naive responders accounted for 37% (n=40).
Response rates for primary subjects, previous relapsers, previous partial responders, and previous null responders are shown in Table 19. SVR rates by METAVIR fibrosis score are shown in Table 20.
Table 19: Virological regression in adult subjects with HCV genotype 4 infection (RESTORE study) Response rates Primary treated subjects
N=35
% (n/N) Previously relapsed subjects
N=22
% (n/N) Previous partial responders
N=10
% (n/N) Previous non-responders
N=40
% (n/N) Overall SVR1283 (29/35) 86 (19/22) 60 (6/10) 40 (16/40) Regression in subjects without SVR12 On-treatment failure* 9 (3/35) 9 (2/22) 20 (2/10) 45 (18/40) Virologic relapse† 9 (3/35) 5 (1/22) 20 (2/10) 15 (6 /40) 150 mg of this product (12 weeks) in combination with PegIFNα-2a and RBV (24 or 48 weeks)
SVR12: Sustained virologic response 12 weeks after planned EOT.
* On-treatment failure rate defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including, but not limited to, subjects who meet protocol-specified treatment discontinuation principles and/or who experience virologic breakthrough).
† Virologic recurrence rates were calculated using the number of subjects with undetectable (or not confirmed detectable) HCV RNA at the time of the actual EOT as the denominator.
 Table 20: SVR12 rates in adult subjects with HCV genotype 4 infection by METAVIR fibrosis score (RESTORE study) subgroup of primed subjects
% (n/N) Previously relapsed subjects
% (n/N) Previous partial responders
% (n/N) Previous non-responders
% (n/N)F0-285 (22/26)91 (10/11) 100 (5/5)47 (8/17) F3-478 (7/9)82 (9/11) 20 (1/5)35 (7/20) This product (150 mg administered for 12 weeks) was combined with PegIFNα and RBV (administered for 24 or 48 weeks).
SVR12: Sustained virologic response 12 weeks after planned EOT.
 [Pharmacology and Toxicology].
Pharmacological effects
Simeprevir is an NS3/4A protease inhibitor essential for HCV virus replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant type 1a and 1b HCV NS3/4A proteases with median Ki values of 0.5 nM and 1.4 nM, respectively.
Toxicological studies
Genotoxicity.
The results of simeprevir Ames test, mouse lymphoma test and mouse micronucleus test were negative.
Reproductive toxicity.
In the rat fertility and early embryonic development toxicity test, an increased rate of post-implantation loss was seen at 50 and 500 mg/kg doses of simeprevir, sperm inactivity, small testes and epididymis were seen in 3 male rats (2/24 in the 50 mg/kg dose group and 1/24 in the 500 mg/kg dose group), and 2/3 of the females they mated with were infertile; the exposure of males at this time The exposure of male animals at this time was lower than that at the recommended human dose.
Administration-associated testicular and epididymal toxicity was also seen in repeated dosing toxicity assays in rats and dogs, but due to the low incidence and lack of a clear dose-response relationship, it is unclear whether the adverse findings in the Chu testis/epididymis were episodic or drug-related.
In embryo-fetal developmental toxicity assays in rats and mice, simeprevir was administered at doses up to 500 mg/kg in rats and 150, 500, and 1000 mg/kg in mice. increased post-arrival loss was seen in mice at exposures equal to or greater than 1.9 times the exposure at the recommended human dose, and decreased fetal weight and increased skeletal variability were seen at exposures equal to or greater than 1.2 times the dose. No embryo-fetal developmental toxicity was observed in mice (150 mg/kg) or rats (up to the highest dose) at exposures equivalent to the recommended human dose.
In the rat perinatal developmental toxicity assay, simeprevir was administered at doses up to 1000 mg/kg, and at the dose where maternal toxicity occurred, a significant reduction in pup weight, delayed physical development, and reduced motor function was seen, at which maternal drug exposure was similar to that at the recommended human dose; offspring survival, behavior, and reproductive performance were not affected.
Simeprevir may be secreted through breast milk at concentrations of approximately 10% of maternal simeprevir blood levels.
Carcinogenicity: No carcinogenicity studies have been conducted.
Other toxicity.
In a 2-week oral repeat dosing toxicity test in dogs, acute endocardial and myocardial necrosis confined to the subendocardial region of the left ventricle occurred in 2/6 animals at an animal exposure of approximately 28 times the mean AUC at the recommended daily human dose of 150 mg. No cardiotoxicity was seen in toxicity tests with repeated oral administration for 6 and 9 months at exposures 11 and 4 times the mean AUC at the recommended human daily dose of 150 mg, respectively.
If this product is used in combination with PegIFNα and RBV, see Animal Toxicology Information for PegIFNα and RBV.
[Pharmacokinetics].
The pharmacokinetic (PK) profile of simeprevir has been evaluated in healthy adult subjects and adult subjects infected with HCV. In the dose range of 75-200 mg, the increase in plasma Cmax and area under the drug-time curve (AUC) was greater than the proportional increase in dose, and drug accumulation occurred after multiple doses. Steady state was reached on day 7 after once-daily sequential dosing. The plasma exposure (AUC) of simeprevir in HCV-infected subjects was approximately 2-3 times higher than that in HCV-uninfected subjects. In combination with PegIFNα and ribavirin, the plasma Cmax and AUC of simeprevir were similar to those when simeprevir was administered alone. In phase III trials conducted in HCV-infected subjects in combination with PegIFNα and RBV, the geometric mean of the steady-state trough concentration was 1009 ng/mL (geometric coefficient of variation [gCV] = 162%) and the geometric mean of the steady-state AUC24 was 39140 ng-h/mL (
gCV=98%).
Absorption
The mean absolute bioavailability of simeprevir after a single oral dose of 150 mg of this product in the fed state was 62%. Cmax is usually reached 4 to 6 hours after administration.
In vitro assays in human Caco-2 cells have shown that simeprevir is a substrate for P-gp.
Effect of food on absorption of orally administered drugs
Compared to the fasted state, the AUC of simeprevir was increased by 61% and 69% in healthy subjects who consumed a high-fat, high-calorie breakfast (928 kcal) and a normal-calorie breakfast (533 kcal), respectively, and drug absorption was delayed by 1 hour and 1.5 hours, respectively.
Distribution
Simeprevir binds extensively to plasma proteins (>99.9%), primarily to albumin, and to a lesser extent to alpha1-acidic glycoprotein. Plasma protein binding was not meaningfully altered in patients with renal impairment or hepatic impairment.
Simeprevir is widely distributed in the intestinal and liver tissues of animals (liver-blood ratio of 29:1 in rats). In vitro data and physiologically based pharmacokinetic modeling and simulation suggest that in vivo hepatic uptake in humans is mediated via OATP1B1/3. Metabolism
Simeprevir is metabolized in the liver. In vitro assays with human liver microsomes suggest that simeprevir is primarily metabolized oxidatively via the hepatic CYP3A system. It cannot be excluded that CYP2C8 and CYP2C19 are also involved in metabolism. Concomitant use of this product with CYP3A intermediate or potent inhibitors significantly increases plasma exposure to simeprevir, and concomitant use with CYP3A intermediate or potent inducers significantly decreases plasma exposure to simeprevir (see [Drug Interactions] for details).
Following a single oral dose of 200 mg (1.3 times the recommended dose) of 14C-simeprevir in healthy subjects, the majority of the plasma radiolabel (mean: 83%) was derived from the prototype drug, with a small proportion of the radiolabel associated with metabolites (all non-major metabolites). Metabolites identified in the feces were formed by oxidation at the macrocyclic and/or aromatic groups and by O-demethylation and subsequent oxidation.
Clearance
Simeprevir is cleared by biliary secretion. Renal clearance of simeprevir is not significant. A single oral dose of 200 mg of 14C-cimeprevir in healthy subjects was followed by a mean of 91% of the total radiolabel found in the feces. Less than 1% of the administered dose was excreted in the urine. The prototype simeprevir drug in the feces accounted for an average of 31% of the dose administered.
The terminal clearance half-life of simeprevir was 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected patients when the 200 mg (1.3 times the recommended dose) dose was administered.
Special Populations
Geriatric Use
There are limited data regarding the use of this product in patients 65 years of age and older. Based on a population pharmacokinetic analysis in HCV-infected patients treated with this product, age (18-73 years) did not have a clinically meaningful effect on the pharmacokinetics of simeprevir (see [Geriatric Dosing] for details).
Renal impairment
The mean steady-state AUC of simeprevir was 62% higher in subjects with severe renal impairment (eGFR<30 mL/min) and no HCV infection than in subjects with normal renal function (categorized according to the Modified Renal Disease Diet [MDRD] eGFR formula; eGFR ≥ 80 mL/min) and no HCV infection.
In a population pharmacokinetic analysis of HCV-infected subjects with mild or moderate renal impairment, creatinine clearance was not found to affect the pharmacokinetic parameters of simeprevir following once-daily treatment with 150 mg of this product. Therefore, no clinically relevant effects on simeprevir exposure would be expected from renal impairment (see [DOSAGE] for details).
Simeprevir is highly bound to plasma proteins and is therefore unlikely to be cleared in significant quantities by hemodialysis.
Hepatic impairment
The mean simeprevir steady-state AUC was 2.4 and 5.2 times higher in subjects with moderate hepatic impairment (Child-Pugh class B), uninfected with HCV, and in subjects with severe hepatic impairment (Child-Pugh class C), uninfected with HCV, compared to subjects with normal hepatic function, uninfected with HCV (see [Dosage] for details).
Based on a population pharmacokinetic analysis of patients with mild liver injury (Child-Pugh class A), infected with HCV treated with this product, liver fibrosis staging did not have a clinically relevant effect on the pharmacokinetics of simeprevir.
Gender, weight, body mass index
Based on a population pharmacokinetic analysis of HCV-infected patients treated with this product, gender, weight, or body mass index did not have a clinically relevant effect on the pharmacokinetics of simeprevir.
Ethnicity
Population pharmacokinetic exposure estimates for simeprevir were comparable in HCV-infected Caucasian and Black/African American patients.
In a phase III study conducted in China and Korea, mean simeprevir plasma exposure among HCV-infected East Asian subjects was 2.1 times higher than among HCV-infected non-Asian subjects in the global pooled phase III study population (see [Dosage] for details).
Patients with co-infection with HIV-1
Exposure to simeprevir was slightly lower in subjects with combined HCV genotype 1/HIV-1 infection compared to subjects with HCV genotype 1 infection alone. The difference was not clinically significant.
Drug Interactions (see [Precautions] and [Drug Interactions] for details)
In vitro studies have shown that simeprevir is a substrate and weak inhibitor of CYP3A. In vivo, simeprevir does not affect CYP2C9, CYP2C19, or CYP2D6. in vitro, simeprevir does not induce CYP1A2 or CYP3A4. in vivo, simeprevir weakly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Simeprevir did not produce clinically meaningful inhibition of tissue proteinase A activity.
In vitro, simeprevir is a substrate for P-gp, MRP2, BCRP, OATP1B1/3, and OATP2B1, and simeprevir is an inhibitor of the uptake transporter proteins OATP1B1/3 and NTCP and the efflux transporter proteins P-gp/MDR1, MRP2, BCRP, and BSEP, and does not inhibit OCT2. simeprevir does not inhibit the bilirubin transporter proteins Inhibition of OATP1B1/3 and MRP2 may cause clinically elevated bilirubin (see [Adverse Reactions] for details).
Simeprevir is transported to the liver via OATP1B1/3 and is metabolized by CYP3A. Based on the results of in vivo studies, the combination of this product with an intermediate or potent inhibitor of CYP3A may significantly increase the plasma exposure of simeprevir, and the combination of an intermediate or potent inducer of CYP3A may significantly decrease the plasma exposure of simeprevir, resulting in a loss of efficacy.
Drug interaction studies were conducted in healthy adult subjects receiving simeprevir (using the recommended dose of 150 mg once daily unless otherwise indicated) and potentially co-administered drugs or drugs that are commonly used as probes of pharmacokinetic interactions. Table 24 summarizes the effect of co-administration of other drugs on the Cmax, AUC, and Cmin values of simeprevir (the effect of other drugs on this product). Table 25 summarizes the effect of the combination of simeprevir on Cmax, AUC, and Cmin values of other drugs (effect of this drug on other drugs). For information on clinical recommendations, see [Drug Interactions].
Table 24: Drug Interactions: Pharmacokinetic Parameters of Simeprevir When Combined Combined Drug Dose (mg) and Effect of Regimen N on PK* Mean LS Ratio of Simeprevir PK Parameters with/without Combination of Drugs
(90% CI) drug simeprevir CmaxAUCCmin cyclosporine† individual dose‡ 150 mg q.d., administered for 14 days 94.74 (3.127.18) 5.81 (3.569.48) NA
Erythromycin 500 mg t.i.d. for 7 days 150 mg q.d. for 7 days 244.53(3.915.25) 7.47(6.418.70) 12.74(10.1915.93) Escitalopram 10 mg q.d. for 7 days
Administered for 7 days 150 mg q.d.
Administration for 7 days 18¯ 0.80 (0.710.89) 0.75 (0.680.83) 0.68 (0.590.79) Rifampicin 600 mg q.d.
200 mg q.d. for 7 days of administration
7 days of administration18¯1.31(1.031.66)0.52(0.410.67)0.08(0.060.11)Tacrolimus† individual dose‡150 mg q.d., 14 days of administration111.79(1.222.62)1.85(1.182.91)NA
Anti-HCV drug sofosbuvir#400 mg q.d.150 mg q.d.21↔0.96(0.711.30)0.94(0.671.33)NA Anti-HIV drug darunavir/ritonavir§800/100 mg q.d.
Dosing 7 days 50 mg and 150 mg q.d.
Administration for 7 days 251.79 (1.552.06) 2.59 (2.153.11) 4.58 (3.545.92) efavirenz 600 mg q.d.
Administration for 14 days 150 mg q.d.
Dosing 14 days 23¯0.49(0.440.54)0.29(0.260.33)0.09(0.080.12)raltegravir 400 mg b.i.d., Dosing 14 days 23¯0.49(0.440.54)0.29(0.260.33)0.09(0.080.12)raltegravir 400 mg b.i.d,
Dosing 7 days 150 mg q.d.,.
Dosing 7 days 24 ↔ 0.93 (0.851.02) 0.89 (0.810.98) 0.86 (0.750.98) rilpivirine 25 mg q.d., dosing 7 days 24 ↔ 0.93 (0.851.02) 0.89 (0.810.98) 0.86 (0.750.98) rilpivirine 25 mg q.d., dosing
Dosing 11 days 150 mg q.d.
Dosing 11 days 21 ↔ 1.10 (0.971.26) 1.06 (0.941.19) 0.96 (0.831.11) ritonavir 100 mg b.i.d., Dosing 11 days 21 ↔ 1.10 (0.971.26) 1.06 (0.941.19) 0.96 (0.831.11) ritonavir 100 mg b.i.d,
Administration for 15 days 200 mg q.d.,.
Administration for 7 days 124.70 (3.845.76) 7.18 (5.639.15) 14.35 (10.2920.01) Tenofovir disoproxil fumarate 300 mg q.d.
Administration for 7 days 150 mg q.d.
Dosing 7 days 24¯ 0.85 (0.730.99) 0.86 (0.760.98) 0.93 (0.781.11) CI = confidence interval; N = number of subjects with data; NA = not available; PK = pharmacokinetics; LS = least squares; q.d. = once daily; b.i.d. = twice daily; t.i.d. = three times daily
* Arrow direction (↑=increased, ↓=decreased, ↔=no change) indicates the direction of change in PK (i.e., AUC).
† Comparison based on historical controls. Interim data from a phase II study of combination study drug and RBV therapy in patients infected with HCV after receiving a liver transplant.
‡ Individual doses were determined by physicians based on local clinical practice.
# Comparisons based on historical controls. Interaction between simeprevir and sofosbuvir was evaluated in the PK sub-study of the Phase II study.
§ The dose in this interaction study was 50 mg in combination with darunavir/ritonavir and 150 mg once daily in the group treated with this product alone.
  Table 25: Drug interactions: effect of combined drug pharmacokinetic parameters combined drug dose (mg) and regimen N on PK when given concomitantly with this drug* Mean LS ratio of combined drug PK parameters when administered with/without this drug
(90% CI) Drug simeprevir CmaxAUCCmin Atorvastatin
 2-Hydroxy-atorvastatin 40 mg single dose 150 mg q.d.
10 days of administration 18 ↑
 ↑1.70(1.422.04)
1.98(1.702.31)2.12(1.722.62)
2.29(2.082.52)NA
 NA Caffeine
150 mg150 mg q.d.
Dosing 11 days 16↑1.12(1.061.19)1.26(1.211.32)NA cyclosporine 100 mg single dose 150 mg q.d.
7 days of administration14↑1.16(1.071.26)1.19(1.131.26)NA dextromethorphan
 Dextromethorphan 30 mg 150 mg q.d.
Administered for 11 days 16↑
 ↔ 1.21(0.931.57)
1.03(0.931.15)1.08(0.871.35)
1.09(1.031.15)NA
 NA digoxin 0.25 mg single dose 150 mg q.d.
Administered for 7 days16↑1.31(1.141.51)1.39(1.161.67)NA erythromycin 500 mg t.i.d.
Administered for 7 days 150 mg q.d.
Dosing 7 days 241.59(1.232.05)1.90(1.532.36)3.08(2.543.73)Escitalopram 10 mg q.d.
Administered for 7 days 150 mg q.d.
Dosing 7 days 17↔1.03(0.991.07)1.00(0.971.03)1.00(0.951.05) Ethinyl estradiol (EE), coadministered with ethinyl estradiol (NE) 0.035 mg q.d. EE+1 mg q.d. NE, dosing 21 days 150 mg q.d.
Dosing 10 days 18 ↔ 1.18 (1.091.27) 1.12 (1.051.20) 1.00 (0.891.13) midazolam (oral) 0.075 mg/kg 150 mg q.d.,
Dosing 10 days 161.31 (1.191.45) 1.45 (1.351.57) NA midazolam (i.v.) 0.025 mg/kg 150 mg q.d.,.
Dosing 11 days 160.78 (0.521.17) 1.10 (0.951.26) NAR(-) methadone†30-150 mg q.d., individual dose 150 mg q.d.
Dosing 7 days 12↔1.03(0.971.09)0.99(0.911.09)1.02(0.931.12) norethindrone (NE), coadministered EE0.035 mg q.d. EE+1 mg q.d. NE, dosing 21 days 150 mg q.d.
Dosing 10 days 18 ↔ 1.06 (0.991.14) 1.15 (1.081.22) 1.24 (1.131.35) omeprazole 40 mg single dose 150 mg q.d.,.
Administered for 11 days 161.14(0.931.39)1.21(1.001.46)NA rifampicin
 25-deacetyl-rifampicin 600 mg q.d.
Administered for 7 days 200 mg q.d.
Administered for 7 days 18
 17↔
 0.92(0.801.07)
1.08(0.981.19)1.00(0.931.08)
1.24(1.131.36)NA
 NA Rosuvastatin 10 mg single dose 150 mg q.d.
7 days of administration16↑3.17(2.573.91)2.81(2.343.37)NA simvastatin
 Simvastatin 40 mg single dose 150 mg q.d.
Administered for 10 days 18 ↑
 ↑1.46(1.171.82)
3.03(2.493.69)1.51(1.321.73)
1.88(1.632.17)NA
 NA Tacrolimus 2 mg single dose 150 mg q.d.
Dosing 7 days 14¯0.76(0.650.90)0.83(0.591.16)NAS – Warfarin 10 mg single dose 150 mg q.d.
Dosing 11 days 16 ↔ 1.00(0.941.06) 1.04(1.001.07) NA anti-HCV drug sofosbuvir‡
 GS-331007#400 mg q.d.150 mg q.d.22
 ↔ 1.91(1.262.90)
0.69(0.520.93)3.16(2.254.44)
1.09(0.871.37)NA
 NA Anti-HIV drugs Darunavir§
 
 Ritonavir§ 800 mg q.d.
Administration for 7 days 50 mg q.d.
Dosing 7 days 251.04 (0.991.10) 1.18 (1.111.25) 1.31 (1.131.52) 100 mg q.d., Dosing 7 days 1.23
(1.44-1.32)1.32
(1.25-1.40)1.44
(1.30-1.61) Efavirenz 600 mg q.d.
Administered for 14 days 150 mg q.d.
Dosing 14 days 23 ↔ 0.97 (0.891.06) 0.90 (0.850.95) 0.87 (0.810.93) raltegravir 400 mg b.i.d.
Dosing 7 days 150 mg q.d.
Dosing 7 days 241.03 (0.781.36) 1.08 (0.851.38) 1.14 (0.971.36) rilpivirine 25 mg q.d.
Dosing 11 days 150 mg q.d.
Dosing 11 days 23 ↔ 1.04 (0.951.13) 1.12 (1.051.19) 1.25 (1.161.35) Tenofovir disoproxil fumarate 300 mg q.d.
7 days of administration 150 mg q.d.
Dosing 7 days 24↔1.19(1.101.30)1.18(1.131.24)1.24(1.151.33)CI=confidence interval; i.v.=intravenous; N=number of subjects with data; NA=not available; PK=pharmacokinetics; LS=least squares; q.d.=once daily; b.i.d.=twice-daily; t.i .d. = three times daily.
* Arrow direction (↑=increased, ↓=decreased, ↔=no change) indicates the direction of change in PK (i.e., AUC).
† Evaluate the interaction of this product with this drug in a pharmacokinetic study in adult subjects receiving stable methadone maintenance therapy and with opioid dependence.
‡ Conduct comparisons based on historical controls. Evaluate the interaction between simeprevir and sofosbuvir in a PK sub-study of a phase II study.
§ Sofosbuvir major circulating metabolite.
§ The dose in this interaction study was 50 mg when used concomitantly with darunavir/ritonavir, which is lower than the recommended dose of 150 mg. Storage]
Store this product in its original packaging at 30°C or below, protected from light.
Package】
7 capsules/box; 28 capsules/box
Expiration date
36 months
Execution Standard
JX20160131
[Imported drug registration certificate number
xxxxxx
Manufacturer
Company Name: Janssen-Cilag S.p.A.
Production Address: Via C. Janssen, Borgo San Michele, 04100 Latina, Italy
Domestic Contact
Name: Xi’an Janssen Pharmaceutical Co.
Address: No. 34, Wanshou North Road, Xincheng District, Xi’an, Shaanxi Province, China
Postal Code: 710043
Telephone number: 400 888 9988
Fax number: (029) 82576616
Website
：http://www.xian-janssen.com.cn
Instructions for use
How to remove the capsule
Press the edge of the blister to squeeze out the capsule from the aluminum foil as shown in the picture. Do not press the capsule from the middle of the blister. This may damage the capsule.